Use Of Medicines

Front 1

Why do drug doses vary so significantly?

Back 1

>Due to binding affinity of drugs at their receptors

Front 2

What is meant by chemical specificity of drugs?

Back 2

>Drug binding is specific to the compound

Front 3

What is meant by biological specificity?

Back 3

>Binding is specific to the macromolecule

Front 4

What are typical molecular targets for drugs?

Back 4

MOSTLY PROTEINS
1. Enzymes - cholinesterase, ACE, calcineurin
2. Carriers and transporters - Na+/K+ ATPase (cardiac glycosides), NaCl transporter (thiazide diuretics)
3. DNA - many anticancer drugs
4. TNF-α - infliximab
5. Receptors
- specialised proteins that physiologically mediate cell-cell communication by initiating a specific response to neurotransmitters, hormones, growth factors

Front 5

What are examples of drugs without a molecular target?

Back 5

>Mannitol
>Osmotic laxatives
>Antacids
>Chelating drugs

Front 6

What are the properties of ligand gated ion channels?

Back 6

>Fast neurotransmission
>Binding of neurotransmitter causes opening of the pore to ions
- cell depolarises (Vm less negative, excitation) or
- hyperpolarises (Vm more negative, inhibition)

Front 7

What are examples of ligand gated ion channels?

Back 7

>Nicotinic superfamily (nicotinic receptors to Ach - excitatory, GABA receptors - inhibitory)
>Glutamate superfamily - excitatory
>Purinergic superfamily (ATP)

Front 8

What substances typically target ligand gated ion channels?

Back 8

>Neuromuscular blockers (suxamethonium)
>Benzodiazepines (e.g. diazepam)
>Alcohol
>General anaesthetics

Front 9

Which other ion channels (not receptors) act as drug targets?

Back 9

>Voltage gated ion channels
- Na+
- Ca++
- K+

Front 10

Which substances act on ion channels?

Back 10

>Local anaesthetics
>Calcium channel blockers
>Antiarrhythmic drugs

Front 11

How do GABA channels work to inhibit cells?

Back 11

>GABA allows anions into the cell
- hyperpolarising the cell
- depressing activity

Front 12

What are the properties of GPCRs?

Back 12

>Slower neurotransmission
- metabotropic receptors
>Utilise signal transduction via G-protein trimer bound to GDP
>Very large family
>7 Transmembrane domains
- many are dimers
>Include adrenoceptors, muscarinic acetylcholine receptors, histamine receptors, glutamate metabotropic, GABA metabotropic, most receptors for peptides (opioid receptors, angiotensin, adhesion proteins), or lipids (cannabinoids, prostaglandins)

Front 13

How do GPCRs work?

Back 13

1. G-protein trimer (GDP bound)
2. Agonist-occupied receptor binds to G-protein GDP exchanged for GTP trimer dissociates to α and βy
3. α and βy reach and activated or inhibit effectors (target 1 and 2)
4. GTP hydrolyses, trimer forms again

Front 14

What are the typical second messengers for GPCRs?

Back 14

>Slow potential amplification in a cascade of reactions
1. cAMP
- synthesised from ATP by adenyl cyclase and activated intracellular kinases which phosphorylate other proteins
- adenyl cyclase can be activated (β adrenoceptors) or inhibited (α2 adrenoceptors, opioid receptors) by G protein linked receptors
2. PLC/Calcium - PLC can be activated (by α1 adrenoceptors) to hydrolyse membrane phosphatidylinositol to produce 2 second messengers, IP3 (releases calcium) and DAG (activated protein kinase C)
3. Direct effects
- α or βy interact with ion channels to open or close them

Front 15

What are properties of catalytic receptors?

Back 15

>e.g. peptide mediators (growth factors, insulin) activate Tyrosine kinase receptors
- blocked by trastuzumab (human epidermal GFRs
- imatinib blocks kinases
- ANF activates a structurally similar guanylate cyclase
>other receptors (cytokine receptors, CD28) lack an integral catalytic domain but are associated to and activate kinases

Front 16

What are properties of nuclear receptors?

Back 16

>Transcription factors
>Cytoplasmic (often bound to a protein in the inactive stage)
>Respond to lipid soluble hormones i.e. steroids (corticosteroids, sex hormones), thyroid hormones, retinoic acid
- after hormone binds, receptor dimerises and binds to DNA
- transcription of specific genes is inhibited (glucocorticoids inhibit COX-2 expression) or activated (mineralocorticoids increase expression of kidney transport proteins)

Front 17

How may receptor occupancy be calculated?

Back 17

Ka is the dissociation constant of the drug A- binding usually reversible

Hint 17

RECEPTOR OCCUPANCY

Front 18

Draw a drug binding curve on a linear and a log scale.

Back 18

Hint 18

LINEAR AND LOG SCALE

Front 19

Draw a functional dose response curve for a full and a partial agonist. Are dose response curves the same as binding curves?

Back 19

>No this is a superficial similarity
- the link between receptor occupancy (p) and biological effect is complicated

Hint 19

FUNCTIONAL DOSE RESPONSE CURVE

Front 20

What is the ED50?

Back 20

>Effective dose for 50% of the sample population upon which a drug is tested

Hint 20

ED50

Front 21

How is the therapeutic index calculated?

Back 21

Therapeutic index = maximum tolerated dose / Minimum effective dose

Front 22

What is an agonist?

Back 22

>An agent that activates a receptor

Front 23

What is an antagonist?

Back 23

>An agent that reduces the action of an agonist
- not involving the receptor through which the agonist acts
- antagonism at the same receptor

Front 24

What four types of antagonism occur not involving the receptor through which the agonist acts?

Back 24

1. Chemical
2. Functional or physiological
3. Indirect
4. Pharmacokinetic

Front 25

What is an example of chemical antagonism, occuring other than at the receptor to which the agonist acts?

Back 25

>Where the antagonist binds to the substance antagonised
- e.g. chelators such as EDTA, which chelates lead
- chelate is then excreted much faster than lead ions

Front 26

What is an example of functional or physiological antagonism, occuring other than at the receptor to which the agonist acts?

Back 26

>Agonist and antagonist have opposite effects
- e.g. adrenaline vs. histamine on bronchial smooth muscle (adrenaline relaxes via beta2 and histamine constricts via H1)

Front 27

What is an example of indirect antagonism, occuring other than at the receptor to which the agonist acts?

Back 27

>The antagonist blocks one of the steps through which the agonists produces an effect
- e.g. propranolol and tyramine
- tyramine releases noradrenaline
- noradrenaline receptors blocked by propranolol

Front 28

What is an example of pharmacokinetic antagonism, occuring other than at the receptor to which the agonist acts?

Back 28

>The antagonist reduces the concentration of the substance antagonised
- phenobarbitone increases the level of cytochrome C liver enzymes which metabolise warfarin and other drugs
- pharmacokinetic enhancement can also occur

Front 29

What are two ways in which antagonism can occur at the same receptor?

Back 29

1. Competitive
- overlapping binding sites
- binding :. mutually exclusive
- can be reversible or irreversible (rare)
2. Non-competitive
 - distinct binding sites
- e.g. channel blocker

Front 30

Draw a log dose response curve for an agonist being antagonised by a reversible competitive antagonist.

Back 30

>Reversible competitive antagonists shift agonist dose response curves to the right.

Hint 30

REVERSIBLE COMPETITIVE ANTAGONISTS

Front 31

What does the Schild equation describe?

Back 31

r-1 = [B] / KB
>Links the extent of the shift r of the dose response curve and the antagonist affinity for the receptor

Front 32

What is the pharmacological classification of receptor subtypes based on?

Back 32

>The use of competitive antagonists
- important for therapeutics

Front 33

Draw a dose response curve to show the action of an irreversible competitive antagonist.

Back 33

Hint 33

IRREVERSIBLE COMPETITIVE ANTAGONIST

Front 34

How do partial agonists behave as antagonists?

Back 34

>Maximum responses to partial agonists are smaller (i.e. lower efficacy)
- partial agonists which act as antagonists have very low efficacy
- acting as antagonists to the full agonist

Hint 34

PARTIAL AGONISTS

Front 35

What two actions can Acetylcholine be divided into?

Back 35

1. Muscarinic actions: produced by muscarine and antagonised by atropine
- produced by low doses of ACh
2. Nicotinic actions: prodcued by nicotine and antagonised by tubocurarine (or by repeated administration of nicotine. (Produced only by high doses of ACh)

Front 36

Describe Dale's experiment on the effect of Acetylcholine on blood pressure.

Back 36

1. Small dose of ACh
- Vasodilatation and bradycardia, due to muscarinic action, ends quickly as acetylcholine is degraded
2. Muscarinic actions blocked by atropine
3. Large dose now stimulates ganglia (nicotinic action) causing vasoconstriction and tachycardia by activating the postganglionic neurones
4. Secondary effect due to adrenaline release from adrenal medulla (nicotinic effect - blocked by the nicotinic blocker HEXAMETHONIUM)

Hint 36

DALE'S EXPERIMENT

Front 37

Are nicotinic receptors in autonomic ganglia different from those in skeletal muscle?

Back 37

YES
> Made up of different subunits
- muscle receptors are potently blocked by TUBOCURARINE, while ganglion receptors are blocked by HEXAMETHONIUM (and by tubocurarine only at high doses)

Front 38

Are receptors found in loci without innervation?

Back 38

YES
e.g. muscarinic receptors in most blood vessels - do not normally see acetylcholine but will respond to externally applied agonists

Front 39

What are parasympathomimetic drugs?

Back 39

>Mimic the effects of stimulating parasympathetic nerves, which may act by:
1. Stimulating muscarinic receptors in the same was as ACh
- muscarinic agonists
2. By inhibiting cholinesterase (ChE) and thereby intensifying and prolonging the action of Ach released at the synapse (anticholinesterases)

Front 40

What are examples of muscarinic agonists?

Back 40

1. Acetylcholine (non selective), hydrolysed rapidly by ChE
2. Carbachol (non selective), not hydrolysed by ChE
3. Methacholine (muscarinic), slowly hydrolysed by ChE
4. Bethanechol (muscarinic), not hydrolysed by ChE
5. Pilocarpine (muscarinic), not hydrolysed by ChE

Front 41

Can acetylcholine be used clinically?

Back 41

>Too rapidly hydrolysed to be of clinical use, but methacholine and carbachol have a longer duration of action
- quaternary amines, and therefor fully ionised, so not absorbed when given orally nor readily absorbed from the conjunctival sac
>Pilocarpine is a tertiary amine, only partially ionised at physiological pH and is absorbed topically (eye drops)

Front 42

What are the main effects of muscarinic agonists?

Back 42

1. Bradycardia and reduced cardiac output, causing a fall in blood pressure
2. Vasodilation
3. Salivation, lacrimation and sweating
4. Bronchoconstriction and increased bronchial secretion
5. Contraction of bladder
6. Increased motility of gastrointestinal tract
7. Pupillary constriction (miosis) leading to reduction of intraocular pressure
8. Contraction of ciliary muscle, accommodation for near vision

Front 43

What are the clinical uses of muscarinic antagonists?

Back 43

>Fairly limited since it is usually more desirable to suppress parasympathetic activity, main uses are:
1. Reduction of intraocular pressure in glaucoma (pilocarpine)
2. Relief of dry mouth (xerostomia, pilocarpine)
3. Relief of urinary retention, when this results from failure of the normal reflex pathway acting on the bladder (bethanechol, superceded by catheterisation)
4. Increasing gastrointestinal motility during the period of inactivity (paralytic ileus) which often follows abdominal surgery (bethanechol - rarely used)

Front 44

What are examples of muscarinic antagonists?

Back 44

>Important drugs are competitive antagonists which block muscarinic receptors in different organs and tissues without much selectivity
- main compounds are Atropine from the deadly nightshade, hyoscine/scopolamine, homatropine and tropicamide (briefer acting, and ipratroprium (quaternary)
>Chemical structures are very similar, all are tertiary bases, therefore they are readily absorbed and enter the brain easily
- quaternary derivatives are sometimes used, in order to avoid CNS effects, but are less selective in their peripheral actions

Front 45

What are the peripheral actions of muscarinic antagonists?

Back 45

NB. result from inhibition of effects mediated by the parasympathetic system via muscarinic receptors, the activity of the parasympathetic nervous system itself is not affected, the block is at the organs innervated by it (useful to memorise these effects because many drugs have antimuscarinic side effects)
1. Block of secretions: saliva, tears, bronchial secretion, sweating
2. Tachycardia, because of block of vagal inhibition of heart (especially in the young and fit)
- no change in blood pressure becuase most blood vessels have no parasympathetic innervation
3. Pupillary dilation (mydriasis), because of block of parasympathetic influence on sphincter pupillae
- interferes with drainage via canal of Schlemm and thus raises intraocular pressure
- Cycloplegia (cililary muscle paralysis), hence paralysis of accommodation
4. Inhibition of motility and secretions of gastrointestinal tract
5. Other smooth muscle is also relaxed (bronchi, bladder)
>Last two effects require much larger doses, and are not complete because there are other transmitters that maintain gastrointestinal and bladder function even when cholinergic transmission is fully blocked
- usefulness is somewhat limited in asthma, as mediators other than ACh are involved in bronchoconstriction

Front 46

What are the CNS actions of antimuscarinics?

Back 46

>Atropine has no effect in small doses but in higher doses causes marked stimulation, resulting in restlessness, disorientation, hallucinations
- in the elderly, the antimuscarinic side effects of many other drugs can cause confusion
>Hyoscine is a powerful CNS depressant, causing sleep and amnesia
- also has an anti-emetic action (used in anti-seasickness pills)
>Atropine-like drugs suppress the tremor of Parkinson's disease, probably by blocking cholinergic transmission in the basal ganglia

Front 47

What are the therapeutic uses of antimuscarinics?

Back 47

1. Anaesthesia
a. as pre-anaesthetic medication to inhibit salivary and bronchial secretion and to cause drowsiness (hyoscine only)
b. during surgery, to prevent vagal inhibition of heart (which occurs with some anaesthetics) and to prevent parasympathomimetic actions of anti-cholinesterases (which may be used for their effects at the NMJ)
2. In opthalmology - (as eye drops)
a. to dilate pupil fully and paralyse lens for opthalmological examination
- atropine or hyoscine cause blurring of vision for several days so shorter acting drugs usually used (homatropine) or even the shorter acting synthetic analogue tropicamide
b. following opthalmic surgery, to prevent contraction of pupil or ciliary muscle (long acting drug)
NB. Pupillary dilatation, can increase intraocular pressure (dangerous in glaucoma)
3. In treatment of AChE poisoning
4. Symptomatic relief of smooth muscle spasm (asthma)
5. Parkinson's disease, initial treatment or adjuvant to levodopa
6. Prevention of motion sickness (hyoscine)
7. To reduce the breathlessness associated with COPD (by inhalation: note 50% increase cardiovascular mortaility, does not modify disease progression)
8. Urinary urgency and incontinence (superceded by catheterisation)

Front 48

What is the general anatomy of the sympathetic nervous system?

Back 48

>Short preganglionic axons
- Cell bodies located within the spinal cord in the intermediolateral column (IML)
- Ganglia mainly run down both sides of the vertebral coumn (paravertebral ganglionic chain)
>Long postganglionic axons
- Termination of the postganglionic axon at target organ = NEUROEFFECTOR JUNCTION
- Major transmitter = NAd and ATP (also can be a transmitter)
- Cotransmitters e.g. NPY
NB. ACh is released from sympathetic innervation of sweat glands which activates muscarinic receptors

Front 49

What are the major agonists of the sympathetic nervous system?

Back 49

Catecholamines (benzene ring with two OH groups attached adjacent to each other - catechol)
>Noradrenaline, adrenaline, dopamine
>Synthetic ISOPRENALINE

Front 50

How are adrenoceptors classified and why?

Back 50

>Ahlquist (1948)
- divided receptors into α and β receptors
- initially carried out by comparing the relative potencies of 5 catecholamines (including Noradrenaline, Adrenaline and Isoprenaline) to elecit a variety of responses in different tissues
>NAd-more active on α-adrenoceptors (e.g. vasoconstriction)
- however inhibitory on the gut!
>Isoprenaline more active on β-adrenoceptors to cause smooth muscle relaxation
- however excitatory on the heart!
>Varied effects led to further subdivision of receptors
- α1 = excitatory e.g. blood vessels and vasoconstriction
- α2 = inhibitory e.g. autoreceptors, inhibiting release of further NAd (realised when α antagonists increased release of NAd
- β1 = excitatory e.g. heart and juxtaglomerular apparatus, releasing renin which cause the production of ATII
- β2 = inhibitory, not innervated e.g. bronchiolar smooth muscle (bronchodilation)

Front 51

What are the molecular characteristics of adrenoceptors?

Back 51

>All GPCR types containing seven transmembrane spanning domains
- different effector mechanisms are linked to the various subtypes
E.g.
- α1 adrenoceptors are primarily coupled to phospholipase C with an increase in IP3 and diacylglycerol (DAG)
- α2 receptors can be negatively coupled to adenylate cyclase
- β receptor activation leads to increases in cAMP and protein phosphorylation via protein kinase A

Front 52

What are the the body's naturally producing catecholamines?

Back 52

>Noradrenaline
- major catecholamine from post-ganglionic sympathetic nerve terminals
- more potent on α1 then α2 than on β receptors
>Adrenaline
- releaseed from the adrenal medulla
- more potent on β receptors
NB. Isoprenaline very selective for β receptors

Front 53

Name a selective α1 agonist and antagonist.

Back 53

Phenylephrine agonist, Prazosin antagonist

Front 54

Name a selective β2 agonist.

Back 54

Salbutamol

Front 55

Name a non selective α antagonist.

Back 55

Phentolamine

Front 56

Name a non selective β agonist.

Back 56

Propranolol

Front 57

How does sympathetic nerve stimulation produce such different effects in different tissues?

Back 57

>Via different subtypes of adrenoceptors
- e.g. stimulation of heart rate and force is via β1 adrenoceptors while bronchodilatation is via β2 adrenoceptors

Front 58

What does sympathetic stimulation of α1 receptors cause in smooth muscle?

Back 58

>Contraction - this can be relaxed via β1 agonism

Front 59

What are the metabolic effects of catecholamines?

Back 59

Mainly β2 mediated
>β2 adrenoceptors mediate the
- breakdown of glycogen to glucose (glycogenolysis) in the liver
- in skeletal muscle they mediate glycogen breakdown to lactic acid causing hyperlactic acidaemia and increase the activity of the Na+K+ ATPase which causes increased uptake of K+ from the blood
- Liver activation of α1 adrenoceptors causes release of K+

Front 60

What is the function of prejunctional (presynaptic) adrenoceptors?

Back 60

>α2 activation causes inhibition of noradrenaline release
>β adrenoceptor activation increases the release of noradrenaline via positive feedback

Hint 60

presynaptic

Front 61

Name four uses of adrenoceptor agonists.

Back 61

1. α1 adrenoceptor agonists e.g. phenylephrine
2. α2 adrenoceptor agonists e.g. clonidine
3. Adrenaline
4. β2 selective agonists e.g. salbutamol

Front 62

How is phenylephrine (an α1 agonist) used clinically?

Back 62

>As a nasal decongestant - causes local vasoconstriction

Front 63

How was/is clonidine (an α2 agonist) used clinically?

Back 63

>As an antihypertensive
>As an anxiolytic

Front 64

How is adrenaline used clinically?

Back 64

1. Anaphylaxis:
- e.g. to a bee sting where there is laryngeal oedema, bronchospasm, and hypotension (effect of systemic release of histamine acting at histamine receptors)
- these effects can be counteracted by administration i.m. of adrenaline which causes vasoconstriction through α1 adrenoceptors to reduce the oedema and increase blood pressure and bronchodilatation (β2 adrenoceptors)
- example of physiological antagonism i.e. the effect of the sting is being counteracted by activating other receptors having the opposite effect to that of histamine (released in mast cell degranulation)
2. Dipivefrine (prodrug-lipid soluble and thus crosses the cornea easier than adrenaline)
- used in open angle glaucoma (intra-ocular pressure aboce 21 mmHg)
- reduces the rate of aqueous humour production by activating α2 adrenoceptors, probably vasoconstringing afferent arterioles on the ciliary body
- CONTRAINDICATED in closed angle because of dilatation of iris
3. Anaesthesia - to prolong action of local anaesthetics e.g. lidocaine
4. Cardiac arrest

Front 65

What is dobutamine (a β1 agonist) used for clinically?

Back 65

>Cardiogenic shock

Front 66

What is salbutamol (a β2 agonist) used for clinically?

Back 66

1. Asthma
- produce bronchodilatation
- effective although evidence starting to show that widespread high dosage use may exacerbate asthma
2. Premature labour - relax the uterus, antagonise effects of oxytocin

Front 67

What may be the unwanted effects of β2 adrenoceptors?

Back 67

>Hypokalaemia, tremor, vasodilatation
- causing a fall in BP and thus reflex tachycardia

Front 68

How might noradrenaline be released in the absence of nerve stimulation?

Back 68

>Via drug action
- e.g. tyramine produces its effects via the displacement of neuronal noradrenaline from the cytoplasmic pool
- termed an indirect acting sympathomimetic
(tyramine is taken by uptake 1 into the terminal and then into vesicle by the vesicular monoamine transporter (VMAT) in ecchange for noradrenaline, which escapes into the cytoplasm. Some of the cytosolic noradrenaline is metabolised by MAO while the rest escapes by uptake 1 'retrotransport' in exchange for the tyramine or the foreign amine. This release does not require Ca++ and thus does not involve exocytosis)

Hint 68

presynaptic adrenoceptors

Front 69

How do ephedrine and amphetamine act on adrenoceptors?

Back 69

>Acting partly indirectly via noradrenaline release and partly directly on post junctional adrenoceptors.

Front 70

What are the cardiovascular effects of noradrnaline, adrenaline and isoprenaline?

Back 70

>In the cardiovascular system the effects of intravenous catecholamines varies depending on their affinities for α and/or β adrenoceptors
- Noradrenaline, acting mainly via α adrenoceptors, causes vasoconstriction and the increased peripheral resistance increases blood pressure
- The rise in pressure activates baroreceptor reflexes to evoke a reflex bradycardia (reflex vagal stimulation releasing acetylcholine onto muscarinic receptors in the heart)
- The slowing of the heart rate occurs in spite of the direct effect of noradrenaline at the β1-receptors in the heart (increasing rate)

>The β-adrenoceptor selective agonist, isoprenaline, evokes vasodilatation in skeletal muscle and other vascular beds resulting in a fall in blood pressure
- This results in a reflex tachycardia
- In addition there is a direct isoprenaline β-adrenoceptor mediated increase in the force and rate of contraction of the heart

>The effects of adrenaline are a combination of those of the other two drugs
- The ability of adrenaline to cause a tachycardia is that there has been no overall change in mean blood pressure
- Thus there is no activation of the baroreceptor reflex and therefore the direct effects of adrenaline on the heart are not masked by an increase vagal drive to the heart
NB. the final effects in vivo may be a combination of the direct effects of an agonist on a tissue combined with indirect (reflex) effects, in some cases these effects may act in the same direction while in other cases they may oppose each other (as with intravenous noradrenaline on the heart, above)

Hint 70

CARDIOVASCULAR EFFECTS

Front 71

What is the effect of a bolus of adrenaline, and then in the presence of an α adrenoceptor antagonist?

Back 71

>Normally adrenaline given i.v. (bolus dose) will cause rise in blood pressure as the dose is usually large enough to cause activation of α-adrenoceptors which cause vasoconstriction and thus rise in blood pressure
- This effect will mask any of the vasodilator actions of adrenaline in the skeletal muscle vasculature (β2-mediated) which would tend to cause a fall in blood pressure
- However in the presence of an α-adrenoceptor antagonist this vasoconstrictor action of adrenaline will be blocked thus unmasking the β2-adrenceptor mediated vasodilation and thus a fall in blood pressure will be observed

Hint 71

ADRENALINE REVERSAL

Front 72

What are ergot alkaloids and what is their therapeutic use?

Back 72

>First α adrenoceptor antagonist
- mixture of alkaloids extracted from ergot (product of Claviceps purpurea, contaiminant of rye grain)
- main alkaloids are derivatives of d-lysergic acid (LSD)
- as well as α antagonism, they have agonist actions on 5-HT and dopamine
>Therapeutic use:
- migraine (ergotamine)
- post partum haemorrhage (ergometrine)

Front 73

How might adrenoceptor antagonists vary?

Back 73

>Selectivity for α / β receptors
>Interaction with receptor
- competitive (e.g. phentolamine / propranolol)
- non-competitive, irreversible (phenoxybenzamine)
- partial agonists (e.g. β adrenoceptor antagonists - oxprenolol, weak agonists which antagonise the effect of noradrenaline)
>Lipid solubility
>Anaesthetic actio

Front 74

What are the characteristics of irreversible non competitive antagonism?

Back 74

>Reduction in the slope of the log-dose response curve
>Decrease in the maximum response to an agonist

Front 75

How might weak agonists affect full agonists?

Back 75

E.g. Oxprenolol (partial β agonist)
- antagonises the effect of a full agonist e.g. noradrenaline

Front 76

What are the physiological consequences of α adrenoceptor blockade?

Back 76

>Vasodilation
- decrease in blood pressure, evoking a baroreflex and consequent increase in sympathetic drive, unopposed on β adrenoceptors this will cause tachycardia and increase in renin secretion from the JGA (resulting in sodium and water retention - oedema)
- sympathetic tone is controlled by α adrenoceptors in the brain (activation of α1 receptors causes excitation while activation of α2 adrenoceptors causes inhibition
- probably explains why α1 adrenoceptor antagonists cause less of the reflex tachycardia and sodium and water retention than non selective α adrenoceptor antagonists
- another problem of α adrenoceptor blockade is postural hypotension
>Stuffy nose

Front 77

Why is postural hypotension worse with non-selective α adrenoceptor antagonists?

Back 77

>Venoconstriction is mediated by α1 and α2 adrenoceptors
- probably why α1 receptor antagonists cause less postural hypotension than non selective antagonists

Front 78

How may β adrenoceptor antagonists be subdivided?

Back 78

>Lipid or water solubility
>Intrinsic sympathomimetic activity
>Selective for β1 receptors (cardioselective)

Front 79

What are β receptor antagonists used for therapeutically?

Back 79

Treatment of:
- angina
- hypertension
- glaucoma
- myocardial infarction
- arrhythmias
- thyrotoxicosis
- CHF
- anxiety
- migraine prophylaxis
CONTRAINDICATED IN ASTHMATICS (bronchospasm)

Front 80

What are the five stages of adrenergic neurotransmitter release that can be affected pharmacologically?

Back 80

1. Synthesis
2. Storage
3. Release
4. Uptake
5. Metabolism

Hint 80

NAD SITES OF DRUG ACTION

Front 81

Which drugs can affect the synthesis of noradrenaline?

Back 81

>L-DOPA
- increases the rate of synthesis
- bypasses the rate limiting step
>Carbidopa
- inhibits L-amino decarboxylase
>Disulfiram
- used to alter ethanol metabolism
- inhibits dopamine β hydroxylase

Hint 81

NAD SYNTHESIS

Front 82

Which drugs can affect the storage of noradrenaline?

Back 82

>Noradrenaline stored in vesicles together with ATP and chromogranin A
- vesicular transporters (12 transmembrane spanning domains) facilitate accumulation of dopamine and noradrenaline in the vesicles
- transporters are affected by reserpine
RESERPINE
- Prevents the passage of catecholamines into the storage vesicles
- Escape into the cytoplasm of the nerve and are inactivated by MAO
TETRABENZENE
- short acting noradrenaline and dopamine depletor
- reversible and used to treat hyperkinetic movement disorders such as Huntington's

Hint 82

NAD STORAGE

Front 83

Which drugs can affect the release of noradrenaline?

Back 83

>Release of noradrenaline from postganglionic sympathetic nerves can be regulated through receptors situated on the sympathetic nerve terminal
>pre-junctionally (synaptically) located α2 adrenoceptors on all sympathetic nerve terminals
- noradrenaline released from nerves can act on these receptors to inhibit its own subsequent release
- termed autoinhibition
- other agonists with affiinity for α2 adrenoceptors can inhibit transmitter release
CLONIDINE:
- α2 agonist and antihypertensive
TYRAMINE:
- displaces neuronal noradrenaline, operates in absence of nerve stimulation
- indirect acting sympathomimetic
AMPHETAMINE / EPHEDRINE:
- acts partily via noradrenaline release and partly directly on post junctional adrenoceptors
GUANETHIDINE:
- adrenergic neurone blocking agents (antihypertensives)
- enter via uptake mechanism and accumulate in the sympathetic neurones to block neurotransmission

Front 84

Which drugs can affect the uptake of noradrenaline?

Back 84

>Much of the noradrenaline released into the neuroeffector junction is recaptured by the sympathetic nerve terminals
- noradrenaline has a higher affinity than adrenaline for this neuronal uptake process
- main route by which the effects of neuronally released noradrenaline are terminated
- transporter protein of the uptake mechanism is different from those transporting catecholamines into vesicles
TRICYCLIC ANTIDEPRESSANTS, COCAINE:
- Desmethylimipramine
- Inhibits uptake mechanism
- Blockade potentiates the effects of sympathetic nerve stimulation and also prevent the action of adrenergic neurone blocking drugs

Front 85

Which drugs can affect the metabolism of noradrenaline?

Back 85

>Noradrenaline and adrenaline are metabolized in the body by two enzymes, monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)
- MAO is found in mitochondria in sympathetic nerve terminals, in the liver and in intestinal epithelium
- There are two isoenzymes, MAO-A and MAO-B
MAO
- e.g. the antidepressant phenelzine
- are non-selective unlike recent drugs e.g. MAO-B selective selegiline (used in Parkinsonism)
CHEESE REACTION
- Foods formed by bacteria e.g. some cheeses, contain large amounts of tyramine
- This is normally metabolized by MAO in the intestinal epithelium
- In the presence of MAO inhibition (as in the patient taking the non-selective phenelzine) the tyramine is absorbed and reaches sympathetic nerve terminals
- The tyramine enters via uptake1 and displaces noradrenaline which evokes vasoconstriction at the post-junctional α-adrenoceptors causing a large rise in peripheral resistance
- This can be lethal due to sub-arachnoid haemorrhage
- The likelihood of this reaction is reduced if a patient is on a selective MAO-B inhibitor
COMT
- occurs in neuronal and non-neuronal tissues
- As its name implies it will only metabolize catechols unlike MAO which metabolizes the catecholamines (dopamine, noradrenaline and adrenaline) and other amines e.g. 5-hydroxytryptamine
- The metabolite of noradrenaline formed by the action of MAO and then COMT (or vice versa) is 3-methoxy-4-hydroxy mandelic acid (vanillyl mandelic acid or VMA) which is found in urine
- High levels of VMA are an indicator of the presence of phaeochromocytoma (a tumour of chromaffin tissue).

Front 86

Which factors contribute to hypertension?

Back 86

>Heredity
>Stress
>Diet
>Lifestyle (e.g. obesity)

Front 87

How is blood pressure regulated in hypertensives and normotensives?

Back 87

Via multiple systems:
- arterioles
- postcapillary venules
- heart
- kidney

Front 88

What would likely occur if hypertension was left untreated?

Back 88

Increased likelihood of:
- atherosclerosis
- coronary artery disease
- stroke
- CHF
- diabetes
:. antihypertensive therapy with its attendant inconvenience, side effects and cost have to be weighed against the future benefits

Front 89

What does the WHO class as hypertension?

Back 89

>BP >160/95 mmHg
- continually evolving

Front 90

What is the recommended treatment for hypertension?

Back 90

MILD HYPERTENSIVES:
- weight loss
- giving up smoking
- reduced alcohol intake
HYPERTENSIVES - one of:
- diuretic
- β adrenoceptor antagonist
- Ca++ channel blocker
- ACE inhibitor
IF RESPONSE INADEQUATE add:
- second drug type (includes vasodilators)

Hint 90

ANTIHYPERTENSIVES

Front 91

How are diuretics used in the treatment of hypertension?

Back 91

BP = CO x TPR
- reducing plasma volume reduces CO and leads to a fall in blood pressure
- diuretics reduce blood volume by increasing excretion of Na+, followed by water
HOWEVER
- Long term the cardiac output and plasma bolume return to their original values but the blood pressure remains lower due to a reduced peripheral resistance
- Mechanism involved is unclear, and not common to all diuretics
- Some diuretics are widely used e.g. bendroflumethiazide and and side effects include hypokalemia, hyperglycaemia, retention of uric acid (gout) and impotence

Hint 91

Crazy Otters Like To Attack ADH
Carbonic Anhydrase Inhibitors e.g. acetazolamide
Osmotic diuretics e.g. mannitol
Loop diuretics e.g. furosemide
Thiazide diuretics e.g. Bendroflumethiazide
Aldosterone antagonists e.g. spironolactone (amiloride is K+ sparing but acts on ENaC)
ADH antagonists e.g. vaptans

Front 92

Name 6 vasodilators.

Back 92

1. ATP sensitive K+ channels (KATP) openers
- diazoxide and minoxidil
2. Calcium channel blockers
- nifedipine and verapamil
3. Nitrovasodilators
- sodium nitroprusside
4. Indirect vasodilators (α1 adrenoceptor antagonists)
- prazosin
5. Adrenergic neurone blocking agents
- guanethidine
6. Ganglion blocking drugs
- hexamethonium

Front 93

How do ATP sensitive K+ channel openers e.g. diazoxide and minoxidil cause vasodilation?

Back 93

>Block the ability of ATP to bind to these K+ channels, causing them to open (ATP binding closes them)
- opening of these causes an increase in membrane potential (hyperpolarisation - i.e. more negative)
- thus closes L type Ca++ channels thus causing relaxation of vascular smooth muscle and a consequent fall in peripheral resistance
>KATP channels are widespread
- sites of relevance are caridac and smooth muscle as well as the beta cells in the pancreatic islets responsible for secreting insulin
- opening these latter channels will cause hyperpolarisation of the beta cell and lead to less insulin being released
DIAZOXIDE
- very potent and only given in hypertensive emergencies, and is diabetogenic
- minoxidil is only given in severe hypertension and causes hypertrichosis

Front 94

How do Ca++ channel blockers e.g. nifedipine and verapamil cause vasodilation?

Back 94

>Lower blood pressure by inhibiting the Ca++ influx ito arterial smooth muscle and to a variable extent into myocardial cells
NIFEDIPINE
- selective blocker for the L-type calcium channels
VERAPAMIL
- pronounced effects on the heart (decreased cardiac output, slows heart rate, used to treat angina)

NB. calcium antagonists can evoke facial flushing, headace and dizziness

Front 95

How do nitrovasodilators e.g. sodium nitroprusside, or GTN cause vasodilation?

Back 95

>Breakdown releases nitric oxide which relaxes vascular smooth muscle
>Some of these drugs are used to treat angina while sodium nitroprusside is given by intravenous infusion to control severe hypertensive crises
NOT USED FOR DAY TO DAY TREATMENT OF HYPERTENSION

Front 96

How do alpha1 adrenoceptor antagonists cause vasodilation?

Back 96

>Reduce peripheral resistance, through blocking the effects of sympathetic stimulation to the vasculature
>Usually used in association with one or other of the main groups of antihypertensives
>First dose of prazosin can be so effective that fainting is a potential problem, due to hypotension
DOXAZOSIN
- longer acting and better tolerated
>Side effects include postural hypotension, tachycardia and dizziness

Front 97

How do adrenergic neurone blockers e.g. guanethidine cause vasodilation?

Back 97

>Rarely used today
>Prevent release of noradrenaline from post-ganglionic sympathetic neurones
>Fall in blood pressure produced by guanethidine is associated with postural hypotension, failure of ejaculation, nasal congestion etc. due to inhibition of sympathetic activity to all tissues and not just to the vasculature

Front 98

How do ganglion blockers e.g. hexamethonium cause vasodilation?

Back 98

>Cause generalised block of sympathetic and parasympathetic nervous systems
>No longer used to treat hypertensive crises, and have been superceded by other drugs such as diazoxide (K+ channel opener) and nitrovasodilators (IV sodium nitroprusside)

Front 99

What physiological response will be generated with use of a vasodilator? How might this be mitigated?

Back 99

>All will cause the baroreceptor reflex to be activated
- as β1 adrenoceptors are not blocked there will be an associated reflex tachycardia and activation of the renal angiotensin system (RAS)
- reflex tachycardia are most prominent with diazoxide, minoxidil and hydralazine
- α1 adrenoceptor antagonists cause a much smaller tachycardia
- no tachycardia observed with Ca++ channel blockers or adrenergic neurone and ganglion blockers
THUS:
- β1 adrenoceptor antagonists are often given with vasodilator drugs

Front 100

How do centrally acting antihypertensives work?

Back 100

>Decrease sympathetic outflow
- mediated via α2 adrenoceptors in the ventrolateral medulla, in the nucleus of the solitary tract

Hint 100

CENTRAL ANTIHYPERTENSIVES

Front 101

What are two examples of centrally acting antihypertensives?

Back 101

>α methyl DOPA which is a prodrug and is converted via α-methyl dopamine to α-methyl noradrenaline (A FALSE TRANSMITTER) to exert its antihypertensive effect
- highly selective for α2 receptors
- safe to use in asthmatics or patients with heart failure or in pregnancy
>Clonidine
- α2 agonist

Front 102

What may occur if a patient is abruptly withdrawn from clonidine?

Back 102

>Rebound hypertension

Front 103

What is the mechanism of β adrenoceptor antagonism?

Back 103

>Unexpected action
>Blockade of β1 adrenoceptors on the heart will cause a fall in cardiac output which would cause a fall in blood pressure if there were no compensatory reflexes
- however as α adrenoceptors are not blocked, a baroreflex mediated rise in peripheral resistance can occur (sympathoexcitation)
- reflex rise in peripheral resistance is believed to be responsible for the unwanted effect of cold extremities observed in some patients
>Fall in pressure is believed to be due to the 'switching off' of the reflex rise in peripheral resistance, which now falls to below that of the original hypertensive value
- resting cardiac output is also believed to return to normal values
- partly explained by central action on the branstem i.e. baroreceptor resetting and or reduction in central sympathetic drive
- propranolol e.g. but not atenolol, β antagonists readily cross the blood brain barrier, explained mainly by lipid solubility
>Some patients have a renin dependent hypertension
- β1 adrenoceptors on the juxtaglomerular apparatus are blocked by β antagonists, inhibiting renin release and contributing to the lowering of blood pressure ('switching off')
>Other mechanisms are an autoregulatory compensation for the reduced cardiac output and blockade of prejunctional β adrenoceptors (involved in positive feedback)
NB. NONE OF THESE MECHANISMS ARE MUTUALLY EXCLUSIVE AND THE OVERALL MECHANISM CAN INVOLVE ALL FIVE POSSIBLE MECHANISMS

Front 104

What are the potential risks and negative side effects of β-blockers?

Back 104

>All β-blockers, e.g. propranolol
- slow the heart and may precipitate heart failure in patients with some heart block
- may also precipitate asthma by blocking the β2 adrenoceptors in the airways
- led to the development of selective β1 adrenoceptor agonists e.g. atenolol (although even these can affect airway resistance and the CSM has recommended these drugs are not used in asthmatics)
>Those drugs which are partial agonists e.g. oxprenolol, cause less bradycardia and may be more useful in patients with incipient (EARLY) cardiac failure or peripheral vascular disease
ADVERSE EFFECTS:
- bradycardia
- cold peripheries
- fatigue
- bronchospasm

Front 105

What are the mechanisms for drugs such as captopril or enalapril?

Back 105

Angiotensin Converting Enzyme (ACE inhibitors):
>Inhibits the renin angiotensin system
- renin released from renal cortex acts on angiotensinogen (released from the liver into the blood), to split off the inactive decapeptide angiotensin I
- ATI is converted by ACE in the lungs primarily to the hightly active angiotensin II (ATII = vasoconstrictor)
- ATII further converts in the adrenals where the octapeptide is converted to angiotensin III
- ATII and III stimulate aldosterone secretion leading to retention of sodium and water

Front 106

What are the effects of ACE inhibitors?

Back 106

>Leads to vasodilatation
- captopril = short acting - 8 hours
- enalapril = long acting - 24 hours
>Well tolerated, although there is limited experience with them in long term use
Side effects include:
- precipitous fall in blood pressure in patients with renal impairment or on diuretics
- block bradykinin breakdown, an endogenous vasodilator and potent tussive, therefore frequent side effect of these drugs is to cause cough
- hypotension
- hyperkalemia
- renal impairment
- angiodema

Front 107

What is the mechanism of drugs such as losartan and candesartan?

Back 107

>Competitive antagonist at AT1 receptors
- in vivo has a plasma half life of about 2 hours
- metabolised in the liver to a non competitive AT1 antagonist which has a longer half-life than the parent compound
- can be given once daily and has been shown to be as atenolol or enalapril in lowering blood pressure
- less likely than the ACE inhibitors to induce cough, but may cause similar side effects

Front 108

What is considered borderline hypertension?

Back 108

>140-160/90-100

Front 109

What is considered normal blood pressure?

Back 109

<140/<90

Front 110

Which percentage of patients with hypertension hae an underlying disease that is putting the BP up?

Back 110

>Only 5%
- underlying causes are rare and include kidney disease, chronic renal failure, renal arter stenosis
- extremely rare is phaeochromocytoma 2-8 cases in 1,000,000

Front 111

Which drugs cause hypertension?

Back 111

>Corticosteroids, NSAIDs
>Rare causes
- hypercalcaemia, coarctation of the aorta, renal tubular defects e.g. Liddle's syndrome

Front 112

What lifestyle factors can cause a reduction in BP?

Back 112

1. Weight loss (2mmHg reduction per Kg)
2. Low salt diet (4mmHg reduction)
3. Regular aerobic exercise (3x per week)
4. Restriction of alcohol intake
5. Increased fruit and vegetable consumption (5mmHg reduction)

Front 113

What is angina?

Back 113

Symptom complex:
- main feature is usually severe pain in the chest and or left arm
- associated with myocardial ischaemia
Occurs when:
- coronary flow is inadequate for the heart's metabolic need
- pain caused by accumulation of metabolites in the myocardium
>Attacks NOT usually associated with irreversible tissue damage (MI)
- however incidence of MI is much higher in patients who are liable to such attacks

Front 114

What are the two common causes of angina?

Back 114

Reduced coronary flow caused by:
1. Atherosclerotic occlusion (the commonest)
2. Coronary artery spasm (variant angina)

Front 115

What three types of angina are there?

Back 115

1. Stable angina
2. Unstable angina
3. Variant angina

Front 116

What is meant by stable angina?

Back 116

>Angina occurring on exertion but relieved by rest
- due to a fixed narrowing of the coronary vessels almost always by atheroma

Front 117

What is meant by unstable angina?

Back 117

>Angina attacks occur with increasig frequency and severity and on lesser exertion or at rest and are unpredictable
>Rupture or dissection of an atheromatous plaque
- causing a thrombus without complete occlusion of the vessel
- pathologic process is similar to that in myocardial infarction where there is complete occlusion of the vessel

Front 118

What is meant by variant angina?

Back 118

>Prinzmetal angina
- occurs at rest and is caused by coronary artery spasm

Front 119

Which four main factors control coronary circulation?

Back 119

1. Arterial pressure
2. Cardiac cycle
- flow occurs mainly during diastole, much less during systole
- increase in heart rate reduces diastolic interval relative to systolic and (other things being equal) reduces coronary flow
3. Direct sensitivity of arterioles to anaerobic metabolites
- major regulatory mechanism by which blood supply is adjusted to need
- identity of metabolites responsible is not certain, but there is evidence that adenosine or ADP may be involved
4. Sympathetic innervation of coronary arterioles and effet of circulating adrenaline
- small dilator effect

Front 120

By what factor can coronary flow increase in healthy individuals?

Back 120

>8x
- however in angina patients, increase in flow is much more limited because of atherosclerosis of large vessels
- in coronary heart disease, collaterals develop and are important in maintaining blood supply

Front 121

What effect does 50% occlusion of a main coronary artery have on blood flow??

Back 121

<50% = no effect, 75% causes exercise angina, 90% occlusion causes angina at rest

Front 122

In which two main ways to antianginal drugs work?

Back 122

1. Increasing coronary perfusion (particularly dilatation of coronary collaterals)
2. Reducing cardiac work by dilatation of systemic vessels and or direct effects on the myocardium

Front 123

The three important groups of anti-anginals are?

Back 123

1. Organic nitrates
2. β-adrenoceptor antagonists
3. Ca++ antagonists

Front 124

What are examples of organic nitrates used in the treatment of angina?

Back 124

1. Glyceryl trinitrate (GTN)
2. Isosorbide mononitrate (ISMN)

Front 125

What is the mechanism of action for organic nitrates?

Back 125

>Non specific relaxation of smooth muscle
- vasodilatation is the most prominent action
>Action is produced by NO2- anion
- liberated within cells when organic nitrates react with tissue sulfhydryl (-SH) groups
- within the cell nitrite anions are converted to nitric oxide (NO)
- Activates the cytosolic form of the enzyme guanylate cyclase which causes an increase in cGMP formation
- cGMP activates protein kinase G and leads to a cascade of efects in the smooth muscle culminating in dephosphorylation of myosin light chains and sequestration of Ca++, with consequent relaxation

Front 126

What are the main effects of organic nitrates?

Back 126

1. Peripheral arteriolar vasodilation (flushing, warm skin, headache), reducing peripheral vascular resistance
2. Dilatation of large veins, reducing central venous pressure and lowering cardiac output
3. As a result of 1. and 2. a fall in arterial pressure (danger of fainting)
4. Reflex tachycardia
5. Increased coronary flow
6. Increased CSF pressure and intraocular pressure due to vasodilatation
7. Relaxation of other smooth muscle e.g. bronchi, biliary tract, ureter, anal sphincter, uterus)

Front 127

How do organic nitrates have an antianginal effect?

Back 127

>the main action of nitrates in angina from the perspective of effort is likely the reduction of cardiac work
- due to dilatation of peripheral arterioles and veins
- has been shown via administration by cardiac catheter to coronary circulation to be less effective than intravenous GTN
>however, sometimes dilatation of collateral vessels is important, causing blood to be redistributed from relatively well perfused to ischaemic areas without an increase in total flow
- in angina associated with coronary spasm, a direct effect on the constricted vessel has been shown

Front 128

Via which routes may organic nitrates be administered?

Back 128

1. GTN - sublingually and buccally
- 10-20min action
- metabolised by liver
- absorbed into hepatic portal system if swallowed (little escapes into systemic circulation)
- also can be given transcutaneously as a skin patch or intravenously
2. Isosorbide mononitrate
- long acting form of GTN
- 4 hours action
- less effective than GTN due to tolerance
- swallowed
- bds
- slow release available

Front 129

What are the side effects of organic nitrates?

Back 129

1. Headache
2. Hypotension with risk of fainting
3. Methaemoglobinaemia (oxidation of Fe2+ to Fe3+, forming brown pigment that does not take up oxygen
- rarely serious and occurs only with a large dosage

Front 130

What is the antianginal mechanism of β adrenoceptor antagonists e.g. (propranolol, atenolol, metoprolol)?

Back 130

>Act by blocking the actions of sympathetic stimulation and of circulating adrenaline on myocardium
- thus limiting increase in cardiac work during exercise or stress
- because they reduce heart rate they increase length of diastole, increasing perfusion of the coronary vessels (does increase O2 demand also)
>As well as reducing the frequency of anginal attacks they also reduce the incidence of myocardial infarction in patients with coronary artery disease
- therefore have a prophylactic use
>Orally or intravenously

Front 131

What is the action of calcium antagonists in angina?

Back 131

>3 types of voltage gated Ca++ channel (L, N and T)
- act by blocking voltage dependent Ca++ channels (sometimes called slow channels in smooth (especially vascular and cardiac muscle, L-type)
EFFECTS:
Cardiac effects
- depression of conduction, particularly in dysrhythmias associated with slow response, also cardiac slowing due to pacemaker depression
- depression of force of contraction, by limiting Ca++ entry during plateau, reduced Ca++ entry also reduces transient inward current and inhibits ectopic beats
- increased resistance to ischaemic damage, this is due to reduction of cardiac work and possibly also to inhibition of depolarisation induced Ca entry, which is thought to initiate ischaemic cell damage
Vascular effects
- vasodilatation due to reduced Ca++ entry mainly affecting small arteries and arterioles (c.f. nitrates) with marked regional variation, peripheral resistance and arterial pressure usually fall

Front 132

What is the difference between nifedipine, diltiazem and verapamil (Ca++ channel blockers)?

Back 132

They differ in their effects
1. Nifedipine (acts mainly on vascular muscle)
- Angina
- Hypertension
2. Verapamil (heart)
- Dysrhythmias
3. Diltiazem (intermediate)
- Angina
- Dysrhythmias

Front 133

What is nicorandil?

Back 133

>Potassium channel activator
- This hyperpolarizes the cell, which inactivates voltage-gated calcium channels and reduces free intracellular Ca2+

Front 134

What is the action of vabradine in angina treatment?

Back 134

>Inhibits pacemaker Na+ funny channels
- activated by hyperpolarisation
- blocking the channel reduces pacemaker activity
- slows heart rate and allowing more time for blood to flow to the myocardium

Front 135

Which other drugs are of prognostic benefit in coronary artery disease?

Back 135

1. Aspirin (antiplatelet)
2. Statins (treat underlying atheromatous disease via inhibition of cholesterol synthesis)
3. Heparins (inhibit coagulation, activating antithrombin III)
4. Glycoprotein Iia/IIIa inhibitors e.g. abciximab (inhibit platelet activation pathways)

Front 136

What is the action of dipyridamole in angina?

Back 136

>Used minimally
- shown experimentally to increase coronary flow in normal subjects
- nonetheless, much less effective than nitrates against angina
>Probably acts mainly by dilating arterioles rather than collateral vessels
- increased flow is restricted to regions where arterioles are partly constricted i.e. where oxygenation is adequate
>Shown to inhibit adenosine uptake by tissue (adenosine accumulation may be involved in vasodilatation that occurs when myocardium is hypoxic
>Acts as an inhibitor of platelet activation
- may be useful in prevention of thrombosis

Front 137

How is heart failure defined?

Back 137

">A condition in which the cardiac output is insufficient to meet the metabolic demands of the body
>It can result from any structural/functional disorder that impairs the ability of the heart to function as a pump to support the circulatory needs of the body
CAUSES INCLUDE:
- ischaemic heart disease
- hypertension
- heart muscle disorders
- valvular heart diseases
CONSEQUENCES:
>Development of clinical features such as
- SOB, thus reduced exercise tolerance
- fatigue
- fluid retention
- negative effect on survival"

Front 138

What five main factors influence cardiac function?

Back 138

"1. Preload
- what determines the ventricular end diastolic pressure and volume
- normal response to increased preload is an increase in end diastolic fibre length
- this should result in increased force of contraction (according to Starling's law)
- in heart failure this response is lost
2. Myocardial contractility
- contraction process of myocardial cells involves the binding of calcium to troponin C, permitting cross bridging of myosin to actin thereby initiating contraction
- any condition leading to a disruption of this process will result in a decreased force of contraction and reduced cardiac output
3. Myocardial compliance
- important determinant of ventricular filling and therefore cardiac output
- compliance decreased by fibrosis, hypertrophy and ischaemia
4. Afterload
- ventricular wall tension developed during ejection
- arterial vasoconstriction and obstruction to outflow increase the afterload
- leads to increased cardiac work and cardiac oxygen consumption
5. Neuroendocrine activation
- any reduction in cardiac output will lead to a reduced renal blood flow
- causing activation of the Renin-Angiotensin-Aldosterone system and sympathetic nervous system
- also causes release of vasopressin (ADH) and atrial natriuretic peptide (ANP)
- net effect produces arterial vasoconstriction, venoconstriction, and increased blood volume in order to compensate
- PROCESS OFTEN AGGRAVATES HEART FAILURE"

Front 139

What is the aim of drug therapy in heart failure?

Back 139

>To improve symptoms and reduce mortality

Front 140

Name 8 drug classes (with examples) used in the treatment of cardiac failure.

Back 140

1. Diuretics e.g. frusemide (loop diuretic)
2. ACE inhibitors e.g. ramipril, lisinopril
3. Angiotensin II receptor antagonists e.g. losartan (antagonise AT1 receptor)
4. β adrenoceptor antagonists e.g. carvedilol, bisoprolol
5. Cardiac glycosides, e.g digoxin
6. Vasodilators e.g. nitrates and hydralazine
7. β adrenoceptor agonists
8. Phosphodiesterase III inhibitors

Front 141

How do diuretics improve the symptoms of heart failure?

Back 141

>By reducing the preload
e.g. loop diuretics such as furosemide
- first line therapy in heart failure
- improves symptom
- inhibits the reabsorption of Na+ and wather from the ascending limb of the loop of Henle
>Common adverse effects include hyponatremia, hypokalemia, hypotension and gout
ROUTE OF ADMINISTRATION
- oral
- IV or IM

Front 142

How do aldosterone antagonists e.g. spironolactone work?

Back 142

>Antagonise effect of aldosterone
- thus reducing the Na+ and water absorption in the distal tubule
- sometimes referred to as a potassium sparing diuretic because it causes retention of potassium
- potentiates the effect of loop diuretics, and in addition to improving symptoms has been shown to reduce mortality in combination with ACE inhibitors
ADVERSE EFFECTS
- hyponatraemia
- hyperkalaemia
- gynaecomastia
ORAL

Front 143

How do thiazide diuretics e.g. bendruflumethiazide work?

Back 143

>Inhibits Na+ reabsorption at the beginning of the distal tubule
>Occasional adjunct in heart failure
ADVERSE EFFECTS
- hyponatraemia
- hypokalaemia
- hypotension
- gout
ORAL

Front 144

How do potassium sparing diuretics such as amiloride, triamterene work?

Back 144

>Act on the distal tubule, on ENaC, inhibiting sodium/potassium exchange
>Used where hypokalaemia is a problem
ADVERSE EFFECTS
- hyperkalaemia
- hypotension
- hyponatraemia

Front 145

How do ACE inhibitors help in heart failure?

Back 145

e.g. ramipril, captopril, lisinopril
>Inhibit Renin-Angiotensin-Aldosterone pathway
- prevent conversion of ATI to ATII (potent vasoconstrictor)
- reduce Na+ absorption also because of their effects on aldosterone
>ACE inhibitors reduce the preload and afterload
- improve symptoms and reduce mortality
ADVERSE EFFECTS
- first dose hypotension
- dry cough
- renal impairment, especially in patients with renal artery stenosis
- hyperkalaemia
ORAL

Front 146

How do ATII receptor antagonists e.g. losartan help CHF?

Back 146

>Used mainly when ACE Is are not tolerated as they do not cause the troublesome cough associated with ACE Is
>Work by blocking ATII receptors (AT1s)
ADVERSE EFFECTS
- hypotension
- worsening renal failure
ORAL

Front 147

How do β adrenoceptor antagonists e.g. carvedilol, bisoprolol help in CHF?

Back 147

>Improve symptoms and reduce mortality
>Antagonise the potentially harmful activation of the sympathetic nervous system as well as the RAS
ADVERSE EFFECTS
- hypotension
- worsening renal failure
ORAL

Front 148

How do cardiac glycosides (inotropes) e.g. digoxin help in CHF?

Back 148

>Used mainly in the treament of cardiac failure associated with atrial arrythmias
- especially atrial fibrillation, where their inotropic action is reinforced by their action on the conducting tissue
- recent evidence suggests that there is a place for the use of digoxin in the treatment of heart failure without arrhythmias (simple CHF) in patients who remain symptomatic despite optimal use of other drugs such as diuretics and ACE Is
>Digoxin increases the force of cardiac contraction by inhibiting Na+/K+ ATPase (the enzyme involved in active Na+ extrusion from cells)
- causing an accumulation of intracellular Na+ and Ca++
- improves symptoms of heart failure
ADVERSE EFFECTS usually associated with excessive dosage
- anorexia
- nausea / vomiting
- diarrhoea
- visual disturbances
- cardiac arrhythmias
ORAL / IV

Front 149

Why is digoxin use controversial?

Back 149

>Today, the most common indications for digoxin are atrial fibrillation and atrial flutter with rapid ventricular response. Beta blockers and/or calcium channel blockers should be the first choice.
- High ventricular rate leads to insufficient diastolic filling time. By slowing down the conduction in the AV node and increasing its refractory period, digoxin can reduce the ventricular rate
- The arrhythmia itself is not affected, but the pumping function of the heart improves owing to improved filling.
>The use of digoxin in heart problems during sinus rhythm was once standard, but is now controversial
- In theory, the increased force of contraction should lead to improved pumping function of the heart, but its effect on prognosis is disputable, and other effective treatments are now available
- Digoxin is no longer the first choice for congestive heart failure, but can still be useful in patients who remain symptomatic despite proper diuretic and ACE inhibitor treatment
>Digitalis/digoxin has recently fallen out of favor because it did not demonstrate a mortality benefit in patients with congestive heart failure however, it did demonstrate a reduction in hospitalizations for this condition
- Because other therapies have shown a mortality benefit in congestive heart failure, maximizing other therapies (e.g., beta blockers) first is recommended before using digoxin

Front 150

How do vasodilators e.g. nitrates and hydralazine help CHF?

Back 150

>In combination, these drugs reduce the pre and afterloads respectively
- useful in patients in whom ACE Is are contraindicated or not tolerated
- improve symptoms and reduce mortality
ADVERSE EFFECTS
- hypotension
- headache
- flushing
- tachycardia
- SLE like syndrome (long term hydralazine use)
ORAL / IV

Front 151

How do β1 agonists e.g. dobutamine helf in CHF?

Back 151

>Has a positive inotropic action on the heart by increasing intracellular levels of cAMP
- ONLY USED IN ACUTE HEART FAILURE when a rapid response is needed
IV

Front 152

How do phosphodiesterase type III inhibitors e.g. milrinone help in CHF?

Back 152

>Increase intracellular levels of cAMP and increase myocardial contractility
- prodysrhythmic and worsen survival so not often used
IV

Front 153

What is the chemistry of the cardiac glycosides?

Back 153

>Same basic chemical structure and similar actions and therapeutic indices, differing only in the rate of absorption and duration of action
>Basic structure:
- steroidal backbone essential
- 5 membered lactone ring for activity
- a side chain of one or more sugar residues - determines pharmacokinetic properties

Front 154

Which three cardiac glycosides are of clinical importance?

Back 154

>Digitoxin (long acting)
>Digoxin (medium acting)
>Ouabain (short acting)

Front 155

What are the actions of cardiac glycosides?

Back 155

1. Increased force of myocardial contraction
- most pronounced in the failing heart
- basis for beneficial effect in congestive heart failure
2. Increased excitability and automaticity of contractile and pacemaker cells
- toxic effect leading to ectopic beats and dysrhythmias

Front 156

What are the reflex vagal effects of cardiac glycosides?

Back 156

1. Sinus bradycardia, can be excessive in toxic doses
2. Reduced refractory period of atrial muscle (since the atria have the most cholinergic innervation)
- enhances reentrant arrhythmias, leading to atrial fibrillation
- although a toxic effect, this can improve atrial flutter by converting flutter to fibrillation
3. Increased refractory period of the AV node and slowed AV conduction
- slowed conduction leads to a prolonged PR interval on the ECG, while the increased refractory period of the AV node leads to partial AV block
- whilst these can be toxic effects with normal heart rates, they can be beneficial in cardiac failure associated with atrial fibrillation or flutter

Front 157

What are the extra cardiac actions of cardiac glycosides?

Back 157

1. Central effects: Anorexia, nausea vomiting
2. Retinal effects: Disturbances of colour vision

Front 158

What are the toxic effects of cardiac glycosides?

Back 158

CARDIAC EFFECTS
>Produce a variety of dysrhythmias, partly as a consequence of their primary action on cardiac muscle and partly because of their reflex vagal effects. Including:
1. Lengthened PR interval due to slowed AV conduction (a reflex vagal effect)
2. Partial or complete AV block, due to the lengthened refractory period of the AV node (reflex vagal)
3. Excessive vagal bradycardia (heart rate below 40/min)
4. Ventricular ectopic beats and extrasystoles due to their direct effects on ventricular muscle
>These arise partly from depolarisation of the bentricle and partly from the rebound increase of Ca++ and Ca++ evoked transient inward current - coupled beats
>Ventricular tachycardia and fibrillation may eventually ensue
EXTRA-CARDIAC EFFECTS
1. Nausea and gastric irritation are early symptoms of digitalis overdose
2. Visual disturbances
NB. Interaction with extracellular K+ - glycoside toxicity is greatly enhanced by hypokalaemia - porbably due to competition between glycosides and K+ for binding to the Na+K+ ATPase
NB. Most diuretics increae K+ exertion and reduce plasma K+ so increasing glycoside toxicity
- diuretics are a usual adjunct to treatment so care must be taken

Front 159

How can overdosage of cardiac glycosides be treated?

Back 159

1. Withdraw drug
2. Raise plasma K+ with KCl if low
3. Administer digitalis antibodies to bind free glycoside
4. Admisister anti-dysrhythmic drugs (lignocaine or phenytoin)
5. Electrical defibrillation

Front 160

What are the pharmacokinetics of glycosides?

Back 160

>Must be kept within narrow limits (about 0.7 to 3 ng/ml for digoxin to produce therapeutic effect without toxic effect
- radio immunoassay is often used to monitor plasma concentration and factors such as drug interaction, renal problems and age of the patients must be considered
- cardiac glycosides are nowadays used primarily in the treatment of cardiac failure associated with atrial arrhythmias, where their inotropic action is reinforced by their action on the conducting tissue
- for simple CHF without arryhthmias, other drugs are more frequently used and, even in atrial arrhythmias, may be used as adjuncts to glycosides
- include:
1. vasodilators
2. diuretics
3. ACE inhibitors
4. PDE inhibitors (e.g. theophylline, milrinone)

Front 161

How are phosphodiesterase inhibitors used in CHF?

Back 161

>Over 30 different phosphodiesterases are known
- non selective drugs e.g. caffeine, theophylline, aminophylline (important in the treatment of asthma)
- selective drugs e.g. milrinone and enoximone raise cAMP levels by inhibiting PDE-3

Front 162

Where are PDEs 3, 4 and 5 found?

Back 162

PDE 3. found in the heart and vascular smooth muscle
- inhibition increases and prolongs influx of Ca++ during cardiac action potential increasing contractility
- inhibition in arterial and venous smooth muscle results in marked vasodilation
PDE 4. found in the lungs: inhibited by rolipram (important in asthma)
PDE 5. found in the corpus cavernosum smooth muscle: inhibited by sildenafil (Viagra)

Front 163

What % reduction in mortality do β1 adrenoceptor antagonists have in CHF?

Back 163

65%
- as such they are considered first line therapy with ACE inhibitors plus spironolactone
- should be noted that ACE inhibitors initially decrease aldosterone, however this is transient

Front 164

What are important clinical considerations in the treatment of heart failure?

Back 164

1. Diagnosis
2. Lifestyle changes MATTER
3. Start one drug at a time (β1 adrenoceptor antagonists / ACE inhibitors)
4. Monitor polypharmacy (careful consideration of Digoxin)
5. Consider ICD / pacemaker
6. Transplant??

Front 165

Explain the mechanism of control of blood pressure via the renin angiotensin system.

Back 165

>Renin, angiotensin and aldosterone are important in the control of blood pressure and electrolyte balance
- if the rate of glomerular filtration drops, renin is released into the circulation from the granular juxtaglomerular cells in the walls of the afferent arterioles at the region of the juxtaglomerular apparatus
- other triggers of renin release are a fall in the sodium content of the fluid entering the distal tubule and an increase in sympathetic activity
RENIN
- is a proteolytic enzyme that acts on ANGIOTENSINOGEN (a plasma globulin) to cleave off a decapeptide
ANGIOTENSIN I
- although having little activity it is the substrate for a second proteolytic enzyme (ACE) which splits off two amino acids to form
ANGIOTENSIN II
- HIGHLY ACTIVE VASOCONSTRICTOR octapeptide
- ACE is particularly abundant on the endothelial cells of the lung
- where most of the conversion of ATI to ATII takes place
- interestingly ACE can inactivate bradykinin (a potent tussive)
- acted on by an aminopeptidase to form
ANGIOTENSIN III
- considerably less active than angiotensin II on blood vessels
- ultimately degraded

Front 166

What are the additional effects to vasoconstriction of Angiotensin II?

Back 166

>Increased growth of smooth and cardiac muscle cells
>ATII and III also increase the secretion of aldosterone from the adrenal cortex
- aldosterone causes sodium and water to be retained so that blood volume tends to increase
- K+ excretion also rises because aldosterone promotes the reabsorption of sodium from the tubular fluid in exchange for potassium from the tubular cells
>Indirectly increases the release of ADH ofrom the posterior pituitary
- contributing to water retention
- ATII also decreases renin release, contributing to a negative feedback loop
- and increases sodium reabsorption at the proximal tubule

Front 167

What occurs if there is overactivity of the RAAS?

Back 167

>Can contribute to hypertension by:
- promoting vasoconstriction (via ATII)
- retaining sodium and therefore water
:. discovery of substances that can block this pathway has been a major advance
>Though it is possible to interfere with each step, so far only ACE inhibitors are widely employed (sartans follow close behind)

Front 168

What is the clinical benefit of using ACE inhibitors?

Back 168

>Consequence of a reduction in
- mean arterial pressure
- systemic vascular resistance
- blood volume
…resulting in a reduction in pre and post load

Front 169

Do ACE inhibitors reduce the risk of myocardial infarction and mortality?

Back 169

>Yes
- Trial data suggests that they are valuable in MI, potentially reducing the risk of a second attack
- associated with reduced mortality

Front 170

What contraindications are associated with ACE inhibitors?

Back 170

>Potassium sparing diuretics e.g. amiloride
- ACE inhibitors reduce aldosterone production, thus decreasing potassium excretion (aldosterone causes sodium retention in favour of potassium secretion in the distal tubule of the nephron)
- therefore may precipitate hyperkalemia and arrhythmias
OTHER CONCERNS
- if a diuretic is already being given in heart failure, then administration of an ACE inhibitor may precipitate a profound drop in blood pressure - therefore care must be taken
- ACE inhibitors can impair renal function, particularly in renal vascular disease (i.e. stenosis), this may be because in these individuals adequate glomerular filtration may depend on the vasoconstrictor effect of angiotensin II, acting on the efferent glomerular arterioles
- dry cough because of the inhibition of bradykinin breakdown, which inreases the activity of irritant sensitive nerve endings in the bronchial mucosa

Front 171

What may be given in a heart failure patient if the cough becomes too much to bear?

Back 171

>Angiotensin II antagonists or 'receptor blockers' are also used for the treatment of hypertension, e.g. losartan
- orally active, causes less coughing due to noninterference with bradykinin metabolism

Front 172

What causes ADH to be released?

Back 172

>Peptide hormone released from the neurohypophysis (posterior pituitary), in response to an increase in plasma osmolality, and a decrease in circulating blood volume
- alters water permeability of the collecting ducts by increasing the number of water channels in the cell membrane

Front 173

Which pharmacological factors can affect ADH release?

Back 173

>ADH release is inhibited by
- alcohol
>Increased by
- angiotensin II
- nicotine

Front 174

How may ADH be used therapeutically?

Back 174

>In the treatment of neurogenic / cranial diabetes insipidus
- in which production of the natural hormone is deficient
>Administered via injection or intranasally due to its peptide structure
>Desmopressin, an analogue of ADH is now more often used as it causes less vasoconstriction
>Chlorpropamide is sometimes also employed because it enhances the renal response to ADH
>Felypressin
- has marked vasoconstrictor activity
- sometimes used in anaesthetics in dentistry

Front 175

Where are V1 receptors found?

Back 175

>In blood vessels - cause vasoconstriction when activated
- in kidney V2 receptors are present

Front 176

What occurs if V2 receptors are mutated?

Back 176

>Nephrogenic diabetes insipidus
- response to ADH is impaired
>Paradoxically thiazides can be useful in this situation, possibly because they impair the ability to produce a dilute urine

Front 177

How do the kidney tubules secrete drugs?

Back 177

WEAK ACID TRANSPORT SYSTEM
>The proximal tubular cells can secrete many weak acids into the lumen
- e.g. PAH (hence its use to evaluate renal blood flow)
- also iothalamic acid (radiocontrast agent)
DRUGS SECRETED INTO THE LUMEN
- sulphonamides, penicillin, thiazide and loop diuretics, salicylates and nitrofurantoin
- in some regards the weak acid transport system is valuable in therapeutics, e.g. delivers thiazides and loop diuretics to the lumen, their site of action
- however it can often clear drugs too rapidly before high enough plasma concentrations have developed, which requires higher concentrations to be administered,
- this was first an issue with penicillin which was eventually coadministered with probenecid (also used in gout as it increases urate excretion)

Front 178

How are bases secreted from the kidney tubules?

Back 178

>Secrete substances including creatinine, atropine, amiloride and morphine
- ability to secrete drugs may be low in neonates and declines again in old age

Front 179

Why might it be necessary to change the pH of urine?

Back 179

>Desirable
1. when some antibiotics are used to treat UTIs
- penicillin and tetracycline are more active in acid solution and sulphonamides become more active and more soluble in an alkaline solution
2. Attempting to increase the excretion of salicylate or phenobarbitone taken in overdose
>The principle used when deliberately changing urinary pH is a simple one: it is to exploit the kidney's homeostatic function
- thus an acid urine can be achieved quite readily by ingestion of a weak acid

Front 180

What substances are used to change urine pH?

Back 180

ACIDIFY
>Ammonium chloride and ascorbic acid orally
ALKALINISE
>Sodium bicarbonate or potassium citrate can be given
- again by mouth
- citrate is in effect metabolised, and the negative charge transferred to bicarbonate
- cation excreted with bicarbonate, resulting in an alkaline urine

Front 181

What is the definition of a local anaesthetic?

Back 181

>Substances that reversibly block the generation and conduction of the action potential

Front 182

What is the general chemistry of a local anaesthetic?

Back 182

>Aromatic group, intermediate chain (ester or amide bond), tertiary or secondary amino group
NB. Different compounds vary in (a) duration of action (b) ability to penetrate tissues, these being the main factors wthat govern the choic of drug for particular purposes

Front 183

What is the mechanism of action for local anaesthetics?

Back 183

>Act by blocking the increase in Na+ permeability, which underlies the upstroke of the action potential
- they have little effect on the resting membrane potential of the nerve fibre

Front 184

What is the pKa for local anaesthetics? How does this affect their use?

Back 184

>Local anaesthetics are weak bases
- exist in ionised or uncharged forms
>Dissociation constant given by the Henderson Hasselbach equation
pKa = pH + log10 [BH+] / [B]
- thus the pKa can be used to predict their ionisation at a given pH
- important because the charged forms cannot penetrate the axon membrane, but uncharged forms can diffuse across the lipid membrane and into the axon
- once inside, 80-90% will become charged at the intracellular pH (7.2)

Front 185

What is meant by use dependance / frequency dependence?

Back 185

>When a Na+ channel opens, the LA plugs the channel from the inside
- main mechanism of many LAs
- shows use/frequency dependence
>Block develops faster and is much greater when the nerve is conducting action potentials at a higher frequency

Front 186

Why does nerve block occur at a faster rate when nerve conducts at a higher frequency?

Back 186

1. Nerve is depolarised more often, making the inside of the nerve more positive on average
- tends to drive the LA into the Na+ channel
2. Secondly, the inactivated form of the Na+ channel has a higher affinity for LA both charged and uncharged, than the resting form of the Na+ channel
- uncharged local anaesthetics are also active and use dependent in their action

Front 187

Aside from Na+ channels, how else do local anaesthetics act on nerves?

Back 187

>Part of their action may result from their dissolution in the lipid cell membrane in the uncharged form
- perhaps similar to that of volatile anaesthetics

Front 188

Describe the characteristics of pain fibres being blocked by local anaesthetics.

Back 188

>Pain sensation is mainly carried by small myelinated (A delta) and unmyelinated c fibres
- because small diameter fibres are blocked more easily than large diameter fibres, pain sensation tends to disappear first, followed by temperature, touch and deep pressure
- there is however great individual variation
- motor axons, being large in diameter are also relatively resistant

Front 189

What occurs to the nerve impulse in a nerve fibre during anaesthetisation?

Back 189

>Impulse is slowed down and reduced in amplitude
- if the degree of block is sufficient, the impulse dies out altogether
- otherwise it returns to normal when it has passed through the region where the local anaesthetic is operating
- note that the compound action potential recorded from a whole nerve trunk will be reduced in size, even distal to a region of partial anaesthetisation, because
1. fewer nerve fibres will be contributing to the compound action potential, the impulses in some having been stopped, the remainder of course being normal
2. becuase the slowing of the impulses that get through the anaesthetised region spreads them out further - more temporal dispersion

Front 190

Why are vasoconstrictors used in local anaesthesia?

Back 190

>Adrenaline or noradrenaline or vasopressin may be added to LA solutions
>Resulting vasoconstriction, delays absorption of the anaesthetic from its site of injection which
1. prolongs its action
2. reduces the danger of systemic toxicity

Front 191

How are local anaesthetics metabolised? Why is this important?

Back 191

>Metabolism is important because large amounts of LA are injected for local effect
- this must eventually be reabsorbed with the consequent risk of systemic toxic effects
>Ester type (e.g. procaine, tetracaine and benzocaine) are hydrolysed
- e.g. procaine is hydrolysed quite rapidly in the plama by plasma cholinesterase (CSF contains little esterase however)
>Amide type e.g. lidocaine, prilocaine are catabolised more slowly by the liver

Front 192

What are the adverse effects of local anaesthetics?

Back 192

ADVERSE EFFECTS
1. Local tissue injury, occasionally with infiltration and spinal anaesthesia
2. Effects on CNS
- stimulation with hyperactivity and manic behaviour
- occasionally convulsions followed by coma and respiratory depression
3. Effect on cardiovascular system
- vasodilator action
- depression of myocardium and cardiac slowing leading to hypotension (except with cocaine, which has the opposite effect because of sympathetic potentiation)
4. Allergic reactions, possibly dangerous but occur very rarely

Front 193

Name 6 methods for administration of local anaesthesia.

Back 193

1. Surface anaesthesia
2. Infiltration anaesthesia
3. Nerve block
4. Spinal anaesthesia
5. Epidural anaesthesia
6. Intravenous regional anaesthesia

Front 194

What types of surface anaesthaesia are typically used and when?

Back 194

>Used on cornea, mouth and pharynx, bronchial tree for bronchoscopy, urethra and bladder
- lidocaine good
- benzocaine poorly soluble and may be used as powder for prolonged anaesthesia of skin ulcers and burns
- lidocaine and prilocaine can form a non crystalline mixture (EMLA) which can be applied directly to the skin and produces complete anaesthesia in about one hour

Front 195

What does EMLA stand for?

Back 195

>Eutectic mixture of local anaesthetics

Front 196

How does infiltration anaesthesia work?

Back 196

>Drug is injected directly into tissues to anaesthetize nerve endings
- e.g. in wound stitching, minor surgery, episiotomy, vasectomy
>Large amounts may be needed with danger of systemic toxicity
- also danger of accidental intravascular injection, and of local tissue irritation or necrosis
- lidocaine, prilocaine and procaine are good
- vasoconstrictors used most often for infiltration anaesthesia, but must be avoided in extremities such as fingers or toes because of the danger of ischaemic tissue damage

Front 197

What is nerve block anaesthesia?

Back 197

>Drug injected close to (not into) the nerve trunk, to anaesthetise the whole area of distribution of the nerve
- e.g. block of mandibular nerve in dentistry
- brachial plexus block for hand surgery

Front 198

What is spinal anaesthesia?

Back 198

>Drug injected into the subarachnoid space of the spine (containing the CSF), between the second and fifth lumbar vertebrae so that the needle is below the conus medullaris, and injury to the spinal cord is avoided
- used for various types of major surgery, e.g caesarian section, rectal surgery
- considerable technical skill is needed
- lidocaine and prilocaine are used
- may be combined with glucose to adjust the density of the solution so anaesthesia can be controlled by tilting the patient with glucose to adjust the density of the solution so anaesthesia can be controlled by tilting the patient
>There are many dangers
- respiratory paralysis, severe hypotension, post operative pain, headache and paralysis, vomiting and visceral pain (vagal afferents not blocked)
- possibility exists of neurological complications or meningitis due to toxic effects of high drug concentration, or accidental introduction of bacteria

Front 199

What is epidural anaesthesia?

Back 199

>Where the drug is injected into the epidural space, from which it diffuses to block nerve roots
- cannot spread to the brain as the epidural spaces end at the foramen magnum
- similar effects to spinal anaesthaesia, and the same drugs used, but larger amounts are required to elicit a comparable effect therefore subarachnoid injection must be avoided
- used in obstetrics - mainly lidocaine and bupivacaine

Front 200

What is intravenous regional anaesthesia?

Back 200

>The anaesthetic is injected intravenously distal to a cuff on the limb
- The anaesthetic diffuses retrogradely into the tissues within a few minutes
- Danger of systemic toxicity if the cuff is released prematurely
- Mainly lidocaine and prilocaine

Front 201

What is a dysrhythmia?

Back 201

>An alteration in the beat or rhythm of the heart, often abnormal
- abnormal rhythms are more appropriately called dysrhythmias (arrhythmia means without rhythm and some dysrhythmias are rhythmic)

Front 202

What are the 5 phases of the cardiac action potential?

Back 202

Phase 0: Fast inward Na+ current
Phase 1: Na+ current inactivation
Phase 2: Slow inward Ca++ current
Phase 3: Ca++ current inactivation, outward K+ current
Phase 4: K+ channel closing

Front 203

What is the myocardial refractory period?

Back 203

>Immediately after the action potential most voltage-dependent Na channels will be inactivated
- time course of their recovery from inactivation, (in combination with some K+ channel deativation) is the is the main determinant of the myocardial refractory period
- during this refractory period, a second action potential cannot be elicited
- due to the refractory period, the cardiac action potential normally dies out after it has activated the ventricles, since it is surrounded by refractory tissue which it has just crossed

Front 204

What four underlying mechanisms are responsible for dysrhythmias?

Back 204

1. Delayed after depolarisation
2. Disordered conduction pattern (re-entry)
3. Abnormal pacemaker activity
4. Heart block

Front 205

What is delayed after-depolarisation?

Back 205

>The after-depolarisation normally follows the action potential
- this occurs when [Ca++] increases above normal
- it is the result of a net inward current known as the transient inward (TI) current, possibly carried by the Na+ / Ca++ exchanger

Front 206

What is meant by disordered conduction pattern (re-entry)?

Back 206

>Damaged myocardium can develop unidirectional conduction block, which can result in a re-entrant dysrhythmia in which the impulse circulates indefinitely in a localised region of the myocardium, acting as a source of excitation (independent of the normal pacemaker) for the rest of the heart
>Conduction through depolarised parts of the myocardium often depends more on Ca++ current rather than Na+ current
- the action potential (known as a slow response) has a slow rising phase and is conducted very slowly
- this thype of conduction is much more sensitive than normal conduction to agents that modify Ca++ current e.g. β agonists, which enhance it and thus favour re-entrant rhythms, and Ca-antagonists which block Ca++ currents and suppress re-entrant rhythms
>For a re-entrant rhythm to develop, the refractory period must be shorter than the circulation time of the impulse
- prolongation of the refractory period thus suppresses this type of dysrhythmia

Front 207

What is meant by abnormal pacemaker activity?

Back 207

Damaged myocardium can cause the appearance of an ectopic pacemaker in atria or ventricles which initiates beats out of synchrony with the normal rhythm
- such ectopic beats commonly occur immediately after a normal beat and appear to be triggered by it
- because increase [Ca++] produced by the action potential causes a secondary depolarisation associated with a transient inward (TI) current
- factors that increase or decrease Ca entry tend to encourage or discourage ectopic beats

Front 208

What is meant by heart block?

Back 208

>Impulse may fail to be initiated by the SA node, or fail to propagate through the AV node or conducting system
- in either case, ventricular beating is maintained by an abnormal pacemaker (e.g. in the Purkinje system)
- such pacemakers tend to be slow and unreliable, causing loss of consciousness or death if the rhythm becomes too slow or stops altogether this is in contrast to delayed after-depolarisation, disordered / re-entry and abnormal pacemaker activity

Front 209

What are possible causes of dysrhythmia?

Back 209

>Various types of damage can affect the heart rhythm (e.g. myocardial infarction, stretching of atria by raised central venous pressure in cardiac failure, congenital malformations of the heart
>Tendency for dysrhythmias to develop is often enhanced by sympathetic activity

Front 210

What are the two common patterns of dysrhythmia?

Back 210

1. Supraventricular
- drugs commonly used to treat these dysrhythmias in clinical practice
- ectopic beats - causing paroxysmal atrial tachycardia (rapid but regular atrial contraction (120-240 per minute)
- low frequency reentrant rhythm - causing atrial flutter (rapid regular atrial contractions (occurring ~300 per minute)
- high frequency reentrant rhythm - causing atrial fibrillation (very rapid, irregular, and chaotic atrial activity 350-600 per minute
2. Ventricular
- drugs becoming infrequently used in the treatment of these dysrhythmias
- ectopic beats - causing ventricular tachycardia (multiple similar ventricular ectopic beats in rapid succession)
- reentrant rhythm - causing ventricular fibrillation (rapid, uncoordinated contraction with irregular chaotic electrical activity - leading to circulatory arrest and unconsciousness)

Front 211

How are antidysrhythmics classified?

Back 211

Via the Vaughan William's (1970) classification
- considered not entirely satisfactory, as it doesn't inform at all on the use of these drugs in clinical practice...
- Classes I-IV

Front 212

What are class I antidysrhythmics?

Back 212

>Drugs producing use dependent block of voltage-sensitive Na+ channels thus reducing electrical excitability and slowing conduction velocity in regions where Phase 0 is produced by inward Na current
>These drugs are divided into three sub-casses because the early drugs (Class Ia) have different effects and uses to the newer Ib and Ic drugs
- key feature underlying the differences between classes a, b and c is differences in the use dependence of their block
Ia e.g. QUINIDINE, DISOPYRAMIDE
- oldest group (properties midway between Ib and Ic)
- also prolongs repolarisation (but less than class III)
- used to treat supraventricular and ventricular dysrhythmias
Ib e.g. LIDOCAINE
- associate with and dissociate from Na+ channel rapidly (within a single beat)
- little effect on rate of AP rise but channels are blocked following peak so any premature beat is aborted
- also bind preferentially to inactivated Na+ channel - selective block in depolarised regions
- used to treat ventricular tachycardia, particularly following infarction
Ic e.g. FLECAINIDE, ENCAINIDE
- associate with and dissociate from Na+ channel slowly (so level of block constant through cardiac cycle)
- show only marginal selectivity for inactivated channels
- not selective for damaged myocardium but reduce general excitability
- used to treat atrial fibrillation and reentrant ventricular dysrhythmias

Front 213

What are class II antidysrhythmics?

Back 213

β blockers e.g. propranolol, metoprolol, atenolol
- block the excitatory effects of sympathetic activity on the heart by blocking β1 receptors
- reduces the slow inward Ca++ current, reducing pacemaker activity, slowing AV conduction, and inhibiting ectopic beats
- thus they reduce force and rate
- used in atrial dysrhythmias and also to prevent exercise induced ventricular extrasystoles

Front 214

What are class III antidysrhythmics?

Back 214

>Prolongs the cardiac action potential and increases the refractory period
- it is slow in onset and has an extremely long plasma half-life (10-100 days)

Front 215

What are class IV antidysrhythmics?

Back 215

e.g. VERAPAMIL, DILTIAZEM
>Drugs inhibit the slow inward Ca++ current (indirectly reducing TI current) thus reducing pacemaker activity, slowing AV conduction and inhibiting ectopic beats

Front 216

What other treatments are available other than those classified by Vaughan Williams?

Back 216

1. Cardiac glycosides
2. Adenosine
3. Electrical defibrillation, often used in conjunction with drug treatment
4. Implanted electrical pacemakers - the only reliable way to treat heart block
5. Implanted cardioverters

Front 217

Which are the major CNS neurotransmitters?

Back 217

>Glutamate - excitatory
>GABA - inhibitory
MIXED EFFECTS:
- Acetylcholine
- Noradrenaline
- 5HT
- Dopamine
PEPTIDES:
- Substance P - excitatory
- Opioids - inhibitory
OTHER:
- Nitric oxide - excitatory
- Adenosine

Hint 217

SNOG A GONAD 5x

Front 218

What four main groups can CNS 'loss of function' disorders be grouped?

Back 218

1. Depression
2. Parkinson's disease
3. Alzheimer's diseases
4. Schizophrenia (negative symptoms)

Front 219

What four main groups can CNS excessive function' disorders be grouped?

Back 219

1. Pain
2. Epilepsy
3. Anxiety
4. Schizophrenia

Front 220

How do drugs act to treat CNS diseases?

Back 220

1. Increasing transmitter function
- increasing availabilty of a transmitter (Parkinson's disease and depression where more precursor is supplied or metabolism or uptake is blocked)
- receptor activation (e.g. in anxiety or epilepsy with the benzodiazepines or as in opiate analgesia)
2. To decrease transmitter function via antagonists (e.g. anti schizophrenic drugs)

Front 221

What general issues are encountered when manipulating the CNS with drugs?

Back 221

Largely due to the fact that the CNS has several billion neurones which form hundresds of contacts with each other
1. Measurement of assessment of disorders and appraisal of treatments
- e.g. not easily quantifiable, largely rely on patient symptoms
2. Multiple unintended effects of drugs
- multiple receptors for particular transmitters e.g. 5HT, some of which are excitatory and some of which are inhibitory
- therefore increasing availability of transmitter serotonin could affect all receptors
- triptans are useful in migraine through selective agonism of a subtype of 5HT receptor
3. Feedback responses
- via prolonged stimulation or blockade there may be receptor down or upregulation
4. Chronicity of diseases
- long term therapies cause not only up/downregulation but also tolerance
- compliance presents as a common issue because of this
5. Side effects
- complexity of human nervous system increases probability of drugs causing side effects through acting on similar / same receptors
6. Blood brain barrier
- presents problems for peptide based treatments which poorly penetrate the CNS
- non peptide drugs acting at the receptors for peptide transmitters indicate that these systems maybe very important therapeutic targets
7. Nature of the neuronal circuitry
- important in determination of the final effects of a transmitter
- Morphine and GABA are both inhibitory (via actions on mu opiod and GABA receptors respectively, and the two can be present on the same neurones
- here morphine may cause disinhibition (turning off inhibition causes excitation)

Front 222

What is the role of peptides in the CNS?

Back 222

>Chain of amino acids which does not exceed 30 aas
>Many of the peptides active in the CNS have additional roles elsewhere in the body, such as somatostatin controlling insuiln and glucagon release, and substance P and bradykinin acting on the vasculature
SYNTHESIS AND RELEASE:
>Starts with large precursors of 300aas which are produced in the nucleus of the cell and then transported to the terminal processed en route
- not only is the production slow, unlike all other transmitters, but in active neurones, depletion of peptides can occur if synthesis lags behind release
- the peptide can diffuse through tissue and act at sites distance from the neurone that released it
REUPTAKE:
>Peptide NOT SUBJECT TO REUPTAKE
- broken down by membrane peptidases
FACTORS AFFECTING PRODUCTION:
>Precursor produced in the nucleus, gene induction and suppression can change the peptide content of neurones
>Nerve growth factor appears important, as does NMDA induced calcium influx
- good evidence that some peptides are always present in neuronal systems, and that others appear as a result of damage and or dysfunction to neurones
- thus pharmacology of a neurone will change as a consequence of pathological changes

Front 223

What are the receptor subtypes, function and potential indications of opioid receptors?

Back 223

>Mu, delta, kappa, ORL-1
>Pain, anxiety, dependence
>Chronic pain, addiction

Front 224

What are the receptor subtypes, function and potential indications of tachykinin receptors?

Back 224

>NK-1
>Inflammation, anxiolysis
>Headache, anxiety

Front 225

What are the receptor subtypes, function and potential indications of cholecystekinin receptors?

Back 225

>A and B
>Anxiogenesis, satiation, dopamine function, pain
>Panic, eating disorders, pain, Parkinsonism, psychoses

Front 226

What are the receptor subtypes, function and potential indications of neuropeptide Y receptors?

Back 226

>Y1-6
>Obesity, mood
>Eating disorders, depression, epilepsy

Front 227

What are the receptor subtypes, function and potential indications of vasopressin receptors?

Back 227

>V1 blood vessels and V2 kidney tubules
>Learning, memory
>Amnesias

Front 228

What are the receptor subtypes, function and potential indications of somatostatin receptors?

Back 228

>Sst1-5
>Analgesia
>Pain

Front 229

What are the receptor subtypes, function and potential indications of galanin receptors?

Back 229

>GalR1 and 2
>Sensory transmission, feeding
>Pain, Eating disorders

Front 230

What is meant by neurotransmission?

Back 230

>The process by which the electrical activity of one nerve is communicated to another

Front 231

Where and how do neurotransmitters act?

Back 231

>They bind to receptors on cells which cause activation of either ion channels or second messenger systems
- ionotropic vs. metabotropic
- majority of metabotropic receptors are GPCRs
- binding of the neurotransmitter to the receptor activates a G protein which then alters the activity of an effector molecule
- this molecule may be an ion channel or an enzyme that produces or hydrolyses a second messenger, such as adenylate cyclase (producing cyclic AMP, PLC (IP3 and DAG), phospholipase A2 (arachidonic acid) or phosphodiesterase (hydrolyses cyclic AMP and cyclic GMP)

Front 232

Where may modulation of neurotransmission take place?

Back 232

>May take place presynaptically or postsynaptically
PRESYNAPTIC:
- regardless of the mechanism, the ultimate effect is a change in the amount of neurotransmitter that is released
POSTSYNAPTIC:
- final outcome is a change in firing pattern of the neuron

Front 233

What are the four stages of presynaptic modulation that may be modulated?

Back 233

1. Synthesis
2. Release
3. Storage
4. Breakdown

Front 234

How may drugs affect synthesis of neurotransmitter?

Back 234

>Through
- modification of enzyme activity
- altering precursor availability
>May lead to changes in the amount of neurotransmitter released and thus the effectiveness of neurotransmission
E.g. LEVODOPA
- precursor of dopamine used in treatment of Parkinson's disease

Front 235

How may drugs affect release of neurotransmitter?

Back 235

>Release of neurotransmitter is a Ca++ dependent process
- signal for transmitter release is the arrival of an action potential which activated voltage gated Ca++ channels, leading to the fusion of neurotransmitter containing vesicles
>Release process can be affected directly by toxins that act on the Ca++ channels or on the vesicle release machinery
- Ca++ channels can also be regulated by neurotransmitters acting on metabotropic receptors
- in this case activation of the receptor leads to activation of a G protein that inhibits the Ca++ channel
- such receptors may be autoreceptors activated by a neurotransmitter to inhibit its own release, or heteroceptors activated by a neurotransmitter released from a different cell
E.g.
- GABA acting via GABAD receptors
- Opioid peptides acting via mu / delta receptors

Front 236

How may drugs affect uptake of neurotransmitter?

Back 236

>Once released, the neurotransmitter diffuses across the synaptic cleft and may interact with postsynaptic receptors
- in most cases, the neurotransmitter is then recovered by uptake into the presynaptic cells or glial cells (exceptions include Ach and peptides which are broken down by extracellular enzymes)
>Blockade of the transporters can extend the time the neurotransmitter is present in the synapse and thus enhance its action
>E.g. TIAGABINE (GABA uptake blocker used in the treatment of epilepsy)
> FLUOXETINE 5HT uptake blocker used in treatment of depression

Front 237

How may drugs affect breakdown of neurotransmitter?

Back 237

>In the same way that increasing the synthesis of a neurotransmitter may modulate neurotransmission, blocking the breakdown of the neurotransmitter may increase its action
>For most neurotransmitters breakdown occurs following re-uptake and is carried out by intracellular enzymes in neurons or glia
- in the case of ACh and peptides the enzymes are extracellular
E.g. SELEGILINE
- MAOB inhibitor, reduces metabolism of dopamine
VALPROATE
- inhibitor of GABA metabolism used in the treatment of epilepsy
TACRINE
- inhibitor of AChE - may be useful in treatment of Alzheimer's disease

Front 238

In what two ways might postsynaptic modulation occur?

Back 238

1. Modulation of receptor function
2. Modulation of postsynaptic ion channels

Front 239

How may drugs affect receptor function?

Back 239

>Many neuroactive drugs act as agonists or antagonists at neurotransmitter receptors
- other drugs are neither agonists nor antagonists, but interact with the receptor to modulate its function, thereby increasing or decreasing the response to the neurotransmitter
- best known examples of this class of drug are the benzodiazepines, which increase GABA(a) receptor affinity, thereby increasing the inhibition mediated by GABA
E.g. DIAZEPAM
- benzodiazepine used as a premedication, an anxiolytic, in status epilepticus

Front 240

How else may postsynaptic receptors be modulated in terms of modulation of receptor function?

Back 240

>By second messengers produced in response to activation of other receptor systems
- one way the receptors may be changed is through phosphorylation
- neurotransmitter receptors are also dynamic and may change in number in response to alterations in synaptic output

Front 241

How are post synaptic ion channels modulated?

Back 241

>Ion channels in the membrane of the postsynaptic cell determine the 'intrinsic properties' of the neuron
- K+ channels are important in determining the resting membrane potential and the electrical resistance (leakiness) of the membrane
TWO IMPORTANT K+ CHANNELS:
1. Inwardly rectifying K+ channels (Kir)
2. 2 pore K+ channels (TASK)
- both types can be inhibited by neurotransmitters including ACh and certain peptides, whcih act on metabotropic receptors coupled to phopholipase C
- inhibition of these K+ channels leads to depolarisation of the postsynaptic cell
Postsynaptic GABA(b) receptors
- other neurotransmitters acting on G protein coupled receptors can activate another class of K+ channels (G protein gated inward rectifiers, GIRK channels) causing hyperpolarisation
>certain slow K+ channels (Ca++ activated KCa channels and voltage gated M channels) that remain open for a ong time following depolarisation can also be inhibited by neurotransmitters
- e.g. both are closed by ACh acting on muscarinic receptors and by glutamate acting on metabotropic receptors
>All of these actions may affect the firing behaviour of the cell directly or modulate the way in which it responds to other synaptic input

Front 242

What are the major steps at which drugs may act at the synapse?

Back 242

1. Uptake of precursor (or of transmitter itself)
2. Synthesis of transmitter - normally occurring in nerve terminals
3. Packaging of transmitter into vesicles (applicable mainly to adrenergic neurones, where drugs may inhibit uptake into vesicles, or release stored transmitter from vesicles into cytosol
4. Release by exocytosis
5. Combination of transmitter with receptors (competitive block)
6. Production of postsynaptic response (inhibition or enhancement)
- at an excitatory synapse, such as the autonomic ganglion or NMJ, this consists of
a. increase in ionic conductance of the postsynaptic membrane
b. depolarisation of postsynaptic cell
c. initiation of action potential in postsynaptic cell
7. Enzymatic destruction of transmitter

Front 243

Is there a a difference between NMJ Acetylcholine receptors and those at autonomic ganglia?

Back 243

>Yes - although are both nicotinic
- drugs affecting ganglia do not however discriminate between sympathetic and parasympathetic ganglia

Front 244

Name an example of a ganglionic stimulant, and its effect upon increasing dose.

Back 244

>Nicotine
- stable volatile tertiary amine, readily absorbed through mucous membranes (e.g. of the mouth and alveoli)
- in small doses its main actions are central, larger doses stimulate ganglia and still larger doses block ganglia (possibly by a mechanism analogous to depolarizing neuromuscular block)

Front 245

What are the main acute effets of absorbing nicotine by smoking?

Back 245

a. CNS stimulation
b. Increased parasympathetic and sympathetic activity, causing rise in blood pressure, tachycardia, inhibition of gastric motility, increased salivation and bronchial secretion
- vasoconstrictor effect of nicotine, by reducing placental blood flow may be responsible for the impaired foetal growth caused by smoking in pregnancy
- it may also be responsible for the increased incidence of coronary attacks in smokers, although CO has also been implicated in both of these effets
c. release of antidiuretic hormone (ADH) from posterior pituitary gland
- smoking does not usually cause ganglionic block, but tobacco chewing may do so because much more nicotine is absorbed

Front 246

How do ganglionic blockers generally work?

Back 246

>Affect sympathetic and parasympathetic ganglia indiscriminately
- most of them are generally stated to act by competition, though recent evidence indicates that many block channels rather than receptors
- the most important is hexamethonium, chemically related to ACh, was introduced in 1949 and was the first effective treatment of hypertension

Front 247

What are the actions and effects of ganglion blocking drugs?

Back 247

>Selective for autonomic ganglia, and do not affect neuromuscular transmission
- do not distinguish between ganglia of the sympathetic and parasympathetic systems
- consequently produce a large number of effects, most therapeutically undesirable
CV EFFECTS:
- depend mainly on block of sympathetic system
- dilatation of arterioles and veins causes a substantial fall in blood pressure
- loss of cardiovascular reflexes (causing postural hypotension, exercise hypotension etc.)
- cutaneous vasodilatation
GASTROINTESTINAL EFFECTS:
- mainly due to block of parasympathetic system
- inhibition of motility and secretion, leading to severe constipation
GENITOURINARY EFFECTS:
- Block of parasympathetic leads to impairment of micturition, and to failure of erection of genital tissue, block of sympathetic inhibits ejaculation, net result is impotence
EYE EFFECTS:
- accommodation is impaired, causing blurred vision
- loss of pupillary reflex can cause photophobia
USES:
- originally introduced to control hypertension
- now superceded by more specific drugs with far fewer side effects
- trimetaphan occasionally used to produce hypotension during surgery

Front 248

How do clinically useful neuromuscular blockers work?

Back 248

1. By competing with Ach for receptor sites
2. Depolarisation of endplate region of muscle fibres, causing the membrane to become inexcitable
>Drugs used during anaesthesia to cause muscle relaxation, and hence reduce the amout of general anaesthetic required

Front 249

Name a substance that inhibits uptake of choline by nerve terminals?

Back 249

>Hemicholinium
- competitive inhibitor of choline uptake by cholinergic nerve terminals
- active carrier mediated transport
- inhibition causes the terminals to run short of choline, so that acetylcholine synthesis cannot keep up with release
- highly active synapse are preferentially affected
- action is too slow for clinical purposes, but has been of experimental value

Front 250

Name a substance which blocks the release of acetylcholine without affecting synthesis or postsynaptic mechanisms.

Back 250

>Botulinum toxin
- high molecular weight protein produced by an anaerobic bacillus (clostridium botulinum) which can grow in badly tinned food
- comparatively rare but highly dangerous cause of food poisoning
- toxin is exceptionally potent (the most poisonous poison) and long lasting, blocking release of ACh

Front 251

Name a substance other than botulinum toxin which blocks release of Ach

Back 251

>Streptomycin, and other aminoglycoside antibiotics
- preferably block Ca entry
- can cause weakness as a side effect, and potentiate the action of NM blocking agents and in anaesthesia

Front 252

Name 2 competitive NMJ blockers.

Back 252

1. Tubocurarine
2. Pancuronium
3. Gallamine

Front 253

What are the features of competitive block?

Back 253

1. Causes relaxation without preliminary excitation of muscles
2. Relaxant effect antagonised by anticholinesterases
3. Tetanic response of muscles poorly sustained
4. Myasthenia gravis patients (autoimmune loss of acetylcholine receptors) are normally sensitive

Front 254

What is alchohol?

Back 254

>Ethanol, a sedative, hypnotic and anaesthetic drug, depending on its dose
- it has little medical use (except as a competitive agonist to methanol in circumstances of poisoning)
- it is mainly consumed as a recreational drug
- it is dependence producing
>Alcohol abuse is a major medical and public health problem in many societies

Front 255

What of beer, cider, strong cider/beer, wine, port and spirits constitutes 1 unit of alcohol?

Back 255

Beer - 1/2 pint
Cider - 1/3 pint
Strong beer - 1/4 pint
Wine - 125mL
Port - 50mL
Spirits - 23.7mL

Front 256

How much ethanol is present in one unit of alcohol?

Back 256

11mL

Front 257

What is the recommended limit for alcohol intake per week M/F?

Back 257

21/14 units per week. Anything above this is considered excessive

Front 258

What is meant by proof spirit?

Back 258

>Defined as the alcohol water concentration with a specific gravity of 0.9198
- it contains 57% of alcohol by volume
:. 70 degrees proof = 70% of 57% alcohol by volume which is 40%
>110 degrees proof, or 10 degrees over proof means 110% of 57% = 63% alcohol by volume

Front 259

Where is alcohol absorbed and distributed in the body?

Back 259

>Absorbed from the stomach (roughly 25%) and even faster from the small intestine (remainder)
- little reaches the colon
- optimally absorbed when the stomach is empty, and at concentrations of 10-15%
NB. absorption is delayed by presence of food in the stomach, partly because access to the small intestine is restricted
>Once absorbed ethanol distributes evenly throughout the body water 2/3 body volume
- volume of distribution is ~0.7L/Kg
- maximum plasma level occurs after 30-60 minutes

Front 260

What percentage of the mother's alcohol concentration does the foetal circulation reach during pregnancy? What are the dangers?

Back 260

80% of that in the mother's circulation
- can cause mental retardation and deformity in the baby
- total abstinence in pregnancy is the only safe rule

Front 261

How is alcohol metabolised?

Back 261

>Ethanol is metabolised first to acetaldehyde
- 90-98% of a dose is metabolised
>Two enzymes perform this task
1. Alcohol dehydrogenase (present in the cytosol of the liver and stomach, it is not inducible)
Ethanol + NAD+ = Acetaldehyde + NADH + H
2. Mixed oxidases of the liver (microsomal enzymes which are inducible , and metabolise higher levels of alcohol - may interact with other drugs)
Ethanol + NADPH + H+ +O2 = acetaldehyde + NADP + H2O

Front 262

How is alcohol excreted?

Back 262

>Exhaled air contains unchanged ethanol at a concentration of 0.05-0.1% of that in the blood (basis of breathalyzer)
>Similarly small amounts are excreted in the urine
BULK METABOLISED BY LIVER 10mg per hour

Front 263

What are the pharmacokinetics of alcohol?

Back 263

>Fall of plasma concentration is almost linear :. slope is independent (almost) of concentration
- rate of decrease of concentration is almost constant, rather than being proportional to blood concentration (as is most observed for many other drugs i.e. exponential rather than linear)
- linear excretion means that with repeated doses the blood concentration does not reach a plateau, but continues to accumulate indefinitely, thus adding further to the dangers of excessive drinking

Front 264

What is the fate of acetaldehyde?

Back 264

>Oxidised in the liver to acetate which is metabolised to yield energy or fat stores

Front 265

What is the energy yield of alcohol?

Back 265

7Kcal/gram

Front 266

What are the pharmacological effects of alcohol?

Back 266

Central nervous system:
- ethanol produces depression, in a manner very much like that produced by volatile anaesthetics
- critical faculties are depressed first and also central inhibition of spinal reflexes producing transient enhancement of reflexes
- there is no evidence that ethanol increases any mental or physical ability (ALL ARE DECREASED, ALTHOUGH OPTIMISM FOR THEM INCREASES)
>With small doses, subject may lose capability of judging his ability, before the ability itself is greatly impaired
- sexual and other athletic functions are impaired
>at higher doses there is marked sedation, ataxia and slurred speech

Front 267

What are the cardiovascular effects of alcohol?

Back 267

>Slight - vasodilatation in skin producing warm flushed skin and increased heat loss
- results from central inhibition of vasoconstrictor tone

Front 268

What are the renal effects of alcohol?

Back 268

>Diuresis produced by inhibition of vasopressin

Front 269

What are the GI effects of alcohol?

Back 269

Low concentrations promote acid secretion, large concentrations denature proteins and are irritant, causing acute vomiting, and chronic gastritis in heavy drinkers

Front 270

What is the specific gravity of alcohol?

Back 270

0.82

Front 271

What effect will 0-30mg/100mL alcohol/plasma have?

Back 271

Little or no effect

Front 272

What effect will 30-100mg/100mL alcohol/plasma have?

Back 272

Impairment of coordination and motor function, judgement is impaired, excess confidence, mood swings, vivaciousness

Front 273

What effect will 100--200mg/100mL alcohol/plasma have?

Back 273

Increased motor and coordination impairment, ataxia, marked sedation

Front 274

What effect will 200-300mg/100mL alcohol/plasma have?

Back 274

Almost incapable, difficulty standing unaided, no coordination, verging on unconscious

Front 275

What effect will 300-400mg/100mL alcohol/plasma have?

Back 275

Coma

Front 276

What effect will 400+mg/100mL alcohol/plasma have?

Back 276

Likelihood of death

Front 277

What are important factors when considering alcohol and driving?

Back 277

>Contributory factor in 50% of road 'accidents'
- in fatal accidents of people 16 or over, occurring between 10pm and 4am, 55% of drivers and 77% of pedestrians have blood alcohol over the legal limit (80mg/mL
- majority of pedestrians killed are innocent passers-by
- one study in the USA found that 23% of drivers involved in crashes had high level (greater than 100mg/dL) compared with 2% in a random sample

Front 278

What concentrations of alcohol already impair driving ability?

Back 278

Well below 50mg/dL impair driving ability, which makes the legal limit of 80mg/dL very generous
- at this level the risk of an accident is increased 2-6x depending on the individual
- only safe rule is DON'T DRINK AT ALL if going to drive

Front 279

What are important factors when considering alcohol and crime?

Back 279

>Alcohol is a factor in 60-80% of homicides, stabbings and beatings, and 50% of fights and domestic assaults

Front 280

What factors should be considered regarding underage drinking?

Back 280

>Convictions for drunkenness in under 18 year olds have increased from 669 in 1955 to 2904 in 1995
- In the narrow age bad of 18-21 alone there were 3748 and 6827 in these years respectively
>50% of 11 year old boys and 30% of girls drink alcohol at least once a week
>~10% of 15 year olds already drink an amount that is considered the maximum safe limit for adults

Front 281

What factors should be considered regarding alcohol abuse?

Back 281

>Alcohol has an impact as drastic as heroin
- far more common
>Alcoholics conceal their habit
- 7-10% men and 2-5% of women have real alcoholism problems , and 27% of men (13% women) drink more than the recommended sensible limits
- 2 million people in Britain who experience symptoms of alcohol dependence
>As with other addiction producing drugs, tolerance is acquired
- costs an alcoholic 2x more than a non alcoholic to get drunk
- tolerance results from cellular adaptation to the presence of alcohol and not from an increased metabolism / excretion,
>Chronic gastritis, loss of appetite and malnutrition contribute considerably to the disease state, withdrawal symptoms are also seen on stopping the drug as with opiates

Front 282

What is the monoamine hypothesis of depression?

Back 282

>Suggests that depression is caused by a functional deficit of NA, 5HT and possibly dopamine in the brain
>Supported by observations that:
- Reserpine (which was used to treat psychotic disorders and hypertension) caused severe depression in approximately 15% of patients (depleting neuronal stores of monoamines)
- Iproniazid (used to treat tuberculosis) sometimes induced euphoria. This prevents metabolic degradation of monoamines by inhibiting the enzyme monoamine oxidase (MAO)

Front 283

What is the key corollary of the monoamine hypothesis?

Back 283

>The therapeutic effects of antidepressant drugs are attributed to augmentation or prolongation of the actions of monoaminergic transmission in the brain (the monoamine hypothesis of antidepression) achieved in two ways
- by increasing the amount of transmitter released from the nerve terminals (e.g. MAO inhibitors or mianserin)
- by preventing reuptake of released transmitter (inactivation) from the synapse (e.g. tricyclics and selective uptake blockers)

Front 284

What is the mechanism of MAO inhibitors?

Back 284

e.g. phenelzine, maclobemide
- Noradrenaline and serotonin / 5HT are metabolised within noradrenergic nerve terminals after reuptake from the synapse
- inhibition of the intraneuronal enzyme monoamine oxidase (MAO) leads to their intraneuronal accumulation
- this increases the amount of neurotransmitter available for vesicular release, thereby increasing monoaminergic transmission
- this sequence of changes is believed to be a key action in the antidepressant effects of MAO inhibitors

Front 285

Name several MAO inhibitors.

Back 285

>Phenelzine
>Moclobemide
>Selegiline

Front 286

What is the difference between MAO A and B?

Back 286

>5HT and NA are metabolised by A
>Dopamine is metabolised by B

Front 287

What type of MAO inhibitor is phenelzine?

Back 287

>Non selective and irreversible
- risk of causing a cheese reaction via interacting with dietary tyramine
- leading to hypertensive crises

Front 288

What is the tyramine cheese reaction?

Back 288

>Tyramine is normally metabolised by MAO in the gut and the liver
- however, when MAO is inhibited, tyramine survives in the circulation and is taken up by sympathetic neurones
- tyramine in noradregnergic neurones disrupts the function of the vesicular transporter VMAT2, causing noradrenaline to leak out of its vesicular stores into the cytosol
- high concentrations in the cytosol drives the membrane bound transporter in the wrong direction so that it carries noradrenaline out of the cell (reverse transport)
- this impulse dependent release of noradrenaline into the synapse culminates in exaggerated sympathetic arousal
NB. because of these potentially dangerous side effects, early MAO inhibitors were reserved mainly for the treatment of agitated depression (depression with anxiety) for which they are particularly effective, however a tyramine free diet is mandatory

Front 289

In which foods is tyramine commonly found?

Back 289

>Cheese, red wine, dried meats, marmite and tinned figs

Front 290

What are the preferred substrates and inhibitors for MAO A?

Back 290

Noradrenaline and 5HT
- moclobemide
- pirlindole
- clorgyline

Front 291

What are the preferred substrates and inhibitors for MAO B?

Back 291

Dopamine
- selegiline

Front 292

What are non selective substrates and inhibitors for MAOs?

Back 292

Beta phenylethylamine, Tyramine
- Tranylcypromine
- Iproniazid
- Phenelzine

Front 293

What are the benefits of MAO inhibitor selectivity and reversibility?

Back 293

>Selective MAOAIs tend to be safer in combination with tyramine e.g. moclobemide
>Selective inhibitors of MAOB are of no benefit in depression, e.g. selegiline, however are sometimes used in Parkinson's
- cardiovascular side effects are problematic
- it is also metabolised to metamphetamine which is neurotoxic

Front 294

What are the adverse effects of MAO inhibitors?

Back 294

>Hepatotoxicity
>CNS effects (insomnia, agitation, convulsions)
>Postural hypotension (probably by potentiating the effects of dopamine in autonomic ganglia)
>Sympathetic effects (dry mouth, sweating, gastrointestinal, sexual and visual disturbances)

Front 295

What different classes of reuptake inhibitor exist?

Back 295

>Tricyclics, selective uptake blockers e.g. SSRIs, Serotonin noradrenaline reuptake inhibitors (SNRIs)

Front 296

What is the mechanism of action for tricyclics?

Back 296

>These drugs block neuronal uptake of both noradrenaline and 5HT
- in vivo the metabolites of most of these compounds inhibit uptake of noradrenaline only (e.g. metabolism of imipramine to desmethylimipramine)
- only clomipramine retains selectivity against 5HT reuptake in vivo

Front 297

What are the adverse effects of tricyclics?

Back 297

>Antimuscarinic activity
- sedation, dry mouth, blurred vision, constipation
>Postural hypotension (probably centrally acting)
>Cardiac dysrhythmias, including ventricular fibrillation
>Convulsions (epileptogenic)
>Confusion (particularly in the elderly)

Front 298

What was the rationale for developing selective uptake inhibitors?

Back 298

To produce drugs with fewer side effects than the tricyclics (especially to avoid antimuscarinic and cardiotoxic effects), and which would be safer in overdose
- include selective NA uptake blockers e.g. maprotilline, and SSRIs such as fluoxetine

Front 299

What occurs if an SSRI is coadministered with an MAO inhibitor?

Back 299

>Severe serotonin toxicity may occur, which can be fatal (as in MDMA overdose)

Front 300

What is the mechanism of SNRIs?

Back 300

>Developed to inhibit the reuptake of Noradrenaline and 5HT
- e.g. venlafaxine

Front 301

How do SNRIs differ from early tricyclics?

Back 301

1. No appreciable antimuscarinic activity
2. Inhibition of 5HT uptake is maintained in vivo

Front 302

What is the mechanism for atypical antidepressants?

Back 302

>Mianserin and its related congener mirtazapine is an alpha 2 adrenoceptor antagonist
- this will prevent feedback inhibition of NA release by terminal alpha 2 autoreceptors, and augment synaptic transmission
- it also binds to HT receptors

Front 303

What are the adverse effects of mianserin?

Back 303

>Epileptogenesis
>Extrapyramidal and skin reactions
>Hepato and renal toxicity
>Postural hypotension
>Blood dyscrasias

Front 304

What is trazodone?

Back 304

Another atypical antidepressant which inhibits reuptake of 5HT but antagonises 5HT2 receptors - thought to contribute to effect

Front 305

What is the mechanism of mirtazapine?

Back 305

Noradrenaline reuptake inhibitor and alpha 2 adrenoceptor antagonist

Front 306

What problems are there with the monoamine hypothesis of depression?

Back 306

>Pharmacological actions of antidepressants are apparent shortly after their administration
- clinically there can be a lag of several weeks
>Some books say that cocaine and d amphetamine are not antidepressant which indicates that monoamine releasing neurones are not the key target of antidepressant drugs
- note that d amphetamine was used to treat depression for >30 years
- cocaine is not a viable treatment for ANY disorder due to its short half life

Front 307

What biochemical changes occur after chronic administration of antidepressants?

Back 307

>Many transmitter systems are affected, either directly or indirectly by antidepressant drugs
- in such cases there are long-latency, long lasting changes in the density and or affinity of neurotransmitter receptors
- unfortunately the changes depend on the particular drug used as well as species and brain region and so it remains to be seen whether any of these receptor changes underlie the therapeutic actions of antidepressants

Front 308

Do antidepressants cause neurogenesis?

Back 308

>There is recent evidence that antidepressants increase production of brain derived neurotrophic factor BDNF and increase neurogenesis in the dentate gyrus of the hippocampus
- intra hippocampal infusion of BDNF affects the behaviour of rats in the same way as antidepressants
- such findings have provoked the suggestion that depression could be a neurodegenerative brain disorder, possibly triggered by proinflammatory cytokines

Front 309

What occurs in bipolar disorder?

Back 309

>Manic depression
>Involves profound mood swings that can be unpredictable or follow a regular cycle
- can be triggered by treatment with tricyclics
- in its mild form, mild mood disorder, it responds better to antiepileptics e.g. carbemazapine or valproate
- mechanisms underlying their therapeutic effects are not clear but are thought to involve modulation of phosphoinositide metabolism
- more severe forms of BP are treated with lithium salts or neuroleptics

Front 310

What are the signs and stages of anaesthesia?

Back 310

Stage I: Analgesia, still conscious
Stage II: Excitement, delirium and excitement, respiration irregular
Stage III: surgical anaesthesia. Unconscious. Respiration and reflexes progressively depressed as anaesthesia deepens.
Stage IV: Medullary depression. No spontaneous respiration and depressed vasomotor centres. Coma and death follow, in absence of artificial respiration and circulatory support

Front 311

What two forms of administration of general anaesthetics are typically used?

Back 311

>Inhaled or volatile anaesthetics
- e.g. isoflurane
>Intravenous anaesthetics
- e.g. propofol

Front 312

What are examples of volatile anaesthetics?

Back 312

>Ether (explosive) and chloroform (hepatotoxic) are no longer used
>N2O is used
Most tend to be volatile liquids:
- halothane (prototype)
- enflurane
- isoflurane

Front 313

What are examples of IV anaesthetics?

Back 313

>Prototype is thiopentone - a thiobarbiturate
>Several others in use, including propofol

Front 314

What are the characteristics of inhaled anaesthetics?

Back 314

>Absorbed and excreted via the lungs
- potency is commonly expressed as the minimum alveolar concentration, which is the alveolar concentration (% by volume) of anaesthetic which will, when equilibrium has been attained, prevent movement in response to surgical incision in 50% of individuals
- despite its name it is an ED50 though expressed as concentration in air, not in blood
- Halothane has a MAC of 0.75%, N2O has a MAC of 105%
- Note that nitrous oxide is far less potent than the hydrogenated hydrocarbons - in fact the MAC can't be achieved at atmospheric pressure (bearing in mind that the patient needs oxygen...)

Front 315

What is the blood:air partition coefficient?

Back 315

>From the alveoli, volatile anaesthetics are absorbed into the blood
>The B:A coefficient is the concentration in the blood, realative to that in the air at equilibrium
- The coefficient is defined as the ratio of the amount dissolved in blood to the amount in the same volume of gas in contact with that blood, it is thus a dimensionless number
- If an anesthetic has a high coefficient, then a large amount of it will have to be dissolved in the body's blood before being passed on to the fatty (lipid) tissues of the brain where it can unfold its activity (think of the circulating blood volume as a large pool, soaking up agent and not allowing the brain to have any)
:. the prouct of MAC and partition coefficient is directly proportional to the blood concentration at equilibrium when 1 MAC is administered

Front 316

Is Nitrous oxide very soluble in blood?

Back 316

No - least soluble of volatile anaesthetics

Front 317

Which general volatile anaesthetics are absorbed into the blood faster, the less soluble or most soluble?

Back 317

>The reason for this is that the less soluble agents like N2O have a larger minimum alveolar concentration, the concentration in inspired air is therefore much bigger, so the amount of anaesthetic required to produce effective blood concentrations can be delivered faster
- e.g. with halothane which has a low MAC, the amount present in the lungs is low, and even if it were all extracted into the blood , there would not be enough to raise the blood concentration very much at each inspiration
- elimination after stopping administration is also fast for N2O, and slow for halothane

Front 318

Why is the rate of onset of anaesthesia irrelevant for volatile anaesthetics?

Back 318

Because induction is via an intravenous agent, the rate of elimination is the inverse of this and is clinically important, and may be very slow in those with large fat depots

Front 319

What is the mode of action of general anaesthetics?

Back 319

NOT BY INSERTING INTO THE LIPID BILAYER OF CELLS
>Anaesthetics bind to hydrophobic regions of proteins, and have selective effects on certain ion channels (demonstrated)
>It is also clear that anaesthetic doses they selectively affect synapses between neurones rather than axons
>GABAA and certain potassium channels that control neuronal excitability have been shown to be important targets

Front 320

What are the side effects of general anaesthetics?

Back 320

>All agents will produce respiratory depression and (especially with halothane, a fall in blood pressure (caused by myocardial depression and vasodilatation
- although the incidence of serious toxic effects is very low, the therapeutic ratio is quite low for general anaesthetics as a result of their principle actions: the dose may not need to be increased much to move from surgical anaesthesia to respiratory paralysis
- safety depends on the skill of the anaesthetist

Front 321

What will a combination of halogenated hydrocarbon with N2O achieve?

Back 321

Anaesthesia with minimisation of vasomotor depression

Front 322

What are the toxic effects of general anaesthetics?

Back 322

>Serious effects are rare
- cardiac dysrhythmia
- 1/100000 cases of halothane use cause liver damage
- nausea and vomiting (metabolites cause this)

Front 323

How are halogenated agents metabolised?

Back 323

60-80% of halothane is exhaled unchanged during the first 24 hours after administratio
- but up to 20% is broken down into compounds such as trifluoroacetic acid
- other volatile anaesthetics are broken down to a smaller extent (up to 3%)

Front 324

What is thiopentone?

Back 324

Agents like thiopentone are very commonly used to induce anaesthesia, and their speed of action is dramatic
- referred to as an ultrashort acting barbiturate, but in fact is not short acting at all, it has a 4.6 hour half life for catabolism
- rapid onset and recovery is due to it's behaviour in different body tissues - rapidly falls in blood, rapidly rises and falls in brain, more slowly in lean tissues and slower still in fat

Front 325

What are the characteristics of intravenous anaesthetics i.e. thiopentone?

Back 325

>Lipid soluble and cross cellular barriers, including the BBB, remarkably quickly
- its peak in the brain is brief because it soon redistributes to other well less perfused parts of the body, lean tissues and eventually into fat
- this fall in blood concentration, consequent on redistribution causes the brain concentration to fall, with consequent recovery
- if repeated doses of thiopentone are given, the blood, and hence the brain concentration will remain high, and thiopentone will be seen to be quite a long acting slowly metabolised barbiturate
- thus the intravenous anaesthetics are normally only used for induction
- the anaesthetist needs to be able to control the level of anaesthesia from moment to moment, and the best control is obtained with inhaled anaesthetics

Front 326

What is the action of thipentone, and its side effects?

Back 326

>Similar actions to inhaled anaesthetics, though without analgesic effects, and respiratory depression is profound
- main hazard in practice is that the solution is very alkaline, and can cause tissue damage if the intravenous injection is not done properly
- effects are via actions on GABAA receptors

Front 327

Is halothane a good analgesic?

Back 327

No

Front 328

Which volatile anaesthetic is a good analgesic?

Back 328

Ether

Front 329

What class of drugs usually treat anxiety?

Back 329

>Antidepressants are more typically used, because sedative/hypnotic anti anxiety drugs are only used for short periods (<3 weeks)
- partly because they are regarded as ineffective at relieving prolonged anxiety disorders
- also concern about dose escalation and dependence after their long term use

Front 330

What are the main uses of anxiolytics?

Back 330

1. Alleviation of anxiety state (generalised anxiety)
- formally called minor tranquilisers but the terms anxiolytics or antianxiety drugs are now preferred
- not that anxiety state is the only one of a cluster of disorders which responds to treatment with antianxiety drugs
- other related disorders e.g. phobias and panic disorder are most effectively treated in other ways e.g. cognitive therapy and antidepressants respectively
2. Sedation (calming of agitation)
3. Hypnosis (induction of sleep in treatment of insomnia c.f. sedation)
other actions include
4. Anticonvulsant effects (e.g. DTs)
5. Muscle relaxation (centrally mediated)
6. Amnesia: this can be an advantage in the surgical context e.g. dental phobia

Front 331

What are the side effects of anxiolytics?

Back 331

>CNS depression, from anxiolysis to anaesthesia, coma and death, can be achieved by increasing the dose of drug or coadministration with another anxiolytic / hypnotic agent e.g. alcohol

Front 332

Which classes of drugs have anxiolytic properties?

Back 332

>Chloral hydrate and bromide salts
>Barbiturates
>Benzodiazepines
>Drugs interfering with monoaminergic transmission
>Alcohol!

Front 333

What are bromides used for?

Back 333

>To prevent epileptic seizures resistant to other treatments
- noted for their narrow therapeutic index and toxicity, which causes many disturbances of CNS function (bromism)

Front 334

What are barbiturates?

Back 334

>Derivatives of urea and malonic acid which were first introduced for the treatment of epilepsy
- Phenobarbitone was used for anxiolysis, and is still used as an anticonvulsant
- Thiopentone used rarely for anaesthesia

Front 335

Why is phenobarbitone not recommended for the treatment of anxiety or insomnia?

Back 335

>No barbiturates are recommendend for the the treatment of anxiety or insomnia because
1. anxiolytic effects are apparent at sedative doses only
2. induction of CYP450 enzymes in the liver contribute to drug tolerance i.e. an increase dose of drug is required to maintain its therapeutic effect
3. drug dependence and abuse is a notable problem
4. barbiturates are dangerous in overdose (respiratory depression and cardiovascular collapse, progressing to coma and death), especialy problematic in suicide prone individuals
5. Barbiturates have additive effects with other CNS depressants e.g. alcohol, presenting a significant risk of accidental overdose

Front 336

What is the mechanism of action of barbiturates?

Back 336

>Barbiturates augment the binding of GABA at the GABAA receptor and also bind directly to the chloride channel, both actions increase Cl- conductance
- causing postsynaptic hyperpolarisation
- reducing cell firing
>Anxiolytic, hypnotic and antiepileptic and possibly anaesthetic effects of these drugs are thought to involve actions at this receptor site

Front 337

What is meprobamate (Miltown)?

Back 337

>This carbamate derivative was the first drug to have clear anti-anxiety effects at non sedative doses
- unlike barbiturates, does not induce anaesthesia, but was widely abused and induces dependence with an abstinence (withdrawal) syndrome
- rarely used as an anxiolytic agent but is still licensed as a muscle relaxant
- mechanism is unclear

Front 338

What are benzodiazepines?

Back 338

>Similar to barbiturates in their anticonvulsant effects, also used as an adjunct to anaesthesia
- muscle relaxant effects (central) and anxiolysis at doses producing little sedation
- certain derivatives e.g. clonazepam are said to have relatively greater anticonvulsant than antianxiety or sedative effects and consequently are reserved for treatment of epilepsy
- others, the triazolobenzodiazepines (e.g. alprazolam) may be even effective at treating some forms of depression

Front 339

What is the mechanism of action for benzodiazepines?

Back 339

>Benzodiazepines bind to a specific binding site with forms part of the GABAA receptor complex
- causing an allosteric change in the receptor which increases its affinity for GABA
- however the extent to which this happens depends on the subunit composition of the GABAA receptor (benzodiazepines do not bind to the alpha 4 subunit)
- thought that the extent of CNS depression depends on receptor occupancy and that anticonvulsant or anxiolytic effects require lower receptor occupancy (about 5-20% than sedation or hypnosis (about 80%)

Front 340

What are the three therapeutic actions for benzodiazepines?

Back 340

1. Anxiolytics e.g. diazepam (T1/2 = 32h)
- has an active metabolite, desmethyldiazepam, with a long half life of 65h and so has long lasting antianxiety effects which wear off slowly
- reduces the risk of rebound anxiety
2. Antiepileptics e.g. diazepam and clonazepam (t1/2 = 55h)
- these long acting compounds ensure a sustained anticonvulsant effect
- the slow decline in plasma levels of active compound is thought to reduce the possibility of withdrawal seizures
3. Hypnotics e.g. triazolam and temazepam (t1/2 = 8-16h)
- so as to avoid residual daytime sedation (hangover)
- this may increase the incidence of rebound anxiety however

Front 341

What are the pharmacokinetics of benzodiazepines?

Back 341

>Numerous benzodiazepine derivatives and many have common active intermediate metabolites
- they are all lipophilic and so cross the blood brain barrier easily
- low plasma solubility is compensated by extensive binding to plasma proteins (>90%)
- inactivation depends on conjugation of either unmetabolised drug e.g. lorazepam or active metabolites e.g. diazepam with glucoronic acid in the liver
- some elimination also occurs in the renal filtrate

Front 342

Which other drugs act at benzodiazepine receptors?

Back 342

1. Inverse agonists e.g. beta carboline
2. Benzodiazepine receptor antagonists e.g. flumenazil
3. Partial agonists e.g. alpidem

Front 343

What are inverse agonists of the benzo receptor?

Back 343

e.g. beta carboline or beta CCE
- bind to the benzodiazepine binding site on the GABAA receptor and depending on the subunit composition of the GABAA receptor, can have the opposite effects to benzodiazepines
- induce convulsions and anxiety and reduce Cl- conductance
- specific effects of inverse agonists depend on the subunit composition of the GABA receptor
- some have been explored as potential treatments for dementia but, so far, all reduce seizure threshold and so cannot be used for this clinical indication

Front 344

What are benzodiazepine receptor antagonists?

Back 344

e.g. flumenazil
- these compounds bind to the benzo receptor but block the actions of both benzodiazepines and their inverse agonists
- flumenazil is now used (albeit rarely) to reverse the CNS depressant effects of benzodiazepines in anaesthesia and overdose
- it has a short half-life (approx. 20m)

Front 345

What are partial agonists of the benzo receptor?

Back 345

e.g. alpidem
- since these have submaximal efficacy at the receptor, they produce less CNS depression than full agonists at equivalent levels of receptor occurpancy
- this means that anxiolytic doses of aplidem produce little or no sedation
- none is yet licensed for use in the clinic

Front 346

Which two monoamines are implicated in anxiety?

Back 346

Noradrenaline and 5HT

Front 347

How is 5HT implicated in anxiety and how may it be modulated?

Back 347

>The firing of 5HT releasing neurones in the the brain is attenuated by activation of 5HT1A autoreceptors on the cell bodies in the raphe nuclei
- therefore agonists of this receptor attenuate 5HT function
>Buspirone a 5HT1A receptor agonist is used in the clinic, albeit rarely in the UK
- one difficulty with explaining its action however is that there are also postsynaptic 5HT1A receptors in the brain
- buspirone should activate these receptors directly irrespective of its effects on neuronal firing
- however there is evidence that pre and postsynaptic 5HT1A receptors differ in their affinity for buspirone
- it is also thought that buspirone acts as a full agonist at the autoreceptors but a partial agonist of postsynaptic receptors but this is equivocal

Front 348

How is noradrenaline implicated in anxiety and how may it be modulated?

Back 348

>By analogy with 5HT1A autoreceptors, activation of alpha 2 autoreceptors on noradrenergic cell bodies, attenuates neuronal firing
>In addition, terminal alpha 2 autoreceptors depress impulse evoked release of noradrenaline
>alpha 2 adrenoceptor agonists e.g. clonidine are effective anxiolytics and are sometimes used in conjunction with anaesthesia and in treatment of alcohol withdrawal
- otherwise they are rarely used for their anxiolytic effects because of their marked hypotensive actions
>Noradrenaline function is also attenuated by administration of postsynaptic beta adrenoceptor antagonists
- thought to explain the anxiolytic effects of propranolol
- however these drugs are only really effective in situational anxiety (competition nerves) and this is attributed to their peripheral actions (e.g. reduced tremor, sweating, dry mouth, tachycardia)
- they are not effective in long term treatment of generalised anxiety and can even exacerbate it or trigger a full blown depression

Front 349

How may benzodiazepine receptor ligands be exploited in insomnia?

Back 349

e.g. zopiclone
- are used to treat insomnia, but they disrupt sleep architecture and cause REM deficiency
- prolonged sedation (hangover) effects can be problematic

Front 350

What are the potential benefits of orexin receptor antagonists?

Back 350

Under development as the next generation of hypnotics
- evidence suggests that they promote sleep induction without disrupting sleep rhythms

Front 351

What is epilepsy?

Back 351

>The repeated occurrence of sudden excessive or synchronous discharges in cerebral cortical neurons resulting in a disruption of consciousness, disturbance of sensation, movements, impairment of mental function, or some combination of these

Front 352

Define epileptic disorder.

Back 352

>A chronic neurological condition characterised by recurrent epileptic seizures

Front 353

Define epileptic seizure.

Back 353

>A seizure resulting from epileptic (excessive and/or hypersynchronous), usually self-limited, activity of neurons in the brain

Front 354

Define seizure.

Back 354

>A sudden short event involving a change in a person's awareness of where they are or what they are doing, their behaviour or their feelings
- may be of varied origin

Front 355

Define convulsion.

Back 355

>A lay term, one form of physical manifestation of a seizure, involving episodes of excessive abnormal contractions (usually bilateral), which may be sustained or interrupted

Front 356

Describe the aetiology of epilepsy.

Back 356

>Classified as symptomatic or idiopathic
>Symptomatic indicates that a probable cause exists
- cerebrovascular lesions
- perinatal or postnatal trauma
- CNS infections
- tumours
- congenital malformations of the CNS

Front 357

How may epilepsies be classified?

Back 357

>Type of seizure e.g. partial or primary generalised
PARTIAL FOCAL SEIZURES
- simple partial
- complex partial
- secondary generalised
PRIMARY GENERALISED SEIZURES
- absence (petit mal)
- tonic clonic (grand mal)
- myoclonic
- atonic

Front 358

How do partial seizures begin in the brain?

Back 358

With a local electrical discharge in one area of the brain

Front 359

How do primary generalised seizures begin in the brain?

Back 359

>Widespread electrical discharge that involves both sides of the brain at once

Front 360

What does a simple partial seizure involve?

Back 360

>Motor spasms, sensory hallucination
- most common in frontal cortex

Front 361

What does a complex partial seizure involve?

Back 361

>Impaired consciousness, possible automatisms
- most common in temporal lobes

Front 362

What does a secondary generalised seizure involve?

Back 362

Partial spreading to generalised

Front 363

What does a petit mal seizure involve?

Back 363

Absence seizure
>Brief interruption of consciousness (awareness) and motor activity
- thalamocortical mechanism

Front 364

What does a grand mal seizure involve?

Back 364

>Loss of consciousness, convulsions

Front 365

What does a myoclonic seizure involve?

Back 365

>Brief contraction of muscle groups
>May accompany other seizures

Front 366

What does an atonic seizure involve?

Back 366

>Sudden loss of muscle tone, widespread or local

Front 367

What is status epilepticus?

Back 367

>Repeated seizures with no recovery between attacks
>Causes additional problems - metabolic disturbance, neuronal damage

Front 368

Describe the pathogenesis of epilepsy / epileptogenesis.

Back 368

>Results from abnormal, hyperexcitability of neurones
- often originates in a localised area of the brain
- the epileptic focus, in which some neurones undergo synchronous, repetitive depolarisations called paroxysmal depolarisation shifts (PDS)
- this synchronous activity is propagated to connected brain regions
>The transition from normal spiking to PDS may involve changes in intrinsic properties of neurons (increased Ca++, increased Na+, decreased K+ channel activity can promote bursting), changes in synaptic efficacy (increased EPSPs - excessive activation of NMDARs, decreased IPSPs - loss of GABA mediated inhibition) and or changes in synaptic connectivity

Front 369

Which voltage gated ion channels are affected in idiopathic epilepsy?

Back 369

Na+ (gain of function via impaired inactivation), K+ and Cl- (loss of function)

Front 370

Which ligand gated ion channels are affected in idiopathic epilepsy?

Back 370

GABAA (reduction in function via desensitisation or failed insertion in the membrane), and Nicotinic Ach (gain of function: prolonged opening)

Front 371

How may epilepsy be treated?

Back 371

>Via dampening the hyperexcitability in neurones that lead to or sustain an epileptic attack
- in principle this can be achieved by reducing excitation or enhancing inhibitory influences
>A reduction in excitation can result from decreased activity of voltage dependent Na+ and Ca++ channels or decreased efficacy of excitatory synapses
- enhanced inhibition is achieved by an increased efficacy of inhibitory synapses or an increase in K+ channel activity
- not all of these strategies have been successful in developing current antiepileptic drugs

Front 372

What are examples of established antiepileptics?

Back 372

>Phenytoin, carbamazepine, ethosuximide, phenobarbitone, primidone, diazepam, clonazepam, sodium valproate

Front 373

What are examples of newer antiepileptic drugs?

Back 373

>Lamotrigine, gabapentin, topiramate, tiagabine, levetiracetam, vigabatrin, oxcarbazepine

Front 374

What is the mechanism of action of carbamazepine, phenytoin, valproate, lamotrigine, topiramate, gabapentin?

Back 374

Use dependent channel block?

Front 375

What is the mechanism of action of ethosuximide, topiramate and gabapentin?

Back 375

Ca++ channel block

Front 376

What is the mechanism of action of diazepam, clonazepam, phenobarbitone and topiramate?

Back 376

Allosteric modulation of GABAA receptors

Front 377

What is the mechanism of action of tiagabine?

Back 377

Inhibition of GABA uptake

Front 378

What is the mechanism of action of valproate, vigabatrin and gabapentin?

Back 378

Inhibition of GABA metabolism

Front 379

What is the mechanism of topiramate?

Back 379

NMDAR antagonist at the glutamate site

Front 380

What is the mechanism of felbamate?

Back 380

NMDAR antagonist at the glycine site

Front 381

What is the mechanism of action of lamotrigine?

Back 381

Inhibition of glutamate release

Front 382

What governs choice of AED?

Back 382

">Dictated by type of seizure and efficacy but also tolerability
>AEDs are associated with dose-relate and idiosyncratic side effects (important with long term use)
- usually given as monotherapy but may be used in combination
- after failure of two AEDs, surgery may be considered

Front 383

What are newer AEDs indicated for?

Back 383

>For the management of epilepsy in people who have not benefited from treatment with the older antiepileptics, such as carbamazepine or sodium valproate
OR FOR WHOM THE OLDER AEDS ARE UNSUITABLE BECAUSE
- could interact with other drugs e.g. oral contraceptives
- known to be poorly tolerated
- the person is a woman of childbearing potential

Front 384

What drugs are typically given for partial seizures?

Back 384

>Valproate, phenytoin

Front 385

What AEDs are prescribed for generalised, tonic clonic seizures?

Back 385

>Carbemazepine

Front 386

What AEDs are prescribed for generalised absence?

Back 386

>Ethosuximide, valproate, clonazepam, lamotrigine

Front 387

What is prescribed for status epilepticus?

Back 387

>Clonazepam

Front 388

What are important factors when treating women of childbearing potential with AEDs?

Back 388

>Changes in oral contraceptive metabolism
- pharmacokinetic effects due to enzyme induction
- phenytoin, phenobarbital, carbamazepine
>Developmental toxicity
- all established AEDs show some teratogenicity
- major congenital malformations 4-10%
- particularly with valproate

Front 389

What is the defining feature of psychotic disorders?

Back 389

>Patients have lost insight into their mental condition
- includes bipolar disorder, major depressive disorder, as well as a family of illnesses which include schizophrenia and several similar conditions e.g. schizophreniform disorder and schizoaffective disorder
- distinguished from one another on the basis of differences in their duration and symptom profile

Front 390

What is the typical onset of schizophrenia?

Back 390

>Typically in the late teens to mid-30s (giving rise to one theory that this is a disorder of brain development)

Front 391

What is the life time prevalence of schizophrenia?

Back 391

>1% approximately

Front 392

What is the mean duration of schizophrenia?

Back 392

>15 years although 10-15% of patients show rapid and intractable deterioration

Front 393

What is the cost to society of schizophrenia?

Back 393

>USA = 2.5% of total healthcare expenditure
- <3% of that is spent on medication

Front 394

What are the positive symptom features of schizophrenia?

Back 394

>Grouped into positive and negative symptoms
POSITIVE SYMPTOMS - excess or distortion of normal function
1. Perceptual disturbances (hallucinations - auditory hallucinations or 'voices' is a specific diagnostic requirement)
2. Thought disorders (delusions: e.g. paranoia or thought insertion)
3. Disorganised speech (word salad)
4. Disorganised behavioural monitoring or physical catatonia e.g. unpredictable agitation, catalepsy (waxy flexibility) or catatonia (rigid unresponsive posture)

Hint 394

Voices That Don't Seem 2 Belong to Me

Front 395

What are the negative symptom features of schizophrenia?

Back 395

NEGATIVE SYMPTOMS - attenuation or loss of normal function
5. Blunting of emotions and reduced 'physical language' e.g. unresponsive face
6. Poverty of thought or speech (alogia - decreased fluency and productivity)
7. Difficulty with goal-directed behaviour (avolition e.g. feeding and hygiene)

Hint 395

Psychotic Schizophrenics 'Ave Blunted Emotions

Front 396

What are possible neuronal aetiologies of schizophrenia?

Back 396

>Different theories point to disorders in different neurotransmitter systems
SEROTONERGIC:
- excessive serotonerginc (5HT) transmission in the brain
- all drugs activating 5HT2A receptors are profoundly hallucinogenic (e.g. LSD, tryptamine and some amphetamine derivatives such as MDMA)
DOPAMINERGIC:
- excessive dopaminergic transmission in the brain
- all neuroleptics show some degree of dopamine D2 receptor antagonism
- however no convincing evidence that DA transmission is excessive in schizophrenia
- neuroleptics might relieve schizophrenia through a process that bypasses the neurobiological lesion (i.e. drives an alternative route through the network)

Front 397

What are the targets of drug treatments for psychosis? Consequentially what side effects might they cause?

Back 397

>Generally thought that neuroleptics act via antagonising D2 receptors in mesocorticolimbic pathways
- however, DA releasing nerones are also found in the basal ganglia (nigrostriatal pathway) and in the hypothalamus (tuberoinfundibular pathway)
- neuroleptics disrupt the function of all of these pathways
- as a consequence, all neuroleptics cause EXTRAPYRAMIDAL SIDE EFFECTS e.g. pseudoparkinsonism

Front 398

What are examples of typical neuroleptics?

Back 398

>Phenothiazines e.g. chlorpromazines, thioridazine
>Thioxanthines e.g. flupenthixol
>Butyrophenones e.g. haloperidol

Front 399

What are the advantages of typical neuroleptics?

Back 399

>Relieve positive symptoms
>Sedative (which can also be disadvantageous)

Front 400

What are the disadvantages of typical neuroleptics?

Back 400

>Ineffective against negative symptoms
>Extrapyramidal side effects (akathisia, dystonia)
>Tardive Dyskinesia (repetitive stereotypic movements, continuing after withdrawal of the the drug)
>Hyperprolactinaemia (dopamine = prolactin inhibitory factor), galactorrhea, impotence and amenorrhea)
>Aplastic anaemia

Front 401

Typical neuroleptics bind to which receptors, and what effects do they cause as a consequence?

Back 401

Antagonise:
>D2 receptors - to treat the positive symptoms
>H1 receptors - causing sedation
>Alpha 1 adrenoceptors, causing hypotension
>mACh - causing anticholinergic effects (may also ameliorate pseudo-Parkinsonism to an extent

Front 402

What are examples of atypical neuroleptics?

Back 402

>Dibenzazepine derivatives - clozapine, olanzepine, quetiapine
>Benzisoxazole derivatives - risperidone

Front 403

What are the advantages of atypical neuroleptics?

Back 403

>Can relieve both positive and negative symptoms
>Can relieve psychosis resistant to typical neuroleptics
>Lower incidence and severity of EPS and tardive dyskinesia than with the typicals

Hint 403

ORPEPS

Front 404

What are the disadvantages of atypical neuroletptics?

Back 404

Marked sialorrhea
Agranulocytosis (Clozapine)
Weight gain (systemic fat) leading to diabetes and cardiovascular disease
Prolongation of the cardiac QT interval

Hint 404

SWAP

Front 405

Upon which receptors is Clozapine thought to work?

Back 405

>Clozapine shows relatively weak binding to D2 receptors
- suggesting D2 antagonism not a key relevant factor in the therapeutic effects of neuroleptics
>Antagonises
- 5HT2A/2C receptors which may contribute to its antipsychotic effects
- Muscarinic ACh and alpha 2 adrenoceptor antagonism, which is thought to contribute to the lower incidence of EPSs experienced with these drugs
>Partially agonises
- 5HT1A receptors, thought to lead to an increased release of DA from mesocortical neurones projecting to the frontal cortex, may benefit negative symptoms

Front 406

What is the third generation antipsychotic?

Back 406

>Aripiprazole

Front 407

Which receptors does the third generation Aripiprazole act on?

Back 407

Antagonises:
- D2
- 5HT2A
Partially agonises:
- 5HT1A, indirectly increasing Dopamine release in the cortex and relieve the negative symptoms

Front 408

What are the side effects of aripiprazole?

Back 408

HYPERPROLACTINAEMIA
HYPERCHOLESTEREMIA,
HOWEVER:
>Incidence of EPS = that of placebo
>Little weight gain
>Few CV (QT) abnormalities
>Apparently safe in overdose

Front 409

How is mania treated?

Back 409

>In its MILD form, mania is treated with antiepileptics
- valproate
- carbemazepine
>Problematic in women of child bearing age due to teratogenicity, i.e. causing birth defects
>MORE SEVERE forms are treated with antipsychotics, or lithium

Front 410

What are the pharmacological properties of lithium?

Back 410

>High plasma levels (1mM) are required for therapeutic activity, however very toxic and has a narrow therapeutic window
>Therapeutic effects are unexplained
- accumulates intraneuronally, causing partial depolarisation, and attenuation of transmitter release
- disrupts cAMP formation and PI metabolism, preventing its regeneration and possibly IP3 formation

Front 411

What are the adverse effects of Lithium?

Back 411

>Nephrotoxicity
>Hypothyroidism
>CNS effects which can culminate in coma and death

Front 412

What are the tricyclic class of compounds e.g. imipramine?

Back 412

>Antidepressants
 - structurally related to phenothiazines, and share many of their side effects e.g. dry mouth, sedation
>most of their adverse side effects are all caused by antagonism of 
 - alpha 1 adrenoceptors
 - muscarinic receptors
 - histamine 1 receptors

Front 413

What are the advantages of benzos over barbiturates?

Back 413

1. No respiratory depression, hence comparatively safe in overdose and in combination with alcohol
2. No enzyme induction, hence no metabolic tolerance (but pharmacodynamic tolerance does develop)
3. Dependence liability at clinical doses is equivocal but is certainly less than for the barbiturates or alcohol

Front 414

What is the importance of lipid solubility and ionisation for pharmacologically active substances?

Back 414

>Most drugs pass directly through lipid regions of the cell membrane
- therefore, penetration is dependent upon LIPID SOLUBILITY of a drug
- lipid solubility is commonly described in terms of an oli/water partition coefficient, e.g. heptane/water
- also therefore DEGREE OF IONISATION is important
- most drugs being weak acids or weak bases will be partially ionised within the body
- ionised drugs are lipophobic, and will not cross cell membranes by simple diffusion through the lipid component

Front 415

How may the degree of ionisation of a drug be calculated (for a weak acid)?

Back 415

>By using the Henderson Hasselbalch equation:
ci = conc. of drug in ionized form
cu = conc. of drug in unionized form
pKa = -log Ka (acid dissociation constant)

Hint 415

HENDERSON HASSELBALCH

Front 416

How may the degree of ionisation of a drug be calculated (for a weak base)?

Back 416

>By using the Henderson Hasselbalch equation:
ci = conc. of drug in ionized form
cu = conc. of drug in unionized form
pKa = -log Ka (acid dissociation constant)

Front 417

What is the significance of the Henderson Hasselbalch equation in the context of drug absorption?

Back 417

>Ionisation and therefore absorption of drugs will vary with pH, e.g. as the drug passes along the gastrointestinal tract
- where a membrane separates solutions of different pH, the process of ion trapping may occur
- thus a weak base such as morphine will tend to concentrate within the stomach

Front 418

What are the features of active transport for drugs?

Back 418

>Active absorption (e.g. methyldopa) and distribution (e.g. guanethidine) occurs for only a few drugs, which are able to exploit carriers for important nutrients or endogenous compounds
>Active elimination via the kidney or liver however, occurs for a wide range of drugs
Features include:
- specificity (low for drug elimination)
- competition (e.g. penicillin/probenecid)
- saturation
- can operate against an electrochemical gradient, allowing high clearance (e.g. penicillins)

Front 419

What rate of drug transport or kinetic is relevant to passively diffusing substances?

Back 419

>First order kinetics, i.e. the rate is proportional to the concentration at the site of administration or in the plasma
- this describes an exponential decay process, which may be linearised using logarithms

Front 420

What is the plasma half-life of a drug?

Back 420

The time taken for the plasma concentration to decrease by 50%

Front 421

What kinetic do drugs which are transported by carrier mediated mechanisms follow?

Back 421

>Michaelis Menten kinetics
- when the concentration is low, relative to Km, then the drug will follow 1st order kinetics
- when the concentration is high (i.e. the elimination process is saturated), then ZERO order kinetics apply

Front 422

What kinetic does alchohol elimination exhibit at low concentrations?

Back 422

Zero order kinetics

Front 423

What is the volume of distribution of a drug?

Back 423

Vd = dose/Cp(0)
>The volume in which the total amount in the body would have to be dissolved to give the observed plasma concentration
>For a drug of restricted distribution Vd may be much less than body volume, but for drugs bound extensively to tissue components, Vd may exceed body volume several fold

Front 424

What is the difference between drugs that follow the one compartment model vs. that of drugs following the >1 compartment model?

Back 424

>The volume of distribution appears to be a single entity in the one compartment model
- for other drugs it is found that different tissues equilibrate with the drug at different rates (e.g. general anaesthetics)
- where the tissues fall easily into two groups (e.g. well perfused and less well perfused, a two compartment model is sometimes applicable
- the kinetics of the two compartment model will be more complicated, and the plot of log Cp vs. time after i.v. administration will not yield a straight line

Front 425

What is the purpose of repeated drug administration?

Back 425

>Commonly drugs are given as repeated doses, separated by a more or less constant dosing interval
- since in most cases drugs are eliminated exponentially, whenever a second dose is administered, the peak concentration achieved will exceed that after the first dose i.e. cumulation occurs
- as repeated dosing continues, the plasma concentration, and hence elimination, increases until a plateau is reached where the whole of the dose is eliminated during the dosing interval
- the half life for attainment of the plateau is the same as the half time for elimination
- drugs with a long half life will thus attain a steady state slowly

Front 426

What is the purpose of administering a loading dose of a drug?

Back 426

>In order to achieve a therapeutic concentration of a drug more rapidly e.g. digoxin
- the peaks and valleys occurring during the plateau can be minimised by giving smaller doses more frequently

Front 427

What is the preferable route of administration for systemic action of a drug?

Back 427

>Orally is best, for convenience and for systemic action

Front 428

What are the key considerations when administering drug via the gastrointestinal tract?

Back 428

>A significant proportion of the drug absorbed from the stomach or intestine, reaching the liver via the portal vein, will be biotransformed before ever reaching the general circulation - the first pass effect
- lignocaine and propranolol are both subject to a large first pass effect
- sublingual and to some extent, rectal absorption avoid first pass elimination
- thus isoprenaline and glyceryl trinitrate are both well absorbed from the mouth but to a much lesser extent from the intestine

Front 429

Which factors modify absorption from the GIT?

Back 429

1. Lipid solubility and ionisation of the drug
2. Aqueous solubility of the drug - an adequate concentration of the drug is needed to produce a diffusion gradient
3. Drug formulation - disintegration and dissolution rate
4. Gastrointestinal motility
5. Absorptive capacity, blood flow, pathological changes
6. Gut flora - may metabolise some drugs
7. Gut contents, food, other medicines

Front 430

Why are drugs absorbed from the gut usually incompletely absorbed into the general circulation?

Back 430

Quantified by BIOAVAILABILITY:
1. Incomplete release from the drug preparation
2. Poor penetration of the mucosa
3. Metabolism or inactivation within the gut
4. First pass elimination

Front 431

What is meant by bioavailability?

Back 431

>The relative amount of an administered dose which reaches the general circulation
- for drugs with a low therapeutic index it is important that bioavailability should be the same from one prescription to the next
- bioavailability may be assessed by measuring the area under the curve (AUC) of plasma concentration against time

Front 432

Through which routes may drugs be administered?

Back 432

>Gastrointestinal tract
>Intravascularly (IV more commonly)
>Intramuscularly (IM)
>Subcutaneously (SC)
>Inhaled (gaseous anaesthetics, bronchodilators)
>Topical application (skin and eyes)

Front 433

What are sustained release formulations?

Back 433

>Provide a relatively large dose in a formulation which releases the drug into free solution over an extended period of time, avoiding frequency of administration and therefore aiding compliance
>Sustained release preps are available for oral, IM, and SC routes
- other sophisticated delivery systems have been developed e.g. ocuserts

Front 434

How are drugs distributed around the body?

Back 434

>Varies depending on their physicochemical properties, and affinities for particular tissues
- selective localisation may confine drug action or toxicity to particular organs (tetracycline binding to bone and teeth)
- tissues vary from being well perfused (lungs, liver, brain) to being very poorly perfused (fat, bone)
- poorly perfused tissues will usually equilibrate with drug slowly
- the redistribution of thiopentone from well perfused to less well perfused tissues is responsible for its short duration of action

Front 435

How do plasma proteins affect drug action?

Back 435

>A wide range of drugs bind reversibly to plasma proteins, particularly, but not only to albumin
- the amount bound for some drugs reaches 98-99%
1. Bound drug is normally inactive
2. Distribution of bound drug follows that of the protein
3. Bound drug may act as a reservoir, tending to reduce fluctuations in the free drug concentration
4. Effect on elimination is less predictable
- glomerular filtration will not occur for bound drug, tending to prolong half life, but tubular secretion and biotransformation in the liver may be enhanced by the carrier role of the plasma protein e.g. penicillin, propranolol
5. Interactions, binding is of low specificity, many drugs bind to the same site, a second drug may displace a drug already bound to protein, resulting in a rise in the free concentration of the first drug and enhanced activity (toxicity)
- e.g. phenylbutazone vs. warfarin, sulphonamides vs. bilirubin

Front 436

How are drugs eliminated from the body?

Back 436

>Via biotransformation or excretion

Front 437

What is biotransformation?

Back 437

>Normally terminates pharmacological activity and leads to more polar compounds with reduced lipid solubility, which are more readily excreted in urine or bile
- metabolite may share the actions of the parent drug e.g. phenacetin/paracetomol, propranolol/4hydroxypropranolol, aspirin/salicylate
- metabolite may cause toxicity e.g. thalidomide

Front 438

What are the two major classes of biotransformation?

Back 438

Phase I:
- oxidations, reductions, hydrolyses
Phase II:
- conjugations

Front 439

What is responsible for oxidations in the liver?

Back 439

CYP450 - present in the hepatic endoplasmic reticulum

Front 440

How are drugs excreted renally?

Back 440

>Unbound drug is filtered in the glomerulus and may be subject to tubular reabsorption according to its lipid solubility and degree of ionisation
- excretion of weak acids and bases can be enhanced by appropriate manipulation of urinary pH as shown below for salicylate

Front 441

What is manipulation of the renal pH to increase drug elimination termed?

Back 441

Forced diuresis

Front 442

How are drugs excreted hepatically?

Back 442

>Bile produced at a rate of 0.5-1L per day and is a major route of excretion for a few drugs e.g. cromoglycate, and many more drug metabolites
- drugs excreted from bile may be reabsorbed from the intestine and enter the enterohepatic circulation
- significant proportion of drug in the body may be held in this enteric pool which may act to increase the half life of a drug
- drugs pass from blood to bile by active transport and competition may occur
- process may be very efficient
- transport systems for anions, cations and neutral compounds are present

Front 443

What is drug clearance?

Back 443

The volume of plasma cleared of drug per unit time
- total body clearance is the sum of the clearances occurring by whatever routes are applicable to the drug in question, usually only renal (CLR) and hepatic (CLH) clearances are important

Front 444

How is drug clearance calculated?

Back 444

Clearance = Elimination rate / Plasma concentration

Front 445

Under what conditions does a drug have a half life of 15 min?

Back 445

Small volume of distribution e.g. extracellular water, and maximum secretion

Front 446

Under what conditions does a drug have a half life of 50 min?

Back 446

Distribution in total body water and secreted at a maximal rate

Front 447

Under what conditions does a drug have a half life of 5 hours?

Back 447

Distribution in total body water and filtered, not reabsorbed

Front 448

Under what conditions does a drug have a half life of 24 days?

Back 448

Distribution in total body water and filtered, reabsorbed in proportion to water

Front 449

Under what conditions does a drug have a half life of several months?

Back 449

Extensive plasma or tissue binding (large Vd) filtered and reabsorbed

Front 450

What is Parkinson's disease?

Back 450

>James Parkinson described the 'Shaking Palsy' in 1817
>Eponymous disease is unique in that the symptoms result from a single transmitter deficit due to the loss of dopamine neurones in the substantia nigra
- degeneration of these neurones means that dopamine is depleted from the nigrostriatal projection zones in the striatum
- cause of neuronal death is unknown but likely that about 70-80% of the nigrostriatal neurones have to die before the symptoms appear
>Although flawed designer drugs (MPTP) and environmental chemical factors have been implicated in the aetiology of PD, there is little evidence to suggest that the disorder is anything other than an ongoing loss of vulnerable neurones as part of the ageing process

Front 451

What are three key symptoms of PD?

Back 451

1. Muscle rigidity
2. Akinesia (poverty of movement)
3. Resting tremor

Front 452

Describe the anatomy of the dopaminergic pathway.

Back 452

>The substantia nigra contains dark pigmented neurones, hence the name
- project to the striatum
>Striatum (caudate-putamen) projects to the thalamus via the globus pallidus and receives inputs from the cortex
- this circuitry allows motor programs to be established
- loss of the nigrostrialtal projection could be likened to 'clutch failure' so the basal ganglia 'gearbox' locks up - hence the rigidity
>There are inhibitory GABA projections from the striatum back to the substantia nigra and intrinsic excitatory cholinergic striatal neurones
- activity in these latter neurones which lose their inhibitory dopamine control are mostly responsible for tremor in PD
- the loss of the inhibitory GABA striato nigral pathway produces the uncontrolled motor activity seen in Huntingdon's chorea (a genetic disorder)

Front 453

What does therapy in PD aim to achieve?

Back 453

>To restore function of the transmitter

Front 454

In what two ways may dopamine transmission be restored in PD patients?

Back 454

1. Replenishment of the transmitter or
2. Mimicking the receptor effects of dopamine

Front 455

What may be used to dampen the cholinergic resting tremor which occurs in PD?

Back 455

>Muscarinic antagonists
- act on ach neurones in the striatum
- no effect on akinesia/rigidity however

Front 456

Why are their side effects using dopaminergic based therapies in PD?

Back 456

>Due to the presence of other dopamine pathways in the CNS and PNS
e.g.
1. Nigrostriatal pathway (A9 nucleus to caudate-putamen) - fails in PD
2. Mesolimbic pathway (A10 nucleus to nucleus accumbens)
- reward pathways, psychosis?
3. Mesocortical pathway (A10 nucleus to frontal cortex)
- Psychosis?
4. Median eminence to anterior pituitary
- inhibition of prolactin secretion
5. Chemoreceptor trigger zone (CTZ) / vomiting centre
- dopamine induces emesis via disinhibition

Front 457

What is the pathway and corresponding enzymes for dopamine synthesis?

Back 457

Tyrosine -> L-DOPA -> Dopamine -> DOPAC/HVA
- tyrosine hydroxylase
- DOPA decarboxylase
- monoamine oxidase B

Front 458

How many dopamine receptors are present in the CNS?

Back 458

5 receptors have been cloned
- largely inhibitory, although some excitatory D1 effects have been reported
- G protein coupled
>D1 and D2 are coupled to adenyl cyclase and IP3 respectively
>D1 and D5 appear to be similar and the D2, D3 and D4 have similar pharmacological profiles

Front 459

How does L-DOPA work?

Back 459

>Dopamine does not cross the blood brain barrier but L-DOPA
- it is then converted to dopamine by DOPA decarboxylase
- since most dopamine neurones are dead it is thought that some L-DOPA may be converted in other monoamine neurones or the remaining cells have increased compensatory capacity
- akinesia are improved more than the tremor
>L DOPA works best in the less elderly patients, producing improvements in movement over the first 18 months or so of therapy
- this is then maintained for about 2-3 years before a gradual decline occurs, probably as more and more dopamine neurones die

Front 460

Why are large does of DOPA given per day (100-500mg)?

Back 460

>Only 2% enters the brain, due to metabolism in the periphery

Front 461

What are the central side effets of dopamine production?

Back 461

a. Dyskinesia
b. Psychotic effects (schizophrenia is treated using dopamine antagonists)
c. Reductions in prolactin release
d. ""On-off"" effects
- uncontrolled swings from akinesia to dyskinesia, usually occurring after several months of therapy and as the dose of L-DOPA wears off

Front 462

What are the peripheral side effects of dopamine administration?

Back 462

a. hypotension - displacement of noradrenaline, so reducing sympathetic tone
b. nausea - dopamine activates the CTZ which although is in the brainstem, lacks a blood brain barrier
>as a consequence, adjuncts are used to prevent peripheral formation of dopamine

Front 463

Name five adjunctive therapies to L-DOPA.

Back 463

1. DOPA decarboxylase inhibitors
2. Dopamine receptor agonists
3. Muscarinic antagonists
4. Amantadine (shown to be ineffective)
5. Transplants

Front 464

What is the mechanism of DOPA decarboxylase inhibitors in PD?

Back 464

>Carbidopa and benserazide are inhibitors of DOPA decarboxylase and so prevent the L-DOPA being converted to dopamine
- these do not cross the blood brain barrier and so allow conversion to only occur in the brain
- thus doses of L-DOPA can be reduced so that peripheral side effects are reduced
- used in combination tablets with L-DOPA and the improvement in movement is faster in onset and smoother
>Monoamine oxidase inhibitors e.g. selegiline
- selective monoamine oxidase B inhibitor that reduces the breakdown of dopamine in the CNS, allowing more effective therapy
- thought to reduce the ongoing neuronal degeneration to some extent

Front 465

What is the mechanism of Dopamine receptor agonists in PD?

Back 465

BROMOCRIPTINE:
- D2 receptor agonist has no advantage over L-DOPA but can be useful in the oldest patients where L-DOPA is no longer effective
- APOMORPHINE a D1 and D2 agonist can also be used
>DOMPERIDONE a D2 receptor antagonist, is an antiemetic that does not cross the blood brain barrier which has to be given in conjunction with these drugs

Front 466

What is the mechanism of muscarinic antagonists in PD?

Back 466

>Atropine and benzotropine correct the relative cholinergic excess that occurs as a result of the dopamine deficiency
- tremor is reduced and they can be useful supplements to L-DOPA therapy

Front 467

What is the mechanistm of amantadine in PD?

Back 467

>Antiviral drug
- may increase dopamine release by poorly understood mechanisms which may involve NMDA receptors

Front 468

What is the role of transplantation in PD?

Back 468

>1500 patients have received transplants of adrenal medulla or foetal mesencephalic dopamine neurones into striatum
- there is little doubt that foetal tissue into the putamen can be useful and increase dopamine levels in the striatum
- however none of the grafts restore the lost neurones which continue to die alongside the healthy graft

Front 469

What is the mechanism for dyskinesia in Huntingdon's chorea?

Back 469

>Loss of striatal neurones, particularly GABA ones which project back down to the substantia nigra
- this loss of inhibition results in a lack of inhibition of the dopaminergic neurones and can be partly controlled by D2 receptor antagonists
- reducing the dyskinesia without causing akinesia is very difficult

Front 470

What are the characteristics of opiate receptors?

Back 470

>The opiate receptors in the spinal cord are predominantly of the mu and delta type and are found in the C-fibre terminal zone (the substantia gelatinosa) in the superficial dorsal horn
- Up to 75% of the opiate receptors are found pre-synaptically on the C-fibre terminals and when activated inhibit neurotransmitter release
- The opening of potassium channels will reduce calcium flux in the terminal and so there will be a resultant decrease in release of all the transmitters in the C-fibres
- The remaining post-synaptic receptors appear to hyperpolarize the dendrites of projection neurones, interneurones and disinhibit inhibitory interneurones the net result is further inhibition of the C-fibre induced activity.
>This spinal action of opiates can be targeted by using the intrathecal or epidural routes of administration which have an advantage over systemic application of avoiding the side effects mediated by opiate receptors in the brain and periphery.

Front 471

Why do opiates not cause a complete block of pain transmission?

Back 471

>Complete C-fibre inhibitions can be produced under normal conditions but opiates do not always produce a complete analgesia in some clinical situations especially when the pain arises from nerve damage
>Reasons for this are suspected to be excessive NMDA mediated activity which is hard to inhibit and the mobilization of cholecystokinin in the spinal cord which can interfere with opiate actions.
- The idea that pre-emptive analgesia aids post-operative pain relief by preventing the pain induced activation of these systems is becoming popular.

Front 472

What are the central sites and mechanisms for pain relief?

Back 472

>5-HT and noradrenergic nuclei of the brain stem and midbrain including the
- raphe nuclei
- periaqueductal grey matter
- locus coeruleus
>Opiate receptors in these zones, (mu, delta and kappa) when activated alter the level of activity in descending pathways from these zones to the spinal cord
>The mechanisms of action of opioids at supraspinal levels is still poorly understood
1. descending controls filter sensory messages at the spinal level allowing a pain message to be extracted from the incoming barrage
- supraspinal morphine is thought to reduce these controls so blurring the perception of pain
2. morphine turns on descending controls which simply inhibit spinal pain transmission
NB. opioid mechanisms at a number of other supraspinal sites (thalamic levels, the amyglada and the sensory cortex) are likely to be of relevance to analgesia

Front 473

Which other receptors in the spinal cord play a role in pain relief? How?

Back 473

>The relative roles of the 5-HT receptors in the spinal cord are yet unknown but the spinal target for NA released from descending pathways are alpha-2 receptors which have similar actions and distribution to the opiate receptors
- sedation and hypotension with alpha-2 agonists presently limit their use as analgesics
- antidepressants (amytryptiline) are used in neuropathic pains states and increase synaptic levels of NA and 5-HT by block of uptake

Front 474

What are the central side effects of opioids?

Back 474

>SOLITARY TRACT AND ADJACENT AREAS
- cough suppression (inhibition of brainstem nuclei)
- nausea and vomiting (CTZ activation)
- reduce the sensitivity of the respiratory centres to pCO2 (the most common cause of death from overdose with street use of opiates)
>Dextromethorphan is the non-opiate isomer of levorphanol and is an effective cough suppressant

Front 475

What is thought to cause dependence on opioids?

Back 475

>Sites in the monoamine nuclei such as the well demonstrated actions of opioids on noradrenergic transmission in the locus coeruleus and enhancing dopamine release in the ventral tegmental area are likely to be associated with reward processes and so relate to dependence
- Psychological dependence does not occur in the presence of pain.

Front 476

How do opiate receptor agonists vary in their side effects?

Back 476

>There are good indications that the KAPPA and DELTA receptor agonists cause less respiratory depression than mu and that prolonged protection of the enkephalins by the peptidase inhibitors has no dependence liability
- this lack of dependence is also seen with kappa agonists but is accompanied by aversive or non-rewarding effects that limit their usefulness in humans

Front 477

What are the peripheral side effects of opiates?

Back 477

>Opiates constrict the pupils by acting on the oculomotor nucleus
>cause constipation by causing a maintained contraction of the smooth muscle of the gut which reduces motility
- this diminished propulsion coupled with opiates reducing secretion in the gut underlie the anti-diarrheal effect
>contract sphincters throughout the g.i.t. (although these effects are predominantly peripheral actions there are central contributions as well)
>morphine can also release histamine from Mast cells and this can produce irritation and bronchospasm in extreme cases
NB. opiates have minimal cardiovascular effects at therapeutic doses

Front 478

Using 3 examples how do opiate agonists differ from each other?

Back 478

>All clinically used opiates have the same pharmacology since they all act on the mu receptor with the exception of the kappa agonist, pentazocine
>Opiates are used to relieve moderate to severe pain whatever the cause (accidents, post-operative pain, cancer etc) and are used pre-, intra- and post-operatively
>The mu opiates differ only in potency and pharmacokinetics.

Examples are:
Codeine: weak opiate - orally effective
Methadone: long duration - orally effective
Fentanyl: very potent - short duration

Front 479

What is the mechanism of action of heroin?

Back 479

>Heroin (diacetylmorphine) is a highly lipophilic drug but has no affinity for opiate receptors
- it penetrates the brain rapidly whereupon it is metabolized to morphine which then binds to the mu receptor
- used as analgesic

Front 480

What is the mechanism of action of tramadol?

Back 480

>Tramadol is a weak opioid that also blocks the reuptake of NA and 5-HT
- these combined actions synergise to give a good analgesia without some of the typical opioid side-effect

Front 481

What is the mechanism of action of naloxone?

Back 481

>Naloxone is a potent competitive antagonist at mu, delta and kappa receptors with
- highest affinity for the mu receptor
>It will rapidly reverse all opiate actions but has a short half-life
- It is used in cases of overdose but usually to reverse the respiratory depression but with the cost of also reversing the analgesia

Front 482

What are three key differences between type I and type II diabetes?

Back 482

TYPE I:
- insulin dependent
- juvenile onset
- autoimmune destruction of beta cells in the islets of Langerhans in the pancreas
TYPE II:
- non-insulin dependent
- maturity onset
- reduced insulin secretion and insulin resistance

Front 483

Which main hormones control blood sugar?

Back 483

>Insulin lowers blood sugar
>Glucagon, adrenaline, glucocorticosteroids and growth hormone raise blood sugar

Front 484

What are the actions of insulin?

Back 484

>Mediated through the insulin receptor
>Immediate effects: enzyme phosphorylation
>Delayed effects: enzyme synthesis and cell proliferation and growth
ALL CELLS:
- increased glucose uptake
- increased utilisation of glucose, amino acids and fats
- increased uptake of potassium and calcium
LIVER:
- increased glycogen synthesis
- reduced glycogenolysis and gluconeogenesis
MUSCLE:
- increased amino acid uptake and protein synthesis
- increased glucose transport, glycolysis and glycogen synthesis
ADIPOSE TISSUE:
- increased glycerol synthesis and triglyceride formation
- reduced lipolysis

Front 485

What are the uses of insulin?

Back 485

>Used to maintain type I diabetics
>Used to treat hyperglycaemic ketoacidosis
>Used in severe type II diabetics where diet and other antidiabetic drugs fail

Front 486

What two main forms of insulin are available?

Back 486

>Soluble insulin - rapid action but limited duration
>Lente insulins - slow release preparations of insulin, combined with zinc or protein protamine
Both are subcutaneous for maintenance, soluble may be used IV also for ketoacidosis with NaCl and K+

Front 487

What are the unwanted effects of insulin?

Back 487

>Hypoglycaemia
>Antibody formation
>Allergic reactions
>Lipodystrophy
>Somogyi rebound hyperglycaemia

Front 488

What is the Somogyi rebound effect?

Back 488

>Somogyi and others have claimed that if prolonged hypoglycemia is untreated, then stress due to low blood sugar can result in a high blood glucose rebound
>The physiological mechanisms driving the rebound are defensive:
- When the blood glucose level falls below normal, the body responds by releasing the endocrine hormone glucagon as well as the stress hormones epinephrine, cortisol and growth hormone
- Glucagon facilitates release of glucose from the liver that raises the blood glucose immediately, and the stress hormones cause insulin resistance for several hours, sustaining the elevated blood sugar

Front 489

What are oral antidiabetics for?

Back 489

>Used if dietary control of type II diabetes fails
>Three main classes of antidiabetic drugs
1. Sulphonylureas: glibenclamide, tolbutamine
2. Biguanides: metformin
3. Thiazolidinediones: piaglitazone

Front 490

What is the mechanism of action of sulphonylureas?

Back 490

>Block ATPase sensitive potassium channels
- causing the beta cell of the islet of Langerhans to depolarise
- voltage sensitive calcium channels
- Ca++ entry into cell stimulates insulin release (normally the potassium channel is closed by ATP synthesised when glucose enters cell)

Front 491

What is the difference between Tolbutamide and Glibenclamide?

Back 491

>Tolbutamide = short acting
- both cross the placenta
- both protein bound
- both excreted by the kidney

Front 492

What are the unwanted effects of sulphonylureas?

Back 492

1. Hypoglycaemia: more likely with longer acting drugs (e.g. glibenclamide) and if there is displacement of protein binding
2. Increased appetite with weight gain

Front 493

What is the MoA of biguanides?

Back 493

>Increased uptake of glucose by tissues
- do not require functional islets of Langerhans
>Orally active
>Suppress appetite
>Reduce plasma LDL
>Excreted via the kidney

Front 494

What are the unwanted effects of biguanides?

Back 494

>Lactic acidosis
>Reduced B12 absorption

Front 495

What is the MoA of thiazolidinediones?

Back 495

>Active PPAR gamma receptors (peroxisome proliferator activation receptor)
>Sensitise peripheral tissue to the actions of insulin

Front 496

What are the mechanisms of thyroid function?

Back 496

>TRH is released from the hypothalamus, stimulating the release of thyrotropin (TSH) from the anterior pituitary
>Protirelin, a tripeptide derivative of TRH is used to test for subclinical hyperthyroidism
>Thyrotropin (TSH) regulates iodide uptake by the thyroid gland
>Thyroperoxidase, together with hydrogen peroxide, mediates the oxidation and linking of iodide to tyrosine residues in thyroglobulin
>Mono and di-iodo forms are made
>One mono and di-iodo forms yield T3
- MAIN ACTIVE THYROID HORMONE
>Two di-iodo forms yield the hormone T4 or thyroxine
- large reserves and slow turnover
- converted to T3 in the periphery

Front 497

What is the MoA of thyroid hormone?

Back 497

>Receptors for thyroid hormone are intracellular, like those for steroids and not the membrane
>Receptors activation increase glucose and amino uptake
>Receptor activation initiates the transcription of mRNAs
>Translation yields proteins that have a regulatory effector function

Front 498

What are the actions of thyroid hormone?

Back 498

>Raised basal metabolic rate - heat production in response to cold
>Increased metabolism of carbohydrates, protein and fat - moderation of the actions of other hormones
>CNS development and growth

Front 499

What are the three main types of thyroid disease?

Back 499

>Simple goitre hypertrophy of the gland in response to low iodine intake
>Hyperthyroidism (toxic goitre), diffuse (Grave's disease, long acting thyroid stimulator)
>Hypothyroidism - Hashimoto's thyroiditis (autoimmune)

Front 500

How is thyroid disease treated?

Back 500

>Thiourylenes
- methimazole, propylthiouracil
- inhibit iodination of tyrosine residues, propylthiouracil also inhibits the peripheral conversion of T4 to T3
- used for diffuse toxic goitre (nodular goitres are removed surgically)
- drugs are orally active and 90% inhibition of iodination occurs within 12 hours of achieving the therapeutic plasma level
- however because of large T4 reserve, the onset of clinical effect is slow
>Propylthiouracil has a faster onset of clinical effect than methimazole because it also inhibits T4 to T3
- can inhibit granulocyte formation in bone marrow

Front 501

What is the use of radioiodine in thyroid disease?

Back 501

>I131 is a beta and gamma emitter
>Given orally as iodide
>Irradiation can be used to ablate the overactive gland, followed by T4 maintenance therapy

Front 502

Which drugs may reduce symptoms of hyperthyroidism?

Back 502

>Propranolol used to reduce tachycardia, tremor and agitation
>Guanethidine may reduce exopthalmos

Front 503

What is the treatment for hypothyroidism?

Back 503

>T4 is given
>Danger of overdose: angina and heart failure
>T3 is reserved for myxodema coma

Front 504

What are the 5 cardinal characteristics of inflammation?

Back 504

>Increased blood flow (CALOR / RUBOR)
>Increased vascular permeability, cellular infiltration (TUMOR)
>Pain (DOLOR)
>Loss of function (FUNCTIO LAESA)

Front 505

What is meant by the term autacoid?

Back 505

>Mediators of inflammation are often produced locally around the site of the stimulus to inflammation, hence the term hormone or autacoid

Front 506

What causes RUBOR/CALOR?

Back 506

>Increased blood flow to the site of inflammation which is caused by:
- relaxation of vascular smooth muscle by direct-action of mediators on smooth muscle cells or by the release of vasodilator substances (e.g. NO, PGI2) from endothelial cells

Front 507

What causes TUMOR?

Back 507

>Increased vascular permeability caused by:
- contraction of endothelial cells, converting them from flat pavement linings of blood vessels to a structure with spaces between cells that permit the egress of protein and fluid
- swelling occurs when the rate of loss of fluid from the vessel exceeds the rate of lymphatic drainage
>Cellular infiltration, resulting from
- sticking of leukocytes in blood to endothelial cells (adhesion molecules) and then movement of leukocytes from the vessel towards a chemical mediator by chemotaxis

Front 508

What causes DOLOR?

Back 508

>Results from stimulation and or sensitisation of primary afferent neurones (C fibres) in response to inflammatory mediators

Front 509

What causes FUNCTIO LAESA?

Back 509

>Mainly a result of pain and stiffness that follows swelling

Front 510

What are examples of local hormone mediators of inflammation?

Back 510

Peptides:
- Cytokines, TNF alpha, IL1, 5 and 8, interferons
- Neuropeptides - substance P, neurokinin A, calcitonin gene related peptide
- Complement anaphylatoxins C3a, C5a
- Kinins - bradykinin, kallidin

Front 511

How is histamine formed?

Back 511

By decarboxylation of histidine via histidine decarboxylase
- inhibited by alpha methyl histidine

Front 512

Where is histamine located?

Back 512

1. Blood
- basophil leucocytes
2. Present in all connective tissue within mast cells
- skin and lung particularly rich
- connective tissue mast cells located around blood vessels, mucosal surfaces, GI tract, stomach
3. Histaminergic neurones
- hypothalamus, projections into the cortex, thalamus, striatum and hippocampus

Front 513

Where is histamine stored?

Back 513

>Mast cell granules, basophils

Front 514

What stimulates release of histamine?

Back 514

>Antigen-antibody (IgE class) reaction on the mast cell membrane
- antigens e.g. pollen, house dust mites, bee venom proteins
- allergy determined by the capacity to bind IgE to specific receptors on mast cells or basophils and the capacity of these cells to release histamine and other substances in response to antigen-IgE interaction
- antigen and IgE reaction cross linkes membrane proteins (IgE receptors)
- cross linking induces increased membrane permeability to calcium
- calcium entry and release of calcium from intracellular stores initiates exocytotic release of granules
- agents which increase intracellular cyclic AMP (B2 agonists) reduce histamine release

Front 515

Other than IgE which mediators stimulate histamine release?

Back 515

>C5a and C3a
>Substance P, VIP
>Tubocurarine, morphine

Front 516

Where does histamine act (6 places)?

Back 516

1. Smooth muscle (H1)
RELAXATION
- arteriolar and arterial
CONTRACTION
- Veins
- Bronchial
- Uterine
- Gastrointestinal
2. Endothelial cells
- respond to histamine by rounding up (H1) so intracellular spaces form, increased vascular permeability follows
- NB. histamine causes a fall in BP by increasing venular permeability and relaxing arteriolar smooth muscle
- histamine induced adrenaline release from the adrenal may partly counteract the effet on smooth muscle by physiological antagonism
3. Glands
- stimulates gastric secretion (H2)
- H1 adrenal medulla, pancreas, salivary, lacrymal and bronchial glands
4. Heart
- positive chronotropic (H2) and ionotropic actions (H2 + H1)
- reduced AV conduction (H1)
- induction of arrythmias
5. Neurotransmitter function
- histaminergic neruones are involved in the release of vasopressin from posterior pituitary, emesis, consciousness and temperature regulation
- cell bodies of histaminergic neurones in hypothalamus project to caudate, amygdala, hippocampus and central gray matter
- presynaptic histamine receptors H3
6. Pain
- histamine H1 stimulates c fibres

Front 517

What is a selective agonist of H1 receptors?

Back 517

2 methyl histamine

Front 518

What is a selective H2 agonist?

Back 518

4 methyl histamine, dimaprit, impromidine

Front 519

What is a selective H3 agonist?

Back 519

R-alpha-methyl histamine

Front 520

What is diphenhydramine?

Back 520

>Antihistamine, with sedating effect

Front 521

What is chlorpheniramine?

Back 521

>Antihistamine, less sedating than diphenhydramine

Front 522

Why do cetirizine, astemizole and terfenadine not have sedative actions?

Back 522

>They do not enter the CNS

Front 523

What are selective antagonists at H2 receptors?

Back 523

>Cimetidine, ranitidine
- competitive antagonists

Front 524

What is thioperamide?

Back 524

A selective H3 antagonist

Front 525

What are the functions of H3 receptors?

Back 525

Unknown - however act as autoreceptors

Front 526

What messenger systems are activated by H1 receptors?

Back 526

>H1
- depolarisation brings about increased concentration of free calcium ions within the cell
- calcium comes from extracellular medium and intracellular stores
- histamine has actions in K+ depolarised, voltage insensitive Ca++ channels may be involved or Ca++ release from intracellular stores

Front 527

What messenger systems are activated by H2 receptors?

Back 527

>stimulation of adenylate cyclase, increased levels of cyclic AMP in cells acts to reduce intracellular free Ca++ or prevent intracellular response to Ca++

Front 528

In what three ways is histamine metabolised?

Back 528

1. Oxidation: Diamine oxidase (histaminase)
2. N-methylation: N-methyltransferase
3. Acetylation: gut flora

Front 529

What are kinins?

Back 529

>Peptides e.g. bradykinin (literally 'slow mover') is a nonapeptide

Front 530

How are kinins formed?

Back 530

>Formed when kallikrein (from either plasma or tissue cells) acts on a substrate called kininogen in the plasma)

Front 531

What are the actions of kinins?

Back 531

>Very potent vasodilator
>Increases venular permeability
>Vasodepressor
>Bronchoconstrictor
>Pain (blocked by aspirin)
>Contracts uterus
>Slow contraction of intestinal smooth muscle
>Releases histamine which mediates some indirect effects of bradykinin

Front 532

What two kinin receptors are there? What is their function?

Back 532

>B1, B2
- significance of B1 receptors is unclear
- most effects of bradykinin appear to be mediated by B2 receptors
>Icatibant is a B2 antagonist in humans (used in HAE)

Front 533

What are Dale's three criteria for what constitutes a neurotransmitter?

Back 533

1. Transmitter must be present in presynaptic neurone
2. Transmitter must be released by Ca++ dependent exocytosis
3. A receptor must be activated by the neurotransmitter

Front 534

Which inflammmatory mediators are implicated in production of heat and redness (increased blood flow)?

Back 534

>Histamine
>Serotonin
>PGE2
>PGI2
>PAF
>Nitric oxide
>Bradykinin

Front 535

Which inflammmatory mediators are implicated in production of oedema?

Back 535

>Anaphylatoxins (C3a and C5a)
>PGE2
>LTB4
>TNF alpha
>IL-1 and 8
>VEGF
>PAF
>Bradykinin

Front 536

Which inflammmatory mediators are implicated in production of pain?

Back 536

>Substance P
>CGRP
>Bradykinin
>H+

Front 537

Which inflammmatory mediators are implicated in causing loss of function?

Back 537

>Free radicals
>Proteases
>Lipases
>TNF alpha
>RANK-L
>LTC4
>LTD4

Front 538

What is PAF and what is it formed by?

Back 538

>Platelet activating factor (MISNOMER - MAINLY INDEPENDENT OF PLATELET ACTIVATION)
- acetyl glyceryl ether phosphorylcholine
- formed from Acyl-PAF by actions of PLA2
- manufactured by basophils, eosinophils, macrophages and platelets
- antigen IgE interaction can release PAF from all of these

Front 539

What are the actions of PAF?

Back 539

1. Bronchoconstrictor when inhaled in vivo - no effect on airway smooth muscle in vitro
2. Increases permeability of postcapillary venules in airways - leads to mucosal swelling
3. Produces hyper-reactivity of airways to other stimuli
4. Potent chemotactic agent for eosinophils
>Actions make PAF a likely mediator of asthma, no clinically useful antagonists available

Front 540

What are prostaglandins synthesised from?

Back 540

>Arachidonate, which is synthesised to a prostanoid by CYCLOOXYGENASE, and to the relevant prostaglandin by the relevant SYNTHASE

Front 541

What are the physiological effects of prostaglandins on bronchial smooth muscle?

Back 541

>PGF2alpha, PGE2, TXA and LTCDE4 are potent bronchoconstrictors
>PGI2 is a bronchodilatory

Front 542

What are the physiological effects of prostaglandins on the GI tract?

Back 542

>PGE2 and PGF2a = contract longitudinal muscle
- PGE2 causes it to relax (EP2), role in diarrhoea
>PGI2 relaxes smooth muscle
>PGE1 and PGI2 reduce gastric secretion
- PGE2 analogues (enprostil) used to treat duodenal ulcer (c.f. H2 antagonists)
>PGI2 increases gastric blood flow
>PGE2 causes increased mucous and water secretion into gut (role in diarrhoea

Front 543

What are the physiological effects of prostaglandins on the uterus?

Back 543

PGE2 and PGf2a cause contraction of pregnant uterus
- non pregnant uterus PGF2 induces contractions and increases blood flow
- role of PGs in physiological control of labour, menstruation - not proven
>Uses: therapeutic abortion, potential use as post-coital contraception

Front 544

What are the physiological effects of prostaglandins on the vasculature?

Back 544

>PGI2 is a powerful vasodilator and it inhibits platelet aggregation (IP)
- produced by vascular endothelial cells, not by platelets
>TXA2 (thromboxane A2) and cyclic endoperoxides are vasoconstrictor and induce the aggregation of platelets (TP)
- promote the release of ADP from platelets
- ADP also aggregates platelets
- produced by platelets and the outer layers of vessel walls

Front 545

What are the pathophysiological effects of prostaglandins?

Back 545

Largely inflammatory
VASCULAR EFFECTS
- PGE2 is a vasodilator (arterioles)
- produces little increase in vascular (postcapillary venules)
- permeability but also potentiates the effects of other agents e.g. histamine, by increasing the flow into the permeabilised vessel
LEUKOCYTIC EFFECTS
- PGE2 can also inhibit monocyte activation and suppress T cell activation
- PGD2 regulates Th2 lymphocytes
- leukotrienes esp. LTB4 cause leukocyte chemotaxis (also important targets in asthma)
- hypothalamus produces PGE in response to endogenous pyrogen (IL-1), generated when bacteria interact with leukocytes
- injection of pGE into ventricles causes temperature rise when bacteria are injected
- anterior hypothalamus responds similarly, not posterior hypothalamus however
PAIN
- PGE2 cause the sensitisation of sensory neurons, enhancing the generator current and increasing the likelihood of a neuron eliciting an action potential

Front 546

What class of drugs inhibit prostaglandin synthesis?

Back 546

NSAIDS

Front 547

What are the actions of TNF-alpha?

Back 547

>Cytokine
- associated with chronic inflammation
- induces fever
- stimulates acute phase protein release
- cytotoxic to cells
- activates granulocytes and MCV
- promotes bone resorption by osteoclasts
- inhibits collagen synthesis and promotes breakdown
- induces cytokine synthesis
- promotes fibroblast proliferation
- increases metabolic activity of muscle
- activates endothelial cells
- promotes angiogenesis
- increases lipolysis and decreases lipid synthesis

Front 548

What is the mechanism of aspirin in preventing thrombus formation?

Back 548

>IRREVERSIBLY acetylates COX
- platelets are more sensitive than other tissue (platelets do not synthesise proteins, therefore the effect of aspirin disappears only when MKCs release new platelets
- low dose of 75mg / day effective against arterial thrombi
- elevated cAMP reduces aggregation so aspirin combined with dipyridamole

Front 549

How else may thrombus formation be reduced?

Back 549

1. Infusion of PGI2 in man increases flow in vessels partially obliterated by platelet thrombi
2. Diet low in saturated fat (sat fats become peroxidated, which inhibits PGI2 synthesis, PGI2 a platelet activation inhibitor, thus a high sat fat diet leads to more thrombus formation)
3. Relative excess of eicosapentanoic acid produces PGG3, TXA3 and PGD3
- Inuits have a high intake of this, longer bleeding times, less ischaemic heart disease

Front 550

What is the body's naturally occurring anti-inflammatory? What are the advantages of synthetic versions of this?

Back 550

>Hydrocortisone = naturally occurring glucocorticoid
- roughly equal potency as antiinflammatory and a mineralocorticoid
>Synthetic compounds offer
- improved potency
- greater selectivity for anti inflammatory action over mineralocorticoid action

Front 551

What are examples of synthetic glucocorticoids?

Back 551

>Prednisolone
>Betamethasone
>Dexamethasone

Front 552

What are the general effects of glucocorticoids?

Back 552

A. Antiinflammatory
B. Immunosuppressive
>Suppress early events of inflammation, vasodilatation, oedema, leukocyte infiltration and activation
- also suppress later events of inflammation e.g. cell proliferation, MCV activity, fibroblast activity, angiogenesis
- some effects are caused by suppression of autacoid production e.g. PG, LT, TX, PAF
- inhibits basophil release of histamine

Front 553

What is the mechanism of action of glucocorticoids?

Back 553

>Glucocorticoids are lipid soluble so easily cross the cell membrane
- bind the glucocorticoid receptor (GR)
- results in loss of HSP complex, revealing a translocation and DNA binding region on GR, the receptor enters the nucleus with 4 key effects:
1. Binds glucocorticoid regulatory element (GRE) and activates gene transcription of anti inflammatory proteins e.g. lipocortin-1
2. Binds GRE negatively regulating pro-inflammatory gene transcription e.g. IL1
3. Transrepression of NFkB at DNA
4. Direct bind of soluble transcription factors or transactivators

Front 554

What are the effects of steroids?

Back 554

>Synthesis of new protein or the suppression of protein synthesis are not immediate effects
>Antiinflammatory actions of steroids are not manifest for several hours
>Reduced cyclooxygenase products, resulting in reduced oedema, blood flow and pain at site of inflammation
>Reduced lipoxygenase products (LTB4, LTC4 and LTD4) results in reduced leukocyte infiltration and activation (LTB4) and reduced bronchoconstriction (LTC4 and D4 oedema, blood flow and pain)
>Reduction of the expression of COX2, NOS, adhesion molecules and some cytokines results in
- reduced COX products
- reduced blood flow due to inhibition of NO synthesis
- reduced cellular infiltration (IL-5 and 8)
- reduced proinflammatory effects of cytokines (IL1 and TNF)

Front 555

What are the unwanted effects of steroids?

Back 555

>Suppression of hypothalamic, pituitary and adrenal function
>Iatrogenic Cushing's Syndrome
>Immunosuppression
>Mineralocorticoid effects - salt and water retention

Front 556

What are the metabolic effects of steroids?

Back 556

Carbohydrates:
- Decreased uptake and use of glucose
- Increased gluconeogenesis
- Hyperglycaemia
Proteins:
- Increased protein catabolism
- Decreased protein synthesis
Fats
- Redistribution of body fat (central adiposity)
- Permissive effect on lipolytic hormones

Front 557

What are the effects of NSAIDS?

Back 557

1. Analgesic
2. Antiinflammatory
3. Antipyretic

Front 558

What is the mechanism of NSAIDS?

Back 558

>Common mechanism is inhibition of COX
>Two types
- COX1 = constitutive enzyme
- COX2 = induced at site of inflammation
>Most of the older NSAIDS are either unselective or mainly act on COX1
- NSAID toxicity has been thought to be associated with COX1 inhibition, COX2 appears to have a protective cardiovascular role
- newer NSAIDS selective for COX2 may have reduced toxicity

Front 559

What is the mechanism for the anti pyretic effect of NSAIDS?

Back 559

1. Exogenous pyrogens e.g. bacteria are engulfed by MCV
- MCV make endogenous pyrogen (IL1, TNF alpha)
2. Endogenous pyrogen causes PGE formation in the hypothalamus
- resetting the body's thermostat in the hypothalamus to a higher level
>Inhibition of PGE formation in the hypothalamus causes thermostat to be set back to a normal level

Front 560

What is the mechanism for the analgesic effect of NSAIDS?

Back 560

1. PGE formed at the site of inflammation PGE formed
- sensitising sensory nerves, lowering pain threshold and increasing perception of pain
2. NSAIDs reduce PGE formation, reducing the sensory neuronal sensitisation and lowering pain, also an effect on the CNS

Front 561

What is the mechanism for the antiinflammatory effect of NSAIDS?

Back 561

>PGE, PDG and PGI are all vasodilators and promote oedema formation, the heat redness and swelling
>NSAIDs inhibit formation of these prostanoids and reduce the heat redness and oedema of inflammation

Front 562

What are the unwanted effects of NSAIDs?

Back 562

>Cause damage to upper GI tract
- 40 deaths from haemorrhage
>PGE from COX1 in the stomach inhibits gastric acid secretion and promotes protective mucus formation and bicarbonate release
- the mucosa ulcerates and bleeds
>One aspirin tablet increases GI blood loss from 2ml per day to 12ml per day, annual blood loss caused by aspirin = 20000 gallons
>COX2 selective drugs cause less GI damage

Front 563

What is adalimumab and infliximab?

Back 563

>Humanised anti-TNF antibodies
- disease modifying in chronic inflammatory diseases due to neutralisation of TNF alpha

Front 564

What is etanercept?

Back 564

>A soluble TNF alpha receptor

Front 565

Other than glucocorticoids and NSAIDs what other types of antiinflammatory are clinically available?

Back 565

>Gold e.g. auranofin
>Penicillamine
>Chloroquine
>Immunosuppressants e.g. cyclosporin, methotrexate
>Sulphasalazine

Front 566

What is the definition of a clinical trial?

Back 566

>An unbiased determination of the effectiveness of a new therapy in patients
- how big an effect can be achieved and whether an effect of this size is likely to be therapeutically useful are relevant factors, in addition to adverse effects and toxicity
- 'no pain no gain' all drugs must be demonstrably effective and have adverse effects, although an assessment of benefit vs. risk is necessary

Front 567

What is the purpose of conducting a pre-clinical study?

Back 567

>To provide proof of concept in a mammal
- evidence of pharmacodynamics and pharmacokinetics
- evidence of toxicology is also required from in vitro and animal studies

Front 568

What occurs in phases I-III of clinical development of a therapy?

Back 568

PHASE I
>Normally conducted in healthy volunteers
- aim is to determine pharmacokinetics following single and multiple doses
- to confirm pharmacodynamics, record general tolerance and adverse effects
PHASE II
>Involve patients with the disease, for determining efficacy and safety
PHASE III
>Full scale clinical trials, in patients, for confirmation of efficacy and safety prior to marketing

Front 569

What are typical controls in a clinical trial?

Back 569

>Essential to compare a new drug with placebo or, more usually, an existing drug of known efficacy
>Placebos are dummy medications, and may themselves have an effect, related to the psychological 'expectation' of an effect
>It may not be ethical to use a placebo if these means withholding a known effective treatment in a disease that is life threatening or is causing significant pain or discomfort

Front 570

How are the number of subjects in a trial determined?

Back 570

POWER CALCULATION
- statistical test
- to ensure that no more subjects than necessary for the desired outcome are exposed to the risks of taking a new drug
- requires a predetermined acceptance of the likelihood of type I and II errors, the variance of the measurement being made and an expectation of the size of the difference between the two compared groups
>Subjects who will receive the new and standard (or placebo) must be matched for age, sex, race, disease severity, other diseases, other medications
>RANDOMISATION is crucial to avoid bias

Front 571

What is subjective bias and how may it be avoided in a clinical trial?

Back 571

>Arises in both subject and physician from expectations about the new drug
- avoided by the DOUBLE BLIND technique where neither the patients nor the doctor asessing the response of the drug knows what drug or treatment is being given to a particular subject
- SINGLE BLIND technique is sometimes employed where only the subject doesn't know whether they are receiving the new drug or control

Front 572

What is the difference between concurrent/parallel design and cross over design?

Back 572

>CONCURRENT = two groups of patients, one receiving the new drug and one the control
>CROSS OVER = one group of patients, new drug and control administered at different times, with wash out between
- Latin square is used where more than two treatments are being compared to avoid any bias arising from the order of administration of the treatments

Front 573

What are sequential trials?

Back 573

>Patients allocated at random to control or new drug sequentially, outcome is continuously plotted and trial ended when a predetermined result is achieved
- minimises the number of subjects required

Front 574

What is enriched enrolment?

Back 574

>Subjects enter a drug
- sometimes versus placebo stage and only those who respond then enter the full trial where half get drug and half get placebo
- aim to assess the benefit to those who respond rather than a larger population where many may not respond

Front 575

What methods of assessment may be used?

Back 575

>Objective = e.g. particular markers for efficacy e.g. BP
>Subjective = patient's feelings about their symptoms e.g. mood in an antidepressant trial

Front 576

What are the statistical considerations for a clinical trial?

Back 576

>Null hypothesis necessary
- no difference between new and control treatments
>Non parametric or parametric testing, depends on whether data is distributed in a Gaussian fashion
>ITA - once a subject has been randomised for inclusion in a treatment group and then defaults, they should be included as if they had completed the trial

Front 577

What are the ethical considerations when conducting a clinical trial?

Back 577

>Protocols must be approved by an independent ethics committee
- national process now available for this
>Factors relevant to a trial being ethical are
- correct design
- assessment of likely benefit against likely risks
- full patient information and informed consent
- placebos - is it justifiable to withhold and effective treatment?

Front 578

What is evidence of Level I?

Back 578

>Evidence obtained from at least one properly designed randomised controlled trial

Front 579

What is evidence II-1?

Back 579

>Evidence obtained from well designed controlled trials without randomisation

Front 580

What is evidence II-2?

Back 580

>Evidence obtained from well designed cohort or case control studies, preferably from more than one site

Front 581

What is evidence level III?

Back 581

>Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees

Front 582

What is the strongest form of evidence?

Back 582

>Systematic review of RANDOMISED, DOUBLE BLIND, PLACEBO CONTROLLED trials, involving a HOMOGENEOUS PATIENT POPULATION

Front 583

What is the NNT?

Back 583

The number needed to treat (NNT) is an epidemiological measure used in assessing the effectiveness of a health-care intervention, typically a treatment with medication
>The NNT is the average number of patients who need to be treated to prevent one additional bad outcome (i.e. the number of patients that need to be treated for one to benefit compared with a control in a clinical trial). It is defined as the inverse of the absolute risk reduction

Front 584

What is doxapram?

Back 584

>Stimulates respiration by acting on carotid chemoreceptors and the respiratory centre in the medulla
- used in COPD with respiratory failure
- administered IV to tide patients over a crisis
- no long term value
SIDE EFFECTS
- may induce convulsion
- not used in asthma or respiratory depression arising from drug overdose or CNS disease

Front 585

What are the features of asthma?

Back 585

>Reversible bronchoconstriction and airway obstruction
>Airway hyperactivity
>Inflammation of the bronchial mucosa
>Loss of bronchial epithelium
>Mucus plugging airway
>Easrly and late phases of airway obstruction

Front 586

What are common stimulants of asthma?

Back 586

>Allergic reaction
>Exercise - cold and dry air
>Irritants - SO2, industrial chemicals
>Respiratory infections
>Situations and emotional responses

Front 587

Describe the pathogenesis of allergic asthma.

Back 587

Allergen>Ab (IgE) response>Cell fixation of IgE>Allergen/IgE interaction>Cell activation>Mediator production>Multiple tissue effects

MEDIATORS:
- Histamine, LTs, PAF, Cytokines, Growth factors, Eosinophil derived proteins, Neuropeptides, other neurotransmitters, Kinins, Complement
- some of the features of asthma depend on direct action of mediators on cells but some are secondary to the activation of neural reflexes and the effects of released neurotransmitters

Front 588

Which two principles of treatment are available?

Back 588

>Inhibition of mediator or neurotransmitter release or formation
>Pharmacological antagonism of the effects of mediators

Front 589

What are the two main treatments for asthma?

Back 589

>Bronchodilators
>Anti-inflammatory agents

Front 590

What are examples of bronchodilators used in asthma treatment?

Back 590

i. beta2 adrenoceptor agonists (salbutamol or long acting salmeterol)
ii. methylxanthines e.g. theophylline
iii. muscarinic antagonists e.g ipratroprium
iv. leukotriene receptor antagonists e.g. montelukast

Front 591

What are examples of antiinflammatory drugs used in asthma?

Back 591

i. glucocorticoids e.g. beclamethasone (inhaled), prednisolone (oral)
ii. anti allergics e.g. cromoglycate
iii. leukotriene receptor antagonists e.g. montelukast

Front 592

What is the mechanism of action of anti-allergics?

Back 592

E.g. cromoglycate (inhaled) and nedocromil (oral)
>Mechanism of action not known but evidence supports two hypotheses
1. inhibition of the release of mediators of inflammation from cells involved in the pathogenesis of asthma e.g. mast cells, eosinophils, neutrophils
2. Inhibition of sensory nerve activity involved in the reflexes which promote bronchoconstriction and neurogenic inflammation of the airways
>PREVENTATIVE - NOT CURATIVE

Front 593

What is the mechanism of action of salbutamol and salmeterol?

Back 593

>Beta 2 adrenoceptor agonists
- relax bronchial smooth muscl
- also prevent release of mediators derived from mast cells
>Salmeterol useful for nocturnal asthma

Front 594

What is the mechanism of action of ipratroprium bromide?

Back 594

>Inhaled muscarinic antagonist (oral or parenteral use precluded by extensive side effects from muscarinic blockade)
- most effective in asthma where reflex bronchoconstriction predominates

Front 595

What is the mechanism of action of montelukast?

Back 595

>Antagonises the action of LTD4 at its receptors
>Bronchodilator and anti inflammatory action because leukotrienes causes bronchoconstriction and airway inflammation

Front 596

What is the mechanism of action of methylxanthines?

Back 596

1. action on calcium movement
- at high concentrations can release Ca++ from intracellular pools
2. Inhibition of cAMP and cGMP phosphodiesterases to reduce intracellular catabolism of these cyclic nucleotides
- can potentiate a rise in intracellular cAMP induced by other drugs e.g. beta adrenoceptor agonists
3. competitive antagonism of adenosine at adenosine receptors

Front 597

What is the effect of methyxanthines?

Back 597

>Bronchodilation
>Relax vascular smooth muscle except cerebral arteries which contract
>Diuresis (weak effect - increase blood flow increase glomerular filtration, may inhibit Na+ reabsorption)
>Positive ionotropic and chronotropic action on heart (possible toxicity)
>Increased secretions from GI tract (diarrhoea limits use)
>CNS stimulant

Front 598

How is theophylline administered?

Back 598

>Orally, aminophylline is used for severe asthma
SIDE EFFECTS:
- tachycardia with dysrhythmias, diarrhoea, tremor and wakefulness

Front 599

What is the mechanism of action of antiinflammatory glucocorticoids in asthma?

Back 599

>Oral use associated with major unwanted side effects of steroids but oral, potent steroids have to be used for severe asthma
- inhaled steroids e.g. beclamethasone is preferred
- oral prednisolone is reserved for severe disease
- delayed action for either

Front 600

What is the mechanism of action of H1 antagonists in asthma?

Back 600

>e.g. cetirizine
NO VALUE in asthma
- only partiy reduces the acute airway obstruction

Front 601

What is omalizumab?

Back 601

>An anti IgE antibody (IgG)
- t1/2 of 10-20 days

Front 602

What is the pathophysiology of atherosclerosis?

Back 602

1. Endothelial dysfunction, leading to loss of cytoprotective mediators
2. Macrophages are activated and adhere to endothelium
3. Production of reactive oxygen species by macrophages leads to LDL oxidation and further damage to endothelium
4. Modified LDL not cleared from plasma
5. Macrophages take up modified LDL and migrate into the vessel wall (foam cells)
6. Platelets also activated and adhere to endothelium
7. Macrophages and platelets release cytokines, growth factors, reactive oxygen species to cause further damage, hyperplasia and attract additional cells

Front 603

What are the cytoprotective mediators of endothelium?

Back 603

>NO
>Prostacyclin (PGI2)
>Endothelial derived hyperpolarising factor

Front 604

What do endothelial mediators do to prevent atherogenesis?

Back 604

1. Inhibit activation of leukocytes and platelets
2. Prevent vascular smooth muscle proliferation
3. Vasodilate
4. Promote regeneration of damaged / lost endothelium

Front 605

What is the physiological role of cholesterol?

Back 605

1. Integral component in the synthesis of steroid hormones
2. Structural role in cell membrane
3. Fat soluble vitamin synthesis (e.g. vitamin D)

Front 606

How are lipids transported in the body?

Back 606

>Complexed with proteins
- lipoproteins (fatty acids transported on albumin)
>Lipoproteins
- core triglyceride and cholesterol ester and a coat of phospholipid, free cholesterol and apoprotein
- classified by size / density
a. HDL
- transports cholesterol from periphery to liver (for removal) and steroidogenic organs e.g. ovaries, testes)
b. LDL
- transports cholesterol from liver to cells that require it (express LDL receptors)
- often termed bad cholesterol
c. VLDL
d. chylomicrons

Front 607

What is type I hyperlipidaemia?

Back 607

TYPE I - familial hyperlipoproteinaemia
- low lipoprotein lipase
- increased chylomicrons
- treated with diet control

Front 608

What is type IIa hyperlipidaemia?

Back 608

TYPE Iia - familial hypercholesteremia
- LDLR deficiency
- increased LDL
- treated with sequestrants, statins, niacin

Front 609

What is type IIb hyperlipidaemia?

Back 609

TYPE IIb - combined hyperlipidaemia
- decreased LDLR, increased ApoB
- increased LDL, VLDV, triglycerides
- treated with statins, niacin, fibrates (PPARa agonists)

Front 610

What is type III hyperlipidaemia?

Back 610

TYPE III - familial disbetalipoproteinaemia
- ApoE deficiency
- increased LDL
- treated with fibrates

Front 611

What is type IV hyperlipidaemia?

Back 611

TYPE IV - familial hyperlipidaemia
- increased VLDL production and clearance
- increased VLDL
- treated with fibrates and niacin

Front 612

What is type V hyperlipidaemia?

Back 612

TYPE V - familial hypertriglyceridaemia
- increased VLDL production and clearance
- increased VLDL and chylomicrons
- treated with niacin and fibrates

Front 613

What is drug treatment in hyperlipidaemias targeted at?

Back 613

1. Dietary modification
2. Lowering LDL
3. Increasing HDL
4. Sequestering cholesterol and bile acids
5. Preventing cholesterol absorption
6. Facilitating LDL breakdown

Front 614

What are 5 examples of lipid lowering drugs?

Back 614

1. Statins
2. Bile acid binding resins
3. Fibrates
4. Cholesterol absorption inhibitors
5. Cholesterol ester transfer proteins (cetrapibs)

Front 615

What is the mechanism of action of simvastatin?

Back 615

>HMG CoA reductase inhibition
- blocks conversion of HMG CoA to mevalonate in the synthetic pathway for cholesterol
>Reduction of hepatic cholesterol synthesis leads to increased synthesis and expression of LDL receptor so that LDL clearance is increased
>Strong clinical evidence that they have a benehficial effect in atherogenic cardiac disease with an increase in life expectancy for those treated with these drugs
SIDE EFFECTS:
- may impair liver function other than cholesterol synthesis
- can cause inflammatory reaction in skeletal muscle (myositis and rhabdomyolysis)

Front 616

What is the mechanism of action of cholestyramine?

Back 616

1. Basic anion exchange resin
2. Not absorbed from the gut
3. Bind bile acids and prevents entero-hepatic recirculation
4. Reduced cholesterol absorption and increase in the metabolism of of endogenous cholesterol to form bile acids

Front 617

What is the mechanism of action of fenofibrate?

Back 617

1. Primarily decrease serum triglycerides
2. Increase fatty acid oxidation in muscle and liver
3. Increase lipoprotein catabolism
- decrease VLDL and LDL
- increase HDL
4. Most used in type III, IV and V hyperlipidaemias
5. Like statins they can cause an inflammatory reaction in skeletal muscle

Front 618

What is the mechanism of action of nicotinic acid (B3)?

Back 618

>Reduce fatty acid mobilisation from the periphery and reduce hepatic VLDL synthesis
>Drug with the largest impact on HDL and the only agent that lowers lipoprotein A
>Usually employed in combination with fibrates, resin or statins
- avoids side effects of higher doses due to prostaglandin release (e.g. flushing, palpitations, GI intolerance)

Front 619

What is the mechanism of action of ezetimibe?

Back 619

>Prevents absorption of cholesterol from diet
>Reduces serum LDL, cholesterol and triglycerides and increases HDL
>Effective in mild / moderate hypercholesterolaemia as monotherapy or in combination with statins for moderate / severe hypercholesterolaemia (synergistic actions)

Front 620

What is the mechanism of action of anacetrapib / torcetrapib?

Back 620

Novel inhibitor of CHOLESTEROL ESTER TRANSFER PROTEIN
- normally responsible for transfer of these esters from HDL to ApoB1 (LDL)
- causes increase in HDL levels and decrease in LDL levels
- clinical trial ILLUMINATE recently halted due to increased adverse CV events, off target effect of torcetrapib

Front 621

What is an adverse drug reaction?

Back 621

>A negative, unwanted effect of a drug seen at therapeutic doses

Front 622

What is the definition of a side effect?

Back 622

>A non elective action of the drug which is unavoidable and often quite predictable e.g. respiratory depression with morphine, or sedation with antihistamines taken for hay fever

Front 623

What is the definition of a secondary effect?

Back 623

>Unwanted effects resulting from the action of the drug e.g. opportunistic fungal infections

Front 624

What is the definition of an idiosyncratic effect?

Back 624

>Effects occuring in susceptible individuals - allergic or genetic basis (hypersensitive / intolerant may also be used)

Front 625

What are 5 main types of toxic effect?

Back 625

>Mutagenicity (e.g. anticancer mustards)
>Drug Allergy (e.g. penicillins)
>Carcinogenicity (e.g. stilboestrol)
>Cytotoxicity (e.g. paracetomol)
>Teratogenicity (e.g. thalidomide)

Hint 625

Multiple Drugs Are Causing Cellular Toxicity

Front 626

What are the 6 main targets of drug toxicity?

Back 626

>Immune system
- drug molecules are in general too small to be immunogenic and must combine covalently with endogenous proteins to form an effective antigen
- drugs themselves are rarely reactive enough to bind covalently, and it is more commonly a metabolite which binds
- penicillin allergy is due to the formation of penicillinoic acid-protein conjugates
>Foetal
- teratogenesis, dependent on stage of organogenesis when exposure occurred
>DNA mutagens
- alkylation of guanine bases is particularly involved
- initiation and promotion phases for carcinogenesis
- initiators react with DNA
- promotors may cause a variety of biochemical changes
- carcinogens may also activate oncogenes
>Receptors / ion channels
- morphine, deadly nightshade, picrotoxin
>Calcium homeostasis
- elevation of intracellular Ca++ causes various effects, membrane blebbing, leakiness, activation of Ca++ dependent degradative enzymes (glutamate excitotoxicity)
>Biochemical pathways/energy supply
- salicylate - uncoupling of oxidative phosphorylation
- CN- inhibition of cytochrome oxidase

Hint 626

IF DRs Can't Bother

Front 627

What are active metabolites?

Back 627

>Stable metabolites with increased toxicity compared to parent molecule
>Formation of chemically reactive species (paracetomol), commonly electrophiles
>Generation of reactive oxygen species (peroxide, hydroxyl radical, singlet oxygen, lipid peroxides) e.g. quinones such as adriamycin

Front 628

Which organs commonly suffer from drug toxicity?

Back 628

>Liver - hepatotoxicity (paracetomol, chloroform, halothane, alcohol)
>Kidney - nephrotoxicity (sulphonamides, aminoglycosides)
>Ears - ototoxicity (streptomycin, loop diuretics, aspirin)
>Eyes - oculotoxicity (methanol, chloroquine)
>Blood
- chloramphenicol and anaemia
- phenylbutazone and agranulocytosis
- oestrogen and thrombosis

Front 629

What is the LD50?

Back 629

>Simple measure of the acute toxic potential of a drug
- dose of drug which kills 50% of treated animals within a specified 'short' period of time
- provides no information on non-lethal or long term effects
- testing on relatively few numbers of animals means that it will not detect rare effects

Front 630

How can drug toxicity be avoided?

Back 630

>Testing and monitoring helps to identify substances which can be banned or have their use strictly controlled
>Clear labelling to inform of risk
>Prescribing small quantities
>Minimising polypharmacy
>Child proofing containers

Front 631

How can drug toxicity be treated?

Back 631

>Reducing absorption
- gastric lavage, activated charcoa, purgatives)
>Promoting elimination
- forced alkaline diuresis, haemodialysis
>Antidotes
- naloxone for opioids, methionine for paracetomol, oximes for organophosphates, ethanol for methanol)
>Supportative therapy (to allow time for drug to be eliminated or for damaged tissue to recover e.g. liver regeneration

Front 632

What are the conclusions reached by Laurence and Black regarding drug benefit vs. risk?

Back 632

1. drugs RELIEVE untold SUFFERING and PRESERVE LIFE
2. drugs can CAUSE unavoidable ILLNESS
3. by rational attitudes to drug use the BENEFITS can be MAXIMISED, and ADVERSE EFFECTS REDUCED though not eliminated
4. a BLIND FAITH in 'wonder drugs' is as FOOLISH as a blind rejection of drugs as wholly unnatural and wholly harmful
5. the MEDICAL PROFESSION is under JUSTIFIED CRITICISM for uncritical and casual use of drugs
6. the PUBLIC is RELUCTANT to ACCEPT that RISKS are inevitable and has unduly HIGH EXPECTATIONS of drugs
7. the PUBLIC has yet to recognise that it has a SUBSTANTIAL PART TO PLAY and a responsibility to use DRUGS RATIONALLY
8. blaming the medical profession for not forcing rational drug policies on the public may satisfy the emotions of the public but is unlikely to be successful in improving matters
9. the DRUG INDUSTRY has PRODUCED VALUABLE new DRUGS and is adapted to this function
10. the drug INDUSTRY though providing much useful information about its products is also PRONE TO EXCESSES IN PROMOTION and to the multiplication of similar drugs to an unnecessary degree
11. the problem of ENSURING that PATIENTS WHO will BENEFIT from drugs RECEIVE DRUGS and that patients who will not benefit from drugs do not receive drugs are extremely COMPLEX
12. government drug REGULATORY authorities, which in their present form derive from justified concern at the thalidomide disaster, CAN DO HARM as well as good, that if the public demands benefits but is unwilling to accept any risks then the natural bureaucratic reaction will be to eliminate risks at all costs, even though this must mean eliminating at the same time progress in the treatment of disease
13. these PROBLEMS will ONLY be SOLVED by addressing ourselves, that is patients, doctors, industry, drug regulatory organisations, politicians to them WITH a WILL to solved them by REASON and not by blaming everyone except ourselves
14. the objective, RATIONAL drug USE will be assisted by INFORM the public of the issues so that it can JUDGE FOR ITSELF

Front 633

What two underlying reasons are there for variability in drug response e.g. amount required for therapeutic effect or particular adverse effects with a safe dose?

Back 633

1. Pharmacokinetic factors
- modify the relationship between the dose administered and the concentration achieved at the site of action
2. Changes in the relationship between the concentration of drug at its site of action and the response produced

Front 634

What are the key factors when discussing pharmacokinetic differences in drug response?

Back 634

1. Absorption
2. Distribution
3. Metabolism
4. Excretion

Front 635

How might drug absorption behave differently in individuals?

Back 635

- changes in absorptive surface of GIT in disease
- interaction with food / other drugs

Front 636

How might drug distribtution affect variation in drug response?

Back 636

>difference in volume of distribution
i) body size per se (can adjust dose in accordance with body weight)
ii) oedema
iii) obesity
>difference in protein binding
i) changes in protein concentration in disease
ii) drug interactions (competition for binding)
iii) binding to specfic antibodies e.g. insulin resistance

Front 637

How might drug elimination affect variation in drug response?

Back 637

>Drug metabolism
>Age
- incompletely developed systems in neonates
- general impairment in the elderly e.g. reduced requirement for propranolol, opren toxicity
>Liver disease
>Genetic differences e.g. suxamethonium, isoniazid
>Interactions, enzyme induction or inhibition

Front 638

How might drug excretion affect variation in drug response?

Back 638

>Age is associated with a decline in renal clearance
>Renal disease, profound effect on t1/2 of drugs excreted unchanged
>Creatinine clearance may be used to assess degree of renal failure and indicate appropriate dose of drug
>Competition with other drugs for active transport systems in renal tubules e.g. probenecid/penicillin

Front 639

What factors might affect how individuals respond to a drug?

Back 639

1. Receptor numbers
2. Desensitisation
3. Changes in transduction response mechanism
4. Adaptive changes
5. Genetic change to target
6. Resistant bacteria

Front 640

What is an example of receptor numbers changing as a consequence of drug response?

Back 640

>Downregulation e.g. beta receptor in beta agonist treatment of asthma and in heart failure, of insulin receptors in obesity
>Increase in receptor number e.g. cardiac beta receptors increase with thyroxine, uterine oxytocin receptors with oestrogens
>Anti receptor antibodies, myasthenia gravis
- disease states producing insulin resistance (acanthosis nigricans)

Front 641

What is an example of receptor desensitisation as a consequence of drug response?

Back 641

>Agonist induced conversion of a receptor to an inactive state e.g. nicotinic receptor

Front 642

What is an example of change in transduction response mechanism as a consequence of drug response?

Back 642

>Receptor phosphorylation of the receptor
- with beta adrenoceptors, this reduces the subsequent activation of adenylate cyclase
>Exhaustion of mediator e.g. tachyphylaxis to ephedrine

Front 643

What is an example of adaptive changes as a consequence of drug response?

Back 643

>Homeostatic mechanisms e.g. tolerance shown to opioids (however receptor downregulation also occurs)

Front 644

What is an example of genes changing as a consequence of drug response?

Back 644

>Coumarin resistance
- enzyme which keeps vitamin K in its active form is aberrant, less sensitive to coumarin

Front 645

What is an example of resistance as a consequence of drug response?

Back 645

>Selection of bacterial strains resistant to particular antibiotics

Front 646

What effect does propranolol have on salbutamol?

Back 646

>Non selective beta antagonist will reduce the effect of salbutamol (a beta2 agonist used in asthma)

Front 647

What effect does coadministration of a diuretic and a cardiac glycoside have?

Back 647

>Diuretics lower plasma concentration of K+, enhancing the action of digoxin, which compete with K+ for the Na+/K+ ATPase

Front 648

What effect does cheese plus MAOI have?

Back 648

>Tyramine found in cheese, displaces noradrenaline from vesicles when MAO (type A primarily) is inhibited - known as the cheese reaction

Front 649

What is the issue with administration of warfarin and aspirin?

Back 649

>Aspirin, inhibits platelet function, and increases the effect of warfarin which reduces blood clot formation

Front 650

What is the effect of taking H1 antagonists with alcohol?

Back 650

>H1 antagonists such as diphenhyramine which acts in the CNS causing drowsiness, which is enhanced by alchohol

Front 651

What effects atropine and opiates have on drug absorption?

Back 651

>They may delay absorption of drugs which occurs in the lower GI tract due to inhibition of gastric emptying

Front 652

What effect does metoclopramide have on drug absorption?

Back 652

>Accelerates gastric emptying, which increases absorption in the lower GI tract

Front 653

What effect does drug binding have on absorption? Give examples.

Back 653

e.g. Ca++ binds tetracyclines
- reduces adsorption can occur

Front 654

How may drug interactions influence drug distribution?

Back 654

>Many drugs are carried in plasma bound to plasma proteins
- free drug is active
>If drug A displaces drug B from its protein binding, the concentration of free B rises and its effect increases (e.g. NSAIDs displace warfarin from plasma protein)

Front 655

How is drug metabolism affected by other drugs?

Back 655

1. Induction of enzymes by drug A can increase the metabolism of drug B and therefore reduce its effect
2. Inhibition of enzymes by drug A can reduce the metabolism of drug B and increase its effect

Front 656

Which drugs induce CYP450?

Back 656

>Chronic high doses of alcohol and carbemazepine, affecting warfarin, oral contraceptives and other drugs

Front 657

Why does alcohol increase the toxicity of paracetomol?

Back 657

>Induction of P450 linked enzymes in the liver by ethanol increases the toxicity of paracetomol because the enzymes generate the toxic metabolite of paracetomol

Front 658

What effect do grapefruit psoralens have on drug metabolism?

Back 658

>Inhibit CYP450 - can reduce the metabolism of Ca++ blockers and other drugs

Front 659

What is the effect of cimetidine on CYP450?

Back 659

>H2 antagonists inhibit CYP450 that metabolise warfarin

Front 660

What effect does propranolol have on first pass metabolism?

Back 660

>Drop in cardiac output, causes a fall in hepatic blood flow, reducing the metabolism of drugs that are largely metabolised by their first pass through the liver

Front 661

Which factors affect the excretion of drugs from the kidney?

Back 661

- Protein binding
- Tubular secretion
- GFR (blood flow)
- Urine pH

Front 662

What effect does probenecid have on AZT secretion?

Back 662

>Inhibits tubular secretion of AZT, increasing its plasma concentration

Front 663

What effect do NSAIDS have on secretion of thiazides and loop diuretics?

Back 663

>Inhibit their secretion, preventing access to their site of action in the kidney tubule

Front 664

What effect do drugs changing GFR and urinary pH have on the clinical impact of other drugs?

Back 664

>Little clinical impact

Front 665

What occurs during haemostasis?

Back 665

>When a blood vessel is cut, three processes stem the loss of blood
1. Vasoconstriction
2. Platelet adherence and aggregation to plug the hole
3. Blood coagulation to lay down fibrin in the hole, trapping red cells and thereafter providing a scaffold for repair

Front 666

What is thrombosis, how does it differ in veins c.f. arteries?

Back 666

>The pathological occlusion of a blood vessel
- mainly by platelet aggregates, because fast flow deters fibrin deposition
- in veins the occlusion is mainly deposited fibrin (blood clot)

Front 667

What are the three factors which predispose venous thrombosis?

Back 667

1. Endothelial damage
2. Venous stasis
3. Hypercoagulability

Front 668

What is an embolism?

Back 668

>One of the main dangers of thrombosis is that part of the thrombus breaks away from its attachment to the vein wall and moves through the circulation to occlude pulmonary vessels
- broken off thrombus is called an embolus
- pulmonary embolus compromises gas exchange in the lungs and may be fatal

Front 669

Which agents enhance blood coagulation?

Back 669

1. Vitamin K1 and K2
- acts as a cofactor for glutamic acid residues in precursor proteins to give activatable factors II, VII, IX and X
2. Whole blood, FFP, recombinant factor VIII

Front 670

Which agents decrease coagulation?

Back 670

1. Heparins
2. Oral Anticoagulants

Front 671

What is the mechanism of action of heparin?

Back 671

>INACTIVATES THROMBIN IIa and also Xa, Ixa, XIIa, probably by combining with and accelerating the action of antithrombin III (a physiological inhibitor of these factors)
>Administered IV or SC
- reduces risk of DVT and PE in perioperative patients
>Bound to plasma protein
>Acts for 2-4 hours
>Metabolised by heparinase in the liver
>Unwanted effects, haemorrhage and thrombocytopenia

Front 672

What is a clinically used heparin antagonist?

Back 672

>Protamine sulphate

Front 673

How is dose control of heparin measured?

Back 673

>By measuring activated partial thromboplastin time (APPT)

Front 674

What is dalteparin?

Back 674

>A lower molecular weight heparin, with a longer duration of action
- low dose prophylaxis can be achieved by one s.c. dose per day and needs no monitoring

Front 675

What is the mechanism of action of warfarin?

Back 675

>Act by interfering with the reduction of vitamin K1, preventing its action as a co-factor in the post translational gamma carboxylation of a set of glutamic acid residues at the N terminal ends of factors II, VII, IX and X
- if these residues are not carboxylated the factors are non-functional

Front 676

What extra factor is required for the generation of IIa by Xa?

Back 676

>Calcium mediated binding of coagulation factors to a phospholipid surface, which serves to localise the integrating factors
- factor Va on a negatively charged phospholipid surface forms a binding site for II and Xa
- Ca++ links the negative charge of the phospholipid surface to the negatively charged gamma carboxyl groups on II and Xa
- Xa liberates ensymic thrombin

Front 677

What is the main hazard of oral anticoagulant use?

Back 677

>Bleeding
- may be counteracted with Vitamin K, delivered IV if necessary
- no response until new factors are synthesised
- haemorrhage may require treatment immediately by whole blood transfusion

Front 678

What is the T1/2 of warfarin?

Back 678

>40 hours given orally
- since it interferes with gamma carboxylation of factors II, VII, IX and X, the level of functional factors drops as they are degraded
- onset of effect of the drug thus depend on the half lives of the factors which are 40 and 60 hours for X and II respectively
- rates are increased in fever and hyperthyroidism

Front 679

How are warfarin patients typically tested?

Back 679

>Using INR
- results are reported as patients prothrombin time compared with that of a normal control i.e. as a ratio
- 2-4 is a normal aim
- >4 increases risk of bleeding significantly
- home test kits for INR determination allow patients to control their own dose

Front 680

What are the pharmacokinetic differences between warfarin and heparin?

Back 680

>Warfarin
- onset 12-16 hours
- peak effect 36-48 hours
- duration 4-5 days
>Heparin
- onset immediate
- peak effect immediate
- 2-4 hours

Front 681

How much may daily dose of anticoagulant therapy vary between patients?

Back 681

As much as 10x
- also affected by amount of vitamin K in the diet, changes in dietary fat, lactation

Front 682

Which drugs decrease the response to oral anticoagulants?

Back 682

1. Prior administration of drugs which cause the induction of the mixed oxidases (CYP450) in the liver which metabolise oral anticoagulants
2. Oral contraceptives

Front 683

Which drugs increase the response to oral anticoagulants?

Back 683

1. Displacement of oral anticoagulants from binding to plasma protein e.g. aspirin
2. Impairment of platelet aggregation e.g. aspirin
3. Inhibition of the mixed oxidases of the liver e.g. imipramine, cimetidine
4. Reduction of vitamin K availability e.g. broad spectrum antibiotics
5. Increased catabolism of clotting factors e.g. thyroxine

Front 684

What is thrombolysis / fibrinolysis?

Back 684

>Same meaning
>Clot dissolving
- involves the formation of plasminogen activators from zymogens
- derived from endothelium of small vessels, phagocytic cells and action of FXII on proactivators in plasma or tissues

Front 685

What is plasminogen?

Back 685

>Precursor to plasmin (also known as fibrinolysin)
- converted to plasmin by plasminogen activators with short half lives
- digests fibrin and fibrinogen, any plasmin which escapes into the circulation which is inactivated by plasmin inhibitors

Front 686

What are examples of drugs which enhance fibrinolysis?

Back 686

1. Streptokinase
2. Urokinase
3. Tissue plasminogen activator (TPA)
4. APSAC (p-anisolyated lysplasminogen-streptokinase-activator-complex)

Front 687

What is streptokinase?

Back 687

>Non enzymic protein, prepared from streptococci
- forms a stable complex with plasminogen which gains enzymic activity due to a conformational change
- antigenic therefore may be blunted by antistreptococcal antibodies

Front 688

What is urokinase?

Back 688

>Prepared from human urine or from cultures of human embryonic kidney cells
- can be made recombinantly
- NOT ANTIGENIC

Front 689

What is TPA?

Back 689

>Synthesised in vivo, primarily by endothelial cells but has been made available as a therapeutic agent by recombinant DNA technology
- more active on fibrin bound plasminogen
- CLOT SELECTIVE

Front 690

What is APSAC?

Back 690

>human plasminogen-streptokinase complex which is inactive
>can be given as a single IV injection which is active for 4-6 hours

Front 691

What are the toxic effects of fibrinolytics?

Back 691

>BLEEDING
- treated giving aminocaproic acid or tranexamic acid, and if necessary fresh whole blood
- streptokinase may cause low grade fever (antigenic)
- contraindicated in patients with internal bleeding and cerebrovascular disease, any situation where clotting required e.g. surgery, of course a risk in patients on anticoagulant therapy

Front 692

What are tranexamic acid, aminocaproic acid and aprotinin?

Back 692

>Tranexamic acid and aminocaproic acid are plasminogen inhibitors
- prevent fibrinolysis
>Aprotinin inhibits proteolytic enzymes and in addition for use in hyperplasminaemia (caused by fibrinolytics), used to treat disseminated intravascular coagulation, and has been used for treatment of acute pancreatitis

Front 693

What is the hypothalamic hormone controlling fertility?

Back 693

>Gonadotrophin releasing hormone (GnRH)
- gonadorelin is a synthetic form
>Pulsatile release stimulates gonadotrophin production, continuous release inhibits FSH and LH production
>Gonadorelin is used in two ways
CONTINUOUS DOSING
- to depress FSH / LH formation in endometriosis, precocious puberty, and sex hormone dependent tumours
PULSATILE DOSING
- to stimulate ovulation

Front 694

What are the gonadotrophins?

Back 694

secreted by the ANTERIOR PITUITARY
>FSH - follicle stimulating hormone
>LH - luteinising hormone
involved in the control of the cyclic development of the ovarian follicles, ovulation and the cyclic secretion of oestrogens and progesterone

Front 695

What do FSH and LH do in males?

Back 695

>FSH - controls spermatogenesis
>LH controls secretion of testosterone

Front 696

What are the pharmacological uses of gonadotrophin - in females and males?

Back 696

>Menotrophin (LH>FSH), HCG, given parenterally
- female infertility, which is due to pituitary insufficiency, multiple births may occur (20% incidence)
- cryptorchidism (undescended testis)

Front 697

What are the oestrogens?

Back 697

>Oestradiol, oestrone, oestriol
>Steroids, synthesised mainly in the ovary, main stimulus is FSH
- small amounts secreted from the adrenal cortex and testis
- large amounts secreted from the placenta

Front 698

What are the physiological actions of the oestrogens? (6)

Back 698

1. Development of reproductive organs and secondary sex characteristics at puberty
2. Menstrual cycle control, promoting early phase endometrial proliferation
3. Stimulate the activity of the cervical mucous glands
4. Influence gonadotrophin secretion by actions on hypothalamus and pituitary
5. Promote the formation of progesterone receptors
6. Have metabolic effects (salt and water retention, anabolic, altered blood coagulation)

Front 699

What are two pharmacological preparations of oestrogen?

Back 699

>Ethinyloestradiol, mestranol - steroidal
>Stillboestrol - non steroidal, with oestrogenic activity, used mainly in cancer therapy

Front 700

What are the main uses of oral oestrogens? (4)

Back 700

a. oral contraceptives, in combination with a progestogen
b. replacement therapy (hypoovarian syndromes)
c. treatment of hormone dependent tumours (e.g. prostate)
d. treating menopausal symptoms and for post-menopausal replacement therapy

Front 701

What is clomiphene used for?

Back 701

>Clomiphene inhibits estrogen receptors in hypothalamus, inhibiting negative feedback of estrogen on gonadotropin release, leading to up-regulation of the hypothalamic–pituitary–adrenal axis
- used to induce ovulation

Front 702

What is tamoxifen used for?

Back 702

>Oestrogen antagonist in breast tissue - used in breast cancer

Front 703

What stimulates progestogen secretion?

Back 703

>LH
>Progesterone is secreted by the ovary from the corpus luteum, vascularises the endometrium
>In males and postmenopausal women, progesterone is released from the adrenal cortex and the blood levels are equivalent to those found in the first half of the cycle

Front 704

What are the actions of progestogens? (4)

Back 704

1. progesterone is responsible for the secretory phase of endometrial change in the second half of the cycle and its withdrawal results in menstruation
2. affects cervical glands, secreting a scanty, thick, tenacious and less alkaline fluid than during the first half of the cycle
3. essential in pregnancy, acting both on the uterus and later on mammary tissue
4. negative feedback effect on the hypothalamus and anterior pituitary

Front 705

What are two pharmacological preparations of progestogens?

Back 705

>Progesterone: injected
>Norethisterone: given orally, used in the contraceptive pill, has mildly androgenic actions
>Both used mainly in contraception (danazol, a derivative of ethisterone has a fairly specific effect as an inhibitor of gonadotrophin secretion

Front 706

What 3 forms of oral contraceptive are available?

Back 706

1. Combined pill (oestrogen and progestogen)
2. Minipill - progestogen alone
3. Post coital oral contraceptives (not routinely used)

Front 707

What is the mechanism of the combined pill?

Back 707

>Taken for 21 days, followed by 7 pill-free days
>Mode of action
- oestrogen inhibits release of FSH and therefore inhibits development of the ovarian follicle
- progestogen makes cervical mucous less suitable for the passage of sperm and may decrease secretion of LH
- they alter the endometrium so as to discourage implantation
- may also interfere with coordinated contractions of cervix, uterus and fallopian tubes thought to be necessary for succesful fertilisation and implantation

Front 708

What is the mechanism of the minipill?

Back 708

>Mainly acting on endometrium and cervical mucous
- possibly causes decreased motility of the fallopian tube
- possibly decreases LH secretion and thus less luteinising effect on the follicle, although the effect on gonadotrophin release is variable and ovulation may occur
- doses are only marginally above the threshold required for adequate contraception, thus missing a dose can result in conception
- can be taken after parturition when the combined pill would interfere with lactation

Front 709

What is used for post coital oral contraceptive?

Back 709

>Combination of oestrogen and progesterone, in two doses, 12 hours apart
>Equivalent to oestrogen content of 6 low dose pills
>Nausea and vomiting occurs in 30-60%
>Single dose of mifepristone may also be effective

Front 710

What are the androgens?

Back 710

>Natural androgen is testosterone (as is androstenedione)
>Some androgen secreted from the ovary and the adrenal cortex in the female
- stimulus for secretion = LH

Front 711

What are the main actions of androgens?

Back 711

1. Development of sex organs and secondary sex characteristics in the male
2. Involved in spermatogenesis with FSH
3. Metabolic actions, protein anabolism, retention of salt and water, increase in bone growth and later closure of the epiphysis
4. Possibly a negative feedback effect on gonadotrophin production

Front 712

What are examples of pharmacological preparations of androgens?

Back 712

>Testosterone, sublingually or by subcutaneous implantation
>Fluoxymesterone - absorbed in the GIT
>Nandrolone, predominantly anabolic action with relatively less androgenic effect

Front 713

What are the actions of pharmacological preparations of androgens?

Back 713

1. For replacement therapy
2. As anabolic agents
3. In the treatment of certain tumours

Front 714

What are androgen antagonists used for?

Back 714

>Used in prostate cancer
- some progestogens have a partial agonist effect on testosterone receptors in the hypothalamus and in peripheral tissues, acting as antagonists