Pharmacology And Toxicology

Front 1

What is pharmacology a study of?

Back 1

The action of drugs

Front 2

What is a drug?

Back 2

Any substance or product that is used or intended to be used to modify or explore physiological systems or pathophysiological states for the benefit of the recipient.

Front 3

What is pharmacodynamics?

Back 3

How the drugs acts on the body

Front 4

What are the levels of the biological system can a drug have effects on?

Back 4

- Biological molecules

- Subcellular structures

- Cells

- Tissues and organs

- Intact organism

Front 5

What is pharmacokinetics?

Back 5

How the body deals with drugs

Front 6

In which 2 ways can a drug produce its effect?

Back 6

1. Non Specific Effects - related to the nature of the chemical. The act by their physical characteristics.

2. Specific Effects - due primarily to specific chemical interactions. This interaction involves binding to proteins.

Front 7

What are the 4 main types of proteins?

Back 7

1. Carrier Molecules

2. Enzymes

3. Ion channels

4. Receptors

Front 8

What is a carrier molecule?

Back 8

A carrier molecule binds the transported substance and shuttles it to the other side of the membrane for release

Front 9

What are the 2 methods a carrier molecule can shuttle a substance across a membrane?

Back 9

1. Facilitated Diffusion - no energy required. Carrier facilitated equilibrium of transported complex across membrane. It is transported in the direction of the concentration gradient.

2. Active transport - energy required. A substance is transported against its concentration gradient, therefore metabolic energy is required. (Na/K ATPase Pump)

Front 10

What 3 groups can the targets of enzymes be grouped into?

Back 10

1. Metabolic Processes - drugs that influence the synthesis of genetic material (DNA) (e.g Zidovudine (AZT))

2. Ion Pumps - substances that are transported against their concentration gradient (eg. Digoxin)

3. Synthesis, degradation and action of hormones and transmitters (eg. Paracetamol, Aspirin)

Front 11

How do ion channels work?

Back 11

- An ion channel is generally selective for a particular ion/ionic species

- An ion channel is a pore that allows ions to flow into or out of the cell depending on the ions concentration gradient

- Ion channels can interact with drugs via direct targets (drugs bind to the channel directly to alter its function) or via receptors (linked channels)

Front 12

What is the primary function of receptors?

Back 12

The act as a recognition site. Binding of the drug initiates effects.

They work like a 'lock and key' to produce a response

Front 13

What are the characteristics of drugs receptor interactions?

Back 13

1. Selectivity - only a narrow range of drugs of a similar type (complementary structure) are effective

2. Sensitivity - low concentrations of drugs produce the effect

3. Specificity - the SAME response elicited by activation of a particular receptor in a cell

Front 14

What is a receptor agonist?

Back 14

An agonist is a drug that activates the receptor to produce a response. Increasing the amount of the drug will increase the percentage of the Max response until it reaches its maximum possible value

Front 15

What is a receptor antagonist?

Back 15

An antagonist is a drug that binds to the receptor, however it doesn't activate the receptor. it prevents the agonist effect.

- Reversible - increasing the amount of the agonist will restore its response

- Irreversible - increasing the amount of the agonist will never restore its response.

Front 16

What are the 4 main types of receptors?

Back 16

1. Ligand-gated channel

2. G-Protein coupled

3. Kinase - linked

4. Intracellular Steroid

Front 17

Describe ligand-gated channels

Back 17

- Drug binding leads to opening/closing of the channel

- Na+ channels or Cl- (GABA) channels

- Time: very fast = milliseconds

- Example: benzodiazepines (Valium) -> used to treat insomnia (sedative) and anxiety (anxiolytic)

Front 18

Describe G-Protein coupled receptors

Back 18

- These receptors affect the intracellular mechanisms via a G-Protein

- Effects can be on an ion channel or a second messenger mechanism

- Time: fast = seconds

- Examples: muscarinic acetylcholine receptor; agonist carbachol; antagonist atropine

- beta-adrenoceptor; agonist salbutamol; antagonist propanolol

Front 19

Describe Kinase-linked receptors

Back 19

- Involves a receptor in the membrane that incorporates a protein kinase domain. Phosphorylates a protein (usually a tyrosine residue) to get a response

- Time: minutes

- Examples: Insulin, Growth factors

Front 20

Describe Intracellular Steroid receptors

Back 20

- Drug binds to a receptor in the cytosol then is transported into the nucleus.

- Drug needs to be lipid soluble

- Binds ot DNA to affect gene transcription

- Time: slow = hours

- Examples: oestrogen, testosterone

Front 21

What is Tubocurarine?

Back 21

A poison that was used on the tip of arrows to cause paralysis

(binds to receptor, but doesn't cause a response)

Front 22

What are the 4 main processes of pharmacokinetics?

Back 22

The drug enters the body:

- Absorption: process of a substance entering he blood/systemic circulation, dependent on the route of administration

- Distribution: the distribution of a substance throughout the tissues/compartments of the body

The drug leaves the body:

- Metabolism: the biotransformation (chemical transformation) of a substance/drug by the body (removal/excretion) - occurs mainly in the liver

- Excretion: the process of removal of the substance/drug from the body (e.g.. excretion by kidneys)

Front 23

Define bioavailability

Back 23

Bioavailability its the fraction of the administered dose that reaches the systemic circulation (relatively to an intravenous bolus injection)

Front 24

What are the main parameters influencing drug absorption?

Back 24

- route of administration

- blood flow

- drug properties: some drugs are better absorbed than others

Front 25

What are the main DRUG parameters influencing absorption?

Back 25

- formulation

- molecular size

- lipid solubility

- ionisation state

Front 26

What is bioequivalence?

Back 26

Two drugs are considered bioequivalent of they have similar bioavailabilities and show no clinical differences in either their therapeutic or adverse effects.

Bioequivalence is particularly important for the market authorisation of generic products.

Front 27

Is aspirin well absorbed from the small intestine?

**ASH**

Back 27

It is uncharged at a low pH (stomach) so it is absorbed easily, however at a charged pH (blood) it is not so easily absorbed

Front 28

What factors affect GI absorption?

Back 28

- pH - dissolution ionisation and degradation of active drug

- volume of GI contents

- proteolytic enzyme action

- bacterial metabolism

- gastric retention time

- intestinal transit time and GI motility

- drug interactions in the GI tract

- blood supply

These also affect bioavailability

Front 29

Factors affecting bioavailability after GI absorption include?

Back 29

- first pass hepatic metabolism

- entero-hepatic shunting

Front 30

what is drug distribution?

Back 30

the process of reversible transfer of a drug between one location and another once the drug is in the systemic system: more or less crossing of vascular endothelium/lipid membranes

Front 31

what is drug distribution influenced by?

Back 31

the affinity of drug for various tissue constituents:

- lipid soluble vs water soluble drugs

- more or less binding to plasma proteins (bound drug isn't active)

- affinity for fat tissues, muscles, etc.

Front 32

what is the apparent volume of distribution?

Back 32

- a characteristic of the drug (given value for a drug, obtained from PK analysis of clinical trials)

- depicts where the drug goes into the body (the value range is an indication of the relative distribution amongst plasma/tissues)

Front 33

What is metabolism?

Back 33

the biotransformation of an administered drug in the body

Front 34

why does the body metabolise drugs?

Back 34

The body metabolises drugs (mainly in the liver) with the aid of enzymes to transform them into a generally more water soluble substance for easier excretion

Front 35

where does metabolism mainly occur?

Back 35

liver (main), gut wall, muscles, fat, other tissues

Front 36

Is the extent of metabolism the same for everyone?

Back 36

No. Because there are various factors that influence metabolism; such as age, pregnancy, disease condition; from person to person

Front 37

What are the outcomes of metabolism?

Back 37

- inactive metabolites (most drugs, easy to eliminate via the kidneys)

- active metabolites (administration of an inactive prodrug; eg. codeine is transformed into morphine/activated in the liver)

- toxic metabolites (transforming drug into a toxic molecules via metabolism by liver enzymes eg. paracetamol; more water soluble so excreted in urine)

Front 38

What is first pass metabolism and where does it occur?

Back 38

- First pass metabolism is metabolism of a drug before it reaches the systemic circulation.

- it occurs mainly in the liver, but also in the gut wall, muscles, fat, and other tissues

Front 39

What routes of administration does first pass metabolism occur by?

Back 39

- oral administration

- rectal route

Front 40

what is the main mechanism of drug absorption through lipid membranes?

Back 40

Passive Diffusion

Front 41

what are two important drug physiochemical properties that affect absorption through lipid membranes?

Back 41

- ionisation (related to lipid solubility)

- lipid solubility (ability to cross cell lipid membrane)

(also molecular size and formulation)

Front 42

What are phase 1 reactions?

Back 42

- redox reactions

- catalysed by CYP450 enzymes family (oxidation) and others (reduction)

- in phase one, the molecule is oxidised and made more water soluble to make it ready for conjugation

Front 43

What are phase 2 reactions?

Back 43

- conjugation reactions

- catalysed by enzyme families specific to each conjugated chemical group

- Phase 2 uses enzymes (transferases) to attach (conjugation) endogenous water soluble molecules on drugs.

Front 44

Describe the enzymes used in Phase 1 metabolism

Back 44

- enzymes from the cytochrome P450 family for oxidation

- Main CYP450 enzymes are:

CYP3A4 - metabolises more than 50% drugs

CYP2D6 - known for genetic variations (slow vs high metabolisers eg. codeine)

CYP2C8

Front 45

Why is the extent of metabolism of codeine (inactive) into morphine (active) variable between individuals?

Back 45

- because the enzyme CYP2D6 is highly dependent on individuals

- the is one of the main enzymes involved in oxidation of a drug

- known for genetic variations (slow vs high metabolisers eg. codeine)

Front 46

Describe the enzymes used in Phase 2 metabolism

Back 46

UGTs - for glucuronidation

GSTs - glutathione conjugation

NATs - acetylation

SULTs - sulfation

Front 47

what is first order elimination?

Back 47

- the rate of drug metabolism is not constant, but proportional to the drug plasma concentration

- more drug = more enzymes recruited

- the amount f the drug eliminated by the liver is proportional to the amount of drug getting into the liver

- the most common elimination kinetics (most drugs at most doses)

Front 48

what is zero order elimination?

Back 48

- the rate of drug metabolism is constant; not dependent on drug plasma concentration

- more drug = if the enzymes are already at full capacity/saturated, no more enzymes are recruited

- the amount of drug eliminated by the liver is not proportional to the drug getting into the liver

- drug can build up in the body = toxicity, side effects

Front 49

What is clearance? Where does it mainly occur?

Back 49

- clearance is the volume of plasma that is cleared of drug per unit of time

- main organ is the kidneys

Front 50

Why is sodium bicarbonate given in a paracetamol overdose?

Back 50

- it has an ion trapping effect for enhancing elimination

- aspirin is a weak acid and sodium bicarbonate is a base that displaces the pH towards a basic pH

- aspirin is more soluble so more aspirin is excreted

Front 51

What are the ANS functions

Back 51

control of involuntary function

- smooth muscle

- cardiac muscle

- glands

Front 52

Describe the somatic nervous system

Back 52

- link between the CNS and effector tissues via motor neurons

- no synapse - the cell body terminal is at the effector tissue

- controls voluntary movement of skeletal muscle

- ACh neurotransmitter; acts on nicotinic receptors in skeletal muscles

Front 53

What are the neurotransmitters of the ANS

Back 53

- ACh (cholinergic nerves)

- Noradrenaline (adrenergic nerves)

- others (non-adrenergic, non-cholinergic or non-noradrenergic, non-cholinergic transmitter)

Front 54

Describe the PNS

Back 54

- controls what is happening at rest (rest and digest system)

- 2 nerves with a ganglion in the middle - located close to their effector organs

preganglionic = ACh acting on nicotinic receptors

postganglionic = there are differentiations as they act on different receptors for different regions (either ACh muscarinic, peptide peptidergic or NO nitrergic receptors)

Front 55

Describe the SNS

Back 55

Fight or flight system

SNS ganglia lie on either side of the vertebral column

preganglionic = ACh to nicotinic receptors

postganglionic = NA to a adrenoceptors; NA to b adrenoceptors; ACh to muscarinic or peptide to peptidergic

Front 56

describe features of the autonomic nerve terminal

Back 56

- action potenitals: code used by other neurons to transfer information from one neutron to another

- myelinated

- can be taken to or broken down in the cleft

Front 57

describe the events involved in neurotransmission (drugs can affect these)

Back 57

1. action potential propagation

2. substrate availability or transmitter production

3. metabolism of transmitter

4. uptake of transmitter

5. release of transmitter, depletion of transmitter

6. modulate presynaptic receptor

7. metabolism of transmitter

8. effector response

Front 58

what type of pathway is the parasympathetic nerve pathway?

Back 58

cholinergic pathway

Front 59

what are the responses to cholinergic stimulation?

Back 59

S- salivation

L- lacrimation (tears)

U- urination

D- defecation

G- GI distress

E- emesis (increases secretion, urination, vomiting)

Front 60

describe the cholinergic nerve terminal

Back 60

- presynaptic vesicles containing ACh

- Action potential stimulates ACh release

- ACE enzyme and ACh molecule

- nicotinic (ligand) and muscarinic (G-Protein coupled) receptors

- termination of action is predominantly due to the breakdown of ACh

Front 61

What drug affects cholinergic transmission and why?

Back 61

botulinum

- prevents the release of ACh from nerve terminals by preventing fusion of the vesicles with the membrane

- causes local muscle weakness/paralysis

Front 62

Describe cholinergic agonist and antagonist effects on the eye

Back 62

agonists - lead to constriction of the pupil and allows for accomodation for near vision

antagonists - (atropa belladonna/atropine) cause dilation of the pupil

Front 63

What are 2 therapeutic uses of muscarinic antagonists

Back 63

Ipratropium - inhaled - for COPD

- inhibits parasympathetic mediated bronchoconstriction

-AEs include dry mouth, blurred vision, urinary retention

Hyoscine - motion sickness/nausea

- penetrates the BBB, and is a CNS depressant

- AEs include sedation, confusion in the elderly

Front 64

How is cholinergic transmission terminated?

Back 64

ACh is hydrolysed by esterase enzymes (AChE), which terminates ACh action.

-drugs that inhibit AChE, will enhance the effect of endogenous ACH because you are blocking the enzyme that breaks it down

Front 65

What are 2 therapeutic uses of AChE inhibitors?

Back 65

Donezepil - alzheimers disease

- short acting

- makes ACh more available in the brain

- AEs - nausea, vomiting, insomnia, urinary incontinence (cholinergic)

Neostigmine - myasthenia gravis (autoimmune, skeletal muscle weakness)

- medium acting

- enhances transmission at the NMJ

- AEs - nausea, vomiting, insomnia, urinary incontinence (cholinergic)

Front 66

Describe irreversible AChE inhibitors

Back 66

- organophosphates (pesticides, chemical warfare agents)

- can lead to cholinergic crisis, and overstimulation of nicotinic and muscarinic receptors

- Muscarinic (SLUDGE)

- Nicotinic (stimulation of somatic NS, catecholamine release)

Front 67

how do NMJ blockers work

Back 67

- They block neuromuscular transmission at the neuromuscular junction, producing paralysis of skeletal muscle

- used adjectively to anaesthesia

- can be depolarising or non-depolarising

depolarising - Suxamethonium (nicotinic receptor agonist)

- causes continuous stimulation and ongoing depolarisation.

- short acting muscle relaxant causing temporary paralysis of affected muscle

non-depolarising - Pancuronium (nicotinic receptor antagonist)

- prevents the binding of ACh, reversed by AChE inhibitors (increase ACh loves)

- used in surgery to obtain skeletal muscle relaxation

Front 68

What type of receptors are Adrenoceptors?

What are adrenoceptor agonist effects?

Back 68

G-Protein coupled

• A1 – vasoconstriction of peripheral blood vessels; Dilation (contraction) of pupil; Increased contractility of the heart (inotropic effects)

• A2 – inhibition of transmitter release; Aggregation of platelets; Contraction of smooth muscle

• B1 – increased heart rate (chronotropic effect); Increased contractility of the heart (inotropic effects)

• B2 – relatation of uterus; Glycogenolysis; Dilation of bronchial smooth muscle

Front 69

What are adrenergic agonist effects?

Back 69

• Alpha - Vasoconstriction; Pupil dilation; Decreased gut motility and secretions; Glycogen breakdown; Urinary retention; Contraction of the smooth muscle of vas deferens; Contraction of non pregnant uterus; Sweating; Goose flesh

• Beta 1 - Cardiac acceleration; Lips lysis; Decreased gut motility and secretions; Renin release

• Beta 2 - Bronchodilation; Fine skeletal muscle tremor; Vasodilation of blood vessels to skeletal muscles; Glycogen breakdown; Relaxation of the pregnant uterus; Mast cell stabilisation

Front 70

What are therapeutic uses of adrenergic stimulating drugs?

Back 70

Directly acting

- adrenaline, noradrenaline, dobutamine, phenylephrine, salbutamol and salmeterol

Indirectly acting

- tricyclic antidepressants, MAOi, cocaine, amphetamine

Front 71

Describe Adrenaline

Back 71

- alpha and beta agonist (treatment of anaphylactic shock, cardiac arrest, adjunct to local anaesthetics)

- pharmacokinetics: it is rapidly metabolised, therefore only IM or SC injections

- cardiac - ^HR and force of contraction (B1)

- vascular - constriction of skin blood vessels (a1) and dilation of skeletal muscle blood vessels (B2)

- respiratory - bronchodilation (B2)

Front 72

Describe Noradrenaline

Back 72

- alpha and beta agonist (acute hypertension)

- pharmacokinetics: administered IV

- vascular - constriction of blood vessels (a)

- contraindications: caution in patients with atherosclerosis, occlusive vascular disease, hypertension

Front 73

describe dobutamine

Back 73

- B1 agonist (used in acute cariogenic shock)

-cardiac - increases force of contraction to increase cardiac output

- pharmacokinetics: administered IV

Front 74

describe phelylephrine

Back 74

- a agonist (decongestant)

- vascular - constriction of blood vessels (a)

- pharmacokinetics: nasal decongestion, oral administration

- interactions - MAOi

- AEs - rebound congestion with intranasal; stimulatory effects (insomnia, nervousness) with ora preparation

- contraindicated in hypertension

Front 75

describe salbutamol and salmeterol

Back 75

- B2 agonist (short and long acting respectively)

- treat acute bronchoconstriction

- respiratory - bronchial dilation (B2)

- pharmacokinetics - inhaled, salmeterol is usually combined with a steroid anti-inflammatory agent

- AEs - skeletal muscle tremor, palpitations, headache, hyperglycaemia (infrequent)

Front 76

What are the different sites at which drugs can act to modify neurotransmission?

Back 76

1. Synthesis of neurotransmitter

• uptake of precursors into terminal

• synthesis of transmitter

2. Storage of transmitter in vesicles

3. Degradation of surplus transmitter in cytoplasm

4. Depolarisation by propagated action potential– influx of Ca2+ in response to depolarisation

5. Release of transmitter by exocytosis– fusion of vesicles to terminal membrane– diffusion to postsynaptic membrane

6. Interaction with postsynaptic receptors

7. Inactivation of neurotransmitter

All steps are potential sites for drug action

Front 77

describe indirect sympathomimetic agents and their mode of action

Back 77

Cocaine- blocks the reuptake of catecholamines into presynaptic nerve terminals

Amphetamine- taken up via reuptake pump and displaces catecholamines

Tricyclic Antidepressants- inhibit the reuptake of NA and serotonin into presynaptic terminals

(AE - sedation, dry mouth, constipation = likely due to blocking cholinergic receptors)

Front 78

Describe monoamine oxidase inhibitors

Back 78

- metabolises amines such as noradrenaline

- MAO is a mitochondrial enzyme

- located in most tissues, nervous system, liver and GIT

Non-selective - in noradrenergic, dopaminergic and serotonin nerve terminals - antidepressant (phenylzine)

MAO a - in noradrenergic and serotonin nerve terminals - antidepressant (moclobemide)

MAO b - in dopaminergic nerve terminals - parkinsons (selegiline)

Front 79

Describe Dopamine

Back 79

- catecholamine, immediate precursor of NA

- release is increased by amphetamine

- deficient in parkinson disease

- major target of antipsychotics

-CNS: mood and motor function

Front 80

How does the body respond to a drop in arterial pressure/

Back 80

Mean Arterial Pressure - controls perfusion of organs

A decrease in BP= stimulation of the SNS which results in an increase in HR, SV and constriction of vasculature, to increase the cardiac output

This increases renin release which starts a cascade that produces angiotensin 2 (which helps to retain/^fluid= maintain blood volume and balance pressure)

Front 81

describe the renin-angiotensin system

Back 81

- a hormonal system

- the body releases renin which acts on angiotensinogen and forms angiotensin 1, which interacts with ACE which chops off some amino acids to turn it into angiotensin 2 (active)

- it promotes thirst and acts to increase the circulating fluid volume

Front 82

What is essential hypertension and secondary hypertension

Back 82

Essential hypertension - increased blood pressure due to an unknown cause, likely a combination of diet, genetics and lifestyle

Secondary hypertension - due to a specific underlying pathology (renal, endocrine etc)

Front 83

Describe left ventricular hypertrophy

(consequences of hypertension)

Back 83

Increased afterload on the heart increases cardiac work; the heart hypertrophies in response to this.

Major risk factor for congestive heart failure

Front 84

Describe Stroke/MI

(consequences of hypertension)

Back 84

Rupture of cerebral/coronary blood vessels

Front 85

Describe endothelial damage

(consequences of hypertension)

Back 85

promotes arteriosclerosis

Front 86

Describe renal failure

(consequences of hypertension)

Back 86

impairment of renal blood flow

Front 87

describe retinal damage

(consequences of hypertension)

Back 87

-alterations in retinal blood vessels

-occurs in type 2 diabetes

Front 88

How is hypertension treated?

Back 88

- antihypertensive drugs to reduce TPR, CO or both

- lifestyle interventions

- treatment on uncomplicated hypertension usually begins with a single drug (usually ACE inhibitor)

- if control is inadequate, addition of second drug usually preferred (vs increasing dose) to achieve good BP control

Front 89

How do drugs reduce total peripheral resistance?

Back 89

- calcium channel blockers inhibit L-type Ca2+ channels in vascular smooth (and myocardium) to reduce Ca2+ influx

- a reduction in intracellular Ca2+ leads to vasodilation and a reduction in TPR

- they reduce cardiac contractility and heart rate , thus reducing cardiac work

-Dihydropyridines such as nifedipine and amloidipine are calcium channel blockers

- AEs - peripheral oedema, flushing, headache, bradycardia

Front 90

Describe ACEi action in hypertension

Back 90

-ACEi reduce Ang.2-induced vasoconstriction, aldosterone release and Na+ retention. (first line hypertension therapy: also heart failure, STEMI, diabetic nephropathy)

- prevents the conversion of Ang.1 to Ang.2

- reduces salt and water retention to target cardiac output and TPR

- AE- cough, first dose and/or orthostatic hypotension, hyperkalaemia, angioedema

- contraindicated in pregnancy

(ARBs have a very similar action and AEs)

Front 91

How do B Blockers work (B adrenoceptors)

Back 91

Beta blockers competitively block B receptors to prevent an increase in HR or cardiac output that is generally stimulated by the SNS or adrenaline; to reduce cardiac work

-B-adrenoceptor antagonists antagonise these receptors in the heart, vasculature, kidney, bronchi and pancreas

- B1 - selective for B1 receptors in the heart, and are less selective for B2 receptors at the other organs, but this can be overcome with higher doses

AEs - bradycardia, bronchospasm, fatigue, cold extremities

- they can reduce angina frequency nd decrease adverse cardiac events/mortality

Front 92

What do thiazide diuretics do?

eg. hydrochorothiazide

Back 92

they bind to and inhibit the Na+/Cl- cotransporter to reduce Na reabsorption and cause a moderate diuresis (increase in urine). They also increase potassium excretion and can impair glucose tolerance.

AEs - hypotension, dizziness, electrolyte disturbances

- for hypertension and mild heart failure

Front 93

what is the ABCD of anti-hypertensive drugs?

Back 93

A - ACE inhibitors (-pril) and AT1R antagonists (-sartan) also in limited quantity a1-adrenoceptor antagonists (prazosin)

B - B adrenoceptor antagonists (-olol)

C - Calcium channel antagonists (dihydropyridines)

D - diuretics (thiazide diuretics)

Front 94

Describe the pathology of heart failure

Back 94

- heart failure occurs when the heart cannot maintain end-organ perfusion (reduced cardiac output)

- it results from he inability of the ventricle to fill or eject blood, and can be from a range of causes (hypertension, ischaemic heart disease, cardiomyopathy)

- reduction in cardiac output can be due to systolic/diastolic dysfunction

- may require a variety of different therapeutic approaches

Front 95

List the goals, strategy and pharmacological therapies for the treatment of heart failure

Back 95

Goals

- symptomatic relief

- prevent further cardiac dysfunction

- reduce mortality

Strategy

- correction of systematic factors and comorbidities

- lifestyle modifications

- treatment of underlying CVD

Pharmacological Therapy

- ACE inhibitors

- Beta blockers

- Diuretics for fluid overload

- aldosterone antagonists

- Digoxin

- Inotropes for acute HF

Front 96

How does Digoxin treat heart failure?

Back 96

Digoxin inhibits the Na/K ATPase pump found on the membrane of the muscle cell.

- Digoxin is a positive inotrope that increases the force of cardiac contraction and slows cardiac conduction.

- Used in heart failure especially with atrial fibrillation/flutter

AE - risk of arrhythmias

- narrow therapeutic range

- polar molecule so predominantly renal excretion

- excretion time - ~36hours with normal renal function

- reduced plasma K+ increases digoxin effects due to reduced competition at the K+ binding site

Front 97

What is coronary heart disease?

(ischaemic heart disease)

Back 97

- The most common form of CVD

Acute IHD - can be due to worsening/unstable angina, or sudden occlusion of a coronary artery due to rupture of an atherosclerotic plaque (MI)

Chronic IHD - usually presents as angina (predictable chest pain upon exercise/exertion)

- both are characterised by a lack of blood supply to the myocardium, resulting in inadequate O2 to meet metabolic/tissue demand.

Front 98

What is atherosclerosis?

Back 98

A progressive disease of the large arteries characterised by the local accumulate o lipids and fibrous elements together with chronic inflammation.

(fibrous plaques are vulnerable to rupture = thrombosis)

Front 99

What happens when myocardial O2 is insufficient?

(eg. an atherosclerotic plaque in a coronary vessel)

Back 99

- limits supply to demanding tissues

- during exercise/stress, there is an increased demand for O2 which cannot be met, and therefore pain occurs

- Can have Stable Angina, Unstable Angina or Myocardial Infarction

Front 100

Describe Stable Angina

Back 100

Predictable chest pain with exertions due to underlying narrowing of the coronary vessels by atheroma.

Target: cardiac work (organic nitrated, B Blockers, Ca2+ antagonists)

- underlying atherosclerosis (statins)

- anti-thrombotic therapy (aspirin)

Front 101

Define unstable angina

Back 101

Pain occurring with reduced exertion, culminating in pain at rest.

Treatment: anti platelet drugs and organic nitrates

Front 102

Define myocardial infarction

Back 102

Sudden occlusion of a coronary vessel leading to death of cardiac tissue due to O2 deprivation. The location and size of the blockage determines the extent of damage

Target: restore myocardial flow (physical or pharmacological methods

Front 103

What is the pharmacological treatment of IHD

Back 103

reduce cardiac work

- nitrates

- calcium channel antagonists

- B adrenoceptor antagonists

treatment of underlying atherosclerotic disease

- lipid lowering therapy (statins)

- anti platelet drugs

removal of blockage and restoration of coronary flow

Front 104

Define Preload and Afterload

Back 104

Preload

-the degree of tension on the muscle when it begins to contract

(the load on the heart before it begins to contract)

- determined by the end diastolic pressure

Afterload

- the load against which the muscle is working (mainly affected by the resistance downstream - in the artery or the circulation = affected by the pressure in arterial circulation leading forth ventricle)

**Treatment of IHD involves targeting these processes to reduce cardiac work**

Front 105

Describe the mechanism of organic nitrates

Back 105

They cause vasodilation (more commonly in the venous than arterial system).

This decreases the venous/arterial pressure.

Which in turn reduces the preload/afterload.

Leading to reduced myocardial work and O2 consumption

Front 106

Describe GTN (organic nitrates)

Back 106

- GTN is a prodrug that requires metabolism to release nitric oxide and relax vascular smooth muscle

- given sublingually due to extensive first pass metabolism

- AEs - vasodilatory effects (flushing, headache due to influx of blood in the rain leading to static hypertension, reflex tachycardia, orthostatic HT, fainting, peripheral oedema

- tolerance can develop quickly and wear off quickly, therefore when Pts are reexposed to the nitrates, they will re-experience the AEs, therefore the drug isn't given continually. Pts need to have nitrate free intervals to avoid tolerance and see a clinically beneficial effect

Front 107

What is the role of cholesterol in the body?

Back 107

- biosynthesis of steroid hormones

- constituent of cell membranes

- synthesis of bile acids

- absorption of lipid soluble vitamins from GI tract

Front 108

How is cholesterol transported within the body?

Back 108

- Lipids and cholesterol are transported in the bloodstream as lipid/protein complexes

(LDLs are highly atherogenic, readily oxidised and cross the endothelial barrier easily)

(HDLs transport cholesterol back to the liver for excretion, they are anti-atherogenic)

Front 109

How do we lower LDL-C levels

Back 109

Statins are used to competitively inhibit HMG-coA reductase (rate limiting step in cholesterol biosynthesis). this leads to an increase in LDL-C uptake.

-> reduced mevalonate production

-> reduced hepatic cholesterol synthesis

-> increased LDL receptor synthesis on hepatocytes

-> increased uptake of LDL-C from bloodstream

-> reduced plasma LDL-cholestrol

AEs - myalgia, dizziness, headache

Front 110

what is haemostasis

Back 110

A complex and highly regulated process involving:

-vasoconstriction

-formation of a platelet plug

-stabilisation of he platelet plug by fibrin

-fibrinolysis

The major classes of drugs that interfere with haemostats include:

-antiplatelet drugs

-anticoagulants

Front 111

What is thrombosis

Back 111

- the formation of a haemostatic plug within the vasculature in the absence of bleeding

Venous thrombi - red clots, erythrocytes and fibrin

Arterial thrombi - white clots, platelet aggregation

Front 112

What is Virchow's triad?

(thrombosis)

Back 112

- injury to vessel wall (eg. rupture of atherosclerotic plaque)

- altered blood flow (eg. veins in the legs during prolonged sitting, turbulence)

- increased coagulability of the blood (thrombophilia)

Front 113

How do anti platelet drugs act?

eg. Aspirin

Back 113

- Aspirin irreversible acetylates active site of COX1, inhibiting enzyme activity and reducing cyclic endoperoxide production.

- inhibition of COX 1 for the lifespan of the platelet reduce aggregation.

AEs - GIT irritation, increased bleeding time, asymptomatic blood loss

Front 114

How do anti platelet drugs act?

eg. P2Y12 antagonists

Back 114

- ADP induces platelet aggregation by activating purinergic receptors (GPCRs)

-P2Y12 antagonists (Clopidogrel) irreversible inhibit P2Y12 receptors to inhibit platelet aggregation

- Clopidogrel is well absorbed orally; prodrug; converted to active metabolite by CYP enzymes

AEs - increased risk of bleeding, diarrhoea, GI ulcer

Front 115

Describe the coagulation cascade

Back 115

- it converts soluble fibrinogen (inactive precursor) int he blood to fibrin that stabilises the clot

- components of the coagulation cascade print int he blood as zymogens (inactive precursors = require enzymatic cleavage)

- activation initiate cascade, amplifying signal

- Thrombin (factor 2a) cleaves fibrinogen to form fibrin

Front 116

How is the formation of trombone controlled?

Back 116

Formation of thrombin form prothrombin requires interaction with factor Xa (enzyme for prothrombin cleavage).

The interaction of another clotting factor (Va) and activated platelets provides a mining site for the interaction

Platelets are critical for correct localisation

Front 117

Describe Warfarin

Back 117

- widely used oral anti-coagulant (orally active, rapidly absorbed)

- it competes with vitamin K for binding at vitamin K reductase (reduces amount of vit.K for carboxylation reaction -> for the production of mature clotting factors)

- difficult to dose and maintain -> narrow therapeutic range, requires dose individualisation

-AE - bleeding

- can be affected by diet

Front 118

What is selective toxicity?

Back 118

Selective toxicity is the concept which relies on targeting biochemical processes that differ in some way between the host and int invading organism

Front 119

Describe prokaryotes and eukaryotes

Back 119

Prokaryotes

- bacteria

- no nuscleus

- cell wall and membrane

- single chromosome

- no mitochondria

- Ribosomes - 705

Eukaryotes

- mammalian

- nucleus

- no cell wall

- chromosomes (condensed mitochondria

- ribosomes - 805

Front 120

Define bactericidal

Back 120

Death of bacteria.

Usually results form drugs that interfere with cel wall synthesis or disrupt the cell membrane

The cell dies in response

Front 121

Define bacteriostatic

Back 121

Growth of bacteria is prevented. Body's own immune system takes care of the rest.

Prevent it from growth, but if it is already fully formed, there isn't much of an effect.

Usually drugs that interfere with protein or nucleic acid synthesis

Front 122

Define Broad and Narrow spectrum

Back 122

Differences int e cell wall are believed to account for the spectrum of effectiveness of antibiotics

Broad - wide susceptibility, both gram types

Narrow - smaller susceptibility (works on a smaller number of bacteria)

Front 123

Describe Bacteria Gram positive and negative testing (3 points)

Back 123

1. a way of identifying different toes of grouping of bacteria

2. allows you to see the cells - when they take up the dye - they wither retain the colour or lose it

3. if they retain the colour they are gram positive, if they lose it they are gram negative

Front 124

What are the 4 major sites of antibacterial drug action?

Back 124

- inhibition of DNA replication

- inhibition of cell wall synthesis

- interference of cell membrane

- interference with protein synthesis

Front 125

Drugs affecting DNA synthesis/replication?

Back 125

Sulphonamides

Use: broad spectrum, bacteriostatic. Infections oft he urinary tract, upper/lower respiratory tract, skin, wound and eye infections

Pharmacokinetics: readily absorbed by GIT, Oraly active, 50-70% bound to plasma proteins

Metabolism: mainly acetylated (destroyed) in liver, excreted in urine

AE - rashes, nausea, vomiting, GIT disturbances

Trimethoprim

Use: Bacteriostatic. Infections of the urinary tract

Pharmacokinetics: rapidily absorbed by GIT, Oraly active, 44% protein bound in plasma

Metabolism: excretion via tubular secretion and glomerular filtration, mainly unmetabolised

AE - rash, pruritus, nausea, vomiting, GIT disturbances (hyperkalaemia with higher doses)

Sulphonamides and Trimethoprim

Use: bactericidal. Infections of the urinary tract and respiratory tract,

Pharmacokinetics: as when given alone

Metabolism: as when given alone

AE - rashes, nausea, vomiting, GIT disturbances (as when given alone)

Front 126

Drugs affecting bacterial cell wall synthesis?

Back 126

Penicillins (Beta Lactams) - occasionally cephalosporins

MOA -penicillin binds to cell via penicillin binding proteins and then it inhibits the cross linking process by permanently inactivation a transpeptidase involved in cross linking peptidoglycan chains

Pharmacokinetics: poor to very good GIT absorption, oral absorption capability; eliminated via tubular secretion (urine)

AE - hypersensitivity, possibly alteration in GIT flora and hyper infection

Types:

- Benzylpenicillin (G) (naturally made) for Gram +ve bacteria

- for meningococcal meningitis, pneumococcal, streptococcal, leptospiral infections

-Phenoxymethylpeniillin (V) - less potent, Reasonable GIT absorption - similar spectrum to pen G

-Procaine Penicillin, benzathine penicillin -longer acting, depot form (IM)

-Ampicillin, Amoxycillin - broad spectrum, less GT disturbance

Front 127

Drugs affecting Bacterial cell membrane

Back 127

Polymyxins (B)

-MOA - cationic detergent properties and interfere wth phospholipids in the cll membrane (bactericidal)

- disrupt the bacterial cell membrane, prevent it from functioning

-Use - effective against gram +ve bacilli (pseudomonas and coliforms) Toxicity mainly restricts use to gut sterilisation and topical use

-AE - interferes with neuromuscular transmission and toxic to the kidney

Front 128

Drugs affecting protein synthesis

Back 128

Tetracyclines (bacteriostatic)

MOA - active transport into susceptible organisms. Concentration in the cell builds up. Blocks the binding of tRNA to A site in ribosome/mRNA complex. Prevents binding, and attachment of the amino acid and therefore prevents synthesis of the protein

Use - broad spectrum gram +ve and -ve. (Rickettsia, Mycoplasma and Chlamydia, Cholera Organisms and in respiratory and urinary infections

Pharmacokinetics - Swift but incomplete GIT absorption. Metal chelator (milk etc will reduce absorption) Excreted in urine and bile unmetabolised

AE - GIT disturbances (nausea, vomiting, diarrhoea), sensitisation to light

Macrolides (bacteriostatic or bactericidal)

MOA - Inhibit protein synthesis. Binds to 50s ribosomal subunit to inhibit translocation of tRNA from A site to P site

Use - Narrow spectrum against gram +ve bacteria. Not effective against gram -ve except Gonorrhoea, mycoplasma pneumonia and legionella

Pharmacokinetics - acid stable, orally active. Penetrate into most tissues except CSF and synovial fluid Inactivated partly in the liver. Mainly excreted in bile. May interfere with other drugs (warfarin)

AE - GIT disturbances, unpleasant but usually not serious. Opportunistic superinfection esp. in GIT and urinary tract.

Front 129

How do DNA viruses replicate?

Back 129

-Viral DNA gets into a host nucleus and uses the host enzymes to produce more viral DNA, RNA and Proteins necessary for viral replication

-It can be difficult to treat as it becomes part of the host cell

-Viral genetic information is incorporated into the genetic information of the host cell, then all the mechanics of the host cell can be utilised by the viral cell to produce viral proteinsEg Herpes viruses (HSV), VZV (chicken pox, shingles), EBV (glandular fever)

Front 130

How do RNA viruses replicate?

Back 130

Virus binds to the host cell, this enables it to release its genetic information into the host cell. But it can't be utilised as mRNA, so it reverses RNA into DNA via reverse transcriptase. Then it acts like a DNA virus -> is incorporated into the nucleus of the cell then host cell machinery is used and viral proteins are produced

Front 131

What are the main mechanisms for antiviral therapy?

(inhibition of...(4))

Back 131

1. penetration of virus into host cell

2. nucleic acid synthesis

3. protease enzyme

4. secretion of virus form host cell

Front 132

drugs that interfere with the penetration of virus into host cell

Back 132

Amantadine

MOA - blocks an ion channel involved in the entry process of the virus into host cell. Narrow spectrum. Inhibits penetration of the virus into the cell, via inhibition of an ion channel that is involved in entry to the cell

Pharmacokinetics - Given orally. Excreted unchanged via urine.

Use - Active against influenza A (not B). May be used prophylactically.

AE - Infrequent. Dizziness, insomnia, slurring speech. Not serious.

Front 133

drugs that interfere with nucleic acid synthesis

Back 133

Zidovudine (AZT)

MOA - Inhibits viral reverse transcriptase. Terminates viral DNA chain. May also affect cellular mitochondrial DNA polymerase.

Pharmacokinetics - Oral or iv. Metabolised in the liver and 20% excreted unmetabolised in the urine. Probenicid inhibits liver metabolism and urinary excretion.

Use - Used in the treatment of HIV. Delays onset of AIDS. Reduces risk of transmission from mother to fetes. Reduces viral load

AE -Mainly anaemia and neutropenia. Resistance develops with long term use.

Front 134

drugs that interfere with protease enzyme

Back 134

Antiviral therapy protease inhibitors

(Ritonavir, Saquinavir)

MOA - Interrupt the way HIV uses healthy cells to produce more virus.

Pharmacokinetics - Oral, usually with a meal.

Use - Used in the treatment of HIV. Increases CD4 (T cell) count. Decrease viral load. Usually in combination with one or more reverse transcriptase inhibitors.

AE - GIT disturbances, nausea, vomiting

Front 135

drugs that interfere with secretion of virus form host cell

Back 135

Neuramidase inhibitors

(Zanamivir, Ostelamivir)

MOA - Neuraminidase is important in the penetration of the virus into the host cell and in the release of the virus from the host cell.

Pharmacokinetics - Zanamivir – powder taken via nose (Relenza) Oseltamivir – orally (a prodrug(needs to be metabolised to be activated), hydrolysed in the liver to active form) (Tamiflu)

Use - Used in the treatment of influenza A and B

AE -Diarrhoea and nausea most common

Front 136

what are they symptoms of malaria?

Back 136

Respiratory distress

Neurological problems

Anaemia

Front 137

What are the 4 sites of action for antimalarial therapy?

Back 137

1. Red Blood Cells. Effective against erythrocytic form. Treat acute attacks. Affect a cure for P. falciparum and P. malaria (insignificant/no exo erythrocytic forms.). Suppress attacks from P. vivax and P. ovale but can have relapse due to hypnozoites).

2. Liver. Radical cure. Effective against parasites in the liver.

3. Blood. Block link between exo erythrocytic and erythrocytic stages. Prevent attacks. Agents given as prophylactic to people travelling in malaria regions. Need to be taken before and after return of travel.

4. Transmission. Effective against gametocytes. Prevent transmission in human population.

Front 138

Anti malarial therapy -

Chloroquine and Quinine

Back 138

Chloroquine

MOA - accumulates in parasite, prevents parasite breaking down Hb. Inhibits haem polymerase. Converts toxic breakdown products of Hb into harness by-products. Prevents DNA replication and protein synthesis

Pharmacokinetics - complete absorption form GIT. Extensive distribution. Concentrated in parasitised RBC. In severe cases (IM, SC, slow IV) infusion. Released slowly from tissues, excreted mainly unchanged in urine and metabolised in liver

Use - for all susceptible plasmodia infections and chemoprophylaxis in combination with other drugs

AE - dizziness, burred vision, headache, nausea, vomiting, heart rhythm disturbances

Quinine

MOA - similar to chloroquine

Pharmacokinetics - complete absorption form GIT. Extensive distribution. Concentrated in parasitised RBC. In severe cases (IM, SC, slow IV) infusion. Released slowly from tissues, excreted mainly unchanged in urine and metabolised in liver

Use -for plasmodia infections including those not susceptible to chloroquine. Usually given in combination with other drugs

AE - more toxic than chloroquine. Irritates bowel (nausea, vomiting). Cinchonism syndrome (dizziness, blurred vision, headache, tinnitus) At higher doses (heart rhythm disturbances, hypotension)

Front 139

Anti malarial therapy

Mefloquine

Back 139

MOA - Interferes with the parasites ability to use Hb as a nutrient source(blocks transport of Hb metabolites into parasite food vacuole).Formation of a complex with breakdown products of Hb - toxic toparasite.

Pharmacokinetics - Rapid GIT absorption. Long duration

Use - Effective against P. falciparum and P. vivax (erythrocytic stage only).

Mainly used in malaria due to resistant strains.

Resistance to mefloquine has been reported.

Can be used for prophylaxis.

AE - GIT disturbances common. CNS disturbances (giddiness,§ dysphoria and insomnia) transient. Rare – psychoses

Front 140

Anti malarial therapy

Pyrimethamine and Sulphadoxine

Back 140

MOA

Pharmacokinetics

Use

AE

Front 141

Anti malarial therapy

Primaquine and Qinghaosu

Back 141

MOA

Pharmacokinetics

Use

AE

Front 142

Define Superficial and Systemic Mycoses

Back 142

Superficial Mycoses

- Infections of skin, hair and nails (dermaphytes). Superficial candidiasis invasion of mucous membrane

Systemic Mycoses

- Infections of deeper tissues. Often originate in the lung but can spread to many other organs

Front 143

Anti fungal Drugs

Amphotericin B

Back 143

MOA

Pharmacokinetics

Use

AE

Front 144

Anti fungal Drugs

Azalea Derivatives

Back 144

MOA

Pharmacokinetics

Use

AE

Front 145

Anti fungal Drugs

Griserulvin

Back 145

MOA

Pharmacokinetics

Use

AE

Front 146

Anti fungal Drugs

Terbinafine

Back 146

MOA

Pharmacokinetics

Use

AE

Front 147

What are the classical signs of injury/inflammation? (5)

Back 147

-redness (vasodilatation of pre-capillary arterioles - synergistic effect with other vasodilator (histamine) = increased blood flow)

-warmth (as above)

-swelling (increased vascular permeability - indirect effect via histamine - exudate and oedema)

-pain (sensitisation of afferent C fibres (PGE2) potentiate effects of bradykinin and histamine)

-loss of function

Front 148

During inflammation, what local mediators are released?

Back 148

– arachidonic acid metabolites

– kinins

– histamine

– nitric oxide

– cytokines

Front 149

Describe COX 1 and COX 2

Back 149

COX-1 (constitutive enzyme, ‘house keeping’ role) produces prostanoids that

–protect gastric mucosa

–cause platelet aggregation

–regulate renal blood flow

COX-2 (upregulated during inflammation)

produces prostanoids that cause

– inflammation

–sensitisation of pain fibres

Front 150

What are the therapeutic effects of NSAIDS? (3)

Back 150

Analgesic

Antipyretic

Anti-inflammatory

Front 151

What are the Adverse Effects of NSAIDS?

(similar profile for all NSAIDS)

Back 151

GIT bleeding/ulcer formation

Renal dysfunction/nephrotoxicity

Cardiovascular toxicity

Hypersensitivity; precipitation of asthma

Front 152

What are NSAIDS and what are they indicated for?

Back 152

NSAIDS are cyclo-oxygenase inhibitors. They reduce inflammation by preventing prostaglandin synthesis. (pain sensitisation and inflammation)

They have opioid sparing effects.

They are indicated for treatment of:

- arthritis

- rheumatic diseases

- pain (mild o moderate)

- gout

- inflammation

- dysmenorrhoea

Front 153

NSAIDS: Aspirin

Back 153

Inhibits COX1 and COX2

Use - Mild-moderate pain, Fever, Inflammation, Antiplatelet effects (low doses)

Adverse effect: gastrointestinal irritation, Indigestion, nausea, vomiting, diarrhoea, ulcers, Caused by inhibiting gut-protective prostaglandins (secrete cytoprotective mucus,inhibit gastric acid secretion).

Strategies to overcome this: Buffered preparations, Enteric coated tablets, Co-treatment with proton pump inhibitor or misoprostol (PGE analogue)

Front 154

Describe the prostaglandin analogue: Misoprostol

Back 154

– Stable synthetic analogue of PGE that acts on PGE receptors

– Inhibits gastric acid secretion

– Increases mucosal blood flow and secretion of mucus and HCO3-

Use for both ulcer treatment and prevention of NSAID-induced ulcers (co-administration with NSAIDs)

Adverse effects: diarrhoea, abdominal cramping

– Contraindicated in pregnancy (can induce premature labour)

Front 155

Describe the clinical uses and contraindications of NSAIDS

Back 155

Acute and chronic inflammation

- rheumatoid arthritis

- osteoarthritis

- gout

Analgesia

- headache

- dysmenorrhoea

- post-operative pain

- Short term: aspirin, ibuprofen

- Chronic pain: naproxen (longer lasting)

- Decrease need for opioid analgesics

Fever

Contra-Indications

- Active peptic ulcer or GIT bleeding

- Allergic reactions to NSAIDS (skin reactions, asthma)

- Renal insufficiency (PGE2 & PGI2 regulate RBF)

- CV disease/increased CVD risk; coagulation disorders

Front 156

List the non-selective and selective NSAIDS

Back 156

Non selective

- Aspirin

- Ibuprofen

- Naproxen (long 1/2 life, may have lower risk of CV events)

- Diclofenac (rectal/topical use, may have higher risk of CV events)

Selective

Celecoxib - COX 2 inhibitor for rheumatoid and osteoarthritis

Contraindicated in patients with CVD, increased CVD risk, peptic ulcer, history of GI bleeds, renal impairment

Front 157

Describe glucocorticoids

Back 157

GCs are potent anti-inflammatory andimmunosuppressant agents that bind to intracellularglucocorticoid receptors(nuclear receptors) to alter genetranscription. They inhibit expression of COX2 and phospholipase A2 (PLA2),the enzyme that releasesarachidonic acid from themembrane – Reduced synthesis ofprostanoids

Uses - chronic inflammation (RA), Skin Disorders (psoriasis, eczema) Inflammatory bowel disease (ulcerative colitis, crohns) Asthma

Front 158

Describe Rheumatoid arthritis

Back 158

- chronic inflammatory condition

- Joint inflammation and damage: Auto-immune reaction, Proliferation of synovium, Erosion of cartilage and bone, Pathogenesis involves IL-1 and TNF-α

Treatment: -Glucocorticoids (reduce symptoms early)

- Disease modifying any-rheumatic drugs (DMARD) - sulfasalazine (1st line, also in IBD), Hydroxychloroquine (1st ling, anti-inflam), Methotrexate (folic acid biosynthesis, AE = bone marrow toxicity and GI damage)

- TNF a antagonists (prevent cytokine from interactive with its receptor = reduce inflammatory mediators)

Front 159

Describe Gout

Back 159

Characterized by acute pain,swelling and tenderness injoints.

Due to high concentrations ofuric acid in the blood, resultingin deposition of uric acidcrystals in the joints and otherareas (eg kidneys).

Deposition causes aninflammatory response.

Treatment

Acute - for symptomatic relief = NSAIDS, Corticosteroids and Cholchine(prevent neutrophil invasion)

Long term - rate lowering therapy

Front 160

Describe Asthma

Back 160

- Asthma is a chronic obstructivedisease of the airways.

- Symptoms include wheezing, chesttightness, shortness of breath,coughing.

- Characterised by reversiblebronchoconstriction, airwayhypersensitivity and increased mucussecretion.

- Chronic changes include airway wallremodelling, fibrosis, inflammationand epithelial cell apoptosis.

Treatment:

Inhaled bronchodilators - B2 adrenoceptor agonists cause bronchodilation. AE=CV (tachycardia) and muscular (tremor) effects

Inhaled corticosteroids - decrease inflamm. response in airways; AE=hoarse voice, local fungal infections

Front 161

What is Pain?

Back 161

- An unpleasant sensory or emotional experience associated with actual orpotential tissue damage, or described in terms of such damage

- Important protective mechanism that warns of injury or potential injury.

- Pain signals are transmitted by small diameter peripheral nerve fibres (C and Aδ)

Front 162

Describe acute vs chronic pain

Back 162

- Acute pain usually has sudden onset with an obvious cause.

- Many chronic pain states are associated with hyperalgesia (heightened sensitivity of pain) or allodynia (stimuli that would not normally be perceived as painful is perceived as painful – response to non noxious stimuli)

Front 163

What is Nociceptive Pain

Back 163

Nociceptive pain arises from stimulation of nociceptors by injury, inflammation ordisease.

- Somatic nociceptive pain originates in the skin, bones/joints, mucosalsurfaces. Usually well-localised; can be described as sharp/stabbing/shooting.

- Visceral nociceptive pain originates in visceral organs (eg liver). Usually amore diffuse/aching pain that can be accompanied bynausea/vomiting/sweating. Can be referred from other areas in the body.

- C fibres (unmyelinated) tend to transmit diffuse/dull/aching pain; Aδ fibres(myelinated) tend to transmit localised/fast/transient pain.

Front 164

What is Neurogenic Pain

Back 164

Neurogenic pain arises from dysfunction in the peripheral or central nervous system due to injury or disease (eg phantom limb pain, diabetic neuropathy, spinal cord injury).

- Often associated with parasthesia, hyperalgesia, allodynia.

- Tends to respond poorly to NSAIDs and opioid analgesics; adjuncts often required.

- Hard to treat pharmacologically

Front 165

What is specific pain?

Back 165

Generally predictable

- Psychogenic pain can be due to psychiatric, psychological and/or psychosocial causes

- Distressing despite the lack of obvious somatic source

- Pharmacotherapy alone rarely provides relief.

- Breakthrough pain (incident pain) can occur in patients with chronic pain between regular analgesic administration.

- Postoperative pain

Front 166

How do we assess pain?

Back 166

- Assessment involves severity, time course, extent, associations, effects.

- Pain scales can be useful as a gauge over time

- Children can be harder to assess - face pain scales can help them visually interpret their pain

Front 167

How do we treat pain?

Back 167

–Treat cause in preference to symptoms

–Use accurate assessment to ensure appropriate analgesic prescription/use

–Keep ‘pain-free’. Sufficient analgesic to prevent pain

–Prevent adverse effects (eg of opioids) rather than treating upon occurrence

–Avoid under-treatment –Stepwise management

Front 168

Describe Paracetamol

Back 168

- analgesic and antipyretic

- less GIT irritation, allergic reactions rare - however can have fatal effects at larger doses (liver/kidney damage)

- Thought to reduce pain by inhibition of COX in the CNS.

- Combination therapy of NSAIDS and paracetamol is advantageous as it allows you toobtain the same amount of analgesic effect with lower doses. This allows you toreduce the risk of dose related adverse effects

Front 169

How is paracetamol metabolised?

Back 169

- Metabolism reactions are intended to make the drug more water soluble to facilitate excretion from the body. The different pathways are subject to saturation (wherethere enzyme/substrates are overwhelmed by the amount of drug present and cantmetabolise all of it)

- Paracetamol is processed down an alternate metabolic pathway. This requirescofactors such as glutathione, to allow it to be excreted. When the glutathionesupply is exhausted, paracetamol is then metabolised down another pathway thatleads to lipid peroxidisation, reactive oxygen species production and hepatocyte celldeath.

- Alternate pathway req. glutathione to be excreted

- Supplies are limited so when stores are exhausted, derivates are metabolised down a pathway that can lead to liver cell death

- If found acutely, there are options for treatment to neutralise/help with the excretion of paracetamol

Front 170

Describe opioid mechanism of action

Back 170

Opioids act at opioid receptors – GPCRs that reduce cAMP production

Three main subtypes

– mu (μ), MOR – most effects via.

– kappa (κ), KOR

– delta (δ), DOR

- Different effects at different receptor subtypes. Degree of analgesia and GIT effects via all three receptors.

- Different types have different localisations and distributions

- Constipation get drugs, also respiratory depression

Front 171

What are endogenous opioids?

Back 171

Endogenous opioids include endorphins (family of endogenous analgesics that act at opioid receptors) and enkephalins

Physiological role

–Endogenous analgesics

–Regulation of intestinal motility

–“feel good” hormones / “endorphin rush”

Pharmacology

–Rapidly metabolised, not absorbed from GIT, won’t pass through BBB, not useful as therapeutics

Front 172

Describe Opioid Analgesics

Back 172

- Opioid analgesics bind to and activate opioid receptors (peripherally and centrally)to produce analgesia (primary clinical use).

- Variety of administration routes/dosage forms; generally opioids are poorlyabsorbed orally with low bioavailability due to first-pass metabolism.

MOA - Activation of opioid receptors produces analgesia by inhibiting transmission through the spinal cord and activating descending inhibitory pathways. Inhibition of afferents in the periphery.

Front 173

Describe Morphine

Back 173

Morphine remains the prototypical opioid analgesic to which all others are compared.

Agonist at MOR.

Clinical effects include analgesia, sedation, euphoria, cough suppression. Used in the treatment of moderate to severe pain.

AEs include reduced GIT motility (constipation common), nausea/vomiting, respiratory depression

High first-pass metabolism and low bioavailability

Front 174

Describe Codeine

Back 174

Codeine is used for the treatment of mild pain, and as a cough suppressant.

Codeine is a prodrug – metabolised to morphine by CYP2D6 –Variability in response based on genetics

Codeine has minimal euphoric activity; constipation is a common AE.

Fentanyl is a highly potent opioid used for moderate to severe pain, as an adjunct analgesic in general anaesthesia and for breakthrough pain (especially in cancer patients).

Various formulations (SM/IV, patch, ‘lollipop’).

Front 175

What is drug tolerance

Back 175

Drug tolerance occurs when the effectiveness of the drug diminishes over time/repeated administration. Higher doses of the drug will be required to produce the same effect.

Front 176

What is dependence?

Back 176

Dependence has multiple components

–Physical (development of tolerance). Withdrawal symptoms when ceasing drug administration; reversed by re- administration.

–Psychological (craving). Less evident in patients receiving opioids for analgesia.

Withdrawal symptoms for opioids include anxiety and agitation, shivered and sweating, diarrhoea.

Precipitate withdrawal symptoms when drug use is ceased

Front 177

What do opioid receptor antagonists do?

Back 177

Opioid receptor antagonists reverse the effects of opioid receptor agonists (eg respiratory depression).

–Binds all three opioid receptors subtypes; higher affinity for MOR.

–Mostly used for treatment of overdose, parenteral administration.

Front 178

What is Tramadol

Back 178

• Tramadol is an agonist at MOR but also inhibits re-uptake of serotonin and noradrenaline

- Antidepressant as it inhibits the reuptake of serotonin

Front 179

What are the analgesics of choice during pregnancy?

Back 179

Paracetamol and Codeine

(NSAIDS - adverse fetal effects, prolongs gestation and labour)

(opioid use can leas to physical dependence in fetus)

Front 180

What is the analgesic of choice for children?

Back 180

Paracetamol

Front 181

What needs to be considered prior to analgesic use in the elderly?

Back 181

–Impaired liver/kidney function may slow metabolism/excretion. Dosage adjustment may be required

- May have reduced tolerance of adverse effects

-Presence of co-morbiditie. May alter drug responsiveness -> Polypharmacy

- NSAIDs in particular require care due to GIT/renal/CV adverse effects.

Front 182

Briefly describe the endocrine system

Back 182

System composed of specialised glands

Glands secrete hormones that act on specific targets

Integrates and regulates body functions

Disruptions in these systems result in pathological conditions

Front 183

What is a hormone

Back 183

A hormone is a chemical mediator secreted by a cell into the bloodstream where it is transported to a distant target cell and exerts effects at low concentrations.

Hormones act by binding to receptors in the target cell. These receptors can be intracellular or located at the cell surface

Front 184

List the 3 Chemical classes of hormones

Back 184

Peptides (insulin)

Amines (Catecholamines = Noradrenaline, adrenaline, dopamine)

(thyroid hormone

Steroid (mineralcorticoid, glucocorticoids)

(oestrogen)

Front 185

How are peptide hormones produced?

Back 185

Many peptide hormones are produced as inactive precursors, and require furtherprocessing to produce the active molecule

Front 186

How are amine hormones produced?

Back 186

*CHECK PP NOTES*

Front 187

How are steroid hormones produced?

Back 187

Produced by the parent hormone cholesterol

In the adrenal cortex – aldosterone and cortisol

In the ovary – estradiol

*CHECK PP NOTES*

Front 188

How do hormones act?

Back 188

Peptide and amine hormones cannot enter the cell, and therefore must interact with cell surface receptors

The downstream signalling mechanisms will vary depending on the receptor.

Steroid hormones are lipophilic

They act predominantly at intracellular receptors to alter gene transcription

Front 189

what are the 3 types of stimuli for hormone release?

Back 189

Humoral. Hormone release is triggered (or supressed) depending on theblood concentrations of particular ions or nutrients. (eg. glucose and insulin)

2. Neural. Hormone release is controlled by neural input.

3. Hormonal. Hormone release is caused by another hormone. A hormone that controls the release of another hormone is known as a trophic hormone.

Front 190

List the endocrine and exocrine functions of the pancreas

Back 190

Endocrine functions

islets of Langerhans

–subpopulation of cells

–secrete hormones

Exocrine functions

–involved in digestion

–secrete digestive enzymes

Front 191

Describe Insulin

Back 191

- Polypeptide hormone

- Secreted from β cells in response to increased blood glucose

- Decreases blood glucose levels by increasing glucose uptake into muscle and fat cells

- Regulates metabolism of

-carbohydrates

-fats

-proteins

Front 192

Define Glycolysis, Glycogenesis, Glycogenolysis and Gluconeogenesis

Back 192

Glycolysis - glucose metabolism

- the oxidation metabolism of glucose molecules to obtain ATP andpyruvate

- Pyruvate from glycolysis enters the Krebs cycle

Glycogenesis - glucose storage

- the conversion of excess glucose into glycogen as a cellular storagemechanism

Glycogenolysis - glucose release from stores

- the breakdown of glycogen into glucose, which provides a glucose supply for glucose-dependent tissues

Gluconeogenesis - glucose formation

- de novo synthesis of glucose molecules from simple organic compoundseg. the conversion of amino acids in cellular protein to glucose

Front 193

Describe how insulin is released.

Back 193

Low glucose = decreases metabolism and low ATP production.

- K+ channel then opens; Channel closes when ATP level is high

- When the channels closed it means that K+ is retained in the cell.

- This depolarises the membrane potential/cell. This triggers voltage activated calcium channels, whichacts as an intracellular signal and triggers exocytosis which will lead to the secretionof insulin

- Increases in glucose levels stimulate insulin secretion from pancreatic β cells

Front 194

What are the actions/causes of insulin

Back 194

↑ Glycolysis (glucose metabolism)

↑ Glycogenesis (glucose storage)

↓ Glycogenolysis (glucose release from stores)

↓ Gluconeogenesis (glucose formation)

All of these act to reduce blood glucose levels

Front 195

Describe type 1 and type 2 diabetes

Back 195

Type1 –autoimmune destruction of pancreatic beta cells

–insulin deficiency

–also known as: § –juvenile onset§ –insulin-dependent (IDDM)

Type2 –insulin resistance

–also known as § –mature onset § –non insulin-dependent (NIDDM)

Front 196

What are the adverse effects of insulin

Back 196

Rare with human insulin

Hypoglycaemia is most common

–Anxiety

–Cold sweating, pallor

–Shakiness, weakness

–Drowsiness, headache, nausea, confusion

If severe may result in:

–coma

–brain damage

Treatment:

–sweet drink/snack

- intravenous glucose (patient unconscious)

–glucagon

Front 197

For which type of diabetes are oral hypoglycaemic agents used? Why?

Back 197

Only useful in T2DM, as they require residual insulin secretion from the pancreas

However, many patients with T2DM will require additional treatment with insulins

(metformin, sulphonureas, thiazolidinediones, incretin enhancers)

Front 198

Describe Metformin

Back 198

Metformin is usually first-line OHA

MOA not completely understood

Increases glucose uptake and use

Reduces gluconeogenesis

Improves insulin sensitivity and blood lipids

Doesn’t affect insulin release (hypoglycaemia unlikely)

Major AEs primarily GI related

Front 199

Describe Suplhonureas

Back 199

Sulphonylureas – requires residual insulin secretion – function – as Sulphonylureas such as glibenclamide stimulate insulin secretion

MOA involves inhibition of ATP-sensitive potassium channels

Blockade of K+ channels causes depolarization and insulin secretion (requires functioning β cells)

AEs include hypoglycaemia (taken with food; care with alcohol consumption required)

Front 200

Describe Thiazolidindiones

Back 200

Thiazolidinediones (‘glitazones’) such as pioglitazone and rosiglitazone increaseinsulin sensitivity

Activate PPAR nuclear receptors that regulate expression of genes in glucoseand lipid metabolism.

AEs include peripheral oedema, dizziness, fractures (rare).

Front 201

Describe Incretin Enhancers

Back 201

Incretin – peptides – that are broken down and inactivated by peptidases

If you inhibit breakdown of incretin, you end up with higher levels of incretin and stimulate insulin secretion

Incretins are peptides released from the GIT and increase insulin release

DPP-4 is a peptidase that inactivates incretins

‘Gliptins’ such as sitagliptin are DPP-4 inhibitors. They increase the concentration of incretins and therefore increase insulin secretion

AEs include hypoglycaemia, headache and musculoskeletal pain

Front 202

How is hormone release controlled?

Back 202

- Hypothalamus releases inhibitory or secretory factors onto the pituitary.

- Anterior pituitary releases tropic hormones

- Tropic hormones act on target gland

- Increase hormone levels in the blood, send signal to Ant. Pituitary and hypothalamus, then the signal can be turned off

- Secretion of hormones is regulated by various feedback loops. Often the hormones themselves are the feedback signal. Each hormone in the pathway canfeed back to suppress hormone secretion by acting earlier in the pathway.Feedback can be long-loop or shortloop.

Front 203

Describe the pituitary gland

Back 203

The pituitary gland is located below the hypothalamus and is divided into two parts; the anterior and posterior lobes. The anterior lobe is considered the ‘true; endocrine gland as it is derived from epithelial tissue. It secretes the majority of the glands hormones. The posterior lobe is anatomically an extension of the neural tissue of the hypothalamus. It secretes 2 hormones: ADH and Oxytocin.

Front 204

List hormones released by the anterior and posterior pituitary

Back 204

Anterior

- ACTH (regulated production of corticoids

- Growth hormone

Posterior

- vasopressin/ADH (regulate water balance, inhibits diuresis)

- oxytocin (muscles in uterus)

Front 205

How are adrenal hormones regulated?

Back 205

- Increased levels of corticosteroids suppress the hypothalamic-pituitary axis andinhibit glucocorticoid release

- This is a major adverse effect for the chronic use of corticosteroid drugs

- HPA function can take a long time to recover after extended corticosteroid therapy

- Sudden withdrawal can be hazardous; tapering of dose is recommended

Front 206

What is primary hyper secretion

**

Back 206

An increase in cortisol will feedback and suppress CRH and ACTH

Low levels of upstream hormones

The adrenal gland doesn't respond to the anterior pituitary

Front 207

Describe hypothyroidism

Back 207

Can be due to autoimmune, iodine deficiencies, radiation therapy

Clinical signs include bradycardia, fatigue, infertility, lethargy, cold intolerance, weight gain

Can be primary (dysfunction of thyroid gland: low T3, T4; high TSH) or secondary/tertiary

Treated with T4 replacement; AEs usually correspond to hyperthyroidism

Front 208

describe hyperthyroidism

Back 208

Excessive thyroid hormone production = thyrotoxicosis

Primary hyperthyroidism characterised by elevated T3/T4 despite decreased TSH

Clinical features include bulging eyes, intolerance to heat, ↑appetite, weight loss, nervousness and irritability, diarrhoea

Treatment options include: Anti-thyroid drugs that inhibit thyroid hormone synthesis –Iodine(suppresses TRH/TSH in large doses); Surgery; Radioactivity iodine therapy

Front 209

Describe the function of FSH and LH

Back 209

FSH = follicle stimulating hormone

–Stimulates follicles in preparation for ovulation

–Development of seminiferous tubules and spermatogenesis

LH = Luteinising hormone (aka ICSH = interstitial cell stimulating hormone)

–Promotes maturation of the follicle and formation of corpus lute

–Stimulates spermatogenesis

–Formation of androgens

FSH and LH control the menstrual cycle and stimulate the release of oestrogen and progesterone

Front 210

Describe the follicular/luteal cycle

Back 210

- A portion of primary follicles are beginning to develop throughout thecycle, however development beyond the early stages only occurs duringthe follicular phase.

- Follicles that have developed sufficiently to respond to FSH are recruitedwhen FSH levels rise.

- Recruited follicles undergo rapid enlargement and development, andbegin producing oestrogen.

- The ‘dominant’ follicle that develops into a mature follicle usually hasthe most FSH receptors. - Follicle rupture is facilitated by enzymes that digest the connectivetissue in the follicular wall.

- Developing follicles that failed to reach maturation degenerate.

Front 211

Describe Oral Contraceptives

Back 211

-Provides exogenous hormones

-Exploit the negative feedback mechanisms and suppress the production of FSH and LH from the anterior pituitary

-Prevents the development of the follicle (FSH) and prevents ovulation (LH)

-Additional effects: thicken cervical mucous – increase the physical barrier

- Adverse effects: menstrual related and emotional, fluid retention, weight gain o Increase the chance of thrombotic events

Front 212

How does the combined oral contraceptive work?

Back 212

The combined oral contraceptive (COC) pill is extremely effective and commonly used to prevent pregnancy

Combination of an oestrogen (usuallyethinylestradiol) and a progestogen

Oestrogen acts via negative feedback on theanterior pituitary to suppress FSH release and follicle development

Progestogeninhibits LH surge and ovulation; also thicken cervical mucus

Also alter theendometrium to reduce susceptibility to implantation

Front 213

How does the Progesterone only contraceptives work?

Back 213

Progestogen-only contraceptives thicken cervical mucus and alter endometrium

Suppress LH surge, may inhibit ovulation –Variability based on route ofadministration; oral forms suppress ovulation in < 50% of women; depot andimplant reliably suppress ovulation (AMH 2016).

Preferred contraceptivesduring breast-feeding as no effect on lactation; safer in women with CV riskfactors (vs COC)

Can be administered by depot injection or implant

High oral dose can be used foremergency contraception within 72 (preferably) to 96 hours

Front 214

What is Mifepristone and how does it work?

Back 214

- Block the action of endogenous progesterone

- Partial agonist at progestogen receptors

–Blocks action of endogenousprogesterone

–Breakdown of the uterine lining

–Cervical softening anddilatation

–Release of prostaglandins

–↑contractile effects of prostaglandin

Used in combination with a prostaglandin (eg misoprostol) to terminatepregnancy in the first or second trimester

Front 215

Describe hormone replacement therapy

Back 215

- Daily low doses of oestrogen or oestrogen combined with progesterone.

- Treat the symptoms of menopause (hot flushes, nausea, insomnia, vaginitis, palpitations, fatigue, depression) – due to decreased oestrogen

-Provide symptomatic relief

-Prevent complications of post menopause (osteoporosis)

Front 216

What are the symptoms of schizophrenia

Back 216

Positive symptoms

–Auditory hallucinations

–Delusions (often paranoid)

–Abnormal experiences (wild trains of thought, irrational conclusions)

Negative symptoms

–Loss of motivation

–Lack of self-care

–Social withdrawal

–Blunted (flat) mood (anhedonia)

–Diminished speech

Cognitive function

–Deficits in executive (planning) function

–Deficits in attention

–Deficits in working memory

Front 217

Describe the aetiology of schizophrenia

Back 217

Genetic

- It appears that multiple “susceptibility genes” are involved in creating apredisposition to develop the disorder. There is an increased risk ofsuffering from schizophrenia if a sibling or a parent has a schizophrenicdisorder.

Environmental

- Perinatal complications: maternal complications, nutritional inadequacy, urban birth Stressful life events, drug abuse

Front 218

Describe the pathology of schizophrenia

Back 218

- Increased ventricles

- Decreased hippocampus size

- Hypofrontality - lower metabolic activity in the frontal regions of the brain

- Decreased neuronal #, and disorientation and abnormal grouping of neurons

Front 219

What are typical antipsychotics?

Back 219

- Typical antipsychotics are effective in alleviating positive symptoms (hallucinations and delusions) in a proportion of patients with schizophrenia.

- Typical antipsychotics have high affinity for dopamine receptors

- AE - extrapyramidal symptoms (acute parkinsonian symptoms = rigidity, akinesia, akathisia (restlessness) dystonia, and chronic, usually delayed onset, tar dive dyskinesia

Antidopaminergic effects (through the tuberoinfundibular system) • -hyperprolactinaemia, galactorrhea, sexual dysfunction

Anticholinergic effects -dry mouth, blurred vision, constipation, urinary retention

Antiadrenergic effects • -sedation, hypotension

Anti-histamine Anti-serotonin • -weight gain, sedation

Front 220

What are atypical antipsychotics?

Back 220

eg. Clozapine

- Affinity for D2 and 5HT2A receptors

- Treats positive symptoms and negative symptoms

- Very low incident EPS

- Side effects include constipation, drooling, muscle stiffness, sedation, tremors and weight gain

- Principally used in treating treatment-resistant schizophrenia

Front 221

What is depression

Back 221

One or more distinct periods with dysphoric mood or pervasive loss of interest or pleasure.

1. Increase or decrease in appetite or weight.

2. Excessive or insufficient sleep

3. Low energy, tiredness, fatigued Pharmacology and Toxicology

4. Psychomotor agitation or retardation

5. Loss of interest or pleasure in usual activities

6. Feelings of self-reproach, guilt

7. Decreased ability to think or concentrate

8. Recurrent thoughts of death or suicide

Duration of features for at least 2 weeks.

Front 222

What are the 2 causes of depression

Back 222

Exogenous (reactive)

- Life events that may cause a depressed mood such as bereavement,employment issues, relationship problems

- Medications (e.g.contraceptives, statins)

- Non-psychiatric illness (e.g. chronic pain,cardiovascular disease, Parkinson’s disease)

Endogenous

- Absence of external causes

Front 223

Describe the neuroplasticity theory of depression

Back 223

Neuroplasticity is the changing of neurons and the organization of their networks, and so their function, by experience. Some brain structures (e.g. thehippocampus and prefrontal cortex) are reduced in size in depressive disorder.Neuronal loss is also observed in these regions. There is evidence that someantidepressant medications promote neurogenesis.

Front 224

Describe the genetic theory of depression

Back 224

Stressful life events can influence the onset and course of depression However not all people who encounter a stressful life experience succumb to itsdepressogenic effect. Predisposition stress theories of depression predict thatindividuals' sensitivity to stressful events depends on their genetic makeup

Front 225

Describe the Monoamine theory of depression

Back 225

- Suggests that clinical depression results from low levels of the monoamines, serotonin and noradrenaline, in the brain. All antidepressants raise levels of these two neurotransmitters.

- Many areas of the brain appear to be involved in depression. However, it is not clear if the changes in these areas cause depression or if the disturbance occurs as a result of the aetiology of psychiatric disorders.

Front 226

Describe the classes of antidepressants

Back 226

Tricyclic Antidepressants- inhibit the reuptake of NA and serotonin into presynaptic terminals

(AE - sedation, dry mouth, constipation = likely due to blocking cholinergic receptors)

MAOi - MAOA inhibitors bind to and inhibit MAOA, preventing monoamine degradation.

(AE - postural hypotension, occasional psychosis, tremor, sexual dysfunction, anticholinergic effect)

Selective Serotonin/Noradrenaline Reuptake inhibitors (SSRIs/SNRIs) (fluoxetine)

- restore the levels of 5-HT in the synaptic cleft by binding at the 5-HT re-uptake transporter preventing the re-uptake and subsequent degradation of 5-HT

(AE - emergent anxiety and dizziness (5-HT2), nausea, headaches (5-HT3), sexual dysfunction (5-HT2), hypertension

Front 227

What are anticholinergic effects

Back 227

Sedation, blurred vision, urinary retention, constipation, dry mouth

Front 228

Describe bipolar disorder

Back 228

The affected person jumps between states of mania, depression and normalmood.

(Mania - inflated self esteem, decreased sleep, unusual talkativeness, racing thoughts, distractibility, increased goal directed activity, unusual activity = have a high potential for painful consequences)

Front 229

What is Lithium used in treatment for?

Back 229

Lithium salts are mood stabilizers used in the treatment of bipolar disorder since, unlike most other mood altering drugs, they counteract both mania and depression.

MOA - Inhibition dopamine release –Enhancement serotonin release –Decreased formation of second messengers

AE - nausea, vomiting, diarrhoea, weight gain, fatigue, tremor, headache, polyuria

Toxicity - very dangerous; early signs = exacerbation of normal AEs

Later signs - coarse tremor, ataxia, poor coordination, confusion, disorientation, convulsions, coma, death

Front 230

Describe the polypharmacy for bipolar disorder

Back 230

Patients are not just on one type of medication:

- mood stabilizers for aggression and violence

- benzodiazepines for agitation, anxiety, and insomnia

- antipsychotics for psychosis

Front 231

Describe anxiety

Back 231

Feelings of apprehension, agitation, uncertainty and fear

Extreme -> autonomic responses including rapid heart rate, dry mouth, sweatypalms, insomnia, loss of appetite, muscle tremor, diarrhoea

- subjective responses include feelings of fear, nervousness, excessiveworry

- escape behaviour, avoidance behaviour, freezing

Front 232

What are anxiolytics used for?

Back 232

Anxiety disorders

Sleep disorders

Seizure disorders

Pre operative medication

Muscle spasms

CNS depressant withdrawal

Front 233

Describe benzodiazepines

Back 233

Most widely used anxiolytics and hypnotics

MOA - Bind to distinct ‘benzodiazepine regulatory sites’ on GABAA receptors - Increase receptors affinity for GABA, and thus enhance the neuroinhibitory actions of GABA

Children - More sensitive to CNS depressant drugs •BNZ only really used for night terrors and sleep walking

Elderly - Usually take a variety of medications so there could be druginteractions, altered pharmacokinetics; Risk of falls due to increased sensitivity to CNS effects

Front 234

Describe Beta Blockers

Back 234

β-adrenoceptor antagonists e.g. propanolol

Reduce peripheral manifestations of anxiety such as tremor, sweating and tachycardia

No effect on the CNS

Front 235

Depression is a progressive neurodegenerative disorder characterised by what?

Back 235

- Chronic personality disintegration

- Confusion

- Deterioration of mental capacity

Front 236

Describe how dementia occurs.

(features observed)

Back 236

- Plaques develop in the brain – clumps of protein – contain amyloid

- Stop neurones from talking to each other

- Fibrous tangles (aggregates of Tau) don't know what causes it or what comes first

- Separation of the meninges and shrinkage of the cerebral cortex as the brain degenerates

- Shrinkage of the hippocampus (memory) bilateral holes in the brain

- Evidence of increased Alzheimer's disease and plaque development in the obese population

- Changes in acetylcholine – important in memory

Front 237

List the cognitive deficits present in Alzheimers

Back 237

- memory impairment

- Aphasia - problems with language (receptive and expressive)

- Apraxia - inability to carry out purposeful movements even though there is no motor or sensory impairment

- Agnosia - failure to recognise, especially people

(decreased need for sleep)

Front 238

In patients with Alzheimers, what deficits are seen in the cortex and hippocampus?

Back 238

1. Choline acetyltransferase activity (ChAT)

2. Acetylcholine content

3. Choline transport

4. Nicotinic Acetylcholine receptors

Front 239

Describe the treatments for Alzheimers

Back 239

Acetylcholinesterase inhibitors

- donepezil, galantamine, rivals timing

- Efficacy: some improvement of cognition in mild cases

- Side effects: nausea and vomiting

NMDA antagonist

- Memantine

- Glutamate antagonist

- Treatment of moderate to severe cases

- Efficacy: moderately efficacious in the treatment of moderate to severe

- Side effects: CNS effects - confusion, dizziness, drowsiness

Polypharmacy

- Often patients are not just on one type of medication:

- antidepressants for depression or obsessive-compulsive symptoms,

- mood stabilizers for aggression and violence

- benzodiazepines for agitation, anxiety, and insomnia

- antipsychotics for psychosis

Front 240

Describe Parkinsons Disease and the symptoms

Back 240

- Progressive debilitating disorder

- Occurs between 50 and 80 years

- Dopamine-deficient state of the extrapyramidal motor system,particularly a loss of dopaminergic neurons in the nigrostriatalpathway Decrease in dopamine (inhibitory) leading to adopamine/acetylcholine (excitatory) imbalance

- Tremors at rest Bradykinesia – slowing of all voluntary movements

- Forward flexion of the trunk

- Muscle rigidity

Front 241

Describe Levodopa and how it treats Parkinsons

Back 241

- Decarboxylated to dopamine within surviving nigrostriatal fibres or in other monaminergic neurons to provide some restoration of nigrostriatal activity.

- Prescribed with carbidopa (a dopamine decarboxylase inhibitor which decreases the production of dopamine in the periphery and reduces levodopa dosage)

- Tries to make dopamine from the receptors that are still there but there isn't any improvement in the condition of the Brain; however over time the neurones degrade/degenerate

Pro - improves the slowness of movement, rigidity and tremor

AE - Anxiety, dyskinesias, confusion, hypotension, moodchanges, nausea, Effectiveness wears off after chronic use, chronic use = other movement alterations unrelated to Parkinsons

Interactions: –Anticonvulsants and neuroleptics (decreaselevodopa effects by increasing metabolism) –Antihypertensives (increased risk hypotension) –MAO-A inhibitors (hypertensive crisis)

Front 242

Describe the other therapeutics used for Parkinsons

Back 242

Dopamine agonists (Pramipexole, Apomorphine, Pergolide)

- improve motor function and improve the off time (when dopamine stops working)

- Similar AE to L-Dopa

Selegiline

- Selectively Blocks MAO-B - prevents dopamine from being degraded resulting in more dopamine

AE - metabolised to amphetamine ->excitement, anxiety and insomnia

Entacapone

- blocks COMT, doesn't cross the BBB

- prevents the breakdown of L-Dopa

- AE - dyskinesia (^ voluntary movement) and some GIT problems

Front 243

Describe epilepsy

Back 243

- Group of chronic disorders characterised by sporadic recurrent episodes of convulsive seizures

- Seizures associate with episodic high-frequency discharge by a group of neurones in the brain

- Site of primary discharge (focus) and extent of spread determine kind of seizure

- There are around 40 different types of seizures.

- Abnormal activity during and following a seizure can be detected by electroencephalogram (EEG) recordings

Front 244

Describe the different types of seizures

Back 244

Simple Partial

- no loss of awareness

- motor symptoms, altered hearing, smell, taste, sight, tactile perception

- laboured speech/ inability to speak

Complex Partial

- change in awareness/behaviour

- Sudden and inexplainable feelings of fear, anger, sadness, happiness or nausea

- Aura, automatism (chewing, swallowing movements)

- Motor symptoms

Tonic Clonic

- contracture of the whole musculature causing spasm followed by a series of violent synchronous jerks

- Respiration stops; defecation, urination, salivation occurs, Face becomes blue (important clinical symptom) Patient can stayunconscious for a few minutes followed by recovery

EEG = continuous high frequency activity in tonic phase, intermittent discharge in clonic phase

Absence

- everything stops abruptly – unaware, stare vacantly – then recover abruptly

- children

- EEG - rhythmic discharge

Status Epilepticus

- continuous seizure, longer than 30mins or 2 consecutive without recovery of consciousness

- In humans sustained seizures can cause selective neuronal loss invulnerable regions (eg. hippocampus and cortex)

- The extent of the neuronal injury is closely related to the duration ofthe seizure, therefore Status Epilepticus requires rapid control

(Drug overdose, low glucose, head trauma)

Front 245

Describe pharmacological treatment for epilepsy

(Sodium Channel inhibition)

Back 245

Carbamazepine

MOA - –Prevents repetitive neuronal discharge by blocking voltagedependent and use-dependent sodium channels. This stops it from returning to resting stage ad prevents the generation of action potentials = reduced membrane excitability

Indication - simple and complex patrol, tonic-clonic

AE - –Drowsiness, ataxia, dizziness, blurred vision,nausea, vomiting, rash, dry mouth

Pharmacokinetics - absorbed orally, t1/2 of 30hrs, mainly metabolised by the liver by CYP3A4

Interactions - oral contraceptives, anticonvulsants, warfarin, antipsychotics, corticosteroids, benzodiazepines

- interacts with grapefruit, affects the plasma

Phenytoin

MOA - –Prevents repetitive neuronal discharge by blocking voltagedependent and use-dependent sodium channels. This stops it from returning to resting stage ad prevents the generation of action potentials = reduced membrane excitability

Indication - simple and complex partial, tonic-clonic, status epilepticus

AE - –Nausea, vomiting, insomnia, agitation, sedation, ataxia, confusion, behavioral disturbances, teratogenic

Pharmacokinetics - absorbed orally, mainly metabolised by the liver by CYP3A4

Interactions - lowers blood concentration of anti-epileptics, chronic alcohol abuse lowers phenytoin concentration

- diabetes = increases risk of hyperglycaemia

Front 246

Describe pharmacological treatment for epilepsy(Calcium Channel and GABA inhibition)

Back 246

Calcium Channel

Ethosuximide

MOA - Reduces low threshold voltage-dependent calcium conductance in neurons

Indications - absence seizures

AE - Anorexia, nausea, vomiting, drowsiness, ataxia

Pharmacokinetics - well absorbed orally, t1/2 60hrs

Interactions - other anti-epileptic drugs (valproate)

GABA

Benzodiazepines

MOA - Potentiates the inhibitory effects of GABAacting on GABAa receptors

Indications - all seizures including status epileptics and febrile

AE - Main side effect is sedation, however may also include memory loss, ataxia

Pharmacokinetics - generally not suited for long term use due to sedative and tolerance effects

Valproate

MOA - Makes GABA more available by inhibiting the GABE transaminase

Indications - generalised and partial seizures

AE - Nausea, vomiting, increased appetite (weight gain), ataxia, baldness,teratogen, liver damage

Pharmacokinetics - well absorbed orally, t1/2 15hrs; metabolised by P450 enzymes,

-teratogen

Interactions - clearance impaired by aspirin, caffeine and antibiotics (lead to increased toxicity, hepatotoxicity)

Gabapentin

- Used with other drugs to treat Partial and some generalised seizures

- Few lasting side effects, some sleepiness and dizziness

Elderly - Interactions with warfarin, anti-hypertensive, anti-depressants; Ageing population hepatic and renal systems may be reduced

Pregnancy - Several anti-epileptics induce hepatic enzyme CYP3A4 (increaseoral contraceptive metabolism); Teratogenic effects are produced; Risk benefit assessment

Front 247

Describe ADHD

Back 247

- People with ADHD show a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development

Genetics - twin studies show heritability

Environment - Low birth weight, maternal infection, premature birth

Pathology

- General reduction of brain volume

- Significant global thinning of the cortex, corpus callosum volumetric reductions

- Frontal lobe dysfunction

- Reported abnormalities in the functioning of dopaminergic, adrenergic, serotoninergic and cholinergic pathways

Front 248

Describe ADHD Treatment

Back 248

Methylphenidate (ritalin)

Noradrenaline and dopamine reuptake inhibitor

- Psychostimulant

- Stimulates the release of dopamine and noradrenaline into the synapse

- Increases or maintains alertness, improves attention

- Stimulate brain changes involved in learning and memory

- Side effects: nausea, loss of appetite, anxiety, insomnia, irritability, drymouth, tachycardia, palpitations, tremor

Dextroamphetamine

- Psychostimulant o

- Enhances dopamine and noradrenaline neurotransmission

- Side effects: headache, nausea, loss of appetite, anxiety, insomnia, dry mouth, tachycardia, palpitations

Front 249

Describe Autism and Asbergers

Back 249

- No medication recommendations listed in the AMH

- antidepressants may be prescribed for anxiety

- antipsychotics to treat severe behavioural problems

- ADHD medications may be prescribed for hyperactivity

Front 250

What are the 4 forms of drug abuse?

Back 250

Experimental abuse - use drugs in an exploratory way, may accept or reject to take drug action

Recreational abuse - social contexts

Compulsive drug abuse - irrational abuse of drug

Polydrug abuse - depressants and stimulants

Front 251

list the stages of addiction

Back 251

1. acute reinforcement/social drug taking

2. escalating/compulsive use/binging

3. dependence

4. withdrawal

5. protracted withdrawal

6. recovery

(stages 4 and 6 can relapse back to stage 2)

Front 252

What are the 3 most important predictors of abuse in relation to personality?

Back 252

1. rebelliousness

2. tolerance of deviance

3. low school performance

Front 253

Describe the pharmacological aetiology of addiction

Back 253

- Drugs of abuse act on different chemicals/pathways in the brain, however they can cause certain common effects after both acute and chronic exposure

- Drugs are all acutely rewarding, but chronically in vulnerable individuals can lead to addiction

- All drugs upon withdrawal, produce similar negative emotional symptoms, a prolonger period of sensitisation toward drug related environmental cues

- this contributes to drug craving and relapse, even after long periods of abstinence

Front 254

What is the mesolimbic pathway important for?

Back 254

-memory

-motivating behaviours

Front 255

list different parts of the brain and what they play an important role in.

Back 255

Prefrontal cortex - decision making

Amygdala- emotion

Hippocampus - memory

Nucleus Accumbens - reward centre

Ventral tegmental area - dopamine tracts

Front 256

Describe the acute effects of alcohol

Back 256

- causes progressive and continuous depression from the forebrain to hindbrain (enhances GABAergic inhibition)

- vasodilation = hypothermia

- stimulation gastric juice and salivary secretions = vomiting

- lowers ADH = diuresis

- uncoordination = accidents/injury

- lowers blood sugar = possible seizures

- disinhibition, lack of emotional control, memory loss

Front 257

Describe the chronic effects of alcohol

Back 257

brain = dementia, korsakoffs syndrome, cerebellar degeneration

neurological = neuropathy

muscle = chronic myopathy (wasting of proximal limb muscles)

liver = cirrhosis

pancreas/GIT = abdominal pain, fat malabsorption, diabetes

CV system = hypertension, CVD

Malignancy = cancer of mouth, larynx, pharynx, oesophagus

foetal alcohol syndrome

Psyche = hallucinations, depression, anxiety