Acem Primary Pharmacology

Front 1

What is potency?

Back 1

the amount of drug required to produce an effect of given intensity.
Potency is measured by the ed50 which is the amount (dose) of drug required to produce 50% of the drug's maximal effect

Front 2

What is efficacy?

Back 2

measure of the maximum clinical respose to the drug regardless of dose

Front 3

What is the ec50?

Back 3

the dose at which 50% of people exhibit a quantified effect.

Front 4

What is td 50?

Back 4

The dose required to produce a toxic response in 50% of subjects (LD 50 has same definition but the toxic response is death)

Front 5

What is the therapeutic index?

Back 5

TD50/EC50 ratio

Front 6

Give examples of lipid soluble ligands that cross the membrane and act on intracellular receltors?

Back 6

steroids such as corticosteriods, sex steroids and vitamin D
These bind to the nucleus to stimulate transcription of genes and make new proteins- therefore the lag is 30 minutes to hours while the proteins are being made.
They persist in their effect over days when the agonist concentration goes to zero due to slow turnover of most enzymes and proteins

Front 7

Give examples of substances that trigger ligand gated ion channels?
How does this work?

Back 7

acetylcholine, gaba, excitatory amino acids
Receptor alters transmembrane conductance of ions and thereby alters electrical potential across the memebrane

Front 8

Describe the nicotinic acetylcholine receptor?

Back 8

pentamer made up of 5 polypeptide units (2 alpha, 2 beta, 1 gamma) which each cross the lipid bilayer 4 times and form a cylindrical structure. Binding of ach causes structural change that opens sodium channel. Occurs in milliseconds.

Front 9

Give examples of substances that bind to a transmembrane receptor that stimulates a tyrosine kinase.

Back 9

Insulin, PDGF, ANF

Front 10

How do tyrosine kinase receptors work in general?

Back 10

Receptor polypeptide consists of a hormone binding domain (extracellular) and an enzyme domain (cytoplasmic) which are connected through the membrane. Hormone binds with extracellular receptor, resulting conformational change that brings together the protein tyrosine kinase domains that become enzymatically active.

Front 11

What are the three mechanisms by which a drug/ligand binding to a transmembrane protein can cause change?

Back 11

1. The transmembrane receptor contains an ion channel which changes shape e.g. gaba, ach
2. The transmembrane receptor has a tyrosine kinase on the insidene.g. insulin, pdgf, anf
3. Transmembrane receptor stimulates a g-protein- the activated g-protein changes the activity of a receptor element (usually an enzyme or an ion channel)

Front 12

What is the advantage of signalling via g-proteins?

Back 12

Signalling via G proteins allows effect to persist long after the extracellular receptor has dissociated from its agonist molecule

Front 13

What do Gs G-proteins do?

Back 13

increase adenylyl cyclase, causing increased cAMP

Front 14

Give example of Gs G-proteins?

Back 14

Beta adrenergic amines, glucagons, histamine, serotonin.

Front 15

What do Gi G-proteins do?
Give examples of these?

Back 15

decrease adenylyl cyclase, causing decreased cAMP Open cardiac potassium channels causing decreased heart rate

Alpha2 adrenergic amines, acetylcholine (muscarinic only), opioids, serotonin

Front 16

What do Gold g-proteins do

Back 16

Stimulate adenylyl cyclase causing increased cAMP.
stimulated by odourants

Front 17

What do Gq G-proteins do?
Give examples of these?

Back 17

Increase adenylyl cyclase causing increased cAMP Increase phopholipase C resulting in increased IP3, diacylglycerol and cytoplasmic calcium.

Acetylcholine (muscarinic), serotonin

Front 18

What is the structure of g-protein coupled receptors?

Back 18

serpentine receptors- polypetide chains which cross the membrane 7 times.

Front 19

How does cAMP work?

Back 19

G protein stimulates membrane adenylyl cyclase that converts ATP to cAMP. cAMP exerts most effects by stimulating cAMP dependent protein kinases.

Front 20

How does calcium and phospholipase second messaging work?

Back 20

G protein stimulates membrane enzyme phospholipase that hydrolyses PIP2 to DAG and IP3. DAG is confined to the membrane and activates protein kinase C.

IP3 diffuses through the cytoplasm to trigger release of calcium from internal stores. Calcium binds to calmodulin, which regulates calcium dependent protein kinases.

Front 21

How are DAG and IP3 inactivated?

Back 21

DAG inactivated by phosphorylation back to phospholipid.
IP3 rapidly inactivated by dephophorylation.

Front 22

How does cGMP work?

Back 22

small role -mainly intestinal mucosa and vascular smooth muscle. G protein stimulates membrane guanylyl cyclase which converts GTP to cGMP. cGMP exerts most effects by stimulating cAMP dependent protein kinases.

Front 23

What is the volume of distribution?
What are the units?

Back 23

It relates the amount of drug in the body to its concentration in blood or plasma- depends what it is soluble in/binds to.
Vd=Amount of drug in body /concentration. Most commonly expressed in units of litres per kilogram

Front 24

Give an example of a drug that is distributed in the total body water?
What is the volume of distribution?

Back 24

ethanol and other small water soluble molecules
0.61L/kg (42L)

Front 25

Give an example if a drug that is distributed in the extracellular water?
What is the volume of distribution?

Back 25

Mannitol, gentamycin
larger water soluble molecules
0.2l/kg
14 L

Front 26

What is the volume of distribution of blood?

Back 26

0.08l/kg= 5.6L

Front 27

Give an example if a drug that is distributed in plasma? (and explain why it is largely confined to plasma)
What is the volume of distribution?

Back 27

Heparin
0.04l/kg
Bound to a plasma protein

Front 28

Give an example if a drug that is distributed in fat?
What is the volume of distribution?

Back 28

DDT (insecticide)
0.2-.35l/kg (14-24l)

Front 29

Give an example if a drug that is distributed in bone?
What is the volume of distribution?

Back 29

0.07l/kg
(4.9L)
lead and flouride

Front 30

What drugs cannot be removed by dialysis?

Back 30

drugs with large volumes of distribution

Front 31

Give examples of drugs with large volumes of distribution? (5-10L/kg)

Back 31

Antidepressants
Phenothiazines
Propanolol
Verapamil

Front 32

Give examples of drugs with small volumes of distribution? (<1l/kg)

Back 32

Theophylline
Salicylate
Phenobarbitone
Lithium
Phenytoin
Heparin
Warfarin

Front 33

What is the half life of a drug?

Back 33

Time required to change the amount of drug in the body by 1/2 during elimination or during a constant infusion
T1/2=0.7xVd / CL
Half life can refer to the drug itself or the active metabolites of the drug

Front 34

What is allosteric action?

Back 34

drugs that bind to the same receptor but do not prevent binding of the receptor molecule, may enhance or inhibit action

Front 35

How is the action of transmembrane receptors terminated?

Back 35

ligand binding often causes acellerated endoscytosis of reception followed by the degradation of the receptors and their bound ligands

Front 36

Why are volumes of distribution greater than actual volumes found in the human body?

Back 36

because it is the volume apparently necessary to contain the concentration found in blood, plasma or water
Drugs with very high volumes of distribution have much higher concentrations in the extravascular compartment then in the vascular compartment- i.e. not homogenously distributed.
Drugs that are completely retained within the vascular compartment have a minimum volume of distrubution

Front 37

What is drug clearance?

Back 37

Rate of elimination/concentration, this is additive when more than one organ clears it

i.e. CL(liver)= rate of elimination by liver/C

kidney generally excretes unchanged drug while liver metabolises

Front 38

What is the rate of elimination?

Back 38

CLx C when clearance is first order
calculated using the area under the time concentration curve (dose/AUC)

Front 39

When is rate of elimination not first order?

Back 39

capacity limited elimination e.g. phenytoin and ethanol, aspirin
also known as dose/concentration and saturatable elimination
cannot use auc to measure rate of elimination

rate of elimination = vmax x c/ km x c

Front 40

What is flow-dependent elimination?

Back 40

relevant for drugs that are cleared mainly on the first pass and therefore elimination depends on blood flow to the organ

Front 41

What is bioavailability?

Back 41

The fraction of the drug reaching the systemic circulation following administration by any route- IV has greatest bioavailability because it avoids first pass metabolism, extent of absorption (liphophilicity, reverse transporter associated with p glycoprotein)

Front 42

How do your calculate the dosing rate for a drug?

Back 42

CL x target concentration (TC)

Front 43

How do you calculate the maintenance dose?

Back 43

Drugs are usually administered in order to achieve a steady state where dosing equals elimination.
Dosing rate=CL X target concentration (TC)
Maintenance dose=dosing rate x dosing interval

Front 44

When is a loading dose needed?
How does one calculate the loading dose?

Back 44

Loading doses are required if the half-life of a drug is prolonged and the time taken to reach steady state would otherwise be prolonged

If the target concentration is known the clearance will determine the dosing rate
Loading dose=Vd X TC(target concentration)

Front 45

Give a formula for systemic clearance of a drug?

Back 45

Clearance can pertain to each organ and is additive in effect CLrenal+CLliver+CLother=CLsystemic.

Front 46

What is another work for capacity limited clearance?

Back 46

zero order kinetics

Front 47

Describe how zero order kinetics works?

Back 47

Drug elimination pathway becomes saturated at high concentration of drug. Elimination is proportional to concentration of the drug at low concentrations but at high concentrations elimination is constant.

e.g. Aspirin, Phenytoin, Ethanol

Front 48

What is first order clearance?

Back 48

First order clearance = clearance proportional to concentration

Front 49

What are some drugs that exhibit flow dependent elimination? Give 3 examples?

Back 49

Extraction is chiefly dependent on blood flow through the organ and the drug is almost completely extracted by the organ on first pass

Morphine Lignocaine Propanolol

Front 50

What are some limitations to drug absorption in the gut?

Back 50

Lipophilic (acyclovir) versus hydrophilic (atenolol) drugs
Bacterial metabolism within the gut (digoxin) Absorption abnormalities in small bowel.

Front 51

What is the extraction ratio?

Back 51

Extraction ratio defines the degree of first pass metabolism.
ER=CL liver /Q
(Q is hepatic blood flow = 90l/h)

Front 52

Where does first pass elimination occur?

Back 52

Can occur in gut wall, portal blood, or by excretion in bile. Most important is metabolism by liver.

Front 53

What is the formula for systemic bioavailability?

Back 53

Systemic bioavailability (F)
=extent of absorption (f) X (1-ER)

Front 54

How do you avoid hepatic first pass metabolism?

Back 54

Hepatic first pass metabolism can be avoided by sublingual, transdermal and to a lesser extent, rectal administration

Front 55

What is biotransformation?

Back 55

Biotransformation is the metabolism of drugs that allows for the renal excretion of lipophilic, un-ionised or partially ionised drugs that would otherwise fail to be effectively excreted and have a prolonged duration of action.

Biotransformation transforms a lipophilic molecule into a more polar and therefore more readily excretable product.

Front 56

Where does biotranformation occur

Back 56

Biotransformation can occur in GIT (eg clonazepam, penicillin), lungs, skin, kidneys, but most important site is liver.

Front 57

What are the two phases of biotransformation reactions?

Back 57

Phase 1 reactions Convert the parent drug to a more polar metabolite by introducing or unmasking a functional group such as OH, NH2, SH.

Phase 2 reactions The introduced functional group combines with an endogenous substrate to form a highly polar conjugate. Enzymes for phase 2 reactions may be located in microsomes or in the cytosol. Phase 2 reactions can sometimes precede phase 1 reactions.

Front 58

How do phase 1 reactions work?

Back 58

Phase 1 reactions utilise mixed function oxidases located on the ER of liver cells and other tissues.

Require oxygen and NADPH to function. Mixed function oxidases include NADPH-cytochrome P450 reductase and cytochrome P450.

Front 59

How many major CYP450 isoforms are there? What is the most important one?

Back 59

Different P450 isoforms are responsible for metabolism of different drugs. 7 main isoforms account for most metabolism. CYP3A4 is the largest component, responsible for 60% of clinically prescribed drugs metabolised by the liver.

Front 60

Where do phase 1 and 2 reactions occur?

Back 60

Whase 1 occur on the ER, Phase 2 occur in microsomes and the cytosol

Front 61

What are some genetic factors that affect biotransformation?

Back 61

Suxamethonium - genetic defect in
pseudocholinesterase, causes suxamethonium to remain active for prolonged periods. Other examples - oxidation of ethanol, acetylation of isoniazid

Front 62

What are some environmental factors that affect biotransformation?

Back 62

Enzymes may be induced or inhibited by environmental factors.
Charcoal - induction
grapefruit juice -inhibition of CYP3A4 (responsible for 60% of drug metabolism)

Front 63

What dies phenytoin do to digoxin metabolism?

Back 63

Phenytoin enhances digoxin metabolism

Front 64

What do barbituates do to warfarin metabolism?

Back 64

Barbiturates enhance warfarin metabolism

Front 65

The metabolism of what drugs does cimetidine affect?

Back 65

Cimetidine inhibits warfarin and diazepam metabolism

Front 66

The metabolism of what drugs is affected by cardiac disease?

Back 66

Cardiac disease can affect drugs that are flow-limited
e.g. Morphine, Verapamil

Front 67

What are the physical barriers to drug distribution? list 4

Back 67

1. Aqueous diffusion -generally determined by fixed law though if a drug is charged its flux will be influenced by electrical fields.

2. Lipid diffusion - most important limiting factor for drug permeation. Lipid:aqueous partition coefficient determines how readily the molecule moves between acid aqueous and lipid media. The abililty of weak acids and bases to move between aqueous and lipid mediums depends on pH.

3. Special carriers (active transport/facilitated diffusion) - for molecules that are too large or too insoluble - eg peptides, amino acids, glucose

4. Endocytosis and exocytosis for very large molecules -eg vit B12, iron

Front 68

What is fick's law of diffusion

Back 68

Passive flux of molecules down a concentration gradient equals the difference in concentration across the membrane (C1- C2) multiplied by the area of the membrane and the permeability coefficient, divided by the thickness of the membrane

conc grad x sa x perm coeff /thickness

Front 69

Define weak acid?

Back 69

a neutral molecule that can readily dissociate into an anion and a proton

Front 70

Define weak base?

Back 70

A neutral molecule that can combine with a proton and form a cation

Front 71

What is the pKa?

Back 71

pKa =the pH at which the concentrations of ionized and and inionized forms are equal

Front 72

When are weak acids and bases more likely to be in a lipid soluble form?

Back 72

More of a weak acid will be in a lipid soluble from at an acid pH.
More of a weak base will be in a lipid soluble form at an alkaline pH

This is important for excretion of drugs by the kidney.

Front 73

What is the henderson hasselbach equation?

Back 73

pH = pKa + log [base]/[acid]

Front 74

What is the general structure of local anaesthetics?

Back 74

Consist of a lipophilic group, ester or amide chain and ionisable group (usually a tertiary amine)

Front 75

What are the two types of local anaesthetics?

Back 75

Esters: Cocaine (procaine) (benzocaine)
Amides: Lignocaine Bupivicaine Prilocaine (etidocaine)

Front 76

Define local anaesthetics?

Back 76

Agents which reversibly block impulse conduction along nerve axons, thereby reducing pain sensation- usually do this by blocking voltage gated sodium channels

Front 77

Where do local anaesthetics act on the sodium channel?

Back 77

Blockade occurs at the intracellular end of the sodium channel

Front 78

What are the pharmacodynamics of local anaesthetics?

Back 78

Activated channels have higher affinity for drug therefore drug effect is more marked in rapidly firing fibres.
Progressive increase in drug concentration causes increased threshold, reduced action potential amplitude, then failure to produce an action potential.

Front 79

What ion concentration changes increase and decrease the effects of local anaesthetics?

Back 79

Local anaesthetic effect is increased by hyperkalaemia and decreased by hypercalcaemia

Front 80

How does fibre type (size and myelination) affect how local anaesthetics work on the nerves?

Back 80

Large diameter fibres less sensitive than small diameter fibres. (3 successive nodes required for blockade, nodes are further apart in large fibres).

Myelinated fibres of the same diameter as unmyelinated fibres tend to become blocked first.

Front 81

Why are sensory nerves more sensitive to local anaesthetics?

Back 81

Sensory fibres tend to have a fast firing rate and long action potential therefore are more sensitive to blockade.

Front 82

How does the position of a nerve in the bundle affect how sensitive it is to local anaesthetics?

Back 82

Peripheral nerves exposed first -motor nerves tend to be peripheral in large trunks.

Front 83

What are the safe doses for lignocaine with/without adrenaline?

Back 83

2mg/kg IV, 3mg/kg SC, 5mg/kg with adrenaline.

Front 84

What is 1% solution of drug?

Back 84

10mg/ml

Front 85

What is the safe dose of bipivicaine and prilocaine?

Back 85

Bupivacaine 2mg/kg SC
Prilocaine 3-5mg/kg IVRA

Front 86

What are the relative potencies of the local anaesthetics, say lignocaine = 4

Back 86

(if procaine = 1)
Cocaine =2
Lignocaine =4
Bupivacaine = 16
Prilocaine = 3

Front 87

What is the CNS toxicity of local anaesthetics?

Back 87

Drowsiness, visual and auditory disturbance, restlessness, nystagmus, shivering, convulsions, CNS depression.

Front 88

How do you manage convulsions caused by local anaesthetics?

Back 88

If convulsion occurs, the patient should be hyperventilated to induce respiratory alkalosis as this lowers extracellular potassium and favours rested, low affinity sodium channels

Front 89

Which local anaesthetics cause the most CNS and CVS toxicity?

Back 89

Bupivacaine>lignocaine> prilocaine

Bipivicaine is most cardiotoxic -Although all local anesthetics potentially shorten the myocardial refractory period, bupivacaine avidly blocks the cardiac sodium channels, thereby making it most likely to precipitate malignant arrhythmias.

Front 90

What are the cardiovascular effects of local anaesthetics?

Back 90

Depression of cardiac pacemaker activity, excitability and conduction. Negative inotropic effect and decreased peripheral resistance.

Front 91

How is cocaine different from other local anaesthetics in its cardiovascular effect?

Back 91

noradrenaline uptake blockade and subsequent vasoconstriction and hypertension.

Front 92

What haemotological toxicity do local anaesthetics have?

Back 92

Prilocaine in high doses liberates the 0-toluidine metabolite that causes methaemoglobinaemia.

Front 93

Which drug interract with local anaesthetics?

Back 93

Fentanyl and midazolam utilise same microsomal enzymes in liver

Halothane, cimetidine and beta blockers decrease hepatic blood flow and therefore reduce metabolism

Enzyme inducers such as phenytoin may increase metabolism

Front 94

Are local anaesthetics acid or base?

Back 94

most are weak bases, potency depends on how liphophilic it is and therefore depends on the pH of the tissue

Front 95

What is the active form of local anaesthetics? Is this the form that gets into the tissues?

Back 95

Most are in a charged, cationic form and this is the active form at the receptor site, but the uncharged form is required for penetration - hence poor penetration in acidic (infected) tissue

Front 96

How protein bound are local anaesthetics?

Back 96

bupivicaine 95%, prilocaine 50%

Front 97

What affects systemic absorption of local anaesthetics?

What does local effect depend on?

Back 97

dose, vascularity of site of injection, drug-tissue binding, presence of vasoconstrictors (more effective for short acting highly lipid soluble drugs), chemical properties of the drug.

Local effect is proportional to the amount of drug that penetrates the nerve fibre

Front 98

What is the comparative duration of action of the common local anaesthetics?

Back 98

Cocaine -medium
Lignocaine -medium
Bupivacaine - long (up to 12 hours for peripheral nerve blocks)
Prilocaine - medium.

Front 99

Why do ester local anaesthetics have a very short plasma half life?

Back 99

Rapidly metabolised by pseudo- cholinesterase therefore half life less than 1 minute.

Front 100

How are amide local anaesthetics metabolised?

Back 100

Slowly hydrolysed by liver enzymes and excreted by kidney: Dosage reduction required in liver disease and reduced hepatic blood flow

Prilocaine metabolised most rapidly, lignocaine intermediate, bupivacaine slowest: Prilocaine metabolism produces O- toluidine

Front 101

What are guedel's stages of anaesthesia?

Back 101

Stage of analgesia
Stage of excitement
Stage of surgical anaesthesia
Stage of medullary depression

Front 102

What are the 5 factors that affect the brain uptake of an inhaled anaesthetic?

Back 102

1. Partial pressure of inspired anaesthetic agent

2. Solubility (blood:gas partition coefficient)
The more soluble an agent the longer it takes for its partial pressure in blood to rise therefore the slower the onset of anaesthesia.

2. Pulmonary ventilation Increases the rate of induction of anaesthesia for drugs with high solubility - little effect on drugs with low solubility

3. Pulmonary blood flow
Increased flow decreases the rate of induction with
soluble agents, little effect with poorly soluble agents.

4. Arteriovenous concentration gradient (tissue:blood solubility coefficient)
Gradient between arterial and mixed venous blood determined by uptake of agent by highly perfused organs such as brain, heart, liver, kidneys and gut. Drugs with high tissue:blood solubility coefficient take longer to reach equilibrium.

Front 103

Define the MAC (minimal alveolar concentration).

Give an example of a drug with a high MAC?
What are the limits to using MAC?

Back 103

The partial pressure (% concentration) of an agent which results in immobility of 50% of patients undergoing a surgical incision.

For nitrous oxide, MAC>100% means that even if the partial pressure of nitrous oxide is 760mmHg, incomplete anaesthesia is achieved.

There may be vast individual differences and the MAC gives no indication where the other 50% lie on the curve.

Front 104

Why is steady state alveolar concentration a useful measure of potency?

Back 104

When steady state is achieved, the partial pressure of an inhaled anaesthetic in the brain equals that in the lung, therefore measurement of steady state alveolar concentration gives a measure of potency

Front 105

How do inhaled general anaesthetic agents work?

Back 105

Increase in cellular threshold to firing with subsequent decreased spontaneous and evoked neuronal activity.
Ionic basis of effect includes activation of potassium currents to cause hyperpolarisation and opening of cation channels to decrease synaptic transmission.
Research suggests that agents interact with lipid membranes to cause distortion of ion channels.

Front 106

What are the cardiovascular effects of general anaesthetic agents?

Back 106

Dose related variable reduction in mean arterial pressure and myocardial oxygen demand. Effects may be masked by nitrous oxide which causes sympathetic stimulation

Nitrous oxide causes minimal depressant effects

Halothane sensitises the myocardium to catecholamines and is arrhythmogenic.

Front 107

What are the respiratory effects of general anaesthetics? List 5

Back 107

1. Respiratory depression due to reduced TV and inadequate increased rate. (except nitrous oxide)

2. Increase apneic threshold to pCO2.

3. Decrease ventilatory response to hypoxia.

4. Decrease mucociliary function leading to atelectasis.

5. Most have bronchodilator action.

Front 108

What are the CNS effects of general anaesthetics?

Back 108

Increase metabolic rate and blood flow to brain due to reduced cerebrovascular resistance. Hyperventilation reduces this effect.

Front 109

What are the GI and GU effects of general anaesthetics?

Back 109

GUS
Reduced renal blood flow and GFR. Uterine relaxation (minimal with nitrous oxide)

GIT
Reduced hepatic blood flow.

Front 110

Describe the acute and chronic toxicity of general anaesthetic agents?

Back 110

Halothane -1 in 35000 cases of fatal hepatic necrosis.

Methoxyflurane -fluoride related nephrotoxicity.

Malignant hyperthermia -tachycardia, hypertension, acidosis, hyperkalaemia, muscle rigidity, hyperthermia ,more common if suxamethonium also used -treated with dantrolene.

Chronic exposure to Nitrous oxide is associated with megaloblastic anaemia

Front 111

What is the MAC of the common anaesthetic agents?

Back 111

Nitrous oxide >100
Isoflurane - 1.4
Halothane - 0.75
Methoxyfluorane - 0.16

Front 112

What are the solubilities and the brain:blood partition coefficients of the common anaesthetic agents?

Back 112

Solubility (blood:gas partition coefficient) :
Nitrous oxide - 0.47
Isoflurane -1.4
Halothane - 2.3
Methoxyfluorane - 12

Brain:blood partition coefficient Nitrous oxide ␣ 1.1 Isoflurane - 2.6
Halothane - 2.9
Methoxyfluorane - 2.0

Front 113

Give some examples of IV general anaesthetics?

Back 113

Barbiturates Benzodiazepines Opioids Propofol Ketamine

Front 114

Give examples of barbituate general anaesthetics?

Back 114

Phenobarbitone
Thiopentone -ultra short acting barbiturate intravenous anaesthetic

Front 115

How do barbituates work? (3 mechanisms)

Back 115

1. Barbiturates bind to components of the GABA receptor and facilitate its action by increasing the duration of chloride channel opening.
2. At high concentrations GABA may directly stimulate the receptor.
3. Also depress actions of other excitatory neurotransmitters and have non-synaptic membrane effects.

Front 116

What is the structure of the GABA receptor in the CNS?

Back 116

GABA receptor consists of 5 alpha, beta and gamma membrane-spanning proteins which can form different pentameric combinations.

Front 117

What are the indications for barbiturates in humans?

What is the dose of thiopentone?

Back 117

Phenobarbitone - neonatal seizures.
Thiopentone -anaesthesia
Dose Thiopentone 3-5mg/kg

Front 118

What are the adverse effects of thiopentone?

Back 118

Toxicity CVS Depression at high doses.

Dose dependent decreased blood pressure, stroke volume and cardiac output.
Respiratory depression.
Decreased cerebral metabolism and blood flow. Nystagmus.
Reduces hepatic and renal blood flow.
Dizziness, fatigue, amnesia, blurred vision. Tolerance. Dependence.

Front 119

What interactions do barbituates have with other drugs?

Back 119

Effects are potentiated by other sedatives such as alcohol or other sedatives-may cause fatal CVS depression.

Induction of liver enzymes - decreases effect of warfarin, anticonvulsants, digoxin.

Front 120

What are the contraindications for barbiturates?

Back 120

Precaution with liver failure. Readily crosses placenta and enters breast milk. Porphyrias

Front 121

What is the absorption and distribution of thiopentone and phenobarbitone?

Back 121

Phenobarbitone -Orally active, rapidly absorbed. 50% protein bound.
Thiopentone - intravenous
Highly lipid soluble and rapidly distributed to brain, then redistributed to other tissues. Redistribution from CNS to skeletal muscle and adipose tissue is important process that contributes to termination of CNS effects.
Initial redistribution to brain and viscera, then to lean tissues and then to fat
Metabolised slowly in liver to water- soluble inactive metabolites that are excreted in urine.

Front 122

What are the half lives of thiopentone and phenobarbitone?

Back 122

Phenobarbitone plasma half life 4 hours, excretion half life 4-5 days (therefore has a tendency to accumulate)

Thiopentone Produces hypnosis in one circulation time. Plasma:brain equilibrium occurs rapidly (< 1 minute) due to high lipid solubility. Rapid redistribution is responsible for short acting effect of 20-30minutes

Front 123

How much of thiopentone and phenobarbitone is excreted unchanged?

Back 123

Phenobarbitone 20% excreted unchanged.
Thiopentone - 1% excreted unchanged, metabolised at 12- 16% per hour.

Front 124

What is propofol?

Back 124

Phenol derivative.
Short acting intravenous anaesthetic agent.
Presented as an oil in water emulsion.

Front 125

How does propofol work?

Back 125

Potentiates the action of inhibitory neurotransmitters including GABA and glycine.

Front 126

What is the dosage of propofol?

Back 126

Sedation 0.5-1mg/kg Usually given in 20mg increments

Induction of anaesthesia 2-2.5mg/kg Usually given in 40mg increments.
Dose can be repeated as required.

Front 127

What are the adverse effects and contraindications of propofol?

Back 127

1. Marked hypotension (15- 25%) due to reduced peripheral vascular resistance (direct effect of propofol). Potent negative inotropic effects. No compensatory increase in heart rate.
2. Potent respiratory depression. Brief apnoea common. Infusion produces decreased tidal volume. Some bronchodilation due to direct effect on smooth muscle.
3. Rapid, smooth induction and clear headed recovery. Cerebral blood flow and ICP decrease slightly.
4. General Pain in injection in 25%.

Contraindications: Acidosis and possible neurological sequelae in children therefore contraindicated under 3 years.

Given as an intravenous fat emulsion - previous vehicle cause hypersensitivity reactions.

Front 128

Onset, distribution and elimination of propofol?

What is the volume of distribution and why?

Back 128

Rapid onset (30 seconds) and recovery

Distribution half life (t1/2 alpha) : 2-8 minutes,

Elimination half life (t1/2 beta): 30- 60 minutes.

90% protein bound. Small volume of distribution.

Front 129

Where and how quickly is propofol metabolised?

What determines the distribution of effect of propofol?

Back 129

Rapidly metabolised in liver (10 times faster than thiopentone) and excreted in urine.
Duration of effect largely determined by redistribution.

Less than 1% excreted unchanged.

Front 130

What is ketamine and how does it work?

Back 130

Short acting non-barbiturate intravenous anaesthetic agent. Chemically related to PCP

Action may involve blockade of glutamic acid (NMDA) receptors.
Mechanism of action largely unknown

Front 131

What kind of anaesthesia does ketamine produce?

Back 131

Characteristic
dissociative anaesthesia :amnesia, profound analgesia, normal or slightly increased muscle tone without loss of consciousness or loss of protective reflexes.

Front 132

What is the IV dose of ketamine?

Back 132

1-4mg/kg Administer slowly over 60 seconds to avoid respiratory depression and pressor response

Front 133

What is the onset and offset of ketamine?

Back 133

Onset 30 seconds, duration of action 5- 10 minutes. Additional doses can be given without accumulation

(Intramuscular 6.5-13mg/kg
Onset 2 minutes, duration 20 minutes)

Front 134

What are the organ effects and toxicity of ketamine?

Back 134

1. CVS: Increased heart rate, blood pressure and cardiac output via inhibition of noradrenaline reuptake -peaks 2-4 minutes after injection, declines after 20 minutes.
2. RS: May increase or decrease respiratory rate for several minutes. Upper airway tone is maintained.
3. CNS Marked increase in cerebral blood flow and intracranial pressure. Nystagmus

4. Emergence phenomena in 12% -disorientation, sensory and perceptual illusions and vivid dreams. Less incidence in children and elderly.
Reduced by minimising verbal, tactile and visual stimuli during recovery Interactions

Avoid hypertensive agents
Contraindications Uncontrolled hypertension, severe cardiovascular disease

Front 135

Where does ketamine distrubute to and how is the effect of ketamine terminated?

Back 135

Distribution Highly lipid soluble.
Rapid distribution to all tissues.
Termination of effect due to redistribution from brain to peripheral tissues

Front 136

What is the metabolism of ketamine?

Back 136

Metabolised by liver to 4 different metabolites including norketamine which has one sixth the potency of ketamine
Metabolites excreted in urine.

Front 137

What is the structure of muscle relaxants?
What are the 2 types of muscle relaxants?

Back 137

Structure: All bear a structural resemblance to acetylcholine

Depolarising Suxamethonium= 2 acetylcholine molecules linked end-to-end.

Non- depolarising (NDPMRs) Isoquinolone, tubocurarine, atracurium.
Steroid: pancuronium, vecuronium, rocuronium.

Front 138

How do depolarising muscle relaxants work?

Back 138

1. Binds with the nicotinic receptor at the neuromuscular junction to cause the sodium channel to open and the end plate to depolarise. This results in generalised disorganised contraction. Suxamethonium is not metabolised effectively at the synapse, therefore depolarised membranes remain depolarised and unresponsive to subsequent impulses.
2. Phase 2 block (Desensitising): depolarisation gradually decreases and the membrane becomes repolarised. Membrane cannot become repolarised while suxamethonium is present- essentially this is the same as non-depolarising blockade.

Front 139

How do non-depolarising muscle relaxants work?

Back 139

Reversible blockade, act predominantly at nicotinic receptors. Prevents opening of the sodium channel, may also enter ion pore at higher does and cause blockade.

Front 140

What are the doses of suxamethonium and verocuronium?

Back 140

Suxamethonium 1-1.5mg/kg (children relatively resistant) May be given IM
Vecuronium 0.1mg/kg

Front 141

What are the adverse effects of depolarising and non-depolarising muscle relaxants?

Back 141

1. CVS: Pancuronium causes a moderate increase in heart rate and cardiac output due to vagolytic action.
Vecuronium, rocuronium (and most others) have little or no cardiovascular effects
2. Suxamethonium stimulates all autonomic cholinoceptors to some extent.
Bradycardia and negative inotropic effects at low doses and especially after a second dose.
Prevented by premedication with atropine and by giving a minimum dose.
3. Hyperkalaemia Due to exaggerated release of potassium from extra- junctional nicotinic receptors. There is an exaggerated release with burns, renal failure.
4. Raised intraocular pressure Raised intragastric pressure Raised intracranial pressure
5. Muscle pain This is the most common side effect

Malignant hyperthermia: Tachycardia, tachypnoea, rigidity

Front 142

Contraindications to muscle relaxants?

Back 142

Personal or family history of malignant hyperthermia Muscular dystrophy

Front 143

Absorption and distribution of muscle relaxants?

Back 143

All are highly polar and inactive orally.


Non-depolarising : Rapid initial distribution, small volume of distribution.

Front 144

Metabolism and excretion of depolarising muscle relaxants?

What defects in excretion are there and what effect can this cause? Is there a test for this?

Back 144

Onset of action 30s, duration of action 5-10 minutes due to rapid hydrolysis by pseudo- cholinesterase.

This limits the amount of drug reaching the synaptic cleft. Very little plasma cholinesterase at end plate neuromuscular blockade is terminated by diffusion away from the endplate into extracellular fluid.

95% of the population will have a normal pseudo- cholinesterase response. 5% will have prolonged apnoea up to 10 minutes. <<1% have profound apnoea lasting several hours - this may be treated with fresh frozen plasma.

Plasma cholinesterase may also be reduced in pregnancy, cardiac or renal failure, liver disease, hypoproteinaemia, and thyrotoxicosis -this will result in prolonged action.

Front 145

Metabolism and excretion of non depolarising muscle relaxants?

Back 145

Onset of action 2-3 minutes Route of elimination correlates with duration of action.

Renal excretion is slow, hepatic excretion fast.

Steroid -metabolised to 3 hydroxy, 17 hydroxy and 3,17 hydroxy metabolites that also have clinical effect and may persist.

Vecuronium - duration of action 20-35 minutes, minimal cardiovascular effects, hepatic elimination - 85% eliminated into bile.

Pancuronium -duration of action 35minutes - 1 hour, mainly excreted by kidney.

Rocuronium - very rapid onset of action.

Front 146

What is the fastest onset non-depolarising muscle relaxant?

Back 146

rocuronium

Front 147

Mechanism of action of dantrolene?

Back 147

Acts on the sarcoplasmic reticulum of skeletal muscle
Causes reduced release of calcium from the sarcoplasmic reticulum

Front 148

What is malignant hyperthermia?

Back 148

Malignant hyperthermia can be triggered by general anaesthesia and neuromuscular blockade and is a hereditary impairment of the ability to sequester calcium in the sarcoplasmic reticulum
Trigger results in massive release of calcium with prolonged muscle contraction, lactic acidosis and hyperthermia

Front 149

What are the classes of antipychotics?

Back 149

1. Phenothiazine derivatives: Chlorpromazine
2. Thioxanthene: Thiothixene
3. Butyrophenone derivatives : Haloperidol
4. Miscellaneous: Clozapine, Rispiradone, Olanzapine

Front 150

Mechanism of action of antipsychotics?

Back 150

Dopamine antagonist ␣ antipsychotic action related to dopamine receptor blockade in mesolimbic and mesofrontal systems.

Chlorpromazine Alpha1=5H T2>D2>D1
Haloperidol D2>D1=D4>Alpha1> 5H T2
Clozapine Alpha1 =D4 >5HT2> D2=D1
Rispiridone D2=5HT2
Olanzapine 5HT2>D2=D1=Alpha1> H1

Front 151

Potency of various antipsychotics?

Back 151

Chlorpromazine -low
Thiothixene - high
Haloperidol - high
Clozapine - medium
Rispiradone - high
Olanzapine - high

Front 152

Dosing of antipsychotics?

Back 152

Haloperidol Oral 1-15mg/day in divided doses. IM - 2-30mg IV - 1-5mg
Chlorpromazine PO/IM 25-50mg tds
Olanzapine 10mg PO/IM

Front 153

CNS Toxicity of antipsychotics?

Back 153

Toxicity CNS Extrapyramidal effects Extrapyramidal toxicity related to high D2 affinity; manifest as parkinsonism, akathisia, acute dystonic reactions, tardive dyskinesia.

Chlorpromazine -high
Thiothixene - medium
Haloperidol - very high
Clozapine - very low
Rispiradone - low
Olanzapine - very low

Sedation: esp chlorpromazine

Clozapine -2% incidence of seizures (can also occur with other antipsychotics)

Front 154

ANS Toxicity of antipsychotics?

Back 154

Autonomic effects Antimuscarinic actions. Loss of accommodation, dry mouth, difficulty urinating, constipation : Alpha1 antagonist actions.

Front 155

CVS Toxicity of antipsychotics?

Back 155

Tachycardia, reduced stroke volume, decreased peripheral resistance, orthostatic hypotension

Thioridazine causes T wave abnormalities and is associated with prolonged QT, ventricular arrhythmias and sudden death

most- chlorpromazine, least: olanzapine and haloperidol

Front 156

What is NMS and how is it treated?

Back 156

Neuroleptic malignant syndrome Muscle rigidity, reduced sweating, fever, autonomic instability, leukocytosis

Marked increases in CK may result in renal failure -use bromocriptine

Front 157

Endo, haem effects of antipsychotics?

Back 157

Amenorrhoea, galactorrhoea, increased or decreased libido, impotence -secondary to blockade of dopamine induced tonic inhibition of prolactin secretion.

Clozapine, chlorpromazine may cause agranulocytosis

Chlorpromazine - corneal and lens deposits

Front 158

Absorption and distribution of antipsychotics?

Back 158

Orally active. Readily but incompletely absorbed.

Chlorpromazine Significant first pass metabolism :bioavailability 30%. Half life 30 hours.

Others- Moderate first pass metabolism : bioavailability 65%

95% protein bound, lipid soluble, high distribution volumes

Front 159

Presentation of antipsychotic overdose?

Back 159

Drowsiness, coma, neuromuscular excitability, convulsions. Miosis and loss of deep tendon reflexes. Hypotension and hypothermia.
Activated charcoal effective.
Supportive therapy.

Avoid adrenaline and lignocaine.

Front 160

Mechanism of action of lithium? 3 broad effects

Back 160

1. Closely related to sodium -inhibits sodium exchange across membranes but no effect on sodium/potassium or sodium/calcium exchange.

2. Effects on neurotransmitters Enhances the action of serotonin. Decreases noradrenaline and dopamine turnover. Augments the synthesis of acetylcholine.

3. Effects on second messengers. Inhibits enzymes responsible for recycling of inositol compounds, resulting in depletion of PIP2, IP3 and DAG.

Front 161

Usual maintenance dose of lithium

Back 161

dose 500mg-1g/day

Front 162

Interractions of lithium?

Back 162

Renal clearance reduced by diuretics and some NSAIDs.
Increased extrapyramidal effects when used with antipsychotics (except newer drugs) May increase the duration of muscle relaxnants.

Front 163

Lithium toxicity?

Back 163

Tremor (alleviated by propanolol), choreoathetosis, motor hyperactivity, ataxia, dysarthria, aphasia.

Mental confusion, drowsiness and seizures at higher levels.

Endocrine: Reversible reduction in thyroid function.

GUS: Nephrogenic diabetes insipidus, chronic interstitial nephritis, minimal change glomerulonephritis.

CVS: Nodal depression and T wave flattening.

General Oedema and weight gain.

Front 164

Lithium in pregnancy?

Back 164

Clearance increases during pregnancy and falls following delivery.
??dysmorphogenesis - unsettled.

Lithium toxicity in newborns characterised by lethargy, cyanosis, poor suck and reflexes

Front 165

Absorption and distribution of lithium?

Back 165

Orally active, completely absorbed in 6-8 hours, peak levels 30 minutes. 100% bioavailability.

Distribution Total body water, slow entry into intracellular compartment. Some sequestration into bone.

Front 166

Excretion of lithium?

Back 166

Not metabolised. Excreted into urine at 20% of the rate of creatinine clearance.
Elimination half- life 20 hours.

Front 167

Presentation and management of lithium overdose?

Back 167

anorexia, nausea, vomiting, diarrhoea, muscle weakness, lack of cooordination

No specific antidote.

Clearance increased by osmotic diuresis and urinary alkalinisation. Readily removed by haemodialysis.

Front 168

Give four examples of antidepressant classes?

Back 168

tricyclincs- amytriptilline, imipramine
Heterocyclics:
SSRI:
MAOI's

Tricyclics Imipramine
Amitriptyline
Heterocyclics

Second generation: Maprotiline (tetracyclic) ,Buproprion

Third generation: venlafaxine

SSRIs
fluoxetine

MAOs: Phenelzine, Moclobamide

Front 169

How do tricyclic antidepressants work?

Adverse effects?

Back 169

Blockade of amine (serotonin >>noradrenaline) reuptake pumps.

Antimuscarinic actions Alpha1, H1, H2 antagonist

>1000mg toxic
CNS Sedation, seizures, psychosis, coma Antimuscarinic effects very common Tremor, insomnia
CVS Orthostatic hypotension Tachycardia and minor T/ST changes very common Conduction defects (long PR, wide QRS>0.1s, long QT and ST) and arrhythmias also common.
GIS Nausea, raised liver enzymes

Front 170

How do heterocyclic antidepressants work?

Adverse effects?

Back 170

Buproprion alters noradrenaline neurotransmission by an unknown mechanism. Third generation heterocyclics have additional antagonist of 5HT receptors.

Same as TCAs though less pronounced.

Front 171

How do MAOI's work?

Adverse effects?

Back 171

Blockade of MAO mediated amine degradation. MAO-A metabolises noradrenaline and serotonin, MAO-B metabolises dopamine.

Initial increase in amine leads to down-regulation of receptors.

Front 172

Adverse effects of SSRI?

Back 172

Anxiety, insomnia, tremor, nausea, rash (may lead to severe vasculitis), decreased libido. SSRI use in combination with MAO may lead to toxic build up of serotonin and serotonin syndrome

Front 173

What is serotonin syndrome?

Back 173

TCAs and SSRIs Serotonin syndrome if characterised by hyperthermia, muscle rigidity, myoclonus.

Front 174

Antidepressant interactions with other drugs?

Back 174

Phenothiazines displace TCAs from protein binding site and potentiate action.

Nefazodone can inhibit P450-3A4 and block the metabolism of terfenadine and cisapride.

F luoxetine and paroxetine are potent inhibitors of P450-2D6 -desipramine, nortriptiline and flecainide are dependent on same enzyme system for clearance.

MAOs : Accumulation of tyramine (fermented foods and drinks) results in hypertension. Moclobamide is relatively short acting compared with older drugs therefore this effect is rare

Front 175

Absorption and distribution of tricyclics?

Back 175

Incompletely absorbed. Slow gastric emptying due to antimuscarinic effect. Significant first pass metabolism (bioavailability 30- 70%)

80-90% protein bound. High lipid solubility. Large Vd

Front 176

Absorption and distribution of tetracyclics?

Back 176

Incompletely absorbed. Significant first pass metabolism (bioavailability 30- 70%)
80% protein bound. High lipid solubility. Large Vd

Front 177

Absorption and distribution of SSRI's?

Back 177

Well absorbed orally. Moderate first pass metabolism (bioavailability 50- 70%) 95% protein bound.
High lipid solubility. Large Vd

Front 178

Absorption and distribution of MAOI's?

Back 178

Well absorbed orally.

Front 179

Metabolism of tricyclics, tetracyclics, MAOI's?

Back 179

Tricyclics: Metabolised in liver to active metabolites. Half life 10-40 hours

Heterocyclics: Metabolised in liver to active metabolite. Half life 10-40 hours

SSRIs Metabolised in liver. Fluoxetine forms an active metabolite, nil with paroxetine. Half life 24-96 hours.

MAOs: Metabolised in liver. Acetylation of phenelzine varies between individuals and may persist for several weeks.

Front 180

Antidepressant overdose?

Back 180

Severe antimuscarinic response is common Extension of toxic effects listed plus respiratory depression, metabolic acidosis, heart failure, cardiac arrest

Front 181

Give 4 examples of anticonvulsants that are sodium channel blockers/membrane stabilisers?

Back 181

Phenytoin
Carbamazepine Sodium valproate Lamotrigine

Front 182

Give 4 examples of anticonvulsants that are GABA modulators?

Back 182

Benzodiazepines Gabapentin Vigabatrine Phenobarbitone

Front 183

What kind of antiarrhythmic is phenytoin?

Back 183

class 1b

Front 184

Mechanisms of phenytoin?

Back 184

Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.

Reduces calcium permeability therefore inhibits calcium related secretory processes.
May potentiate the effects of GABA

Inhibits release of serotonin and noradrenaline, promotes uptake of dopamine.

Inhibits monoamine oxidases.

Front 185

Uses of phenytoin?

Back 185

Prophylaxis and treatment of partial seizures and generalised tonic clonic seizures.
Fast atrial and ventricular arrhythmias resulting from digoxin toxicity.
Trigeminal neuralgia.

Front 186

Dosing of phenytoin?

Back 186

10-15mg/kg not exceeding 50mg/minute then 100mg orally every 8 hours

(slow administration due to propylene glycol diluent which may induce cardiac arrhythmias

Front 187

Toxicity of phenytoin?

Back 187

Dose related CNS: Nystagmus and loss of smooth ocular pursuit. Diplopia and ataxia. Sedation.

CVS: Cardiovascular collapse (diluent effect if rapid administration)

Idiosyncratic: Chronic use frequently leads to gingival hyperplasia and hirsutism, coarsening of facial features, diminished tendon reflexes and osteomalacia.
Rash, fever, rare agranulocytosis.

Front 188

Interractions of phenytoin with other drugs?

Back 188

Protein binding : Phenytoin is displaced by highly protein bound drugs such as sulphonamides, calcium channel blockers. Hypoproteinaemia causes increased free drug.

May confuse thyroid function tests due to affinity for TBG.

Enzyme inducers: Phenytoin induces liver enzymes and affects the metabolism of other drugs such as warfarin, opioids, neuromuscular blockers, beta blockers

Other inducers may reduce phenytoin levels - anticonvulsants, rifampicin, ciprofloxacin
Enzyme inhibitors Erythromycin, cimetidine

Front 189

Absorption and distribution of phenytoin?

Back 189

Orally active. Intramuscular absorption unpredictable. 90% bound to plasma proteins.
Maximal effect after IV dose occurs after 30-60 minutes and may persist for 24 hours
Accumulates in endoplasmic reticulum of brain, liver, muscle and fat.

Therapeutic concentration 10- 20ug/l

Front 190

Where is phenytoin metabolised and what kind of kinetics does it display?

Back 190

Metabolised by liver, excreted in bile, reabsorbed and excreted in urine.

Variable order kinetics: Elimination rate is dose dependent - at low doses there is first order kinetics but metabolism is saturated at therapeutic concentrations and small increases in dose quickly lead to toxicity.

Front 191

Half life and steady state of phenytoin?

Back 191

Half life 12-36 hours -much higher at high concentrations.

5-7 days to reach steady state.

Front 192

Overdose of phenytoin

Back 192

Overdose Toxicity varies between individuals CNS effects predominate though bradycardia and heart block can also occur

Front 193

Mechanism of carbamazepine?

Back 193

Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.
Also acts pre-synaptically to decrease synaptic transmission.

Inhibits reuptake and release of noradrenaline.
Interacts with adenosine receptors - ?significance

Front 194

Toxicity of carbamazepine?

Back 194

Skin rash common.
Diplopia, ataxia - often mild and reversible.
Drowsiness at high concentration.

Hyponatraemia and water intoxication rarely.

Rare agranulocytosis , leukopenia is common and just requires monitoring.

Front 195

Interractions of carbamazepine?

Back 195

Induces liver enzymes and affects own metabolism : half-life is typically halved from 40 to 20 hours with continuous therapy.

Phenytoin, carbamazepine, barbiturates and lamotrigine induce liver enzymes and reduce levels of each other.

Reduces effectiveness of benzodiazepines, pethidine, and warfarin.

Front 196

Pharmacokinetics of carbamazepine?

Back 196

Orally active

Rate of absorption variable but complete
Slow distribution. 70% protein bound.

Metabolised in liver -metabolite may have some clinical activity.

Front 197

What is the active constituent of sodium valproate?

Back 197

Fully ionised at body pH therefore active constituent is the valproate ion.

Front 198

Mechanism of sodium valproate?

Back 198

Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.

Increases levels of GABA - likely insignificant
Increases membrane potassium conductance

Front 199

Toxicity of sodium valproate?

Back 199

Dose related nausea vomiting and abdominal pain.
Sedation (particularly if used with phenobarbitone)
Tremor, weight gain, hair loss.

Idiosyncratic hepatotoxicity -may be fatal, more common in children under 2 years, usually occurs within 4 months of starting the drug.

Front 200

Inerractions of sodium valproate?

Back 200

Dose related nausea vomiting and abdominal pain.
Sedation (particularly if used with phenobarbitone)
Tremor, weight gain, hair loss.

Idiosyncratic hepatotoxicity - may be fatal, more common in children under 2 years, usually occurs within 4 months of starting the drug.

Front 201

Absorption and distribution of sodium valproate?

Back 201

Orally active. 80% bioavailability. 90% plasma protein bound. Distribution confined to extracellular water due to ionised status and protein binding.

Front 202

Metabolism and excretion of sodium valproate?

Back 202

Clearance is dose dependant - it inhibits its own metabolism at low doses. At higher doses there is increased free valproate.

20% excreted as a direct conjugate of valproate. 80% metabolised in liver and excreted in urine.
Half life 9-18 hours.

Front 203

What does lamotrigine resemble in structure?

Back 203

Phenytoin

Front 204

Mechanism of lamortigine

Back 204

Membrane stabiliser - preferentially binds to inactivated sodium channel and maintains inactivated state and therefore blocks sustained high frequency repetitive firing of action potentials.

Front 205

Indication for lamictal

Back 205

Partial seizures. Usually used in add- on therapy but increasingly used alone.

Front 206

What is valproate best for?

Back 206

Absence seizures. Generalised tonic- clonic seizures

Front 207

Inerractons of lamortigine

Back 207

`Phenytoin, carbamazepine, barbiturates and lamotrigine induce liver enzymes and reduce levels of each other.
Reduces effectiveness of benzodiazepines, pethidine, warfarin.

Front 208

Side effects of lamrtigine

Back 208

rash- if rash then cease lamortigine as linked to SJS, aseptic meningitis, leukopaenia, dizzyness, headache diplopia

Front 209

Absorption and excretion of lamotrigine?

Back 209

Orally active. 50% protein bound.

Linear kinetics. Metabolised by liver and excreted by urine.
Half life 24 hours, reduced to 15 hours if taking enzyme inducing drugs.

Front 210

Mechanism of vigabatrine?

Absorption and excretion of vigabatrine?

Back 210

Reversible inhibitor of GABA aminotransferase which degrades GABA. GABA levels are therefore increased. Indicated for partial seizures.

Orally active. Renally excreted. Short (5-8 hour) half life)

Front 211

Toxicity of vigabatrine?

Back 211

Dizziness, drowsiness and weight gain. Agitation and confusion rare

Front 212

Structure and action of gabapentin?

Indications in epilepsy?

Back 212

Amino acid analogue of GABA.

Despite structural relationship to GABA, does not act on GABA receptors but may alter GABA metabolism.

Partial seizures. Usually used in add- on therapy but increasingly used alone.

Front 213

Interractions of gabapentin?

Back 213

Does not induce liver enzymes. No significant interactions.

Front 214

Absorption and excretion of gabapentin?

Back 214

Orally active. Not protein bound.

Renally excreted. Short (5-8 hour) half life)

Front 215

Mechanism of action of benzodiazepines?

Back 215

Bind to GABA receptor in CNS

Benzodiazepines bind to the gamma subunit and in association with GABA, triggers chloride channel opening and subsequent hyperpolarisation.

Benzodiaepines increase the efficacy of GABAergic synaptic transmission -they do not cause chloride channel opening alone.

Front 216

Structure of the GABA receptor in the CNS

Back 216

GABA receptor consists of 5 alpha, beta and gamma membrane-spanning proteins which can form different pentameric combinations.

Front 217

Dose of diazepam and midazolam used for sedation:

Back 217

Diazepam Oral, IV or PR
Adult 5-40mg Child 0.1-0.3mg/kg

Midazolam
IV/IM 0.03-0.2mg/kg (higher dose used for induction of anaesthesia)

Front 218

Does tolerance occur to resp depression with benzo's?

Back 218

no

Front 219

Do benzodiazepine cross breast milk and placenta?

Back 219

yes

Front 220

What interracts with benzodiazepines?

Back 220

Effects potentiated by other sedatives such as alcohol - may cause fatal CVS and respiratory depression.

Front 221

What does benzo absorption depend on?

Which benzodiazepines are best and worst absorbed?

Back 221

Orally active. Absorption dependent on lipid solubility.

Diazepam most lipid soluble. Oxazepam, lorazepam and temazepam least lipid soluble. They are highly protein bound and CNS uptake dependent is also dependent on lipid solubility.

Front 222

What is the timeline of sedation by temazepam

Back 222

Peak sedation 15 minutes after IM injection, 4 minutes after IV injection

Front 223

How are benzo effects terminated?

Back 223

Redistribution from CNS to skeletal muscle and adipose tissue is important process that contributes to termination of CNS effects.

Front 224

How are benzodiazepines metabolised?

Back 224

Metabolised in liver to water-soluble metabolites that are excreted in urine.
Metabolites may be more active than parent drug (diazepam forms desmethyldiazepam which is transformed to oxazepam and temazepam)

Front 225

What are the half lives of diazepam, temazepam and midazolam?

Back 225

Diazepam -20-80 hours (metabolite persist much longer)
Temazepam -10-40 hours.
Midazolam 2-4 hours

Elimination may increase up to 6 times in elderly patients in ICU

Front 226

What is the action of flumazenil?

Back 226

Reversal of benzodiazepine induced clinical effect.
Reversal of respiratory depression is unpredictable.

Front 227

Side effects of flumazenil?

Back 227

Agitation, confusion, dizziness, nausea May precipitate severe withdrawal syndrome if existing physiological dependence.

Very likely to induce convulsions if patient has a known seizure disorder or in TCA overdose.

Front 228

Absorption of flumazenil?

Back 228

Undergoes significant first pass metabolism if administered orally.

Intravenous administration. Rapid onset.
50% protein bound. Small volume of distribution.

Front 229

Metabolism of flumazenil?

Back 229

Rapid hepatic metabolism to inert metabolites and excreted in urine.

Short half life 0.7- 1.3 hours. Infusion may be necessary.

Front 230

What are the spinal and supraspinal sites of pain transmission?

Back 230

Spinal
Dorsal horn pain transmission neurons of
spinal cord.

Pain transmission:
Ventral caudal thalamus
Diencephalon

Pain modulation:
Cortex
Midbrain periaqueductal gray area
Rostral ventral medulla

Front 231

What is the mechanism of mu opioid receptors?

What are the subtypes?

Back 231

Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release. Also causes opening of potassium channels on post synaptic neurons resulting in hyperpolarisation and formation of IPSPs

mu1, mu2

Front 232

Action of mu opioid receptors?

Back 232

Analgesia
Euphoria
Sedation
Respiratory depression
Tolerance and dependence

Front 233

Agonists of mu opioid receptors

Back 233

F ull: Morphine Pethidine Fentanyl
Partial: Codeine

Front 234

Delta opioid receptors types and mechanisms?

Back 234

delta 1 delta 2

Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release. This causes spinal analgesia.

Front 235

Agonists of delta opioid receptors?

Back 235

morphine and codeine are partial agonists

Front 236

Subtypes and action of kappa opioid receptors

Back 236

kappa 1, kappa 2 , kappa 3

Receptor binding causes closure of voltage gated calcium channels on presynaptic neurons and decreased transmitter release.

Front 237

What are morphine, codeine and heroin classified as?

Back 237

Phenanthrenes

Front 238

What are the Phenylheptylamines?

Back 238

methadone

Front 239

What are Phenylpiperidines?

Back 239

pethidine, fentanyl, loperamide

Front 240

Can endogenous opioids cause release of exogenous opioids?

Back 240

yes

Front 241

What receptors does morphine act on?

Back 241

mu, delta, kappa

Front 242

What is paperveretum?

Back 242

mixture of 253 parts morphine, 23 parts papaverine, 20 parts codeine - sometimes used as a premedication. Essentially identical actions as morphine though greater sedation and relief of anxiety.

Front 243

Endocrine effects of opioids?

Back 243

stimulates ADH, prolactin and somatotropin, inhibits LH

Histamine release- itching and urticaria

Front 244

General effects of opioids on smooth muscles?

Back 244

increase tone e.g.increased biliary smooth muscle contraction, increased GI smooth muscle contraction

Front 245

Action of morphine in APO?

Back 245

Reduced preload and afterload, reduced anxiety, reduced dyspnoea

Front 246

Respiratory effects of opioids

Back 246

respiratory depession
truncal rigidity- reduces thoracic compliance and increases work of breathing- likely supraspinal effect

Front 247

Withdrawal to opioids?

Back 247

rhinorrhea, lacrimation, yawning, chills, piloerection, hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhoea, and anxiety.

Onset 6-10 hours, Peak 36-48 hours, Lasts 5 days

Front 248

Absorption of opioids?

Back 248

Rapid absorption orally but high (and unpredictable) first pass metabolism therefore low bioavailability.

Variable protein binding.
Concentrates in highly perfused organs.

Structure determines how readily the drug crosses the blood/brain barrier -codeine and fentanyl cross quite readily, morphine less so.

Front 249

Excretion of opiates?

Back 249

Metabolised in liver and excreted in urine.
Morphine, codeine - metabolised in liver to active metabolites that may have greater activity than parent drug.

Excreted in urine. Small amount excreted in bile.
Metabolites may accumulate in renal failure.

Front 250

Codeine mechanism?

Back 250

Less efficacious - partial agonist at mu and delta receptors only.

Few side effects due to low potency. Constipation is prominent.

Front 251

Absorption and metabolism of codeine?

Back 251

The structure of codeine protects it from first pass effects and increases ability to cross the blood brain barrier.

10% is metabolised to morphine

Front 252

Potency of pethidine?

Back 252

One tenth as potent as morphine.

Front 253

Metabolism of pethidine?

What interracts with this?

Back 253

Metabolite 50% as active as parent drug - and is associated with seizures.

Halothane and enflurane decrease clearance by 50%.

Front 254

Mechanism of fentanyl

Back 254

highly selective mu agonist only

Front 255

Toxicity of fentanyl:

Back 255

CNS toxicity: Little hypnosis or sedation
Potent respiratory depression
Truncal rigidity
Marked muscle rigidity at high doses.

Peripheral toxicity:
Bradycardia with little effect on cardiac output or blood pressure.
Obtunds the cardiovascular response to intubation.
Minimal histamine release.

Halothane and enflurane decrease clearance by 50%.

Front 256

Fentanyl potency, onset of action, duration of action?

Back 256

IV or transdermal
33% bioavailability given PO

More lipid soluble than morphine therefore crosses the blood/brain barrier more readily.
Rapid onset of action.
50-80 times more potent than morphine.

Small dose has a shorter duration of action (1-1.5 hours) - larger doses 4-6 hours.

Front 257

What is heroin metabolised to?

Back 257

converted to morphine by tissue esterases

Front 258

Tramadol mechanism?

Back 258

Centrally acting analgesic with some opioid properties.
Not structurally related to opioids

Weak mu agonist actions
Noradrenaline inhibition and serotonin reuptake inhibition.

Front 259

Dose of tramadol:

Back 259

Mild to moderate pain
Dose PO/IV 50-100mg tds- rapidly orally absorbed

Front 260

Side effects of tramadol?

Back 260

Similar CNS and peripheral side effects

No respiratory depression except at high doses
No cardiac effects
No histamine release
Does not suppress opioid withdrawal symptoms
Increased risk of seizures

Avoid with SSRIs and MAOs due to actions on serotonin
Increased tramadol metabolism with enzyme inducers such as tramadol

Front 261

Methadone potency?

Back 261

Orally active, equivalent potency, longer duration of action

Tolerance and dependence develop and resolve more slowly and symptoms are milder.

Front 262

Naloxone mechanism of action?

How does it act at the organ level?

Back 262

Antagonist action at opioid receptors. More potent action at mu receptors than delta or kappa.

Inert if no agonist present. Antagonist action results in reversal of opioid induced effects in 1-3 minutes.

Front 263

Duration of action of naloxone vs naltrexone?

Back 263

naloxone: Extensive first pass metabolism therefore IV only. Short half life 1-2 hours (duration of action usually 20 minutes) therefore frequent dosing required in overdose

naltrexone: Longer half life than naloxone (10 hours) and will block the effects of injected heroin for 48 hours

Front 264

Mechanism of ethanol?

Back 264

No specific receptor.

Affects broad range of molecular processes including neurotransmission, enzyme action, electron transport chain, ion transport.

Enhances the action of GABA
Inhibits the action of glutamate

Front 265

Oran effects of ethanol?

Back 265

Intoxication. Myocardial depression. Smooth muscle relaxation.

Front 266

Liver and GI toxicity of ethanol?

Back 266

Increased alcohol metabolism leads to increased NADH/NAD+ ratio, resulting in reduced gluconeogenesis, hypoglycaemia, ketoacidosis and promotion of TG synthesis from FFA.
Accumulation of acetaldehyde promotes inflammation.

Nutritional deficiency is due to reduced intake and reduced absorption due to small bowel injury - reduces free radical scavengers such as glutathione
Increased gastric and pancreatic secretion, alteration of mucosal barriers resulting in gastritis.

Front 267

Non-GI toxicity of ethanol?

Back 267

CNS:
Nystagmus. Generalised symmetrical peripheral neuropathy. Gait disturbance and ataxia. Dementia. Wernicke-Korsacoff syndrome - paralysis of external ocular muscles, ataxia, acute confusion, memory loss.

CVS toxicity
Dilated cardiomyopathy, ventricular hypertrophy, fibrosis. Atrial and ventricular arrhythmias. Hypertension.

Blood:
Mild anaemia due to folate deficiency.

Immune system: Higher rates of infection

Foetal alcohol syndrome: Poor growth, microcephaly, poor coordination, flattened facial features, minor joint abnormalities, congenital heart defects.

Cancer: Mouth, pharynx, larynx, oesophagus, liver.

Interactions: Additive effect with other sedatives.

Acute use tends to inhibit enzymes, chronic use induces. Additive effect with hypoglycaemics and vasodilators.

Front 268

Absorption and distribution of ethanol?

Back 268

Small, water soluble molecule rapidly absorbed from GIT. Vd approximates TBW. Concentration in CNS rises quickly due to large blood flow.

Front 269

Metabolism of ethanol?

Back 269

90% metabolised by liver, 10% excreted by lungs and urine.
Metabolism follows zero order kinetics at approximately 1 standard drink per hour.
Ethanol converted to acetaldehyde by alcohol dehydrogenase in liver and stomach and by mixed function oxidase.

MFO activity increases in alcoholism.
Acetaldehyde converted to acetate by aldehyde dehydrogenase.

Acetete converted to carbon dioxide and water.

Front 270

Mechanism of disulfram and the effect this causes with alcohol?

Back 270

Inhibition of aldehyde dehydrogenase therefore aldehyde accumulates.

Flushing, throbbing, headache, nausea, vomiting, sweating, hypotension, confusion within a few minutes of alcohol consumption.

Front 271

Interractions of disulfram with other drugs?

Back 271

Interactions Inhibits the metabolism of phenytoin, warfarin, isoniazid.

Other drugs including metronidazole, cephalosporins may have disulfiram like effects.

Front 272

Absorption and excretion of disulfram?

Back 272

Orally active. Rapidly and completely absorbed

Slow elimination

Front 273

How does methanol affect the human body?

Back 273

No specific receptor. Affects broad range of molecular processes including neurotransmission, enzyme action, electron transport chain, ion transport.
Enhances the action of GABA. Inhibits the action of glutamate.

Front 274

Symptoms of methanol consumption?

Back 274

Visual disturbance predominates -may take 30 hours to be present. Formaldehyde may be detectable on breath.

Front 275

Treatment of methanol intake?

Back 275

Charcoal ineffective Supportive Intravenous ethanol- higher affinity for alcohol dehydrogenase therefore less formate.
Haemodialysis effective

Front 276

Toxicity of methanol

Back 276

Toxicity is probably related to the formation of formate. Visual disturbances (snowstorm sensation) is typical. CVS and CNS depression, metabolic acidosis.

Front 277

Distribution of methanol?

Back 277

Small, water- soluble molecule rapidly absorbed from GIT.

Vd approximates TBW. Concentration in CNS rises quickly due to large blood flow.

Front 278

Treatment of ethylene glycol overdose?

Back 278

Charcoal ineffective. Supportive.
Intravenous ethanol -higher affinity for alcohol dehydrogenase.
Consider alcohol dehydrogenase inhibitor - 4- methylpyrazole.
Haemodialysis effective.

Front 279

Toxicity of ethylene glycol poisoning?

Back 279

Transient excitation followed by CNS depression. Severe high anion gap metabolic acidosis after 4-12 hours.
Renal insufficiency due to deposition of oxalate.

Front 280

Metacolism of ethylene glycol?

Back 280

Converted to toxic aldehydes and oxalate by alcohol dehydrogenase.

Front 281

Mechanisms of sodium chromoglycate?

Toxicity?

Back 281

Alteration of function of chloride channels in cell membranes
Inhibition of mast cell degranulation
Likely inhibits mediator release from other cells
Used for asthma prevention through MDI or inhaler

toxicity: Reversible dermatitis, myositis or gastroenteritis in 2%

Front 282

Theophilline structure and mechanism

Back 282

Inhibits phosphodiesterase at high concentrations resulting reduced degradation of cAMP and high intracellular cAMP.
Increased intracellular cAMP leads to smooth muscle relaxation.
Increased cAMP in the heart leads to calcium influx and positive chronotropic and inotropic action
Inhibition of respiratory mucosal adenosine receptors which cause contraction of smooth muscle and histamine release
Blockade of cardiac adenosine receptors leading to increased catecholamine release
Possible anti-inflammatory action.

Front 283

Dosing of theophilline in asthma?

Back 283

Loading dose should be given slowly as rapid loading results in transient toxic plasma levels.
Dose Orally 3-4mg/kg tds
Tends to be avoided IV due to toxicities but can be given as an intravenous loading dose followed by infusion

Front 284

Toxicity and interractions of theophilline?

Back 284

Therapeutic and toxic effects closely related to blood level.
Therapeutic range 5-20mg/l

Anorexia, nausea, vomiting, headache at 15mg/l
Seizures or arrhythmias at >40mg/l

Interactions : Clearance enhanced by liver enzyme inducers -phenytoin, phenobarbitone.

Clearance reduced by propanolol, macrolides, cimetidine, OCP, calcium channel blockers.

Front 285

Absorption and distribution of theophilline?

Back 285

Absorption Well absorbed orally.
Distribution Volume of distribution is proportional to lean body weight.

Rapid intravenous loading causes transient toxic plasma levels

Front 286

Metabolism of theophilline?

What type of kinetics does it display?

Back 286

Metabolised by liver
(therefore reduced dose in liver disease, heart failure).

Variable order kinetics Elimination rate is dose dependent -at low doses there is first order kinetics but metabolism is saturated at therapeutic concentrations and small increases in dose quickly lead to toxicity.

Children clear theophylline most rapidly -poor in neonates and young infants

Front 287

Mechanism of salbutamol at the molecular and cellular level?

Back 287

B2 receptor agonists
Stimulation of adenylyl cyclase results in increased cAMP
Inhibits release of mediators

Bronchodilation due to smooth muscle relaxation. Inhibition of mediator release from mast cells. Inhibition of microvascular leakage. Increase mucociliary transport.

Front 288

IV dosing of salbutamol?

Back 288

Intravenous/SC
Adults Loading dose 200ug then 5-20ug/min
Children Loading dose 7.5ug/kg then 5ug/kg/hr

Front 289

Toxicity of salbutamol

Back 289

Predictable beta agonist actions
Tachycardia, palpitations, nausea, dizziness, tremor are common
May cause an initial reduced pO2 due to ventilation/perfusion mismatch

Hypokalaemia - especially high doses in combination with methylxanthines and diuretics
Hyperglycaemia and possible ketoacidosis in diabetics
Excessive use may result in tolerance

Front 290

Metabolism of salbutamol

Back 290

Metabolised by liver.
28% excreted unchanged by kidney
Half life 4 hours.
Salmeterol has long duration of action due to high lipid solubility rather than long duration of action

Front 291

Mechanism of ipratropim

Back 291

Muscarinic antagonist
Comtetitively inhibits the action of acetylcholine at muscarinic receptors

Front 292

Toxicity of ipratropium

Back 292

Predictable antimuscarinic effects though poor systemic absorption minimises this

Front 293

Absorption and excretion of ipratropium

Back 293

Absorption Poor systemic absorption
Quaternary ammonium structure leads to poor penetration into CNS.
10% of dose reaches airways, 90% swallowed.
Onset 1-3 minutes. Peak effect 1-2 hours.

90% excreted unchanged in faeces
Half life 3 hours.

Front 294

List the common air pollutants

Back 294

Carbon monoxide 52%
Sulphur oxides 14%
Hydrocarbons 14%
Nitrogen oxides 14%
Particles 4%

Front 295

Toxicity of carbon monoxide?

Back 295

Colourless, tasteless, odourless by product of incomplete combustion
Combines reversibly with haemoglobin to form carboxyhaemoglobin 220 times more avid binding than oxygen

An individual breathing air containing 0.1% CO (1000ppm) would have a carboxyhaemoglobin level of 50%

Front 296

Treatment of carbon monoxide poisoning?

Back 296

Removal of source ABC Oxygen
Room air at 1atm, elimination half life of CO 320 minutes

100% oxygen at 1atm elimination half life 80 minutes
100% oxygen at 2atm elimination half life 20 minutes

Front 297

List 3 classes of insecticides and give examples?

Back 297

Chlorinated hydrocarbons:
DDT Lindane

Organophosphates and carbamates:
Parathion Malathion

Naturally-derived insecticides:
Pyrethrum

Front 298

Give an example of a herbicide

Back 298

Paraquat

Front 299

Give examples of commercially available cholinesterase inhibitors? list 3 types with examples

(Indirect-acting cholinoceptor stimulants)

Back 299

Alcohols - edrophonium.
Carbamates - neostigmine, physostigmine
Organo- phosphates - parathion, malathion.

Interact with acetylcholinesterase and therefore blocks the hydrolysis of acetylcholine.

Front 300

What are the mechanisms of the 3 types of cholinesterase inhibitors?

How long does the effect last for each of the 3 classes?

Back 300

Alcohols - short lived reversible binding lasting 2- 10 minutes.

Carbamates -2 step hydrolysis to form a covalent bond, lasts 30mins-6hours

Organophosphates - initial hydrolysis results in a phosphorylated active site. This undergoes aging that involves strengthening of the phosphorus-enzyme bond that may last for hundreds of hours.

Front 301

What are the effects of cholinesterase inhibitors at a molecular level?

Back 301

Effects are similar to direct acting cholinomimetics. At the NMJ, therapeutic effects prolong and intensify the physiological action of acetylcholine resulting in increased strength of contraction.

Higher does may result in fibrillation.

Front 302

What are the clinical indication for the 3 types of cholinesterase inhibitors?

Back 302

Alcohols (edrophonium):
Diagnosis of myasthenia gravis = tensilon test.

Carbamates (neostigmine, physostigmine):
Reversal of non- depolarising neuromuscular blockade. Myasthenia gravis Glaucoma
Paralytic ileus Urinary retention

Organo-phosphates (parathion, malathion): Glaucoma

Front 303

Side effects of cholinesterase inhibitors (describe muscarinic and nicotinic effects separately)

Back 303

Muscarinic agonists: nausea, vomiting, diarrhoea, salivation, sweating, vasodilation, bronchoconstriction.

Nicotinic agonists: CNS stimulation, convulsions, coma, flaccid paralysis, hypertension and cardiac arrhythmias.

Organophosphates may also cause delayed neurotoxicity

Front 304

Absorption and distribution of
1) carbamates?
2) organophosphates?

Back 304

Carbamates - absorption poor due to permanent charge and lipid insolubility. Physostigmine has better absorption due to tertiary amine group.

Organophosphates - well absorbed from skin, lung, gut, conjunctiva and distributed into CNS.

Distribution:

Carbamates - distribution in CNS negligible. Physostigmine is widely distributed.

Organophosphates - widely distributed including the CNS.

Front 305

Metabolism and excretion of
1) carbamates?
2) organophosphates?

Back 305

Carbamates: majority of the dose is excreted in the urine.

Organo-phosphates: Malathion is rapidly metabolised to inactive products and therefore relatively safe. Parathion is metabolised less effectively and is therefore more toxic.

Front 306

What are 2 naturally occuring antimuscarinic agents?

Back 306

Atropine: found in Atropa belladonna (deadly nightshade) and datura stramonium

Hyoscine: found in hyoscyamus niger

Front 307

What are the 2 types of synthetic antimuscarinic agents?

Back 307

Tertiary amines - pirenzepine, tropicamide

Quaternary amines - propantheline, glycopyrrolate, ipratropium, benztropine.

Front 308

How does atropine work?

Back 308

Competitive antagonist of acetylcholine at muscarinic receptors. Reversible blockade.

No distinction between M1,2 and 3

Salivary, bronchial and sweat glands are the most sensitive.

Front 309

What are the organ effects of atropine?

Back 309

Mydriasis
Cycloplegia
Decreased lacrimal secretion
Tachycardia (note - may cause initial bradycardia at low dose)
Increased contractility
Arterial constriction (Dilation - high dose direct effect)
Venoconstriction (Dilation - high dose direct effect) Bronchiolar smooth muscle relaxation
Decreased mucus secretion
Gut relaxation
Contraction of sphincters
Decreased salivary, gastric and pancreatic secretion.
Bladder wall relaxation
Bladder sphincter contraction Uterus smooth muscle relaxation
Decreased sweating
Drowsiness, confusion, hallucinations, dysarthria

Front 310

Clinical uses of antimuscarinic agents?

Back 310

Bradycardia due to increased vagal tone, including cardiac arrest -Atropine

Cholinomimetic (direct or indirect) poisoning -Atropine

Mydriasis -Tropicamide, Atropine

Motion sickness -Hyoscine

Bronchodilation -Ipratropium

Diarrhoea - Atropine

Urinary urgency -Oxybutynin

Front 311

Toxicity of antimuscarinic agents?

Back 311

In adults, toxic effects are an extension of the clinical effect.
Children are sensitive to hyperthermic effects that are centrally mediated.

Produce very similar effects to LSD in high doses though delusions tend to be bizarre. Effects are very long acting (several days).

Delerium, fluctuating level of awareness, difficulty in thinking and marked loss of memory are particularly characteristic.
Contraindications Glaucoma.

Front 312

Absorption and distribution of antimuscarinic agents?

Back 312

Absorption
Naturally occurring agents: Well absorbed from gut, skin and conjunctival membranes.

Synthetic agents (quaternary amines) : only 10-30% absorbed orally.

Distribution:
Naturally alkaloid esters of tropic acid - widely distributed.
Synthetic antimuscarinic agents (quaternary amines) - mostly peripheral distribution.

Front 313

Metabolism and excretion of antimuscarinic agents?

Back 313

Metabolised in liver and excreted in urine
Half life 4 hours

Front 314

What is pralidoxime?

Back 314

Cholinesterase regenerator:
The Acetylcholinesterase enzyme has two parts to it. An acetylcholine molecule bound at both ends to both sites of the enzyme, is cleaved in two to form acetic acid and choline. In organophosphate poisoning, an organophosphate binds to just one end of the acetylcholinesterase enzyme [ the esteric site ], blocking its activity. Pralidoxime is able to attach to the other half [ the unblocked, anionic site ] of the acetylcholinesterase enzyme.It then binds to the organophosphate, the organophosphate changes conformation, and loses its binding to the acetylcholinesterase enzyme. The conjoined poison / antidote then unbinds from the site, and thus regenerates the enzyme, which is now able to function again.

After some time though, some inhibitors can develop a permanent bond with cholinesterase, known as aging, where oximes such as pralidoxime can not reverse the bond

Front 315

What is pralidoxime?

Back 315

Hydrolysis of phosphorylated acetylcholinesterase
Slows aging process
Pralodoxime is only effective if aging has not occurred

Front 316

Dosing of pralidoxime?

Back 316

Pralidoxime is initially administered intravenously in a dose of 1 to 2 g. Signs of recovery appear rapidly. If the symptoms reappear, then an infusion of 2.5% is infused at a rate of 0.5 g/hour.

Front 317

What is paraqat and why is it toxic?

Back 317

herbicide

Paraquat forms a potent free radical that accumulates in the lung: Oedema, alveolitis, progressive fibrosis

Front 318

Lethal dose of paraqat

Back 318

50-500mg/kg

Front 319

Toxidrome of paraqat?

Back 319

Initial gastrointestinal symptoms Delayed onset respiratory distress Death may occur after several weeks Oxygen aggravates pulmonary effects

Front 320

How does arsenic affect tissues and what effects does this cause?

Back 320

Inhibition of enzymes of oxidative phosphorylation

Shock Arrhythmias Encephalopathy Peripheral neuropathy Pancytopenia

Front 321

How is arsenic absorbed and excreted?

Back 321

absorbed: All mucosal surfaces Widely distributed
Excreted by kidney

Front 322

How does lead affect tissues and what effects does this cause?

Back 322

inorganic oxides: Inhibition of enzymes, interferes with essential cations, alters membrane structure

Inorganic oxides and salts: Anaemia, peripheral neuropathy, nephropathy, hypertension
Organic: Encephalopathy

Front 323

How is lead absorbed and excreted?

Back 323

Inorganic oxides and salts: Gastrointestinal and respiratory tracts
Organic: All mucosal surfaces

Excretion:
Organic -Metabolised by liver to lead, excreted in urine and faeces

Front 324

How does mercury affect tissues and what effects does this cause?

Back 324

Inhibition of enzymes and membrane alterations

Elemental:
Behavioural disturbance (erethism) Gingivostomatitis
Peripheral neuropathy
pneumonitis

Inorganic: (Hg+ less toxic than Hg2+)
ATN

Organic:
CNS effects, birth defects

Front 325

How is mercury absorbed?

Back 325

Elemental: Respiratory tract

Inorganic:
Gastrointestinal tract
Skin

Organic:
All mucosal surfaces
Tend to concentrate in soft tissues, especially kidney

Front 326

How is mercury excreted?

Back 326

Elemental: Converted to Hg2+
Excreted in urine and faeces

Inorganic: Excreted in urine

Front 327

Symptoms of iron toxicity

Back 327

Nausea Epigastric pain Abdominal cramps Constipation Diarrhoea
Black stools

Front 328

Symptoms of iron overdose?

Back 328

Seen commonly in young children (10 tablets can be lethal)
Necrotising gastroenteritis with vomiting, abdominal pain and bloody diarrhoea
Shock

Improvement followed by severe metabolic acidosis, coma and death
Treated with desferrioxamine

Front 329

What is desferrioxamine?

Back 329

Used for iron poisoning

Avidly binds to iron
Competes for iron binding with haemosiderin and ferritin

Iron-chelator complex is excreted in urine

Front 330

Side effects of desferroxamine?

Back 330

Flushing
Gastrointestinal symptoms
ARDS

Front 331

Toxic dose of tricyclic antidepressants?

Back 331

>1000mg

Front 332

Toxic side effects of tricyclic antidepressants?

Back 332

1. CNS: Psychosis, sedation, seizures, coma
Antimuscarinic
Sympathomimetic: Tremor, insomnia

2. CVS: Orthostatic hypotension
Conduction defects (long PR, wide QRS>0.1s, long QT and ST), arrhythmias.

3. Respiratory depression and apnoea.

4. Metabolic acidosis

Front 333

Toxicity of salycilates?

Back 333

1. Salicylism: tinnitus, reduced hearing, vertigo.
2. Hyperventilation, fever, dehydration
3. Metabolic acidosis due to salicylic acid dissociation, deranged carbohydrate metabolism and reduced renal function.
4. Respiratory alkalosis due to central stimulation of respiratory centre Eventual renal and respiratory failure

Front 334

Norml anion gap?

Back 334

12-16meq/L

(Na+ + K+) - (HCO3- + Cl-)

Front 335

What causes an increased anion gap metabolic acidosis?

Back 335

Methanol
Ethylene glycol
Lactic acid
Cyanide
Carbon monoxide
Salicylates
Metformin

Front 336

What is the osmolar gap and what are some causes of increased osmolar gap?

Back 336

Alcohols:
ethanol intoxication
methanol ingestion
ethylene glycol ingestion
acetone ingestion
isopropyl alcohol ingestion

Sugars:
mannitol
sorbitol
glucose (in those with insulin resistance, such as diabetics)

Lipids:
Hypertriglyceridemia

Proteins:
Hypergammaglobinemia (M. Waldenström)

Front 337

What is the calculated osmolality?

Back 337

2 x [Na mmol/L] + [glucose mmol/L] + [urea mmol/L]

Front 338

Causes of increased anion gap metabolic acidosis?

Back 338

Causes include:
lactic acidosis
ketoacidosis
chronic renal failure (accumulation of sulfates, phosphates, urea)

intoxication:
organic acids (salicylates, ethanol, methanol, formaldehyde, ethylene glycol, paraldehyde, INH)
sulfates, metformin (Glucophage)
massive rhabdomyolysis

Front 339

Causes of normal anion gap metabolic acidosis?

Back 339

U - ureterosigmoidostomy
S - saline administration (in the face of renal dysfunction)
E - endocrine (Addisons, spironolactone, triamterene, amiloride, primary hyperparathyroidism)
D - diarrhea
C - carbonic anhydrase inhibitors
A - ammonium chloride
R - renal tubular acidosis
P - pancreatitis

Front 340

Is peritoneal dialysis an option for getting rid of drugs?

Back 340

no, not effective for most drugs

Front 341

What determines whether a substance is dialisable?

Back 341

Molecular weight
Water solubility
Protein binding
Endogenous clearance
Volume of distribution (small)

Front 342

What drugs is dialysis ineffective for?

Back 342

Amphetamines, cocaine
Benzodiazepines
Phenothiazines
Digoxin
Opioids
Quinidine
Tricyclics

Front 343

What drugs is dialysis effective for?

Back 343

Ethylene glycol
Methanol
Salicylate
Theophylline
Procainamide

Front 344

Features of benzo and barbiturate withdrawal?

Back 344

Withdrawal - agents with short half lives produce rapidly evolving severe withdrawal. Longer half life produces gradual, less severe withdrawal. Withdrawal similar to alcohol - agitation, nausea and vomiting reduced seizure threshold, delirium, psychosis.

Front 345

Mechanism of caffeine as a stimulant?

Back 345

Inhibits phosphodiesterase at high concentrations resulting reduced degradation of cAMP in high intracellular cAMP. Possible inhibition of adenosine receptors.

Front 346

Mechanism of nicotine?

Back 346

Causes release of catecholamines from central and peripheral nerves.
Produces insidious onset central euphoriant effect. Withdrawal characterised by pronounced and long lasting craving.

Front 347

Mechanism of cocaine?

Back 347

Inhibition of dopamine and noradrenaline reuptake Produces marked increased mental alertness and euphoria then may progress to delusions and psychosis.
Short acting compared with amphetamines but magnified effect.

Front 348

Mechanism of amphetamine?

Back 348

Cause central increased catecholamine neurotransmitter release Produces marked increased mental alertness and euphoria then may progress to delusions and psychosis

Withdrawal - lethargy, increased appetite, depression

Methamphetamine - speed
Methyeledoxymethamphetamine - ecstasy

Front 349

Mechanism and effects of LSD?

Back 349

The psychedelic effects of LSD are attributed to its strong partial agonist effects at 5-HT2A receptors but exact mechanism unknown. LSD affects a large number of the G protein-coupled receptors, including all dopamine receptor subtypes, and all adrenoreceptor subtypes, as well as many others.

Mechanism unknown ␣ interacts with several serotonin receptor subtypes. Produces dizziness, weakness, tremors, nausea and prominent visual illusions and other perceptive abnormalities. Also causes pupillary dilation, tachycardia and increased blood pressure.

Front 350

PCP mechanism and effects?

Back 350

Related to ketamine.

May act at opioid, dopamine or glutamate receptors. NMDA antagonist, D2 partial agonist, nAchR antagonist.

Produces detachment, disorientation, distortion of body image, nystagmus (vertical and horizontal), sweating, tachycardia, hypertension. Overdose can be fatal (in contrast with LSD).

Front 351

Effect of antimuscarinics (in drug abuse setting)?

Back 351

Produce very similar effects to LSD in high doses though delusions tend to be bizarre.

Effects are very long acting (several days). Delirium, fluctuating level of awareness, difficulty in thinking and marked loss of memory are particularly characteristic.

Front 352

Pharmacological profile of marijuana?
Where does it act?

Back 352

Contains several cannaboids including tetrahydrocannabinol (THC). Stimulates a specific receptor located in basal ganglia, substantia nigra, globus pallidus, hippocampus and brain stem. May also have a non-specific membrane effect.
Produces euphoria and characteristic uncontrollable laughter, alteration of time sense, sharpened vision followed by extreme relaxation and dream like states. Tachycardia and conjunctival reddening are characteristic.

Therapeutic use likely to increase due to antiemetic and
analgesic actions

Front 353

How does activated charcoal work as a decontaminant?

Back 353

Large surface area available to adsorb many drugs and poisons. 1 gram has a surface area of 1000m2 Manufactured by heating charcoal under pressure. Most effective in a 10:1 ratio of charcoal to poison.

Front 354

What substances is activated charcoal not effective for?

Back 354

does not bind:

Ions - lithium, potassium, cyanide
Heavy metals - iron Hydrocarbons
Acids/alkalis
Alcohols: ethanol, methanol

Front 355

What is whole bowel irrigation and what substances is it useful for?

Back 355

Balanced polyethylene glycol-electrolyte solution: used for iron, enteric coated medications, foreign bodies.

Front 356

Antidote to paracetamol?

Back 356

acetylcysteine

Front 357

Antidote for anticholinesterases? (organophosphates and carbamates)?

Back 357

pralidoxime

Front 358

Antidotes of tricyclic antidepressants and quinine?

Back 358

bicarbonate

Front 359

Antidote for iron salts?

Back 359

desferrioxamine

Front 360

Antidote for digoxin?

Back 360

digibind, digoxin antibodies

Front 361

Antidote for methanol and ethylene glycol?

Back 361

rthanol

Front 362

Antidote for benzodiazepines?

Back 362

flumazenil

Front 363

Antidote for beta blockers?

Back 363

glucagon

Front 364

Antidote for opioids?

Back 364

naloxone

Front 365

Antidote for carbon monixide?

Back 365

oxygen

Front 366

Antidote for antimuscarinics?

Back 366

physostigmine

Front 367

Mechanism of aspirin?

Back 367

Reduced synthesis of eicosanoid mediators:
Irreversible inhibition of cyclooxygenase
Reduced synthesis of thromboxane A2 Reduced synthesis of prostaglandins

Central blockade of CNS response to IL1 in causing fever

Front 368

Effects of aspirin and how long does it last?

Back 368

Antiplatelet
action lasts for the lifespan of the platelet - thromboxane A2 stimulates platelet aggregation and granule release

Antiinflammatory Analgesic Antipyretic

Front 369

Effects of aspirin at therapeutic, anti-inflammatory and toxic range?

Back 369

1. Therapeutic range
0-10mg/kg
Gastritis, ulceration Impaired haemostasis

2. Anti-inflammatory range 50mg/kg
Salicylism: tinnitus, reduced hearing, vertigo.

3. Toxic range 50-150mg/kg hyperventilation, fever, dehydration, metabolic acidosis

4. Serious intoxication >150mg/kg
Respiratory alkalosis due to central stimulation of respiratory centre
Renal compensation for respiratory alkalosis. Metabolic acidosis due to salicylic acid dissociation, deranged carbohydrate metabolism and reduced renal function.
Eventual renal and respiratory failure

Front 370

Interactions of aspirin with other drugs?

Back 370

Displaces from protein binding (phenytoin, methotrexate)
Decreased activity of spironolactone
Decreased tubular secretion of penicillin

Front 371

Absorption and distribution of aspirin?

Back 371

Orally active Rapidly absorbed. Acidity of stomach keeps aspirin in nonionised form that is more readily absorbed

Bound to albumin in low doses. As serum concentration rises, increasing fraction is unbound

Front 372

Metabolism and excretion of aspirin?

Back 372

Hydrolysed to acetic acid and salicylate by blood and tissue esterases.
Salicylate conjugated by liver and excreted by kidney.
Demonstrates variable order kinetics ␣ metabolism is saturable and small further increases in aspirin dose results in large rise in salicylate levels.
Half life 3-5 hours at low dose, 12 hours at anti- inflammatory doses

Alkalinisation of the urine increases rate of excretion of free salicylate
Haemodialysis indicated in severe toxicity

Front 373

Mechanism of nsaids?

Back 373

Reduced synthesis of eicosanoid mediators
Reversible inhibition of cyclooxygenase (COX1, COX2 or both)
Reduced synthesis of thromboxane A2 Reduced synthesis of prostaglandins

Prostaglandins are important mediators of inflammation

Inhibition of mediator release from leukoctes
Decreased sensitivity of vessels and pain sensors to bradykinin and histamine
Central blockade of CNS response to IL1 in causing fever

Front 374

Toxocity of ibuprofen?

Back 374

Gastritis, ulceration and minor gastrointestinal disturbance
Impaired haemostasis
Nephrotoxicity and reduced renal function in those with renal disease

Hepatotoxicity and increased liver enzymes in those with hepatic disease
Oedema, especially if pre- existing heart failure
Visual disturbances
Aseptic meningitis

Front 375

What does ibuprofen interact with?

Back 375

Warfarin: risk of fatal haemorrhage due to displacement from albumin
Lithium/digoxin: increased plasma levels Antihypertensives: reduced effect

Front 376

Contraindications of ibuprofen?

Back 376

NSAID/aspirin sensitive asthma
3rd trimester of pregnancy: may cause closure of the fetal ductus arteriosus, fetal renal impairment, inhibition of platelet aggregation and delay labour and birth

Front 377

Absorption of ibuprofen?

Back 377

Orally active
Rapidly absorbed.
Absorption slowed by food
Highly protein bound

Front 378

Metabolism and excretion of ibuprofen?

Back 378

Metabolised by liver to inactive metabolites.
Excreted in urine and bile
Half life 2 hours

Front 379

Dising of naproxen and toxicity of naproxen?

Back 379

10mg/kg in 2 divided doses slow release formulation available

may impair feritlity

Front 380

Excretion of naproxen

Back 380

Mostly excreted unchanged Half life 12 hours

Front 381

Mechanism of indomethasin, ketoprofen and diclofenac?

Back 381

Indomethacin, ketoprofen and diclofenac inhibit lipoxygease and therefore reduce formation of leukotrienes

ketoprofen Half life 2 hours

Front 382

Mechanism of mefanamic acid?

Back 382

May antagonise the actions of prostaglandins PGE2 and PGF2alpha at uterine receptors

Front 383

Is indomethacin more or less potent than aspirin?

Most effective absorption?

Back 383

Potent prostaglandin inhibitor 28 times more potent than aspirin

PR more rapid
T 1/2 4 hours

Front 384

Indications for indomethacin?

Back 384

Patent ductus arteriosus
Gout
Preterm labour (though may cause closure of the ductus, renal toxicity, delayed labour, impaired haemostasis

Dose 50-200mg/day in 2- 3 divided doses

Front 385

Indications and dosing for kerolac?

Back 385

Short-term management of post operative pain
Equally effective as 10mg morphine/100mg pethidine IM or panadeine forte
Dose 10-30mg IM every 6 hours for a maximum of 5 days

Front 386

Mechanism of paracetamol?

Back 386

Para-aminophenol derivative
Weak prostaglandin inhibitor
Probably has COX3 antagonist actions in the CNS

Front 387

Symptoms of paracetamol toxicity/overdose?
What doses typically cause this?

Back 387

Toxic symptoms include vomiting, abdominal pain, hypotension, sweating, central stimulation with exhilaration and convulsions in children, drowsiness, respiratory depression, cyanosis and coma.
Hypokalaemia and ECG changes have also been noted
In adults, hepatotoxicity may occur after ingestion of a single dose of paracetamol 10 to 15 g
25 g is potentially fatal.
Symptoms during the first two days of acute poisoning by paracetamol do not reflect the potential seriousness of the intoxication.

Major manifestations of liver failure such as jaundice, hypoglycaemia and metabolic acidosis may take at least three days to develop.

Front 388

Medications which interact with paracetamol?

Back 388

Alcohol and enzyme inducers :increased risk of toxicity

Front 389

Absorption of paracetamol?

Back 389

Orally active
Peak blood levels 30- 60 minutes Food intake delays paracetamol absorption. Partially protein bound

Front 390

Metabolism of paracetamol?

Back 390

Metabolised in liver In adults at therapeutic doses, paracetamol is mainly conjugated with glucuronide or sulfate.
Also metabolised to a toxic metabolite (cyp3a4 and cyp2a1) that is detoxified by conjugation with glutathione
Excreted in the urine

Elimination half- life varies from one to three hours.
Overdose Activated charcoal IV fluids
If 15g or more ingested, acetylcysteine

Front 391

Mechanism of paracetamol toxicity?

Back 391

Paracetamol is metabolised in the liver, mainly by conjugation with glucuronide and sulfate. It is also metabolised by cytochrome P450 to form a reactive, potentially toxic, metabolite.
This metabolite is normally detoxified by conjugation with hepatic glutathione, to form nontoxic derivatives.
In paracetamol overdosage, the glucuronide and sulfate conjugation pathways are saturated, so that more of the toxic metabolite is formed.

As hepatic glutathione stores are depleted, this toxic metabolite may bind to hepatocyte proteins, leading to liver cell damage and necrosis.

Front 392

Mechanism of NAC in paracetamol toxicity?

Back 392

Acetylcysteine is a sulfydryl (SH) group donor, and may protect the liver from damage by restoring depleted hepatic reduced glutathione levels, or by acting as an alternative substrate for conjugation with, and thus detoxification of, the toxic paracetamol metabolite.

Front 393

Dosing of NAC in paracetamol overdose?

Back 393

8 hours or less since overdose ingestion.
Initial dose 150 mg/kg over 15 minutes, followed by continuous infusion of 50 mg/kg in glucose 5% 500 mL over four hours and 100 mg/kg in glucose 5% 1 L over 16 hours.

If more than eight hours have elapsed since the overdosage was taken, the antidote may be less effective.

Rumack-Matthew nomogram gives indication of likelihood of toxicity as a function of time since ingestion and plasma levels

Front 394

NAC toxicity and contraindications?

Back 394

Nausea and vomiting
Allergic reactions
Tachycardia, chest pain

Contraindications: Asthma, renal and hepatic failure - administer with caution

Front 395

Mechnism of colchicine?

Back 395

Binds to intracellular tubulin, therefore inhibiting leucocyte migration and phagocytosis (also anti- mitotic)
Inhibits formation of leukotriene B4
Inhibits urate crystal deposition

Front 396

Dosing of colchicine?

Back 396

Acute gouty arthritis
Dose 0.5-1mg then 0.5mg every 2 hours until pain is relieved or diarrhoea occurs
Do not exceed 8mg

Front 397

Toxicity of colchicine?

Back 397

Diarrhoea (80% in 8-12 hours)
Nausea and vomiting
Bone marrow suppression (especially in overdose) inhibition of B12 absorption

Front 398

Contraindications of colchicine?

Back 398

Hepatic or renal disease
Cardiac disease
Gastrointestinal disease

Front 399

Toxicity of colchicine? Describe the dose and the two phases of toxicity

Back 399

Toxic dose >0.5mg/kg

Latent period- 2-12 hours:
Burning throat pain, bloody diarrhoea, dehydration

Second phase 24-72 hours: Shock, renal failure, muscular weakness and ascending paralysis, bone marrow suppression, DIC, multiorgan failure

Front 400

Absorption and distribution of colchicine?

Back 400

Rapidly absorbed
Bioavailability 25- 50%

Front 401

Metabolism of colchicine?

Back 401

Metabolised by liver, excreted in bile and urine.
Some enterohepatic circulation
Half life 4 hours

Front 402

Management of colchicine overdose

Back 402

Activated charcoal
Supportive measures

Front 403

Mechanism of alloprinol?

Back 403

Xanthine oxidase inhibitor
Urate formed from amino acids and purines
Xanthine oxidase is required for formation of urate therefore its inhibition will decrease production

Front 404

Toxicity of allopurinol?

Back 404

May precipitate acute gout unless given with colchicine or probenicid
Rash
Nausea and vomiting
Bone marrow depression
Impaired renal function
Impaired hepatic function

Front 405

Absorption of allopurinol?

Metabolism of allopurinol?

Back 405

80% absorbed not bound to plasma proteins

Metabolised by xanthine oxidase which it also inhibits
Half life 1-2 hours

Front 406

Describe the anatomy of sympathetic pre and post ganglionic fibres?

Back 406

Sympathetic preganglionic fibres terminate in ganglia in paravertebral chains.
Post ganglionic fibres then pass to the organs

Front 407

Describe the anatomy of parasympathetic pre and post ganglionic fibres?

Back 407

Parasympathetic fibres: some terminate in parasympathetic ganglia (ciliary, pterygopalatine, submandibular, otic, pelvic), majority terminate in organs.

Front 408

Where is acetylcholine found as a neurotransmitter?

Back 408

All pre-ganglionic autonomic
All parasympathetic post-ganglionic
All somatic motor

Front 409

How is acetylcholine made? Where do the components come from?

What can block this production?

Back 409

Acetylcholine synthesised in cytoplasm from acetyl-CoA (made in mitochondria) and choline (transported from extracellular fluid by sodium dependent carrier) - enzyme=choline acetyltransferase.

Hemicholiniums block choline carrier

Front 410

Where is acetycholine stored?

What can block the storage?

Back 410

Acetylcholine transported from cytoplasm to storage vesicle by proton antiporter.

Vesamicol blocks antiporter.

Front 411

What causes acetylcholine release?
What proteins are involved?
What blocks this?

Back 411

Calcium influx causes the vesicle to fuse with the terminal membrane and release acetylcholine into the synaptic cleft.

Synaptobrevin, SNAP and syntaxin required.

Botulinum toxin blocks release by enzymatic removal of 2 amino acids from synaptobrevin.

Front 412

What terminates the action of acetylcholine?

Back 412

Acetylcholine degraded by acetylcholinesterase into acetate and choline.

Front 413

Where is noradrenaline found?

Back 413

Most post-ganglionic sympathetic

Front 414

How is noradrenaline synthesised?

What inhibits this?

Back 414

Tyrosine carried into cell by sodium dependent carrier.
Converted to DOPA by tyrosine hydroxylase.
DOPA converted to Dopamine by DOPA decarboxylase.

Metyrosine inhibits action of tyrosine hydroxylase.

Front 415

What blocks the storage of dopamine in vesicles?

Back 415

Dopamine transported into vesicle by a carrier. Reserpine blocks carrier.

Front 416

What is the mechanism of noradrenaline release into the synapse?

What drugs potentiate this? What drugs block this?

Back 416

Calcium influx causes the vesicle to fuse with the terminal membrane and release noradrenaline into the synaptic cleft. ATP and dopamine beta hydroxylase are also released into the cleft.

Tyramine and amphetamines are capable of noradrenaline release by a displacement process that is not calcium dependent.
Release can be blocked by bretylium and guanethadine

Front 417

What terminates the action of noradrenaline at the synapse?

What stops this termination?

Back 417

Noradrenaline diffuses away from the cleft or is transported back into the cytoplasm or into the post-junctional cell.
Noradrenaline is then metabolised by MAO and COMT.
Reuptake is blocked by cocaine and tricyclic antidepressants.

Front 418

Where are muscarinic M1 receptors found?

Back 418

CNS, sympathetic postganglionic, some pre-synaptic

Front 419

What is the result of M1 muscarinic receptor binding?

Back 419

IP3, DAG, increased calcium

Front 420

Where are M2 muscarinic receptors found?

Back 420

heart, smooth muscle, endothelium, some pre- synaptic

Front 421

What is the binding result if M2 muscarinic receptors?

Back 421

Inhibit adenylyl cyclase, open potassium channels, stimulates release of EDRF.

Front 422

Where are M3 muscarinic receptors found and what is the result of receptor binding at M3 receptors?

Back 422

Exocrine glands, vessels, eye, lungs, GIT, bladder

IP3, DAG, increased calcium

Front 423

Where are nicotinic N receptors bound and what does binding result in?

Back 423

Postganglionic neurons, some pre-synaptic cholinergic terminals

Open sodium and potassium channels, depolarisation

Front 424

Where are nicotinic M receptors found and what is the result of activation of these receptors?

Back 424

Skeletal muscle endplates
Open sodium and potassium channels, depolarisation

Front 425

Where are alpha 1 adrenoceptors found and what is the result of binding to these?

Back 425

mostly smooth muscle IP3, DAG, increased calcium

Front 426

Where are alpha 2 adrenoceptors found and what is the result of binding to these?

Back 426

pre-synaptic terminals, platelets, lipocytes, smooth muscle inhibition of adenylyl cyclase, reduced cAMP

Front 427

Where are beta 1 adrenoceptors found and what is the result of binding to these?

Back 427

heart, brain, lipocytes plus presynaptic stimulation of adenylyl cyclase, increased cAMP

Front 428

Where are beta 2 adrenoceptors found and what is the result of binding to these?

Back 428

heart, lungs, smooth muscle stimulation of adenylyl cyclase, increased cAMP

Front 429

Where are beta 3 adrenoceptors found and what is the result of binding to these?

Back 429

lipocytes stimulation of adenylyl cyclase, increased cAMP

Front 430

What receptor dilates the pupil

i.e. constricts radial (pupillary dilator) muscle of iris?

Back 430

A1

Front 431

What receptor constricts pupil?

i.e. constricts circular (pupillary constrictor) muscle

Back 431

M3

Front 432

What receptor contracts the ciliary muscle?

Back 432

M3

Front 433

What receptor increases aqueous humour?

Back 433

B

Front 434

What receptors increase and decrease heart rate at the sa node?

Back 434

B1, B2 (acellerate)
M2 (decellerate)

Front 435

What receptors increase cardiac contractikity?

Back 435

B1, A1, B2 (increase)
M2 (decrease)

Front 436

What receptor contracts Skin, splanchnic blood vessels?

Back 436

A1

Front 437

What receptor relaxes skeletal muscle blood vessels?

Back 437

B2

Front 438

What adrenoceptor aggregates platelets?

Back 438

A2

Front 439

What adrenoceptors relax and contract gut wall?

Back 439

relax a2, b2
contracts M3

sphincters contract a1, relax m3

Front 440

What adrenoceptor increases secretions (salivary, gastric, pancreatic)?

Back 440

M3

Front 441

What adrenoceptor causes
1. gluconeogenesis?
2. glycogeniolysis?
3. Lipolysis?
4. Decreases lipolysis?

Back 441

1. B2, A
2. B2, A
3. B3
4. A2

Front 442

What adrenoceptor increases renin release at the kidney?

Back 442

b1

Front 443

What adrenoceptor causes
1. bladder wall contraction?
2. Bladder wall relaxation?
3. Bladder sphincter contraction?
4. Bladder sphincter relaxation

Back 443

1.B2
2. M3
3. A1
4. M3

Front 444

What adrenoceptor causes uterine contraction and relaxation?

Back 444

relax: b2
contract: A, M3

Front 445

What adrenoceptor causes
1) piloerection in the skin?
2. Increased sweating?

Back 445

1) A1
2) A, M

Front 446

Describe the 2 classes of cholomimetic drugs with examples?

Centrally mediated alerting action, tremor, emesis, convulsions.

Back 446

Choline esters: Acetylcholine (both), Methacholine (muscarinic), Carbachol (both), Bethanecol (muscarinic)

Alkaloids: Pilocarpine (muscarinic), Nicotine (nicotinic), Lobeline (nicotinic), Muscarine (muscarinic).

Front 447

Indications for cholomimetic drugs?

Back 447

1. Glaucoma: pilocarpine, methacholine, carbachol.
2. Paralytic ileus: bethanechol
3. Urinary retention: bethanechol
4. Antimuscarinic drug intoxication.

Front 448

Absorption and distribution of choline esters and alkaloids?

Back 448

Choline esters: Poorly absorbed orally.
Alkaloids: Well absorbed orally and transcutaneously.

Distribution: Choline esters Hydrophilic therefore poorly distributed in CNS
Alkaloids: Nicotine very lipid soluble therefore widely distributed in CNS

Front 449

Metabolism and excretion of choline esters and alkaloids?

Back 449

Choline esters: Hydrolysed in GIT (acetylcholine more than others, carbachol and methacholine negligible)

Alkaloids: Renally excreted, increased by acidification of the urine.

Front 450

What are the 2 types of direct acting sympathetomimetics?

Give examples of these?

Back 450

catecholamine and non-catecholamine

Catecholamines:
Adrenaline, Noradrenaline, Isoprenaline, Dopamine Dobutamine

Non-catecholamines:
Ephedrine
Phenylephrine, Amphetamine

Indirect acting sympathomimetics:
Cocaine
Tyramine

Front 451

Give an example of an alpha 1 agonist and antagonist.

Back 451

agonist: Phenylephrine A1>A2>>>>>B
antagonist: prazocin

Front 452

Give an example of an alpha 2 agonist and antagonist?

Back 452

Agonist: Clonidine A2>A1>>>>>B
antagonist: Yohimbine

Front 453

Give an example of an beta 1 agonist and antagonist?

Back 453

agonist: Dobutamine B1>B2>>>>A
antagonist: Betaxolol

Front 454

Give an example of an beta 2 agonist and antagonist?

Back 454

agonist: Terbutaline/Salbutamol (B2>>B1>>>>A)
antagonist: Butoxamine

Front 455

What is a mixed beta agonist and antagonist?

Back 455

agonist: isoprenaline
antagonist: propranolol

Front 456

What receptors does dopamine activate?

Back 456

D1=D2>>B>>A

Front 457

How are adrenoceptors regulated and what is the mechanism of this?

Back 457

Number and function of adrenoceptors may be regulated to modify physiological response. Desensitisation may occur after exposure over a period of time and results in lesser response to further stimulation.

Mechanisms:
1. Receptor sequestration -rapid and transient event decrease in receptor availability.
2. Down-regulation -reduced receptors due to reduced synthesis.
3. Receptor phosphorylation - resulting in impaired binding

Front 458

What is the general structure of sympathomimetic drugs?

What happens if you substitute at the
1) benzeine ring?
2) amino group?
3) alpha carbon?

Back 458

Sympathomimetic drugs are based on a benzene ring structure with an ethylamine side chain. Substitutions made on the terminal amino group, benzene ring or the alpha or beta carbons modify the affinity of binding at specific receptors.

Catecholamine formed by substitution with hydroxy groups on the benzene ring this increase potency but decreases bioavailability and decreases duration of action by making the drug subject to inactivation by COMT.

Substitution on the amino group increases beta receptor activity. Substitution at the alpha carbon blocks oxidation by MAO. Substitution on the beta carbon is important for storage.

Front 459

What are the catecholamine sympathomimetics?

Back 459

Adrenaline, Noradrenaline, Isoprenaline, Dopamine, Dobutamine.

Front 460

What are the non-catecholamine sympathomimetics?

Back 460

Ephedrine, Phenylephrine, Amphetamine.

Front 461

Mechanism of:
1. adrenaline?
2. Isoprenaline?
3. Noradrenaline
4. Dopamine
5. Dobutamine

Back 461

Adrenaline: Non-selective alpha and beta- adrenergic agonist.

Noradrenaline: Non-selective alpha agonist, B1 greater than B2.

Isoprenaline: Selective beta agonist Potent beta agonist, little alpha agonist effect.

Dopamine: D1 and D2 agonist with beta and alpha actions at high doses.

Dobutamine: B1 selective agonist.
(Dobutamine is a racemic mixture -the positive isomer has B1 agonist and A1 antagonist actions, the negative isomer has A1 agonist actions - the net effect is positive inotrope action with little peripheral effect hence less reflex tachycardia)

Front 462

Phenylephrine mechanism?

Back 462

Relatively pure alpha agonist with limited beta action

Front 463

Ephedrine mechanism?

Back 463

Some direct non-selective action on adrenoceptors, also causes release of stored catacholamines.

Front 464

Amphetamine mechanism?

Back 464

Causes release of stored catecholamines

Front 465

Methyldopa and clonidine mechanism?

Back 465

Methyldopa - centrally acting A2 agonist.
Clonidine - centrally acting A2 agonist).

causes centrally mediated reduction in TPR (clonidine also causes bradycardia)

Front 466

Cardiovascular effects of adrenaline and noradrenaline?

Back 466

Adrenaline: Rise in systolic blood pressure due to positive inotropic and chronotropic effects via B1 receptors. Total peripheral resistance and hence diastolic blood pressure may fall due to vasodilation mediated by B2 receptors. Bolus doses tend to have mainly peripheral vasoconstrictor effect whereas infusions have the effect described above

Noradrenaline: Rise in systolic blood pressure due to positive inotropic and chronotropic effects via B1 receptors. Total peripheral resistance and diastolic pressure also increase due to alpha effect and lack of B2 mediated vasodilation

Front 467

Cardiovascular effects of isoprenaline and dopamine?

Back 467

Isoprenaline: Marked increase in cardiac output due to positive inotropic and chronotropic effect mediated by B1 receptors. Total peripheral resistance and diastolic blood pressure fall due to vasodilation mediated by beta receptors. Systolic pressure typically falls by a small amount though may rise.

Dopamine: Reduction in TPR mediated by D1 receptors on blood vessels and pre-synaptic D2 receptors that result in reduced noradrenaline secretion. Most important effects are renal vasodilation. At higher doses, dopamine acts on beta receptors then alpha receptors to cause vasoconstriction and has an adrenaline-like action.

Dose: Renal 0.5-2ug/kg/min
Beta 2-10ug/kg/min
Alpha >10ug/kg/min

Front 468

Cardiovascular effects of dobutamine?

Back 468

Increased stroke volume and cardiac output mediated by B1 receptors. Less chronotropic effects. Mild vasodilation, sometimes vasoconstriction.

Front 469

Cardiovascular effects of phenylephrine and ephedrine and adrenaline?

Back 469

Phenylephrine: Marked increase in peripheral vascular resistance and decrease in venous capacitance mediated by alpha receptors and resulting in hypertension, and reflex vagally-induced mild bradycardia.

Ephidrine: Mainly used as a nasal decongestant, mild central stimulant effect.

Amphetamine: Marked central stimulant effect on mood and alertness. Appetite suppressant. Some efficacy in ADHD. Most have marked central stimulant effect, especially amphetamine.

Front 470

Catecholamine absorption, distribution and excretion?

Back 470

Poor bioavailability after oral administration due to catechol structure and subsequent inactivation by COMT found in gut and liver

Poor distribution to CNS due to catechol structure.
Metabolised by COMT and MAO and excreted in the urine.

Front 471

Non catecholamine sympathomimetic absorption, distribution and excretion?

Back 471

Orally active, longer duration of action.
Readily enters CNS, especially amphetamine.
Significant fraction excreted unchanged.
Weak base therefore excretion enhanced by acidification of the urine.

Front 472

Give an example of an indirectly acting sympathomimetic?
What does this do

Back 472

Cocaine

Inhibition of noradrenaline reuptake at noradrenergic synapses

Widely distributed and readily enters CNS, short duration of action

Front 473

Give 3 examples of alpha antagonists and their structure?

Back 473

Phentolamine imidazoline derivative.
Phenoxy- benzamine
Prazosin (Piperazinyl quiazoline)

Front 474

What are the receptor selectivities of
1. Phentolamine?
2. Phenoxybenzamine?
3. Prazosin?

Back 474

1. Phentolamine: Non selective mixed A1 and A2 antagonist.
Reduction in peripheral vascular resistance mediated by blockade of alpha receptors. This may result in a reflex tachycardia. Antagonism of pre- synaptic A2 receptors may cause noradrenaline release. (Also inhibits response to 5HT and H1/H2)

2. Phenoxybenzamine: A1 selective antagonist. (also blocks Ach, H1, 5HT). Blockade of catecholamine induced vasoconstriction.

3. Prazosin: Potent A1 antagonist. Decreased total peripheral resistance due to relaxation of arterial and venous smooth muscle mediated by alpha 1 blockade.

Front 475

Toxicity of
1. Phentolamine?
2. Phenoxybenzamine?
3. Prazosin?

Back 475

Phentolamine: Reflex tachycardia due to greater release of noradrenaline and its action on beta receptors

Phenoxybenzamin: Postural hypotension and reflex tachycardia. Inhibition of ejaculation, fatigue, sedation.

Prazosin: Less reflex tachycardia
1st dose hypotension
Tends to cause salt and water retention
Dizziness Palpitations Headache No effect on lipids

Front 476

Absorption and distribution of
1. Phentolamine?
2. Phenoxybenzamine?
3. Prazosin?

Back 476

Phentolamine: Poorly absorbed orally. Duration of action determined by half life and rate of dissociation from the receptor.

Phenoxybenzamine: Well absorbed orally.

Prazosin: Well absorbed orally Highly protein bound

Front 477

Metabolism and excretion of prazocin?

Back 477

Extensively metabolised by liver
50% bioavailability. Half-life 3 hours.

Front 478

Mechanism of
1. Propanolol?
2. Metoprolol?
3. Atenolol?
4. Esmolol?
5. Labetolol?
6. Carvedilol?

Back 478

1. Propanolol: Non-selective beta antagonist No action at alpha or muscarinic receptors
2. Metoprolol: B1 selective
3. Atenolol: B1 selective.
4. Esmolol B1 selective
5. Labetolol: Mixed B1 antagonist and alpha antagonist
6. Carvedilol: Mixed non-selective beta blocker and alpha antagonist

Front 479

Which beta blockers also have local anesthetic actions?

Back 479

The following beta blockers also act as membrane stabilisers by sodium channel blockade
Acebutolol Betaxolol Labetolol Metoprolol Pindolol Propanolol

Front 480

CVS, respiratory, eye and metabolic effects of beta blockers?

Back 480

CVS
Negative inotropic and chronotropic effect on the heart. (including slowed AV conduction and increased PR interval)
Increased peripheral vascular resistance due to unopposed alpha effects. Antagonism of the release of renin (B1) resulting in reduced TPR

RS
Increased airway resistance (largely avoided by B1 selective agents but not completely).

Eye
Decreased aqueous humour production leading to reduced intraocular pressure.

Metabolic and endocrine: Inhibition of catecholamine induced lipolysis and glycogenolysis via B2 receptors.
Impair the recovery from hypoglycaemia as this is usually mediated by catecholamines.
Masking of clinical signs of hypoglycaemia and impaired recovery from hypoglycaemia
Increased VLDL, decreased HDL

Front 481

Metoprolol and propranolol CNS side effects?

Back 481

Sedation, sleep disturbance, depression, psychotic episodes.

Front 482

What do beta blockers interract with?

Back 482

Calcium antagonists - leading to severe hypotension, bradycardia, congestive cardiac failure

Front 483

Absorption and distribution of beta blockers?

Back 483

Absorption Well absorbed orally.

Distribution Large volume of distribution.

Propanolol: Lipid soluble Readily crosses BBB
Metoprolol: Moderate lipid solubility
Atenolol: Low lipid solubility
Esmolol: Low lipid solubility

Front 484

Metabolism and excretion of propranolol?

Back 484

Extensive first pass metabolism Excreted in urine Variable between individuals
Low bioavailability
Half life 3-6 hours
Dose reduction required in hepatic failure

Front 485

Metabolism and excretion of
1. metoprolol?
2. atenolol?
3. esmolol?

Back 485

1. Metoprolol: Extensive first pass metabolism
Low bioavailability, Half life 3-4 hours
2. Atenolol: Less extensive first pass metabolism Low bioavailability. Half life 6-9 hours
3. Esmolol: Rapidly hydrolysed by esterases in red blood cells. Half life 10 minutes.

Front 486

What does Trimethaphan do?

Back 486

ganglion blocking agent: Competitive antagonist at nicotinic cholinoceptors on sympathetic and parasympathetic postganglionic neurons.
Causes pooling of blood in capacitance vessels.

Abandoned due to side effects ␣ sympathoplegia (excessive orthostsaic hypotension, sexual dysfunction) and parasympathoplegia (constipation, urinary retention, glaucoma, blurred vision, dry mouth)

IV administration

Front 487

Mechanism of Guanethidine?

Back 487

Inhibitor of noradrenaline release from postganglionic sympathetic neurons: Guanethidine is transported across the nerve membrane by uptake 1. Concentrated in transmitter vesicles where it replaces noradrenaline causing depletion of noradrenaline stores.

Causes reduced cardiac output due to bradycardia and relaxation of capacitance vessels.

Postural hypotension common. Overdosage may result in severe hypotension or shock. May induce hypertensive crisis in those with phaechromocytoma due to release of noradrenaline. Effects are attenuated when TCAs are coadministered due to their effect on blocking reuptake.

Very large volume of distribution and long half life.

Front 488

Mechanism of reserpine?

Back 488

Reserpine blocks carrier mediated transport of dopamine into the vesicle. Results in depletion of dopamine, noradrenaline, and serotonin in central and peripheral neurons.

Causes antihypertensive effect by reduction in cardiac output and total peripheral resistance.

Effects are largely irreversible and last for several days.

Front 489

For methyldopa state the:
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 489

1. Centrally acting alpha agonist. Inhibition of dopa decarboxylase and depletion of noradrenaline
A2 actions greater than A1
2. Centrally mediated reduction in total peripheral resistance with variable reduction in heart rate and cardiac output.
3. Mild to moderate hypertension.
Pregnancy induced hypertension
Dose 0.5-3g/day in divided doses 0.25-1g IV over 20 minutes.

Front 490

For methyldopa state the:
1. Toxicity and interactions

Back 490

CVS
May cause postural hypotension and bradycardia.

CNS
Sedation and loss of concentration Depression Nightmares.

Endocrine: Lactation -mediated by inhibiting action on dopaminergic mechanisms in the hypothalamus.

Other: Positive Coombs test is 25%.
Interactions May result in lithium toxicity if co-administered

Front 491

For methyldopa state the:
1. Absorption and distribution
2. Metabolism and excretion

Back 491

1. Absorption Orally active. Occasional IV use occasional.
Distribution Active transport into brain
2. Extensive first pass metabolism.
Metabolised in liver ␣ likely production of an active metabolite.
Most is renally excreted.
Antihypertensive effect in 4-6 hours, clinical effect may last 24 hours due to active metabolite.

Front 492

For clonidine state the:
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 492

1. Centrally acting partial agonist at alpha receptors, causing reduced sympathetic tone and increased parasympathetic tone. Preference for A2
2. Reduction in blood pressure and mild bradycardia.
3. Hypertension

Front 493

For clonidine state the:
1. Toxicity and interactions

Back 493

Sedation, dry mouth. Depression. Reactive hypertensive crisis if rapidly withdrawn.

Front 494

For clonidine state the:
1. Absorption and distribution
2. Metabolism and excretion

Back 494

Orally active, bioavailability 75%.
Distribution Lipid soluble and rapidly enters the brain.
Half life 8-12 hours

Front 495

For acetazolamide state the:
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 495

1. carbonic anhydrase inhibitor: Carbonic anhydrase most prominent in the luminal membrane of the PCT
2. Profound depression of bicarbonate reabsorption in the proximal tubule
Reduced production of bicarbonate by the ciliary body
3. Glaucoma Urinary alkalinisation Metabolic alkalosis Acute mountain sickness
Epilepsy
Dose 250mg-1g/24hours

Front 496

For acetazolamide state the:
1. Toxicity and interactions

Back 496

Toxicity: Hyperchloraemic metabolic acidosis
Renal stones
Renal potassium wasting
Skin reactions

Interactions :
Salicylates - increased risk of metabolic acidosis Phenytoin - reduced excretion of phenytoin resulting in toxic levels

Contraindications:
Hepatic failure - acetazolamide will decrease the urinary loss of ammonia.

Front 497

For acetazolamide state the:
1. Absorption and distribution
2. Metabolism and excretion

Back 497

Well absorbed orally Increased urinary pH within 30 minutes

Front 498

For frusemide state the:
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 498

1. Inhibition of the Na/K/2Cl cotransporter in the thick ascending limb of the loop of Henle resulting in reduced reabsorption of sodium chloride
Indirect increase in calcium and magnesium excretion
3. Acute pulmonary oedema Hypertension Hyperkalaemia Hypercalcaemia
Dose 20-80mg PO/IV

Front 499

For frusemide state the:

1. Toxicity and interactions

Back 499

Toxicity Hypokalaemic metabolic acidosis
Dose related ototoxicity
Hyperuricaemia
Hypomagnesaemia
Allergic reactions

Hyperbilirubinaemia -displaces bilirubin from albumin

Contraindications: Known hypersensitivity to sulphonamides (cross- sensitivity may occur) ARF

Front 500

For frusemide state the:

1. Absorption and distribution
2. Metabolism and excretion

Back 500

Absorption: Well absorbed orally Diuretic response in less than 5 minutes with intravenous use

Distribution: Bound to albumin
Half life 2-3 hours

Diuretic response is proportional to their excretion in the urine
One third is filtered, two thirds is secreted by the proximal tubule

Front 501

For thiazide state the:
1. Mechanism?
2. Clinical use?

Back 501

Inhibition of sodium/chloride cotransporter in the early DCT

Hypertension Congestive cardiac failure Urolithiasis due to idiopathic hypercalciuria Nephrogenic diabetes insipidus
Dose 25-50mg/day

Front 502

For thiazide state the:

1. Toxicity and interactions

Back 502

Toxicity: Hypokalaemic metabolic alkalosis Hyperuricaemia
Hyperlipidaemia
Hyponatraemia
Allergic reaction

Front 503

For thiazide state the:
1. Mechanism?
2. Organ effects?
3. Clinical use?
1. Toxicity and interactions
1. Absorption and distribution
2. Metabolism and excretion

Back 503

Absorption Well absorbed orally
Distribution Bound to albumin
Eliminated rapidly by the kidney
Half life 5-14 hours

Front 504

For potassium sparing diuretics state the:
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 504

1. Spironolactone: Competitive antagonism of aldosterone at mineralocoticoid receptors

Triamterene, amiloride: Direct inhibition of sodium reabsorption in the CD

2. Decreased sodium reabsorption Decreased potassium excretion
3. Most useful when there is a mineralocorticoid excess such as Conn syndrome or secondary aldosteronism due to congestive heart failure

Front 505

For potassium sparing diuretics state the:

1. Toxicity and interactions

Back 505

Toxicity: Hyperkalaemia Hyperchloraemic metabolic acidosis Gynaecomastia

Interactions: Triamterene and indomethacin have caused acute renal failure

Front 506

For potassium sparing diuretics state the:

1. Absorption and distribution
2. Metabolism and excretion

Back 506

Spironolactone: Metabolised by liver
Triamterene: Metabolised by the liver and excreted by the kidney
Amiloride: Excreted unchanged in urine

Front 507

For osmotic diuretics state the:
1. Mechanism?
2. Clinical use?

Back 507

Mannitol :
Filtered
Not metabolised Not secreted Not reabsorbed
Maintains osmotic gradient in the lumen of the tubule and therefore preventing absorption of water

Increase urine volume in haemolysis or rhabdomyolysis
Reduction in intracranial and intraoccular pressure
Dose 1-2g/kg

Front 508

For osmotic diuretics state the:

1. Toxicity

Back 508

Extracellular volume expansion -may exacerbate pulmonary oedema of CCF
Dehydration

Front 509

For Hydralazine state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 509

1. Direct acting vasodilator
Mechanism unknown -may interfere with calcium entry into the cell and cause electromechanical decoupling.
2. Arterial dilator - little effect on veins.
Lowers systemic vascular resistance to cause decreased blood pressure.
3. Severe hypertension.
Severe pre- eclampsia
Dose Oral : 50- 200mg/day in divided doses IV ␣ 20-40mg slowly

Front 510

For Hydralazine state the

1. Toxicity and interactions

Back 510

CVS
Reflex tachycardia - may provoke angina. (can be used in combination with a beta blocker) Increases plasma renin activity

CNS
Increased cerebral blood flow
Others Headache Nausea Flushing

Front 511

For Hydralazine state the

1. Absorption and distribution
2. Metabolism and excretion

Back 511

1. Oral or intravenous preparations
2. Extensive first pass metabolism. (variable between individuals due to acetylation status)
Low bioavailability.
Half life 2-4 hours.
Mostly excreted in urine.

Front 512

For sodium nitroprusside state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 512

1. Direct acting vasodilator.
Acts by activation of guanylyl cyclase resulting in increased cGMP which relaxes smooth muscle.
No effect on other smooth muscle
2. Arterial and venous dilator (more active on veins)
Lowers peripheral vascular resistance and venous return to cause decreased blood pressure
3. Hypertensive crisis Aortic dissection prior to surgery
Dose 0.5-10ug/kg/min if blood pressure is not controlled at maximum rate in 10 minutes the infusion should be terminated
500ug/kg of SNP produces toxic amounts of cyanide

Front 513

For sodium nitroprusside state the

1. Toxicity and interactions

Back 513

CVS
Compensatory tachycardia. Compensatory increase in catecholamines and renin.

RS
May causes reduced PaO2 due to attenuation of hypoxic pulmonary vasoconstriction

CNS: Increased cerebral blood flow and increased intracranial pressure

Endocrine: Delayed hypothyroidism can occur due to take up by thyroid tissue.

Other: Cyanide combines with cytochrome C and leads to impairment of aerobic metabolism. Accumulation can cause metabolic acidosis, arrhythmias and hypotension.
Cyanide toxicity related to rate of infusion rather than dose.

Exacerbated by B12 deficiency, hypothermia, renal and hepatic impairment. Thiocyanate toxicity may occur after several days and cause weakness, disorientation and psychosis.

Front 514

For sodium nitroprusside state the

1. Absorption and distribution
2. Metabolism and excretion

Back 514

Given by IV infusion. Sensitive to light therefore IV line covered in foil.
Distribution Extracellular fluid volume

Rapidly metabolised by uptake into red cells
Effectively combine with methaemaglobin to form cyanomethaemaglobin
One molecule of SNP combines with haemoglobin to form cyanmethaemoglobin and 4 molecules of cyanide
Cyanide ions combine with methaemoglobin to form cyanomethaemoglobin.
Cyanide also reacts with thiosulphate in the plasma to form thiocyanate.
Saturation of the above mechanisms leads to the accumulation of cyanide

Free cyanide reacts with cytochromes and prevents their participation in oxidative metabolism, resulting in severe metabolic acidosis

Front 515

For Diazoxide state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 515

1. Direct acting vasodilator Mechanism unclear
May act by opening potassium channels in smooth muscle membrane.
May have a calcium antagonist action
2. Arteriolar dilator ␣ little effect on veins. Lowers systemic vascular resistance to cause decreased blood pressure.
Effect is rapid and profound and is associated with significant reflex tachycardia.
3. Hypertensive emergencies.
Intractable hypoglycaemia
Dose 5mg/kg

Front 516

For Diazoxide state the

1. Toxicity and interactions

Back 516

CVS
Excessive hypotension. Reflex tachycardia - may provoke angina. Increased plasma renin activity.
Endocrine: Inhibits insulin release.

Front 517

For Diazoxide state the

1. Absorption and distribution
2. Metabolism and excretion

Back 517

Intravenous
Extensive albumin binding.
Metabolised in liver and excreted in urine.

Front 518

For minoxidil state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 518

1. Arterial dilator - little effect on veins. Lowers systemic vascular resistance to cause decreased blood pressure. Tends to have a greater effect than hydralazine.
Direct acting vasodilator - acts by opening potassium channels in smooth muscle membrane.
2. Severe hypertension refractory to other antihypertensives
Dose 5-40mg/day

Front 519

For minoxidil state the

1. Toxicity and interactions

Back 519

Headache, nausea, anorexia, palpitations. Reflex tachycardia - may provoke angina.

Front 520

For minoxidil state the

1. Absorption and distribution
2. Metabolism and excretion

Back 520

1. Well absorbed orally Does not enter CNS
2. Metabolised by liver and excreted in urine
Half life 4 hours.

Front 521

For ACEI state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 521

1. Inhibition of angiotensin converting enzyme that converts angiotensin I to angiotensin II and inactivates bradykinin.
Angiotensin II is a potent vasoconstrictor. Bradykinin is a potent vasodilator.
2. CVS
Reduced peripheral vascular resistance due to:
Inhibition of renin- angiotensin system
Stimulation of the kallikrein-kinin system.
Cardiac output and heart rate are unaffected.
Most effective in individuals with high plasma renin activity.
Effective in improving intrarenal haemodynamics due to reduction in intraglomerular capillary pressure. Subsequent reduction in proteinuria.
3. Hypertension. Diabetes.
Congestive cardiac failure.
Post myocardial infarction to reduce the risk of heart failure
Dose Captopril 25mg tds Enalapril 10-20mg od Lisinopril 10-40mg od

Front 522

For ACEI state the

1. Toxicity and interactions

Back 522

Toxicity: First dose hypotension - profound hypotension especially if hypovolaemic.
Dry cough and angioedema - due to effects of bradykinin.
Acute renal failure -can occur with all ACE inhibitors particularly associated with renal artery stenosis. due to dependence on renin- angiotensin system for renal function

Hyperkalaemia (more likely in renal failure or diabetes) -important consideration with potassium sparing drugs.

Mild hepatitis, rare hepatic failure
Altered taste. Rash.

Interactions: NSAIDs should be avoided as they inhibit prostaglandin synthesis that is crucial to the bradykinin mechanism for inducing vasodilation

Contraindications: Pregnancy (2nd and 3rd trimester) due to fetal malformations, fetal hypotension and fetal renal abnormalities.

Front 523

For ACEI state the

1. Absorption and distribution
2. Metabolism and excretion

Back 523

Captopril Rapidly absorbed.
Bioavailability 70%
Wide distribution except CNS.

Lisinopril: Slowly absorbed

Captopril 70% bioavailability.
Metabolised to disulphide conjugates and excreted in urine
Dose reduction required in renal failure
Half life 3 hours.

Enalapril - prodrug that is converted to enalaprilat.
Lisinopril - a lysine derivative of enalaprilat
All others are prodrugs converted to active agents by hydrolysis in the liver
Long half lives - up to 12 hours

Front 524

For nitratesstate the
1. Mechanism?
2. Organ effects?
3. Clinical use?


Glyceryl trinitrate, Isosorbide mononitrate, Isosorbide dinitrate
Nitric or nitrous acid esters of polyalcohols.

Back 524

1. Cause release of NO from vascular smooth muscle endothelium.
Nitric oxide causes activation of guanylyl cyclase and an increase in cGMP
cGMP causes dephosphorylation of myosin light chain to result in relaxation of muscle.
2. Direct effects: Relaxation of smooth muscle. Veins respond at a lower drug concentration than arteries. Arterioles and pre- capillary sphincters have a lesser response due to local reflex responses and decreased ability to secrete NO.
Venodilation causes marked increase in venous capacitance, decreased preload and in most cases reduced cardiac output, thereby reducing myocardial oxygen demand.
Systolic BP decreases more than diastolic.
Arterial dilation also reduces afterload.
There is dilation of the coronary arteries that may reduce spasm.
Nitrates tend to causes bronchiolar and gut smooth muscle relaxation also.

Indirect effects: Compensatory responses include sympathetic tachycardia and increased contractility.
Also retention of salt and water via renin angiotensin system.
Overall effect is decreased myocardial oxygen requirement.
Relaxation of bronchial and gastrointestinal smooth muscle.
Decreased platelet aggregation.
Nitrate converted in small quantities to nitrite which reacts with haemoglobin to form methaemoglobin.

3. Stable and unstable angina. LVF. Hypertension.
Dose SL 300mcg TD 5-10mg/24hrs IV 10-400mcg/min

Front 525

For nitrates state the

1. Toxicity and interactions

Back 525

CVS
Extension of clinical effect : hypotension, tachycardia, headache.
Tolerance - smooth muscle develops tolerance after continuous exposure. Tolerance may occur at a cellular level but may also result from compensation (indirect) actions of the drug itself. Clinically important tolerance does not occur with IV infusion.
Other Formation of nitrosamines by combination of nitrate/nitrite with amines - potentially carcinogenic.

Coronary Steal Syndrome: If two branches of a coronary artery have different levels of obstruction, the more obstructed branch will have relative arteriolar dilation at rest due to local metabolites. If an arteriolar vasodilator is introduced, both most effect will be to the less obstructed arteriole. Resistance in this vessel will fall and steal blood from the more obstructed vessel worsening the angina.
Therefore, drugs such as nitrates that do not have a profound effect on arterioles are most effective in angina.

Front 526

For nitrates state the

1. Absorption and distribution
2. Metabolism and excretion

Back 526

Absorption: High capacity hepatic nitrate reductase removes nitrate groups and therefore limits bioavailability after oral administration to 10%

Sublingual route bypasses first pass metabolism. If given orally, much larger does required.
Transdermal route also effective.
Distribution 60% protein bound

metabolised in the liver and red cells by reduction to dinitrates, mononitrates and nitrites.
Half-life of short- acting sublingual GTN is 4-8 minutes though clinical effect may persist to 20-30 minutes.
Active metabolites can persist for up to 3 hours.
Excretion is via the kidney.

Front 527

For dihydropyridine and non-dihydropyridine calcium channel blockers state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 527

1. Dihydropyridine and miscellaneous calcium channel blockers bind to slightly different receptors associated with the (L type) calcium channel.
Drugs act from the inner side of the membrane.
Binding is more effective to channels in depolarised membranes. (although drug binds to activated and inactivated channels)
Binding results in the channel failing to open in response to depolarisation.
Decrease in calcium current causes smooth muscle relaxation, reduced contractility and slowing of pacemaker cells.
Blockade can be partially reversed by sympathomimetic that increase transmembrane flux of calcium
Vascular smooth muscle is most sensitive, but other smooth muscle is partially affected
Verapamil and diltiazem may also causes sodium channel blockade
Verapamil may have some anti-adrenergic effect
2. Smooth muscle Most types of smooth muscle are affected ␣ vascular smooth muscle is particularly sensitive.
Arterioles are more sensitive than veins
Results in reduced peripheral vascular resistance
Also may reduce coronary artery tone
Dihydropyridines have a greater vascular selectivity. Nimodipine more effective in cerebral vessels.
Cardiac muscle

Verapamil and diltiazem demonstrate cardiac selectivity
Calcium channel blockade is more marked in those tissues that fire frequently and depend solely on calcium current such as SA and AV nodes. Atrioventricular nodal conduction and refractory period are prolonged.
Verapamil is effective in suppressing early and late delayed after potentials
Negative inotrope.

Skeletal muscle unaffected by calcium channel blockers as it utilises intracellular pools of calcium. Verapamil may have a specific anti-adrenergic effect.

Front 528

For dihydropyridine and non-dihydropyridine calcium channel blockers state the

1. Toxicity and interactions

Back 528

CVS: Extensions of therapeutic effects ␣ hypotension, bradycardia, AV block, cardiac depression.
Hypotension and VF can occur if given for VT.
All cause worsening of heart failure
Verapamil has greatest cardiac depressant effects followed by diltiazem
Dihydropiridines have less cardiac depressant effects and tend to cause a reflex tachycardia

Endocrine: Verapamil inhibits insulin release (not significant) and may be useful in cancer chemotherapy
General: Flushing Dizziness Nausea Constipation

Interactions: Dangerous cardiodepressant effects can occur if co- administered with beta blockers.
Verapamil may cause increased blood levels of digoxin.
Contraindications: Nifedipine has been associated with increased risk of myocardial infarction when used for hypertension in patients with unstable angina

Front 529

For dihydropyridine and non-dihydropyridine calcium channel blockers state the
1. Abosrption and distribution
2. Metabolism and excretion

Back 529

Absorption Orally active
Distribution >90% protein bound

All extensively metabolised
Variable bioavailability -generally greater than 50% except verapamil (20%)
Diltiazem excreted in faeces.
Verapamil metabolised by liver and mostly excreted by kidney, remainder by GIT.
Half lives Amlodipine 30-50 Nifedipine 4 Felodipine 11-16 Nimodipine 1-2
Diltiazem 3-4 Verapamil 6

Front 530

For digoxin state the
1. Mechanism and structure?
2. Organ effects?
3. Clinical use?

Back 530

Steroid nucleus (lipophilic) attached to a lactone ring (hydrophilic).
No ionisable group therefore solubility is not pH dependant.
Found in foxglove, oleander, lily of the valley, toads

1. Inhibition of Na+/K+ ATPase
Several binding sites are present and digoxin binds to the alpha subunit. Very low concentrations of drug may stimulate the enzyme. Toxic doses ␣ sympathetic effects.
2. Direct membrane actions: Increase in intracellular sodium concentration.
Increased intracellular sodium results in increased function of the sodium/calcium exchanger, causing a rise in intracellular calcium.
Increased free calcium results in increased intensity of actin/myosin interaction, resulting in increased force of contraction.
Increased free calcium also reduces potassium conductance and causes shortening of the action potential. (though initial lengthening of the action potential is characteristic)
Inhibition of Na+/K+ ATPase, as well as causing increased intracellular sodium, results in decreased intracellular potassium (toxic effect) and reduced resting membrane potential.
More toxic concentrations of digoxin lead to overloading of calcium stores and fluctuation in concentration, resulting in oscillatory depolarising after potentials that may result in ectopic beats ␣ sometimes resulting in bigeminy/VT/VF.
Autonomic actions: Low dose -parasympathomimetic effects via central vagal stimulation, sensitisation of baroreceptors and facilitation of muscarinic transmission.

Front 531

For digoxin state the

1. Toxicity and interactions

Back 531

CVS:
Arrhythmias - due to direct membrane effect and autonomic effect: AV junctional, ventricular ectopics, bigeminy, VT, VF.

GIT:
Anorexia, nausea, vomiting, diarrhoea.

CNS:
Disorientation, hallucinations, visual disturbance of colour perception, convulsions.

Endocrine: Gynaecomastia.

Interactions: Potassium and digoxin inhibit each others binding to Na/K ATPase
Hyperkalaemia therefore reduces digoxin binding and reduces toxicity
Hypokalaemia (and hypomagnesaemia) may result in digoxin toxicity (therefore care with diuretics)
Hypercalcaemia and hypomagnesaemia increases toxic effects of digoxins as they accelerate cellular calcium overload

Quinidine displaces digoxin from binding site but more importantly markedly reduces digoxin clearance

Contraindications WPW syndrome: digoxin increases the probability of conduction through alternative pathways.
Increased sensitivity of the myocardium in elderly patients

Front 532

For digoxin state the

1. Absorption and distribution
2. Metabolism and excretion

Back 532

Well absorbed orally. 10% have gut bacteria that inactivate digoxin therefore require higher dose Care when these people are then given antibiotics as they may become digitoxic
Distribution Widely distributed in all tissues including CNS
Tends to accumulate in heart, kidney and liver due to propensity to bind tissue proteins in these organs

2/3 excreted unchanged by kidneys.
Renal clearance proportional to creatinine clearance
Dose adjustment required in renal insufficiency
Half life 40 hours
Loading dose is given
Narrow therapeutic window.

Front 533

Dosing of digoxin?

Back 533

Non-emergency administration Oral 125-250ug/day

Rapid oral digitalisation Adult 750-1500ug Elderly 500-750ug as a single dose or 3-4 divided doses, then maintenance

Emergency parenteral digitalisation
Adult 500-1000ug Elderly 250-500ug as a single dose or 3-4 divided doses, then maintenance

Front 534

What determines the pacemaker rate? (i.e. what slows it down)

Back 534

More negative potential in phase 4 (ie resting potential)
Reduction in the slope of phase 4
More positive threshold potential
Prolongation of the action potential duration.

Front 535

What are early depolarisations?

Back 535

Occur in phase 3 Arise from plateau Exacerbated by slow heart rates Contribute to development of QT related arrhythmias.

Front 536

What do class 1a, 1b, 1c, 2, 3, 4 antiarrhythmics do?

Back 536

1 are sodium channel blockers
1a: Quinidine Procainamide Disopyramide TCAs- shorten action potential duration
1b- shorten action potential duration Lignocaine Tocainide, Mexilitine, Phenytoin
1c- No effect or may minimally lengthen action potential duration Flecainide
class 2 - beta blockers
Class 3 potassium channel blockers
Class 4 calcium channel blockers

Front 537

For quinidine state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 537

1. Class 1a antiarrhythmic: Binds to and blocks activated sodium channels. Block results in: Reduced rate of rise of phase 0 of the cardiac action potential, causing lengthening of the action potential
Lengthening of the refractory period
Alpha adrenoceptor properties (may be prominent with IV injection)
2. Increased QRS and QT intervals
3. Atrial flutter/fibrillation. Ventricular tachycardia

Front 538

For quinidine state the

1. Toxicity and interactions

Back 538

Pro arrhythmogenic
Antimuscarinic actions: May inhibit vagal effects - this may result in increased sinus rate and increased atrioventricular conduction
syncope
Prolonged QT may lead to VF or torsades de pointes in 2-8%

Cardiac depression: May cause asystole, more likely at high concentrations and hyperkalaemia.

Preceded by 30% increase in QRS duration.

Extracardiac: Nausea, vomiting and diarrhoea. Rash, fever, hepatitis

Quinidine only Cinchonism - headache, dizziness, tinnitus. Angioneurotic oedema.

Interactions: Reduces digoxin clearance therefore increases levels
Increased effect with hyperkalemia
Inhibition of metabolism of TCAs, beta blockers

Front 539

For quinidine state the

1. Absorption and distribution
2. Metabolism and excretion

Back 539

1. Well absorbed orally. 80% bound to plasma proteins.
2. Metabolised in liver. 20% excreted unchanged in urine - enhanced by acidic urine.
Half life 6 hours.

Front 540

For procanimide state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 540

1. Binds to and blocks activated sodium channels.
Block results in: Reduced rate of rise of phase 0 of the cardiac action potential, causing lengthening of the action potential Lengthening of the refractory period
Blocks potassium channels and reduces outward repolarising current. Lengthens action potential duration (reflected by a lengthening of QT interval) - reduces the time spent in diastole and therefore makes more activated sodium channels available for blockage.
2. Action potential and refractory period are lengthened
Increased QRS and QT intervals
3. Atrial flutter/fibrillation. Ventricular tachycardia

Front 541

For procanimide state the

1. Toxicity and interactions

Back 541

Pro arrhythmogenic
Antimuscarinic actions: Mild compared with quinidine
syncope
Prolonged QT may lead to VF or torsades de pointes in 2-8%
Cardiac depression May cause asystole, more likely at high concentrations and hyperkalemia. Preceded by 30% increase in QRS duration.

Ganglion blocking actions Can cause hypotension with IV use though usually not a problem with oral use.
Extracardiac: Nausea, vomiting and diarrhoea. Rash, fever, hepatitis
0.5% risk of serious blood dyscrasia

Drug-induced lupus Interactions
Increased effect with hyperkalemia
Amiodarone causes increased effect

Front 542

For procanimide state the

1. Absorption and distribution
2. Metabolism and excretion

Back 542

Oral or intravenous Widely distributed
Metabolised in liver. Major metabolite N acetyl procainamide (NAPA) has class 3 actions.
Metabolism reduced in slow acetylators
Renal excretion important for NAPA - therefore dose adjustment is required in renal failure.
Half life of procainamide 3-4 hours.
Half life of NAPA is considerably longer and therefore may accumulate.

Front 543

For Lignocaine state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 543

1. Blocks both activated and inactivated sodium channels.
Shortens the action potential thereby increasing diastole.
Lignocaine suppresses activity of depolarised arrhythmogenic tissue but has minimal effect on normal tissue.
Most cells become drug free in diastole.
2. Action potential and refractory period are shortened
3. Ventricular tachycardia and fibrillation after defibrillation.
Local anaesthetic.

Front 544

For Lignocaine state the

1. Toxicity and interactions

Back 544

CVS
Pro arrhythmogenic
Depression of cardiac pacemaker activity, excitability and conduction.
Negative inotropic effect and decreased peripheral resistance.
Exacerbates ventricular arrhythmias in <10%.
May causes hypotension.

CNS
Drowsiness, visual and auditory disturbance, restlessness, nystagmus, shivering, convulsions, CNS depression.

Interactions: Drugs that decrease liver blood flow (propanolol, cimetidine) reduce lignocaine clearance.

Front 545

For Lignocaine state the

1. Absorption and distribution
2. Metabolism and excretion

Back 545

1. Widely distributed after intravenous administration to highly perfused organs.
Extensive first pass metabolism - 3% bioavailability.

(note - Tocainide and mexiletine are cogeners of lignocaine that are resistant to first-pass metabolism and have similar effects)

2. Metabolised in liver and plasma.
Clearance dependent on hepatic blood flow
Excreted in urine.
Half life 1.5 hours

Front 546

For Flecanide state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 546

Sodium channel blocker
Decreases rate of rise pf phase 0 of the cardiac action potential
Little effect on action potential duration
Lengthens refractory period
Greatest action in the His-Purkinje system
SVT Pre-excitation syndromes Ventricular arrythymias

Front 547

For flecanide state the

1. Toxicity and interactions

Back 547

Safe drug with few side effects.
Pro arrhythmogenic

Front 548

For Flecanide state the
1. Mechanism?

1. Absorption and distribution
2. Metabolism and excretion

Back 548

Well absorbed orally.
Half life 20 hours, usually given twice daily. Metabolised by liver and excreted by the kidney.

Front 549

For Amiodarone state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 549

1. Potassium channel blockade - class 3 action Results in lengthening of the action potential even at high heart rates.
Increased refractory period

Sodium channel blockade - class 1 action
Acts on inactivated channels only
Most pronounced in tissues that have long action potentials, frequent action potentials or less negative diastolic potentials.

Calcium channel blockade - class 4 action

Non competitive beta blockade - class 2 action
Also causes partial inhibition of beta receptors.

2. CVS
Slows sinus rate. Slows AV nodal conduction. Markedly prolongs QT interval.
Prolongs QRS duration.
Increases refractory period duration.
Increases coronary blood flow and reduces myocardial oxygen demand
Extra-cardiac effects: Peripheral vascular dilation due to beta and calcium blocking effects.
3. Supraventricular and ventricular tachyarrhythmias including in cardiac arrest protocols.
Dose Intravenous 5mg/kg usually administered as an infusion over 20 minutes but can be given as a bolus.
Oral 200mg tds reducing to 100- 200mg od after a week.

Front 550

For Amiodarone state the

1. Toxicity and interactions

Back 550

CVS: Bradycardia or heart block in those with existing nodal disease. May precipitate heart failure.

Respiratory effects: Pulmonary fibrosis.
Eye effects: Corneal deposits
Skin effects: Skin deposits and photodermatitis. Grey skin discolouration with chronic use in 5%.
Neurological effects: Peripheral neuropathy, paresthesia, tremor, ataxia, headaches.
Thyroid effects: Hypo or hyperthyroidism can occur in 5%.
Gastrointestinal effects: Constipation, hepatocellular necrosis.
Contraindications: Porphyria

Front 551

For Amiodarone state the

1. Absorption and distribution
2. Metabolism and excretion

Back 551

Bioavailability 20- 80%
95% protein bound.
Small volume of distribution.
Active metabolite may accumulate.
Excreted in bile, faeces and urine.
Half-life highly variable 14-110 days.
15-30 days required for loading.
Toxic effects may continue after drug is ceased.

Front 552

For sotalol state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 552

class II and III
Non-selective beta blocker
Lengthens the action potential and causes increased refractory period

2. CVS: Negative inotropic and chronotropic effect on the heart. (including slowed AV conduction and increased PR interval)
Increased peripheral vascular resistance due to unopposed alpha effects. Antagonism of the release of renin.
Increase in length of action potential and refractory period

RS:
Increased airway resistance (largely avoided by B1 selective agents but not completely).

Eye: Decreased aqueous humour production leading to reduced intraocular pressure

Metabolic and endocrine Inhibition of lipolysis and glycogenolysis via B2 receptors.

used: Supraventricular and ventricular arrhythmias.

Front 553

For sotalol state the

1. Toxicity and interactions

Back 553

CVS: Prolongation of repolarisation may lead to torsades de points - risk greatest at high concentrations.
Myocardial decompensation in pre-existing abnormal myocardial function.
Decreased perfusion in severe peripheral vascular disease.

RS:
Airway obstruction in pre- existing asthma/reactive airways.

Endocrine: Masking of clinical signs of hypoglycaemia

Interactions: Calcium antagonists - leading to severe hypotension, bradycardia, congestive failure

Front 554

For sotalol state the

1. Absorption and distribution
2. Metabolism and excretion

Back 554

Well absorbed orally
Largely excreted unchanged by kidney therefore dosage adjustment is required in renal impairment

Front 555

For adenosine state the
1. Mechanism?
2. Organ effects?
3. Clinical use

Back 555

Adenosine
Naturally occurring nucleoside
Miscellaneous
Acts via adenosine receptors
Enhanced potassium conductance and inhibition of cAMP-induced calcium influx.
Results in marked hyperpolarisation and suppression of calcium- dependent action potentials.
2. Inhibits AV nodal conduction and increases AV nodal refractory period.
Mild effects on SA node.
3. SVT
Diagnosis of narrow or broad complex tachyarrhythmias
Dose 3,6,9,12mg with rapid flush

Front 556

For adenosine state the

1. Toxicity and interactions

Back 556

Transient arrhythmias in >50% including bradycardia and ventricular standstill Generally short lived due to short half life
Flushing in 20% Hypotension <1%

Shortness of breath and chest burning in 10%.

May cause bronchospasm therefore caution in asthmatics.

Interactions: Less effective in the presence of adenosine receptor blockers such as caffeine and theophylline.
Contraindications 2nd or 3rd degree AV block, sick sinus syndrome Specific risk of torsades in long QT interval

Front 557

For adenosine state the

1. Absorption and distribution
2. Metabolism and excretion

Back 557

inactive when administered orally. Absorbed into red blood cells and vascular endothelium where it is phosphorylated or deaminated.
Half life less than 10 seconds.

Front 558

For heparin state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 558

Binds to endothelial cell surfaces
Biological activity dependent on the presence of antithrombin III that inhibits clotting factor proteases by forming complexes with them.
Heparin binds to antithrombin III and causes a conformational change resulting in more rapid interaction with clotting factors IX, X, XI and XII
Binding to clotting factors is accelerated 1000 fold.
In particular, inactivation of factor X results in reduced conversion of prothrombin to thrombin
Higher doses of heparin also inhibit thrombin and therefore reduce conversion of fibrinogen to fibrin
One third of molecules in heparin have biological effect. Heparin is not consumed in the binding process.
HMW fractions (5000- 30000) have a marked affinity for thrombin.
LMW fractions (<9000) inhibit activated factor X but have a lesser effect on thrombin.
2. Prevention and treatment of thromboembolic disease.
Treatment of DIC and fat embolism.
Priming of vascular catheters -haemodialysis, cardiac bypass machines etc.
Treatment of unstable angina and non-Q wave MI
Dose: Heparin 5000u bd 1000u/hr
Enoxaparin

Front 559

For heparin state the
1. Toxicity and interactions
2. reversal (how does this work?)

Back 559

Bleeding.: Higher risk in elderly and renal failure.
Long term use associated with osteoporosis and fractures.
Transient thrombocytopenia in 25% of patients. Severe thrombocytopenia in 5%.
Can cause paradoxical thromboembolism due to heparin induced platelet aggregation.

Contraindications: Active bleeding.
Clotting disorders - haemophilia, thrombocytopenia, purpura.
Severe hypertension.
Recent neurosurgery, eye surgery or LP. A ny condition where the likelihood of uncontrolled bleeding exists.

Reversal: Protamine - highly basic peptide that combines with heparin to form a complex that has no anticoagulant activity. Excess protamine also has an anticoagulant effect.

Front 560

For heparin state the

1. Absorption and distribution
2. Metabolism and excretion

Back 560

1. Absorption Heparin Peak plasma levels 2- 4 hours after subcutaneous injection Highly bound to plasma proteins
LMW heparin Increased bioavailability from subcutaneous site.
Distribution Vascular compartment
2. Largely unknown Probable metabolism by the liver

Front 561

For Warfarin state the
1. Mechanism?

Back 561

Vitamin K dependent oral anticoagulant
Racemic mixture of 2 stereoisomers
S isomer is 4 times more potent than R isomer

Blocks gamma carboxylation of several glutamate residues in factors II, VII, IX, X and protein C resulting in biologically inactive molecules.
Carboxylation is physiologically coupled to Vitamin K metabolism and Vitamin K is oxidised to an inactive form.
In order for carboxylation to occur, Vitamin K must be reduced back to an active form.
Warfarin inhibits Vitamin K epoxide reductase and therefore prevents formation of active vitamin K.

Front 562

For Warfarin state the

1. Toxicity and interactions

Back 562

Bleeding. Toxic to fetus - causes haemorrhagic defects and bone malformations. Cutaneous necrosis due to depression of protein C synthesis.
Interactions

Increased INR:
Metronidazole Fluconazole Trimethoprim - sulfamethoxazole (inhibition of metabolism of S isomer) Cimetidine
Amiodarone (Inhibition of metabolism of both isomers)

Pharmcodynamic Aspirin (additive effect) 3rd generation cephalosporins (elimination of bacteria in the GIT that produce Vitamin K) Heparin
Hepatic disease Hyperthyroidism (increased turnover of clotting factors)

Decreased INR:
Pharmacokinetic Barbiturates
Rifampicin
(enzyme induction)

Pharmcodynamic Diuretics (increased clotting factor concentration) Vitamin K
Hereditary resistance
Hypothyroidism (decreased turnover of clotting factors)

Front 563

For Warfarin state the

1. Absorption and distribution
2. Metabolism and excretion

Back 563

1. Absorption Orally active with 100% bioavailability.
8-12 hour delay in effect as pre- synthesised factors must degrade - this takes up to 60 hours in the case of factor II.
Maximal clinical effect takes 1-3 days.
Distribution Small volume of distribution as tightly bound to albumin.

2. Half life in plasma is 36 hours.
Metabolised in the liver and conjugated to glucuronide. Metabolites excreted in urine and faeces.

Front 564

For streptokinase state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 564

Fibrinolytic
Protein synthesised by group c beta haemolytic streptococci.
Combines with plasminogen.
Streptokinase/plasminogen complex catalyses conversion of further plasminogen to active plasmin.
(plasmin is protected from plasma antiplasmins while it is within the clot)
Fibrinolysis
Fibrinolytic effect lasts a few hours.
APTT elevated for approximately 24 hours

Acute myocardial infarction PE Proximal DVT Arterial thromboembolism
Dose 1.5 million units over 30-60 minutes

Front 565

For streptokinase state the

1. Toxicity and interactions

Back 565

Transient hypotension
Arrhythmias -1-10%
Haemorrhage (clotting factors return to normal after 24 hours
Pyrexia
Hypersensitivity.

Contraindications: Clotting disorder Recent (10/7) major gastrointestinal haemorrhage Recent (2/12) CVA or neurosurgery
Recent (10/7) major surgery, trauma or CPR. Uncontrolled hypertension. Pregnancy.
Previous use >5/7 <12/12
Recent streptococcal infection (complex is inactivated by streptococcal antibodies)

Front 566

For streptokinase state the

1. Absorption and distribution
2. Metabolism and excretion

Back 566

Intravenous administration, remains intravascular
Half life 23 minutes

Front 567

For TPA (tenecteplase) state the
1. Mechanism?
2. Organ effects?

Back 567

t-P A Tenecteplase
recombinant tissue plasminogen activator
Preferentially activates plasminogen that is bound to fibrin therefore theoretically more specific to formed thrombus.

Dose Weight dependent 30-50mg

Front 568

For TPA (tenecteplase) state the

1. Toxicity and interactions

Back 568

Transient hypotension
Arrhythmias - 1-10%
Haemorrhage (clotting factors return to normal after 24 hours
Pyrexia
Hypersensitivity.

Contraindications: Recent major haemorrhage Clotting disorder Recent (2/12) CVA or neurosurgery Recent (10/7) major surgery. Uncontrolled hypertension. Pregnancy.

Front 569

For TPA (tenecteplase) state the

1. Absorption and distribution
2. Metabolism and excretion

Back 569

Intravenous administration, remains intravascular
Binds to heptic receptors and is catabolised to small peptides
Kidney not involved with clearance

Front 570

For aspirin state the
1. Mechanism?
2. Organ effects?

Back 570

Reduced synthesis of eicosanoid mediators
Irreversible inhibition of cyclooxygenase
Reduced synthesis of
thromboxane A2 Reduced synthesis of prostaglandins
Central blockade of CNS response to IL1 in causing fever

Antiplatelet
action lasts for the lifespan of the platelet - thromboxane A2 stimulates platelet aggregation and granule release
Antiinflammatory Analgesic Antipyretic

Front 571

For aspirin state the
1. Toxicity and interactions

Back 571

Therapeutic range 0-10mg/kg Gastritis, ulceration Impaired haemostasis

Anti-inflammatory range 50mg/kg Salicylism ␣ tinnitus, reduced hearing, vertigo.

Toxic range 50-150mg/kg hyperventilation, fever, dehydration, metabolic acidosis

Serious intoxication >150mg/kg Metabolic acidosis due to salicylic acid dissociation, deranged carbohydrate metabolism and reduced renal function.
Respiratory alkalosis due to central stimulation of respiratory centre
Renal compensation for respiratory alkalosis.
Eventual renal and respiratory failure
Interactions
Displaces from protein binding (phenytoin, methotrexate) Decreased activity of spironolactone Decreased tubular secretion of penicillin

Front 572

For aspirin state the
1. Absorption and distribution
2. Metabolism and excretion

Back 572

Orally active Rapidly absorbed. Acidity of stomach keeps aspirin in nonionised form that is more readily absorbed
Bound to albumin in low doses. As serum concentration rises, increasing fraction is unbound
Hydrolysed to acetic acid and salicylate by blood and tissue esterases.
Salicylate conjugated by liver and excreted by kidney.
Demonstrates variable order kinetics ␣ metabolism is saturable and small further increases in aspirin dose results in large rise in salicylate levels.
Half life 3-5 hours at low dose, 12 hours at anti- inflammatory doses
Alkalinisation of the urine increases rate of excretion of free salicylate

Front 573

For tirofiban state the
1. Mechanism?
2. Toxicity?
3. ADME?

Back 573

Gp IIb/IIIa antagonist
Potent inhibition of platelet function
Antithrombotic in unstable angina and myocardial infarction
2. Nausea, dyspepsia, diarrhoea. Haemorrhage. Leukopenia.
3. Guven as IV infusion. Metabolised by liver and excreted in urine

Front 574

Forticlopidine state the
1. Mechanism?
2. Toxicity?
3. ADME?

Back 574

1. Inhibition of ADP pathway of platelets
2. Bleeding Leukopenia. Nausea, dyspepsia, diarrhoea.
3. orally active

Front 575

For Abciximab state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 575

Monoclonal antibody that binds to GpIIb/IIIa receptors and prevents binding of fibrinogen and vWF

Antithrombotic Used in patients undergoing angioplasty or stent placement

Front 576

For Abciximab state the

1. Toxicity and interactions

Back 576

Bleeding Thrombocytopenia Multiple minor toxicities

Front 577

For Abciximab state the
1. Absorption and distribution
2. Metabolism and excretion

Back 577

Intravenous bolus dose or infusion

Front 578

For Dipyridamole state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 578

Inhibition of uptake of adenosine into red blood cells and potentiation of NO

Antiplatelet action
Also has vasodilator actions
Antithrombotic
Often combined with aspirin as a slow-release preparation

Front 579

For Dipyridamole state the

1. Toxicity and interactions

Back 579

Potent vasodilator therefore caution in severe coronary artery disease
Headache Nausea, vomiting

Front 580

For Dipyridamole state the

1. Absorption and distribution
2. Metabolism and excretion

Back 580

Orally active
Widely distributed

Metabolised in the liver Excreted in bile

Front 581

For Clopidogrel state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 581

Inhibits binding of ADP to GpIIb/IIIa and therefore inhibits platelet aggregation

Antithrombotic
Dose 75mg daily

Front 582

For Clopidogrel state the

1. Toxicity and interactions

Back 582

Toxicity Bleeding
Interactions Aspirin, heparin -additive effect

Front 583

For Clopidogrel state the
1. Absorption and distribution
2. Metabolism and excretion

Back 583

Orally active Widely distributed
Metabolised in the liver
Active metabolite is responsible for clinical effect Excreted in bile

Front 584

Vitamin K
1. subtypes?
2. Mechanism?
3. ADME

Back 584

Fat soluble - K1 found in food, K2 found synthesised in intestine by bacteria.
Necessary for formation of factors II, VII, IX and X

Orally active - requires bile slats for absorption. IV should be given slowly. Clinical effect delayed for 6 hours

Front 585

For Insulin state the
1. Synthesis
2. Mechanism?
2. Organ effects?
3. Clinical use?
1. Toxicity and interactions
1. Absorption and distribution
2. Metabolism and excretion

Back 585

Polypeptide containing 2 chains (A and B) of amino acids linked by disulfide bridges. Synthesised as part of preproinsulin. Removal of a peptide leader sequence forms proinsulin. Connecting peptide is removed in the granules prior to release

Insulin binds with an insulin transmembrane receptor that binds and stimulates a protein tyrosine kinase. Exposure to increased insulin down regulates receptor concentration and affinity.

Front 586

What are the 4 types of glucose transporters and where are they?

Back 586

Glucose enters cells by facilitates diffusion through glucose transporters

GLUT1: brain, red cells, placenta, many other organs GLUT2 : B cells, liver, intestine, kidney -transport glucose out of the cell
GLUT4 - adipose tissue and muscle

A pool of GLUT4 transporters is maintained in the cytoplasm of insulin sensitive cells and when these cells are exposed to insulin the transporters move to the cell membrane. Secondary active transport (intestine and kidney) Utilise sodium dependent glucose transporters - SGLT1 and SGLT2.

Front 587

What are the tissue effects of insulin?

Back 587

Rapid (seconds) Increased transport of glucose, amino acids and potassium into insulin sensitive cells.

Intermediate (minutes) Stimulation of protein synthesis Inhibition of protein degradation Activation of glycolytic enzymes and glycogen synthase Inhibition of phophorylase and gluconeogenic enzymes

Delayed (hours) Increase in mRNAs for lipogenic and other enzymes.

Liver: Decreased glucose output due to decreased gluconeogenesis and increased glycogen synthesis.
Increased protein synthesis
Increased lipid synthesis
Decreased ketogenesis

Fat:
Increased glucose entry
Increased fatty acid synthesis
Increased triglyceride deposition
Activation of lipoprotein lipase
Increased potassium uptake

Muscle:
Increased glucose entry
Increased glycogen synthesis Increased amino acid uptake
Increased protein synthesis
Decreased protein catabolism
Decreased release of gluconeogenic amino acids Increased ketone uptake
Increased potassium uptake

Increased cell growth

Front 588

What are the types of insulin used for diabetes?

Back 588

Ultra short acting: Clear solution at neutral pH. Contains small amounts of zinc to improve stability and shelf life

Short acting: Clear solution at neutral pH. Contains small amounts of zinc to improve stability and shelf life. Used for DKA.

Intermediate: Neutral pH with protamine or phosphate buffer or zinc in acetate buffer. This delays absorption and prolongs duration of action.

Long acting: Neutral pH with protamine or phosphate buffer or zinc in acetate buffer. This delays absorption and prolongs duration of action.

Insulin can be derived from beef, pork or from humans.

Front 589

For commonly used insulins describe the ?
1. Toxicity and interactions
2. Absorption and distribution
3. Metabolism and excretion

Back 589

1. Hypoglycaemia Insulin allergy and resistance Lipodystrophy
2. Ultra short acting Short acting Effect within 30 minutes, lasts 5-7 hours. Intermediate Neutral pH with protamine or phosphate buffer or zinc in acetate buffer. Long acting
Neutral pH with protamine or phosphate buffer or zinc in acetate buffer.
3. Half life 5 minutes. Binds to insulin receptors and is internalised. Destroyed by insulin protease. 80% is degraded in liver and kidney. (this ratio is reversed in diabetics on insulin)

Front 590

For sulphonylureas state the
1. Mechanism?
2. Organ effects?
3. Clinical use?


(second generation agents) Glibenclamide Glimepiride

Back 590

1. Increased release of insulin from B cells
Inhibition of glucagon release
Potentiation of insulin action on target tissues

Dose Gliclazide 80-160mg/day in divided doses Glimepiride 1-8mg/day in single dose

Front 591

For sulphonylureas state the

1. Toxicity and interactions

(second generation agents) Glibenclamide Glimepiride

Back 591

Hypoglycaemia (alcohol predisposes)
Tachyphylaxis - B cells may become refractory to response
Blurred vision
Rash
Blood dyscrasias
Hepatic toxicity
Renal insufficiency

Contraindications: Severe renal or hepatic impairment

Front 592

For sulphonylureas state the

1. Absorption and distribution
2. Metabolism and excretion

(second generation agents) Glibenclamide Glimepiride

Back 592

Well absorbed orally
Half life 5 hours Metabolised by liver and excreted in urine

Front 593

For biguanides (metformin) state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 593

1. Unclear mechanism Direct stimulation of glycolysis Reduced gluconeogenesis Decreased glucose absorption
Reduced plasma glucagon
2. Dose 500mg-3g/day

Front 594

For biguanides (metformin) state the

1. Toxicity and interactions

Back 594

Nausea, vomiting, diarrhoea Reduced B12 absorption Lactic acidosis - increased risk with renal insufficiency, age and alcohol (does not cause hypoglycaemia) Contraindications Alcoholism Renal or hepatic disease

Front 595

For biguanides (metformin) state the

1. Absorption and distribution
2. Metabolism and excretion

Back 595

Well absorbed orally Not bound to plasma proteins
Excreted unchanged in urine
Half life 1-3 hours

Front 596

For glucagon state the
1. Mechanism?
2. Indications

Back 596

Binds with transmembrane receptor protein that stimulates a GTP-binding signal transducer protein (G protein) that in turn generates an intracellular second messenger. Second messengers include cAMP, calcium and phosphoinositides.
Glycogenolysis (liver but not muscle) Gluconeogenesis Lipolysis
Ketogenesis
Secretion of growth hormone, insulin and pancreatic somatostatin.
Potent inotropic and chronotropic effect on the heart independent of metabolic effects and without requiring functioning adrenoceptors
Profound relaxation of smooth muscle at high doses

Severe hypoglycaemia
Beta blocker overdose
Oesophageal foreign body
Dose

Front 597

For carbimazole state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 597

Inhibition of thyroid peroxidase resulting in reduced formation of thyroid hormones
Inhibition of peripheral deiodination of T4

Reduced thyroid hormone synthesis
Onset of effect may take several weeks due to stored hormone

Front 598

For carbimazole state the

1. Toxicity and interactions

Back 598

Nausea, vomiting Rash (10%) Fever Marrow depression (0.5%) Jaundice

Front 599

For carbimazole state the

1. Absorption and distribution
2. Metabolism and excretion

Back 599

Well absorbed orally
Accumulates in thyroid gland
Half life 6 hours Excreted in urine

Front 600

For Iodine state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 600

Inhibition of organification and release of thyroid hormones
Decreases size and vascularity of the gland
Pre-operative decrease in gland size and vascularity
Thyroid storm

Front 601

How does radioactive iodine work?

Back 601

Concentrated by thyroid, emission of beta rays results in parenchymal destruction

Front 602

What drugs are used to treat hypercalcaemia?

Back 602

Saline diuresis
Bisphosphonates (inhibition of bone resorption) Etidronate
Calcitonin Gallium (inhibition of bone resorption) Phosphate

Front 603

What glucocorticoids are available for pharmacological use?
What is prednisone?

Back 603

Natural agents Hydrocortisone (cortisol)
Synthetic agents: Prednisolone, methylprednisolone Betamethasone, Dexamethasone
Prednisone is a prodrug of prednisolone

Front 604

For glucocorticoids state the
1. Mechanism?

Back 604

Steroid enters the cell as a free molecule
Binds to intracellular receptor that is bound to stabilising heat shock protein
Heat shock protein is released and the steroid- receptor complex enters the nucleus and bind to glucocorticoid response element on the DNA

This causes regulation of transcription and production of appropriate protein

Front 605

For glucocorticoids state the
1. Toxicity and interactions

Back 605

Cushings syndrome
Excessive acid and pepsin secretion by the stomach
Myopathy Psychosis Adrenal suppression
Contraindications Uncontrolled infection

Front 606

For glucocorticoids state the
1. Absorption and distribution
2. Metabolism and excretion

Back 606

Oral Topical Intramuscular Intravenous
Well absorbed orally
Bound to corticosteroid binding globulin and albumin

Hydrocortisone, prednisolone and methylprednisolone are short acting agents

Betamethasone and dexamethasone are long acting

Half life of hydrocortisone is 60-90 minutes
Metabolised by liver to active and inactive metabolites and excreted in the urine

Dose should be increased for patients on long term therapy during times of stress

Front 607

Organ effects of glucocorticoids?

Back 607

Intermediary metabolism:
Protein catabolism Gluconeogenesis and decreased peripheral glucose utilisation Ketogenesis

Permissive action effects: Required for glucagon and catecholamines to exert their effects
Inhibition of ACTH secretion
Facilitation of effective water excretion (unknown mechanism)

Therapeutic effects: Anti-inflammatory and immunosuppressant effects

Due to effects on concentration, distribution and function of peripheral white cells.
Increased circulating neutrophils, platelets and red blood cells
Reduced lymphocytes, eosinophils, monocytes and basophils
Reduced secretion of cytokines
Increased neutrophils results in decreased neutrophils at site of inflammation

Inhibition of leucocyte function, especially macrophages due to decreased mediator production

Reduced synthesis of prostaglandins and leukotrienes via action on phospholipase A2 and COX2
Vasoconstriction
Reduced capillary permeability

Front 608

What are the relative potencies of the glucocorticoids?

Back 608

Hydrocortisone - 1
Prednisolone - 5
Betamethasone - 25
Dexamethasone - 30

Hydrocortisone has mixed glucocorticoid and mineralocorticoid actions, prednisolone has minor mineralocorticoid actions, nil for betamethasone and dexamethasone

Front 609

For ranitidine, cimetidine, famotidine state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 609

Competitive antagonism at H2 receptors.
H2 receptors found in gastric enterochromaffin-like cells, cardiac muscle, mast cells and brain

Reduced gastric acid secretion
90% reduction in basal, food-stimulated and nocturnal secretion of gastric acid after a single dose
Reduced volume of gastric secretion and concentration of pepsin

Little effect on heart or blood pressure.

Peptic ulceration Oesophagitis and gastritis. Zollinger Ellison syndrome. Prevention of stress ulceration in critically ill.
Dose Ranitidine Oral 150mg twice daily

Cimetidine 400mg twice daily
Famotidine 20mg twice daily

Front 610

For ranitidine, cimetidine, famotidine state the

1. Toxicity and interactions

Back 610

Minor toxicities: Diarrhoea, dizziness, headache, rash.

GIT
May mask gastric malignancy Reversible cholestasis and hepatitis

CNS
acute confusion (cimetidine >> ranitidine)
Antiandrogen effects Gynecomastia, galactorrhoea. (cimetidine only)

Marrow
Blood dyscrasias (cimetidine >> ranitidine)
(Famotidine free of above effects)

Interactions Inhibition of cytochrome P450 and reduction of liver blood flow. Care with warfarin, phenytoin, beta blockers, benzodiazepines, tricyclics, calcium channel blockers, antiarrhythmics, alcohol. (cimetidine >> ranitidine)
Histamine antagonists reduce the absorption of ketoconazole
Inhibition of renal clearance of drugs (cimetidine >> ranitidine)

Contraindications: Porphyria

Front 611

For ranitidine, cimetidine, famotidine state the
1. Absorption and distribution
2. Metabolism and excretion

Back 611

20% plasma bound. 70% bioavailability.
Half life 1-3 hours
Mostly renal metabolism.

Front 612

For proton pump inhibitors state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 612

?Reversible inhibition of parietal cell proton pump

Front 613

For proton pump inhibitors state the

1. Toxicity and interactions

Back 613

May mask gastric malignancy
May increase the risk of gastrointestinal infection
Nausea, vomiting, abdominal pain
Headache

Interactions:
Diazepam - decreased clearance Contraindications Severe hepatic dysfunction

Front 614

For proton pump inhibitors state the

1. Absorption and distribution
2. Metabolism and excretion

Back 614

Well absorbed orally Highly protein bound
Metabolised by liver and excreted in urine

Front 615

For octreotide state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 615

Somatostain analogue
Reduced portal pressure in chronic liver disease resulting in decreased risk of variceal haemorrhage

Front 616

For prochlorperazine state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 616

Phenothiazine Strong antiemetic and antipsychotic actions
Antidopamine action - therapeutic effect and unwanted effects including extrapyramidal disorders and endocrine disturbances.
Alpha-adrenoreceptor antagonism, which contributes to cardiovascular side effects, e.g. Orthostatic hypotension and reflex tachycardia.
Potentiation of noradrenaline by blocking its reuptake into nerve terminals.
Weak anticholinergic action, weak antihistamine action. Weak serotonin antagonism.
Prochlorperazine also has an effect on temperature control and blocks conditioned avoidance responses.

Front 617

For prochlorperazine state the

1. Toxicity and interactions

Back 617

Sedation, Hypotension
Anticholinergic effects, especially in elderly, especially constipation, dry mouth, blurred vision Severe acute dystonic reactions in children
Tardive dyskinesia
Neuroleptic malignant syndrome

Hypo/hyperthermia

Interactions: Enhances the effect of other CNS depressants

Contraindications: Hypotension (alpha- adrenoreceptor antagonism)

Drowsiness, coma, neuromuscular excitability, convulsions.
Miosis and loss of deep tendon reflexes. Hypotension and hypotermia.
Activated charcoal effective.
Supportive therapy.
Avoid adrenaline and lignocaine.

Front 618

For prochlorperazine state the
1. Absorption and distribution
2. Metabolism and excretion

Back 618

Orally active.
Metabolised by liver and excreted in faeces and urine.

Front 619

For metoclopramide state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 619

Dopamine antagonist
Increased upper gastrointestinal motility
Dose Oral-10mg tds
Intravenous -10mg tds, slowly Rapid injection leads to feelings of anxiety

Daily dose should not exceed 0.5mg/kg

Front 620

For metoclopramide state the
1. Toxicity and interactions

Back 620

Restlessness, fatigue, drowsiness in 10% Dystonic reaction ␣ more common in children and young adults Tardive dyskinaesia in chronic use Neuroleptic malignant syndrome
Interactions May affect absorption of other drugs due to effects on motility

Contraindications Phaechromocytoma ␣ causes increased release of catecholamines

Epilepsy - may increase the frequency of seizures Porphyria, Parkinson's

Front 621

For metoclopramide state the

1. Absorption and distribution
2. Metabolism and excretion

Back 621

Orally active
Metabolised in liver and excreted in urine

Front 622

For ondansetron state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 622

5HT3 antagoni

Front 623

For ondansetron state the
1. Toxicity and interactions

Back 623

Dizziness Muscle pain Chest pain Seizures

Contraindications: IHD
Severe hepatic impairment

Front 624

For ondansetron state the

1. Absorption and distribution
2. Metabolism and excretion

Back 624

Orally active Protein bound
Metabolised by liver

Front 625

For promethazine state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 625

First generation H1 antagonist
Phenothiazine derivative
Other agents: Diphenhydramine Chlorpheniramine
Competitive antagonism at H1 receptors. (note that some cardiovascular effects of histamine are mediated by H2 receptors)
also have antimuscarinic, anti-adrenergic, antiserotonin actions

Anaphylaxis Allergic reactions Motion sickness and vestibular dysfunction. Nausea (can also be used as a local anaesthetic as has some sodium blocking actions)
Dose 10-25mg orally, intravenous or intramuscular

Front 626

For promethazine state the
1. Toxicity and interactions

Back 626

Marked sedation. Antimuscarinic actions. Orthostatic hypotension Excitation and convulsions in children. Postural hypotension.

Front 627

For promethazine state the

1. Absorption and distribution
2. Metabolism and excretion

Back 627

Orally active. Widely distributed. Readily enter the CNS
Extensively metabolised by liver and excreted in urine.

Front 628

For loratidine state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 628

Second generation H1 antagonist
Other agents Terfenadine (terfenadine is a prodrug of fexofenadine that lacks cardiotoxic effects)
Competitive antagonism at H1 receptors. (note that some cardiovascular effects of histamine are mediated by H2 receptors)
also have anticholinergic, anti-adrenergic, antiserotonin actions

Front 629

For loratidine state the

1. Toxicity and interactions

Back 629

Mild toxicities compared with first generation agents
Interactions Terfenadine and astemizole metabolised by CYP3A4 which is inhibited by grapefruit, ketoconazole and macrolides ␣ associated with QT prolongation and potentially toxic arrhythmias

Fexofenadine is the metabolite of terfenadine and lacks cardiotoxic effects

Front 630

For loratidine state the
1. Absorption and distribution
2. Metabolism and excretion

Back 630

Widely distributed except CNS
Extensively metabolised by liver and excreted in urine.

Front 631

For Penicillin V state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 631

Inhibition of cell wall synthesis Penicillins bind to penicillin binding proteins and inhibit transpeptidation in peptidoglycan synthesis and therefore formation of cross- links in the cell wall that confer rigidity.

Active against gram positive cocci, gram negative cocci, some anaerobes
Destroyed by beta lactamases
Inactive against enterococci, some anaerobes, gram negative rods
Streptococci Meningococci Enterococci Pneumococci Staphylococci Treponema pallidum Bacillus anthracis Clostridium
Dose 10-50mg/kg/day in 3-4 doses orally or IV

Front 632

For Penicillin V state the
1. Toxicity and interactions

Back 632

Minor toxicities such as nausea, vomiting, diarrhoea
Important cause of type I hypersensitivity. Type III hypersensitivity can also occur.
5-8% claim penicillin allergy but only 5-10% of these will have a reaction.

High doses in renal failure can causes seizures

Front 633

For Penicillin V state the
1. Absorption and distribution
2. Metabolism and excretion

Back 633

Original penicillins such as penicillin G acid labile.
Penicillin V is acid stable and well absorbed orally but has poor bioavailability
Avoid administration with meals
60% protein bound.
Penetrates tissues very well except eye, prostate and CNS - though penetration is better if inflammation is present.

Renal excretion 10% by filtration, 90% by tubular secretion.
Half-life 30 minutes, increases to 10 hours in renal failure.
Dose adjustment required in renal failure
Frequent dosing required

Front 634

For Flucloxacillin/dicloxacillin state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 634

Beta lactam antibiotic with resistance to staphylococcal betalactamases.
Penicillins bind to penicillin binding proteins and inhibit transpeptidation in peptidoglycan synthesis and therefore formation of cross- links in the cell wall that confer rigidity.
Active against gram positive cocci including beta lactamase producing staphylococci
Inactive against enterococci, anaerobes, gram negative.

Front 635

For Flucloxacillin/dicloxacillin state the

1. Toxicity and interactions

Back 635

Minor toxicities such as nausea, vomiting, diarrhoea
Important cause of type I hypersensitivity. Type III hypersensitivity can also occur.
5-8% claim penicillin allergy but only 5-10% of these will have a reaction.
High doses in renal failure can causes seizures
Small risk of hepatitis hence introduction of dicloxacillin

Front 636

For Flucloxacillin/dicloxacillin state the

1. Absorption and distribution
2. Metabolism and excretion

Back 636

Acid stable and well absorbed orally.
Absorption impaired by food.
Highly protein bound.
Penetrates tissues very well except eye, prostate and CNS -though penetration is better if inflammation is present.

Hepatic metabolism and rapid renal excretion ␣ 10% by filtration, 90% by tubular secretion.
No adjustment in renal failure.

Front 637

For Amoxicillin/Ampicillin/Piperacillin/Ticarcillin state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 637

Inhibition of cell wall synthesis Penicillins bind to penicillin binding proteins and inhibit transpeptidation in peptidoglycan synthesis and therefore formation of cross- links in the cell wall that confer rigidity

Similar spectrum to penicillin but better penetration of gram negative bacteria, though still sensitive to beta lactamases

Streptococci Meningococci Pneumococci (particularly active therefore 1st choice for respiratory infection)
Staphylococci
Treponema pallidum
Bacillus anthracis
Clostridium
(not enterobacter)
Ampicillin effective for Shigella

Ampicillin not active against E coli Proteus
Haemophilus Klebsiella Pseudomonas
Enterobacter Citrobacter Serratia

Ticarcillin is also active against Pseudomonas Enterobacter

Piperacillin is also active against Klebsiella

Front 638

What are some resistance mechanisms to penicillin? (name 3 )

Back 638

1. Beta lactamases: Destroyed by beta lactamases produced by staphylococci, haemophilus, E coli, pseudomonas, enterobacter

2. Alteration on target penicillin binding proteins. Resistant organisms have binding sites with low affinity for binding - particularly seen with MRSA and pneumococcus

3. Poor ability to penetrate outer membrane Gram-negative organisms

Front 639

For Amoxicillin/Ampicillin/Piperacillin/Ticarcillin state the
1. Absorption and distribution
2. Metabolism and excretion

Back 639

Acid stable and well absorbed orally.
Highly protein bound.
Penetrates tissues very well except eye, prostate and CNS - though penetration is better if inflammation is present.

Front 640

For clavulanic acid state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 640

Resemble beta lactam molecules and protect against many beta lactamasesActive against beta lactamases produced by Haemophilus Neisseria gonorrhoea Salmonella
Shigella E coli Klebsiella Legionella Bacteroides
Not active against beta lactamases produced by Enterobacter Citrobacter
Serratia Pseudomonas

Front 641

For 1st generation cephalosporins state the
1. Mechanism?
2. Organ effects?
3. Clinical use?
4. examples

Back 641

Cefadroxil Cefazolin Cephalexin Cephalothin Cephadrine
Cephalosporins bind to penicillin binding proteins and inhibit transpeptidation in peptidoglycan synthesis and therefore formation of cross-links in the cell wall that confer rigidity.

Gram positive cocci plus E coli Klebsiella
Proteus Anaerobic cocci
Peptococcus Peptostreptococcus

Not active against:
Listeria MRSA Haemophilus Pseudomonas Some proteus Enterobacter Serratia Citrobacter

Surgical prophylaxis Uncomplicated UTI, skin and soft tissue infection

Front 642

For 1st generation cephalosporins state the

1. Toxicity and interactions

Back 642

Cross allergy between penicillins and cephalosporins is 5-10% - withhold in anaphylaxis only.
Toxicity Local irritation.
Superinfection.

Front 643

For 1st generation cephalosporins state the

1. Absorption and distribution
2. Metabolism and excretion

Back 643

Well absorbed orally
Renal excretion 10% by filtration, 90% by tubular secretion.
Half-life 30 minutes, increases to 10 hours in renal failure.Gram positive cocci plus E coli Klebsiella
Proteus Anaerobic cocci
Peptococcus Peptostreptococcus
Plus extended gram negative cover against Haemophilus Some serratia
Not active against Listeria MRSA Pseudomonas Some proteus Enterobacter Some serratia Citrobacter
Dose adjustment required in renal failure

Front 644

For 2nd generation cephalosporins state the
1. Examples and Mechanism?
2. Organ effects?
3. Clinical use?

Back 644

Cefaclor Cefuroxime Cefoxitin
Cephalosporins bind to penicillin binding proteins and inhibit transpeptidation in peptidoglycan synthesis and therefore formation of cross-links in the cell wall that confer rigidity.

Front 645

For 2nd generation cephalosporins state the
1. Toxicity and interactions

Back 645

Cross allergy between penicillins and cephalosporins is 5-10% - withhold in anaphylaxis only

Local irritation. Cefaclor associated with serum-sickness like reaction
Superinfection.

Front 646

For 2nd generation cephalosporins state the

1. Absorption and distribution
2. Metabolism and excretion

Back 646

Renal excretion 10% by filtration, 90% by tubular secretion.
Half-life variable
Dose adjustment required in renal failure

Front 647

For 3rd generation cephalosporins state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 647

Ceftriaxone Cefotaxime Cephtazidime
Extended coverage of gram-negative organisms compared with first and second generation.
Citrobacter Serratia Haemophilus Neisseria
Particularly pseudomonas.
Less active against gram-positive organisms.
Not active against enterococci or listeria.

Treatment of serious infections by susceptible organisms.
Treatment of serious infection if organism unknown.
Especially useful for CNS infection.
Treatment of penicillin resistant infections including MRSA and gonorrhoea
Dose 10-50mg/kg/day. Ceftriaxone suitable for once daily dosing.

Front 648

For 3rd generation cephalosporins state the
1. Toxicity and interactions

Back 648

Allergy Cross allergy between penicillins and cephalosporins is 5-10% - withhold in anaphylaxis only.
Toxicity Local irritation

Front 649

For 3rd generation cephalosporins state the
1. Absorption and distribution
2. Metabolism and excretion

Back 649

Intravenous dosing. Good tissue penetration, especially into CNS.
Half-life 7-8 hours.
Metabolised by liver and excreted in bile.
No dosing adjustment required in renal failure

Front 650

For Meropenem/Imipenem state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 650

Structurally related to beta lactams
Inhibition of cell wall synthesis Binds to penicillin binding proteins and inhibit transpeptidation in peptidoglycan synthesis and therefore formation of cross- links in the cell wall that confer rigidity.

nfections due to resistant organisms
Highly active against resistant pneumococci and enterobacter

Front 651

For Meropenem/Imipenem state the

1. Toxicity and interactions

Back 651

Minor toxicities including nausea, vomiting, diarrhoea and skin rashes
High doses in renal failure can causes seizures

Front 652

For Meropenem/Imipenem state the

1. Absorption and distribution
2. Metabolism and excretion

Back 652

Inactivated by dehydropeptidases in renal tubules therefore administered with cilastatin

Front 653

For Vancomycin state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 653

Binds to peptidoglycan and inhibits transglycosylase therefore preventing peptidoglycan elongation and cross-linking that confers rigidity.
Active against gram positive bacteria (plus flavobacterium)
Bactericidal
Synergistic with gentamicin

Resistance mechanisms: Alteration of binding site.

Front 654

For Vancomycin state the
1. Toxicity and interactions

Back 654

Minor reactions in 10% Phlebitis Histamine release (red man/red neck syndrome)
Ototoxicity and nephrotoxicity, especially if administered with aminoglycoside

Front 655

For Vancomycin state the
1. Absorption and distribution
2. Metabolism and excretion

Back 655

Poorly absorbed orally -used orally for the treatment of resistant clostridium difficile
90% filtered by kidney
Dose adjustment required in renal failure
Not removed by haemodialysis

Front 656

For Teicoplanin state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 656

Binds to peptidoglycan and inhibits transglycosylase therefore preventing peptidoglycan elongation and cross-linking that confer rigidity.

Active against gram positive bacteria (plus flavobacterium)
Synergistic with gentamicin

Front 657

For Teicoplanin state the

1. Toxicity and interactions

Back 657

Poorly absorbed orally ␣ used orally for the treatment of resistant clostridium difficile

Front 658

For Teicoplanin state the
1. Absorption and distribution
2. Metabolism and excretion

Back 658

Poorly absorbed orally -used orally for the treatment of resistant clostridium difficile
90% filtered by kidney
Dose adjustment required in renal failure

Front 659

For chloramphenicol state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 659

Potent inhibition of microbial protein synthesis
Reversibly binds to 50S subunit of bacterial ribosome
Bacteristatic

Broad spectrum
Not effective for
chlamydia

Effectively obsolete as a systemic drug due to other less toxic agents
Eye infections ␣ due to broad spectrum and good tissue penetration
Not effective for chlamydia

Front 660

For chloramphenicol state the
1. Toxicity and interactions
2. resistance mechanisms

Back 660

1.Toxicity GIT Nausea, vomiting, diarrhoea
Bone marrow Commonly causes dose related reversible bone marrow suppression
Rare idiosyncratic aplastic anaemia (1 in 30000)
Neonates: Grey baby syndrome

Interactions: Inhibition of hepatic microsomal enzymes -prologed half life and increased concentrations of phenytoin and warfarin

2. Decreased permeability
Production of chloramphenicol acetyltransferase that inactivates the drug

Front 661

For chloramphenicol state the
1. Absorption and distribution
2. Metabolism and excretion

Back 661

Well absorbed orally
Widely distributed
Good tissue penetration

Metabolised by liver and excreted by kidney
Dose adjustment required in hepatic failure

Front 662

For tetracyclines state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 662

Potent inhibition of microbial protein synthesis
Reversibly binds to 30S subunit of bacterial ribosome
Enter microorganisms by diffusion and active transport

Broad spectrum
Active against Rickettsiae, Chlamydiae, Mycoplasma, Vibrio
Also active against some protozoa

Front 663

For tetracyclines state the
1. Toxicity and interactions

Back 663

GIT Nausea, vomiting, diarrhoea Bacterial overgrowth
Liver toxicity
ATN

Bones and teeth: Tooth discolouration due to chelation with calcium
Other Photosensitivity

Interactions: Enzyme inducers such as phenytoin and carbamazepine reduce half life by 50%

Front 664

For tetracyclines state the
1. Absorption and distribution
2. Metabolism and excretion

Back 664

Well absorbed orally
Absorption not impaired by food
Impaired by divalent cations and dairy products
40-80% protein bound
Widely distributed
except CNS

Metabolised by liver, excreted in urine and bile.
Bile concentration 10 times serum concentration
Dose reduction required in renal failure
Doxycycline is excreted by non- renal mechanism and therefore is drug of choice in renal failure
Half life 12-16 hours

Front 665

For macrolides state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 665

Potent inhibition of microbial protein synthesis
Reversibly binds to 50S subunit of bacterial ribosome
Concentrated in polymorphs and macrophages
Bacteristatic at low concentrations, bactericidal at high concentrations

Erythromycin
Semi-synthetic Roxithromycin Clarithromycin Azithromycin

Broad spectrum
Gram positive (strep>>staph) Gram negative
Neisseria Bordetella Rickettsia Treponema Campylobacter
Chlamydia Mycoplasma Legionella
Less active against haemophilus and staphylococcus
Clarithromycin more active against mycobacterium avium intracellulare

Front 666

For macrolides state the
1. Toxicity and interactions

Back 666

Nausea, vomiting, diarrhoea
Acute cholestatic hepatitis
(semi-synthetic macrolides better tolerated)

Interactions: Erythromycin and clarithromycin Inhibition of cytochrome P450 resulting in increased concentrations of theophylline, warfarin, antihistamines

Causes increased bioavailability of digoxin
Semi-synthetic macrolides relatively free of above effects due to less avid binding to P450

Front 667

For macrolides state the
1. Absorption and distribution
2. Metabolism and excretion

Back 667

Erythromycin base combined with stearate or ester confers acid stability
Widely distributed
except CNS

Erythromycin Metabolised by liver, excreted in bile
No adjustment necessary for renal impairment.
Half life 1.5 hours
Synthetic macrolides metabolised by liver and excreted in bile and urine therefore dose adjustment in renal failure is recommended

Front 668

For aminoglycosides state the
1. Mechanism?
2. Organ effects?

Gentamycin Tobramycin Netilmycin

Back 668

Aminoglycoside enters the bacteria by passive diffusion via porin channels across the outer membrane (this process is aided by penicillins)
Aminoglycoside is then actively transported into the cytoplasm
Binds to 30S subunit of bacterial ribosome
Bactericidal

Gram negative Pseudomonas
Proteus Enterobacter Klebsiella Serratia
E coli
Some gram positive activity Streptococci and enterococci are relatively resistant
No action against anaerobes
Tobramycin is more active against pseudomonas


concentration dependent killing is more important than time-dependent killing therefore once daily dosing

Front 669

For aminoglycosides state the
1. Toxicity and interactions

Gentamycin Tobramycin Netilmycin

Back 669

Ototoxic, vestibulotoxic and nephrotoxic ␣ more likely in prolonged use, elderly, renal insufficiency and concurrent use of other nephrotoxic substances
Ototoxicity manifests mainly as vestibular dysfunction
Gentamycin is mostly nephrotoxic and vestibulotoxic (less ototoxicity)

Nephrotoxicity occurs in 5- 25% of patients receiving drug for more than 3-5 days
Neuromuscular blockade can occur in very high doses

Front 670

For aminoglycosides state the
1. Absorption and distribution
2. Metabolism and excretion

Gentamycin Tobramycin Netilmycin

Back 670

Not orally active -virtually the entire oral dose is excreted in faeces
Highly polar compounds poorly distributed to CNS and eye though inflammation increases penetration.
Poor activity in low pH or low oxygen tension.

Half life 2-3 hours
Renally excreted
Dose adjustments required in renal insufficiency
Trough concentration should be less than 2ug/ml
Aminoglycoside clearance is directly proportional to creatinine clearance Cockcroft-gault formula

Front 671

Resistance mechanisms and contraindications for tetracyclines?

Back 671

Resistance mechanisms:
Decreased intracellular accumulation due to impaired active transport
Decreased binding to ribosome due to production of inhibitory proteins
Enzymatic inactivation
(note resistance is common)

Contraindications Children under 8 years

Front 672

Resistance mechanisms to macrolides?

Back 672

Decreased intracellular accumulation due to decreased permeability
Decreased binding to ribosome due to modification of the binding site by methylase (accounts for 90% of resistance)
Enzymatic inactivation by enterobacter

Front 673

Resistance mechanisms to gentamycin?

Back 673

Decreased intracellular accumulation due to abnormal porins or anaerobic conditions Gram positive organisms are resistant by this mechanism

Decreased binding to ribosome due to modification of the binding site

Enzymatic inactivation by transferases (most important for gram negative resistance ␣ netilmycin is relatively resistant to this)

Front 674

For sulphonamides state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 674

A nti-folate
Sulphonamides are structural analogues of para- aminobenzoic acid that bind to dihydropteroate synthase and competitively inhibit folic acid synthesis
Bacteriostatic Bacteriocidal when given with trimethoprim

Broad spectrum
Gram positive and gram negative actions
Includes Chlamydia
Stimulates growth of Rickettsia

Used in combination with trimethoprim in the treatment of urinary tract infection, respiratory tract infections and in episodes of resistance
Resistance common Use is limited by toxicity Very cheap therefore extensive use in 3rd world

Front 675

For sulphonamides state the
1. Toxicity and interactions

Back 675

5% of patients have side effects
Nausea, vomiting, diarrhoea Fever Exfoliative dermatitis Photosensitivity
Stevens Johnson syndrome
GIT
Sulfonamides may precipitate in urine and may cause obstruction
Marrow
Aplastic anaemia
Contraindications Porphyria

Front 676

For sulphonamides state the
1. Absorption and distribution
2. Metabolism and excretion

Back 676

Orally active (slow)
Sulfamethoxazole chosen due to its similar half life to trimethoprim
Wide distribution

Metabolised in liver and excreted in urine.
Metabolised impaired in slow acetylators
Dose adjustment required in renal insufficiency
Half life 10-12 hours

Front 677

For Trimethoprim state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 677

A nti-folate Inhibition of dihydrofolate
reductase
Synergistic effect when given with sulphonamide due to sequential action in folate synthesis

Used in combination with trimethoprim in the treatment of urinary tract infection, respiratory tract infections, skin infections



Broad spectrum
Especially E coli Enterobacter Proteus
Neisseria Salmonella Klebsiella
Haemophilus
Not active against Pseudomonas Mycoplasma Mycobacterium Treponema

Front 678

For Trimethoprim state the
1. Toxicity and interactions

Back 678

Toxicity Nausea, vomiting, diarrhoea

GIT
Sulfonamides may precipitate in urine and may cause obstruction

Marrow
Megaloblastic anaemia

Contraindications: Porphyria

Front 679

For Trimethoprim state the
1. Absorption and distribution
2. Metabolism and excretion

Back 679

Concentrated in prostate, vagina., kidney and lungs
Metabolised in liver and excreted in urine.
Dose adjustment required in renal insufficiency
Half life 10-12 hours

Front 680

Difference between heparin and LMWH?

Back 680

Heterogeneous mixture of sulphated muco-polysacc- harides.
Enoxaparin Low molecular weight heparin

Front 681

For Quinolone state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 681

the important quinolones are synthetic fluorinated analogues of nalidixic acid.
Nalidixic acid Norfloxacin Ciprofloxacin Ofloxacin Sparfloxacin

DNA gyrase inhibitors
Block relaxation of positively supercoiled DNA required for normal transcription and replication of bacteria.


Active against a variety of gram negative and gram-positive bacteria.
Nalidixic acid ␣␣␣␣␣␣␣␣␣␣␣␣␣␣␣␣ systemic levels therefore only used for urinary tract infections.
Norfloxacin Least active Ciprofloxacin Particularly active against gram-negative cocci and bacilli including enterobacter, pseudomonas, neisseria, haemophilus and campylobacter.
Less effective against gram-positive organisms especially streptococci.
Ofloxacin Sparfloxacin Improved gram-positive action. Longer half-life.
Anaerobes are generally resistant though intracellular organisms are susceptible.

Front 682

For Quinolone state the

1. Toxicity and interactions

Back 682

Well tolerated.
General Nausea Diarrhoea Headache Rash
May damage growing cartilage therefore not recommended in children unless no other drug available or suitable
Little data on pregnancy. Excreted in breast milk.

Interactions: Enzyme inducer - increases the metabolism of phenytoin

Front 683

For Quinolone state the
1. Absorption and distribution
2. Metabolism and excretion

Back 683

Well absorbed orally with greater than 80% bioavailability.
Concentrates in prostate and kidney.

Half-life 3-4 hours.
Excreted renally therefore accumulates in renal failure.

Front 684

For metronidazole state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 684

Antiprotozoal agent with potent anti-anaerobic actions
Reduction of the nitro group produces toxic metabolites

Only active against obligate anerobes

Bacteroides Fusobacterium
Clostridium
Anaerobic streptococci
Trichomoniasis
Giardiasis
Amoebiasis

Front 685

For metronidazole state the
1. Toxicity and interactions

Back 685

General: Nausea, vomiting, diarrhoea Metallic taste Dry mouth Headache Disulfiram-like effect with alcohol Pancreatitis

CNS: Ataxia, seizures
Interactions Potentiates the effect of warfarin

Reduced half life if taken with enzyme inducers phenytoin, phenobarbitone Increased half life if taken with enzyme inhibitors cimetidine

Front 686

For metronidazole state the
1. Absorption and distribution
2. Metabolism and excretion

Back 686

Well absorbed orally Also given rectally and intravenously

Metabolised by liver
Half life 7 hours
May accumulate in hepatic dysfunction

Front 687

For acyclovir state the
1. Mechanism?
2. Organ effects?
3. Clinical use?

Back 687

Antiherpes agent
Selectively activated by phosphorylation in infected cells only.
Acyclovir triphosphate inhibits vial DNA synthesis

Active against HSV1 and HSV2 Varicella zoster

Front 688

For acyclovir state the
1. Toxicity and interactions

Back 688

Nausea, vomiting Headache
Rapid intravenous administration may be associated with renal insufficiency and neurological toxicity

Front 689

For acyclovir state the
1. Absorption and distribution
2. Metabolism and excretion

Back 689

Oral, topical and intravenous formulations
Well absorbed orally, low bioavailability, hence frequent dosing
Distributed to most tissues

Cleared by glomerular filtration and tubular secretion.
Half life 3-4 hours
Dosage adjustment required for renal impairment

Front 690

Mechanism of resistance to quinolones?

Back 690

Uncommon point mutation in the quinolone-binding region.

Front 691

Define
1. disinfection
2. antiseptic
3. sterilisation
4. autoclaving

Back 691

1. a chemical or physical process that kills micro-organisms
2. a disinfectant with sufficiently low toxicity to use on skin, mucous membranes and wounds
3. a process to remove all micro-organisms, spores and viruses
4. sterilisation using pressurised steam at 120 degrees for 20 minutes

Front 692

Resistance mechanisms to sulphonamides?

Back 692

Some bacteria utilise exogenous folate therefore are not susceptible
Decreased intracellular accumulation reduced permeability
Decreased binding to dihydropteroate synthase
Resistance is common

Front 693

Resistance mechanisms to trimethoprim?

Back 693

Resistance mechanisms Some bacteria utilise exogenous folate therefore are not susceptible
Decreased intracellular accumulation due to reduced permeability
Decreased binding to dihydrofolate reductase