Pre-2016

From Ethans Wiki

2016 (1st sitting)

Question 8

Question

Describe the characteristics of a drug that influence its excretion by the kidneys


Example answer

Renal excretion of drugs is related to factors which affect

  • Filtration at the glomerulus
  • Secretion into the tubules
  • Reabsorption in the tubules


Factors affecting glomerular filtration

  • GFR
    • Increased GFR (e.g. increased CO) will lead to increased filtration and clearance of hydrophilic drugs
  • Drug size
    • Increasing drug size = decreased renal clearance
    • Only drugs <7kDa (weight) or <30 Angstrom units (width) are able to pass the capillary BM
  • Protein binding
    • Only unbound drugs can pass the glomerular BM (hence highly protein bound drugs are poorly filtered)
  • Charge
    • Negatively charged molecules cannot readily pass BM (as it is also negatively charged)


Factors affecting drug secretion

  • Active process
  • Protein binding, renal blood flow (GFR) as per above
  • Concentration: Increased concentration = increased secretion (until transporters are saturated)
  • Concomitant drugs - competition for receptors


Factors affecting drug reabsorption

  • Can be active or passive (most are passive)
  • Also depends on charge (ionised drugs cannot pass through BM) and become trapped in the urine
    • Ionisation depends on pH urine, pKa drug (acidic drugs are ionised in alkaline urine)
  • Concentration (as passive diffusion depends on concentration gradient)
  • Urine flow rate
    • Increased urine flow rate > reduces concentration of drug in urine > increased concentration gradient + elimination


Examiner comments

29% of candidates passed this question.

Drug characteristics that might influence the renal excretion processes include charge, size, solubility, and binding to specific structures or protein. Whether the drug is unchanged versus metabolised can influence these factors. This question tests core knowledge of pharmacology principles and should be answered with equations, graphs or simple clear descriptions of physical and chemical principles. Extended examples and hedged statements about “influencing” without the direction, magnitude and necessary conditions for the influence did not score marks.



Question 13

Question

Describe the cardiovascular effects of a sudden increase in afterload.


Example answer

Afterload

  • Force that must be overcome prior to the sarcomere being able to shorten during contraction (i.e. the forces opposing ventricular ejection)


CVS effects

  • HR
    • If the increase in afterload is associated with increase in carotid pressure > baroreceptor reflex activation > compensatory decrease in HR
  • SV
    • The increased afterload > earlier closure of the AV valve (increased diastolic pressure) and decrease in velocity of myocyte shortening > increased end-systolic volume (and pressure) > decreased stroke volume > decreased CO
  • Preload
    • Increase in afterload > decrease in SV > increase in LV end systolic volume (and pressure) > Increase in EDV (preload)
  • Contractility
    • Increases due to the Anrep effect
      • Increase in afterload > increased LV EDP > frank starling effect > Calcium accumulation > increased contractility > increased SV
  • Cardiac output
    • Decreases in short term
    • Ideally recovers quickly if the compensatory mechanisms work
    • If the LV is impaired, or the body is unable to compensate > LV heart failure
  • Myocardial oxygen consumption
    • Increases due to increased contractility and increased work to overcome afterload
  • Coronary blood flow
    • Remains stable due to autoregulation




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Examiner comments

21% of candidates passed this question.

It was expected the answer would start with a definition of afterload and then proceeded to indicate what effects this increase in afterload would have on ventricular end-systolic pressure, ventricular end-diastolic pressure, left atrial pressure, cardiac output, myocardial oxygen demand and myocardial work, coronary blood flow and systemic blood pressure.
Most candidates who failed to pass this question submitted answers that were just too brief, only including a small subset of the material required. Very few candidates included any mention of myocardial oxygen demand or myocardial work or the impact upon the cardiac output. A number of candidates included a detailed description of the Sympathetic Nervous System and the Renin-Angiotensin system, material which was not asked for. There were quite a number of incorrect perceptions about what effect a sudden increase in afterload would have on the systemic blood pressure. Candidates who mentioned the baroreceptor response and the stretch receptor response where rewarded with additional credit.


Online resources



Question 20

Question

Outline the role of the liver in drug pharmacokinetics


Example answer

Absorption

  • The liver will affect the bioavailability of drugs which are subject to first pass metabolism

  • Hence, oral absorption, high PR, > subject to hepatic extraction and metabolism

  • Drugs which are not subject to first pass metabolism e.g. inhalation, intravenous, IM ,> higher bioavailability if hepatically metabolism/cleared

  • Liver dysfunction > alter first pass metabolism

Distribution

  • The liver is responsible for producing majority of the proteins that drugs bind
  • Hence, for highly protein bound drugs (e.g. warfarin), small changes in protein levels, can lead to large changes in the proportion of unbound (active drug)
  • Liver dysfunction > alter protein binding


Metabolism

  • The liver is a primary organ of drug metabolism and biotransformation
  • Phase 1 reactions
    • Hydrolysis, Reduction, Oxidation
    • Small increase in hydrophilicity
  • Phase 2 reactions
    • Glucuronidation, sulfation, conjugation, methylation
    • Significantly increased hydrophilicity
  • Liver dysfunction can alter biotransformation
    • E.g. liver damage > unable to process paracetamol > increased toxicity


Elimination

  • The hepatic system is important for drug elimination
  • Drugs with a high hepatic extraction ratio, will also be dependant on the hepatic blood flow. Drugs with a low hepatic extraction ratio will depend on the function of the liver
  • For hydrophilic drugs, that are highly protein bound, decreased proteins related to hepatic dysfunction will increase elimination
  • Biliary section
  • Drugs which rely on biliary exertion will be retained in liver dysfunction
  • Portal hypertension > shunting of blood > decreased first pass metabolism


Examiner comments

62% of candidates passed this question.

Most candidates structured their answer to this question well – they were aware of first pass metabolism and the effect of protein synthesis upon volume of distribution of drugs. Knowledge concerning Phase I and Phase II reactions was frequently inadequate. Many candidates were aware that these processes as well as inactivating or activating drugs resulted in increased water solubility to aid excretion via bile or urine. Few candidates discussed the significance of the large blood flow to the liver or the implications of high and low extraction ratios especially in relation to liver blood flow



Question 24

Question

Describe the ideal sedative agent for an Intensive Care patient (50%). How does midazolam compare to this (50%)?


Example Answer

Name Midazolam Ideal sedative agent
Class Benzodiazepine (sedative) -
Pharmaceutics Clear colourless solution

pH 3.5.
Diluted in water.

- Water soluble

- Chemically stable with long shelf life (various temperatures)
- Does not need reconstitution.

- Compatible w. all drugs / IVF

- Enantiopure preparation
- No additives

Routes of administration IV, IM, S/C, intranasal, buccal, PO Multiple routes of administration available
pKa 6.5 -
Dose Variable Predictable response for a given weight based dosing regime
Pharmacodynamics
MOA Midazolam (BZD) binds to GABAA receptors (ionotropic ligand gated channel) in the CNS. Cl enters > hyperpolarisation. Known MOA with specific and targeted receptors
Effects CNS: sedation, amnesia, anxiolysis, hypnosis, anticonvulsant effects, decreased cerebral O2 demand, MSK: muscle relaxant CNS: sedation, amnesia, anxiolysis, decreased cerebral O2 demand
Side effects CVS: bradycardia, hypotension

CNS: confusion, restlessness
RESP: respiratory depression/ apnoea

No side effects, including no cardiorespiratory depression or emergence delirium
Pharmacokinetics
Onset peak effect 2-3 minutes (IV), offset variable Rapid onset / offset
Absorption ~40% oral bioavailability

- Absorbed well, but sig. 1st pass metabolism

Absorbed well from all routes, including oral and inhaled with minimal first pass metabolism
Distribution Vd = 1L / kg

95% protein bound

Vd = <0.3L/Kg

Minimal protein binding (decreases availability)

Metabolism Hepatic metabolism by hydroxylation

Active (1-a hydroxymidazolam) and inactive metabolites

Either no metabolism or organ independent metabolism with inactive metabolites (prevents accumulation)
Elimination Renal excretion

T 1/2 = 4 hours

Rapidly cleared with a short and predictable half life and small CSHT
Reversal Flumazenil - antagonist (reversal agent) Readily reversible with no rebound/side effects


Examiner comments

60% of candidates passed this question.

Candidates who had a structured approach (i.e. pharmaceutical, pharmacokinetic, pharmacodynamic) provided more content and scored higher. Candidates who also approached pharmacodynamic effects in an organ system based approach scored higher. Relating a pharmacokinetic property of midazolam (e.g. volume of distribution or half-life) to a un/desirable attribute e.g. offset of action and accumulation displayed a greater understanding of the question. For many candidates, the description of an ideal drug contained more detail and candidates were not able to adequately state how midazolam compares.


Online resources





2016 (2nd sitting)

Question 4

Question

Categorise the drugs used in the treatment of asthma, give examples and outline their mechanism of action


Example Answer

Oxygen

  • Increases FiO2 > increased SaO2 (by increasing PAO2 as per Alveolar gas equation).
  • Given by numerous devices (nasal prongs, masks, NIV, ETT)
  • Dose titrated to SaO2
    • Hypoxemia is harmful (but optimal target SaO2 unclear)
    • Generally titrated to Sats 94-98% (with caveats for some subgroups of patients)
    • Hyperoxia may lead to hypercapnia, worsening of V/Q mismatch (through alteration of HPVC), lung damage


Beta-adrenergic agonists

  • Long acting B2 selective agonists (e.g. salmeterol) are used in prevention
  • Short acting B2 selective agonists (e.g. salbutamol) are preferred first line therapy for exacerbation
  • Nonselective adrenergic agonists (e.g. adrenaline) can also be used in severe exacerbations
  • SABAs can be given inhaled (via spacer), nebulised or via IV infusion (if unresponsive to inhaled)
  • Example: Salbutamol
    • Short acting B2 agonist
    • MOA: Acts on B2 receptors (Gs protein coupled receptors) in bronchial smooth muscle cells > activates activates adenyl cyclase-CAMP system > increase cAMP > decreased intracellular Ca > SM relaxation / bronchodilation
    • Side effects: Tachycardia, Anxiety, tremor, Hypokalaemia, lactic acidosis


Anticholinergics

  • Example: ipratropium bromide
  • Routes: Inhaled, nebuliser
  • MOA: Competitive antagonism of muscarinic ACh receptors > bronchodilation + decreased secretions
  • Side effects: dry mouth, N/V, headache, blurred vision


Corticosteroids

  • Examples: hydrocortisone (IV), prednisone (PO), budesonide (inhaled)
  • Systemic corticosteroids should be given to all mod-severe asthma > improve outcomes
  • MOA: bind to cytoplasmic glucocorticoid receptors > change in gene transcription > down-regulates the synthesis of proinflammatory cytokines/mediators
  • Effects: increased B receptor responsiveness, decreased inflammation, decreased mucus secretion
  • Side effects: numerous! Depends on dose/duration. Examples:
    • Short term: hyperglycaemia, hypokalaemia, immunosuppression, insomnia/confusion/psychosis,
    • Long term: cushings, osteoporosis, skin thinning, weight gain, immunosuppression


Other potential treatment options (and MOA)

  • Magnesium sulphate > inhibits L type calcium channels > bronchodilation/SM relaxation
  • Ketamine >inhibits L type calcium channels > Bronchial smooth muscle relaxation
  • Aminophylline > PDEI > SM relaxation / bronchodilation
  • Heliox > Improves laminar airflow > may improve ventilation
  • Inhaled anaesthetics (e.g. sevoflurane)
  • Montelukast (leukotriene receptor antagonist used in children)


Examiner comments

71% of candidates passed this question.

Asthma drugs are typically categorised according to mechanism of action. A reasonable alternative is to categorise by clinical use, e.g. short acting, long acting, preventer, rescue etc.
A lot of emphasis in marking was placed on an understanding of the beta-adrenergic pathway, its secondary messenger system and how this medicates smooth muscle relaxation. Candidates whose answers had structure as well those who described the wide range of drugs used to treat asthma scored well.




Question 9

Question

Describe the immunology and drug treatment of anaphylaxis.


Answer

Anaphylaxis

  • Life threatening systemic hypersensitivity reaction
  • May be immune mediated (IgE or non IgE) or non immune mediated


IgE immune mediated anaphylaxis (a Type-1 hypersensitivity reaction)

  • Initial contact between a B-cell and an antigen (allergen) leads to the formation of a IgE against it
  • The specific IgE then binds to Fc receptors on mast cells (in tissues) and basophilis (in circulation)
  • Further exposure of the antigen leads to formation of cross links between IgE-Fc complex and the antigen which leads to activation and release of pre-synthesised mediators
    • Mediators
      • Histamine -> vasodilation, increased vascular permeability, increased chronotropy
      • Leukotrienes -> bronchoconstriction, increased vascular permeability
      • Serotonin -> SM contraction
      • Tryptase -> activates complement, coagulation and Kallikrein-kinin pathways
      • Platelet activating factor --> platelet activation
  • This manifests as
    • CVS: Hypotension/cardiovascular collapse, flushing
    • RESP: Bronchospasm, airway oedema, angioedema, dyspnoea, stridor, hypoxaemia
    • DERM: pruritis, urticaria, angioedema,
    • GIT: abdominal pain, nausea, vomiting, diarrhoea


DRUG TREATMENT


Oxygen

  • Increase FiO2 > improved oxygenation whilst there is bronchoconstriction/airway oedema


Fluids

  • Increase in MSFP > increase VR > increased CO > increased BP


Adrenaline

  • Mainstay of treatment for anaphylaxis

    • Treats cardiovascular collapse, bronchospasm and prevents further degranulation of mast cells

  • Dose is 0.3-0.5mg IM (adults), 0.01mg/kg IM (children), every 5-15 mins (or infusion as needed)

  • Effects

    • Alpha 1 mediated vasconstriction > increases SVR > increases BP

    • B1 mediated increase in inotropy > increase in CO > increase in BP

    • B2 mediated bronchodilation and mast cell/basophil stabilisation

Supplemental drug treatment


Bronchodilators

  • E.g. salbutamol, adrenaline
  • Supportive management for severe bronchospasm
    • B2 agonism > bronchodilation > decrease airways resistance > improve WOB and oxygenation
  • Does not alter the course of the illness


Glucocorticoids

  • e.g. methylpred, pred, hydrocort

  • binds to intracellular steroid receptors > alters gene transcription > anti-inflammatory & immunosuppressive effects

  • Do not alter acute course of illness

  • May prevent biphasic responses / prolonged course of illness

Antihistamines

  • e.g. loratadine, premethazine
  • Symptomatic treatment strategy in mild disease
    • May provide some relief from pruritis/rash (via blocking H1 receptor)
    • Minimal effects on systemic mast cell and basophil degranulation
    • No effects on outcomes
  • Not recommended for severe disease


Glucagon

  • For patients who have taken b-blockers (and thus have reduced responsiveness to adrenaline)



Examiner comments

32% of candidates passed this question.

It was expected candidates would detail the process of IgE mediated type I hypersensitivity reaction with some discussion of the mediators (Histamine / tryptase and others) and their consequences. Some detail describing time frame of response and the pre-exposure to Antigen (or a similar Antigen) was expected. Drug treatments would include oxygen and fluids as well as more specific agents such as adrenaline and steroids. Adrenaline is the mainstay of therapy and some comment on its haemodynamic role and prevention of ongoing mast cell degranulation was required.
Better answers noted steroids take time to work and some also discussed the role of histamine blocking agents


Online resources






Question 16

Question

Outline the influence of pregnancy on pharmacokinetics


Example answer

Absorption

  • Oral
    • Nausea and vomiting in early preg > reduced PO absorption
    • Increased intestinal blood flow (due to increased CO) > increased PO absorption
    • Decreased gastric acid production > increased pH > unionised drugs absorbed more
    • Delayed gastric emptying peri-labour may increase/decrease absorption depending on drug
  • IM / SC / Transdermal
    • Increased absorption due to increased CO + increased skin/muscle blood flow
  • IV
    • Faster IV onset due to increased CO
  • Neuraxial
    • Decreased peridural space (venous engorgement) > decreased dose required


Distribution

  • Volume of distribution
    • Increased total body water > increased Vd for hydrophilic drugs
    • Increased body fat > increased Vd for lipophilic drugs
  • Plasma proteins
    • Decreased protein binding (increased free fraction) due to reduced concentrations albumin and a-1 glycoprotein


Metabolism

  • Hepatic
    • Some metabolic enzymes reduced / some increased (due to progesterone/oestrogen ratio)
    • Leads to variable drug responses
    • E.g. increased metabolism of midazolam, phenytoin, but decreased caffeine.
  • Placenta metabolises some drugs (COMT and MOA enzymes > metabolises catecholamines)
  • Decreased plasma cholinesterase (though no change in Succinylcholine effect)


Elimination

  • Renal
    • Increased clearance due to increased GFR (e.g. gentamycin)
  • Hepatobiliary
    • Decreased clearance due to cholestatic effects of oestrogen (e.g. rifampicin)
  • Resp
    • Increased volatile washout due to increased minute ventilation


Examiner comments

47 % of candidates passed this question.

Most candidates divided the answer into effects on absorption, distribution, metabolism and elimination, which is a good way of presenting the answer. However, the good candidates also mentioned effects on the foetus due to ion trapping caused by the more acidic foetal blood.
Many candidates forgot to include effect on epidural administration of drugs in pregnancy caused by engorged epidural veins during labour.
Candidates lost marks for omitting the effect of increased cardiac output on the rate of distribution of IV drugs to effector sites, the effect of increased hepatic blood flow on drugs with high intrinsic clearance, the increased clearance of drugs with renal clearance due to increased GFR & renal plasma flow



Question 23

Question

Compare and contrast the mechanism of action, spectrum of activity and adverse effects of benzyl penicillin and fluconazole.


Answer

Benzylpenicillin Fluconazole
Mechanism of action Penicillin antibiotic

Both disrupt cell wall synthesis (but different mechanisms): Binds to penicillin binding proteins > inhibits peptidoglycan cross linking > bactericidal

Azole antifungal

Inhibits the fungal CYP450 enzyme responsible for ergosterol production (needed for fungal cell membrane synthesis) > cell death

Spectrum of activity Narrow spectrum penicillin

Covers: Most GPC (staph, strep, enterococci), some GPB (e.g. listeria), very few GNC (e.g. Neisseria sp).
Does not cover: MRSA, CRE, VRE, manty other GN bacteria + anaerobes, all fungi/yeasts, all parasites/ protozoans

Narrow spectrum azole

Covers: Candida and cryptococcal species
Does not cover: some candida sp (e.g. krusei), aspergillus and most other fungi/yeast, all bacteria (GP and GN), all parasites/protozoa

Adverse effects CNS: confusion, coma, seizure

CVS: Nil major
RESP: Nil
GIT: Raised LFTs, nausea and vomiting and abdominal pain, pseudomembranous colitis
HAEM: agranulocytosis
RENAL: Interstitial nephritis
IMMUNO: rash, allergy, anaphylaxis
OTHER: less drug interactions, not a teratogen

CNS: headache

CVS: Prolonged QTc
RESP: Nil
GIT: Raised LFTs, nausea, vomiting, abdo pain
HAEM: thrombocytopaenia, leukopaenia
RENAL: Nil
IMMUNO: rash, allergy, alopecia, anaphylaxis
OTHER: Drug interactions (CYP450), teratogen


Examiner comments

8% of candidates passed this question.

To pass this question each of the three components needed to be compared and contrasted for both agents. A tabulated answer helped in this regard but was not essential.
Some answers included information that could not gain marks, as it was not directly relevant to the question asked (e.g. presentation and dose).
In spectrum of activity, as well as what important organisms the agents were effective against, marks were also given for the important organisms that they were not effective against (e.g. MRSA and beta-lactamase producing organisms for penicillin G; and aspergillus for fluconazole).
In general, of the two agents, fluconazole was the least well answered. For example, a common omission either in mechanism of action or in adverse effects was that fluconazole inhibits microsomal P450 enzymes.
Some candidates confused fluoroquinalone with fluconazole.


Online resources







2015 (1st sitting)

Question 10

Question

Compare and contrast the pharmacology of mannitol and hypertonic saline.


Example Answer

Name Mannitol Hypertonic saline
Class Osmotherapy agent / osmotic diuretic Osmotherapy agent / concentrated electrolyte
Indications Temporary reduction in ICP / IOP

Diuresis

Temporary reduction in ICP / IOP

Hyponatraemia

Pharmaceutics Clear colourless solution (10-25% conc)

- 10% = 10g/100ml
Precipitates at low temperatures

Clear colourless solution (various concentrations)

- 3% saline = 513 mmols Na + Cl (= osmolarity 1026)

Routes of administration IV IV (central)

- Risk phlebitis, necrosis

Dose 0.25-1g/kg bolus (max 100g)

repeated 3 hourly

3ml/kg (3% saline) bolus over 10 mins. Can be repeated to target Na 145-155
pKa 12.6 3.1
Pharmacodynamics
MOA ↑ osmolality of ECF > ↓ volume of ICF (through osmotic shift) > ↓ cerebral volume > ↓ ICP.

Also --> freely filtered at glomerulus (but not reabsorbed) > acts osmotically to ↓ H2O reabsorption.

Increases osmolality of ECF > decreases volume of ICF (through osmotic shift) > decreases cerebral volume > decreases ICP
Effects/side effects RENAL: osmotic diuresis, electrolyte disturbances (variable)

CNS: increased osmolality of ECF > osmotic fluid shifts out of cells > decreased ICP/IOP
CVS: initial rise in MSFP>preload>BP (fluid load) which then decreases with diuresis > hypotension
RESP: Pulmonary oedema (increased in ECF volume)

Renal: Increases Na, Cl, NAGMA, osmolality

MSK: necrosis/phlebitis if given peripherally/extravasates
CVS: increased ECF > overload
RESP: pulmonary oedema (fluid overload)

Pharmacokinetics
Onset / duration Onset <15 mins

Duration = 4-6 hours

Onset <15 mins

Duration = 1 hour

Absorption Given IV only (PO bioavailability - 0%) IV only
Distribution Does not cross BBB

VOD = 0.2L / Kg
75% becomes interstitial fluid, 25% intravascular

Does not cross BBB

VOD = 0.2L / Kg
75% becomes interstitial fluid, 25% intravascular

Metabolism Nil (negligible hepatic metabolism) Nil
Elimination Renal elimination (unchanged)

T 1/2 = 2-3 hours

Renal elimination (unchanged)

T 1/2 =

Monitoring Monitoring (osmolality, 320) Monitoring (Na 145-155)
Advantages Relatively cheap, as effective as HT saline Cheap, stable, small volumes

No diuretic effect > no hypoT
Easily monitored

Disadvantages Unstable at low temps, leads to diuresis, more cumbersome to monitor Needs central access, can cause hypernatraemia,


Examiner comments

8 % of candidates passed this question.

A structured approach is important and a table worked best for most candidates, although a few attempted this in free text. Despite attempting a structured answer very few candidates provided information in regards to preparation, dose, monitoring of osmolarity, adverse effects or contraindications. Understanding of the action of these drugs was expected and factual inaccuracies were common with many candidates suggesting hypertonic saline acts as an osmotic diuretic. Better answers mentioned other potential mechanisms of action of mannitol. Many candidates failed to appreciate the impact on raised intracranial pressure.


Online resources



2015 (2nd sitting)

Question 24

Question

Compare and contrast the pharmacology of valproic acid and carbamazepine


Example Answer

Name Sodium valproate (valproic acid) Carbamazepine
Class Anticonvulsant Anticonvulsant
Indications - Migraine

- Epilepsy (simple-complex and focal-generalised)
- Status epilepticus

- Epilepsy

- Trigeminal neuralgia
- Bipolar disorder

Pharmaceutics Enteric coated tablets, oral liquid

Powder for reconstitution

IR and MR tablets

Oral liquid

Routes of administration IV, PO PO
Dose 15-30mg/kg in divided doses 400mg-1.2g in 2/3 divided doses
Pharmacodynamics
MOA Stabilises Na channels in their inactive state, thereby inhibiting the generation of further action potentials. Also by stimulating GABAergic inhibitory pathways Stabilises Na channels in their inactive state, thereby inhibiting the generation of further action potentials. Also by stimulating GABAergic inhibitory pathways
Effects CNS: Anticonvulsant, drowsiness, dizziness, ataxia

GIT: Nausea, dyspepsia, liver failure, pancreatitis
HAEM: thrombocytopaenia, neutropoenia
Other: teratogen, hair loss

CNS: Anticonvulsant, drowsiness, dizziness, ataxia, headache, diplopia

GIT: Nz, Vz, Dz, raised LFTs
HAEM: neutropoenia, thrombocytopaenia
OTHER: severe skin reactions, teratogen

Pharmacokinetics
Onset TMax 2 hrs (PO), immediate (IV) TMax 1.5 hours PO
Absorption PO bioavailability = 90% PO bioavailability = 80%
Distribution Protein binding 90%

VOD = 0.2L / Kg

Protein binding = 75%

VOD = 1L/kg

Metabolism Hepatic metabolism (glucuronidation)

Active and inactive metabolites

Hepatic (98%)

CYP3A4
Active metabolites

Elimination Renal elimination of metabolites (85%)

T 1/2 = 12 hours

Renal (70%) and faecal (30%) elimination

T 1/2 = 14 hours (metabolites 30 hours)

Special points Monitor LFTs first 6 months given risk of liver failure


Examiner comments

6% of candidates passed this question.

Both these agents are listed as “level B” in the syllabus pharmacopeia and as such a general understanding of each class and relevant pharmacokinetics and pharmacodynamics was expected. Most candidates had better knowledge of valproate than carbamazepine. Some description of the toxicological features for intensive care practitioners was expected.


Online resources





2014 (2nd sitting)

Question 13

Question

Outline the pharmacology of amiodarone


Answer

Name Amiodarone
Class Antiarrhythmic (Class III)

- However, also has class I, II, and IV activity

Indications Tachyarrhythmias (e.g. SVT, VT, WPW)
Pharmaceutics 100-200mg tablets

Clear solution in 150mg ampoules for dilution in dextrose

Routes of administration IV and PO
Dose IV: 5mg/kg, then 15mg/kg infusion / 24hrs.

Oral: 200mg TDS (1/52) > BD (1/52) > daily thereafter

pKA 6.6
Pharmacodynamics
MOA - Blocks K channels (Class III effects) prolonging repolarisation and therefore refractory period.

- Decreases velocity of Phase 0 by Blocking Na channels (Class I effects)
- Non-competitive inhibition of Ca channels prolonging depolarisation + AV nodal conduction time (Class IV effects)
- Slows AV/SA nodal conduction via anti-adrenergic activity (Class II effects)

Effects Rhythm / rate control of tachyarrhythmias
Side effects Side effects worsen/increase with duration of therapy!

RESP: pneumonitis, fibrosis
CVS: bradycardia, QT prolongation
CNS: peripheral neuropathy
Thyroid: Hypo/hyperthyroidism
LIVER: cirrhosis, hepatitis
DERM: photosensitivity, skin discolouration

Pharmacokinetics
Onset / TMax Immediate (IV), 4 hours (PO)
Absorption PO bioavailability 40-60%
Distribution Highly protein bound (>95%)

VD ~70L /kg

Metabolism Hepatic (CYP3A4) with active metabolites (desmethylamiodarone)
Elimination T1/2 = 1 month

Faces, urine, skin elimination

Special points Many drug-drug interactions (e.g. digoxin and warfarin) due to high PPB and enzymatic system


Examiner comments

77% of candidates passed this question.

This was a repeat question and was generally answered well. Some candidates lost marks for being too approximate on the pharmacokinetics.








Question 17

Question

Describe the pharmacology of Oxygen


Answer

Name Oxygen
Class Naturally occurring gas (atomic number 8, atomic weight 16)
Indications Supplementation (i.e hypoxia)

Prophylaxis (e.g. prior to intubation)
CO poisoning
Pneumothorax
Decompression sickness

Pharmaceutics Diatomic gas, normally present at 21% in atmosphere

Colourless, tasteless, odourless
Stored in cylinders (various forms), flammable

Routes of administration Inhaled (variety of delivery devices)

Intravenous (i.e. ECMO)
External (hyperbaric oxygen therapy)

Dose 0.21 - 1.0 FiO2 (generally targeting SaO2 >94%; or 88-92% on CO2 retainers; though exact target not entirely evidenced based)
Pharmacodynamics
MOA Oxygen is delivered to tissues for aerobic metabolism via oxidative phosphorylation
Effects RESP: improved oxygen saturations (may also improve DO2), decreased respiratory drive (very minimal), pulmonary toxicity (free radical generation), may worsen V/Q mismatch (impairs HPVC), drying of mucous membranes

CVS: decreased pulmonary vascular resistance (vasodilation) due to reversal of HPV, increased HR/SV/SVR if hypoxic (via chemoreceptor reflex) > increased CO and BP
CNS: anxiety, nausea, visual changes (neonates), seizures (hyperbaric hyperoxia), decreased CBF (vasoconstriction)
MET: oxidative phosphorylation > ATP production

Pharmacokinetics
Absorption Diffusion across the alveolar capillary membrane.

Rate of diffusion is governed by Fick's Law and is therefore proportional to the lung area, gas diffusion constant, partial pressure gradient and inversely proportional to membrane thickness

Distribution Bound to plasma Hb (98%)

Dissolved in plasma (<2%) - related to Henrys Law

Metabolism Metabolised in mitochondria during the Citric acid cycle, to produce ATP and generate CO2 and H2O
Elimination Exhalation of CO2 via lungs
Special points


Examiner comments

35% of candidates passed this question.

Use of a general "pharmacology" structure to answer this question would help avoid significant omissions such as only discussing pharmacokinetics or only discussing pharmacodynamics. Oxygen has a well described list of pharmacodynamics effects that includes, cardiovascular, respiratory and central nervous system effects. Candidates’ knowledge of the pharmaceutics was limited for a routine drug. It was expected candidates would mention the potential for oxygen toxicity including a possible impact on respiratory drive in selected individuals, retrolental fibroplasia and seizures under some circumstances. Many candidates did not answer the question asked, and instead focussed on the physiology of oxygen delivery and binding of oxygen to haemoglobin


Online resources



2014 (1st sitting)

Question 5

Question

Describe the pharmacological effects of paracetamol (40% marks). Outline its toxic effects and their management (60% marks).


Example Answer

Pharmacological effects

  • MOA
    • Not entirely understood
    • Analgesic effect thought to be related to
      • Decreased central prostaglandin synthesis by inhibition of COX-3
      • Modulation of 5-HT pathways (increased descending inhibition)
      • Activation of endocannabinoid (CB1) and capsaicin (TRPV1) receptors
    • Antipyretic effect thought to be due to decreased PG synthesis in hypothalamus by COX-3
  • Effects/side effects
    • CNS: analgesia, antipyretic
    • CVS: Hypotension (IV preparation, related to excipients)
    • GIT: deranged LFTs, liver failure/damage in high doses/toxicity (below)
    • Other: hypersensitivity reactions


Toxic effects

  • Mechanism
    • Paracetamol is normally hepatically metabolised
      • Principally it is conjugated (glucuronide and sulfate) > eliminated
      • Small amounts undergo oxidation > toxic metabolites (NAPQI)
    • In regular amounts, the NAPQI can be neutralised by hepatic glutathione (anti-oxidant)
    • In excess/toxicity, the conjugative pathways are saturated and there is increased oxidation > increased NAPQI. The hepatic glutathione is exhausted > build up of NAPQI > liver damage
  • Effects of toxicity:
    • GIT: Liver failure / hepatitis, abdominal pain, nausea, vomiting
    • HAEM: coagulopathy (related to liver failure)
    • MET: impaired glucose homeostasis, lactataemia
    • CVS: peripheral vasodilation > shock
  • Management
    • Immediately post ingestion
      • activated charcoal
    • N-acetylcysteine infusion
      • Converted to glutathione > replenishes stores
      • Increased inactivation of the toxic metabolites (NAPQI) > reduced liver damage
      • 200mg/kg over first 4 hours, then 100mg/kg over next 16 hours
    • Supportive care
      • Fluids, antiemetics, etc
      • Complications of acute liver failure
      • Dialysis, ventilation etc


Examiner comments

63% of candidates passed this question.

This question was generally well answered with narrow variance; very few candidates discussed factors predisposing to hepato-toxicity or renal toxicity. Discussion of pharmacokinetics only gained marks when relevant to toxicity.


Online resources



Question 17

Question

Classify local anaesthetic agents and give examples (30% marks). Describe the pharmacology of lignocaine (70% marks).


Example Answer

Local anaesthetics

Classified according to the linkage between the hydrophilic and lipophilic groups

Esters Amides
Link Ester link Amide link
Examples Cocaine, tetracaine, procaine Lidocaine, bupivacaine, ropivacaine
Stability in solution Unstable More stable
Metabolism Plasma esterase's Hepatic (CYP450) dealkylation
Onset Slow Faster
Duration Shorter Longer
Toxicity Less likely More likely
Allergy Possible Very rare


Lignocaine/Lidocaine

Name Lidocaine (lignocaine)
Class Amide local anaesthetic / Class 1b antiarrhythmic
Indications Local/regional/epidural anaesthesia, ventricular dysrhythmias, pain
Pharmaceutics Clear colourless solution (1%, 2%, 4%).

Can come with/without adrenaline. Also available as cream/spray

Routes of administration SC, IV, epidural, inhaled, topical, PO
Dose Regional: Toxic dose 3mg/kg (without adrenaline), 7mg/kg (with adrenaline)

IV use: 1mg/kg initially, then ~1-2mg/kg/hr

pKA 7.9, 25% unionised at normal body fluid pH
Pharmacodynamics
MOA Class 1b anti-arrhythmic: blocks Na channels, raising threshold potential + reducing slope of Phase 0 of action potential, shortened AP

Local anaesthetic: binds to, and blocks, internal surface of Na channels

Effects Analgesic, anaesthetic, anti-arrhythmic
Side effects CNS: headache, dizziness, confusion, paraesthesia, reduced LOC, seizures, tinnitus, burred vision

CVS: hypotension, bradycardia, AV Block, arrhythmia
CC:CNS ratio = 7 (lower number = more cardiotoxic)
Other: allergy, anaphylaxis, methaemaglobinemia,

Pharmacokinetics
Onset Rapid onset (1-5 minutes)
Absorption IV > Epidural > subcut .

Oral bioavailability ~35%.
S/C Dependant on site of injection, blood flow, use of adrenaline.

Distribution 70% protein bound

Vd ~0.9L/kg.
Crosses BBB

Metabolism Hepatic (CYP450 dealkylation)

Some active metabolites

Elimination Renal excretion (98%) of metabolites

Half life ~90mins --> Increased with adrenaline (SC).
Reduced in cardiac/hepatic failure.

Special points Intralipid can be used in LA toxicity


Examiner comments

71% of candidates passed this question.

The first part of this question was answered well by most candidates.
Generally, the second part of the question was poorly organised by many candidates, the consequence being that many opportunities for picking up marks were lost. A brief statement as to what lignocaine is, its presentations and dose, some facts about PD and PK followed by a few lines on toxicity (CC/CNS ratio) was mostly what was required. Only a few candidates mentioned lignocaine toxicity.


Online resources




Question 20

Question

Describe the factors affecting drug absorption from the gastrointestinal tract


Example answer

Drug factors

  • Concentration of drug
    • Increased concentration gradient = more rapid absorption
  • Physical form of drug
    • Liquid drug > faster gastric transit time
    • Ability to dissolve (e.g. enteric coatings) > delays time
    • MR preparations > delayed absorption
  • pKa of drug
    • Weaker acids better absorbed
  • Lipophilicity of the drug
    • Lipophilic drugs better absorbed
  • Size of the drug
    • Smaller = faster/more readily absorbed
  • Drug-drug interactions
    • E.g. vitamin c increases absorption of iron
    • activated charcoal prevents absorption of some drugs through chelation


Patient factors

  • Gastric emptying time
    • Diarrhoea, constipation, ileus will all influence this > slow/fasten absorption
  • Food intake
    • Drugs can interact with food (e.g. iron absorbed better with orange juice due to vitamin C)
  • Altered surface area of the GIT
    • E.g. chrons or surgical short gut > decreased absorption
  • GIT blood flow
    • Reduced blood flow > decreased rate of absorption
  • Biliary function
    • Emulsifying effect of bile important for absorption of fat soluble vitamins and steroids
  • Pancreatic function


Examiner comments

45% of candidates passed this question.

This is a very broad and open question. While a structured approach was useful, a sound knowledge of first principles or even being able to “think on the fly” would have provided candidates with enough opportunities to generate a pass.



2013 (1st sitting)

Question 1

Question

List the different mechanisms of drug actions with examples


Answer

Classification Mechanism Example
NON RECEPTOR
Physiochemical actions Drug exerts its effects due to its physiochemical composition Antacids (basic) which neutralise gastric acid > decreased GORD symptoms
Colligative properties Drug exerts its effect due to the concentration of solute, not the identity of the solute Mannitol > increased plasma osmolality > diuresis
Actions on enzyme systems Decreased concentration of the substrate or product of the enzyme system ACE inhibitors > decreased concentration of angiotensin II
Prodrugs Converted from inactive drug > active drug following administration Levodopa > dopamine
Alteration of a carrier protein Alter the normal function of a carrier protein Frusemide which inhibits NaK2Cl co transporter in LOH > diuresis
Voltage gated ion channels Activated by changes in membrane potential near the ion channel Local anaesthetics > block voltage gated Na channels
RECEPTOR
Binding to intracellular receptors Lead to changes in cell function by altering DNA/RNA transcription Steroids (nuclear receptor)
Binding to ionotropic receptors Lead to changes in cell function by allowing flow of ions down a concentration/electrical gradient GABAA receptor: GABA binds > Cl channel opens > hyperpolarisation > inhibitory post synaptic potential
Binding to metabotropic receptors Bind to G protein coupled receptors and lead to changes in cell function through chemical second messenger systems Adrenaline binds to Gs PCR in myocardium > activation of cAMP 2nd messenger pathway > increased inotropy
Binding to enzyme coupled receptors Lead to changes in cell function through activation of an intracellular enzyme system Tyrosine kinase receptor (class II): insulin binds > activates tyrosine kinases on intracellular domain > phosphorylates IRS > cellular cascade


Examiner comments

A good answer to this question required candidates to think broadly about how drugs act and have a system for classifying their actions. One possible classification is action via receptors or non-receptor actions. Many candidates used categories such as physiochemical, receptor and enzymes. Common problems were failure to mention a whole class of drug actions e.g. drugs acting via voltage-gated ion channels or gene transcription regulation. Candidates also gave far too much detail in some sections e.g. a description of zero order and first order kinetics is not required. Candidates often did not give examples of the drug action they described.


Online resources


Question 4

Question

Describe the pharmacology of tranexemic acid.


Answer

Name Tranexamic acid (TXA)
Class Antifibrinolytic
Indications Trauma (within 3 hours)

Cardiac/obstetric/orthopaedic/dental surgery
Haemorrhage/Coagulopathy
Hereditary angioedema
Heavy menstrual bleeding
Epistaxis

Pharmaceutics 500mg Tablets (PO)

Clear colourless solution (100mg/ml) for injection (IV)

Routes of administration PO, IV, nebulised, topical, IM
Dose Trauma: 1 g (slow IV push) -->infusion of 1g over 8 hrs (if needed)

1g TDS/QID (PO) for most other conditions

pKA 10.2
Pharmacodynamics
MOA Competitive inhibition of plasminogen activation

-> binds to lysine binding sites of plasminogen
-> prevents the activation of plasminogen > plasmin
-> decreases fibrinolysis

Effects HAEM: Decreased fibrinolysis > prothrombotic complications in those patients with risk factors

GIT: nausea, vomiting, diarrhoea
CNS: seizures, headache, dizziness (dose related)
CVS: hypotension (rapid administration)
DERM: allergic skin reactions

Pharmacokinetics
Onset / duration Immediate (IV), 1 hour (IM), 2 hours (PO)

Duration = 18-24 hours

Absorption PO bioavailability = 50%

IM/IV bioavailability 100%

Distribution Protein binding: very low (<5%)

VOD = 0.3L / kg

Metabolism Minimal (<5%) hepatic metabolism

Inactive metabolites

Elimination Renal elimination of active drug (95% unchanged)
T 1/2 = 2hrs (IV), 12 hrs (PO)
Special points Dose reduce in renal failure


Examiner comments

Tranexamic acid is a drug used to reduce bleeding in trauma or surgery. It is also used for hereditary angioedema and menstrual bleeding. It is being increasingly used in critically ill patients. As a Level B listed drug within the Primary Syllabus candidates would be expected to know it in some depth. Often basic information such as mechanism of action, pharmacokinetics and adverse effects was lacking.


Online resources





Question 13

Question

Outline the effects of critical illness on drug pharmacokinetics


Example answer

Absorption

  • Oral
    • Decreased CO > decreased GIT blood flow > decreased absorption PO drugs
    • Ileus + uraemia > decreased gastric emptying > decreased absorption of PO drugs
    • Diarrhoea > fast transit time > decreased absorption
    • Change in gastric pH (e.g. with PPI) alters drug absorption
  • Topical/IM/SC
    • Vasoconstriction > poor tissue perfusion > decreased/slow absorption
  • Inhalational
    • Decreased MV / TV > decreased delivery of aerosolised medications


Distribution

  • Altered Vd
    • Decreased CO (e.g. shock) > slower redistribution
    • Increased CO (e.g. hyperdynamic sepsis) > faster residistribution
    • Hypervolaemia (e.g. renal, cardiac, liver failure) > increased Vd (vice versa)
    • Critical illness > muscle wasting > alter lean mass percentage (alters Vd)
  • Protein binding
    • Decreased protein synthesis > increased unbound fraction of drug > increased Vd and activity
    • Acid-base disturbances will alter free drug levels depending on drug pKa and the pH
  • Inflammation > impairs barrier function (e.g. BBB) > increased penetration of meds (e.g. penicillins)


Metabolism

  • Decreased CO > decreased hepatic/renal blood flow > decreased metabolism (e.g. propofol)
  • Liver dysfunction > Impaired phase 1 and 2 reactions and reduced 1st pass effect > (e.g. labetalol, metoprolol)
  • Renal dysfunction > decreased renal metabolism > prolonged drug effect (e.g. morphine)
  • Hypothermia > decreased metabolism > Prolonged effect (e.g midazolam)
  • Resp dysfunction > Decreased resp metabolism of drugs (e.g. opioids) > prolonged effect


Elimination

  • Decreased CO (e.g. cardiogenic shock) = decreased GFR / HBF > decreased clearance (e.g. gentamicin)
  • Increased CO (e.g. hyperdynamic sepsis) > increased GFR > increased clearance
  • Liver dysfunction > impaired biliary excretion of drugs (e.g. vecuronium)
  • Decreased GFR (e.g. AKI) > decreased renal elimination drugs (e.g. Gentamicin, milrinone)
  • Reduced MV > decreased / slower clearance of volatile anaesthetics > prolonged effect


Examiner comments

Most candidates answered the question under the subheadings absorption, distribution, metabolism and elimination. However, they didn’t give any details of the direction or mechanism of change, often used vague statements without specifically addressing the question and failed to give examples. The impact of the shock state on different kinetic parameters including absorption from skin, tissue, muscles, enteral absorption and inhalational was often overlooked. Similarly, the consequences of changes in volume of distribution, protein binding (e.g. albumin and globulin, ionisation) was poorly understood as was alteration in liver and kidney function. Although this topic is very broad candidates were asked to only outline the details of this topic




Question 23

Question

How do chemical messengers in the extracellular fluid bring about changes in cell function? Give an example of a chemical messenger for each mechanism noted


Example Answer

Chemical messengers (ligands) bind to receptors to elicit a response.

Receptors may be located on the cell surface or within the cell.


Intracellular receptors

  • Proteins located in the cytosol or cell nucleus
  • Activated by lipid soluble ligands (as they must be able to penetrate the lipid bilayer)
  • Lead to changes in cell function by altering DNA/RNA transcription
  • Example:
    • Steroids (nuclear receptor) and milrinone (cytosolic receptor)
    • Specific effects depend on the ligand and the receptor location


Ionotropic receptors

  • Membrane spanning proteins
  • Lead to changes in cell function by allowing flow of ions down a concentration/electrical gradient
  • Examples:
    • GABAA receptor: GABA binds > Cl channel opens > hyperpolarisation > inhibitory post synaptic potential (drug example = benzos)
    • nAChR receptor: acetylcholine binds > non selective cation channel opening - Na/K/Ca > depolarisation > excitatory post synaptic potential (drug example is sux, which is agonist)
    • NMDA receptor: glutamate binds > non selective cations > Na/K/Ca > depolarisation > excitatory post synaptic potential (drug example = ketamine which is an antagonist)


Metabotropic (G protein coupled) receptors

  • Transmembrane proteins with 7 regions

  • Lead to changes in cell function through chemical second messenger systems

    • Activation of the extracellular domain > conformation change in intracellular domain > activation of G proteins > second messenger pathway

  • Three subtypes

    • Gs (stimulatory; increased cAMP)

      • Example: adrenaline (beta-1 receptor) > increased inotropy

    • Gi (inhibitory; decreased cAMP)

      • Example: clonidine (alpha-2 receptor) > decreased SNS outflow

    • Gq (stimulatory; increased IP3)

      • Example: noradrenaline (alpha-1 receptor) > vasoconstriction

Enzyme coupled receptors

  • Transmembrane protein receptor linked to an intracellular receptor
  • Lead to changes in cell function through activation of an intracellular enzyme
  • Example
    • Tyrosine kinase receptor (class II): insulin binds > activates tyrosine kinases on intracellular domain > phosphorylates IRS > cellular cascade


Examiner comments

Overall answers lacked structure and depth, to what is a very fundamental topic. This topic is generally covered within the opening chapters of most physiology texts. Common errors were not answering the question, writing lists rather than describing and explaining, and poor categorisation. Candidates were expected to mention and give example for mechanisms such as hormones binding to cytoplasmic or intra-nuclear receptors, binding to transmembrane receptors coupled to G proteins, cAMP, cGMP, tyrosine kinase, etc.


Online resources



Question 24

Question

Describe the mechanism of action and side effects of 3 classes of drugs that increase uterine tone and 3 classes of drugs that decrease uterine tone.


Answer

INCREASE TONE

Class Oxytocin derivative Ergot derivative Prostaglandin
Example Syntocin Ergometrine Carboprost
MOA Binds to GqPCR in uterus > IP3/DAG pathway > uterine contraction Not fully understood Synthetic PGF2a analogue > binds to PG receptor > myometrial contraction
Effects - Uterine SM contraction

- Weak antidiuretic effect

- Uterine SM contraction - Uterine SM contraction
Side effects IMMUNO: Allergic reactions

CVS: transient hypotension > reflex tachycardia, arrhythmias, flushing
CNS: headache
GIT: nausea, vomiting

CVS: Hypertension

GIT: nausea, vomiting, abdominal pain

CVS: Severe hypertension

RESP: bronchospasm (rare)
GIT: nausea, vomiting, abdominal pain
OTHER: fever


DECREASE TONE

Class Beta agonist CCB NSAIDs
Example Salbutamol Nifedipine Indometacin
MOA Activate B2 receptors (GsPCR), ↑ cAMP > activates protein kinase A > inhibition of MLCK > relaxation Block L-type Ca2+ channels, causing relaxation of SM Inhibit prostaglandin synthesis (via inhibition of COX1/2) > decreased uterine contraction
Effects Decrease uterine tone Decrease uterine tone Decrease uterine tone
Side effects CNS: headacge, hyperactivity

CVS: tachycardia, palpitations
CNS: Anxiety, tremor
RENAL: hypokalaemia
HAEM: lactatemia, hyperglycaemia

CVS: hypotension, flushing, pulmonary oedema

CNS: headache, dizziness
GIT: nausea, vomiting

Mother: gastritis, nausea, vomiting, platelet dysfunction, AKI

Baby: premature closure of ductus arteriosus


Examiner comments

Candidates often appeared to have a sufficient awareness of the choice of drugs (e.g. oxytocin analogues, ergot alkaloids, beta-receptor agonists, calcium channel blockers, etc.), but then failed to produce sufficient depth of knowledge to adequately describe their mechanisms of action in respect to uterine tone. Candidates are reminded that if asked to mention side effects, mentioning side effects of greatest relevance to intensive care (e.g. bronchospasm) in addition to the more generic side effects (e.g. rash).


Online resources




2013 (2nd sitting)

Question 6

Question

Describe the pharmacology of short acting insulin (actrapid).


Answer

Name Short acting insulin (e.g. actrapid)
Class synthetic polypeptide hormone
Indications Diabetes / hyperglycaemia

Hyperkalaemia (in conjunction with dextrose)
B-blocker toxicity (high dose insulin therapy)

Pharmaceutics Clear colourless solutions (generally 100IU/ml)
Routes of administration SC, IV
Dose Variable, titrated to effect (generally bSL)
Pharmacodynamics
MOA The same pharmacodynamic profile of endogenous insulin

> Insulin binds to the alpha subunit of the insulin receptor (tyrosine kinase receptor). Leads to activation of tyrosine kinases on intracellular domain > phosphorylates IRS > cellular cascade

Effects Increased: glucose uptake in cells, glycogenesis, protein synthesis

Decreased: BSL, gluconeogenesis, lipolysis, proteolysis
Cellular shift of potassium (intracellular) due to increased Na/K activity

Side effects Hypoglycaemia (excessive dosing) --> decreased LOC, seizures, death

Hyperglycaemia / DKA (inadequate dosing)
Hypokalaemia --> arrhythmias
Weight gain (long term)

Pharmacokinetics
Profile (SC admin) Onset: 15-30 mins

Peak: 1-2 hours
Duration: 6-8 hours

Absorption No oral absorption (inactivated by GIT enzymes)

SC administration is close to 100%

Distribution Protein binding <10%

VOD = < 0.1 L/Kg

Metabolism Hepatic proteases
Elimination Renal elimination of inactive metabolites

T 1/2B = 90 mins

Monitoring BSL levels (frequency depends on indication, glycaemic stability, route etc)


Examiner comments

In general candidates lacked a sufficient depth of knowledge for this commonly used drug. Some candidates confused actrapid with novo rapid. A structured approach (e.g. pharmaceutics, mode of action, pharmacokinetics, etc.) was expected.


Online resources



2012 (2nd sitting)

Question 5

Question

How does liver failure affect the pharmacology of drugs?


Example answer

Absorption

  • Drugs which are absorbed orally are subject to first pass metabolism by the liver

  • Liver failure > decreased first pass metabolism > increased bioavailability > potential for toxicity

  • oedema (from liver failure) > impair subcut absorption

Distribution

  • The liver is responsible for producing majority of the proteins that drugs bind to in plasma
  • Therefore liver failure > decreased plasma proteins
  • Highly protein bound drugs (e.g. warfarin) are greatly affected by reduced plasma proteins
    • Small decrease in plasma protein levels > large change in the proportion of unbound (active) drug


Metabolism

  • The liver is a primary organ of drug metabolism and biotransformation
    • Phase 1 reactions by liver
      • Hydrolysis, Reduction, Oxidation
      • Small increase in hydrophilicity
    • Phase 2 reactions
      • Glucuronidation, sulfation, conjugation, methylation
      • Significantly increased hydrophilicity (for renal excretion)
  • Liver damage > impaired metabolism / biotransformation > accumulation > toxicity (e.g. diazepam in liver failure)
  • Portal hypertension > shunting of blood > decreased first pass metabolism > accumulation


Elimination

  • Liver failure > decreased hepatic blood flow > decreased elimination of drugs with high hepatic extraction ratio
  • Liver failure > decreased elimination of drugs with low hepatic extraction ratio (regardless of HBF)
  • Liver failure > decreased plasma proteins > increased unbound fraction drug > increased renal elimination of hydrophilic drugs
  • Liver failure > decreased elimination on lipophilic drugs excreted in biliary system


Examiner comments

59% of candidates passed this question.

Good answers were structured using pharmacokinetic and pharmacodynamics headings.
They included some mention of changes in absorption, volume of distribution (an increase
in Vd in liver failure), altered protein binding, altered metabolism and thus change in
clearance, and changes in excretion (decreased biliary excretion of drugs). In respect to
pharmacodynamics candidates could have mentioned increased sensitivity and prolonged
action of sedative drugs, oral anticoagulants, etc. Good candidates also differentiated for
acute (often hepatocellular dysfunction) and chronic liver failure (cirrhosis and changes in
liver blood flow). Common problems were not using a logical structure to answer the
question and stating an effect but not describing how this affected pharmacology. For
example stating decreased albumin production but then not stating the consequence of this
on drug distribution. Primary examination questions may often require candidates to
integrate knowledge from across different sections of the syllabusor apply basic
physiological or pharmacological principles.


Question 9

Question

Classify the anti-arrhythmic drugs using the Vaughan-Williams classification (30% of marks). Compare and contrast the electrophysiological effects of Class 1 anti-arrhythmics (70% marks).


Answer

Class Ia Ib Ic II III IV
Mechanism Blocks Na channels Blocks Na channels Blocks Na channels \beta-adrenergic blockade Blocks K+ channels Blocks Ca channels
Example Procainamide Lidocaine Flecainide Propranolol Esmolol, Atenolol Sotalol Amiodarone (also I,II,IV effects) Sotalol Verapamil Diltiazem
Effects on
Phase 0 ↓ - ↓ - - -
Conduction velocity ↓ - ↓ ↓ ↓ -
ERP ↑ ↓ ↑ ↓ ↑ -
APD ↑ ↓ - ↑ ↑ ↓
QRS duration ↑ - ↑ - ↑ -
QTc ↑ ↓ ↑ ↓ ↑ - 
Drugs not included
  • Digoxin
  • Adenosine
  • Magnesium


Examiner comments

Most candidates displayed a basic knowledge of the Vaughan-Williams classification and gave an example of each class. The remainder of the question lent itself very well to a tabular format. Better answers included the effect on the action potential (diagrams were useful here), channel dissociation kinetics (this was frequently omitted) and examples from each class of drug. There is an excellent table in Stoelting which answers this question nicely. Marks were not awarded for clinical effects. Overall, this question was generally well answered.



Question 13

Question

Describe the effects of obesity on drug pharmacology (70% of marks). Give examples of those drugs that illustrate those effects (30% of marks)


Example answer

Obesity

  • BMI > 30
  • Alters all aspects of pharmacology to varying degrees


PHARMACOKINETICS


Absorption

  • Increased gastric emptying > increased absorption
  • Decreased subcutaneous blood flow (increased adiposity, no increase in vascularity) > slow rate of SC absorption
  • Difficulty with IM administration due to tissue (may lead to inadvertent SC injection)
  • Increased CO > delayed onset of inhalation anaesthetics


Distribution

  • Increased body adiposity > Increased volume of distribution of lipid soluble drugs (e.g. benzodiazipines, thiopentone)
  • Small (relative to body fat) increased Vd for hydrophilic drugs e.g. gentamicin (due to increased blood volume, total body water).
  • Generally lipid soluble drugs dosed on actual body weight, hydrophilic drugs on ideal body weight


Metabolism

  • Increased hepatic blood flow (due to increased CO) = increased clearance of high extraction ratio drugs (flow dependant extraction) e.g. propofol
  • Decreased hepatic blood flow (due to dysfunction, fatty infiltration) > decreased hepatic extraction and metabolism
  • Increased activity of plasma and tissue esterases > increased metabolism/clearance of drugs using these systems (e.g. remifentanil)
  • Increased pseudocholinesterase levels in obesity (sux to be doses on total body weight)


Elimination

  • Increased GFR (due to increased CO) – increased renal clearance of hydrophilic drugs (e.g vancomycin)
  • Decreased GFR due to diabetic nephropathy = decrease renal clearance
  • Due to distribution, lipid soluble drugs may have increased elimination half life


PHARMACODYNAMICS

  • Receptor resistance (e.g. insulin resistance in obesity)


Examiner comments

36 % of candidates passed this question.

This question could be approached by describing the effects of obesity on drug distribution,
binding and elimination. Candidates that took this approach generally did better than those
with a less structured approach. With obesity, fat body mass increases relative to the
increase in lean body mass leading to an increased volume of distribution particularly for
highly lipid soluble drugs, e.g. midazolam. However, the dosing of non-lipid soluble drugs,
e.g. non-depolarising muscle relaxants, should be based on ideal body weight. An increase in
blood volume and cardiac output associated with obesity may require an increased loading
dose to achieve a therapeutic effect, e.g. thiopentone. Plasma protein binding of drugs may
be decreased due to an increased binding of lipids to plasma proteins, resulting in an
increased free fraction of drug. A reduction in plasma protein concentration due to an
increase in acute phase proteins may also result in decreased plasma protein drug binding
and increased free fraction of drug. Pseudocholinesterase levels are increased in obesity and
therefore the dose of suxamethonium should be based on total body weight. Plasma and
tissue esterase levels are increased resulting in the increased clearance of drugs by these
enzymes e.g. remifentanil. Hepatic clearance is usually normal but may be impaired in liver
disease caused by obesity. Renal clearance is usually increased due to increased body
weight, increased renal blood flow and increased glomerular filtration rate. Renal clearance
may be impaired in renal disease caused by obesity related diseases, e.g. diabetes. Insulin
doses may be increased due to peripheral insulin resistance in type 2 diabetes caused by
obesity. Most answers were deficient in examples of drugs to illustrate the effects of obesity
on drug pharmacology.



Question 20

Question

What are drug enantiomers? (20% of marks). Explain the clinical relevance of enantiomers (60% marks). Give clinically relevant example (20% of marks)


Example answer

Enantiomers

  • A stereoisomer which has identical chemical formula and bond structure, but the relative positions of the functional groups in 3D space differ such that the molecules are not superimposable (they form mirror images of each other)
  • Named according to their absolute configurations in 3D space
    • R (rectus) atomic numbers descend clockwise
    • S (sinister) atomic numbers descend anticlockwise


Example

  • Ketamine is typically presented in a racemic mixture
  • However, R- is less effective and has a higher incidence of adverse effects compared to S+ ketamine enantiomer.


Relevance

  • Enantiomers, due to their different configurations in space, interact differently with receptors, transport proteins and enzymes > differing pharmacokinetics and dynamics
  • Pharmaceutics
    • Enantiopure preparations are more expensive (hence racemic mixtures more common)
  • Pharmacodynamics
    • Will interact with receptors differently > differing degrees of agonism/antagonism + also compete for receptors > variable effects (R-ibuprofen 100X more portent inhibitor COX than S ibuprofen)
    • Enantiopure preparations are more likely to include the most active or least toxic isomer (e.g. s-ketamine)
  • Pharmacokinetics
    • Absorption
      • No change in passive absorption
      • Active transport may favour one enantiomer over another (e.g methotrexate)
    • Distribution
      • Stereoselectivity in protein binding which will also affect the Volume of distribution and proportion of active drug (e.g. propranolol)
    • Metabolism
      • Stereoselectivity in metabolism due to varying degrees of interaction with enzymes (e.g. warfarin and CYP450)
    • Elimination
      • Stereoselectivity in elimination (e.g. ibuprofen)


Examiner comments

41% passed

Enantiomers refer to isomeric molecules with centres of asymmetry in 3 dimensions that are mirror images of each other but not superimposable. Enantiomers may be distinguished by the direction in which polarised light is rotated. Interactions involving weak drug-receptor bonds feature a dependence upon recognition of shape, i.e. stereochemical structure is often important. Frequently one enantiomer may bind to a given receptor more avidly than the other, thus pharmacodynamics, pharmacokinetics and toxicity may vary between enantiomers. Many drugs are supplied as racemic mixtures, the components of which have different activity. Clinically relevant examples that candidates could have mentioned, included bupivacaine, ropivacaine, ketamine and carvedilol.



2011 (1st sitting)

Question 14

Question

Describe the mechanisms of action and adverse effects of pulmonary vasodilators that are administered via the inhalational route.


Answer

Oxygen

  • A pulmonary vasodilator in hypoxic patients (reverses hypoxic pulmonary vasoconstriction)
  • MOA
    • Initial phase HPVC: Decreased O2 (hypoxia) > altered redox state in mitochondria of SM muscles > inhibition of K channels > depolarisation > Ca influx > vasoconstriction
    • Prolonged hypoxia: maintains HPVC through decreased NO release +release of endothelin derived vasoconstrictors
    • O2 therefore reverses this process of HPVC
  • Effects
    • RESP: improved oxygen saturations (may also improve DO2), decreased respiratory drive (minor), pulmonary toxicity (free radical generation), may worsen V/Q mismatch, absorption atelectasis, hypercapnoea (in chronic CO2 retainers)
    • CVS: decreased pulmonary vascular resistance (vasodilation) due to reversal of HPV, increased HR/SV/SVR in setting of hypoxia (via chemoreceptor reflex) > increased CO and BP, coronary vasoconstriction
    • CNS: anxiety, nausea, seizures (hyperbaric hyperoxia)
    • MET: oxidative phosphorylation > ATP production


Nitric oxide

  • Class:
    • Pulmonary vasodilator / Inorganic gas
  • MOA:
    • Binds to guanyl cyclase > Increases cGMP > reduction in intracellular Ca > relaxation of SM.
    • As inhaled > selectively vasodilates in regions of well ventilated alveoli
  • Effects
    • RESP: pulmonary artery vasodilation > improves V/Q matching > dec. WOB
    • CVS: decreased pulmonary VR, decreased mPAP, decreased RHS, hypotension, rebound pHTN following cessation
    • CNS: Increased CBF
    • HAEM: thrombocytopaenia, methemoglobinemia


Prostacyclin

  • Class
    • Pulmonary vasodilator / prostacyclin analogue
  • MOA:
    • Binds to prostacyclin receptor (IP receptor) > Activates GPCR > increases cAMP > decreased platelet activation and increased SM relaxation.
    • If given inhaled > local effects in regions of well ventilated alveoli only
  • Effects
    • RESP: pulmonary arterial vasodilation > improve V/Q matching + oxygenation in patients with ARDS if inhaled (goes to ventilated regions only), but may worsen it if given intravenously (goes to all pulmonary blood vessels > worsening shunt)
    • HAEM: inhibition of platelet aggregation > increased risk bleeding
    • CVS: flushing, hypotension, reflex tachycardia, decreased pulmonary vascular resistance and mPAP > decreased RV afterload (may improve CO in RHF)
    • CNS: headache, increased CBF


Examiner comments

Many candidates neglected to include oxygen which is also a drug with significant pulmonary vasodilating properties. Accurate detail concerning the receptor and second messenger effects of drugs was expected. The importance of V/Q matching and reduction in systemic effects via inhalational administration needed to be stated. Better answers included discussion of serious adverse effects such as methaemoglobinaemia, acute lung injury, systemic hypotension, rebound phenomena and heart failure.


Online resources




2010 (2nd sitting)

Question 5

Question

List the antiplatelet drugs and outline their mechanism of action, adverse effects, mode of elimination and duration of action


Answer

Class Example Mechanism of action Elimination Reversibility Duration of antiplatelet effect Adverse effects
COX inhibitors Aspirin Inhibits COX on platelets > ↓ thromboxane A2 > ↓ platelet aggregation and activation Renal (100%) Irreversible inhibition Life of platelet (~7 days) -Haemorrhage

- GIT ulcers
- Allergy, angioedema, bronchospasm
- AKI

ADP receptor antagonists Clopidogrel Binds to P2Y12 subtype of the ADP receptor on platelets > ↓ GP IIb/IIIa activation > ↓ platelet activation Renal (50%) Faecal (50%) Irreversible inhibition Life of platelet (~7 days) - Haemorrhage

- Non responder (CYP2C19 polymorphism)
-CYP450 drug interactions
- aplastic anaemia, thrombocytopaenia, anaemia,
- GIT ulcers
- Rash, urticaria, angioedema, TTP

Prasugrel As above Renal (70%)

Faecal (30%)

Irreversible inhibition Life of platelet (~7 days) - Haemorrhage

- Rash, urticaria, angioedema, TTP

Ticagrelor As above (but binds to a different binding site) Faecal (70%)

Renal (30%)

Reversible inhibition 2-3 days - Haemorrhage

- Dyspnoea
- Rash, urticaria, angioedema, TTP

GP IIb/IIIa receptor antagonists Abciximab Directly bind to GP IIb/IIIa and block the final common pathway of platelet aggregation Renal Reversible inhibition 1-2 days - Haemorrhage

- ↓ PLTs

Tirofiban As above Renal (70%)

Faecal (30%)

Reversible inhibition 4-6 hours - Haemorrhage

- ↓ PLTs, TTP
- Allergy

Phospho-diesterase inhibitors Dipyridamole Inhibits platelet adhesion to walls (by inhibiting adenosine uptake). Also inhibits phosphodiesterase activity > increased cAMP > decreased calcium > inhibition of platelet aggregation Faecal Reversible inhibition 1-2 days - Haemorrhage

- Hypotension
- GIT upset (nausea, vomiting, diarrhoea)
-Rash, urticaria

Prostacyclins Epoprostenol Binds to IP receptors > increased cAMP > ↓ calcium > ↓ platelet aggregation Renal (70%), Faecal (15%) Reversible inhibition < 5 mins - Hypotension, headache, flushing, Haemorrhage
File:Https://www.mja.com.au/sites/default/files/issues/178 11 020603/han10033 fm-1.gif

Examiner comments

67% of candidates passed this question

Most candidates did reasonably well by including aspirin, ADP receptor blockade and glycoprotein 2b/3a blockade in their answers. The best approach to answer this type of question was to use a table with each anti-platelet agent within a column and headings for the rows such as mechanisms of action, adverse effects, mode of elimination and duration of action.
Common omissions included the irreversibility of the blockade of the platelet function by many of these agents, renal toxicity and bronchospasm as side effects of aspirin, bone marrow toxicity of ADP receptor blockers, and dipyridamole as an anti-platelet agent. Some candidates classified clopidogrel as a glycoprotein 2b/3a blocker incorrectly and thought clopidogrel has a relative short duration of action on platelet function because of its half-life. Clopidogrel as a prodrug requiring activation by cytochrome P450 and hence significant potential drug interactions were not mentioned by any candidates.


Online resources




Question 20

Question

Outline the pharmacokinetic consequences of old age. Illustrate your answer with examples


Example answer

Absorption

  • Decreased cutaneous blood flow > slower/reduced absorption of transdermal (GTN patch) and subcut routes (e.g. heparin)
  • Decreased intestinal absorptive capacity with age > decreased PO absorption (e.g. digoxin)
  • Decreased gastric emptying rate > decreased PO absorption (e.g. digoxin)
  • Decreased acid secretion > increased pH gastric > decreased absorption strong acids (e.g. amoxicillin)


Distribution

  • Decreased TBW > decreased Vd of hydrophilic drugs > increased effect (e.g. ethanol, gentamicin)
  • Increased fat / decreased muscle mass > increased Vd of lipophilic drugs > prolonged effect (e.g. amiodarone, diazepam)
  • Decreased plasma proteins (e.g. albumin) > increased unbound (active) drug > increased redistribution and potency (e.g. phenytoin, warfarin)
  • Reduced CO > altered redistribution


Metabolism

  • Decreased portal blood flow = increased oral bioavailability (e.g. labetalol)
  • Decreased hepatic blood flow = decreased clearance (e.g. morphine) and phase 1 metabolism (e.g. ibuprofen)
  • Decreased hepatic tissue mass = decreased Phase 1 reaction (e.g. ibuprofen)


Elimination

  • Decreased renal mass / nephrons with age > decreased GFR > reduced clearance > prolonged effects (e.g. vancomycin) or increased toxicity (e.g. gentamicin)
  • Decreased hepatic blood flow / tissue mass > impaired liver/GIT clearance of drugs (e.g. morphine)


Examiner comments

53% of candidates passed this question.

As the general population ages, and many elderly are admitted to intensive care units and/or
encountered during intensive care ward consultations, this topic is highly relevant. Unfortunately
candidate performance generally lacked sufficient depth and breadth in this area. Good answers
were expected to mention changes in body compartments (eg total body water, lean body mass
decrease, etc), consequences of changes in organ function (eg deteriorating glomerular filtration
rate, reduced liver blood flow, etc), alterations in protein levels and binding, increased likelihood of
drug interactions and the influence of disease states.


Question 24

Question

Classify anti-hypertensive agents by their mechanism of action with a brief outline of each mechanism and an example of a drug in each class.


Answer

Sympatholytic's

Class Example MOA
Alpha blockers Prazosin <math display="inline">\alpha</math>1 antagonist > arterial and venous vasodilation > ↓ SVR > ↓ BP
Beta blockers Metoprolol <math display="inline">\beta</math>1 antagonist > ↓ inotropy and ↓ chronotropy > ↓ BP
Centrally acting Clonidine Central <math display="inline">\alpha</math>2 agonist > ↓ SNS tone (via ↓ NA release) > ↓ BP


RAAS inhibitors

Class Example MOA
ACE inhibitors Ramipril Block the conversion of angiotensin I to angiotensin II by ACE > decreased AG2 > ↓ SVR and ↑ natriuresis > ↓ BP
ARBs Candesartan Same as ACEI (above) but blocks AG2 directly.


Calcium channel blockers

Class Example MOA
Dihydropyridine Amlodipine Blocks L-Type calcium channels in SM > ↓ intracellular Ca > vasodilation > ↓ SVR > ↓ BP
Non-dihydropyridine Verapamil Same as dihydropyridines, but additionally preferentially acts on cardiac cells > ↓ HR and ↓ contractility > ↓BP


Diuretics

Class Example MOA
Loop diuretic Frusemide Blocks to NK2Cl transporter in the aLOH> ↓ Na,K, Cl reabsorption > ↓ medullary tonicity + ↑ Na/Cl delivery to distal tubules > diuresis > ↓ BP. N.B Direct vasodilation effect - MOA unclear
Thiazide diuretic Hydrochlorothiazide Blocks Na/Cl cotransporter in DCT > ↓ Na+ and Cl- reabsorption > diuresis > ↓ BP
Potassium sparing diuretic Spironolactone Competitive aldosterone antagonist > ↓ Na reabsorption in DCT > diuresis > ↓ BP


Vasodilators

Class Example MOA
Nitrates GTN Dinitrated to NO > diffuses into SM > binds to guanylyl cyclase > ↑ GMP > ↓ intracellular Ca > vasodilation > ↓ BP
Hydralazine Hydralazine Not fully understood. Though to also activate guanylyl cyclase > ↑ GMP > ↓ intracellular Ca > arteriolar vasodilation > ↓ BP



Examiner comments

67% of candidates passed this question.

There are many valid lists that can be used as a template to answer this question. One such list might broadly classify antihypertensive agents into sympatholytic agents, vasodilators, calcium channel antagonists, renin-angiotensin inhibitors and diuretics. Within each of these categories are a variable number of sub classes, for example diuretics might include thiazides, loop diuretics and potassium sparing diuretics. A good answer would include such a listing with a brief description of the mechanism of action with respect to the antihypertensive effect and the name of a typical drug that acts in the manner described. Most candidates were able to generate such a list and populate it as required by the question, thus being rewarded with good marks. Poorer answers lacked any logical classification system and were merely a random list of antihypertensive drugs and their actions. Candidates are reminded that organisation within an answer helps in answering the question and achieving marks.


Online resources




2009 (2nd sitting)

Question 5

Question

Outline the kinetic characteristics and the mode of action of digoxin (75% marks). List the cardiovascular effects of digoxin (25% marks).


Answer

Pharmacokinetics

  • Onset/duration
    • Onset; 2-3 hours (PO), 10-30mins (IV)
    • Duration of action: 3-4 days
  • Absorption
    • Well absorbed from GIT
    • 80% oral bioavailability
  • Distribution
    • Protein binding ~25%
    • VOD 6-7L/kg
    • High lipid solubility
  • Metabolism
    • Minimal hepatic metabolism (15%)
      • Oxidation and conjugation
      • Active and inactive metabolites
  • Elimination
    • Renal elimination (70% unchanged)
    • Small amounts of faecal/biliary elimination <15%
    • T 1/2 = 48 hours
    • Not readily dialysable


Cardiovascular effects

  • Positive inotropy
    • Inhibits Na/K ATPase > Increased Na > impairs Na/Ca exchanger > increased intracellular Ca > increased inotropy > increased CO
  • Negative chronotropy and dromotropy
    • Increased PSNS release of ACh at M receptors > decreases SA node firing (chronotropy) + prolongs AV conduction (dromotropy) > increased diastolic filling time > increased preload > increased SV > increased CO + BP
    • Can also lead to bradycardia, AV block, bradyarrhythmia's
  • Increased excitability
    • Increases slope of phase 4 > enhances automaticity of atrial, junctional, ventricular tissue > arrhythmias
      • Not nodal tissue (due to vagal effects)
  • ECG changes
    • Shortens phase 2 > shortened QT interval
    • AV nodal inhibition > prolonged PR interval
    • Shortened Phase 2 > repolarisation abnormalities (scooped ST, TWI)


Examiner comments

0 (0%) of candidates passed this question.

The Syllabus for the Primary examination describes an outline to be “Provide a summary of the important points.” Thus candidates were expected to briefly mention the fundamental pharmacokinetic characteristics (eg highly lipid soluble, well absorbed from small intestine, oral bioavailability of 60 - 90%, protein binding of 20 - 30%, volume of distribution, half life, etc) and mode of action. This was poorly done and candidates’ answers often lacked structure. The question outlines the distribution of marks, being 25% for listing cardiovascular effects. Thus candidates were expected to broadly list the important cardiovascular effects relating to mechanical (eg increase intensity of myocardial contraction, direct venous and arteriolar constriction, etc) and electrical ( increase phase 4 slope & automaticity, hyperpolarization, shortening of atrial action potentials, decrease AV conduction velocity and prolong AV refractory period, increase PR & QT intervals, dose and baseline autonomic activity dependent actions, etc).



Question 17

Question

Explain the difference and clinical relevance between zero and first order kinetics (60% marks). Give an example that is relevant to intensive care practice (40% marks)


Example answer

First order kinetics

  • A constant proportion of a drug is eliminated per unit time
  • Enzyme/elimination systems are working below their maximum capacity
  • Therefore, elimination is proportional to drug concentration
    • Increasing concentration of drug will increase elimination of drug
    • Exponential concentration per time graph
  • Most drugs eliminated in this way


Zero order kinetics

  • A constant amount of drug is eliminated per unit time
  • Enzyme/elimination systems are saturated/working at maximal capacity
    • Increasing concentrations will not lead to increase in elimination
    • Linear concentration vs time graph
  • The transition from first order kinetics to zero order kinetics is described in the Michalis-Menten equation
  • Only some drugs are eliminated this way
    • Example: phenytoin, ethanol, salicylates
  • Because of this, increasing concentrations > increased risk of toxicity
  • Phenytoin reaches the therapeutic range at the point at which it transitions from first to zero-order kinetics > very narrow therapeutic range > requires monitoring / dosage adjustment


Examiner comments



2008 (1st sitting)

Question

Question

Describe the role of the kidney in drug excretion and the factors affecting this. Briefly outline how you would alter the dosing of gentamicin in a patient with renal impairment


Example answer

Renal excretion/elimination

  • Principle mechanism of drug elimination

  • Renal elimination is a balance between glomerular filtration, tubular secretion and reabsorption.

Factors affecting glomerular filtration

  • GFR
    • Increased GFR = increased filtration = increased clearance of hydrophilic drugs
  • Drug size:
    • Increasing drug size = decreased renal clearance
    • Only drugs <7kDa (weight) or <30 Angstrom units (width) are able to pass the capillary BM
  • Protein binding
    • Only unbound drugs can pass the glomerular BM
      • Highly protein bound drugs are poorly filtered
  • Charge
    • Negatively charged molecules cannot readily pass BM (as it is also negatively charged)


Factors affecting drug secretion

  • Protein binding and renal blood flow as per above
  • Concentration: Increased concentration = increased secretion (until tubular transporters are saturated)
  • Multiple substrates competing for the same transporters


Factors affecting drug reabsorption

  • Can be active or passive (most are passive)
  • Affected by charge (ionised drugs cannot pass through BM) and become trapped in the urine
  • Concentration (as passive diffusion depends on concentration gradient)
  • Lipophilicity - Lipophilic drugs are often reabsorbed


Gentamicin

  • Basic pharm overview
    • Bactericidal aminoglycoside, demonstrates concentration dependant activity
    • Small volume of distribution (0.3L/kg), minimal protein binding (15%), not metabolised
    • Renally excreted (GFR limited) unchanged with a normal T 1/2 of 3 hours
    • Narrow therapeutic index
  • Adjustments
    • Loading dose
      • Loading dose is the same (though some antibiotic guidelines will recommend lower end-normal if reduced GFR)
    • Ongoing therapy (if needed)
      • If CrCl <40 strongly consider ongoing need
      • If ongoing need - stretch interval due to reduced renal clearance
      • Consider plasma concentration monitoring if therapy > 48 hours needed


Examiner comments



2008 (2nd sitting)

Question 8

Question

Compare and contrast the pharmacology of sodium nitroprusside and glyceryl trinitrate


Answer

Name Sodium nitroprusside Glyceryl trinitrate
Class Nitrate vasodilator Organic nitrate
Indications Hypertensive emergencies (or need for strict BP control) Hypertension, acute pulmonary oedema, angina, ACS/LV failure,
Pharmaceutics IV solution (50mg/2mL)

Light sensitive

Clear liquid (IV), Patch (transdermal), tablet (SL), spray (SL)
Routes of administration IV only (non PVC giving sets) Sublingual, intravenous, transdermal
Dose Titrated to effect (0-2mcg/kg/min) Patch: 5-21 mcg/hr

SL: 400mcg PRN
IV: titrated to effect

pKA 3.3 5.6
Pharmacodynamics
MOA Prodrug

- Diffuses into RBCs and reacts with Oxy-Hb to produce NO
- NO diffuses into cell > incr cGMP > decreased Ca > SM relaxation

Prodrug

- Dinitrated to produce active nitric oxide (NO).
- NO diffuses into smooth muscle cell > binds to guanylyl cyclase > increased cGMP > decreased intracellular Ca > SM relaxation > vasodilation

Effects CVS: Arterial+venous vasodilation > decreased BP + afterload

RESP: impairs HPVC
CNS: cerebral vasodilation
GI: ileus
Metabolic: acidosis

CVS: systemic vasodilation (preferentially venodilation) > decreased VR > decreased stretch > decreased O2 consumption, coronary arterial dilation

CNS: Increased CBF > inc ICP
RESP: Bronchodilation, decreased PVR

Side effects headache, hypotension, rebound hypertension (abrupt withdrawal), cyanide toxicity (high doses), metabolic acidosis, hypoxia, raised ICP CVS: reflex tachycardia, hypotension

CNS: Headache, increased ICP
Derm: flushing

Pharmacokinetics
Onset/offset Immediate onset + offset 1-3 mins (SL), <1 min (IV), Patch variable.
Absorption 0% oral bioavailability Oral bioavailability 3%

(hepatic - high first pass effect)

Distribution VOD 0.25L/Kg (confined intravasc).

Nil protein binding

60% protein bound.

Vd 3L/kg

Metabolism Nitroprusside > cyanide > prussic acid > thiocyanate

site: RBC (and liver secondarily)

Hydrolysis into inactive compounds

Site: liver + RBC cell wall + vascular cell walls.

Elimination Metabolites via urine (major)

T 1/2 = 3 mins

80% urine.

T 1/2 = 5 minutes.

Special points Can develop tachyphylaxis (depletion of sulfhydryl groups)


Examiner comments

80% of candidates passed this question

It was expected candidates would address specific aspects of pharmacology such as action, mechanism of action, half life and duration of effect, route of administration, potential toxicity and special precautions. These agents lend themselves to comparison and contrast as several distinct similarities and differences exist and credit was given for highlighting these. Specific comments should include that both agents result in blood vessel dilation with extra credit given for detailing the differences in the balance of arterial versus venous effects between them. For both agents the effect is mediated through nitric oxide and it was expected candidates would identify that nitroprusside releases NO spontaneously and GTN requires enzymatic degradation with the resultant effects on smooth muscle mediated via c GMP. They are both short acting agents when used intravenously and require careful titration to measured blood pressure for effect. Extra credit was given for mentioning that routes other than IV are available for GTN (topical / oral) but not for nitroprusside. Comments on special precautions such as Nitroprusside should be protected from light and GTN given via non PVC giving sets gained additional marks. In addition to the well described adverse effects of each agent, it was expected candidates would mention the potential for cyanide toxicity with nitroprusside and extra marks were awarded for an indication of usual doses.




2007 (2nd sitting)

Question 2

Question

Outline the sites and mechanisms of action of diuretics. Give one example of drug acting at each site and list two side effects of each drug.


Example Answer

Site of action Example Mechanism of diuresis Side effects
Entire Mannitol Freely filtered at glomerulus (but not reabsorbed). Acts osmotically to ↓ H2O reabsorption - ↓ Na, K, Cl

- Hypotension, hypovolaemia

PCT Acetazolamide Inhibits carbonic anhydrase in PCT > ↓ reabsorption of filtered HCO3 + Na > ↑ tubular osmolality > diuresis - Metabolic acidosis (↓ HCO3)

- ↓ Na, K, Cl

LOH Frusemide Binds to NK2Cl transporter in the thick ascending limb LOH > ↓ Na,K, Cl reabsorption > impairs counter current multiplier + ↓ medullary tonicity - ↓ Na, K, Cl

- Metabolic alkalosis (↓ K, Cl)
- Hypovolaemia, Hypotension

DCT HCT Inhibit Na+ and Cl- reabsorption (Na/Cl cotransporter) > ↓ H2O reabsorption - ↓ K, Na, Cl

- ↑ BSL, lipids
- Metabolic alkalosis

CD Spironolactone Competitive aldosterone antagonist > inhibition of ENaC > ↓ Na reabsorption (and ↓K excretion) > diuresis -↑ K and metabolic acidosis

- Anti-androgen effects (decreased libido, menstrual irregularities, gynecomastica)

CD Amiloride Blocks ENaC > ↓ Na/Water reabsorption - HypoNa (blocked ENaC)

- HyperK (ENaC drives ROMK channels)


Examiner comments

Good answers to this question were those that had a tabular format to the structure of the answer — for example columns headed mechanism, sites, drug and side effects. Most common omissions were not to further describe how the different mechanisms of action of diuretics increased urine output, e.g. "disruption of the counter current multiplier system by decreasing absorption of ions from the loop of Henle into the medullary interstitium, thereby decreasing the osmolarity of the medullary interstitial fluid". There was often little mention of increased urine solutes and the effect the electro chemical effect had in promoting a diuresis. Examples of drugs were well done


Online resources




Misc / not previously examined

Question a

Question

Outline with examples the role of excipients in drug formulations.


Example answer

Excipient

  • Components of a drug preparation that do not exert the pharmacological effect
  • Function: assists with optimal delivery of the active ingredient
  • Ideally: nontoxic, inactive, and don’t interact with active ingredient


Preservatives

  • Prevent/inhibit growth of microorganisms in the drug preparation
  • Generally weak acids (pKa 4-5)
  • Example: benzyl alcohol


Antioxidants

  • Prevent/limit the degree of chemical breakdown due to oxidative reactions
  • Example: ascorbic acid


Solvents

  • A liquid (usually) substance which can dissolve another substance
  • Water is the most common solvent (most drugs are water soluble to an acceptable degree)
  • For non-water-soluble drugs, or drugs unstable in water, non-aqueous solvents are used (e.g. mannitol, propylene glycol)


Buffer

  • A solution consisting of a weak acid and its conjugate base
  • Maintains the pH of a drug preparation to maximise stability and/or maintain solubility
  • Example: acetic acid / sodium acetate


Emulsifying agents

  • Substances that stabilise emulsions which are typically unstable
  • Example: soya bean oil / egg lethicin in propofol


Diluents

  • Provide bulk and enable accurate dosing of potent ingredients
  • E.g. glucose, lactose


Binders

  • Bind tablet ingredients together for form/strength
  • Example: starches, sugars


Flavours

  • Added to increase compliance / ease of use
  • Example: aspartame


Colouring

  • Added for marketing purposes / compliance
  • E.g. beta caroteine


Coatings/film

  • Designed to make tablets easier to swallow, improve predictability of absorption, protect from environment e.g moisture
  • Example: cellulose for enteric coating to delay release of agent


Examiner comments

Not previously examined



Question b

Question

Describe the mechanism of action and effects of corticosteroid drugs with particular reference to asthma


Answer

Asthma

  • Asthma is an inflammatory condition of the airways characterised by airway narrowing, mucous secretion and expiratory airflow limitation.


Corticosteroids

  • Steroid hormones normally produced by the adrenal cortex
  • Two main classes of corticosteroids
    • Glucocorticoids (secreted from zona fasciculata and reticularis)
    • Mineralocorticoids (secreted from zona glomerulosa)
  • Glucocorticoids are used in the treatment of asthma
    • Systemic: Prednisone, Hydrocortisone
    • Inhaled: Beclomethasone, Budesonide
  • Note: prednisone and hydrocortisone also have some mineralocorticoid effect


Glucocorticoids

  • Mechanism of action
    • Lipid soluble hormone > crosses cell membrane > binds to intracellular steroid receptors > translocate to nucleus > alters gene transcription > metabolic, anti-inflammatory & immunosuppressive effects in tissue-specific manner
    • The anti-inflammatory process is mediated by suppression of phospholipase A2 > decreased arachidonic acid > decreased PGs, TXA2, Leukotrienes
    • Inhaled steroids (e.g. budesonide) at regular dosage tend to have only respiratory (local) effects, whereas systemic glucocorticoids (e.g. hydrocortisone, prednisone) exhibits effects at all sites.
  • Effects on asthma
    • RESP
      • Reduced airway oedema > bronchodilation
      • Increased SM responsiveness to catecholamines and B2 agonists > bronchodilation
      • Decreased mucous secretion > reduced mucous plugging
      • Bronchodilation + decreased mucous secretion > improved ventilation + oxygenation > decreased work of breathing
    • CVS
      • Increased BP (Due to mineralocorticoid effect on kidneys (increased H2O reabsorption) and increased alpha adrenergic responsiveness to endogenous catecholamines)
  • Other effects of systemic steroids
    • RENAL
      • Increased fluid reabsorption (Due to mineralocorticoid effect on kidneys > increased Na/H20 reabsorption in DCT > increased BP, oedema)
    • Metabolic
      • Hyperglycaemia (Due to increased gluconeogenesis, protein catabolism, lipolysis)
      • Adrenal suppression (Due to negative feedback on the pituitary (inhibits ACTH) and hypothalamus (inhibits CRH))
    • CNS
      • Sleep disturbance, mood changes, psychosis
    • IMMUNE
      • Immunosuppression (particularly mast cells, eosinophils, T cells) > decreased cytokines/pro inflammatory mediators
    • GIT
      • GIT ulceration (inhibition of COX systems)
    • MSK
      • Skin thinning and muscle wasting (due to increased protein/fat catabolism)
      • Osteoporosis



Question c

Question

Pharmacology of aminophylline


Answer

Name Aminophylline (and Theophylline)
Class Methylxanthine derivative
Indications Severe airway obstruction, including acute asthma (less commonly used nowadays)
Pharmaceutics (aminophylline) Complex of 80% theophylline (active component) and 20% ethylenediamine (improves solubility, no effect). Concentration of 25mg/ml in 10ml vials
Routes of administration IV (aminophylline) , PO (aminophylline and theophylline)
Dose (Aminophylline) Loading = 5mg/kg (slow injection)

Maintenance = 0.5mg.kg.hr

Pharmacodynamics
MOA - Non selective phosphodiesterase inhibitors > increased cAMP > decreased Calcium > SM + bronchial relaxation

- Also block adenosine receptors > decreased inflammatory response

Effects Narrow therapeutic window

RESP: Bronchodilation (via SM relaxation), increased respiratory centre sensitivity to CO2, improved diaphragm contractility
CNS: headache, irritability, tremor, seizures
CVS: palpitations, tachycardia, arrhythmia, increased inotropy/chronotropy
GIT: Nausea, vomiting, diarrhoea
RENAL: natriuresis

Pharmacokinetics
Absorption PO bioavailability > 90%
Distribution Vd = 0.5 L /kg

Protein binding = 40%

Metabolism Hepatic metabolism (90%) via CYP450 mechanisms to active and inactive metabolites. 10% unchanged
Elimination Renal elimination of active and inactive metabolites

Dialysable
T 1/2 = 6-12 hours (longer in children)

Special points Therapeutic concentration 10-20mg/ml


Examiner comments

Not previously examined



Question dnus

Question

Outline the pharmacology of metoclopramide.


Answer

Name Metoclopramide
Class Antiemetic / Prokinetic
Indications - Nausea and vomiting

- Prokinetic

Pharmaceutics Clear colourless solution (5mg/ml).

Tablet (10mg)

Routes of administration IV, PO, IM
Dose 10mg TDS (adults) for short duration (max 5 days)
Pharmacodynamics
MOA Central D2 antagonism at chemoreceptor trigger zone > reduced afferent input to vomiting centre in medulla
Effects GIT: Anti-emetic, Prokinetic (acceleration of gastric emptying)

CNS: EPSE (akathisia, dystonia, tardive dyskinesia) in children, drowsiness, dizziness, headache, worsening of Parkinson symptoms
CVS: arrhythmias

Pharmacokinetics
Onset Tmax < 1 hour (PO), <15 mins (IV)
Absorption PO bioavailability 80%
Distribution VOD = 3L / Kg

Protein binding 30%

Metabolism Minimal hepatic metabolism (conjugation)
Elimination Renal elimination (85%)

Active and inactive metabolites
T 1/2 = 4 hrs

Special points - Contraindicated in pheochromocytoma (precipitates pheo crisis), Parkinson's (Blocks Dopamine receptors), GI obstruction/perforation (prokinetic), avoid in children <20 years old (risk of EPSE)
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