FC Clin Pharm(SA) Part I

THE COLLEGES OF MEDICINE OF SOUTH AFRICA

Incorporated Association not for gain Reg No 1955/000003/08

Part I Examination for the Fellowship of the College of Clinical Pharmacologists of South Africa

23 March 2010 Paper I (3 hours)

All questions are to be answered. Each question to be answered in a separate book (or books if more than one is required for the one answer)

Answer questions 1 and 2 in one book. Discuss the pathophysiology and clinical manifestations of the 4 major types of drug hypersensitivity reactions. Give an example of a drug for each type of drug hypersensitivity reaction. [15] Discuss the management of the following two cases a) A 23-year-old man is given 2.4 MU benzathine penicillin intramuscularly for a genital ulcer. Within minutes he loses consciousness and collapses with cold extremities and a rapid thready pulse. Blood pressure is unrecordable. (5) b) A 40-year-old woman with hypertension was commenced on enalapril. Three weeks later she presents with a swollen lower lip and tongue. She is noted to have inspiratory stridor. (5) [10]

Answer questions 3 and 4 in one book. 3 Answer the questions in the following three cases a) Digoxin 0.25 mg daily is prescribed for a 56-year-old woman with atrial fibrillation and severe cardiac failure. How would you establish when is the earliest follow up appointment when the digoxin concentration is expected to be at steady state? (3) b) A 15-year-old boy with epilepsy was well-controlled on phenytoin 200 mg daily for the past year. He presented with confusion, nystagmus and drowsiness for the past 5-days. Oedema and proteinuria were noted and a diagnosis of nephrotic syndrome was subsequently made. Phenytoin concentration was in the therapeutic range (15 mg/L). His serum creatinine was normal, albumin 16 g/L, cholesterol 8.4 mmol/L. His neurological symptoms resolved on lowering the phenytoin dose to 150 mg. Explain why he had features of phenytoin toxicity with a therapeutic phenytoin concentration. (3) c) A 19-year-old woman took an accidental overdose of phenobarbitone. She had been instructed to double the dose of phenobarbitone after 7 days, but instead, she took four times more. She was drowsy but did not require intubation. Why did the dose of phenobarbitone require upward adjustment after seven days? (2) List two ways by which you can increase the elimination of [10]

Explain what is meant by the term saturable metabolism. Discuss the clinical relevance of drugs that undergo saturable metabolism, and give two examples. [10]

Answer questions 5 and 6 in one book. 5 Write short notes on the following topics in drug discovery a) The meaning and determination of the no-observed-adverse-effect-level (NOAEL) derived from toxicology studies. (5) b) The main issues to be considered when planning a phase I clinical trial in healthy subjects to examine the potential effect of a new chemical entity on QTc prolongation. (5) [15] 6 Dose response information is important for the choice of the optimum dose of a new drug for phase III studies and for the labelling of its therapeutic use. Useful study designs for deriving dose response information related to short-term or long-term effects of a drug include: Parallel dose-response studies; Cross-over dose response studies; forced titration studies; optional titration studies (placebo- controlled titration to endpoint). Briefly describe each of these study designs and discuss their advantages and disadvantages. [15]

Answer questions 7 and 8 in one book. 7 Discuss the molecular targets and types of neural circuits of the dopaminergic systems. [15] 8 Discuss the activation of central and peripheral adrenergic -receptors. [15]

FC Clin Pharm(SA) Part I

THE COLLEGES OF MEDICINE OF SOUTH AFRICA

Incorporated Association not for gain Reg No 1955/000003/08

Part I Examination for the Fellowship of the College of Clinical Pharmacologists of South Africa

24 March 2010 Paper II (3 hours)

All questions are to be answered. Each question to be answered in a separate book (or books if more than one is required for the one answer)

Answer questions 1 and 2 in one book. A randomised trial of a new drug Skitite is conducted in World Cup skiers who take the drug/placebo for one year. A reduction is reported in knee ligament tears of 8% in the Skitite arm versus 16% of the placebo arm (relative risk 0.5; P=0.01). Depression, the only significant adverse event, occurs in 5% of athletes taking Skitite versus 2% taking placebo. a) Discuss the value and limitations of the relative risk and P value in clinical decision-making. (6) b) What is the number needed to treat and harm? (show how you calculated these) (4) c) Your patient, who is a keen weekend skier, reads about Skitite in Ski Magazine and asks you to write a prescription. Discuss how you would use the evidence to decide whether you would recommend Skitite for her. (5) [15] A North American company has developed a novel hepatitis B recombinant vaccine. Phase I and II trials have demonstrated that the vaccine is safe with good immune responses in children and adults. Asia is a hyperendemic area for HBV infection, and the government of a large Asian country has approved an application to conduct a clinical trial of the vaccine in its jurisdiction. An institute in one of its largest cities plans to carry out a randomised, double-blind study with one experimental group and two control groups. The experimental group would receive the new recombinant HBV vaccine, one control group would receive the plasma-derived HBV vaccine (which has previously been shown to be highly immunogenic and effective for prevention of acute and chronic HBV infection), and the second control group would receive a placebo. The sample size has adequate power with the margin of non-inferiority set at 12%. At the time the study was carried out, immunisation with HBV vaccine was a paid service and was not covered by the national Expanded Programme on immunisation. The population to be vaccinated in the study is infants born to HBV surface antigen positive mothers, and therefore at high risk of becoming infected. The researchers plan to brief the infants parents about the study, and explained the purpose and procedure of the research. For each child, at least one parent will provide permission before their child could enrol in the study. You are asked to comment on the ethical standards of the study. Indicate how the study could be improved to conform to these standards. [15] Answer questions 3, 4 and 5 in one book. The fixed ose antimalarial combination, sulfadoxine-pyrimethamine (SP) has been widely used for the treatment of uncomplicated malaria for decades, and more recently

has been used as intermittent preventive treatment ofmalaria in high risk groups (e.g. pregnant women, infants) regardless of whether or not they are symptomatic or parasitaemic. Focusing onpharmacovigilance principles, contrast the nature of the drug safety evidencerequired to support the safe use of sulfadoxine-pyrimethamine for intermittent preventive treatment in pregnant women, with that required for licensing SP as atreatment of falciparum malaria. (3) Give two examples of study designs that would be appropriate to collect data on thesafety of SP for IPT in pregnant women, tabulating the purpose, advantages anddisadvantages of each study design. (12) [15] 4 Artemether-lumefantrine is the recommended treatment for uncomplicated malaria. Pregnant women are at increased risk of malaria morbidity and mortality. A Thai study reported that, compared with women who were not pregnant, pregnantwomen have higher treatment failure rates and lower plasma concentrations ofartemether, dihydroartemisinin (active metabolite of artemether), and lumefantrine.Explain how the physiological changes that occur in pregnancy could affect drugconcentrations [10] Regarding the serotonin syndrome a) Briefly define the serotonin syndrome and list its important clinical features. (5) b) List FIVE different mechanisms of action that can result in the serotonin syndrome, giving an example of drug/substance that can cause each mechanism. (10) [15] Answer questions 6 and 7 in one book. Write short notes explaining the meaning of the following terms in the context of health economic evaluation a) Discounting. (4) b) Cost utility analysis. (5) c) Opportunity cost, direct cost & indirect cost. (6) [15] Pharmacogenomics offers the promise of personalised medicine. Discuss the arguments for and against this statement. Give two examples (one affecting pharmacodynamics and one pharmacokinetics) of drugs where a good case can be made for this statement. [15]