Pharmacology

251. A 24-year-old woman is undergoing chemotherapy for acute leukaemia. She is suffering from severe vomiting and you plan to choose an appropriate antiemetic for her. Which of the following would be the most appropriate choice? Metoclopramide im Prochlorperazine im Oral ondansetron Ondansetron iv Your answer Oral domperidone Ondansetron is a potent 5-hydroxytryptamine-3 (5-HT3)-receptor antagonist. It is usually well tolerated, the main side effect being headache. Given that vomiting is likely to continue, iv would be the preferred route of administration. Studies have shown that 5-HT3 antagonists are generally more effective in treating postchemotherapy nausea and vomiting than traditional agents. Antidopaminergic drugs, such as metoclopramide and prochlorperazine, should be avoided due to increased risk of side effects in young women in particular. If the 5-HT3-receptor antagonist class was not tolerated then domperidone would be an acceptable alternative.

252. A newly diagnosed diabetic patient was started on metformin in addition to being given appropriate dietary advice. He asks you about dangerous side-effects of the drug. Which rare but serious side-effect of metformin treatment should be considered? Rhabdomyolysis

Lactic acidosis Your answer Anaphylaxis Pulmonary fibrosis Cardiotoxicity Lactic acidosis is best known in diabetic patients as a rare but often fatal complication of metformin, which acts mainly by inhibiting hepatic gluconeogenesis. Lactic acidosis presents as coma with metabolic acidosis (reduced arterial pH and venous bicarbonate) and a wide anion gap due to hyperlactataemia. Blood glucose levels are usually raised. Treatment is still unsatisfactory. Intravenous sodium bicarbonate may paradoxically aggravate intracellular acidosis, although forced ventilation to blow off carbon dioxide may help. Haemodialysis may clear lactate and hydrogen ions, and correct any sodium overload following bicarbonate administration. Sodium dichloroacetate, which stimulates pyruvate dehydrogenase to metabolise lactate, is undergoing evaluation. Mortality remains high (over 30%), partly because of the organ failures that commonly coexist.

253. In a pulmonary hypertension clinic, a patient asks you about bosentan, a drug that has recently been licensed and marketed for the management of pulmonary arterial hypertension. Which of the following statements is true concerning the actions and unwanted effects of bosentan? It is a competitive antagonist of the ETA but not ETB receptor Dose-related nephrotoxicity can occur Haemoglobin concentrations rise

It is safe for use in pregnancy Systemic vascular resistance falls Your answer Bosentan is a competitive antagonist of both endothelin-A (ETA) and endothelin-B (ETB) receptors, leading to falls in both pulmonary and systemic vascular resistances without an increase in heart rate. It has been shown to be efficacious in patients with pulmonary arterial hypertension. Common unwanted effects include flushing, hypotension, dyspepsia and fatigue. Haemoglobin concentrations can fall by up to 1 g/dl during bosentan treatment. The most serious unwanted effect is dose-dependent hepatotoxicity, and it is therefore contraindicated in patients with moderate to severe liver disease. Generally, hepatotoxicity occurs within the first 34 months of treatment with bosentan. It is also teratogenic and therefore its use in pregnancy is contraindicated.

254. A 57-year-old with cardiac failure is being managed in the high dependency unit. The decision has ben made to commence inotropic support. Of the following drugs, which is most likely to cause significant tachycardia? Noradrenaline Dopamine Dobutamine Adrenaline Phenylephrine

Your answer

Phenylephrine and high-dose dopamine have adrenergic effects. Noradrenaline exerts largely effects, although it is also a weak -adrenergic agonist. All of these drugs, by causing vasoconstriction, will tend to cause reflex bradycardia. Adrenaline exerts agonist effects on both - and -adrenoceptors, and the effect will cause significant tachycardia. It stimulates both 1- and 2-receptors with approximately equal potency, unlike dobutamine, which is a relatively selective agonist for 1-receptors, hence causing less tachycardia at lower doses. 255. A 60-year-old patient has been commenced on antihypertensive therapy. The next morning he has a dizzy spell and complains of palpitations. Which of the following drugs is the most likely cause?

Doxazosin Your answer Verapamil Hydrochlorothiazide Atenolol Clonidine

-Selective antagonists in particular can cause orthostatic hypotension and patients should be dosed carefully. The same side-effects may also be observed with rapidly absorbed dihydropyridine-type (nifedipine) calcium-channel blockers. Verapamil blocks cardiac calcium channels; there is therefore no compensatory tachycardia. Likewise, compensatory tachycardia does not occur with -blocker therapy and centrally acting drugs such as clonidine.
1

256. hat is the mechanism of action of carbimazole? Destruction of functioning thyroid cells Inhibition of 5'-deiodinase Inhibition of the iodination of tyrosine Your answer Inhibition of thyroglobulin proteolysis Conversion to methimazole, which blocks the TSH receptor Carbimazole is converted to its active metabolite, methimazole, in the body. It reduces the synthesis of new thyroid hormones by inhibiting the iodination of tyrosine and coupling of precursors to form thyroxine. It also has an immunosuppressive action leading to a reduction in serum thyrotrophin (TSH)-

receptor antibody (TRAb) concentrations. It does not destroy functioning thyroid cells. Propylthiouracil inhibits 5'-deiodinase and prevents the release of free T3 and T4 from the thyroid cell. Thyroglobulin proteolysis is inhibited by iodide.

257. What is the mode of action of amiodarone? -adrenoreceptor blocker -adrenoreceptor blocker Potassium channel blocker Calcium channel blocker Sodium channel blocker

Your answer

Amiodarone is a class III antiarrhythmic drug. Class III antiarrhythmics are potassium channel blockers, they prolong duration of action potential with resulting prolongation of effective refractory period. Other Class III antiarrhythmics are sotalol, disopyramide and bretylium.

258. You are reviewing a 36-year-old man with hypertension and decide to commence blocker therapy. Which of the following -blockers has the largest volume of distribution? Atenolol Celiprolol Nadolol Sotalol Metoprolol

Your answer

Metoprolol is the most lipid-soluble of the -blockers listed above and therefore has the largest volume of distribution. The volume of distribution is defined as the amount of drug in the body divided by the concentration, it has units of volume (litres). The clinical significance is that the increased lipid solubility is associated with greater penetration across the bloodbrain barrier (and also into other tissues), and therefore a greater incidence of night terrors. Maximal gastrointestinal absorption of drugs occurs when there is intermediate lipid and water solubility, so that drugs with greater lipid solubility, although allowing greater tissue penetration, may be more poorly absorbed.

259. A 72-year-old man presents with acute onset lumbar spine pain. There is no significant neurology. He has a history of chronic obstructive pulmonary disease. X-ray reveals an osteoporotic fracture of L4. Which of the following would be the most appropriate pain relief in this case? Paracetamol 1 g po qds Diclofenac 50 mg po tds Diclofenac 50 mg po tds, tramadol 100 mg qds and paracetamol Your answer 1 g qds Tramadol 100 mg qds Tramadol 100 mg qds and paracetamol 1 g qds This man has an acute osteoporotic fracture of the lumbar spine. The most likely cause in this case is chronic use of corticosteroids. One class of analgesic is unlikely to provide adequate pain relief and hence the triple combination of diclofenac, tramadol and paracetamol is likely to be most appropriate. It is important however to review long-term non-steroidal use in the context of renal function and cardiac risk factors in this patient. Once pain is controlled, medication could be stepped down to two agents. Suitable longer-term treatments for his osteoporosis would include either the use of bisphosphonate therapy or calcium and vitamin D supplementation.

260. Which drug is most likely responsible for postural hypotension in a 76-year-old man who is taking simvastatin 20mg, ramipril 5mg, nifedipine 40mg SR, bendroflumethiazide 5mg, aspirin 75mg? Simvastatin Ramipril Bendroflumethiazide nifedipine Aspirin

Your answer

Ramipril and nifedipine can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been increased, but 5mg of bendroflumethazide in

particular is associated with a greater degree of symptomatic hypotension than the ramipril or nifedipine SR doses given here. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea, or vomiting.

261. Which of the following statements relates to the pharmacology of trimethoprim? It is a bacteriostatic drug It is combined with sulfamethoxazole for synergistic reasons It requires estimation of serum levels to assess therapeutic efficacy It may cause marrow depression and microcytic anaemia It may cause side-effects such as hepatic toxicity

Your answer

Trimethoprim acts by inhibiting dihydrofolate reductase, an enzyme that is important in the division of cells. The combination, co-trimoxazole, is commonly used to treat urinary tract infections and respiratory illnesses. The synergistic combination makes it a powerful bactericidal drug. No specific hepatic toxicity has been reported with trimethoprim. Megaloblastic anaemia may occur due to folate deficiency. Serum levels are rarely used to maintain a course of trimethoprim, and serum levels have no correlation with guiding dosage.

262. Thiazide diuretics have their mode of action in which part of the kidney? Convoluted tubule Proximal segment of the distal convoluted tubule Ascending limb of Henles loop Distal segment of the distal convoluted tubule Descending limb of Henles loop

Your answer

Most diuretics act by inhibiting sodium reabsorption in the renal tubules. The loop diuretics furosemide and bumetanide inhibit Na+/K+/Cl cotransport in the ascending limb of Henles loop. The thiazide diuretics inhibit Na+/Cl cotransport in the proximal segment of the distal convoluted tubule. The potassium-sparing diuretic amiloride inhibits sodium channels in the distal segment of the distal convoluted tubule.

263. You are reviewing your patients blood results before the weekly ward round and notice that a 53-year-old woman has hyponatraemia that you think could be due to one of the drugs she is taking. Which of the following drugs/groups of drugs that can all cause hyponatraemia, does not cause it by the syndrome of inappropriate antidiuretic hormone (SIADH)? Furosemide Your answer Amitriptyline Chlorpropamide Phenothiazines Clofibrate Hyponatraemia is commonly seen in medical practice and has many causes: Iso-osmolar due to hyperlipidaemia interfering with the analysis of blood samples, but this is rarely seen today with the more advanced laboratory techniques due to hyperglycaemia decreased total body water with oedema: nephrotic syndrome, cirrhosis and CCF decreased total body water no oedema: renal losses (eg diuretics, Addisons disease); extra-renal losses (eg diarrhoea, vomiting, fistulas) increased total body water with no oedema: SIADH and hypothyroidism; drug causes of SIADH include amitriptyline, clofibrate, phenothiazines and chlorpropamide

Hyper-osmolar Hypo-osmolar

264. A patient is to commence on doxorubicin chemotherapy. To monitor potential toxicity, which is the most appropriate investigation to carry out before starting the chemotherapy?

EEG Lung function test Creatinine clearance Echocardiogram Your answer CT brain

The antitumour activity of doxorubicin partly results from the triggering of topoisomerase II-dependent DNA breaks. Doxorubicin can cause cardiac toxicity, including an acute syndrome characterised by arrhythmias and congestive heart failure. In addition, doxorubicin can cause a cumulative, dose-dependent decline in left ventricular ejection fraction, with a higher incidence of myocardial dysfunction being seen in patients receiving a cumulative dose of greater than 500 mg/m2.

265. In a diabetes specialist clinic you are about to review a 59-year-old patient with type-2 diabetes mellitus that is not responding to dietary advice and weight reduction. He therefore needs to commence taking an oral hypoglycaemic agent. Which of the following is true concerning the oral hypoglycaemic agents used in the management of diabetes mellitus? Metformin causes hypoglycaemia Sulphonylureas reduce peripheral insulin sensitivity Glitazones are associated with significant hepatotoxicity Acarbose inhibits -glucosidase Your answer

Metformin increases insulin secretion Biguanides (eg metformin) primarily decrease hepatic glucose secretion. The main unwanted effect is the risk of lactic acidosis, hence they are contra-indicated in patients with renal failure. Sulphonylureas (eg gliclazide, repaglinide, glimepiride) increase insulin secretion in response to a given glucose load. Their main unwanted effects are weight gain and the risk of hypoglycaemia Glitazones (eg rosiglitazone, pioglitazone) reduce peripheral insulin resistance. Unwanted effects include weight gain, hypoglycaemia, fluid retention. Liver toxicity was a feature of troglitazone that was withdrawn for this reason. Acarbose inhibits intestinal -glucosidase, which therefore delays the digestion and absorption of starch and sucrose. Its main unwanted effect is gastrointestinal disturbance

266. A 59-year-old woman who suffers from arthritis and hypertension visits you requesting increased pain relief. Which of the agents is a currently marketed COX-2 inhibitor? Co-proxamol Rofecoxib Celecoxib Your answer Aspirin Diclofenac Both celecoxib and rofecoxib are selective COX-2 inhibitors. There are two isoforms of cyclo-oxygenase (COX-1 and COX-2). Prior to the development of the coxibs it was postulated that the renal toxicity and increased GI bleeding effects of non-steroidal antiinflammatory drugs (NSAIDs) occur as a result of COX-1 inhibition, and that the major antiinflammatory effects of NSAIDs are due to inhibition of COX-2. Recently, it has been postulated that selective inhibition of COX-2 may be associated with increased cardiovascular toxicity. This has arisen because of trials of COX-2 inhibitors as potential treatments to reduce the risk of colon cancer in patients with a family history of familial adenomatous polyposis (FAP). Two studies (one with rofecoxib and one with celecoxib) have been stopped early due to increased cardiac events, and rofecoxib has now

been withdrawn from the market. Celecoxib is still undergoing further studies to determine its cardiac safety profile.

267. A 39-year-old woman who underwent excision of a meningioma 3 months ago, has developed severe bruising and menorrhagia. She has also noticed swelling of her gums and progressive malaise and weakness. Which drug could be responsible for these symptoms? Carbamazepine Phenytoin Your answer Sodium valproate Topiramate Oxcarbazepine Patients are frequently given prophylactic treatment with antiepileptics such as phenytoin following neurosurgical procedures. Side-effects of phenytoin include gum hypertrophy, folate deficiency, aplastic anaemia, osteomalacia and neuropathy.

268. Which of the following measures is documented to be most effective in reducing the risk of transmission of HIV to the newborn child? Oral zidovudine at the time of conception Elective Caesarean section

Postnatal administration of zidovudine to the baby Zidovudine administration to the mother at the time of breastfeeding Vaginal delivery with shortening of the second stage of labour

Your answer

There is no evidence that oral administration of zidovudine at the time of conception reduces the risk of HIV transmission. Oral zidovudine from 28 weeks gestation onwards has been used to reduce the risk of transmission. There is also no evidence that intravenous zidovudine during labour is of any benefit. Zidovudine is effective in reducing the risk of HIV transmission from mother to neonate by 8.3% - 18%. The ideal treatment regimen is to commence zidovudine as an intravenous infusion at the onset of labour and continue it until the baby is 6 weeks of age. Breast-feeding increases the risk of HIV transmission. Elective Caesarean section may reduce the risk compared to vaginal delivery. Shortening the second stage by operative delivery increases the risk of transmission.

269. A 40-year-old woman is brought unconscious to A&E. She apparently has swallowed a large number of pills belonging to her friend who is being treated for a psychiatric ailment. On examination, she is apyrexial, her pulse is 130 bpm and her blood pressure is 90/60 mmHg. Her pupils are dilated. ECG shows sinus tachycardia and occasional ventricular ectopics. Which drug is she most likely to have taken? Imipramine Your answer Chlordiazepoxide Lithium Chlorpromazine

Fluoxetine

Overdosing with tricyclic antidepressants can produce these effects. Phenothiazine (chlorpromazine) poisoning causes dystonia (torticollis, opisthotonos). Lithium causes blurring of vision, diarrhoea, vomiting, hypokalaemia, drowsiness, ataxia, coarse tremors, dysarthria, seizures, psychosis and coma. Fluoxetine is a selective serotonin-receptor inhibitor (SSRI). Overdose can cause blurring of vision, fits, headache, tremors and serotonin syndrome agitation, dysarthria, tremor, myoclonus and restlessness. It is a rare, but serious, disorder.

270. You have seen a patient with bronchiectasis and wish to prescribe a theophylline preparation as a bronchodilator. Which of the following best describes the main feature of this drug's activity? It blocks the adenosine receptor Your answer It enhances diaphragm contractility 50% of the drug is plasma-protein bound Side-effects are dose-related Most of the drug is excreted unchanged in urine Adenosine acts as a local mediator for many organ systems. Blockade of the receptors by theophylline results in: relaxation of smooth muscles, especially bronchial muscles constriction of cerebral blood vessels stimulation of the cardiac pacemaker stimulation of gastric secretions Theophylline also releases calcium ions from the sarcoplasmic reticulum in skeletal and cardiac muscle, thus enhancing their contractility. Because theophylline-metabolising enzymes are saturable, the plasma concentration increases disproportionately on increasing the dose. Only 10% of the drug is excreted unchanged in the urine as most of it is extensively metabolised in the liver.

271. Monitoring serum levels is important in preventing adverse drug effects of which of the following?

Warfarin Theophylline Your answer Carbimazole Rifampicin Cyclophosphamide The INR (International Normalised Ratio) is used to monitor the effect of warfarin. Theophylline has a narrow therapeutic window and needs close monitoring of its serum level to avoid toxicity. The maintenance dose for carbimazole is determined by measuring T4 and TSH levels. Regular full blood counts and urinalysis are used to monitor cyclophosphamide.

272. You are discussing with an obstetric SHO some of the potential teratogenic risks of certain drugs in pregnancy. Which of the drugs listed below is correctly paired with potential teratogenic outcome? Thalidomide : Chondrodysplasia punctata Lithium : Phocomelia Diethylstilbestrol : Vaginal carcinoma Your answer Warfarin : Cretinism Carbamazepine : Macrocephaly

Several drugs have teratogenic effects, and the drugs that should be avoided are listed in the BNF. Some common drugs and their potential teratogenic effect are given below. Drug Androgens Alcohol Carbamazepine Diethylstilbestrol Lithium Phenobarbital Sodium valproate Thalidomide Warfarin Teratogenic effect Cardiac deformities Fetal alcohol syndrome Microcephaly Vaginal carcinoma Cretinism Cleft palate Neural tube defects Phocomelia Chondrodysplasia punctata

273. You review a 58-year-old man with tuberculosis and commence him on triple antituberculous therapy. He has a past history of alcoholism. You are aware of the problem of peripheral neuropathy with isoniazid therapy. Which of the following best fits with isoniazid-associated peripheral neuropathy? It only occurs in alcoholics Those with an N-acetyltransferase type-2 gene defect are predisposed to Your neuropathy answer Those with an N-acetyltransferase type-1 gene defect are predisposed to neuropathy It occurs because of a defect in butyrylcholinesterase Thiamine prophylaxis is usually used to prevent its occurrence Thankfully, isoniazid-associated peripheral neuropathy occurs in less than 1% of those who take the drug, although the incidence is increased at higher drug doses. It is related to a defect in the gene coding for N-acetyltransferase type 2, resulting in abnormal isoniazid metabolism. Pyridoxine 10 mg is given as prophylaxis against peripheral neuropathy occurring. Isoniazid is also associated with raised transaminases in 1020% of those patients for whom it is prescribed. Hepatic necrosis with jaundice occurs in a much smaller percentage of patients and is again associated with abnormalities in acetylator genes. Rifampicin and pyrazinamide, two other antituberculous agents, may also be associated with abnormal liver

enzymes. Butyrylcholinesterase defects are associated with suxamethonium apnoea.

274. A 35-year-old chronic alcoholic was admitted to hospital for a period of detoxification and is now ready for discharge. She is keen to remain abstinent after discharge. Which drug would be most useful in this case? Naltrexone Disulfiram Diazepam Chlordiazepoxide Acamprosate Your answer Benzodiazepines such as diazepam or chlordiazepoxide are useful for initial withdrawal symptoms such as delirium tremens. Naltrexone reduces the pleasure that alcohol brings and craving when it is withdrawn, and can halve the relapse rates. It is, however, associated with a number of adverse effects, including nausea, vomiting, anxiety, nervousness, insomnia, lethargy, arthralgia, increased sweating and lacrimation, diarrhoea or constipation, increased thirst and liver and kidney dysfunction. Acamprosate is derived from taurine and increases the gamma-aminobutyric acid (GABA) level, which inhibits CNS activity. It has a lesser number of side-effects and can treble abstinence rates by decreasing the craving for alcohol. It is contraindicated in pregnancy and severe liver and kidney failure. Disulfiram produces an unpleasant reaction if alcohol is taken and is usually not preferred for the management of alcohol withdrawal.

275. A 35-year-old woman with a bipolar disorder has been prescribed lithium. Which of the following pharmacological features should best be kept in mind when prescribing this drug?

Serum lithium level should not exceed 2 mmol/l Amiloride is a specific antidote for lithium toxicity Lithium may cause nephrogenic diabetes insipidus Your answer Hyperkalaemia may occur Thyroid antibodies may be increased Long-term treatment with lithium causes two renal problems: nephrogenic diabetes insipidus; and reduced creatinine clearance. There is no specific antidote for lithium toxicity. Haemodialysis is the best method for removing excess lithium from the body. Amiloride is the drug of choice for lithium-induced nephrogenic diabetes insipidus. The therapeutic range for lithium treatment is 0.51.0 mmol/l. Toxicity occurs when the serum levels exceed 1.5 mmol/l. Hypokalaemia may occur and can cause T-wave depression in the ECG. The presence of thyroid antibodies increases the risk of hypothyroidism as lithium interferes with thyroid function.

276. A 69-year-old asthmatic hypertensive male with cardiac failure and peptic ulcer disease complains of seeing yellowish-green haloes for the past week. He has also lost appepite and feels nauseated. Physical examination is essentially normal as his conditions appear to be well controlled. Which of the drugs that he has been prescribed could be a cause for his present condition? Digoxin Your answer Enalapril Salbutamol Ranitidine Aspirin The most common features of digoxin toxicity are anorexia, nausea, altered vision and arrhythmias, especially ventricular bigeminy. Hypokalaemia is known to precipitate digoxin toxicity.

277. A 17-year-old woman is bought into A&E by friends after she had taken an overdose of an unknown quantity of a non-steroidal anti-inflammatory drug, thought to be mefenamic acid. Which of the following statements is true concerning NSAID overdoses? Gastrointestinal symptoms are due to the stimulation of cyclooxygenase Mefenamic acid is the NSAID most likely to cause convulsions Alkalosis can occur following large ingestions of NSAIDs Convulsions occurs in 50% of patients following NSAID overdose Multi-dose activated charcoal should be used to treat NSAID overdoses Following overdoses of most NSAIDs, the main effects are mild gastrointestinal upset with epigastric tenderness, nausea, vomiting and diarrhoea. These effects are mainly due to the inhibition of cyclo-oxygenase. However, 1020% of patients will have convulsions following an NSAID overdose. This is more common in patients who have ingested mefenamic acid. Large overdoses can present with an acidosis, renal impairment, gastrointestinal haemorrhage and CNS effects (drowsiness, coma, cerebellar signs). Management of NSAID overdose is with activated charcoal in patients presenting within the first hour, and supportive care. Oral H2-histamine blockers and proton-pump inhibitors may reduce the symptoms of gastrointestinal toxicity. There is no indication for the use of multidose activated charcoal.

Your answer

278. A middle-aged man is rushed in an unconscious state to the A&E department. It is stated that he swallowed a large number of unknown tablets. Investigations reveal: Na+ 137 mmol/l; K+ 3.5 mmol/l; Cl 96 mmol/l; HCO3 16 mmol/l; pH 7.25; anion gap 25 mmol/l. What tablets is he most likely to have swallowed? Allopurinol

Aspirin Your answer Indometacin Benzylpenicillin

D-Penicillamine

Salicylate poisoning is a known cause of an increased anion gap. The anion gap represents those negative ions not normally measured in clinical practice, which include phosphate, sulphate, lactate, ketoacids and albumin. The formula for calculating the anion gap is: Anion gap = plasma [Na+] (plasma [Cl] + plasma [HCO3]). The normal range is 816 mmol/l. The anion gap is increased when excessive acid is added to the plasma, either by disordered metabolism or by the addition of exogenous acid, or there is failure of acid secretion. The causes of an increased anion gap include dehydration and lactic acidosis, diabetic and alcoholic ketoacidosis, uraemia and salicylate, ethylene glycol and methanol poisoning. Allopurinol, benzylpenicillin and indometacin cause acute interstitial nephritis. In these cases, there may be metabolic acidosis but the anion gap will be normal. DPenicillamine may cause membranous nephropathy. Metabolic acidosis with an increased anion gap is not a feature of this condition.

279. A 56-year-old man has recently been diagnosed with type-2 diabetes. His Hb A1c after a period of diet and exercise is still raised at 8.4%. You are considering initial drug treatment. Which of the following has a primary mode of action that is most likely to lead to increased postprandial insulin release? Sulphonylureas Metformin Glitazones Meglitinides Alpha-glucosidase inhibitor

Your answer

Meglitinides (nateglinide and repaglinide) increase postprandial insulin release specifically. Sulphonylureas such as gliclazide increase insulin release over a prolonged period and may be associated with an increased incidence of hypoglycaemia compared to the meglitinides. This remains to be seen, and at present sulphonylureas are still recommended ahead of meglitinides by NICE. Meglitinides may, however, be more appropriate for cultural groups who fast for periods, or those who work shift patterns. Major outcome trials with meglitinides are awaited. Alpha-glucosidase inhibitors (acarbose is the only one marketed in theUK) act by inhibiting the intestinal breakdown of long-chain sugars. This leads to a reduced peak of glucose after meals. Side-effects include flatulence and diarrhoea due to bacterial metabolism of unabsorbed sugars. Glitazones, although having some effect on hepatic glucose output, exert their primary glucose lowering effects by increasing glucose uptake into skeletal muscle and fat. Metformin is a partial insulin sensitiser, exerting its primary effects on blood glucose via a reduction in hepatic glucose output. Metformin is contraindicated in patients with severe hepatic disease or where the serum creatinine level is above 130 mol/l in women and 150 mmol/l in men.

280. The use of performance-enhancing anabolic steroids by professional athletes is generally decreasing due to random drugs testing. However, the use amongst members of the public using gyms is increasing, and, in the clinic, a 19-year-old man asks you some questions about their adverse effects. Which of the following statements is true concerning the cardiovascular effects of anabolic steroids? Haematocrit is decreased Blood concentrations of LDL-cholesterol are decreased Fibrinogen concentrations fall during prolonged use Blood concentrations of HDL-cholesterol are increased Blood pressure decreases during prolonged use

Your answer

Anabolic steroids can be taken orally (eg stanozolol) or may have to be injected due to high first-pass metabolism (eg testosterone enantate). Amongst many unwanted effects, they have effects that increase the risk of cardiovascular disease. Blood pressure is elevated. Blood lipid profiles change, with increased LDL-cholesterol and decreased HDLcholesterol. Haematocrit is increased, leading to a prothrombotic tendency, although there is a protective decrease in plasma fibrinogen concentrations with prolonged use.

290. A 67-year-old man with known long-standing asthma presents to his GP following an overdose of his regular theophylline. Which of the following is true concerning theophylline overdoses? Symptoms of toxicity will always occur within 12 hours Nausea and vomiting are uncommon features of toxicity Bradycardia is the commonest cardiac arrhythmia Hypokalaemia should be rapidly corrected Multi-dose activated charcoal is useful in management Your answer Features of theophylline toxicity include tachyarrhythmias, nausea, vomiting, diarrhoea, central nervous system stimulation and, less commonly, metabolic effects including hypokalaemia and hyperglycaemia. Symptoms of toxicity may be delayed following the ingestion of sustained-release preparations for up to 48 hours. Management of a theophylline overdose in patients who have ingested large quantities of sustained-release tablets includes whole-bowel irrigation and multi-dose activated charcoal, which increases removal from the enterohepatic circulation. Charcoal haemoperfusion is more efficient at enhanced elimination of theophylline than haemoperfusion or haemodialysis. Hypokalaemia should be cautiously corrected at a rate of no more than 10 mmol/l per hour.

291. While prescribing a medication, a doctor tells his patient that it acts directly and is not a prodrug. Which of the following medications would most probably fit in this category? Enalapril Oxcarbazepine Chloral hydrate Vitamin D Diazepam

Your answer

Diazepam is the only one in the list that does not have to be metabolised prior to its initiation of activity in the body. Oxcarbazepine is converted to its main active metabolite, a 10-monohydroxy derivative. Chloral hydrate is rapidly metabolised to trichlorethanol, which is the active molecule. Vitamin D (cholecalciferol) is converted by the liver to 25hydroxycholecalciferol, and then by the kidney tubule enzyme 1a-hydroxylase to the active metabolite 1,25-dihydrocholecalciferol. Enalapril is a prodrug for enalaprat, the active agent.

292. A patient is brought into hospital after accidentally drinking 300 ml diethylene glycol. He presents with a metabolic acidosis and renal failure. What is the most appropriate next step in his management? Haemoperfusion Forced diuresis Haemodialysis and oral ethanol Your answer Oral methanol Gastric lavage Diethylene glycol is used mainly in polyester resins and polyols, as a humectant in the tobacco industry and as a solvent. It achieved notoriety in 1985 when it was discovered that for a number of years it had been added to some wines. Several pharmaceutical errors have also led to fatalities. Nausea, vomiting and abdominal pain frequently occur, and are followed by the development of jaundice and hepatomegaly, pulmonary oedema, metabolic acidosis, coma and renal failure in most cases. Supportive measures to treat the dehydration and to correct the metabolic acidosis should be instituted promptly. Ethanol or fomepizole (4-methylpyrazole) should be administered to block diethylene glycol metabolism, and dialysis should be employed if renal failure supervenes. A loading dose of 50 g of ethanol orally (conveniently given as 125 ml of gin, whisky or vodka) should be administered, followed by an intravenous infusion of 1012 g ethanol/h to produce a blood ethanol concentration of 0.51 g/l. The infusion should be

continued until diethylene glycol is no longer detectable in the blood. If dialysis is employed, the rate of ethanol administration will need to be increased to 17 22 g/h.

293. A 90-year-old man with chronic leukaemia presents with gout, which his general practitioner treats allopurinol. How does allopurinol prevent the accumulation of uric acid? By competing for the uric acid transporter in the kidney By enhancing its solubility By inhibiting a step in purine breakdown By inhibiting a step in purine synthesis By inhibiting the inflammatory response associated with leukaemia

Your answer

Allopurinol blocks the enzyme xanthine oxidase, which is responsible for the conversion of xanthine into urate. This is the final step in the pathway of purine breakdown. Probenecid enhances excretion of uric acid. Leukaemia is associated with gout because of the increased turnover of blood cells, which leads to increased uric acid production. Other conditions associated with gout include myeloproliferative disorders, such as polycythaemia vera, glucose-6-phospate dehydrogenase (G6PD) deficiency, chronic renal disease, drug therapy (thiazide diuretics), lead toxicity, primary hyperparathyroidism, hypothyroidism, and the increased production of lactic acid from alcohol, exercise, or starvation. Treatment of classic acute gout involves the use of nonsteroidal anti-inflammatoy drugs (NSAIDs) during the initial period. Commencement of allopurinol at the time of diagnosis of acute gout may precipitate a worsening of symptoms.

294. A 14-year-old student is on medication for a urinary tract infection. She develops fever, vomiting, diarrhoea and a widespread macular rash with target lesions. Which drug has she been prescribed? Ampicillin Amoxicillin Erythromycin Co-trimoxazole Ciprofloxacin

Your answer

This patient has the StevensJohnson syndrome consequent to co-trimoxazole treatment. It is a particularly serious and potentially fatal type of skin and mucous membrane eruption

associated with sulphonamide use. In domiciliary practice, trimethoprim alone, or in combination with sulfamethoxazole (co-trimoxazole), is useful in the treatment of urinary tract infections (UTI). The macular rash and target lesions are typical of erythema multiforme, which occurs in this syndrome. Ampicillin and amoxicillin are no longer the drugs of choice for the empirical treatment of UTIs because of the widespread emergence of resistance among the various strains of Escherichia coli. Ciprofloxacin is effective in treating UTIs, even when they are caused by multidrug-resistant bacteria, eg Pseudomonas spp. However, they are usually not given as a first-line treatment for UTIs. Moreover, the StevensJohnson syndrome is not associated with ciprofloxacin.

295. A 24-year-old man is bought into A&E after he was found collapsed in the street with hypoglycaemia. Friends commented that he had taken a quantity of unknown tablets a few hours before. Which of the following drugs could he have ingested that would have caused the hypoglycaemia? Theophylline Iron Propranolol Your answer Prednisolone Bendroflumethiazide (bendrofluazide) Alteration in serum glucose concentration, in addition to other clinical signs and symptoms can be helpful in diagnosing the ingestion of an unknown drug:

Hyperglycaemia, eg corticosteroids, thiazide diuretics, theophylline, iron, caffeine and 2-agonists Hypoglycaemia, eg insulin, sulphonylureas, salicylates, sodium valproate, propranolol

296. You review a 44-year-old woman in an out-patient clinic following an urgent referral from her GP. She had recently been started on hydralazine for blood pressure management. Since then she has developed symptoms and signs suggestive of drug-induced lupus. Which of the following statements is true concerning drug-induced lupus disease? It is more common in Caucasians than AfroCaribbeans Your answer HLA-DR4 is not associated with it Rapid acetylator status is a risk factor dsDNA antibodies are positive Antihistone antibody is negative Drug-induced lupus is more common in Caucasians, unlike idiopathic lupus, and the usual female predominance is lost. Risk factors include HLA-DR4 phenotype (hydralazine-induced disease), slow acetylator status and large total daily doses of precipitating drugs. Drugs commonly associated with drug-induced lupus include hydralazine, procainamide and isoniazid. ANF (antinuclear factor) and antihistone antibodies are positive but dsDNA (double-stranded DNA) antibodies are negative. The management of drug-induced lupus is withdrawal of the precipitating drug and supportive care; spontaneous recovery usually occurs promptly.

297. What is the reason for a different dose of sublingual glyceryl trinitrate (GTN) and oral isosorbide mononitrate? Absorption First-pass metabolism Lipid solubility Phase II metabolism More rapid renal clearance

Your answer

Amongst the various routes of drug delivery, the oral route is perhaps the most preferred for the patient and clinician alike. However, oral administration of drugs has disadvantages,

such as hepatic first-pass metabolism and enzymatic degradation within the gastrointestinal (GI) tract, which prohibit oral administration of certain classes of drugs especially peptides and proteins. Consequently, other absorptive mucosae are considered as potential sites for drug administration. Transmucosal routes of drug delivery (ie the mucosal linings of the nasal, rectal, vaginal, ocular and oral cavity) offer distinct advantages over peroral administration for systemic drug delivery. These advantages include possible bypass of first-pass effect, avoidance of presystemic elimination within the GI tract and, depending on the particular drug, a better enzymatic flora for drug absorption.

298. A 22-year-old female student presents to the emergency department complaining of rapid regular palpitations, which started suddenly whilst she was reading. On examination she is tachycardic at 155 beats/min, normotensive, and the rest of the examination is unremarkable. Electrocardiogram (ECG) shows a supraventricular tachycardia. Vagal manoeuvres have no effect. Which of the following subsequent measures would be most appropriate as initial management? Intravenous amiodarone Intravenous digoxin Direct current (DC) cardioversion Intravenous adenosine 24-hour urine collection for phaeochromocytoma screening (vanillylmandelic acid (VMA) or catecholamines) Students studying for exams often consume large amounts of caffeine, or indeed other stimulant drugs, and such substances can provoke supraventricular tachycardia in a heart which is electrically predisposed to such a rhythm. A history of consumption of such substances should be sought. Adenosine is very effective in terminating supraventricular re-entrant tachycardias. The rhythm is benign, intravenous (IV) amiodarone or initial DC shock would be inappropriate, and IV digoxin could render subsequent DC shock (if necessary) more hazardous. Your answer

299. A 39-year-old woman who is planning to travel overseas to a malariaendemic area later this month presents to you (the medical SHO on call) after taking an overdose of her antimalarial medications. Which of the following statements is true concerning overdoses of antimalarials? High-dose diazepam and adrenaline infusion may be useful in the Your answer management of chloroquine toxicity

Blindness associated with quinine toxicity is only transient Lidocaine (lignocaine) is safe in the management of quinineinduced cardiac arrhythmias Hyperkalaemia is initially protective in chloroquine overdoses Urinary acidification has a role in the management of quinine overdoses Symptoms of chloroquine toxicity include nausea, headaches, visual disturbances, cardiac arrhythmias, convulsions and coma. Activated charcoal should be given to patients who present within one hour. The initial hypokalaemia that occurs appears to be cardioprotective and should not be corrected for at least 8 hours postingestion. In patients with severe toxicity, high-dose (2 mg/kg) diazepam and adrenaline (0.25 g/kg per min) have been shown to reduce mortality. Symptoms of quinine toxicity are similar to those of chloroquine. Visual features tend to occur 68 hours after ingestion and, commonly, patients initially complain of blurred vision and decreased colour perception. Other visual complications, including blindness, can occur and may be permanent. Management is supportive with treatment of any associated complications. There is no proven prevention or treatment of quinine-associated visual complications. Lidocaine (lignocaine) should not be used in the management of cardiac arrhythmias as this can increase the risk of seizures.

300. A 45-year-old asthmatic patient with a history of myocardial infarction presents with palpitations. An ECG shows supraventricular tachycardia. Carotid sinus massage is unsuccessful. What treatment would you administer next? Adenosine Verapamil Your answer

Digoxin Flecainide Lidocaine

Although adenosine is the drug of choice for terminating paroxysmal supraventricular tachycardia, it can cause bronchospasm and is thus contraindicated in patients with asthma. Verapamil would therefore be the drug of choice in this case. However, verapamil should not be used for tachyarrhythmias where the QRS complex is wide. It is also contraindicated in patients with the WolffParkinsonWhite syndrome. Flecainide may be hazardous in patients with a history of myocardial infarction as it may precipitate ventricular fibrillation. Digoxin tends to shorten refractory periods and enhance excitability and conduction in other parts of the heart; it may therefore cause more complex atrial and ventricular tachyarrhythmias. 301. Which one of the following is associated with hyperkalaemia? Bartters syndrome Treatment with corticosteroids Liquorice addiction Liddles syndrome Ciclosporin Your answer Bartters syndrome is associated with hypokalaemia due to a number of inherited defects of renal function. Corticosteroids are associated with hypokalaemia due to their mineralocorticoid effects. Liquorice inhibits 11 hydroxysteroid

dehydrogenase causing potassium wasting from the distal tubule. Liddles syndrome is a rare condition of hypokalaemia, hypertension and low aldosterone levels. Some renal transplant patients treated with cyclosporin run serum potassium concentrations in the range 6.07.1 mmol/l. This is probably a variant of hyporeninaemic hypoaldosteronism and is responsive to fludrocortisone.

302. A 44-year-old woman has a fasting triglyceride level of 9.6 mmol/l and total cholesterol of 5.5 mmol/l. Dietary intervention has unfortunately shown no benefit and therefore therapy is needed because of her risk factors. What would be the most appropriate drug? Amlodipine Pravastatin Bezafibrate Your answer Enalapril Cholestyramine In patients whose hypercholesterolaemia is combined with more marked hypertriglyceridaemia, the fibrate drugs (bezafibrate, ciprofibrate, fenofibrate, gemfibrozil) are first-line therapy. They are also often highly effective in type-III hyperlipoproteinaemia (and useful in primary type-V hyperlipoproteinaemia) and in the dyslipoproteinaemia of diabetes mellitus. Fibrates are less effective than statins in lowering low-density lipoprotein (LDL)cholesterol. Most of their cholesterol-lowering effect is due to a decrease in very low-density lipoprotein (VLDL)-cholesterol. They do, however, decrease small, dense-LDL levels. However, this is not readily evident from routine laboratory tests, because the decrease is unaccompanied by any substantial reduction in cholesterol. In some particularly high-risk patients with combined hyperlipidaemia, statin therapy may be added to fibrate therapy to satisfactorily lower LDL-cholesterol. The fibrate drugs raise high-density lipoprotein (HDL)cholesterol more than statins and must be avoided in patients with disturbed

hepatic or renal function. Fibrates also potentiate anticoagulants. The mode of action of fibrate drugs, which diminish serum triglyceride levels by stimulating lipoprotein lipase and decreasing circulating non-esterified fatty acids (NEFA), probably involves stimulation of the nuclear peroxisome proliferator-activated receptor-.

303. A 32-year-old glass etcher presents following a failed suicide attempt having ingested hydrofluoric acid that he uses at work. Concerning the management of poisoning with this acid, which of the following statements is true? Neutralisation of acids is appropriate management Acids cause more severe corrosive effects in the stomach than the oesophagus Hydrofluoric acid can cause severe hypercalcaemia Acids cause liquefactive necrosis (saponification) Gastric lavage is appropriate in early presentations

Your answer

Acids cause injury by coagulative necrosis, whereas alkalis cause saponification (liquefactive necrosis) of tissue. Neutralisation of acids or alkalis is not appropriate, since this can generate increased heat and so exacerbate any injury sustained. Acid effects are mainly topical, with corrosive burns to the mouth, oropharynx and stomach. They are less likely to cause significant localised damage to the oesophagus. Aspiration can lead to inflammation and a chemical pneumonitis. Gastric lavage is contraindicated due to the increased risk of oesophageal perforation. Management consists of supportive care and early endoscopy. Early surgical intervention is required to prevent mediastinitis, from which there is a high mortality, in those patients with signs or symptoms of perforation. Hydrofluoric acid causes significant hypocalcaemia as it binds calcium. Even small amounts (topically or ingested) can produce significant hypocalcaemia and be rapidly fatal. Following ingestion, hypocalcaemia and

plasma calcium concentrations should be regularly measured and treated with intravenous calcium supplementation. Topical exposure can cause severe and painful burns. Calcium gluconate applied both topically and injected around the burn may be required; in cases of significant topical exposure, patients should be monitored for signs of systemic hypocalcaemia.

304. A 30-year-old woman on treatment for secondary generalised tonicclonic seizures complains of anorexia, nausea and general fatigue. On examination, there is no peripheral oedema. Blood tests reveal Na+ 124 mmol/l, K+ 4.0 mmol/l and plasma osmolality 200 mOsmol/kg. What antiepileptic drug has she been prescribed? Lamotrigine Levetiracetam Acetazolamide Topiramate Carbamazepine Your answer Carbamazepine causes hyponatraemia, which is dose-related. Acetazolamide is associated with paraesthesias, nausea, diarrhoea and visual changes. The other drugs are prescribed for secondary generalised tonicclonic seizures but do not cause hyponatraemia.

305. A 67-year-old man on warfarin present with epistaxis. On examination he is tachycardic and requires emergency treatment from the Ear, Nose and Throat Service. It transpires that he has inadvertly taken too much warfarin and his INR is 8.7.

What is the most appropriate management? Vitamin K Cryoprecipitate Fresh-frozen plasma Your answer Desmopressin Tranexamic acid

An INR around this value is accompanied by serious bleeding problems and is best treated by giving fresh-frozen plasma. Cryoprecipitate is a rich source of the factors involved in the intrinsic pathway, eg factors VIII and IX, and is used to treat people with haemophilia and those with von Willebrands disease. Vitamin K (phytomenadione) is useful in warfin overdose but it takes hours to act and may last for weeks. This may not be a satisfactory situation especially if the patient is suffering from a condition that requires anticoagulation. It is preferable to give fresh frozen plasma to reduce the risk of bleeding that is high with an INR at this level. Vitamin K is useful for reversing the antagonism of warfarin. Tranexamic acid is an antifibrinolytic agent and can be used in the treatment of haemophilia and von Willebrands disease (as is desmopressin, which releases the factor into the blood transiently).

306. Which one of the following anticonvulsants has been associated with the development of polycystic ovarian syndrome (PCO)? Vigabatrin Sodium valproate Your answer Phenobarbitone

Phenytoin Topiramate

All anticonvulsants cause adverse effects. The newer anticonvulsants have simpler pharmacokinetics and a reduced potential to cause interactions. Sodium valproate has been associated with the development of PCO, a condition associated with central obesity, hirsutism, irregular periods or secondary amenorrhoea, infertility and insulin resistance. Characteristically there is a low FSH, high LH, high oestradiol and high androgen levels. Occasionally virilism may occur. The underlying defect is not yet established, but there appears to be defective ovarian production of oestradiol, with overproduction of precursor molecules, which are converted into androgens in extra-glandular tissue.

307. A 72-year-old man is reviewed in the Emergency Department. He has been feeling tired and unwell. There is a past history of glaucoma, chronic obstructive pulmonary disease and congestive heart failure. He also has anaemia and type 2 diabetes. Blood tests are unremarkable apart from a normal anion gap metabolic acidosis. Which of the following drugs is most likely to be responsible for the acid-base disturbance? Ramipril Aspirin Metformin Acetazolamide Iron sulphate

Your answer

Normal anion gap acidosis may be caused by gastrointestinal (GI) bicarbonate loss eg due to diarrhoea, pancreatic fistula, renal bicarbonate loss, renal failure and hypoaldosteronism. Drug causes include acetazolamide, used as a treatment for glaucoma. Aspirin and metformin may result in high anion gap lactic acidosis. Iron sulphate in overdose may be associated with the development of lactic acidosis.