Pharmacology 251 307

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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 appropriateantiemetic 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 isusually well tolerated, the main side effect being headache. Given that vomitingis likely to continue, iv would be the preferred route of administration. Studies

have shown that 5-HT3 antagonists are generally more effective in treating post-chemotherapy nausea and vomiting than traditional agents. Antidopaminergicdrugs, such as metoclopramide and prochlorperazine, should be avoided due toincreased risk of side effects in young women in particular. If the 5-HT3-receptorantagonist class was not tolerated then domperidone would be an acceptablealternative.

252. A newly diagnosed diabetic patient was started on metformin in addition to

being given appropriate dietary advice. He asks you about dangerous side-effectsof the drug.

Which rare but serious side-effect of metformin treatment should be considered?

Rhabdomyolysis


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Lactic acidosis

Your answer

Anaphylaxis

Pulmonary fibrosis

Cardiotoxicity

Lactic acidosis is best known in diabetic patients as a rare but often fatalcomplication of metformin, which acts mainly by inhibiting hepaticgluconeogenesis. Lactic acidosis presents as coma with metabolic acidosis(reduced arterial pH and venous bicarbonate) and a wide anion gap due tohyperlactataemia. Blood glucose levels are usually raised.

Treatment is still unsatisfactory. Intravenous sodium bicarbonate mayparadoxically aggravate intracellular acidosis, although forced ventilation toblow off carbon dioxide may help. Haemodialysis may clear lactate and hydrogenions, and correct any sodium overload following bicarbonate administration.Sodium dichloroacetate, which stimulates pyruvate dehydrogenase to metaboliselactate, is undergoing evaluation. Mortality remains high (over 30%), partlybecause of the organ failures that commonly coexist.

253. In a pulmonary hypertension clinic, a patient asks you about bosentan, adrug that has recently been licensed and marketed for the management ofpulmonary arterial hypertension. Which of the following statements is trueconcerning 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


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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 vascularresistances without an increase in heart rate. It has been shown to be efficaciousin patients with pulmonary arterial hypertension. Common unwanted effectsinclude flushing, hypotension, dyspepsia and fatigue. Haemoglobinconcentrations can fall by up to 1 g/dl during bosentan treatment. The mostserious unwanted effect is dose-dependent hepatotoxicity, and it is thereforecontraindicated in patients with moderate to severe liver disease. Generally,

hepatotoxicity occurs within the first 34 months of treatment with bosentan. Itis 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 ismost likely to cause significant tachycardia?

NoradrenalineDopamine

Dobutamine

Adrenaline Your answer

Phenylephrine

Phenylephrine and high-dose dopamine have adrenergic effects. Noradrenaline exerts

largely effects, although it is also a weak-adrenergic agonist. All of these drugs, bycausing 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 for1-receptors, hence causing lesstachycardia 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 ofthe following drugs is the most likely cause?


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Doxazosin

Your answer

Verapamil

Hydrochlorothiazide

Atenolol

Clonidine

1-Selective antagonists in particular can cause orthostatic hypotension andpatients should be dosed carefully. The same side-effects may also be observedwith rapidly absorbed dihydropyridine-type (nifedipine) calcium-channelblockers. Verapamil blocks cardiac calcium channels; there is therefore nocompensatory tachycardia. Likewise, compensatory tachycardia does not occur

with -blocker therapy and centrally acting drugs such as clonidine.

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. Itreduces the synthesis of new thyroid hormones by inhibiting the iodination oftyrosine and coupling of precursors to form thyroxine. It also has animmunosuppressive action leading to a reduction in serum thyrotrophin (TSH)-


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receptor antibody (TRAb) concentrations. It does not destroy functioning thyroidcells. Propylthiouracil inhibits 5'-deiodinase and prevents the release of free T3and 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 Your answer

Calcium channel blocker

Sodium channel blocker

Amiodarone is a class III antiarrhythmic drug. Class III antiarrhythmics are potassiumchannel blockers, they prolong duration of action potential with resulting prolongation of

effective refractory period. Other Class III antiarrhythmics are sotalol, disopyramide andbretylium.

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?

AtenololCeliprolol

Nadolol

Sotalol

Metoprolol Your answer

Metoprolol is the most lipid-soluble of the -blockers listed above and therefore has thelargest 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 clinicalsignificance 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 thereis intermediate lipid and water solubility, so that drugs with greater lipid solubility,

although allowing greater tissue penetration, may be more poorly absorbed.


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259. A 72-year-old man presentswith acute onset lumbar spine pain. There is nosignificant 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 paracetamol1 g qds

Your

answer

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 likelycause in this case is chronic use of corticosteroids. One class of analgesic isunlikely to provide adequate pain relief and hence the triple combination ofdiclofenac, tramadol and paracetamol is likely to be most appropriate. It isimportant however to review long-term non-steroidal use in the context of renalfunction 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 useof bisphosphonate therapy or calcium and vitamin D supplementation.

260. Which drug is most likely responsible for postural hypotension in a 76-year-old manwho is taking simvastatin 20mg, ramipril 5mg, nifedipine 40mg SR, bendroflumethiazide

5mg, aspirin 75mg?

Simvastatin

Ramipril

Bendroflumethiazide Your answer

nifedipine

Aspirin

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


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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 diuretictherapy, 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 Your answer

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

Trimethoprim acts by inhibiting dihydrofolate reductase, an enzyme that is important in thedivision 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 Your answer

Ascending limb of Henles loop

Distal segment of the distal convoluted tubule

Descending limb of Henles loop

Most diuretics act by inhibiting sodium reabsorption in the renal tubules. The loop diureticsfurosemide 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 distalconvoluted tubule. The potassium-sparing diuretic amiloride inhibits sodium channels in

the distal segment of the distal convoluted tubule.


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263. You are reviewing your patients blood results before the weekly ward roundand notice that a 53-year-old woman has hyponatraemia that you think could bedue to one of the drugs she is taking. Which of the following drugs/groups ofdrugs that can all cause hyponatraemia, does not cause it by the syndrome ofinappropriate 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 bloodsamples, but this is rarely seen today with the moreadvanced laboratory techniques

Hyper-osmolar due to hyperglycaemia

Hypo-osmolar decreased total body water with oedema: nephroticsyndrome, cirrhosis and CCF

decreased total body water no oedema: renal losses (egdiuretics, Addisons disease); extra-renal losses (egdiarrhoea, vomiting, fistulas)

increased total body water with no oedema: SIADH andhypothyroidism; drug causes of SIADH include amitriptyline,clofibrate, phenothiazines and chlorpropamide

264. A patient is to commence on doxorubicin chemotherapy. To monitorpotential toxicity, which is the most appropriate investigation to carry outbefore starting the chemotherapy?


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EEG

Lung function test

Creatinine clearance

Echocardiogram

Your answer

CT brain

The antitumour activity of doxorubicin partly results from the triggering oftopoisomerase II-dependent DNA breaks. Doxorubicin can cause cardiac toxicity,including an acute syndrome characterised by arrhythmias and congestive heartfailure. In addition, doxorubicin can cause a cumulative, dose-dependent declinein left ventricular ejection fraction, with a higher incidence of myocardialdysfunction being seen in patients receiving a cumulative dose of greater than500 mg/m2.

265. In a diabetes specialist clinic you are about to review a 59-year-old patientwith type-2 diabetes mellitus that is not responding to dietary advice and weightreduction. He therefore needs to commence taking an oral hypoglycaemic agent.

Which of the following is true concerning the oral hypoglycaemic agents used inthe management of diabetes mellitus?

Metformin causes hypoglycaemia

Sulphonylureas reduce peripheral insulin sensitivity

Glitazones are associated with significant hepatotoxicity

Acarbose inhibits -glucosidase Your answer


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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 insulinsecretion in response to a given glucose load. Their main unwantedeffects are weight gain and the risk of hypoglycaemia

Glitazones (eg rosiglitazone, pioglitazone) reduce peripheral insulinresistance. Unwanted effects include weight gain, hypoglycaemia, fluidretention. 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 unwantedeffect 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-2inhibitor?

Co-proxamol

Rofecoxib

Celecoxib Your answer

Aspirin

Diclofenac

Both celecoxib and rofecoxib are selective COX-2 inhibitors. There are two isoforms ofcyclo-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 anti-

inflammatory drugs (NSAIDs) occur as a result of COX-1 inhibition, and that the major anti-inflammatory 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 offamilial 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


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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 monthsago, has developed severe bruising and menorrhagia. She has also noticedswelling of her gums and progressive malaise and weakness. Which drug could beresponsible for these symptoms?

Carbamazepine

Phenytoin

Your answer

Sodium valproate

Topiramate

Oxcarbazepine

Patients are frequently given prophylactic treatment with antiepileptics such asphenytoin following neurosurgical procedures. Side-effects of phenytoin includegum hypertrophy, folate deficiency, aplastic anaemia, osteomalacia andneuropathy.

268. Which of the following measures is documented to be most effective inreducing the risk of transmission of HIV to the newborn child?

Oral zidovudine at the time of conception

Elective Caesarean section


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Postnatal administration of zidovudine to the baby

Youranswer

Zidovudine administration to the mother at the time of breast-feeding

Vaginal delivery with shortening of the second stage of labour

There is no evidence that oral administration of zidovudine at the time ofconception reduces the risk of HIV transmission. Oral zidovudine from 28 weeksgestation onwards has been used to reduce the risk of transmission. There is alsono 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 zidovudineas an intravenous infusion at the onset of labour and continue it until the baby is6 weeks of age. Breast-feeding increases the risk of HIV transmission. ElectiveCaesarean section may reduce the risk compared to vaginal delivery. Shorteningthe 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 treatedfor a psychiatric ailment. On examination, she is apyrexial, her pulse is 130 bpmand her blood pressure is 90/60 mmHg. Her pupils are dilated. ECG shows sinustachycardia and occasional ventricular ectopics. Which drug is she most likely tohave taken?

Imipramine

Your answer

Chlordiazepoxide

Lithium

Chlorpromazine


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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, psychosisand coma. Fluoxetine is a selective serotonin-receptor inhibitor (SSRI). Overdosecan cause blurring of vision, fits, headache, tremors and serotonin syndrome agitation, dysarthria, tremor, myoclonus and restlessness. It is a rare, butserious, 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 bytheophylline 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-metabolisingenzymes 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 ofwhich of the following?


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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 closemonitoring of its serum level to avoid toxicity. The maintenance dose forcarbimazole is determined by measuring T4 and TSH levels. Regular full bloodcounts and urinalysis are used to monitor cyclophosphamide.

272. You are discussing with an obstetric SHO some of the potential teratogenicrisks 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


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Several drugs have teratogenic effects, and the drugs that should be avoided arelisted in the BNF. Some common drugs and their potential teratogenic effect aregiven below.

Drug Teratogenic effect

Androgens Cardiac deformitiesAlcohol Fetal alcohol syndrome

Carbamazepine Microcephaly

Diethylstilbestrol Vaginal carcinoma

Lithium Cretinism

Phenobarbital Cleft palate

Sodium valproate Neural tube defects

Thalidomide Phocomelia

Warfarin 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 problemof peripheral neuropathy with isoniazid therapy. Which of the following best fits with

isoniazid-associated peripheral neuropathy?

It only occurs in alcoholics

Those with anN-acetyltransferase type-2 gene defect are predisposed to

neuropathy

Your

answer

Those with anN-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 isoniazidmetabolism. Pyridoxine 10 mg is given as prophylaxis against peripheral neuropathy

occurring.

Isoniazid is also associated with raised transaminases in 1020% of those patients for whomit 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


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enzymes. Butyrylcholinesterase defects are associated with suxamethonium apnoea.

274. A 35-year-old chronic alcoholic was admitted to hospital for a period ofdetoxification and is now ready for discharge. She is keen to remain abstinentafter 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 initialwithdrawal symptoms such as delirium tremens. Naltrexone reduces the pleasurethat alcohol brings and craving when it is withdrawn, and can halve the relapserates. It is, however, associated with a number of adverse effects, includingnausea, vomiting, anxiety, nervousness, insomnia, lethargy, arthralgia, increasedsweating and lacrimation, diarrhoea or constipation, increased thirst and liverand kidney dysfunction. Acamprosate is derived from taurine and increases thegamma-aminobutyric acid (GABA) level, which inhibits CNS activity. It has alesser number of side-effects and can treble abstinence rates by decreasing thecraving for alcohol. It is contraindicated in pregnancy and severe liver and kidneyfailure. 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 thisdrug?


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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 forremoving 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 occurand 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 pepticulcer disease complains of seeing yellowish-green haloes for the past week. Hehas also lost appepite and feels nauseated. Physical examination is essentiallynormal as his conditions appear to be well controlled. Which of the drugs that hehas 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, alteredvision and arrhythmias, especially ventricular bigeminy. Hypokalaemia is knownto precipitate digoxin toxicity.


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277. A 17-year-old woman is bought into A&E by friends after she had taken anoverdose of an unknown quantity of a non-steroidal anti-inflammatory drug,thought to be mefenamic acid. Which of the following statements is trueconcerning NSAID overdoses?

Gastrointestinal symptoms are due to the stimulation of cyclo-oxygenase

Mefenamic acid is the NSAID most likely to cause convulsions

Youranswer

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 NSAIDoverdoses

Following overdoses of most NSAIDs, the main effects are mild gastrointestinalupset with epigastric tenderness, nausea, vomiting and diarrhoea. These effectsare mainly due to the inhibition of cyclo-oxygenase. However, 1020% of patientswill have convulsions following an NSAID overdose. This is more common inpatients 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 withactivated charcoal in patients presenting within the first hour, and supportivecare. Oral H2-histamine blockers and proton-pump inhibitors may reduce thesymptoms of gastrointestinal toxicity. There is no indication for the use of multi-dose activated charcoal.

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 16mmol/l; pH 7.25; anion gap 25 mmol/l.

What tablets is he most likely to have swallowed?

Allopurinol


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Aspirin

Your answer

Indometacin

Benzylpenicillin

D-Penicillamine

Salicylate poisoning is a known cause of an increased anion gap. The anion gaprepresents those negative ions not normally measured in clinical practice, whichinclude phosphate, sulphate, lactate, ketoacids and albumin. The formula forcalculating 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 acidis added to the plasma, either by disordered metabolism or by the addition ofexogenous acid, or there is failure of acid secretion. The causes of an increasedanion gap include dehydration and lactic acidosis, diabetic and alcoholicketoacidosis, uraemia and salicylate, ethylene glycol and methanol poisoning.Allopurinol, benzylpenicillin and indometacin cause acute interstitial nephritis. Inthese cases, there may be metabolic acidosis but the anion gap will be normal. D-Penicillamine may cause membranous nephropathy. Metabolic acidosis with anincreased 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 A 1c 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 Your answer

Alpha-glucosidase inhibitor


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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 withmeglitinides 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 ofunabsorbed 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 areduction 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 150mmol/l in men.

280. The use of performance-enhancing anabolic steroids by professional athletes isgenerally 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 Your answer

Blood concentrations of HDL-cholesterol are increased

Blood pressure decreases during prolonged use

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 HDL-cholesterol. Haematocrit is increased, leading to a prothrombotic tendency, although there

is a protective decrease in plasma fibrinogen concentrations with prolonged use.


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290. A 67-year-old man with known long-standing asthma presents to his GPfollowing an overdose of his regular theophylline. Which of the following is trueconcerning 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, metaboliceffects including hypokalaemia and hyperglycaemia. Symptoms of toxicity maybe delayed following the ingestion of sustained-release preparations for up to 48hours. Management of a theophylline overdose in patients who have ingestedlarge quantities of sustained-release tablets includes whole-bowel irrigation andmulti-dose activated charcoal, which increases removal from the enterohepaticcirculation. Charcoal haemoperfusion is more efficient at enhanced elimination

of theophylline than haemoperfusion or haemodialysis. Hypokalaemia should becautiously 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


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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 25-

hydroxycholecalciferol, and then by the kidney tubule enzyme 1a-hydroxylase to the active

metabolite 1,25-dihydrocholecalciferol. Enalapril is a prodrug for enalaprat, the activeagent.

292. A patient is brought into hospital after accidentally drinking 300 mldiethylene glycol. He presents with a metabolic acidosis and renal failure. Whatis 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 humectantin the tobacco industry and as a solvent. It achieved notoriety in 1985 when itwas discovered that for a number of years it had been added to some wines.Several pharmaceutical errors have also led to fatalities. Nausea, vomiting andabdominal pain frequently occur, and are followed by the development ofjaundice and hepatomegaly, pulmonary oedema, metabolic acidosis, coma andrenal failure in most cases.

Supportive measures to treat the dehydration and to correct the metabolicacidosis should be instituted promptly. Ethanol or fomepizole (4-methylpyrazole)should be administered to block diethylene glycol metabolism, and dialysisshould be employed if renal failure supervenes. A loading dose of 50 g of ethanolorally (conveniently given as 125 ml of gin, whisky or vodka) should beadministered, followed by an intravenous infusion of 1012 g ethanol/h toproduce a blood ethanol concentration of 0.51 g/l. The infusion should be


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continued until diethylene glycol is no longer detectable in the blood. If dialysisis employed, the rate of ethanol administration will need to be increased to 1722 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 Your answer

By inhibiting a step in purine synthesis

By inhibiting the inflammatory response associated with leukaemia

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 increasedturnover 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 acutegout 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?

AmpicillinAmoxicillin

Erythromycin

Co-trimoxazole Your answer

Ciprofloxacin

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


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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 erythemamultiforme, 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 ofEscherichia coli. Ciprofloxacin is effective intreating UTIs, even when they are caused by multidrug-resistant bacteria, egPseudomonas

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 thestreet with hypoglycaemia. Friends commented that he had taken a quantity of

unknown tablets a few hours before. Which of the following drugs could he haveingested 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 andsymptoms 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


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296. You review a 44-year-old woman in an out-patient clinic following an urgentreferral from her GP. She had recently been started on hydralazine for bloodpressure management. Since then she has developed symptoms and signssuggestive of drug-induced lupus. Which of the following statements is trueconcerning 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, andthe usual female predominance is lost. Risk factors include HLA-DR4 phenotype(hydralazine-induced disease), slow acetylator status and large total daily dosesof precipitating drugs. Drugs commonly associated with drug-induced lupusinclude hydralazine, procainamide and isoniazid. ANF (antinuclear factor) andantihistone antibodies are positive but dsDNA (double-stranded DNA) antibodies

are negative. The management of drug-induced lupus is withdrawal of theprecipitating drug and supportive care; spontaneous recovery usually occurspromptly.

297. What is the reason for a different dose of sublingual glyceryl trinitrate (GTN) and oral

isosorbide mononitrate?

AbsorptionFirst-pass metabolism Your answer

Lipid solubility

Phase II metabolism

More rapid renal clearance

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


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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 fordrug 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 offirst-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 ofrapid 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 adenosineYour

answer

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 heartwhich is electrically predisposed to such a rhythm. A history of consumption of such

substances should be sought. Adenosine is very effective in terminating supraventricularre-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.

299. A 39-year-old woman who is planning to travel overseas to a malaria-endemic area later this month presents to you (the medical SHO on call) aftertaking an overdose of her antimalarial medications. Which of the followingstatements is true concerning overdoses of antimalarials?

High-dose diazepam and adrenaline infusion may be useful in themanagement of chloroquine toxicity

Your

answer


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Blindness associated with quinine toxicity is only transient

Lidocaine (lignocaine) is safe in the management of quinine-induced cardiac arrhythmias

Hyperkalaemia is initially protective in chloroquine overdoses

Urinary acidification has a role in the management of quinineoverdoses

Symptoms of chloroquine toxicity include nausea, headaches, visualdisturbances, cardiac arrhythmias, convulsions and coma. Activated charcoalshould be given to patients who present within one hour. The initialhypokalaemia that occurs appears to be cardioprotective and should not becorrected 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 beenshown to reduce mortality.

Symptoms of quinine toxicity are similar to those of chloroquine. Visualfeatures tend to occur 68 hours after ingestion and, commonly, patientsinitially 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 visualcomplications. Lidocaine (lignocaine) should not be used in the managementof cardiac arrhythmias as this can increase the risk of seizures.

300. A 45-year-old asthmatic patient with a history of myocardial infarctionpresents with palpitations. An ECG shows supraventricular tachycardia. Carotidsinus massage is unsuccessful. What treatment would you administer next?

Adenosine

Verapamil Your answer


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Digoxin

Flecainide

Lidocaine

Although adenosine is the drug of choice for terminating paroxysmalsupraventricular tachycardia, it can cause bronchospasm and is thuscontraindicated in patients with asthma. Verapamil would therefore be the drug

of choice in this case. However, verapamil should not be used fortachyarrhythmias where the QRS complex is wide. It is also contraindicated inpatients with the WolffParkinsonWhite syndrome. Flecainide may be hazardousin patients with a history of myocardial infarction as it may precipitateventricular fibrillation. Digoxin tends to shorten refractory periods and enhanceexcitability and conduction in other parts of the heart; it may therefore causemore 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 inheriteddefects of renal function. Corticosteroids are associated with hypokalaemia dueto their mineralocorticoid effects. Liquorice inhibits 11 hydroxysteroid


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

302. A 44-year-old woman has a fasting triglyceride level of 9.6 mmol/l and totalcholesterol of 5.5 mmol/l. Dietary intervention has unfortunately shown nobenefit and therefore therapy is needed because of her risk factors. What wouldbe the most appropriate drug?

Amlodipine

Pravastatin

Bezafibrate

Your answer

Enalapril

Cholestyramine

In patients whose hypercholesterolaemia is combined with more markedhypertriglyceridaemia, the fibrate drugs (bezafibrate, ciprofibrate, fenofibrate,gemfibrozil) are first-line therapy. They are also often highly effective in type-IIIhyperlipoproteinaemia (and useful in primary type-V hyperlipoproteinaemia) andin 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 laboratorytests, because the decrease is unaccompanied by any substantial reduction incholesterol. In some particularly high-risk patients with combinedhyperlipidaemia, statin therapy may be added to fibrate therapy to satisfactorilylower LDL-cholesterol. The fibrate drugs raise high-density lipoprotein (HDL)-cholesterol more than statins and must be avoided in patients with disturbed


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hepatic or renal function. Fibrates also potentiate anticoagulants.

The mode of action of fibrate drugs, which diminish serum triglyceride levels bystimulating lipoprotein lipase and decreasing circulating non-esterified fattyacids (NEFA), probably involves stimulation of the nuclear peroxisome

proliferator-activated receptor-.

303. A 32-year-old glass etcher presents following a failed suicide attempt havingingested hydrofluoric acid that he uses at work. Concerning the management ofpoisoning 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 thanthe oesophagus

Your

answer

Hydrofluoric acid can cause severe hypercalcaemia

Acids cause liquefactive necrosis (saponification)

Gastric lavage is appropriate in early presentations

Acids cause injury by coagulative necrosis, whereas alkalis cause saponification(liquefactive necrosis) of tissue. Neutralisation of acids or alkalis is notappropriate, since this can generate increased heat and so exacerbate any injurysustained. Acid effects are mainly topical, with corrosive burns to the mouth,oropharynx and stomach. They are less likely to cause significant localiseddamage to the oesophagus. Aspiration can lead to inflammation and a chemicalpneumonitis. Gastric lavage is contraindicated due to the increased risk ofoesophageal perforation. Management consists of supportive care and earlyendoscopy. Early surgical intervention is required to prevent mediastinitis, fromwhich there is a high mortality, in those patients with signs or symptoms ofperforation. Hydrofluoric acid causes significant hypocalcaemia as it bindscalcium. Even small amounts (topically or ingested) can produce significanthypocalcaemia and be rapidly fatal. Following ingestion, hypocalcaemia and


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plasma calcium concentrations should be regularly measured and treated withintravenous calcium supplementation. Topical exposure can cause severe andpainful burns. Calcium gluconate applied both topically and injected around theburn may be required; in cases of significant topical exposure, patients should bemonitored for signs of systemic hypocalcaemia.

304. A 30-year-old woman on treatment for secondary generalised tonicclonicseizures 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/land plasma osmolality 200 mOsmol/kg. What antiepileptic drug has she beenprescribed?

Lamotrigine

Levetiracetam

Acetazolamide

Topiramate

Carbamazepine

Your answer

Carbamazepine causes hyponatraemia, which is dose-related. Acetazolamide isassociated with paraesthesias, nausea, diarrhoea and visual changes. The otherdrugs are prescribed for secondary generalised tonicclonic seizures but do notcause hyponatraemia.

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


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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 besttreated by giving fresh-frozen plasma. Cryoprecipitate is a rich source of thefactors involved in the intrinsic pathway, eg factors VIII and IX, and is used totreat people with haemophilia and those with von Willebrands disease. VitaminK (phytomenadione) is useful in warfin overdose but it takes hours to act andmay last for weeks. This may not be a satisfactory situation especially if thepatient is suffering from a condition that requires anticoagulation. It ispreferable to give fresh frozen plasma to reduce the risk of bleeding that is highwith 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 thetreatment 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 thedevelopment of polycystic ovarian syndrome (PCO)?

Vigabatrin

Sodium valproate

Your answer

Phenobarbitone


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Phenytoin

Topiramate

All anticonvulsants cause adverse effects. The newer anticonvulsants havesimpler pharmacokinetics and a reduced potential to cause interactions. Sodiumvalproate has been associated with the development of PCO, a conditionassociated with central obesity, hirsutism, irregular periods or secondaryamenorrhoea, infertility and insulin resistance. Characteristically there is a lowFSH, high LH, high oestradiol and high androgen levels. Occasionally virilism mayoccur. The underlying defect is not yet established, but there appears to be

defective ovarian production of oestradiol, with overproduction of precursormolecules, 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 pulmonarydisease 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 Your answer

Iron sulphate

Normal anion gap acidosis may be caused by gastrointestinal (GI) bicarbonate loss eg dueto 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 beassociated with the development of lactic acidosis.

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