clinicalpharmacology

7/30/2019 ClinicalPharmacology

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Chapter 2Clinical Pharmacology,

Toxicology and Poisoning

CONTENTS

1. Drug metabolism and interactions

1.1 Genetic polymorphisms of drug metabolism1.2 Liver enzyme induction1.3 Liver enzyme inhibition1.4 Failure of the combined oral contraceptive pill

2. Prescribing in particular clinical states2.1 Drugs and breast-feeding 2.2 Pregnancy and drug therapies2.3 Prescribing in liver disease and liver failure2.4 Prescribing in renal failure

3. Individual drugs and those used in specific clinical conditions3.1 Cardiology3.2 Endocrinology3.3 Gastroenterology3.4 Neurology3.5 Psychiatry3.6 Rheumatology3.7 Miscellaneous

4. Specific adverse effects

4.1 Secondary amenorrhoea due to drugs4.2 Bronchospasm4.3 Dyskinesia and dystonia4.4 Gynaecomastia4.5 Hypothyroidism4.6 Drug-induced liver disease4.7 Drugs provoking myasthenia4.8 Photosensitivity4.9 Drug-induced vasculitis4.10 Acute pancreatitis4.11 Syndrome of inappropriate ADH (SIADH)

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5. Poisoning5.1 Paracetamol overdose5.2 Tricyclic antidepressant overdose5.3 Theophylline toxicity5.4 Carbon monoxide poisoning

5.5 Quinidine and quinine toxicity5.6 Iron poisoning 5.7 Salicylate overdose5.8 Ethylene glycol poisoning 5.9 Haemodialysis for overdose or poisoning

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Essential Revision Notes for MRCP: Second Edition



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Clinical Pharmacology, Toxicology and Poisoning

Clinical Pharmacology,

Toxicology and Poisoning1. DRUG METABOLISM AND INTERACTIONS

1.1 Genetic polymorphisms of drug metabolism

Genetic determination of enzyme activity may alter the susceptibility of an individual toadverse drug reactions. For example, the slow acetylator phenotype is possessed by 50% of UK

citizens and may be associated with specific adverse effects due to higher drug concentrations:

• drug-induced lupus• isoniazid-induced peripheral neuropathy.

Drug-induced lupus is associated with slow acetylation and possession of HLA DR4. Unlikeautoimmune SLE, male and female incidence are equal. Laboratory findings include antibod-ies to histones and single-stranded DNA. Clinical features include:

• arthralgia•

butterfly rash• pleurisy.

Renal involvement (except with hydralazine) or neuropsychiatric manifestations are unusual.

Drugs causing a lupus erythematosus-like syndrome

• Beta-blockers • Hydralazine • Phenytoin• Chlorpromazine • Isoniazid • Procainamide• Clonidine • Lithium • Sulfasalazine• Flecainide • Methyldopa • Sulphonamides• Haloperidol • Penicillin • Tetracyclines

Poor metabolisers of particular drugs

• Debrisoquine: 6% of the UK population are poor metabolisers of debrisoquine; thesepatients have reduced activity of another liver enzyme which potentiates the effects of metipranolol and nortriptyline.

• s-Mephenytoin: 3–5% of the UK population are poor metabolisers of this anti-epileptic agent.



The metabolism of proton pump inhibitors (eg omeprazole) may be impaired in thesepatients, leading to excess adverse effects, such as diarrhoea.

Rapid acetylators

Rapid acetylators may be more prone to adverse effects due to the actions of excess drug metabolite. This is seen with isoniazid-induced hepatitis.

1.2 Liver enzyme induction

Many drugs are capable of inducing liver enzyme systems. Increased hepatic enzyme activitycan result in more rapid metabolism of other drugs, thereby decreasing their effectiveness.Induction of microsomal enzymes of the cytochrome P450 system occurs over days becauseit requires transcription and translation of the genetic code to produce more enzyme. This

may lead to treatment failure with the following agents:

• hydrocortisone• oral contraceptive pill• phenytoin• warfarin.

The drugs that cause this effect can be remembered by the mnemonic PC BRAS:

(Phenytoin, Carbamazepine, Barbiturates, Rifampicin, A lcohol (chronic excess),Sulphonylureas)

1.3 Liver enzyme inhibition

A number of drugs are capable of inhibiting hepatic enzyme systems, which can occur immediat-ely. Enzyme inhibition can reduce the rate of metabolism of other drugs, thereby increasing plasma concentrations and increasing the risks of adverse effects. Hepatic enzyme inhibition canpotentiate the effects of:

• carbamazepine• ciclosporin• phenytoin• theophyllines• warfarin.

Drugs that are liver enzyme inhibitors may be recalled by the mnemonic AODEVICES:

( A llopurinol, Omeprazole, Disulfiram, Erythromycin, V alproate, Isoniazid, Cimetidine (andciprofloxacin), acute Ethanol intoxication, Sulphonamides)

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1.4 Failure of the combined oral contraceptive pill

Any condition that leads to impaired absorption of the components of the contraceptive pill(eg traveller’s diarrhoea) may result in its failure as a contraceptive agent. In addition:

• The oestrogenic component of the oral contraceptive may be metabolised more rapidly inthe presence of liver enzyme inducers (see previous page), leading to pill failure, but enzyme inhibitors have no clinically significant effect.

• Pill failure may also result from concomitant antibiotic usage. For example, ampicillin,amoxicillin and tetracyclines may damage gut flora that deconjugate bile salts therebyinterrupting enterohepatic cycling of the oestrogenic component.

2. PRESCRIBING IN PARTICULAR CLINICAL STATES

2.1 Drugs and breast-feeding

Infants under one month of age are at greatest risk from drugs excreted in breast milk becausethey have immature metabolism and excretion. Drugs that are definitely excreted in breast milk and are contraindicated during breast-feeding include:

• amiodarone: thyroid anomalies• cytotoxics and chloramphenicol: blood dyscrasia.

Other drugs that should not be taken by breast-feeding mothers are:

• gold: haematological reactions and renal impairment • indometacin: has been reported to cause seizures• iodides: thyroid disturbance• lithium: involuntary movements• oestrogens: feminisation of male infants.

2.2 Pregnancy and drug therapies

During the first 16 weeks of pregnancy, drugs may exert teratogenic effects on the fetusleading to malformations. Particular associations are:

• lithium: cardiac abnormalities• phenytoin: facial fusion abnormalities such as cleft lip and palate• sodium valproate and retinoids: neural tube defects• warfarin: abnormalities of long bones and cartilage.

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Later in pregnancy some drugs may cross the placenta and harm the fetus:

• carbimazole: neonatal goitre (which may even be large enough to obstruct labour)• gentamicin: VIIIth nerve deafness in the newborn.

2.3 Prescribing in liver disease and liver failure

Depressed central nervous system function can result from the accumulation of either highconcentrations of drugs normally cleared by the liver, or toxic substances as a result of impaired hepatic metabolism. Patients with liver impairment are more sensitive to thesedative effects of a number of drugs, and the latter may induce hepatic encephalopathy.Opioids in particular may cause coma due to altered brain sensitivity. Similarly, benzo-diazepines may accumulate and depress the central nervous system. Thiazides and loopdiuretics may cause hypokalaemia, thereby provoking encephalopathy. Other important aspects of drug metabolism in liver disease are listed below:

• Drugs excreted via the bile, such as rifampicin, may accumulate in patients withobstructive jaundice.

• Hypoalbuminaemia, resulting from cirrhosis, may reduce available binding sites forprotein-bound drugs (eg phenytoin) to very low levels.

• Reduced clotting factor synthesis means an increased risk of bleeding for patients taking warfarin.

• Patients with advanced liver disease retain salt and water due to secondary hyperaldoster-onism; the resulting ascites and oedema can be worsened by non-steroidal anti-inflammatory drugs and steroids.

2.4 Prescribing in renal failure

Consideration of drug metabolism is important in patients with renal failure, as nephrotoxicagents may exacerbate renal damage (especially in patients with acute renal failure), and otherdrugs, especially those that are water soluble and therefore eliminated largely by the kidneys,may accumulate in patients with a low glomerular filtration rate (GFR), leading to toxic effects.

Drugs that accumulate and cause toxicity in patients with severe renal failure (GFR <10 ml/min)include:

• digoxin: cardiac arrhythmias, heart block• erythromycin: encephalopathy• lithium: cardiac arrhythmias and seizures• penicillins and cephalosporins (high dose): lead to encephalopathy.

Nephrotoxic drugs may lead to an acute deterioration of renal function in patients withchronic renal failure, and they can severely exacerbate renal damage in acute renaldysfunction. If treatment is considered essential (eg gentamicin or parenteral vancomycin forstaphylococcal infections) then levels should be carefully monitored, otherwise such agents

should be avoided in these patient groups. Examples of nephrotoxic drugs include:

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• aminoglycosides• amphotericin• non-steroidal anti-inflammatory drugs.

Other drugs may have more specific nephrotoxic effects, such as gold-induced proteinuria ornephrotic syndrome, which is usually due to membranous glomerulonephritis. (See alsoChapter 15, Nephrology.)

3. INDIVIDUAL DRUGS AND THOSE USED IN SPECIFICCLINICAL CONDITIONS

3.1 Cardiology

Abciximab (Reopro)This chimeric monoclonal antibody irreversibly binds Gpllb/llla glycoprotein receptors inplatelets, preventing the final common pathway of platelet activation and aggregation. It has apotent long-term anti-platelet effect after intravenous bolus/infusion. Licensed now for high-risk angioplasty (EPIC trial), it prevents acute thrombosis and chronic re-stenosis withincoronary arteries and has recently been shown to be beneficial for unstable angina (EPILOG-Stent trial). Risks of thrombocytopenic haemorrhage are low and reversed by platelet admin-istration. Abciximab should be used only once in a particular patient.

Adenosine

Adenosine is a purine nucleoside with a half-life of 8–10 seconds. It acts via specificadenosine receptors, activating K + channels, in sinoatrial and atrioventricular nodes tocause sinus node arrest, so terminating supraventricular tachycardia (SVT). Its chief therapeu-tic use is to distinguish between SVT and ventricular tachycardia. The action of adenosinemay be inhibited by aminophylline and potentiated by dipyridamole, which interferes withits metabolism.

Side-effects of adenosine

• Anxiety • Chest tightening • Bronchospasm (avoid in asthmatic patients) • Facial flushing

Amiodarone

Amiodarone has anti-arrhythmic action which spans all categories of the Vaughan–Williamsclassification. Its main action is to prolong the refractory period, and thus the QT interval, onthe ECG. Amiodarone may be used to control supraventricular and ventricular arrhythmias. It may prolong the lifespan of patients with recurrent VT or hypertrophic cardiomyopathy.



• It is iodine-containing and has a very long half-life (26–127 days).• Protein binding can displace digoxin or warfarin, so increasing their actions.• Given intravenously, the anti-arrhythmic action occurs within a few hours; given orally this

may take 1–3 weeks.• Amiodarone is the least negatively inotropic anti-arrhythmic with the exception of

digoxin.• Hyperthyroidism may result from enhanced peripheral de-iodination of thyroxine to T3.

Hypothyroidism arises from increased production of reverse T3 in the liver.

Side-effects of amiodarone

• arrhythmias (torsades)• ataxia• alveolitis•

hepatitis• hyperthyroidism• hypothyroidism• metallic taste• peripheral neuropathy• photosensitivity• pulmonary fibrosis• reversible corneal microdeposits• slate grey discoloration of skin.

Angiotensin converting enzyme (ACE) inhibitors ACE inhibitors reduce mortality in all grades of heart failure and may reduce death aftermyocardial infarction, probably by reducing deleterious remodelling. They are contraindicatedin bilateral renal artery stenosis and should be used with caution in severe renal impairment.

• Dry cough may accompany their use; this may be due to persistence of bradykinin and ismore common in women, who have more sensitive cough reflexes.

• Hypersensitivity to ACE inhibitors is manifest as angio-neurotic oedema.• Potassium may rise during therapy due to inhibition of aldosterone production by ACE

inhibitors.

Angiotensin receptor blockers

Angiotensin II receptor (type AT1) antagonists do not inhibit bradykinin breakdown (unlike ACE inhibitors) and so do not provoke cough. They provide more specific AT1 receptor antagon-ism at tissue level, and are indicated for treatment of hypertension and cardiac failure as an alter-native to ACE inhibitor therapy. They may precipitate acute renal failure in patients with reducedrenal blood flow (eg bilateral renal artery stenosis, severe cardiac failure, hypovolaemia) in anidentical manner to that seen with ACE inhibitors.

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Digoxin

Digoxin increases block at the atrioventricular node and so is used to slow ventricular rate inatrial fibrillation and flutter. It has a limited role as a positive inotrope but it may be aneffective treatment in patients with co-existent heart failure and atrial fibrillation.

• Eighty-five per cent of a digoxin dose is eliminated unchanged in the urine; it cantherefore accumulate in renal impairment.

• The steroid-like structure of digoxin has occasionally caused gynaecomastia in chronic use.• Digoxin has a narrow therapeutic window, above which toxic effects are often seen.

Digoxin toxicity

Any arrhythmia may occur with digoxin toxicity; the most common is heart block but evenatrial fibrillation has been observed. Pulsus bigeminus is indicative of a ventricular ectopiccoupled to a normal QRS complex on the ECG and this may herald digoxin toxicity.

• However, note that ‘reversed tick’ ST segment depression is commonly seen in theinferior and lateral leads on the ECG, and represents a sign of digoxin therapy and not specifically toxicity. First-degree heart block is also seen in patients with sinus rhythmwho take digoxin.

• Electrolyte imbalances which may predispose to digoxin toxicity include hypokalaemia,hypomagnesaemia and hypercalcaemia.

• Amiodarone may displace digoxin from tissue-binding sites leading to toxicity, whereasquinidine/quinine and calcium antagonists may interfere with tubular clearance of digoxinleading to accumulation and risk of toxic effects.

Toxic effects of digoxin

• Anorexia • Nausea/vomiting • Arrhythmias (eg atrial fibrillation, heart block) • Yellow vision (xanthopsia)• Diarrhoea

Flecainide

A class 1c agent used for treatment of ventricular arrhythmias, pre-excitation syndromes andfor chemical cardioversion of acute atrial arrhythmias. The CAST trial suggested that flecainide is pro-arrhythmic post myocardial infarction; it should be avoided in left ventricular impairment. Its half-life is about 16 hours; other main side-effects are vertigo andvisual disturbance.

HMG CoA reductase inhibitors

Statins inhibit the rate-limiting enzyme in cholesterol synthesis (HMG CoA reductase), which isnormally predominantly active during sleep (due to fasting and increased hepatic blood flow).They also cause up-regulation of low-density lipoprotein (LDL) receptors thereby reducing LDL

by 30% and increasing the clearance of cholesterol, and increasing high-density lipoprotein



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(HDL). Most statins have minimal effects on triglycerides. However, although atorvastatin mayreduce triglycerides, mortality data are still awaited.

• Statins reduce mortality after myocardial infarction in men who have high cholesterol(‘4 S’ study).

• They have recently been shown to be effective in reducing primary mortality fromischaemic heart disease (WOSCOP trial).

• Statins rarely cause rhabdomyolysis (frequency 1/100, 000), but this is more likely inpatients with renal impairment or when given with a fibrate; drug-induced hepatitis mayalso occur.

• The joint British recommendations on prevention of coronary heart disease recommend atarget total serum cholesterol of <5.0 mmol/l and LDL cholesterol of <3.0 mmol/l.

Nicorandil

A K + channel opener that induces arterial vasodilatation, it also possesses a nitratecomponent that promotes venous relaxation. Used as an anti-anginal agent. Side-effects aretransient headache, flushing and dizziness. In large doses it may cause hypotension with areflex tachycardia.

Thiazide diuretics

Thiazides are capable of lowering blood pressure. The exact mechanism is unclear, but it seems to be independent of the modest diuretic effect provided by these agents. Maximumblood pressure reduction is achieved using low doses (eg bendroflumethiazide 2.5 mg daily).

They are associated with a number of dose-dependent metabolic effects:

• Hyponatraemia, hypokalaemia and hypomagnesaemia; a hypochloraemic alkalosis mayresult.

• Raised plasma urate may occur due to reduction of tubular clearance of urate; rarely, gout may be precipitated.

• Diabetic glycaemic control may worsen on thiazides due to impaired insulin release;tissue-based insulin resistance and cholesterol may rise, at least temporarily.

• Thiazide diuretics may also cause postural hypotension, photosensitivity and impotence(mechanism unclear).

Rare dose-independent side-effects of thiazide diuretics

• Agranulocytosis• Pancreatitis• Thrombocytopenia



Ticlopidine

This is a novel anti-platelet agent, which probably acts via Gpllb/llla glycoprotein. Its usesinclude secondary stroke prevention, treatment of unstable angina and post-coronary stent insertion. It is at least as effective as aspirin. Severe (but reversible) neutropenia occurs in

1% of users and diarrhoea in 20%. Intrahepatic cholestasis and marrow aplasia have alsobeen reported.

Clopidogrel

Like ticlopidine, clopidogrel inhibits ADP-mediated platelet aggregation. It is also used toprevent ischaemic heart disease and stroke. Evidence from the CAPRIE trial suggests that it is at least as effective an alternative as aspirin. It may also cause neutropenia, but less frequently sothan ticlopidine.

3.2 Endocrinology

Carbimazole

Carbimazole acts by inhibiting a peroxidase which catalyses all phases of thyroid hormoneproduction from the amino acid tyrosine. It takes at least 6 weeks to reduce blood levels of thyroid hormones. Therefore, somatic symptoms of hyperthyroidism, such as tachycardia andanxiety, are best suppressed by beta-blockers (eg propranolol).

• Agranulocytosis may occur within the first 16 weeks of therapy and in the event of a sorethroat patients should be advised to seek medical help.

• The drug crosses the placenta; however, if it is given in low dose in pregnancy, fetalhypothyroidism may be prevented.

Hormone replacement therapy

On average, over a third of a woman’s life is in the post-menopausal phase, yet only 12%receive hormone replacement therapy (HRT); 60–75% of menopausal women will expe-rience vasomotor symptoms and these will be reduced by HRT.

• Without HRT, women aged 70 years have a 50% reduction in bone mass and one in two

will have an osteoporosis-related fracture.• HRT therefore leads to a 50% reduction in fractures and may reduce ischaemic heart

disease by 20% and stroke by 15%; this may be at the expense of an increased risk of breast cancer.

• See also Chapter 4, Endocrinology, Section 3.5.

Nateglinide and repaglinide

These agents have a short duration of action and may be used to stimulate insulin release inpatients with type 2 diabetes prior to meals. They may also be given alongside metformin.

Side-effects include gastrointestinal upset and hypersensitivity reactions.

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Acarbose

Acarbose inhibits intestinal alpha-glucosidase and thereby delays absorption of starch andsucrose. It reduces post-prandial hyperglycaemia in type 1 diabetes and is used as anadjunct to metformin or sulphonylurea therapy in type 2 diabetes. Excess flatus is a

common adverse effect.

Thiazolidinediones (pioglitazone and rosiglitazone)

Thiazolidinediones reduce peripheral insulin resistance and are used in combination withmetformin (or sulphonylureas) to treat patients in whom combined therapy with the latter twoagents is inadequate or not tolerated. Thiazolidinediones may delay the requirement forinsulin. Hepatic impairment is a recognised adverse effect, and hence regular monitoring of liver biochemistry is required.

3.3 Gastroenterology

Mesalazine and olsalazine

Mesalazine and olsalazine differ from sulfasalazine in being purely 5-amino salicylic acid (5- ASA) molecules which are split for local action in the colon. They suppress local inflammationin ulcerative colitis.

• They have some systemic side-effects including nausea, abdominal pain, headache andsometimes worsening of colitis.

• Rare side-effects of mesalazine and olsalazine include reversible pancreatitis, blooddyscrasias and interstitial nephritis (with mesalazine).

Sulfasalazine

Sulfasalazine consists of a sulphonamide molecule plus 5-ASA. It is used in the treatment of ulcerative colitis, and also as a disease-modifying anti-rheumatic in rheumatoid arthritis.The sulphonamide moiety frequently leads to gastrointestinal upset. Other key features areas follows:

• Oligospermia, leading to male infertility, may occur but this is usually reversible on

stopping sulfasalazine.• Patients may note orange discoloration of body fluids.• Slow acetylators may experience more toxicity with sulfasalazine due to exposure to

higher levels of the sulphonamide constituent.• Rare side-effects of sulfasalazine include Stevens–Johnson syndrome, blood dyscrasias

(especially agranulocytosis and aplasia) and nephrotic syndrome.

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3.4 Neurology

Treatment of Parkinson’s disease

Enhanced dopaminergic transmission is central to the medical management of Parkinson’s

disease:

• Selegiline is a type B monoamine oxidase inhibitor (MAO-B); inhibition of monoamineoxidase potentiates dopamine and reduces end-dose akinesia. It was thought that selegiline might also retard progression of Parkinson’s disease by preserving dopaminergicneurones. This is now known to be untrue.

• Amantadine potentiates dopamine by preventing its re-uptake into pre-synapticterminals.

• Levodopa (L-dopa) is absorbed in the proximal small bowel by active transport, but thepresence of amino acids (and thus meals) may reduce absorption. It is a pro-drug which

must be converted to dopamine within the nigro-striatal pathway. The drug is largelymetabolised by catechol-o-methyl transferase. After 8 years of therapy with L-dopa, 50%of patients will have choreo-athetoid dyskinesia and end-dose akinesia. By this time manypatients will have deteriorated to pre-treatment levels of disability due to progression of Parkinson’s disease.

• Dopamine receptor agonists include apomorphine, bromocriptine, cabergoline,lisuride, pergolide, pramipexole and ropinirole. These agents cause less dyskinesia than L-dopa but they are associated with more neuropsychiatric adverse effects. Certain of theseagents have been associated with pulmonary and retroperitoneal fibrosis (bromocriptine,cabergoline, lisuride, pergolide). Apomorphine is a powerful dopamine agonist which

needs to be given by parenteral administration under specialist supervision. It is highlyemetogenic and domperidone must therefore be given 2 days prior to thecommencement of therapy.

Side-effects of L-dopa

• Cardiac arrhythmias• Involuntary movements (dyskinesia) occur commonly• Nausea and vomiting • Postural hypotension• Psychosis (depression or mania)• Somnolescence (including sudden onset)

Orlistat

This agent inhibits the action of pancreatic lipase and may be indicated in obesity where thebody mass index is >30 kg/m2 and where the individual has been able to lose 2.5 kg inweight over a four-week period. It causes liquid, oily stools and may reduce the absorptionof fat-soluble vitamins.



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Treatment of epilepsy

Recent developments in the therapeutics of epilepsy have concentrated on agents whichinteract with neurotransmitters.

• Glutamic acid is an excitatory central nervous system neurotransmitter; lamotrigineinhibits it, so suppressing seizures. The side-effects of lamotrigine include mood changes,maculopapular rashes, influenza-like symptoms and Stevens–Johnson syndrome.

• Gamma-aminobutyric acid (GABA) is an inhibitory central nervous system neurotrans-mitter. Gabapentin and vigabatrin potentiate GABA and thus may be used to treat seizures.

• Vigabatrin is used for refractory epilepsy, potentiating GABA by irreversible inhibition of GABA transaminase. Side-effects of vigabatrin include mood disturbance and psychosis in5%. Severe visual field defects may occur from one month to several years after initiationof therapy; regular visual field assessment is advised.

•

Diazepam also terminates seizures by indirectly interacting with GABA transmission. It stimulates the benzodiazepine receptor in the brain which in turn enhances the affinity of the neighbouring GABA receptor for its neurotransmitter.

• Carbamazepine is a derivative of the tricyclic antidepressants and is useful for epilepsyand also neural pain (eg trigeminal or post-herpetic neuralgia). Patients commonly experi-ence headaches and diplopia on starting carbamazepine and 5–15% of patients candevelop a generalised morbilliform rash.

• Sodium valproate is used in absence attacks and temporal lobe epilepsy. It inhibits liverenzymes and may potentiate other anti-epileptics such as phenytoin. It may causealopecia, with curly regrowth after stopping the drug.

Adverse effects of valproate

• Alopecia • Hepatitis (sometimes fatal)• Amenorrhoea • Liver enzyme inhibition• Ataxia • Thrombocytopenia• Gynaecomastia • Weight gain

5-HT agonists (sumatriptan and rizatriptan)

5-HT agonists are used during the acute phase of migraine. They are effective only if takenearly in the attack, and oral and sublingual preparations are available. They maintain vaso-constriction and prevent headache associated with the vasodilator phase of migraine. Theymust not be given in hemiplegic migraine, or within 24 hours of ergotamine, as intensevasospasm may lead to permanent neurological damage. Sumatriptan may lead to permanent neurological damage. It may also cause angina due to coronary vasospasm.



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Side-effects of sumatriptan

• Chest pain • Flushing • Drowsiness • Vasospasm• Fatigue

3.5 Psychiatry

Chlorpromazine

Chlorpromazine blocks many different receptors; for example, it acts as a dopamine blocker,an alpha blocker, anti-cholinergic and anti-histamine. Due to prolongation of the QT intervalon the ECG, ventricular tachycardia may result (particularly when used in high dose).

Adverse effects of chlorpromazine

• Agranulocytosis• Contact dermatitis and purple pigmentation of the skin• Dystonias (including oculogyric crisis)• Neuroleptic malignant syndrome• Photosensitivity• Tardive dyskinesia (chronic use)• Ventricular tachycardia (prolonged QT)

Lithium

Lithium carbonate is used for prophylaxis in bipolar affective disorder, for treatment of acutemania/hypomania and to augment antidepressants in recurrent or resistant depression. It isalso used to treat aggressive behaviour in patients with learning disabilities. It has a narrowtherapeutic range (0.6–1.2 mmol/l). Toxic effects occur at levels >2.0 mmol/l.

• Toxicity is more likely in renal impairment or when there are imbalances of electrolytes; it may also arise when lithium excretion is impaired by thiazide and loop diuretics, ACE

inhibitors and non-steroidal anti-inflammatory drugs.• Lithium may cause histological changes in the kidney and it has been recommended that

long-term treatment is reviewed every 2–3 years.• Polyuria arises due to nephrogenic diabetes insipidus; lithium prevents anti-diuretic

hormone (ADH) from interacting with the collecting duct receptor, so leading to waterloss. There is a compensatory increase in ADH release.



Toxic and side-effects of lithium Side-effects of lithium*

• (At 1–2 mmol/l) • Common Anorexia and vomiting Fine tremor (in about 15% of patients)

Ataxia and dysarthria LeukocytosisBlurred vision Loose motionsCoarse tremor NauseaDiarrhoea OedemaDrowsiness PolydipsiaMuscle weakness Polyuria

Weight gain• (Severe toxicity >2 mmol/l)

Circulatory failure • RareComa Goitre

Convulsions HypothyroidismDeath Interstitial nephritisHyper-reflexia Worsening of psoriasis and acneOliguriaToxic psychoses

*May arise despite therapeutic range dosing

• Antacids, theophylline and acetazolamide lead to decreased plasma lithium carbonate.• CNS toxicity has been described with selective serotonin re-uptake inhibitors (SSRIs),

carbamazepine and phenytoin, methyldopa, antipsychotics (especially haloperidol),calcium channel blockers and sumatriptan.

3.6 Rheumatology

Penicillamine

Penicillamine is used as a disease-modifying agent in rheumatoid arthritis and also to chelatecysteine in cystinuria and copper in Wilson’s disease, respectively. In the first 6 weeks of therapy reversible loss of taste may occur. This may resolve without stopping the drug.

• After 4–18 months of therapy, proteinuria due to membranous glomerulonephritis may ensue.• Thrombocytopenia and neutropenia may result from penicillamine therapy; patients

should be warned to seek medical advice if a sore throat or ready bruising develop.• Myasthenia, drug-induced lupus and Stevens–Johnson syndrome have also been reported.

Treatment of gout

Allopurinol inhibits xanthine oxidase, the enzyme which converts purines into uric acid, andso prevents gout. However, commencement of therapy will occasionally provoke an acute

attack of gout. Established gouty tophi may regress with chronic use of allopurinol.

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• Azathioprine, a pro-drug, is converted to 6-mercaptopurine in the body and may accu-mulate causing bone marrow toxicity in patients receiving allopurinol.

• The renal clearance of cyclophosphamide may also be impeded in patients receiving allopurinol and this again leads to marrow toxicity.

Colchicine inhibits macrophage migration into a gouty joint but its use is limited by thefrequent occurrence of diarrhoea. It has therefore been said that with colchicine ‘you runbefore you can walk’!

Urate oxidase enzymatically degrades urate to allantoin. Intravenous administration causes asignificant reduction in serum urate concentrations (by up to 95%) and is used to prevent renal impairment in tumour lysis syndrome.

3.7 Miscellaneous

A detailed description of the mechanism of action, important pharmacokinetics and charac-teristic or serious side-effects of commonly used antibacterial, antiviral and antihelminthicagents is provided in Chapter 11, Infectious Diseases.

Ciprofloxacin

This 4-quinolone inhibits DNA bacterial gyrase, an enzyme which prevents supercoiling of bacterial DNA; it has activity against both Gram-positive and Gram-negative organisms. It is aliver enzyme inhibitor and particularly potentiates theophylline. Ciprofloxacin is not recom-mended for children under 12 years of age (except in cystic fibrosis) because of the potentialfor bony anomalies (which have been shown in pre-pubertal animal models).

Side-effects of ciprofloxacin

• Anaphylaxis • Photosensitivity• Arthralgia • Sedation (which may affect driving)• Diarrhoea • Seizures• Impaired motor function

• The seizures occur because ciprofloxacin can compete with the inhibitory neurotrans-mitter, GABA, within the brain.

Ciclosporin A

Ciclosporin A is used to reduce transplant rejection and it has significantly improved graft survival. It causes dose-dependent nephrotoxicity and has a narrow therapeutic range. Therisk of toxicity is therefore assessed by therapeutic drug monitoring. (See also Chapter 15,Nephrology.)



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Gum hyperplasia is common; it is increased in individuals with poor oral hygiene, and alsothose concomitantly taking dihydropyridine calcium-channel blockers. As with most immunosuppressives, there is an increased risk of skin and lymphoproliferative malignancywith long-term therapy.

Adverse effects of ciclosporin A

• Burning hands and feet • Hypertension(especially during 1st week of therapy) • Hypertrichosis

• Fluid retention • Liver dysfunction• Gum hyperplasia • Nephrotoxicity• Hyperkalaemia • Oligodystrophy

CytotoxicsThe majority of cytotoxic agents have the potential to cause marrow suppression.

Specific side-effects of cytotoxic agents

• BleomycinCauses dose-dependent lung fibrosis; it is one of the least myelotoxicchemotherapeutic agents

• Cisplatin

May cause ototoxicity, nephrotoxicity (interstitial nephritis), hypomagnesaemiaand peripheral neuropathy• Doxorubicin

May cause skin irritation and cardiomyopathy• Methotrexate

May cause severe mucositis and myelosuppression, which is prevented by theuse of folinic acid rescue. During chronic administration pneumonitis and liverfibrosis may occur

• Vincristine and vinblastineCause a reversible peripheral neuropathy

Leukotriene antagonists

Agents such as montelukast block the effects of leukotriene in the airways. They are used asadd-on therapy in mild to moderate asthma. They should not be used to attempt to relieveacute asthma. Churg–Strauss-like eosinophilic vasculitis and peripheral neuropathy havebeen reported with these agents.



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Retinoids

Oral retinoids are indicated for treatment of severe psoriasis and acne that is resistant toother therapies. They are teratogenic, leading to neural tube defects. Like other vitamin Aderivatives they may cause benign intracranial hypertension. Dryness of mucous membranes

leading to intolerance of contact lenses has been noted during treatment with retinoids.

High-dose retinoids can rarely cause diffuse interstitial skeletal hyperostosis.

Adverse effects of retinoids

• Alopecia • Photosensitivity• Benign intracranial hypertension • Reduced night vision• Dry mucous membranes • Skeletal abnormalities (with• Hepatitis high doses)• Hypertriglyceridaemia • Teratogenicity• Mood changes • Thrombocytopenia

4. SPECIFIC ADVERSE EFFECTS

4.1 Secondary amenorrhoea due to drugs

Dopamine inhibits prolactin release and so dopamine-blocking drugs, such as chlorpro-

mazine and cimetidine (but not ranitidine), may provoke hyperprolactinaemia and henceamenorrhoea. Sodium valproate may also cause amenorrhoea.

4.2 Bronchospasm

Bronchospasm may be induced by aspirin and non-steroidal anti-inflammatory drugs,particularly in patients with late-onset asthma. Sensitivity to these agents is thought to relate topharmacological effects on prostaglandin metabolism; the effect is not immunological, andthus it is termed ‘pseudoallergic’.

• Adenosine should be avoided in asthma, as it may cause bronchoconstriction via stimu-lation of adenosine receptors found in bronchial smooth muscle.

• Even cardioselective beta-blockers, such as atenolol, may provoke bronchospasm.• Sodium chromoglycate is a mast cell stabiliser; it is an inhaled, preventative agent in

asthma. However, bronchospasm has occasionally been reported, because chromoglycateis administered as a dry powder.

• N-Acetyl cysteine may cause bronchospasm and anaphylaxis when given as an antidote toparacetamol overdose.



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4.3 Dyskinesia and dystonia

Both dopamine agonists and antagonists can lead to movement disorders.

•

Drugs with dopamine-like effects that are used to treat Parkinson’s disease may causedyskinesia (L-dopa, bromocriptine, lysuride and pergolide).• Dopamine-blocking agents such as phenothiazines (chlorpromazine) or butyrophenones

(haloperidol) may also cause dyskinesias. This is a recognised complication of treatment with dopamine antagonists such as domperidone. It is less common with metoclopramidedue to poorer uptake of this agent across the blood–brain barrier.

• Fluoxetine and paroxetine, serotonin re-uptake inhibitors used in the treatment of depression, have both been associated with dystonias.

4.4 Gynaecomastia

Gynaecomastia can complicate treatment with drugs that are oestrogen-like in action oranti-androgens.

Oestrogen-like action Anti-androgen action

• Digoxin • Cimetidine• Spironolactone • Cyproterone acetate• Stilboestrol • Luteinising hormone releasing hormone (LHRH)

analogues (eg goserelin)

4.5 Hypothyroidism

Impaired thyroid hormone production may result from:

• amiodarone• carbimazole• lithium•

propylthiouracil• radio-iodine.

4.6 Drug-induced liver disease

Drug-induced liver disease may represent either dose-dependent or dose-independent effects.

• Dose-dependent liver disease includes paracetamol poisoning, fatty change due to tetra-cyclines and alcoholic hepatitis.



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• Dose-independent liver disease usually involves either hepatitis or cholestasis; it generally has an allergic basis and may on occasion be associated with liver failure.

Drug-induced hepatitis occurs with Causes of drug-induced cholestasis

• Amiodarone • Carbamazepine• HMG CoA reductase inhibitors • Chlorpromazine• Isoniazid metabolite • Co-amoxiclav (combination of • Methyldopa amoxicillin and clavulanic acid)• Paracetamol • Erythromycin• Phenytoin • Sulphonylureas• Pyrazinamide• Valproate

• Liver tumours may be associated with use of androgens and oestrogens (which can alsocause Budd–Chiari malformations); liver fibrosis may accompany methotrexate treatment.

4.7 Drugs provoking myasthenia

• Aminoglycosides, certain beta-blockers (propranolol, oxprenolol), phenytoin, ligno-caine, quinidine and procainamide may all impair acetylcholine release, leading toworsening or unmasking of myasthenia.

• Penicillamine may cause formation of antibodies against the acetylcholine receptor, and

a syndrome indistinguishable from myasthenia results. This resolves in two-thirds of casesafter penicillamine withdrawal.

• Lithium may also cause myasthenia-like weakness by impairing synaptic transmission.

4.8 Photosensitivity

Drugs causing photosensitivity

• Amiodarone • Piroxicam

• Ciprofloxacin • Psoralens• Griseofulvin • Retinoids• Loop and thiazide diuretics • Sulphonylureas• Oral contraceptives • Tetracyclines



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4.9 Drug-induced vasculitis

Drug-induced vasculitis can affect the skin or internal organs.

Drugs causing vasculitis

• Allopurinol • Penicillin• Captopril • Quinidine• Cimetidine • Sulphonamides• Hydralazine • Thiazides• Leukotriene antagonists

4.10 Acute pancreatitis

Acute pancreatitis is a recognised adverse effect of a number of drugs.

Drugs causing acute pancreatitis

• Anti-retrovirals (ritonavir, didanosine, zalcitabine, stavudine, lamivudine)• Azathioprine• Corticosteroids• Fibrates• HMG CoA reductase inhibitors• Omega-3 fish oils• Thiazide diuretics

4.11 Syndrome of inappropriate ADH (SIADH)

SIADH is characterised by hyponatraemia, concentrated urine and low plasma osmolality, alloccurring in the absence of oedema, diuretic use or hypovolaemia.

Drugs causing SIADH

• Carbamazepine • Oxytocin• Chlorpropamide • Psychotropic agents• Cytotoxic agents • Rifampicin• Opiates

In addition there are a number of non-pharmacological causes, which include malignancy,central nervous system disorders, suppurative pulmonary disease and porphyria ( see Chapter 4,

Endocrinology, Section 4).



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5. POISONING

5.1 Paracetamol overdose

Overdose with paracetamol is one of the most common causes of self-poisoning. Earlyfeatures are minor (nausea and vomiting) but hepatic or renal failure occur later; and liverdamage peaks at 1–2 days after ingestion. Paracetamol is normally metabolised byglucuronidation in the liver. Toxicity arises because excess oxidation products are formed inoverdose; these overwhelm the capacity for endogenous detoxification (glutathione) and theactive metabolite binds to liver cell macromolecules, causing necrosis.

• The international normalised ratio (INR), or prothrombin ratio, is the most sensitive indi-cator of liver damage. Hypoglycaemia is a feature of advanced liver damage.

• Poor prognosis is indicated by an INR above 3.0, raised serum creatinine or plasma pH<7.3 more than 24 hours after overdose.

• Patients taking enzyme inducers such as phenytoin have an increased risk of hepaticnecrosis after paracetamol poisoning.

• Renal failure may sometimes develop before liver necrosis due to mixed-function oxidasesgenerating the same dangerous metabolites within the renal parenchyma.

• N-Acetyl cysteine binds the hepatotoxic metabolites; it improves prognosis in paracetamolpoisoning even after hepatic encephalopathy has developed. It is now administeredcontinuously until the INR has returned to normal.

5.2 Tricyclic antidepressant overdose

Tricyclic antidepressants have anti-cholinergic (pupillary dilatation, confusion and tachy-cardia) and alpha-blocking (hypotension) side-effects. Sympathomimetic overactivity results.

• Prolonged QT interval on the ECG may predispose to ventricular arrhythmias; the QRScomplex is widened in severe toxicity. Intravenous bicarbonate may reduce the risk of arrhythmias and seizures in these situations. In markedly widened QRS complex, it maybe a prelude to cardiogenic shock and such patients require cardiac pacing.

• The seizure threshold is also reduced and status epilepticus may ensue; abnormalities of thermoregulation can also occur.

•

Treatment is supportive, with emesis, gastric lavage and use of activated charcoal. Fluidand electrolyte balance should be maintained; diazepam is used for convulsions.

5.3 Theophylline toxicity

Theophylline causes tachycardia and may trigger arrhythmias in overdose due to phosphodi-esterase inhibition. These are more likely in the presence of severe acidosis or hypokalaemia,the latter due to intractable vomiting. Seizures and confusion can occur.



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• Treatment is with activated charcoal (which significantly reduces theophylline absorption)and correction of fluid and electrolyte depletion. Upper gastrointestinal endoscopy maybe useful to remove tablet residuum that can remain within the stomach for many hours.

• Haemodialysis or, preferably, charcoal haemoperfusion is indicated for patients withsevere toxicity (plasma theophylline >60 mg/l).

5.4 Carbon monoxide poisoning

Carbon monoxide binds to haemoglobin with high affinity (>200 times that of oxygen);poisoning leads to decreased haemoglobin oxygen-carrying ability, and consequent tissueanoxia. Normal carboxyhaemoglobin levels are <3% in non-smokers and 5–6% insmokers; at 10–30% exposed patients usually only complain of headaches and mild exer-tional dyspnoea.

Signs of marked toxicity (carboxyhaemoglobin 30–60%)

• Acute renal failure • Hypertonia and hyperreflexia• Agitation and confusion • Muscle necrosis• Bullous lesions • Pink mucosae• ECG changes and arrhythmias • Vomiting • Hyperpyrexia

• Severe toxicity is associated with coma, convulsions and cardio-respiratory arrest.• Treatment is with 100% oxygen by mask; hyperbaric oxygen (2.5 atmospheres pressure)

will decrease the elimination half-life of carbon monoxide (from 4 hours to 22 minutes),but this is not often available on site and hence patient transfer to a specialist centre maybe required.

• Neuropsychiatric changes may develop over several weeks after recovery from poisoning and these include intellectual deterioration, personality change, cerebral and cerebellardamage, and midbrain damage (Parkinson’s disease).

5.5 Quinidine and quinine toxicity

Quinidine and quinine poisoning may result in blurred vision and abdominal pain due to anti-cholinergic effects. Other features are:

• arrhythmias: because these drugs prolong the QT interval on the ECG• hypotension: which may occur due to alpha-adrenoceptor blockade• tinnitus and irreversible blindness.



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5.6 Iron poisoning

The key features of iron poisoning are shown in the box below. Gastric lavage should becontemplated if the patient presents within 1 hour of ingestion. Desferrioxamine chelates iron

and improves clinical outcome. It is given by intravenous infusion and the treatment is basedupon the serum iron concentration; however, in severe cases, treatment should becommenced before iron levels are available.

Clinical features of iron poisoning Severe poisoning

• Abdominal pain • Coma• Diarrhoea • Death• Haematemesis • Delayed hepatocellular necrosis• Lower gastrointestinal blood loss • Hypotension

• Nausea and vomiting

5.7 Salicylate overdose

The adverse effects of salicylate poisoning are due to direct stimulation of the respiratorycentre in the CNS (respiratory alkalosis) and to the acidic properties of the drug as well as theaccumulation of organic acids (metabolic acidosis).

Early features of poisoning Later features of poisoning

• Hypokalaemia • Acute renal failure• Respiratory centre stimulation in • Hypoglycaemia

the CNS, and hence alkalosis • Hypoprothrombinaemia• Sweating • Metabolic acidosis• Tinnitus • Pulmonary oedema

Key aspects of management of salicylate poisoning involve:

• activated charcoal• correction of electrolyte and metabolic abnormalities• intravenous fluids to ensure adequate hydration (forced alkaline diuresis is now regarded

as unsafe and is not recommended)• haemodialysis: for very severe salicylism (blood salicylate >750 mg/l).

5.8 Ethylene glycol poisoning

Poisoning with ethylene glycol has the clinical appearance of alcohol intoxication with cere-

bellar symptoms and signs in the first 12 hours, but without any smell of alcohol. Subsequent



breakdown of ethylene glycol to oxalate causes metabolic acidosis; there is a raised anion gapdue to the presence of exogenous organic acid, as well as a raised osmolar gap. Within2–3 days acute tubular necrosis results due to cellular damage by calcium oxalate crystals.Cardiac failure with pulmonary oedema may ensue.

Treatment for ethylene glycol poisoning

• Sodium bicarbonateTo reduce acidosis

• Intravenous ethanolCan inhibit ethylene glycol metabolism

• FomepizoleThis blocks the conversion of ethylene glycol to glycolate and it may beadministered after the overdose

•

CalciumTo correct hypocalcaemia• Haemodialysis

Active elimination of ethylene glycol is by haemodialysis

5.9 Haemodialysis for overdose or poisoning

Drugs or poisons which are poorly removed by haemodialysis are those with a large volumeof distribution (eg amiodarone and Paraquat) or those which are highly protein-bound (eg

digoxin and phenytoin). Repeated or continuous dialysis treatment may be required for drugswhich are widely distributed throughout the body, eg lithium, as there will be reboundincreases in plasma concentration.

Removal of drugs or toxins by haemodialysis/haemoperfusion

• Haemodialysis effective • Charcoal haemoperfusion Alcohol Paracetamol metabolitesBarbiturates TheophyllineEthylene glycol

LithiumMethanolSalicylate


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