Major drug side effects

This presentation is organised as a working table of the adverse effects that a clinician must remember. For each drug or drug class it states the important serious reaction, how to recognise it, and what to do first. It is written as revision for emergency and inpatient practice, not as a substitute for the product information or local formulary for the dose you are actually giving.^[1] Numbers in this page are the exact ranges quoted by the sources; where sources differ the disagreement is stated rather than resolved.

Many drug reactions are expected, dose-related (type A) extensions of the drug's normal action: hypotension with nitrates, bradycardia with digoxin, hypokalaemia with furosemide.^[5] Others are idiosyncratic (type B): aplastic anaemia with chloramphenicol, Stevens-Johnson with co-trimoxazole, halothane hepatitis. A few are delayed by weeks (drug-induced lupus) or by months (amiodarone pulmonary fibrosis). When a patient presents with a new symptom, the first question to ask is "what has changed in the last few days or weeks?", including over-the-counter and herbal medicines.

• Fever, rash and eosinophilia starting 2 to 6 weeks after a new drug: think of DRESS (a drug reaction with eosinophilia and systemic features), Stevens-Johnson syndrome and toxic epidermal necrolysis. Stop the drug now, before the rash spreads.^[1]
• New jaundice or right-upper-quadrant pain within 2 to 12 weeks of starting propylthiouracil, amiodarone, nitrofurantoin or a herb or supplement: drug-induced liver injury; stop the drug and check liver enzymes and INR.^[3]
• Unexplained stroke in a young adult, or embolus without atrial fibrillation: look for a cardiac myxoma, but also ask about oral contraceptives, cocaine and recent amphetamine use.
• Rapid fever, rigid muscles, autonomic instability and a very high creatine kinase: neuroleptic malignant syndrome.^[7]
• Fever, clonus, hyperreflexia and agitation in a patient on antidepressants: serotonin syndrome.^[7]
• Pink or red urine, dysuria and rising creatinine during cyclophosphamide or ifosfamide: haemorrhagic cystitis; the drug damages bladder mucosa via its acrolein metabolite.^[14]
• Hyperthermia, tachycardia and rising end-tidal CO2 after halothane, enflurane, isoflurane, desflurane or sevoflurane, or succinylcholine: malignant hyperthermia. Stop triggers, give dantrolene.^[4]
• Agranulocytosis weeks after starting clozapine or propylthiouracil: stop immediately, start protective isolation and granulocyte colony-stimulating factor.^[7]

ACE inhibitors cause cough, hyperkalaemia, hypotension and angioedema. The cough is dry, persistent and related to bradykinin accumulation; it settles when the drug is stopped. Angioedema can involve the tongue, lips and larynx and is an airway emergency. ACE inhibitors are avoided in pregnancy and in bilateral renal artery stenosis.^[5]

Amiodarone is a class III antiarrhythmic with a full month or more of tissue accumulation. Adverse effects include pulmonary toxicity (often after months), thyroid dysfunction (hypothyroidism and thyrotoxicosis), hepatic injury, corneal microdeposits, photosensitivity and a slate-grey skin discoloration. It also interacts with many other drugs and can prolong the QT interval.^[5]

Digoxin has a narrow therapeutic window. Toxicity produces nausea, vomiting, diarrhoea, confusion, visual disturbance (including yellow-green vision) and almost any arrhythmia. Risk rises with renal impairment, dehydration, hypokalaemia, hypomagnesaemia, concomitant amiodarone and macrolide or tetracycline antibiotics. The serum digoxin level should be interpreted with the clinical picture, not in isolation.^[5]

Nitrates act mainly as venodilators. Common effects are dose-related headache, flushing, dizziness, orthostatic hypotension, syncope and reflex tachycardia.^[2] Headache within the first hour is common and usually fades with time; about 10% of patients cannot tolerate higher doses because of headache.^[2] Tolerance develops within 12 to 24 hours of continuous exposure; a nitrate-free interval of at least 8 to 10 hours restores response. Nitrates are absolutely contraindicated with phosphodiesterase-5 inhibitors.^[2]

Hydralazine is associated with a dose-related, lupus-like syndrome: arthralgia, fever, rash, pleuritis and positive antinuclear antibodies. Slow acetylators and women are at higher risk. The risk of drug-induced lupus with hydralazine is quoted as 5 to 10% (higher with higher doses and in women).^[6]

Procainamide also causes a lupus-like syndrome, reported in up to 30% of patients on long-term treatment (commonly around 20%), and can cause agranulocytosis and reversible cholestatic liver injury.^[6]

All antimicrobials share two harms: disturbance of bowel flora (nausea, diarrhoea, secondary Candida overgrowth) and Clostridioides difficile infection. C. difficile is most associated with ampicillin or amoxicillin, clindamycin, third-generation cephalosporins and fluoroquinolones.^[1]

Aminoglycosides are nephrotoxic and ototoxic. Renal impairment mandates dosing by serum levels and creatinine clearance. Cochlear damage may be irreversible; vestibular damage presents as vertigo and ataxia.^[1]

Chloramphenicol can cause a dose-related, reversible bone-marrow suppression and a rare, usually fatal, irreversible aplastic anaemia. It is now largely restricted to serious infections where safer drugs cannot be used.^[1]

Fluoroquinolones carry a boxed warning for tendon rupture (especially over 60 years or with concurrent corticosteroids), irreversible peripheral neuropathy, central nervous system effects, dysglycaemia and disruption of aortic wall (abdominal aortic aneurysm or dissection). They also prolong the QT interval. Ciprofloxacin and levofloxacin have an important C. difficile risk.^[1]

Isoniazid can cause hepatotoxicity and a peripheral neuropathy due to pyridoxine (vitamin B6) depletion; pyridoxine is given to prevent the neuropathy. Rifampicin induces hepatic cytochrome P450 enzymes, causes orange discoloration of body fluids and commonly causes drug interactions (warfarin, oral contraceptives). Both isoniazid and rifampicin can precipitate drug-induced lupus.^[6]

Tetracyclines (including doxycycline) are associated with photosensitivity, oesophageal ulceration, teratogenicity (permanent dental discoloration in children under 8 years and in late pregnancy) and intracranial hypertension. Minocycline has a higher rate of vertigo, ataxia and drug-induced lupus-like reactions than doxycycline.^[1]

Vancomycin is nephrotoxic, especially over 65 years, and can cause "red man" flushing and hypotension with rapid infusion. Linezolid is a weak monoamine oxidase inhibitor and can precipitate serotonin syndrome with serotonergic drugs; it also causes myelosuppression and peripheral or optic neuropathy with prolonged use.^[1]

Metronidazole causes a metallic taste, nausea, seizures and reversible peripheral neuropathy with prolonged use, and a disulfiram-like reaction with alcohol.^[1]

Antipsychotics share extrapyramidal features (acute dystonia, akathisia, parkinsonism, tardive dyskinesia) and metabolic effects (weight gain, dyslipidaemia, diabetes). Neuroleptic malignant syndrome is rare (roughly 0.01 to 0.02%) but life-threatening, with hyperthermia, rigidity and a raised creatine kinase.^[7] First-generation agents carry the highest extrapyramidal risk; second-generation agents carry the highest metabolic risk.

Clozapine is reserved for treatment-resistant schizophrenia because it can cause agranulocytosis (typically in the first 18 weeks) and myocarditis, often in the first month. It also carries a till-then-undiscovered risk of bowel hypomotility and of laryngospasm or collapse with benzodiazepine co-administration. Full blood count monitoring is mandatory throughout treatment and for four weeks after stopping.^[7]

Benzodiazepines are central nervous system depressants with a high therapeutic index alone, but they potentiate alcohol, opioids and other sedatives and can cause respiratory depression, cognitive impairment (especially in older adults), paradoxical agitation, tolerance and a withdrawal syndrome that includes seizures.^[9] Overdose rarely causes death alone but commonly does so in mixed overdose; flumazenil is not recommended routinely because it can precipitate seizures.^[9]

Carbamazepine causes dose-related diplopia, ataxia, dizziness, hyponatraemia (especially in older adults) and a rash that can progress to Stevens-Johnson. It also causes blood dyscrasias and interacts with many drugs through hepatic enzyme induction. Carbamazepine shares the HLA-B*1502-related Stevens-Johnson risk in some Asian populations.^[10]

Lithium has a narrow therapeutic index (serum level 0.4 to 1.2 mEq per L, with 0.8 to 1.2 mEq per L in some product labelling; toxicity features usually appear above 1.5 mEq per L). Acute toxicity begins with vomiting and diarrhoea and progresses to tremor, ataxia and seizures; chronic toxicity presents mainly with neurological features. Lithium reduces renal water handling (nephrogenic diabetes insipidus), raises creatinine and TSH, and accumulates with dehydration, renal impairment, thiazide diuretics, ACE inhibitors and NSAIDs.^[7]

MAOIs (phenelzine, tranylcypromine, isocarboxazid, selegiline) interact with tyramine-rich foods and sympathomimetic drugs to cause a potentially fatal hypertensive crisis, and with serotonergic drugs to cause serotonin syndrome. A two-week washout (five weeks after fluoxetine) is required between a MAOI and an SSRI or SNRI. Tyramine sensitivity is triggered by as little as 8 to 10 mg of ingested tyramine in a patient on a MAOI.^[8]

Phenytoin causes dose-related ataxia, nystagmus, dysarthria, gum hyperplasia, hirsutism, megaloblastic anaemia (folate antagonism) and serious hypersensitivity such as DRESS and Stevens-Johnson. It is embryotoxic and can precipitate the fetal hydantoin syndrome. Chronic phenytoin toxicity also produces cerebellar degeneration.^[10]

SSRIs are generally well tolerated but can cause gastrointestinal upset, sexual dysfunction, insomnia and, in older adults, hyponatraemia. Serotonin syndrome presents with mental confusion, autonomic instability and neuromuscular hyperactivity and can occur with SSRI monotherapy in overdose or with interacting drugs.^[8]

Tricyclic antidepressants are dangerous in overdose: anticholinergic features, hypotension, seizures and cardiac conduction abnormalities (QRS widening) can progress to ventricular arrhythmias. Their anticholinergic effects are proportionally severe in older adults. Amitriptyline and imipramine also lower the seizure threshold.^[8]

Valproate causes dose-related tremor, weight gain, hair loss, hepatotoxicity (especially in infants, combined therapy or mitochondrial disease) and teratogenicity; it is generally avoided in women who may become pregnant. Pancreatitis and hyperammonaemic encephalopathy are recognised complications; thrombocytopaenia and gastrointestinal upset also occur.^[10]

Metformin is usually well tolerated. Common problems are nausea, diarrhoea and a metallic taste early in treatment. Lactic acidosis is rare (about 9 per 100,000 person-years in some series, and roughly 2.4 to 4.3 per 100,000 person-years in meta-analyses and cohort studies) and occurs almost exclusively with severe renal, hepatic or cardiorespiratory disease, or iodinated contrast injury. Metformin is contraindicated with a serum creatinine at or above 1.5 mg per dL in men or 1.4 mg per dL in women, and it should not be initiated when eGFR is below 45 mL per minute per 1.73 square metres.^[15][16] Vitamin B12 deficiency occurs in 10 to 30% of long-term users.^[11]

Corticosteroids cause, among others, osteoporosis and fragility fractures, hyperglycaemia, hypertension, weight gain, proximal myopathy, cataract and glaucoma, psychiatric disturbance and reactivation of infection. Axis suppression is unpredictable and develops with prolonged exposure; risk and recovery vary with dose, duration and patient factors. Up to 40% of patients on long-term treatment develop bone loss leading to fracture. Adverse effects are dose- and time-dependent.^[12]

Statins can cause myopathy; rhabdomyolysis is reported in about 1 to 3 cases per 100,000 patient-years and occurs more readily with high doses, renal impairment or interacting drugs (gemfibrozil raises the risk considerably compared with fenofibrate). Asymptomatic transaminase elevations occur in 0.5 to 2% of patients. Statins also increase the incidence of new-onset type 2 diabetes modestly. Fibrates cause dyspepsia, gallstones and myopathy; niacin causes flushing (up to 25% of patients discontinue because of it) and can worsen glycaemia.^[13]

Propylthiouracil carries a black-box warning for severe hepatocellular injury, which is more common and more severe than with methimazole. Agranulocytosis occurs in 0.2 to 0.5% of patients, more often in the first 3 months. PTU can also cause ANCA-positive small-vessel vasculitis and, rarely, hypothyroidism. Methimazole is usually preferred except in the last trimester of pregnancy or with methimazole intolerance.^[10]

Cisplatin causes acute kidney injury in 25 to 30% of patients despite forced diuresis; it also causes magnesium and potassium wasting, neurotoxicity in stocking-and-glove pattern, ototoxicity and severe nausea.^[14]

Doxorubicin causes a cumulative, dose-dependent cardiomyopathy. The incidence of congestive heart failure rises steeply above 550 mg per square metre; below 400 mg per square metre it is about 0.14%. Acute toxicity appears as arrhythmias and ECG changes that usually resolve.^[14]

Methotrexate causes mucositis, myelosuppression, nephrotoxicity from intratubular precipitation and, in high-dose or intrathecal use, neurotoxicity and leukoencephalopathy. Folinic acid (leucovorin) rescue is used after high-dose therapy.^[14]

Vincristine is a vinca alkaloid whose dose-limiting toxicity is neurotoxicity: peripheral and autonomic neuropathy, with constipation, ileus, orthostatic hypotension and cranial nerve palsies. Myelosuppression is uncommon with vincristine alone.^[14]

Cyclophosphamide is associated with haemorrhagic cystitis from its acrolein metabolite, alopecia, myelosuppression, cardiotoxicity at high dose and dose-related infertility. Mesna, forced diuresis and hyperhydration prevent most renal and bladder toxicity.^[14]

Azathioprine causes dose-dependent bone-marrow suppression, hepatotoxicity, pancreatitis (more common in women with Crohn disease and usually within 6 weeks), and infection, especially with concurrent corticosteroids. Thiopurine methyltransferase deficiency greatly increases the risk of myelosuppression. Pretreatment testing and regular full blood count and liver function tests are essential.^[7]

Mycophenolate is associated with gastrointestinal upset, myelosuppression, infection and, importantly, teratogenicity; it should be avoided in pregnancy. Liver injury, when it occurs, is usually mild and self-limiting.

Halothane produces two forms of hepatotoxicity: type 1 (a transient, self-limiting aminotransferase rise in 20 to 30% of patients) and type 2 (immune-mediated fulminant hepatitis, with fatal cases occurring in approximately 1 in 35,000 single exposures (range 1 in 15,000 to 1 in 35,000 reported for initial exposure) and approximately 1 in 1,000 after multiple exposures; about 50% mortality once acute liver failure develops). Halothane also sensitises the myocardium to catecholamines. Other halogenated anaesthetics produce similar, though much rarer, hepatotoxicity.^[3]

Succinylcholine is a depolarising neuromuscular blocker. Its important adverse effects are hyperkalaemia (dangerous in burns, crush injury or prolonged immobilisation), prolonged apnoea in pseudocholinesterase deficiency, and triggering of malignant hyperthermia (with all the halogenated anaesthetics). Malignant hyperthermia is treated with dantrolene (2.5 mg per kg intravenously in many references, repeated to response, up to 10 mg per kg; product labelling for RYANODEX uses an initial intravenous dose of 1 mg per kg with additional boluses to a 10 mg per kg cumulative maximum), plus cooling and supportive care; arrhythmias are treated with amiodarone and calcium channel blockers are avoided.^[4]

Loop diuretics (furosemide) cause electrolyte depletion (hypokalaemia, hyponatraemia, hypomagnesaemia), dehydration, hyperuricaemia and gout, hyperglycaemia, ototoxicity (especially with aminoglycosides or renal impairment), and can precipitate hepatic encephalopathy in cirrhosis. A box warning highlights rapid diuresis and electrolyte loss.

Thiazides (hydrochlorothiazide) cause hypokalaemia, hyponatraemia (particularly in older adults), hyperuricaemia and gout, hyperglycaemia, dyslipidaemia and, rarely, photosensitivity rash, acute angle-closure glaucoma and sulphonamide-type hypersensitivity reactions.

The most important step is to stop the drug when a serious reaction is suspected, without waiting for laboratory confirmation. For self-limiting type A reactions (nausea, transient headache), a dose reduction, slower titration or a different formulation is usually enough. For idiosyncratic reactions, re-exposure should be avoided permanently and the reaction recorded in the patient's notes and on the discharge summary.

• ACE-inhibitor angioedema: stop the drug, secure the airway, and consider adrenaline, antihistamines and corticosteroids as for anaphylaxis. ARBs are not a guaranteed safe substitute after ACE-inhibitor angioedema and are best avoided or used only with clear justification and close monitoring.^[5]
• Serotonin syndrome and NMS: stop the offending agents, give benzodiazepines, cool the patient and support organs; cyproheptadine can be used for moderate to severe serotonin syndrome.^[7]
• Lithium toxicity: stop lithium, restore volume with saline and monitor electrolytes and renal function. Haemodialysis is indicated at very high levels or with neurological deterioration.^[7]
• Drug-induced liver injury: stop the suspected drug; most cases recover, but acute liver failure needs specialist hepatology and possibly transplantation.^[3]
• Statin myopathy: stop the statin, check creatine kinase and renal function; re-challenge with a different statin or a lower dose once recovered, and consider CK monitoring thresholds.^[13]
• Anticoagulation-related drug interactions and dosing should always be checked against the manufacturer's or local formulary information.
• Flumazenil should not be given routinely in benzodiazepine overdose because of seizure risk.^[9]

Refer urgently when the reaction threatens the airway, breathing, circulation or a vital organ (angioedema, malignant hyperthermia, NMS, serotonin syndrome, fulminant hepatic failure, severe DRESS or Stevens-Johnson, agranulocytosis, arrhythmia). Refer for specialist advice when the drug is essential and cannot easily be substituted (lithium, antiepileptics, clozapine). Record any suspected reaction and report it to the national pharmacovigilance scheme. All of the drugs in this presentation are best managed with close collaboration between the prescribing clinician, pharmacy and the relevant specialist team.

In low-resource environments the most useful practice is:

• Keep a short printed formulary that lists, for each commonly used drug, its single most dangerous reaction and its first action.
• Do not prescribe a drug if you cannot monitor the reaction it is known for (for example, do not start clozapine without reliable access to neutrophil counts).
• For organ failure that is beyond the local facility, stop the drug, resuscitate and transfer early rather than wait for complete certainty.
• Educate patients starting long-term therapy (corticosteroids, isoniazid, metformin, amiodarone) about the warning symptoms and when to return.

• A useful, dangerous reaction for each drug class is usually one or two: ACE inhibitors (angioedema), amiodarone (pulmonary and thyroid toxicity), digoxin (arrhythmia), nitrates (headache, hypotension, tolerance), hydralazine and procainamide (lupus-like syndrome), fluoroquinolones (tendon and neuropathy), isoniazid (hepatitis, B6 depletion), tetracyclines (photosensitivity, teratogenicity), antipsychotics (EPS, NMS, metabolic syndrome), clozapine (agranulocytosis), lithium (narrow index, nephrotoxicity), MAOIs (tyramine crisis), SSRIs (serotonin syndrome in overdose), tricyclics (cardiac toxicity in overdose), valproate (hepatotoxicity, teratogenicity), metformin (lactic acidosis in renal or hepatic failure), corticosteroids (bone loss, hyperglycaemia, suppression), statins (myopathy), cisplatin (renal toxicity), doxorubicin (cardiomyopathy), halothane (hepatitis), succinylcholine (malignant hyperthermia), and diuretics (electrolyte disturbance).
• Always take a drug history that includes timing, dose and any non-prescription or herbal products.
• Stop the suspected drug first in a serious reaction; do not wait for laboratory proof.
• Prefer dose-related type A reactions are preventable with slow titration, monitoring and renal adjustment.
• Record and report adverse reactions to prevent re-exposure.
• Where guidelines or sources differ, state the range and the clinical context rather than authorising a single number.

None of the following topics are present in the repository's verified topic list yet: hypertensive emergencies, hyperkalaemia management, transfusion reactions, poisoning with specific agents. They should be linked once they are written.