3 Clinical psychopharmacology3.3 Pharmacodynamics
3.3.4.3 Idiosyncratic toxic and allergic reactions
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Written by Resident Doctor Committee · Published
Type A and type B reactions
Type | What it is | Dose | Predictable |
|---|---|---|---|
A | An extension of the drug's known pharmacology, such as alpha-1-mediated hypotension | Dose-dependent | Yes, and reversible |
B | Immune-mediated (hypersensitivity) or idiosyncratic, and rare | Unrelated to dose | No |
Drug toxicity is excess drug acting on its usual targets, as in paracetamol overdose, so it is a predictable, dose-related, non-immunological reaction.
Type B reactions may need urgent withdrawal, targeted monitoring and avoidance of re-exposure.
Hypersensitivity reactions
Type | Mechanism | Onset | Drug reactions |
|---|---|---|---|
I | Immunoglobulin E (IgE) on mast cells and basophils triggers degranulation | Minutes after re-exposure | Urticaria, pruritus, angioedema, anaphylaxis |
II | Immunoglobulin G or M binds an antigen fixed on a cell surface, and complement or phagocytes destroy the cell | Hours to days | Haemolytic anaemia, thrombocytopenia, neutropenia |
III | Circulating immune complexes deposit in tissues | One to two weeks | Serum sickness, vasculitis |
IV | T cells, delayed | Days to weeks, peaking at 48 to 72 hours | Exanthem, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) |
Non-allergic hypersensitivity triggers mast cells directly, so it can occur on first exposure, whereas IgE-mediated allergy needs prior sensitisation.
Anaphylaxis with airway, breathing or circulatory compromise is treated first with intramuscular adrenaline.
A mild immediate reaction confined to the skin, without airway, breathing or circulatory compromise, is managed by stopping the drug and giving an oral antihistamine.
Blood dyscrasias
Agranulocytosis means neutrophils below 0.5 x 10^9/L, with a high risk of bacterial and fungal infection.
Drug | Haematological reaction |
|---|---|
Clozapine | Neutropenia and agranulocytosis, concentrated early in treatment and unrelated to dose |
Carbamazepine | Leucopenia in about 1 in 10; agranulocytosis and aplastic anaemia are rare or very rare |
Valproate | Suppressive: anaemia and thrombocytopenia are common, leucopenia and pancytopenia less often |
Carbamazepine carries an established idiosyncratic risk of agranulocytosis, unlike most other mood stabilisers.
Fever, sore throat, mouth ulcers or a flu-like illness need urgent assessment and a current count, and neutropenic fever needs urgent antibiotics.
Clozapine and the white cell count
Clozapine was withdrawn in the mid-1970s after deaths from agranulocytosis, then reintroduced with mandatory blood monitoring after Kane's 1988 trial.
Agranulocytosis affects about 0.8% and neutropenia about 3% of people treated; agranulocytosis is fatal in about 1 in 4,250 (about 2.4 per 10,000).
After a year of normal counts, the residual agranulocytosis risk is about 0.39 per 1,000 patient-years, roughly 0.04% a year.
Reaction | Risk factors besides early treatment |
|---|---|
Agranulocytosis | Older age, female sex, some Asian and Ashkenazi Jewish groups |
Neutropenia | Younger age, Afro-Caribbean ethnicity, low baseline white cell count |
A red result, with white cells below 3.0 x 10^9/L or neutrophils below 1.5 x 10^9/L, means stopping clozapine at once.
A past red result normally rules out any re-exposure, because the reaction is idiosyncratic and no change of dose, monitoring, co-medication or brand makes restarting safe.
Clozapine and the heart
Clozapine has the highest fatal toxicity index of the commonly used antipsychotics.
Feature | Myocarditis | Cardiomyopathy |
|---|---|---|
Onset | First weeks, median about 3 weeks | Later, median about 9 months |
Picture | Fever, tachycardia, breathlessness, chest symptoms | Gradual heart failure (orthopnoea, oedema, raised jugular venous pressure, cardiomegaly) with normal inflammatory markers |
Confirming test | Troponin I | Echocardiography |
Myocarditis gives widespread concave, saddle-shaped ST elevation across several territories, without territorial reciprocal change, on the electrocardiogram.
Troponin I has a cardiac-only isoform, so it is the most specific and sensitive marker of myocardial injury and the urgent test for suspected myocarditis.
Common protocols stop clozapine when troponin exceeds twice the upper limit of normal or C-reactive protein exceeds 100 mg/L.
Cardiomyopathy is managed by stopping clozapine and referring to cardiology.
Other antipsychotic reactions
Neuroleptic malignant syndrome is an idiosyncratic reaction to antipsychotic dopamine blockade, with hyperthermia, sweating, autonomic instability and a very high creatine kinase, escalating over days.
Its rigidity is uniform and lead-pipe, with normal reflexes and no clonus.
Abruptly stopping an anticholinergic (antiparkinsonian) drug in a patient on an antipsychotic can precipitate it.
Post-injection delirium and sedation syndrome is a rare, non-allergic reaction to olanzapine embonate long-acting injection that resembles olanzapine overdose.
It mostly starts within the first hour, follows under 0.1% of injections and carries the same risk with every dose.
Liver reactions
Transaminases rise in hepatocellular injury, and alkaline phosphatase and gamma-glutamyl transferase in cholestatic injury; transaminases reflect injury, not function.
A mild, asymptomatic transaminase rise on valproate needs a prothrombin time or international normalised ratio, which tests synthetic function and decides whether valproate can continue.
Drug | Liver reaction |
|---|---|
Valproate | Mild enzyme rises or rare severe injury, especially in young children and mitochondrial disease |
Carbamazepine | Often part of a hypersensitivity reaction |
Agomelatine | Dose-related hepatotoxicity; tests at baseline and about 3, 6, 12 and 24 weeks, and again after a dose increase |
Chlorpromazine | Classically cholestatic |
Skin reactions
Stevens-Johnson syndrome (SJS) involves under 10% epidermal detachment, toxic epidermal necrolysis (TEN) over 30%, and overlap 10 to 30%; TEN has substantial mortality.
Lamotrigine is the mood stabiliser most associated with SJS and TEN, which are rare but can be fatal and arise in the first weeks of treatment.
Rash is very common with lamotrigine and occasionally progresses to SJS or TEN.
Risk rises with a high starting dose, fast escalation and valproate co-prescription, so lamotrigine is titrated slowly and patients report any new rash.
A new rash means stopping lamotrigine unless it is clearly unrelated.
Drug | Other skin reactions |
|---|---|
Carbamazepine | SJS and TEN linked to human leucocyte antigen B*15:02, tested according to ancestry |
Chlorpromazine | The classic cause of photosensitivity, as a low-potency phenothiazine; also pigmentation |
Lithium | Induces or worsens psoriasis, including pustular, nail and arthropathic forms, at therapeutic levels |
Acute porphyria
Acute porphyria presents soon after a porphyrinogenic psychotropic is started, with severe abdominal pain but a benign abdomen, constipation, autonomic overactivity, proximal motor weakness and hyponatraemia.
Carbamazepine is the psychotropic most likely to precipitate an attack of acute intermittent porphyria.
Chlorpromazine is regarded as safe and is used during attacks.