3.3.4.1 From general pharmacology

Adverse drug reactions

• A Type A adverse drug reaction (Rawlins and Thompson) is predictable from the drug's known actions, so it is usually dose-related and common.

• A drug's receptor profile predicts its adverse effects better than the label first-generation or second-generation.

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Histamine H1 blockade

• H1 antagonism causes sedation, as with quetiapine under 100 mg and mirtazapine at 15 mg.

• D2 blockade drives the antipsychotic effect, not the sedation.

• Combined depressants, especially opioids with benzodiazepines, add to sedation. Bedtime dosing may help, and tolerance may develop.

Alpha-1 adrenoceptor blockade

• Priapism lasting over four hours needs urgent urological treatment.

• Postural hypotension is likeliest at initiation, rapid titration and restarting after a break. Clozapine stopped for more than two days is restarted at 12.5 mg once or twice on the first day.

• Lying and standing blood pressure is measured, including at three minutes after standing.

Muscarinic blockade

• Urinary retention comes from M3 blockade of the detrusor and is worse with prostatic enlargement.

• Clozapine hypersalivation affects a third or more of patients and is worst at night. It results from M4 agonism, alpha-2 antagonism and impaired swallowing.

Dopamine D2 blockade and prolactin

• D2 antagonism at the pituitary raises prolactin, causing galactorrhoea, amenorrhoea and sexual dysfunction. Sustained hyperprolactinaemia also harms bone health.

• Risperidone and amisulpride raise prolactin most because they cross the blood-brain barrier poorly, and the pituitary lies outside the barrier. Sulpiride also raises it.

• Aripiprazole spares prolactin through partial D2 agonism, so it has the lowest liability for antipsychotic sexual dysfunction.

Serotonergic effects of antidepressants

• Venlafaxine acts mainly on serotonin reuptake at 75 mg and adds substantial noradrenaline reuptake inhibition from about 150 mg, causing sweating and rising blood pressure.

Serotonin syndrome

• Serotonin syndrome starts rapidly after a serotonergic drug is started, increased or combined, for example tramadol with sertraline. It is driven mainly by 5-HT2A stimulation.

• Its three features are altered mental state, autonomic overactivity (sweating, fever, mydriasis, diarrhoea) and neuromuscular excitation with clonus and hyperreflexia.

• Thyrotoxicosis predisposes to NMS, as do iron deficiency, dehydration, exhaustion and heat exposure.

Sexual dysfunction

• Drugs can impair desire, arousal, erection, lubrication, orgasm or ejaculation. Patients often hide it from embarrassment, so ask directly at initiation and review.

• SSRI sexual dysfunction is presumed to follow 5-HT2 stimulation, so 5-HT2 blockers such as mirtazapine and cyproheptadine spare or relieve it.

• Paroxetine has the highest rate among SSRIs. Its short half-life explains dizziness and electric-shock sensations after missed doses.

• Carbamazepine induces cytochrome P450 enzymes and raises sex hormone-binding globulin, leaving less free testosterone, so libido and erection fall.

• Dose reduction or switching is weighed against losing treatment benefit, and patients are advised not to skip doses unsupervised.

Phosphodiesterase type 5 (PDE5) inhibitors

• PDE5 inhibitors stop cyclic guanosine monophosphate (cGMP), made in response to nitric oxide, being broken down, so smooth muscle in the corpus cavernosum stays relaxed longer.

• Adding a PDE5 inhibitor is the evidence-based targeted treatment for SSRI-induced erectile dysfunction when the patient wants to stay on an effective SSRI.

• Headache is the commonest adverse effect of sildenafil and the only very common one (more than 1 in 10), because PDE5 inhibition dilates vessels everywhere.

• Flushing, nasal congestion and dyspepsia are less frequent, and nitrates are contraindicated.

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Weight gain and metabolic effects

• H1 affinity best predicts an antipsychotic's weight-gain liability. Mirtazapine and olanzapine are strongly H1 blocking.

• Clozapine has the highest weight-gain liability of the antipsychotics, and olanzapine is also high.

• Aripiprazole has low liability as a partial D2 agonist with little H1 or 5-HT2C blockade. It suits patients already obese or near diabetic, and switching to it is expected to reduce weight.

• Lurasidone also carries lower metabolic risk.

• Adding aripiprazole to clozapine or another weight-inducing antipsychotic lowers weight and lipids in controlled trials when the causative drug must continue.

• Second-generation antipsychotics can cause new hyperglycaemia or diabetes, sometimes without matching weight gain. Polyuria, thirst and weight loss call for a plasma glucose test.

• Weight gain starts early, especially in young, previously untreated patients.

• Baseline checks are weight, body mass index, waist, pulse, blood pressure, glucose or HbA1c, and lipids.

• Weight is measured weekly for six weeks, then at 12 weeks, one year and annually.

• Metformin is one evidence-based treatment, and hypertension, dyslipidaemia and diabetes are treated directly.

Other predictable effects

Cytochrome P450 interactions

• Enzyme inhibition raises a co-prescribed drug's level: fluvoxamine inhibits CYP1A2 and raises clozapine levels, causing sedation, hypersalivation and seizures.

• Enzyme induction lowers it: St John's wort induces CYP3A4, so ethinylestradiol and progestogen are cleared faster and the pill may fail, with breakthrough bleeding first.

• Induction lasts about four weeks after St John's wort is stopped.

The QT interval

• The QT interval runs from the onset of the QRS complex to the end of the T wave, covering ventricular depolarisation and repolarisation.

• Bazett's formula is QTc = QT / square root of RR, with RR in seconds. When RR is under one second, the QTc is longer than the raw QT.

• Fridericia's formula uses the cube root of RR and is often preferable in tachycardia.

• The upper limit of normal QTc is 440 ms in adult men and 470 ms in adult women.

• hERG potassium channel blockade delays repolarisation and lengthens the QT.

• Torsades de pointes is a polymorphic ventricular tachycardia complicating QT prolongation. It often self-terminates, causing faints, but may degenerate into ventricular fibrillation.

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Risk factors for drug-induced prolongation

• Female sex, old age, ischaemic heart disease, left ventricular hypertrophy, bradycardia, congenital long QT and anorexia raise risk. Male sex does not.

• Low magnesium, potassium or calcium raise risk and are corrected, especially with vomiting, diuretics or eating disorders.

Action bands in antipsychotic treatment

Decisions use the QTc, not the raw QT, on an electrocardiogram (ECG).

• A rise of more than 60 ms from baseline also warrants urgent review.

Antipsychotics

• Pimozide needs an ECG before starting and at intervals, and CYP3A4 inhibitors such as clarithromycin must be avoided because they raise its levels.

Antidepressants

Antidepressants prolong the QTc more as dose and plasma concentration rise, so overdose carries the most cardiac risk.

• Citalopram has been capped by the Medicines and Healthcare products Regulatory Agency since 2011 at 40 mg a day, or 20 mg over 65 or with hepatic impairment.

• Escitalopram is capped at 20 mg a day, or 10 mg over 65 or with hepatic impairment.

Other ECG changes