3 Clinical psychopharmacology3.4 Therapeutics

3.4.5.4 Physical co morbidities

3 min read2 figures

Written by Resident Doctor Committee · Published

Liver disease

  • Reduced first-pass metabolism and portosystemic shunting raise oral drug exposure, and low albumin and fluid retention alter drug handling further.

  • Transaminases show liver injury, not liver function; bilirubin, albumin, international normalised ratio, ascites and encephalopathy show function, and the Child-Pugh score combines them.

  • Sedatives and constipating drugs can worsen hepatic encephalopathy.

Class

Preferred

Avoid

Antipsychotics

Amisulpride, sulpiride, if renal function is preserved

Most others, which need hepatic cytochrome P450 (CYP) metabolism

Antidepressants

Sertraline, started at a reduced dose and titrated slowly

Agomelatine, duloxetine

Benzodiazepines

Lorazepam, oxazepam, temazepam

Chlordiazepoxide, diazepam

  • Substituted benzamides (amisulpride, sulpiride) undergo minimal hepatic metabolism and are cleared mainly unchanged by the kidneys.

  • Agomelatine is contraindicated because it is hepatotoxic, and it needs liver function monitoring.

  • Some antidepressants, such as duloxetine, carry an outright UK licence contraindication in liver disease; other hepatically cleared ones need only a lower dose, a dose ceiling or caution.

  • Glucuronidated benzodiazepines form no active metabolites and are preferred in severe liver disease and alcohol withdrawal, because conjugation is relatively preserved.

  • Oxidised benzodiazepines accumulate, with long-lived active metabolites.

Diazepam and chlordiazepoxide pass through oxidative steps to desmethyldiazepam, a long half-life active metabolite, whereas lorazepam, oxazepam and temazepam are glucuronidated to inactive products, which is why they are preferred in severe liver disease. Drawn for MRCPsychiatrist

Kidney disease

  • Parent drugs or active metabolites accumulate, and creatinine-based estimates are less reliable with low muscle mass or unstable kidney function.

Drug

Advice in renal impairment

Amisulpride, sulpiride

Excreted largely unchanged, so they accumulate; best avoided in established renal failure

Risperidone

Partly renally cleared, so reduce the dose

Hepatically cleared antipsychotics

Low starting dose only

Sertraline

Preferred antidepressant in chronic kidney disease (CKD), with the best support, even when the corrected QT interval (QTc) is at the upper limit of normal

Agomelatine

Set aside for lack of renal data

Duloxetine

Avoid when creatinine clearance is below 30 mL/min

Lithium

Avoid, especially with an angiotensin-converting enzyme (ACE) inhibitor

Valproate

NICE's preferred long-term alternative to lithium for preventing manic relapse in severe CKD

  • Lithium has a narrow therapeutic range and depends on renal excretion linked to sodium handling; ACE inhibitors cut its clearance further.

  • Dehydration, sodium depletion, non-steroidal anti-inflammatory drugs, diuretics and angiotensin receptor blockers also raise the risk of lithium toxicity.

  • Lithium toxicity (coarse tremor, vomiting, ataxia, dysarthria, confusion) can occur at a modest level; withhold lithium, check a level and seek urgent help.

  • Lamotrigine protects against depressive rather than manic relapse, so it does not replace lithium for preventing mania.

With a narrow therapeutic window like lithium's, the same modest rise in level (dashed line) that stays safe for a wide-window drug crosses into the toxic range, which is why toxicity can occur at a modest level. Drawn for MRCPsychiatrist

Heart and lung disease

  • Sertraline has the best safety evidence for depression after myocardial infarction, being neutral on conduction, QTc, blood pressure and heart rate; another selective serotonin reuptake inhibitor (SSRI) prolongs the QTc dose-dependently.

  • Tricyclic antidepressants are often unsuitable in heart disease because of their effects on conduction.

  • Correct electrolytes and review interacting drugs before adding a drug that prolongs the QTc.

  • SSRIs combined with antiplatelets or anticoagulants raise bleeding risk.

  • In chronic obstructive pulmonary disease, an SSRI such as sertraline is the default first antidepressant, avoiding the anticholinergic, sedative and cardiovascular burden of other classes.

  • Sedating antidepressants such as mirtazapine and trazodone are unwelcome when the patient retains carbon dioxide.

Diabetes and metabolic disease

  • An SSRI, fluoxetine being the best studied, is preferred for depression in type 2 diabetes because it is weight-neutral and does not worsen glycaemic control.

  • Mirtazapine, amitriptyline and quetiapine lack these advantages, and monoamine oxidase inhibitors carry hypoglycaemia and interaction risks.

  • Duloxetine holds a UK licence for both major depression and diabetic peripheral neuropathic pain.

  • In the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), about two in five adults with chronic, previously treated schizophrenia met metabolic syndrome criteria at baseline.

  • The rate was about 41% by the National Cholesterol Education Program Adult Treatment Panel III criteria and about 43% by the American Heart Association definition.

Parkinson's disease and hyponatraemia

  • Low-dose quetiapine is the best-tolerated antipsychotic for Parkinson's disease psychosis that persists after reversible causes are treated and anti-parkinsonian drugs reduced.

  • Quetiapine causes fewer extrapyramidal effects because its striatal dopamine D2 blockade is weak and loosely bound.

  • Clozapine improves water balance and raises plasma osmolality in hyponatraemia, so it is the preferred switch when antipsychotic-associated syndrome of inappropriate antidiuretic hormone secretion complicates schizophrenia.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.