NON-NEUROLOGICAL SIDE EFFECTS OF ANTIPSYCHOTIC MEDICATIONS

BY DR.SHALINI PERUGU03-03-2014

• Sedation• Weight gain• Cardiac effects• Haematological effects• Anti-cholinergic effects• Endocrine effects• Sexual adverse effects• Dermatological effects• Occular effects• Hepatic abnormalities• Pregnancy and lactation

Sedation

• H1 histamine block• Histaminergic neurons-posterior

hypothalamus-project to cortex, thalamus , pre optic and anterior hypothalamus , substantia innominata,dorsal pontine tegmentum and raphe dorsalis-important in sleep wake cycle

• Low potency drugs.• Chlorpromazine is most sedating typical

antipsychotic drug.• Bedtime dose.• Switch to anti psychotics with less

sedation(pimozide,fluphenazine,thithixene).

WEIGHT GAIN

• H1 receptor block in venteromedial nucleus of hypothalamus- disinhibits AMPK-(-)POMC-(-) Alfa MSH-increased food intake

• 5HT2C receptor block-(-)POMC-(-)Alfa MSH-increased food intake

• Dopamine D2 block-hyperprolactinemia-decrease insulin sensitivity and increase fat deposition

• Body weight at 4-week intervals and then quarterly• Waist circumference baseline and annually• Olanzepine –most frquently associated with weight

gain• Nutritional or dietary changes• Switching of antipsychotics• SSRI’s• Topiramate-downregulation of NPY receptors• Amantidine-blocks dopamine reuptake• Orlistat-inhibits absorption of fat from GIT

Cardiac effects

• Orthostatic hypotension• QT prolongation• Sudden cardiac death

Orthostatic hypotension

• Alfa-1 adrenergic block• Inhibit vasoconstriction initiated by

baroreceptor reflex• Occurs more frequently during first few days

of treatment• Tolerance

• Low potency drugs• Chlorpromazine,thioridazine,chlorprothixene• Rise slowly after sitting or reclining• Avoid caffeine and alcohol• 2 litres of fluid per day• Increase salt in diet• Foot-end elevation• Norepinephrine,metaraminol• Avoid epinephrine-paradoxical hypotension

QT PROLONGATION

• Blockade of delayed potassium rectifier channels(IKr)

• Prevents outflow of potassium-prolonged depolarisation-QT prolongation

• Dose dependent-serum levels• Torsades de pointes-sudden cardiac death

• Thioridazine – Tdp• Atypical antipsychotics-

Ziprasidone,Quetiapine• >500ms-QT prolongation• Baseline ECG and serum potassium levels and

serum magnesium levels• Periodic evaluation of ECG and s.potassium

levels

Haematologic effects

• Leukopenia (mostly neutropenia- < 1.500/micro L)

• Agranulocytosis - < 0.500/micro L• Thrombocytopenia-< 100.00/micro L• Anemia- < 4 million/micro L,hemoglobin-

<12g/dl• Pancytopenia • Mortality rate high (30%)

• Neutropenia is more common• Occurs in 1-2 wks of treatment• Agranulocytosis-reported with clozapine• Occurs within 3-4 wks of treatment• Transient neutropenia-persists for 2-5 days

and then subsides• Bone marrow supression and peripheral

destruction of neutrophils

• Clozapine-oxidation-nitrenium ions-oxidative stress induced neutrophil apoptosis

• Nitrenium ions-react with neutrophil proteins-hapten formation-antineutrophil antibodies

• WBC count to be monitored weekly for 18 wks then quarterly upto 1 year and then annually

• Look for signs and symptoms of infection-fever,sore throat etc.

• G CSF,GM CSF- filgrastim,silgramostim

Anticholinergic effects

• Dry mouth• Blurred vision• Constipation• Urinary retension• Mydriasis• Diabetes

• Muscarinic MI block-smooth muscle relaxation,spincter contraction and decreased secretions from salivary glands.

• Muscarinic M3 block-impaired glucose tolerence and reduced insulin secretion from pancreatic beta cells

• Clozapine-causes drooling of saliva-spasm of neck muscles

• Low potency antipsychotics-chlorpromazine,thioridazine,mesoridazine

• Constipation-laxatives• Pilocarpine-paralytic ileus• Bethanechol – 20 to 40 mg/day for urinary

retention

ENDOCRINE EFFECTS

• Hyperprolactinemia-D2 block in tuberoinfundibular pathway

• Hyperglycemia-due to insulin resistance

SEXUAL ADVERSE EFFECTS• H1 receptor antagonism-sedation-impaired arousal• Dopamine receptor antagonism-inhibition of motivation and

reward-decreased libido• D2 receptor antagonism in tubero infundibular pathway-

hyperprolactinaemia-decreased libido,impaired arousal and orgasm

• Cholinergic receptor antagonism-reduced peripheral vasodilatation-erectile dysfunction

• Alpha adrenergic receptor antagonism-reduced peripheral vasodilatation-decreased erection/lubrication,abnormal ejaculation

• Only 37% of patients report spontaneously• Thioridazine frequently associated• Risperidone among atypical antipsychotics• Aripiprazole –reduces sexual dysfunction in patients

previously treated with other antipsychotics• Aripiprazole-comparable serum prolactin to placebo• Decreasing the dose of anti psychotic• Switching to other anti psychotic with prolactin sparing effect• Phosphodiesterase 5 inhibitors• Hormone replacement therapy

DERMATOLOGICAL SIDE EFFECTS

• Allergic dermatitis• Photosensitivity-chlorpromazine-blue gray

discolouration of exposed skin• First few weeks• Remit spontaneously

• Switch the medication• Not more than 30-60 mins in sun• sunscreen

OCCULAR EFFECTS

• Irreversible retinal pigmentation-thioridazine >1000mg/day

• Pigmentation –progressive even after stoppage of thioridazine-blindness

• Chlorpromazine-benign pigmentation-whitish brown grannular deposits on anterior lens and posterior cornea

• No retinal damage• Resolves on discontinuation

HEPATIC ABNORMALITIES

• 3 mechanisms associated with liver injury -impair bile secretion and lead to cholestasis. seen with phenothiazines(chlorpromazine) -direct toxic effects on hepatocytes -affect indirectly via increased risk of

metabolic syndrome leading to nonalcoholic fatty liver disease

• 32% show abnormal LFT• 4% show clinically significant LFT(>3 fold for

ALT,AST,GGT.>2 fold for ALP)• Transaminases are most frequently elevated• Minimum time-within one week and most

abnormalities occurred within 6 weeks• Hepatic damage resolved despite continuation of

drug,mostly by 1 month-adaptive changes in the hepatocytes-upregulation of antioxidant genes or chaperone protiens

• Baseline LFT• Chlorpromazine causes fatal hepatic damage

by cholestasis.clozapine is most frequently associated with raised transaminases.

• Monitor LFT annually and for clozapine once in 6 months.

• Switch to antipsychotics with less hepatic side effects(sulpiride,amisulpiride)

PREGNANCY AND LACTATION

• Should be avoided in first trimester unless the benefit outweighs the risk

• High potency drugs-preferrable(fluphenazine)• Low potency drugs cause hypotension• Secreted in breast milk-avoid breast feeding

REFERENCES

• COMPREHENSIVE TEXT BOOK OF PSYCHIATRY• KAPLAN AND SADOCK’S SYNOPSIS OF PSYCHIATRY• Haematological toxicity of drugs used in psychiatry-

Robert J.Flanagan and Louisa Dunk• Blood dyscrasias induced by psychotropic drugs-

S.Stubner,R.Grohmann et al• Sexual side effects of antipsychotic drugs-Shivnaveen

Bains and Asim A. Shah• Antipsychotics and abnormal LFT:Systematic review-

Katie F.M.Marwick et al