Antipsychotics

Antipsychotic drugs and antimaniac drugs

1. Antipsychotics & Anti-maniac drugs Dr Naser Tadvi

2. Objectives Classify antipsychotic drugs Explain mechanism of action, therapeutic uses and adverse effects of antipsychotic drugs Describe management of schizophrenia Describe mechanism of action and adverse effects of lithium Enlist other alternatives to lithium in the treatment of mania Describe management of mania and bipolar disorders Dr Naser Ashraf Tadvi 2016

3. Classification of Antipsychotics Phenothiazines Aliphatic side chain: chlorpromazine, triflupromazine Piperidine side chain: Thioridazine Piperazine side chain: Trifluoperazine , fluphenazin e Butyrophenones : Haloperidol, trifluperidol , droperidol , penfluridol Thioxanthenes : Thiothixene , flupenthixol Other heterocyclics : Pimozide , loxapine Atypical antipsychotics: Clozapine , olanzapine , risperidone , quetiapine , aripiprazole , ziprasidone . Dr Naser Ashraf Tadvi 2016

4. Dr Naser Ashraf Tadvi 2016

5. Chlorpromazine Pharmacological actions (CNS) In Normal individuals: Indifference to surrounding , paucity of thought, psychomotor slowing, emotional quietening , reduction in initiative, tendency to go off to sleep from which pt is easily arousable . Spontaneous movements are minimized. This is called neuroleptic syndrome In psychotic patient : ↓ irrational behaviour ,↓ agitation & aggressiveness, relief of anxiety. Corrects disturbed thought & behaviour ↓ spontaneous movements(hyperactivity ) Reduces delusions and hallucinations Dr Naser Ashraf Tadvi 2016

6. The aliphatic & piperidine side chain compounds : low potency more sedation. Sedative effect develops promptly but antipsychotic effect takes weeks to develop. Chlorpromazine lowers seizure threshold can precipitate seizures Hypothermia: temperature control is knocked off at higher doses All neuroleptics except thioridazine have potent antiemetic action Chlorpromazine Pharmacological actions (CNS) Dr Naser Ashraf Tadvi 2016

7. Pharmacological actions ANS : α -adrenergic blocking & anticholinergic property CVS: Postural hypotension, QT prolongation Local anaesthetic action Endocrine: ↑ release of prolactin - galactorrhoea and gynaecomastia Dr Naser Ashraf Tadvi 2016

8. Tolerance & dependence Tolerance to sedative & hypotensive action develops within days or weeks The antipsychotic, extra pyramidal & other actions based on DA antagonism do not show tolerance. Neuroleptics are pleasurably bland drugs Physical dependence is absent though some withdrawal symptoms may be seen No drug seeking behaviour observed Dr Naser Ashraf Tadvi 2016

9. Other typical antipsychotics Triflupromazine : more potent than CPZ, Antiemetic, frequently produces acute muscular dystonias in children Thioridazine : low potency marked, central anticholinergic action. Low incidence of Extra pyramidal reactions. Cardiac arrhythmias & interference with male sexual dysfunction is more common Trifluoperazine , fluphenazine : High potency, minimum autonomic actions. Marked extrapyramidal reactions Dr Naser Ashraf Tadvi 2016

10. Haloperidol: potent, few autonomic effects, less seizure potential , doesn’t cause weight gain, rarely causes jaundice, preferred agent for schizophrenia, acute mania , senile psychoses, acute psychoses, huntingtons disease, tourette syndrome. Penfluridol : exceptionally long acting neuroleptic , recommended for chronic schizophrenia Pimozide : little adrenergic or cholinergic blocking activity , longer Duration of action for several days. Good for maintenance therapy. Low dystonic reactions , more propensity for arrhythmia Dr Naser Ashraf Tadvi 2016 Other typical antipsychotics

11. Atypical antipsychotics Newer second generation antipsychotics have weak D2 but potent 5HT2 antagonist properties. Extrapyramidal side effects are minimal, they may improve impaired cognitive function in psychotics Dr Naser Ashraf Tadvi 2016

12. Clozapine & olanzapine Atypical antipsychotics Mainly block D4 receptors Have weak D2 blocking effect Also block 5 HT2 & alpha-1 receptors Have H1 blocking & anticholinergic Rarely cause EPS Cause sedation & hypotension Dr Naser Ashraf Tadvi 2016

13. Side effects: Clozapine sedation, salivation, seizures, weight gain, hypotension. Dangerous side effect is agranulocytosis , hence regular monitoring of blood counts is essential Olanzapine : Dry mouth , constipation , weight gain rarely EPS No agranulocytosis Uses: Clozapine is reserve drug for treatment of schizophrenia because of risk of agranulocytosis . Olanzapine is used for treatment of schizophrenia & mania associated with bipolar disorder. They supress both positive & negative symptoms of schizophrenia Dr Naser Ashraf Tadvi 2016 Clozapine & olanzapine

14. Risperidone Atypical antipsychotic Blocks D2,5 HT2, ALPHA1 adrenergic, & has antihistaminic activity EPS are rare at low doses No anti-emetic effect Used for treatment of schizophrenia, & short term treatment of mania associated with bipolar disorder Dr Naser Ashraf Tadvi 2016

15. Adverse effects of antipsychotics CNS( Extrapyramidal side effects) Parkinsonism: (more common with haloperidol ) Dystonic Reactions: Bizarre muscle spasms, mostly involving linguo -facial muscles (Grimacing , tongue thursting , torticollis , locked jaw) Akathisia : Restlessness , feeling of discomfort, desire to move Malignant neuroleptic syndrome: muscular rigidity, hyperpyrexia, mental confusion & coma. Treated with IV dantrolene , anticholinergic are of no help. Bromocriptine in large doses found to be useful Tardive dyskinesia : characterized by involuntary & purposeless movements of the mouth, tongue & upper limbs (chewing , pouting, puffing of cheek, lip licking etc) It develops in about 20% of pts after months or years of antipsychotic treatment . Treatment is usually unsuccessful Dr Naser Ashraf Tadvi 2016

16. Other CNS side effects Drowsiness , lethargy, mental confusion with low potency agents Increase appetite, weight gain (not with haloperidol) Aggravation of seizures in epileptics, even non epileptics may develop seizures with high doses of clozapine , olanzapine Potent phenothiazines risperidone , quetiapine , aripiprazole & ziprasidone low seizure threshold Dr Naser Ashraf Tadvi 2016

17. Other adverse effects Postural hypotension, palpitation, Thioridazine Inhibition of ejaculation , QT prolongation, & cardiac arrhythmias Anticholinergic : Dry mouth, blurring of vision, constipation, urinary hesitancy Blue pigmentation of exposed skin, corneal & lenticular opacities, retinal degeneration Clozapine – hypersalivation Hyperprolactinemia Weight gain, ↑ lipids &BSL Cholestatic jaundice : low potency Skin rashes, urticaria , contact dermatitis, photosensitivity Agranulocytosis Myocarditis : clozapine Dr Naser Ashraf Tadvi 2016

18. Uses Psychoses(treatment of schizophrenia) Mania : CPZ, haloperidol may be given for rapid control 1-3days Organic brain syndromes: Not very effective, used as short term therapy Acute cases to control aggression As an adjunct to non sedatives to control exacerbations of violent behaviour Other uses : intractable hiccough, tetanus Dr Naser Ashraf Tadvi 2016

19. Treatment of schizophrenia Positive symptoms Delusions Hallucinations Hyperactivity Grandioisity Suspiciousness Hositility Relieved by antipsychotics Negative symptoms Blunted effect Emotional withdrawal Poor rapport Passive social wthdrawals Lack of spontaneity Stereotyped thinking Less relieved by antipsychotics Dr Naser Ashraf Tadvi 2016

20. Treatment of schizophrenia Cognitive, affective and motor disturbances- relieved overall Some patients do not respond Little improvement in judgement , memory and orientation Choices of drugs: patient dependent, empirical and guided by presenting symptoms

21. Choice of drugs for schizophrenia Drugs Symptoms CPZ, thioridazine , haloperidol. Agitated, violent trifluperazine , fluphenazine , aripiprazole Withdrawn & apathetic atypical antipsychotics Negative symptoms haloperidol, olanzapine Mood elevation, hypomania Thioridazine , clozapine , atypicals To avoid EPS high potency phenothiazine , haloperidol, aripiprazole Elderly: more prone to sedation

22. Mood stabilizers Control mood swings seen in bipolar mood disorders Mood stabilizers Lithium Sodium valproate Carbamazepine Lamotrigine Gabapentine Dr Naser Ashraf Tadvi 2016

23. Lithium Monovalent cation Li + prevents mood swings reduces both maniac and depressive episodes In Acute mania supresses episodes over weeks Dr Naser Ashraf Tadvi 2016

24. Mechanism of action Dr Naser Ashraf Tadvi 2016 Blocks formation of inositol from IP 3 & thereby inhibits regeneration of Phosphatidyl inositol Phosphatidyl inositol is source for DAG & IP 3 hy peractive neurons involved in mania are preferentially affected Lithium may dampen signal transduction in overactive neurons

25. Other actions of lithium Inhibits action of ADH on distal tubules Causes diabetes insipidus like state Has some insulin like action on glucose metabolism ↑ leucocyte count Reduces thyroxine synthesis by interfering with iodination of tyrosine Dr Naser Ashraf Tadvi 2016

26. Pharmacokinetics: narrow margin of safety monitor 0.8-1.1 meq /l lithium Uses: 1.Acute maniac episodes 2.Bipolar disease. 3.Recurrent unipolar depression Adverse effects : CNS toxicity as tremors, giddiness ,ataxia, delirium, twitchings , and convulsions. Contraindications: pregnancy- foetal goiter Dr Naser Ashraf Tadvi 2016

27. Adverse effects of lithium L eukocytes I ncreased ( Leukocytosis ) I ncreased weight T remors H ypothyroidism I ncreased U rine M oms Beware (teratogenic) Dr Naser Ashraf Tadvi 2016

28. Lithium toxicity Lithium toxicity begins to occur when the serum concentration exceeds 1.5 mmol /L. Symptoms include drowsiness, nausea , vomiting, blurred vision, a coarse tremor, ataxia and dysarthria Such symptoms progress to delirium and convulsions, and coma and death can occur. As a rule, lithium is not advised during pregnancy, particularly in the first trimester, because of an increased risk of fetal malformation ( Ebstein’s anomaly). Dr Naser Ashraf Tadvi 2016

29. Management of mania/ biplolar disorder Acute mania Atypical antipsychotic ( olanzapine , quetiapine and risperidone ), sodium valproate or lithium. Severe mania is best treated with a combination of valproic acid or lithium and a neuroleptic , allowing the neuroleptic to be withdrawn after the first 2 or 3 weeks. First attacks of mania usually require treatment for up to 3 months. Dr Naser Ashraf Tadvi 2016

30. Prevention in bipolar disorders Lithium , olanzapine , and valproic acid Screening prior to starting lithium: ■ Thyroid disease : Lithium can produce hypothyroidism . ■ Renal disease : Longterm treatment with lithium causes nephrogenic diabetes insipidus (DI) and reduced glomerular function The therapeutic range for prophylaxis is 0.5–1.0 mmol /L. Lithium levels should be checked every 3 months, along with regular thyroid (free T4 and TSH) and renal function tests. Patients should carry a lithium card with them at all times, be advised to avoid dehydration, and be warned of drug interactions , such as NSAIDs and diuretics . Dr Naser Ashraf Tadvi 2016