Antipsychotic drugs

1. Antipsychotic drugs

2. Phenothiazines • Aliphatic side chain: -Chlorpromazine -Triflupromazine • Piperidine side chain: -Thioridazine • Piperazine side chain: -Trifluoperazine -Fluphenazine

3. Butyrophenones -Haloperidol -Trifluperidol -Penfluridol • Thioxanthenes -Flupenthixol • Other heterocyclics -Pimozide, Loxapine

4. Atypical antipsychotics -Clozapine -Risperidone -Olanzapine -Quetiapine -Aripiprazole -Ziprasidone

5. Schizophrenia - symptoms Positive Symptoms(↑↑DA) Hallucinations Delusions (bizarre, persecutory) Disorganized Thought Perception disturbances Inappropriate emotions Negative Symptoms(↓↓NMDA) Blunted emotions Anhedonia Lack of feeling FUNCTION Mood Symptoms Loss of motivation Social withdrawal Insight Demoralization Suicide Cognition New Learning Memory

6. Positive/active symptoms include thought disturbances, delusions, hallucinations Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech. impaired personal hygiene

7. Prognosis of Schizophrenia 10% continuous hospitalization < 30% recovery = symptom-free for 5 years 60% continued problems in living/episodic periods

8. Etiology A gene encodes for neuregulin-1 has been associated with schizophrenia. Hereditary Influences may account for 10% of schizophrenia cases Prenatal Biological Trauma 5-10% cases of schizophrenia Perinatal biological trauma

9. Schizophrenia Pathophysiology Schizophrenia Pharmacologic Pathophysiology Profile of APDs Past Excess dopaminergic Dopamine D2-receptor activity antagonists Present -Renewed interest in the Combined 5-HT2/D2 role of serotonin (5-HT) antagonists Future -NMDA NMDA agonists Imbalance in cortical More selective antagonists communication and Mixed agonist/antagonists cortical-midbrain Neuropeptide analogs integration, involving multiple neurotransmitters

10. Dopaminergic Pathways and Innervation

12. Schizophrenia - Dopamine Hypothesis • Repeated administration of stimulantslike amphetamines and cocaine, which enhance central dopaminergicneurotransmission, can cause a psychosis that resembles thepositive symptoms of schizophrenia. • Low doses of amphetamine can induce a psychotic reaction in schizophrenics in remission. • Some early studies with postmortem tissue revealed increased numbers of DA receptors (in particular D2-like) in schizophrenic patients

13. Serotonin Hypothesis of Schizophrenia Hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists 5-HT2A-receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such as clozapine and quetiapine. 5-HT2A-receptor modulate the release of dopamine in the cortex, limbic region, and striatum.

14. Schizophrenia - Glutamate Hypothesis Preclinical as well as clinical studies provide evidence of hypofunction of NMDA receptors asa primary, or at least, a contributory process in the pathophysiologyof schizophrenia Several clinical trials with agentsthat act at the glycine modulatory site on the NMDA receptorhave revealed consistent reductions in negative symptoms andvariable effects of cognitive and positive symptoms These studiesalso provide evidence that suggests the effects of clozapineon negative symptoms and cognition may be through activationof the glycine modulatory site on the NMDA receptor.

15. ANTIPSYCHOTICS • Pre-90’s • “Typical”, conventional, traditional neuroleptics, major tranquilizors • Modeled on D2 antagonism • EPS/TD • Post-90’s • “Atypical”, novel, 2nd generation • Modeled on 5-HT2/D2 antagonism • Less EPS, prolactin effects • Weight gain, sedation, diabetes

16. Adverse Effects Sedation‑ initially considerable; tolerance usually develops after a few weeks of therapy; dysphoria Postural hypotension ‑ results primarily from adrenergic blockade; tolerance can develop Anticholinergic effects ‑ include blurred vision, dry mouth, constipation, urinary retention; results from muscarinic cholinergic blockade Endocrine effects ‑ increased prolactin secretion can cause galactorhea; results from antidopamine effect Hypersensitivity reactions ‑ jaundice, photosensitivity, rashes, agranulocytosis can occur Idiosyncratic reactions ‑ malignant neuroleptic syndrome Weight gain Neurological side effects -

17. Neurological Side Effects of antipsychotics

19. Adverse Effects - EPS Details on two main extrapyramidal disturbances (EPS): • Parkinson-like symptoms • tremor, rigidity • direct consequence of block of nigrostriatal DA2 R • reversible upon cessation of antipsychotics • Tardive dyskinesia • involuntary movement of face and limbs • less likely with atypical antipsychotics (AP) • appears months or years after start of AP • ? result of proliferation of DA R in striatum • presynaptic? • treatment is generally unsuccessful

20. Weight gain – 40% - weight gain now attributed to ratio of binding to D2 and 5-HT2 receptors; possibly also histamine (for newer antipsychotics anyway) • Sexual dysfunction • result from NE and SE blockade • erectile dysfunction in 23-54% of men • retrograde ejaculation in • loss of libido and anorgasmia in men and women • Seizures - <1% for generalized grand mal

21. Neuroleptic malignant syndrome (1-2% early in trt) • combination of motor rigidity, hyperthermia, and autonomic dysregulation of blood pressure and heart rate (both go up) • can be fatal in 5-20% of cases if untreated • treatment – discontinue meds; give trts for fever and cardiac problems

22. Sensitivity to sun • some phenothiazines collect in skin (chlorpromazine) • sunlight causes pigmentation changes – grayish-purple (look bruised) • in eye, browncornea, brownish cloud to vision and possibly permanent impairment • Agranulocytosis - <1% (with clozapine) • reduced white blood cell count • lowered resistance to infection • can be fatal • Jaundice – elevated bilirubin in liver - < ½%

23. Limitations Of Conventional Antipsychotics • Approximately one-third of patients with schizophrenia fail to respond • Limited efficacy against • Negative symptoms • Affective symptoms • Cognitive deficits • High proportion of patients relapse • Side effects and compliance issues

24. Antipsychotic Drugs – New Generations “atypical” • About 40-60% do not respond to phenothiazines or cannot handle side effects • Questions remain about the efficacy of phenothiazines and haloperidole for negative symptoms • Drugs needed that are low in extrapyramidal side effects and at least equal in efficacy for positive symptoms, perhaps better for negative

25. Antipsychotic Drugs – New Generations “atypical” clozapine risperidone olanzapine sertindole Quetiapine Aripiprazole Ziprasidone

26. Clozapine (1989) • Selectively blocks dopamine D2 receptors, avoiding nigrostriatal pathway • α-blockade • Also blocks H1 • More strongly blocks 5-HT2 receptors in cortex which then acts to modulate some dopamine activity • Among non-responders to first generation meds or those who cannot tolerate side effects, about 30% do respond to Clozapine

27. Clozapine • Extrapyramidal side effects are minimal • May help treat tarditive dyskinesia • S/E- orthostatic hypotension effects, sedation, weight gain, increased heart rate • Increased risk for seizures (2-3%) • Agranulocytosis in 1% • Agranulocytosis risks increase when co-administered with carbamazepine

28. Risperidone (1994) • Fewer side effects than Clozapine • Marketed as first line approach to treatment • Blocks selective D2, norepinephrine, and 5-HT2 • effective for positive and negative symptoms • Extrapyramidal side effects low (but are shown at high doses) • Shares sedation, weight gain, rapid heart beat, orthostatic hypotension, and elevated prolactin • No agranulocytosis risks • Increased risk of stroke in elderly • May cause anxiety/agitation (possible OCD)

29. Olanzipine – 1996 • Improved negative symptom reduction • Argued to be better than risperidone in extrapyramidal issues • Does not cause prolactin elevation • reduced agranulocytosis risks

30. Sertindole – 1995 • Improved negative symptom reduction • Low risk for extrapyramidal side effects – major advantage • No sedation and very mild prolactin elevation– major advantages • Shares orthostatic hypotension, tachycardia, and weight gain • Common side effects are rhinitis and reduced ejaculatory volume (not associated with disturbed function) • concern about sudden cardiac death or episodes due to cardiac arrhythmia led to its voluntary removal in 1998

31. Quetiapine - 1997 • No increased risks for extrapyramidal symptoms • Shares sedation (sleepiness), orthostatic hypotension, weight gain • Does cause anticholinergic side effects (like older and Clozapine) – dry mouth, constipation • Does not elevate prolactin • Ziprasidone - 2001 • Similar to advantages of others, but argued not to cause weight gain • May induce cardiac arrhythmias • Also has anxiolytic and antidepressant activity

32. Non- psychiatric Indications • As Antiemetics -chlorpromazine, prochlorperazine, haloperidol • Anaesthesia -droperidol(with fentanyl) • Intractable Hiccups -chlorpromazine -haloperidol

33. MCQs Q1. A female suffering from psychosis, taking fluphenazine now complains of sudden onset of high grade fever, muscle rigidity and altered sensorium. The diagnosis is: A. Malignant hyperthermia B. Tardivedyskinesia C. Akathisia D. Neuroleptic malignant syndrome • Ans- D - Neuroleptic malignant syndrome

34. Q2. Antipsychotic drug induced parkinsonism is treated by: • Levodopa • Selegiline • Amantadine • Central anticholinergic drugs • Ans- D (Trihexyphenidyl Procyclidine Biperiden )

35. Q3. Least extrapyramidal side effects are seen with: • Clozapine • Haloperidol      • Trifluoperazine • Chlorpromazine • Ans- A- Clozapine

36. Q4. Risperidone is associated with the risk of: • Cerebrovascular accidents • Agranulocytosis • Diabetes Insipidus •  Gout • Ans- A - Cerebrovascular accidents

37. Q5. The antipsychotic drug that can also be used as antiemetics: • chlorpromazine • Clozapine • Aripiprazole • Loxapine • Ans- A - chlorpromazine

38. Q6. The antipsychotics that can also be used as anaesthetic drug: • Chlorpromazine • Penfluridol • Clozapine • Droperidol • Ans- D - Droperidol

39. Q7. The antipsychotic drug that can also be used to treat Intractable Hiccups: • Clozapine • Chlorpromazine • Haloperidol • Ziprasidone • Ans- B, C - Chlorpromazine, Haloperidol

40. Thank you

41. Bibliography • Essentials of Medical Pharmacology -7th edition by KD Tripathi • Goodman & Gilman's the Pharmacological Basis of Therapeutics  12th edition by Laurence Brunton (Editor) • Lippincott's Illustrated Reviews: Pharmacology  - 6th edition by Richard A. Harvey • Basic and Clinical pharmacology 11th edition by Bertram G Katzung • Rang & Dale's Pharmacology -7th edition by Humphrey P. Rang • Clinical Pharmacology 11th edition By Bennett and Brown, Churchill Livingstone • Principles of Pharmacology 2nd edition by HL Sharma and KK Sharma • Review of Pharmacology by Gobind Sparsh