Antipsychotic drug

pharmacological aspects of antipsychotic drugs

1. ANTIPSYCHOTIC DRUGS Writing prescription is easy, understanding people is hard Franz Kafka , (1883-1924)

2. Overview History Introduction Different hypothesis for schizophrenia Classification Mechanism of action Uses Adverse effects Recent advances

3. History 1931 S en and B ose – publish therapeutic effect of reserpine in Hypertension and Insanity Hans Laborit – note the antipsychotic effect of chlorpromazine, which was being tried as preanesthetic medication 1950 - Jean Delay and Piere Deniker conducted trial 1960-1970 : identification of D 2 blockade as the key mechanism, development of these first-generation of antipsychotic agents Janssen introduced Haloperidol & Pimozide

4. Introduction Neuroleptics/ Major tranquillisers / Dopamine antagonist Psychoses and Neuroses Psychotic disorders – Schizophrenia, severe forms of depression and mania

5. Symptoms of Schizophrenia Positive symptoms : the presence of inappropriate behaviors Delusions H allucinations D isorganized talking M ovements Negative symptoms : the absence of appropriate behaviors F lat affect A nhedonia C atatonia

6. Dopamine hypothesis Excessive dopaminergic activity: Drugs which increase dopamine activity Postmortem – receptor density high in nucleus accumbens , caudate, putamen Imaging studies – amphetamine – high dopamine in striated areas Diminished dopaminergic activity Cortical/hippocampal – cognitive and negative Postmortem – cortical, limbic, nigral , striatal

7. Serotonin hypothesis 5HT 2A and 5HT 2C – hallucination 5HT 2A - depolarization of glutamate receptors stabilization of NMDA 5HT 2C - inhibition of cortical dopamine release 5HT 1C - anxiolytic effect, exert procognitive effects in schizophrenia

8. Glutamate hypothesis Hypofunctioning of NMDA receptors located on GABAergic interneurons, leading to diminished inhibitory influence on neuron function  GABA ergic activity  induce disinhibiton of downstream glutamate activity  hyperstimulation of cortical neuron through non NMDA receptor NMDA requires glycine In schizophrenia, glycine site is not fully occupied

9. Atypical neuroleptics Typical or first generation antipsychotics (FGA) Atypical antipsychotics or second generation antipsychotics (SGA) D 2 receptor blockade 5HT and Dopamine receptor block Less effective against negative symptoms More effective against negative symptoms Not effective in refractory cases Effective in refractory cases More side effects (EPS) Less side effects profile

10. Increased dopamine Rise in Number of brain D2 receptors Receptor supersensitivity Excess availability of dopamine due to over production Reduced destruction through enzyme deficiency SCHIZOPHRENIA

11. MOA of FGA Typical/ FGA – D2 antagonist Initially – increased s ynthesis of DA – later decreases HVA and DOPAC level in blood & urine Molindone , loxapine , sulpiride and amisulpiride In between typical and atypical antipsychotics

12. Most of the antipsychotics are given orally but incompletely absorbed . Significant first-pass metabolism. Bioavailability is 25-65%. Most are highly lipid soluble. Most are highly protein bound (92-98%). High volumes of distribution ( >20 L/Kg) . Absorption and distribution

13. Plasma half life Quetiapine – 7h Clozapine – 12h Fluphenazine - 20h (depot – 14.3days) Haloperidol – 24-48h (depot – 21days) Olanzapine – 33h Depot preparation – 2-4 weeks Measurable plasma concentration with I.M route is seen within 15-30min

14. Most antipsychotics are almost completely metabolized- phase 1 and subsequent phase 2 Exceptions are asenapine (phase 2), ziprasidone (aldehyde oxidase system) and paliperidone (oxidized metabolite) Most metabolites- inactive. Chlorpromazine – 160 metabolites, 70 have been identified. Metabolism & excretion

15. Uses Psychiatric indication: Schizophrenia – advantage V/s disadvantage First psychotic episode – start with atypical Olanzapine (10mg), risperidone (4mg), quetiapine (25mg) 2 weeks later increase the dose Previously treated with typical – continue Long acting depot preparations – haloperidol, fluphenazine Rapid tranquillizers – lorazepam – 1-2mg i.v Haloperidol – 2-10mg i.m Drug Dose Maximum Chlorpromazine 25-100mg TDS 1g/day Thioridazine 50-100mg TDS 800mg/day Fluphenazine 1-3mg TDS 20mg/day Trifluoperazine 2-5mg BD 40mg/day Flupenthixol 3-9mg TDS 18mg/day Zuclopenthixol 20-50 mg daily 200mg I.M depot Haloperidol 0.5-5mg TDS 60mg /day Penfluridol 20-60mg once a week 250mg once a week Pimozide 2-4mg /day 12mg/day Loxapine 10-25mg BD 75mg/day Drug Dose Maximum dose Sulpiride 400-800mg Amisulpride 200-400mg/day 1g/day Levosulpride 200-300mg/day Aripiprazole 10-15mg/day 30mg/day Clozapine 12.5mg OD/BD 300mg/day Olanzapine 5-10mg/day 20mg/day Risperidone 1mg BD 3mg BD Paliperidone 6mg/day 12mg/day Ziprasidone 20mg BD 80mg BD Quetiapine 25mg BD 300mg BD

16. Drug induced psychoses – LSD , amphetamine Schizo -affective disorder – schizo part – antipsychotic, affective part – anti depressant or lithium Neuro psychiatric indication Tourette’s syndrome – haloperidol or pimozide Huntington’s disease – haloperidol or chlorpromazine Non psychiatric indication: Antiemetic – D 2 block at CTZ,GIT – prochlorperazine , domperidone Preanaesthetic medication - promethazine Intractable hiccups – parenteral haloperidol, CPZ

17. Adverse effects CNS side effects: Behavioral effects – sedation more with phenothiazines , thioxanthenes , olanzapine Less with butyrophenones , pimozide Tolerance and dependence – tolerance develops to sedation and autonomic side effects

18. Treatment : Promethazine, Diphenhydramine Treatment: non selective b-blocker like Propranolol Treatment: T rihexyphenidyl , P rocyclidine Treatment: withdraw neuroleptic drug and add diazepam

19. Parkinsonism Due to disturbance in DA-Ach imbalance T reatment with anticholinergic- antiparkinsonian drugs Trihexyphenyidyl , procyclidine DO NOT START WITH LEVODOPA Neurolept malignant syndrome Hyperpyrexia, muscle rigidity , fluctuating BP, increase CK, myoglobin Central mechanism Peripheral mechanism Stop neuroleptic Supportive care Dantrolene Diazepam, bromocriptine

20. Autonomic (ANS) side effects: Alpha adrenergic blockade- Postural hypotension Antimuscarinic effects- dryness of mouth, constipation etc. (except clozapine) Endocrinal side effects: chlorpromazine, thioxanthene Agranulocytosis - clozapine Photosensitivity – UV rays oxidizes phenothiazines – accumulates in melanin containing tissues R etinal pigmentation, , corneal opacities- thioridazine E pileptogenic effects- clozapine, chlorpromazine P oikilothermic effects- impair the ability of hypothalamic thermoregulation

21. Mechanism Therapeutic effects Adverse effects α 1 block -- Dizziness, orthostatic hypotension, reflex tachycardia. D 2 block + ve symptom ↓ EPS & ↑ Prolactin D 1 & D 4 block - ve symptom & EPS ↓ -- H 1 block Sedation Drowsiness & ↑ appetite & weight M block -- Dry mouth, etc. 5-HT 2 block - ve symptom & EPS ↓ Anxiety & insomnia

22. Toxicities Thioridazine : ventricular arrythmias , cardiac conduction block, sudden death Pimozide , ziprasidone : prolong QT, hypokalemia Quetiapine : cataract formation, priapism, peripheral edema, hyperventilation

23. Drug Effects Antacids Decrease absorption of antipsychotics Anticholinergics Increased anticholinergic effect Alcohol More sedation Antithyroid drugs Agranulocytosis Barbiturates Decreased effect but more sedation Carbamazepines and phenytoin Decreased effect but lower threshold Chloroquine May precipitate EPS Lithium Enhancement of neurotoxicities Levodopa Decrease efficacy Oral contraceptives Hyperprolactinemia Cigarette smoking Increased metabolism

24. Recent advances Aspirin Minocycline Raloxifene Estrogen N-acetyl cysteine

25. Raloxifene Raloxifene  E xhibit agonistic and protective action on the brain by modulating the monoaminergic neurotransmission of dopamine, serotonin and GABA Addition of Raloxifene (60 mg/day) to regular antipsychotic treatment ↓ negative, positive & general psychopathological symptoms in comparison with women receiving antipsychotic medication alone ( Usall et al., 2011 )

26. Estrogen Short term  Rapid membrane effects by altering functional activity in the dopaminergic synapse (Di Paolo, 1994) Long term  Modifies synthesis in dopamine receptors (Di Paolo, 1994) Estrogen alters serotonergic system (Moses et al., 2000) Estrogen promotes neuronal regeneration & blocks mechanisms of neuronal death ( DonCarlos et al., 2009)

27. N acetyl cysteine Glutathione is a major antioxidant that protects cells against oxidative stress (Meister and Anderson , 1983 ) Glutathione potentiates NMDA receptors (Choi and Lipton , 2000)

28. Potential future targets Targeted gene therapy  D ysbindin , Neurogelin 1, COMT , DISC1 Enhancement of BDNF Targets  GSK 3, PKC , GABA A receptor PDE inhibitors (particularly at PDE1B) Cannabinoid receptor antagonist Currently glycine transport inhibitors are in trials Preliminary study with LY2140023 (agonist at glutamate receptor) is also been tried

29. Thank you