ANTIPSYCHOTIC DRUGS.pptx?yr68ijvsetyujgdt7ujh

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1. ANTIPSYCHOTIC DRUGS DR.M.SHAMEEM MBBS, MD, FCCM, FIDM,(MRCEM)

2. Schizophrenia

3. POSITIVE SYMPTOMS: Hallucinations Delusions Disorganized thinking Bizzare behaviour Thought disorder

4. NEGATIVE SYMPTOMS: Lack of drive or initiative Social withdrawal Apathy / Avolution Affective flattening Emotional unresponsiveness, poor eye contact Alogia Attention problem

5. Paranoia: isolated delusions Mania: elation, hyperactivity, uncontrollable thought and speech Depression: sadness, guilt, physical and mental slowing

6. Antipsychotic drugs OTHER NAMES: NEUROLEPTICS ATARACTICS MAJOR TRANQUILLIZER

7. Dopamine hypothesis of psychosis Elevated dopamine in limbic system Stimulates d2 receptors Blocks generation of action potential in neurons Blocks – thought Moa: blocks d2 receptors

8. Phenothiazines: aliphatic side chain: chlorpromazine, triflupromazine, Piperidine side chain: thioridazine,mesoridazine Piperazine chain: trifluoperazine,fluphenazine 2.Butyrophenones: haloperidol,trifluperidol , droperidol 3.Thioxanthenes: thiothixene, flupenthixol 4.Other heterocyclics: pimozide, loxapine 5.Atypical: clozapine, risperidone, olanzapine, quetiapine, Zotepine, ziprasidone, Amisulpiride , Aripiprazole

9. PK oral absorption is erratic and unpredictable Parenteral (IM) -absorption increases to 4-10 fold Highly protein bound Biological effects persist for 24 hrs. Metabolized by oxidation

10. PHARMACOLOGICAL ACTIONS: CNS: IN NORMAL INDIVIDUALS Indifference, pauciness , slow, quiet, initiation, go to sleep IN PSYCHOTICS Irrationaal behavious , agitation, aggressive Disturbed thought Hyperactivity, hallucinations, delusions Lowers seizure threshold Poikilothermia antiemetic

11. ANS: Alpha blocker Anticholinergics Weak antihistaminic Weak anti serotonergics Membrane stabilizing action CVS: POSTURAL HYPOTENSION ANTI ARRHYTHMIC REFLEX TACHYCARDIA

12. ENDOCRINE: Increase prolactin release Decreases the ACTH release Reduce gonadotropin release Decrease release of ADH TOLERANCE & DEPENDENCE: Only to sedation & hypotension No tolerance to antipsychotic action Withdrawal phenomena

13. Uses: Schizophrenia (2 nd line, effective for positive symptoms Tics associated Tourette syndrome Huntington’s chorea Migraine attack Antiemetic-except thioridazone Anti pruritic- because also blocks H1- receptor mania

14. Side effects: NEUROLOGICAL SIDE EFFECTS: ACUTE MUSCLE DYSTONIA Facial grimacing, Torticollis, locked jaw, opisthotonus . PARKINSONIAN SYNDROME Rigidity, tremor, akinesia AKATHISIA Restlessness, agitation, discomfort – compulsion to move  

15. D2 receptor blockage: Hyperprolactinemia- extrapyramidal side effects Other side effects: Muscarinic receptor blocker: constipation, dry mouth H1 receptor blocker: sedation, obesity 5HT blocker: obesity Alpha 1 receptor blocker: postural hypotension

16. Metabolic side effects: Insulin resistance Dyslipidemia Akathisia – restlessness, beta blockers D2 recptor blocker: actute dystonia – involuntary muscle contraction parkinsonism

17. EPS: Tardive dyskinesia: repetitive, painless, involuntary, quick choreiform movements of the face(constant chewing, puffing of cheeks, lip licking, blinking) and limb movement  Occurs after many years due to upregulation of D2 receptors When D2 receptor blocked for many years – D2 upregulation occurs – dopamine acts on D2 receptor- tardive dyskinesia Treatment: Deutetrabenazine , valbenazine - blocks VMAT 4 Change to atypical antipsychotics

18. Neuroleptic malignant syndrome: marked rigidity, immobility, tremor, fever, semi consciousness, fluctuating BP heart rate and respiration rate. Elevation of CK and myoglobinemia D2 receptor blockage Muscle rigidity Hyperthermia, increase in creatinine phosphokinase Hypotension Treatment: Dantrolene- ryanodine receptors, bromocriptine

19. RABBIT SYNDROME: perioral tremor Other side effects: Metabolic and endocrine effects: weight gain – clozapine, olanzapine Hyperprolactinemia, galactorrhea Infertility, amenorrhea G ynaecomastia , Loss of libido

20. Blood dycrasias : leucopenia, leukocytosis, eosinophilia agranulocytosis - clozapine 7.Skin reaction: skin rashes ,photosensitivity reactions cholestatic jaundice. 8.Ocular complications- corneal and lens opacities Pigmentary retinopathy : thioridazine

21. SEROTONIN HYPOTHESIS: IN LYSERGIC ACID DIETHYL AMIDE ABUSERS- INCREASE EXCRETION OF 5HT IN URINE HALLUCINOGEN- SYMPTOMS OF PSYCHOSIS ATYPICAL ANTIPSYCHOTICS: BLOCKS 5HT2 MORE, BLOCKS D2 RECEPTORS LESS SO LESSER EPS

22. ATYPICAL ANTIPSYCHOTICS USES: SCHIZOPHRENIA – 1 ST LINE DRUGS- EFFECTIVE FOR POSITIVE AND NEGATIVE SYMPTOMS MANIA HUNTINGTONS CHOREA DEPRESSION- 0LANZAPINE,CLOZAPINE, RISPERIDONE, QUETIAPINE LEVODOPA INDUCED PSYCHOSIS: RISPERIDONE, ARIPIPRAZOLE

23. Atypical antipsychotics: Clozapine: binds more to D 4 , 5HT 2A , α 1 , and H 1 Risperidone: blocks D 2 and 5HT 2A equally Olanzapine: potent antagonist of 5HT 2 with lesser potency on D 1 , D 2 and α 1 Quetiapine: blocks 5HT 2 D 2 and α 1 Ziprasidone: combined D 2 5HT 2A antagonist and 5HT 1A agonist

24. CLOZAPINE: Weak D2 blockers, strong 5-HT antagonistics Less EPS Useful in refractory cases Half life 12 hours Agranulocytosis – metabolic complications limits Induce seizures Myocarditis, flu like syndrome.

25. QUETIAPINE : USES: MOMOTHERAPY IN DEPRESSION INSOMNIA SIDE EFFECTS: CATARACT QT PROLONGATION RISPERIDONE: D2 + 5-HT receptor blockade High affinity for H1 & alpha receptors EPS less Prolactin level rise Endocrine effects less Less epileptogenic Risk of stroke in elderly

26. OLANZAPINE: Half life 24 – 30 hours Potent antimuscarinic Less EPS, epilepsy More weight gain, DM, increase TGL – discourage No agranulocytosis Stroke risk in elderly

27. ARIPIPRAZOLE: Partial agonist at D2 & 5-HT1; 5-HT antagonist N/V, dyspepsia, constipation, light-headedness Long acting 3 days Indicated in Schizo , Mania, Bipolar ZIPRASIDONE: Combined D2, 5-HT, H1, alpha blockers Also inhibit NA reuptake – antidepressants & anxiolytic Nausea, vomiting, arrhythmias Half life 8 hours

28. AMISULPIRIDE: Less EPS Hyperprolactinemia Insomnia, anxiety, agitation common Metabolic complications less Arrhythmias in elderly Half life 12 hours ZOTEPINE: Similar profile No added advantage Withdrawn in UK Continuing in India

29. CHOICE OF DRUG: Violent: Haloperidol, CPZ, Quetiapine. Withdrawn & apathy: Trifluo , Fluphen , Aripi , Zipra Negative & Resistant: Atypicals Mood elevation, hypomania: Halo, quie , olanz EPS not required: Atypicals Less sedation: Aripi , halo

30. USES: SCHIZOPHRENIA MANIA IN PREGNANCY ACUTE MANIA

31. SIDE EFFECTS: LEASE WEIGHT GAIN AND METABOLIC SIDE EFFECTS ATYPICAL ANTIUPSYCHOTICS- SIDE EFFECTS MUSCARNIC RECEPTO BLOCKER: CONSTIPATION, DRY MOUTH H1 RECEPTOR BLOCKER: SEDATION 5HT BLOCKER: OBESITY ALPHA 1 RECEPTOR BLOCKER- POSTURAL HYPOTENSION METABLOIC SIDE EFFECTS : INSULIN RESISTANCE DYSLIPIDEMIA

32. XVI. Anti-Manic Drugs Lithium (Li + ) remains the drug of choice for the treatment and prophylaxis of mania. Acute manic episodes are managed with lithium salts (carbonate or citrate) alone, or in combination with: 1) Antipsychotics (carbamazepine, similar in structure to TCAs but not effective in depression). 2) Valproic acid 3) Calcium-channel blockers (nifendipine, diltiazem, verapamil).

33. XVI. Anti-Manic Drugs Li + Small monovalent cation (between H + and Na + ). Distributed in total body water, similar to sodium. May partially inhibit Na + -K + ATPase. Inhibits ADH => diuresis. May decrease thyroid function. Teratogenic (tricuspid valve malformation). Excreted by kidney.

34. XVI. Anti-Manic Drugs Li + Not to be taken with thiazide diuretics (e.g. chlorthiazide). Lithium clearance is reduced by 25%. All neuroleptics (with the exception of clozapine), produce more severe extrapyramidal syndromes when combined with lithium.

35. XVI. Anti-Manic Drugs Li + Helps alleviate the depressive phase of bipolar illness. Useful in refractory depression when added to SSRIs or TCAs, but not a good antidepressant alone .

36. XVI. Anti-Manic Drugs Li + Mechanism of action: Does not alter receptor numbers but alters the coupling of the receptors with their second messengers by reducing coupling of G-proteins. Regulation of  -AR and DAR. Can reduce release of NTs (5-HT) and affinity of binding to receptor.

37. XVI. Anti-Manic Drugs Li + Mechanism of action (Con’t): Inhibits breakdown of IP 2 to IP 1 (during PIP hydrolysis) => depletion of DAG and IP 3 and  [Ca 2 + ] in response to receptor activation (i.e. from 5-HT 2 R,  1 -AR, muscarinic receptors and others). Alterations in adenylate cyclase and phospholipase C.

38. XVI. Anti-Manic Drugs PIP PIP 2 G IP 3 IP 2 IP 1 Inositol PI X Li + PLC DAG Ca 2+

39. XVI. Anti-Manic Drugs Valproic Acid A well known antiepileptic has been found to have antimanic effects. Shows efficacy equivalent as that of lithium during the early weeks of treatment and is being evaluated for maintenance treatment. Titrated well, the sedation can be controlled. Nausea being the only limiting factor in some patients. May be used as first line treatment for mania, although it may not be as effective in maintenance treatment as lithium for some patients. Mechanism of action: ???

40. XVI. Anti-Manic Drugs Carbamazepine Effective as an antimania medication Mechanism of action (Con’t): May be due to decrease overexcitability of neurons (anticonvulsive effect).

41. XVI. Anti-Manic Drugs Ca 2+ Channel blockers Nifedeipine Verapamil Mechanism of action (Con’t): NT Release?