Anti - psychotic drugs DRP.pptx anti - psychotics

anti - psychotic drugs used in treatment of psychosis

1. ANTI – PSYCHOTIC DRUGS Dr.S.Santhosh Post - Graduate

2. INTRODUCTION The drugs used to treat psychosis are called Neuroleptics. They are broadly divided into drugs used for treatment of Schizophrenia and other agitated states.

3. SCHIZOPHRENIA Here the patient exhibits functional psychoses in which severe personality changes and thought disorders occur with no evidence of organic cerebral damage. It mainly involves two types of symptoms: Positive symptoms: delusions, illusions, auditory hallucinations, aggressive behaviour . Negative symptoms: introvert behaviour , poor socialization, emotional blunting, lack of motivation and cognitive deficits.

4. PATHOGENESIS Genetic predisposition: In first degree relatives, the risk is about 10%. In monozygotic twins, the risk is about 50%. In dizygotic twins the risk is about 10%. Involvement of genes encoding for Neuregulin – 1 has been reported .

5. Dopamine (DA) hypothesis: It highlights the excessive dopaminergic activity in patients. 1)PET scanning showed increased dopamine receptor density 2)Increased DA receptor densities in schizophrenics in post – mortem studies 3)Drugs like Levodopa and Amphetamine precipitate schizophrenia 4)Blockade of D2 receptors – a major mechaniosm of action of anti – psychotic drugs.

6. 5 – HT hypothesis: It is based on findings that LSD, a central 5 – HT2 receptor agonist, produces hallucinations and sensory disturbances. Atypical anti – psychotics like Clozapine and Olanzapine are potent 5 – HT2A receptor antagonists. But the major shortcoming of this hypothesis is that LSD produces visual hallucinations predominantly while auditory hallucination is the major symptom in schizophrenia.

7. Glutamate hypothesis: Glutamate exerts excitatory while DA expresses inhibitory effect over GABAergic striatal neurons. Increase in glutamate or decrease in DA causes decrease in sensory inputs reaching the cortex and vice versa. Underactivity of NMDA receptors is responsible for negative symptoms and overactivity of DA is responsible for positive symptoms.

8. NEUROLEPTICS - CLASSIFICATION CLASSICAL or TYPICAL NEUROLEPTICS: Phenothiazines: with aliphatic tertiary amine side chain (Chlorpromazine) with piperidine moiety in side chain (Thioridazine) with piperazine moiety in side chain (Trifluoperazine, Perphenazine, Fluphenazine) Thioxanthines : ( Flupenthixol , Thiothixene, Zuclopenthixol) Butyrophenones: (Haloperidol, Benperidol, Droperidol , Domperidone) Miscellaneous: (Pimozide, Penfluridol , Molindone, Loxapine , Amisulpride)

9. ATYPICAL ANTI – PSYCHOTICS: Clozapine, Olanzapine, Quetiapine, Zotepine, Risperidone, Aripiprazole

10. DOPAMINERGIC PATHWAYS Mesolimbic – Mesocortical – Mesofrontal pathway: Substantia nigra to Limbic system controls behaviour Nigrostriatal pathway: Substantia nigra to caudate nucleus and putamen controls voluntary movements Tubero – infundibular pathway: Arcuate nuclei to hypothalamus and posterior pituitary controls prolactin release and other endocrinal functions

11. Medullary periventricular pathway: projects from motor nucleus of the vagus controls eating behaviour Incerto – hypothalamic pathway: connects medial zona incerta to hypothalamus and amygdala controls copulatory behaviour

12. MECHANISM OF ACTION CLASSICAL NEUROLEPTICS: competitive blockade of post – synaptic D2 receptors causes increased synthesis and release of dopamine – increases the dopamine metabolites like HVA and DOPAC D2 blockade also produces extrapyramidal side effects D2 receptor blockade in CTZ – antiemetic effect

13. CHLORPROMAZINE Absorption unpredictable and slow Highly plasma protein bound Metabolized by CYP2D6 in liver T1/2 – 18 -30 hrs Excreted in urine

14. TRIFLUPROMAZINE More potent than CPZ Used mainly as an antiemetic ADR ; muscle dystonia in children

15. THIORIDAZINE Low potency ADR: cardiac arrythmias and male impotence

16. TRIFLUPERAZINE AND FLUPHENAZINE Highly potent Minimal autonomic actions ADR: EPS, tardive dyskinesia

17. HALOPERIDOL Drug of choice for acute schizophrenia High potency Low risk of jaundice and autonomic side effects Also used in Tourette syndrome and Huntington’s disease

18. PENFLURIDOL Long acting Indicated in chronic schizophrenia

19. FLUPENTHIXOL Less sedating Used in withdrawn apathetic patients Not used in agitation and mania patients

20. PIMOZIDE Dopamine antagonist with little alpha adrenergic or cholinergic blocking activity. Used in psychomotor agitation, Tourette syndrome.

21. LOXAPINE Short acting drug

22. ATYPICAL ANTI - PSYCHOTICS Mechanism of action: They mainly act through 5 – HT2 antagonistic activity. They possess only weak D2 blocking property. Extrapyramidal side effects are minimal.

23. CLOZAPINE It antagonizes D4, 5 – HT2, alpha, H1 blocking property. Metabolised by CYP1A2, CYP2C19, CYP3A4. t1/2 of 12 hrs Advantages: No extrapyramidal effects No effect on prolactin levels and does not cause tardive dyskinesia. Indicated in refractory schizophrenia

24. ADR: blood dyscrasias: agranulocytosis, leukocyte count derangement weight gain, hyperlipidaemia , diabetes sedation unstable BP, tachycardia urinary incontinence myocarditis

25. RISPERIDONE MOA: blockade of D2, 5 – HT2, alpha 1,2 , H1 receptor Extrapyramidal side effects are less in only low doses Prolactin levels also increase Low risk for Diabetes and weight gain Caution required for use in elderly due to increased risk of stroke.

26. OLANZAPINE MOA: D2, 5 HT – 2, alpha 1,2, muscarinic and H1 blockade t1/2 is 24 – 30 hrs Weak D2 action – lesser extrapyramidal symptoms Metabolic side effects present

27. QUETIAPINE MOA: 5 HT – 1A, 5 HT – 2, D2, alpha 1,2 , H1 blockade Lower extrapyramidal side effects May cause metabolic derangements moderate QTc prolongation may occur Postural hypotension and sedation may occur

28. ARIPIPRAZOLE MOA: partial agonist at D2 and 5 HT – 1A receptors antagonist at 5 HT – 2 receptor Long acting – t1/2 is 3 days Low intrinsic activity at D2 causes fewer side effects. Toxicity reported when given with Ketoconazole and Quinidine

29. ZIPRASIDONE MOA: D2, 5 HT – 2A/2C, H1, alpha 1 blockade agonist at 5 HT – 1A receptor Lower extrapyramidal side effects and Hyperprolactinaemia . QTc prolongation may occur Potent drug in schizophrenia

30. AMISULPRIDE MOA: D2, D3 and 5 HT – 2 blockade May cause hyperprolactinaemia due to high affinity to D2 receptors t ½ is around 12 hrs Excreted in urine QTc prolongation seen

31. THERAPEUTIC USES Schizophrenia: According to ASA guidelines, atypical antipsychotics are the drug of choice if the patient is experiencing the first episode of schizophrenia. Dosage: Chlorpromazine: 25 – 100 mg TDS Thioridazine: 50 – 100 mg TDS Fluphenazine: 1- 3 mg TDS Trifluoperazine: 2 – 5 mg BD Flupenthixol : 3 – 9 mg TDS

32. Haloperidol: 0.5 – 5 mg TDS Penfluridol : 20 – 60 mg once a week Pimozide: 2 – 4 mg OD Loxapine : 10 – 25 mg BD Aripiprazole: 10 – 15 mg OD Clozapine: 12.5 mg OD or BD increased by 25 mg daily upto maximum of 300 mg / day Olanzapine: 5 – 10 mg OD Risperidone: 1 mg BD slowly increased at 1 mg / day to maximum 3mg BD

33. Drug induced psychoses associated with Amphetamine and LSD Schizo – Affective Disorders schizo component responds to antipsychotics and affective domain is treated accordingly depending on the diagnosis. Tourette syndrome: characterized by tics, grunts and vocalizations treated using Haloperidol and Pimozide

34. Huntington’s disease: characterized by choreoathetosis and dementia treated using Haloperidol or Chlorpromazine

35. Non – Psychiatric indications: Prochlorperazine (anti – emetic) Domperidone and Metaclopramide (Prokinetic) Promethazine (motion sickness) Intractable Hiccups: Haloperidol and Chlorpromazine Pre – anaesthetic medication: Promethazine Droperidol + Fentanyl (Neurolept analgesia)

36. ADVERSE EFFECTS Neurological: Dystonias Akathisia Parkinsonism Neurolept – Malignant syndrome Perioral tremors Tardive dyskinesia

37. Autonomic: Alpha adrenergic blockade Muscarinic Endocrinal Miscellaneous

38. DYSKINESIA It is the weakness of muscles of lingual, neck and back. Treated using Diphenhydramine

39. AKATHISIA It is the aggressive, restless behaviour It is treated using Diphenhydramine

40. PARKINSONISM It occurs due to imbalance in DA and Ach Treated using anti - muscarinic agents like Procyclidine, Benztropine Dopamine agonists are not used as they may precipitate schizophrenia

41. NEUROLEPT – MALIGNANT SYNDROME It is characterized by hyperpyrexia, rigidity, myoglobinemia , and increased creatinine kinase Treated by using Dantrolene sodium Diazepam and Dopamine agonists like Bromocriptine can also be used

42. TARDIVE DYSKINESIA It occurs due to prolonged suppression of dopamine receptors leading to formation of new receptors. These newly formed receptors are very sensitive. This leads to decreased Ach activity leading to suppression of GABA activity. Most commonly caused by typical anti – psychotic drugs. Treated by “neurolept holidays” where drugs are withheld for specified periods and re – instituted. Alternatively atypical anti – psychotics can be used.

43. PERIORAL TREMORS Characterised by chewing movements made by the patients similar to rabbit. Treated using anti – cholinergics and anti – parkinsonian drugs.

44. ALPHA ADRENERGIC BLOCKADE Common with Phenothiazines Postural hypotension Tachycardia Loss of libido

45. ANTI – MUSCARINIC EFFECTS Usually occurs with Clozapine, Quetiapine Dryness of mouth Constipation Urinary retention

46. ENDOCRINAL Blockade of D2 receptors – Hyperprolactinemia Blockade of Medullary Periventricular pathway – increased appetite Decreased FSH and LH secretion – amenorrhea, infertility

47. MISCELLANEOUS Jaundice Photosensitivity Corneal opacities Epileptogenic effects Poikilothermic effects