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PSYCHOPHARMACA

PSYCHOPHARMACA. Sulistia 1209. classification. I. Antipsychotics II. Antidepressants III. Antianxiety and Drug for insomnias IV. Drug for bipolar disorder. I. ANTIPSYCHOTIC (AP). S YNONIMS: antischizophrenic drug, neuroleptics, mayor tranquilizer C LASSIFICATION:

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PSYCHOPHARMACA

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  1. PSYCHOPHARMACA Sulistia 1209

  2. classification • I. Antipsychotics • II. Antidepressants • III. Antianxiety and Drug for insomnias • IV. Drug for bipolar disorder

  3. I. ANTIPSYCHOTIC (AP) • SYNONIMS: antischizophrenic drug, neuroleptics, mayor tranquilizer • CLASSIFICATION: Typical AP : chlorpromazine, fluphenazine haloperidol, thioridazine Atypical AP : clozapine,olanzapine,risperidone quetiapine, aripriprazol

  4. MECHANISM OF ACTION - Blocking the D2-receptors > D1 (mesolimbic / mesocortical dep. pathway) - ! Atypical : clozapine weak D2 blocker ,potent antipsychotic block D4-receptor and 5-HT2 - Varying pattern of selectivity in rec. blocking effect - Take several weeks to clinical response even though their rec. blocking is immediate - The connection between rec. block. activity to clin. response : remains unclear

  5. PHARMACOLOGICAL EFFECTS Slow response to external stimuli : - apathy - reduce initiative - display few emotion - tend to drowse off but easily arouse, and respond to question - strongly inhibit aggressive tendencies - < hallucination & delusion • Antiemetic activity : ~ block. D3 rec. Th/effect 70% of pts 30% resistant

  6. EFFECT ON RECEPTRS • Vary among different AP * Chlorpromazine: α1=5-HT2A>D2>D1 *Haloperidol: D2> α1>5-HT2A>D1>H1 * Clozapine: D4= α1>5-HT2A>D2=D1 * Olanzapine: 5-HT2A>H1> D4>D2 >α1 >D1

  7. * Aripiprazole: D2= 5-HT2A>D4>α1=H1>>D1 * Quetiapine: H1> α1>M1,3>D2>5-HT2A

  8. PSYCHOLOGICAL EFFECTS • In nonpsychotic patients Sleepiness, restlessness, autonomic effectunlike sedative-hypnotics and impaired performance in psychomotor and psychometric tests In Psychotic patients: alleviate psychosis and improve performance

  9. ELECTROENCEPHALOGRAPHIC EFFECTS • Shift the pattern of EEG frequencies: slowing and increasing their synchronization →erroneous diagnostic interpretation • some lower seizure threshold , but can be use safely in epileptic patients with careful dosage titration

  10. PharmacokineticAbsorption and Bioavailabily • Chlorpromazine absorption erratic  interindividual variation up to 90 fold , • bioavailability: chlorpromazine: 25% thioridazine 35%,both undergo first pass metabolism haloperidol 65% - relation between plasma conc – clin. effect : highly variable  tailored individually! - long t½ (15-30 hours)  1  2 dd. - Depot preparation : heptanoic or decanoic acid in oil : IM given each 2-4 weeks overcome compliance problems

  11. DISTRIBUTION • Highly lipid soluble • widely distributed. Vd >7L/kg • Highly protein bound(92-99%) • Prolonged binding to receptors duration of action> than plasma t 1/2

  12. Metabolism and Excretion • Most AP are completely metabolized • Metabolites usually not active except mesoridazine which is more active than thioridazine • Excreted in the urine as inactive metabolites

  13. ADE A. 2 kind of motor disturbance : 1) Acute dystonias & Parkinson-like symptoms ~nigrostriatal block D2 rec., tremor, rigidity (esp. eck muscle), akatisia(uncontrollable restlessness) Th/ anticholiergic drugs: trihexyphenidyl beperiden , diphenhydramine * Levodopa and dopaminergic agonist should never be use (why?)

  14. ADE 2) Tardive diskinesia - involuntary movement of face & limbs, appearing months/years after treatment Th/ usually unsuccessful Extrapyramidal ADE are less likely to occur with atypical AP clozapine : strong antimusc. more selective D block in mesolimbic vs nigrostriatal

  15. B.Cardiovascular adverse effects • Chlorpromazine, thioridazine: orthostatic hypotension;mean arterial pressure, peripheral resistance and stroke volume <; • H Rate ↑, prolonged QT interval sertindole, withdrawn from the market ziprazidone warning about the risk

  16. C.Endocrine ADE • In women : amenorrhoea-galactorrhea, increase libido andfalse positive pregn. Test. • In men: decrease libido, gynecomastia a part cause by hyperprolactinemia due to dopaminergic blocking effect and increase peripheral conversion of androgens to estrogens(>typical AP)

  17. D. Other ADE  antimuscarinic adverse effects : ! - Alzheimer (memory impairment) - prostate hypertrophy - glaucoma,  orthostatic hypotension : associated w alfa adrenergic blocking effect ~ fall and fracture in the elderly  weigh gain : > atypical  agranulocytosis : clozapine  to be monitored by blood count  idiosyncratic : antipsychotic malign. syndrome, rare but dangerous relation of chemical structure to potency & toxicity Table 29-1. p 461.Bertram G Katzung 10th ed.

  18. Indonesian population : as common with other drug tolerate AP less than caucasian • ? poor metabolizer • ! Start with lower dose

  19. DRUG CHOICE • Based mainly on differences and ADE • In using typical AP knowledge of chlorpromazine and haloperidol remains relevant • One should be familiar w 3 subfamily of phenothiazine,a member of thioxanthine and butyrophenone group and all the newer compound

  20. A representative group of AP drugs is presented in: Table 29-1. p 461.Bertram G Katzung 10th ed.

  21. Summary • AP are very useful : for pats & care givers  less hospitalization • Effective in 70% of pts • Atypical : problem with dystonia S.E. • Atypical : - sign less motor disturbance - claimed > effective to control neg. symptoms :* emotional flattening * social withdrawal and * lack of motivation

  22. Summary • Atypical : - > metabolic side effects : * weight gain * hyperglycemia - clozapine : efficacy in treatment resistant pts. - not more effective in every patients - first line drug for those who could afford the cost AP are safe in acute overdose compare to hypnotic-sedatives and tricyclic antidepressant

  23. Cytochrome P450 enzymes involved in psychopharmacological drug 2D6 : - amitriptyline, desipramine, imipramine, haloperidol, nortriptyline - risperidone, thioridazine - venlafaxine 3A4 : amitriptyline, imipramine bupropion clonazepam, diazepam fluoxetine, sertraline zolpidem 2C19 : amitriptyline, clomipramine, imipramin, diazepam, moclobemide

  24. Question to be answered • 1. mention classification of AP(antipsychotic) and 3 examples of each class • 2. explain the differences of pharmacodynamic action of each class • 3. explain important pharmacokinetic issue of AP • 4. Explain difference in ADE of special drugs

  25. 5. Explain factors influencing the use of drugs

  26. I. ANTIDEPRESSANT CLASSIFICATION A.First Generation Tricyclic AD Imipramine  Amitriptyline * Clomipramine B. Second Generation: * Amoxapine, Maprotiline, Trazodone, Bupropion C. Third Generation:Venlafaxine, Mirtazapine, Nefazodone & Duloxetine

  27. D. Selective Serotonin Reuptake Inhibitor (SSRI) Fluoxetine, Sertraline, Fluvoxamine, Citalopram • E. Monoamine Oxydase Inhibitors Phenelzine, Tranylcypromine, moclobemide

  28. A. Tricyclic Antidepressant Mechanism of action • Block the amine transporters (uptake pump) • Block reuptake of NE (NET), 5HT (SERT) (<< dopamin)  catecholamine: mania;  catecholamine :depression • Not clearly understood why blocking transporter occurs rapidly but clinical result is delayed for a few weeks

  29. B.. Second generation of Antidepressant • AD that exhibit less CVS side effects * desimipramine: metabolit of imipramine * nortriptyline: metabolit of triptyline • AD that exhibit less CVS side effects but more sedation: trazodone and bupropion • Amoxapine a metabolite of antipsychotic loxapine: retain AP action of the parent drug

  30. Maprotyline,structure resembles desimipramine is a potent NE reuptake inhibitor, causing <sedation,antimuscarinic and CVS side effects .

  31. C. Third Generation of AD • Venlafaxine: - potent inhibitor of serotonin transporter; & weak inhibitor of NE transporter; in low dose= SSRI, high doses (> 225 mg/d)  mild-moderate increase HR & BP • Nefazodone: as trazodone, but less sedation. potent inhibitor of CYP 3A4 • Duloxetine=SSRI,free of autonomic SE and sedation

  32. Mirtazapine  more rapid in action  no more efficacious than other AD  likely to cause weight gain  substantial sexual side effect  >> sedating because of strong antihistaminergik effect

  33. ADE  Interference with autonomic control - Atropine like : dry mouth blurred vision constipation urinary retention - Orthostatic hypotension : central NE effect - CNS : * sedation, seizure * diff. in concentrating - CVS : prolongation Q-T interval  : risk of sudden cardiac †

  34. Cytochrome P450 enzymes involved in psychopharmacological drug 2D6 : - amitriptyline, desipramine, imipramine, haloperidol, nortriptyline - venlafaxine 3A4 : amitriptyline, imipramine bupropion clonazepam, diazepam fluoxetine, sertraline zolpidem 2C19 : amitriptyline, clomipramine, imipramin, diazepam, moclobemide

  35. Drug Interaction  highly protein bound :  free drug in comb. : aspirin, phenylbutazone  inhibitorof Cyp 2D6 : - nortriptyline - desipramin  TCA + alcohol  severe Resp. depression  TCA + antihypertensive adrenergic neuron blocking agents (guanadrel):  BP ! Should be monitored clinically • conc. by • fluvoxamine • paroxetine

  36. D. SSRI (Selective Serotonin Reuptake Inhibitor) Fluoxetine  Fluvoxamine  Paroxetine  Sertralin Mechanism of action • More selective 5 HT-reuptake Inhibitor more 5 HT at rec.  desensitization of autorec  normal firing rt. • No influence to cholinergic nerves / NE, dopamin  less side effects

  37. ADE  << than TCA : CVS, antimusc.  acute toxicity : << dangerous than TCA  combination with MAOI  serotonin syndrome: tremor, hyperthermia, CVS collaps  † reported  common : nausea anorexia insomnia loss of libido, failure of orgasm

  38. Indication :  major depression  anxiety disorder  panic attacks  obsessive-compulsive disorder (OCD)

  39. ADE • Paroxetine: highest affinity to serotonin receptors….indirectly result in a net decline in dopaminergic transmission leading to extrapyramidal side effects (distonia, akathisia) • Sexual function(delayed ejaculation and anorgasmia) paroxetine>fluoxetine, sertraline> flufoxamine

  40. D. Monoamine oxidase Inhibitors • Than older MAOI : • pargiline • tranylcypromine Moclobemide : selective MAOI ( type A),reversible  less interaction  less CNS ADR Main ADR : - postural hypotension - atropin like action - weight gain - CNS stimulation acute overdose  convulsions - cheese reaction : severe hypertension (tyramine containing food > 10 mg) - hyperpyrexia hypotension in comb. with pethidine

  41. III. ANXIOLYTIC & HYPNOTIC DRUGS • BENZODIAZEPINES  Mechanism of action - facilitate GABA action (≠ receptor binding) : hyperpolarization, Cl channel opening - safe because its action depend on endogenous GABA ≠ barbiturate : direct action in overdose  Pharmacological effects - reduction of anxiety and aggression - sedation and induction of deep - reduction of muscle tonus and coordination - anticonvulsant effect

  42. ADE  Acute overdosage - less dangerous, only rarely  † - in the present of other CNS depressant esp. alcohol : severe resp. disorder or in COPD ! could be counteract by antagonist flumazenil Common side effect : - drowsiness - confusion - impaired coordination - amnesia esp. with long acting drug  impairment of job performance and driving skill

  43. Chronic use :  Tolerance : less than barbiturate  Dependence demonstrate by -  symptoms of anxiety - tremor - dizziness  withdrawal symptoms : slower in onset than barbiturates with triazolam : a short acting BDZ occurred within a few hours : - early morning insomnia - daytime anxiety  Addiction : not a mayor problem after withdrawal

  44. short acting Indication • Hypnotic : - lorazepam - temazepam ! not for chronic use  tolerance • Anxiolytic : acute anxiety state e.g. panic disord. agoraphobia choice : alprazolam 2-3 times daily 0.25-0.5 mg altern. : diazepam 2 times daily 2-5 mg • Muscular relaxant in muscle spasm : diazepam • Other : - Alprazolam : anxiety in major depressive disorder - Clobazam : claimed to cause less sedation as antianxiety drug

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