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ANTIPSYCHOTICS: DA Blockers

ANTIPSYCHOTICS: DA Blockers. Cesar A. Soutullo, M.D. UC-3 Psychopharmacology Series. PSYCHOSIS. Is a symptom with many causes Med (Infec, Metab,Endocr), Tox, Psych Psychotic Symptoms delusions hallucinations disorganized speech: incoherent, derailment

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ANTIPSYCHOTICS: DA Blockers

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  1. ANTIPSYCHOTICS:DA Blockers Cesar A. Soutullo, M.D. UC-3 Psychopharmacology Series

  2. PSYCHOSIS • Is a symptom with many causes • Med (Infec, Metab,Endocr), Tox, Psych • Psychotic Symptoms • delusions • hallucinations • disorganized speech: incoherent, derailment • grossly disorganized or catatonic behavior • negative Sx: flat affect, alogia, avolition

  3. Dopamine Pathways • Nigro-Striatal • Extrapiramidal Movements (EPS) • Mesolimbic (VTA-amygdala) • Positive Symptoms • Mesocortical (VTA-frontal lobe) • Negative Symptoms • Tubero-Infundibular • Inhibits PRL, Thermoregulation

  4. Antipsychotics: Mechanism of Action • Postsynaptic DA Block: D1 & D2 • Typical Antipsychotics • Nigrostriatal DA block: EPS • Mesolimbic DA block: reduces pos. Sx. • Atypicals: also block 5-HT>DA • Less Nigrostriatal block • Also effect on Mesocortical (neg. Sx)

  5. Antipsychotics: Potency • Degree of DA affinity, NOT efficacy • High Potency • High DA Affinity • Low Histamine, Cholinerg, alphaAdrenergic • Low Potency • Low DA Affinity • High Hist, Choliner, alpha-Adrenergic 1 & 2 • Medium Potency

  6. Antipsychotics: Pharmacokinetics • Typicals T-1/2 aprox 24 hrs (hs or bid) • SE limit the amount given in one dose • Peak plasma level: 2-4 hrs (po) 30 min (IM) • Takes 5-7 days to steady-state

  7. Antipsychotics: Initiation of Tx • Start low dose (Range): • 10-20 mg Haldol • 300-500 mg Chlorpromazine equivalents • Divided doses minimize SE • Prophyl. anticholinegics with High Poten. • Acute Agitation: Can combine with Lorazepam 1-2 mg po/IM

  8. Antipsychotics: Side Effects • Neurological (Extrapyramidal) DA-block • Non-Neurological (Low Potency) • Histaminergic: Sedation, Wt gain • Anticholinergic: Perypheral & Central • Alpha-Adrenergic: Orthostasis, EKG • Endocrine-Sexual: PRL, 5-HT • Hematologic: Agranulocytosis • Eye & Skin: retinopathy, photosensitivity • Seizure threshold: lowered • Liver: cholestatic jaundice CPZ

  9. Extrapyramidal Sx. (EPS) • Acute Dystonias • Antipsychotic-induced Parkinsonism • Akathisia • Tardive Dyskinesia (TD) • Neuroleptic Malignat Syndrome (NMS)

  10. Acute Dystonias • Muscle spasm face-neck-trunk-eye-larinx • Early in Tx., young males • Dose Related, Tolerance, incidence 50% • Treatment: Benadryl 50 mg IM (IV 25-50 for laryngospasm), Cogentin 1-4 mg IM • Prevention reduces incidence to 5% • Low dose, • Benztropine 1 mg / every Haldol 5 mg

  11. Antipsychotic-induced Parkinsonism • Incidence 50-75% with high pot. • Rigidity • Bradikinesia: mask face-gait problems • Resting Tremor • Flexed Posture • Dif Dx. with flat affect • Tx: Cogentin, Artane 2 mg bid-tid (elder) • Reduces incidence to 5-10%

  12. Akathisia • Subjective feeling of restlesness • Unable to sit still, pacing • Incidence 20-30%, lower with low dose • Dif Dx.: psychosis, agitation, anxiety • Tx: Propranolol 30-90 mg/d (not in asthma or diabetes), Klonopin 1 mg bid • SSRI Antidepressants cause akathisia too

  13. Tardive Dyskinesia (TD) • Slow choreo-athetotic movements • Oro-facial muscles • Risk 4% per year of exposure • Risk factors elderly women, mood DO, diab. • Risk management • document informed consent, AIMS Tests • Tx?: Vit E 1600 U/d, Clozapine low risk

  14. Neuroleptic Malignant Syndrome (NMS) • Medical Emerg, mort. 20% (now 4%) • 1. Fever >100.4F / 37.5C • 2. Severe EPS: lead-pipe/cogwheel rigidity, sialorrhea, oculogyric crisis • 3. Autonomic DysFx: BP fluctuations, tachycardia, tachypnea, diaphoresis • Also: Alt. conciousness, delirium, leukocytosis (>15.000 WBC), CPK > 300, seizures, arrithmias, mioglobinuria, ARF

  15. NMS • Incidence 0.1-1%, (60% of it in 1st 2 wks) • Risk factors: multiple IM injections, high dose, rapid increase of dose agitation, dehydration, heat, lithium use • Tx: STOP ALL antipsychotics, also antiemetic Reglan (Metoclopramide), antidepr. Amoxapine

  16. NMS Treatment • Stop ALL Antipsychotics • Dif. Dx: fever & delirium • Dantrolene (muscle relax) 1-3 mg/kg/day NTE 10 mg/kg/d • Bromocriptine (DA Agonist) 5 mg tid-qid • Supportive Tx: • IV fluids, antipyretics, cooling blankets, close cardiac & renal monitoring

  17. Clozapine [Clozaril] • Weak D1=D2 block, high 5-HT2 block • (5-HT2/D2 = 20/1) • alpha1, alpha2, H1, M1 • Tx Res. Schizophrenia, mood stabilizer • Effective in Negative and Positive Sx, low EPS, low TD

  18. Clozapine: Side Effects • Agranulocytosis (1%), 80% in 1st 4.5 mo. • If WBC<3,000 and ANC<1,500 stop, wait until it returns to 3,500 CBC bi-wk • If WBC<2,000 and ANC<1,000 stop & do not re-start • Do not use with Carbamazepine or other bone marrow suppressors

  19. Clozapine: Side Effects • Sedation • Dizziness, orthostatic hypotension • Hypersalivation • Weight Gain • Lower Seizure Threshold

  20. Novel Antipsychotics • Risperidone low EPS at doses <6 mg/d, antidepressant?, elevates PRL, [dose 1-8 mg/d] • Olanzapine positive and negative Sx, low EPS, sedation, wt gain, mood stabilizer [dose: 5-20 mg/day] • Quetiapine need bid, low EPS, sedation, hypotension [dose 200-700 mg/day] • Ziprasidone need bid, tid t1/2 5 hrs

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