ANTIPSYCHOTICS: DA Blockers

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ANTIPSYCHOTICSDA Blockers

• Cesar A. Soutullo, M.D.
• UC-3 Psychopharmacology Series

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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

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Dopamine Pathways

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

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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-HTgtDA
• Less Nigrostriatal block
• Also effect on Mesocortical (neg. Sx)

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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

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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

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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

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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

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Extrapyramidal Sx. (EPS)

• Acute Dystonias
• Antipsychotic-induced Parkinsonism
• Akathisia
• Tardive Dyskinesia (TD)
• Neuroleptic Malignat Syndrome (NMS)

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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

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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

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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

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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

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Neuroleptic Malignant Syndrome (NMS)

• Medical Emerg, mort. 20 (now 4)
• 1. Fever gt100.4F / 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
  (gt15.000 WBC), CPK gt 300, seizures, arrithmias,
  mioglobinuria, ARF

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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

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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

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Clozapine Clozaril

• Weak D1D2 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

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Clozapine Side Effects

• Agranulocytosis (1), 80 in 1st 4.5 mo.
• If WBClt3,000 and ANClt1,500 stop, wait until it
  returns to 3,500 CBC bi-wk
• If WBClt2,000 and ANClt1,000 stop do not re-start
• Do not use with Carbamazepine or other bone
  marrow suppressors

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Clozapine Side Effects

• Sedation
• Dizziness, orthostatic hypotension
• Hypersalivation
• Weight Gain
• Lower Seizure Threshold

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Novel Antipsychotics

• Risperidone low EPS at doses lt6 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