ANTIPSYCHOTICS

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ANTIPSYCHOTICS

• Citation Dr. Walters note packet.

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PSYCHOSES

• 1. AFFECTIVE DISORDERS
• Unipolar (depression), mania, bipolar
• 2. SCHIZOPHRENIA
• Type I positive sx delusions, hallucinations
• Type II negative sx social/emotional
  w/drawal, blunted affect, flat face ventricular
  enlargement
• 3. PARANOIAS
• recurrent delusions (false beliefs)

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NEUROSES

• Obsessive-compulsive disorder
• Patient must repeat an action
• Phobias
• Fears that are irrational
• Anxiety
• Sense of apprehension, danger associated w/
  autonomic sx (tachycardia, profuse sweating)

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DA HYPOTHESIS OF SCHIZOPHRENIA

• PSYCHOSES are related to EXCESS dopaminergic
  activity in mesocorticolimbic brain areas
• EVIDENCE classical drugs effective in tx
  schizophrenia do or have the following
• 1. all block DA D2 receptorsgtgtdecr DA
  transmission
• 2. incr DA synthesis, release, and firing of DA
  neurons
• 3. variable effects on other systems
• 4. cause Parkinsons like side effects

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• What are the 2 problems with the DA hypothesis?
• 1. neurochemical effects (ie. DA synthesis,
  firing DA neurons) occur after acute doses,
  whereas therapeutic effects take weeks to months.
• 2. 20 of patients DO NOT RESPOND AT ALL
• Therefore, based on the effects of Rxs such as
  CLOZAPINE, the hypothesis has been expanded to
  include a role for 5HT (serotonin blocking is
  most effective for negative symptoms of
  schizophrenia)

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• What is the mech for all typical antipsychotics
  (neuroleptics)?
• Block DA D2 receptor in mesocorticolimbic brain
  areas.

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• What are 7 side effects of typical
  antipsychotics?
• 1. sedation (due to anti-histamine activity)
• 2. hypotension (alpha block orthostatic,
  therefore concern for falling)
• 3. extrapyramidal (blocking DA D2 receptors)
• 4. sexual dysfunction (problem of compliance)
• 5. hyperprolactinemia
• 6. weight gain
• 7. discolor urine (pink, red-brown)

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• Why do less potent PHENOTHIAZINES cause fewer EPS
  than more potent ones?
• The hi degree of anti-muscarinic activity blocks
  the effects of increased Ach. However, they are
  more sedating and cause more hypotension.
• Do less potent PHENOTHIAZINES increase the risk
  of seizures?
• Yes, they lower the seizure threshold more than
  the more potent ones. (PIPERIDINES, ALIPHATICS
  are less potent)

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• Do more or less potent PHENOTHIAZINES cause more
  EPS?
• More potent - b/c they have LESS anti-muscarinic
  activity.
• Which cause less sedation and hypotension?
• More potent phenothiazines (piperazines).
• Which cause more sedation and hypotension, but
  less EPS?
• Less potent aliphatics, piperidines.
• Which are less likely to cause seizures?
• More potent piperazine phenothiazines,
  thioxanthines, risperidone.

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• The therapeutic effects of typical
  antiphyshotics are from anti-DAergic actions in
  what area of the brain?
• Mesolimbic
• The motor side effects are from anti-DAergic
  actions in what area of the brain?
• Nigrostriatal (extrapyramidal pathway)

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• What is the evidence that EPS are from
  anti-DAergic effects?
• 1. Motor side effects resemble Parkinsons
  disease.
• 2. Parkinsons is due to a deficit in DA in the
  nigrostriatal pathway.
• 3. Typical antipsychotics block DA receptors
  in the nigrostriatal pathway which mimics a
  deficit in DA.

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• What are 5 extrapyramidal side effects?
• 1. Acute dystonia (spasms of facial/neck/ trunk
  mm, abnormal posturing, twisting movements)
• What is the tx?
• Dose reduction, anticholinergics
  (TRIHEXYPHENIDYL, BENZTROPINE)
• 2. Akathisia (restlessness, pacing, shuffling,
  tapping feet)
• What is the tx?
• Dose reduction, anticholinergics
  (DIPHENHYDRAMINE)

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• 3. Parkinsonian syndrome
• What is the tx?
• Dose reduction, anticholinergics
• What other Rxs can be used to manage these first
  3 side effects?
• BZ (diazepam, lorazepam, clonazepam), Beta
  blockers (propranolol)

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• 4. Neuroleptic malignant syndrome catatonia,
  autonomic instability (which can progress to
  malignant hyperthermia)
• Which Rx, at higher doses, are more likely to
  cause this?
• More potent antipsychotics (FLUPHENAZINE,
  TRIFLUOPERAZINE)
• Tx?
• Discontinue STAT, DA agonist (bromocriptine), IV
  Dantrolene (skeletal m relaxant)
• What is the mech of Dantrolene?
• Inhibits release of Ca from sarcoplasmic
  reticulum.
• Can you restart antipsychotic therapy?
• Yes, after 1-2 wks.

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• 5. Tardive dyskinesia
• Orofacial dyskinesias progressing to
  choreoathetosis (worm-like writhing)
• Tx?
• No tx is universally accepted

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Case

• Overdose of a phenothiazine antipsychotic
• Can you use an emetic?
• No, b/c phenothiazine is an anti-emetic.
  Therefore, use gastric lavage.
• What are the 4 most commonly used phenothiazine
  anti-emetics?
• PROCHLORPERAZINE, PERPHENAZINE, CHLORPROMAZINE,
  TRIFLUPROMAZINE
• What Rx has no anti-emetic activity?
• THIORIDAZINE

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TYPICAL ANTIPSYCHOTICS

• CHLORPROMAZINE (CPZ)
• Pigmentation changes gray, violet happens w/
  most typical anti-psychotics, except MOLINDONE
• Photosensitivity avoid UV (not MOLINDONE)
• Lens opacities deposits in LENS/CORNEA,
  browning of vision
• CPZ also treats intractable hiccoughs

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• THIORIDAZINE
• No anti-emetic activity
• Retinal deposits, browning of vision (IN THE
  RETINA, NOT LENS/CORNEA LIKE CPZ)
• T wave abnormalities, ventricular arrhythmias

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• MESORIDAZINE
• Metabolite of thioridazine
• More potent than parent compound
• Prolongs Q-T interval
• Reserved for patients not responding to other Rxs

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• MOLINDONE
• Least likely to cause seizures
• No photosensitivity
• No pigmentation changes
• No lens opacities or pigmentary retinopathy
• No excessive weight gain
• No male impotence

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• PIMOZIDE
• For Tourettes syndrome (motor, vocal tics,
  echolalia, coprolalia)

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ATYPICAL ANTIPHYCHOTICS

• Why are they called atypical?
• 1. hi affinity for 5HT2 receptor, not D2
• 2. few extrapyramidal side effects

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• CLOZAPINE
• Hi incidence of severe agranulocytosis (get
  regular WBC and granulocyte counts)
• Restricted to refractory psychoses
• Significantly increases risk of seizures, use
  only in severely ill (other tx failed)
• Has caused neuroleptic malignant syndrome
• Hi degree of anticholinergic activity, therefore
  caution if patient has what conditions?
• Prostatic hypertrophy, glaucoma, paralytic ileus

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• Mech of CLOZAPINE
• Block 5HT1c and 5HT2 receptors
• Most effective against or symptoms?
• Negative
• Other side-effects
• Sedation (anti-histamine)
• Weight gain (can lead to onset of type II
  diabetes)

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• RISPERIDONE
• Mech
• Blocks D2 and 5HT2 receptors
• Active metabolite
• Side effects
• Hyperprolactinemia
• Sedation (anti-histamine)

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• OLANZAPINE
• Mech
• Blocks 5HT2 receptor
• Side effects
• Weight gain (type II diabetes)
• 2 reports of sleepwalking

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• QUETIAPINE
• Mech
• Blocks D2 and 5HT2 receptors
• Side effects
• Increases liver transaminases
• Hepatic impairment significantly increases the
  levels of this rx

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• ZIPRASIDONE
• Mech
• Blocks D2 and 5HT2 receptors
• Blocks 5HT and NE uptake
• What is the most serious side effect?
• Prolongs Q-T intervalgtgtincrease risk of torsades
  de pointes

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REVIEW

• What are the 5 typical antipsychotics?
• CHLORPROMAZINE (CPZ)
• THIORIDAZINE
• MESORIDAZINE
• MOLINDONE
• PIMOZIDE

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• Which is used for tourettes?
• PIMOZIDE
• Which can prolong the Q-T interval?
• MESORIDAZINE
• Which has no anti-emetic activity?
• THIORIDAZINE
• Which causes lens opacities by depositing in the
  lens and cornea?
• CPZ
• Which is least likely to cause seizures?
• MOLINDONE

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• What are the 5 atypical antipsychotics?
• CLOZAPINE
• RISPERIDONE
• OLANZAPINE
• QUETIAPINE
• ZIPRASIDONE

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• Which is most effective against negative
  symptoms?
• CLOZAPINE
• Which prolongs Q-T interval (torsades d pointes)?
• ZIPRASIDONE
• Which is used only in the severly ill?
• CLOZAPINE
• Which increases liver transaminases?
• QUETIAPINE

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• Which block both D2 and 5HT2 receptors?
• RISPERIDONE, QUETIAPINE, ZIPRASIDONE
• Which blocks only 5HT2 receptors?
• OLANZAPINE
• Which blocks 5HT1c and 5HT2 receptors?
• CLOZAPINE
• Which, in addition to blocking D2 and 5HT2
  receptors, also blocks 5HT and NE uptake?
• ZIPRASIDONE