Antipsychotic Drugs

Antipsychotic Drugs
(Tx of Schizophrenia & more)

Schizophrenia (Sz)
0.81% in the U.S.A. dx. w/ Sz per NIMH.
Sz is a neurodevelopmental disorder > problems with attention & information processing.
The relationship between Sz & neurochemical findings is NOT clear.

Schizophrenia (Sz)
Positive symptoms:
delusions, hallucinations, bizarre behavior, disturbed thinking, incoherence.

Negative symptoms:
blunted affect, apathy, social withdrawal.

Traditional Antipsychotic Drugs
Classical = Traditional = Neuroleptic = Major Tranquilizer = Antischizophrenic.
Block dopamine receptors. The extent of binding to dopamine receptors predicts efficacy, dose, & liklihood of > side effects.
Therapeutic effects are inseparable from side (toxic) effects on the extrapyramidal motor system.
Treats positive symptoms of sz, but may worsen negative symptoms.
Makes the Sz more manageable.

Traditional Antipsychotic Drugs
Extrapyramidal side (toxic) effects:
parkinsonian symptoms (muscle rididity), slow movements, restlessness.
tardive dyskenisia,
NMS (neuroleptic malignant syndrome).

Traditional Antipsychotic Drugs
Phenothiazines
Most widely used and least $ drugs for tx of psychosis.
Also used for: nausea, vomiting, as sedation, premature ejaculation, itch relief, alcoholic hallucinosis, anti-psychedelic, psychosis of acute mania.

Traditional Antipsychotic Drugs
Phenothiazine Pharmacokinetics:
Oral administration most common > Erratic & unpredictable GI tract absorption.
Metabolized slowly by the liver.
IM injections can increase effectiveness.
Level in brain low, compared with levels in other body tissues (lungs, liver, adrenals, spleen).
Dosage decision made on trial and error basis.

Traditional Antipsychotic Drugs
Phenothiazine Pharmacological Effects:
Block dopamine receptors -- as well as: acetylcholine (dry mouth, dilated pupils, blurred vision , constipation, urinary retention, & tachycardia), serotonin, histamine (sedation, anti-nausea), & norepinepherine (hypotension, sedation) receptors.
Decrease: paranoia, fear, hostility, agitation; reduces the intensity of Sz hallucinations and delusions. (limbic system effects).
Decrease: behavioral arousal, vomiting (brain stem effects).

Traditional Antipsychotic Drugs
Phenothiazine Pharmacological Effects: 
Motor disturbances (basal ganglia):
acute extrapyramidal effects: 
akasthesia - subjective anxiety, restlessness, repetitive seemingly purposeless actions; 
dystonia - involuntary muscle spasms, sustained abnormal posturing of limbs, trunk, face, & tongue; 
parkinsonism - resting tremor, limb rigidity, slowing movement, decreased initiation
tardive (late) dyskinesia - involuntary hyperkinetic movements (sometimes severely disabling). It can appear months after initiation of treatment and is often irreversible
less common toxic effects: skin pigmentation changes, permanently impaired vision, liver dysfunction, blood disorders, NMS.

Traditional Antipsychotic Drugs
Phenothiazine Pharmacological Effects: 
(hypothalamus-pituitary):
Decrease: hunger/appetite, temperature regulation ability.
Males: breast enlargement, blocked ejaculation.
Females: lactation, decreased libido, abnormal menstration, infertility.
High-potency phenothiazines (Prolixin, Stelazine, Trilafon) cause less sedation, less anticholinergic effect; more extrapyramidal effect.
Not drugs of abuse; no tolerance, no dependance.
Does not cure mental illness, long term use is associated with serious side effects.
Phenothiazines

Alternative to Traditional Antipsychotic Meds.
Haldol (haloperidol), 1967.
Similar to the phenothiazines (blocks dopamine receptors). However, fewer serious side effects, less sedating, but has potential for great adverse parkinsonian effects.
Provided an alternative for psychotic patients who did not respond to phenothiazines.

Atypical Antipsychotics
Clozaril (clozapine) 1989.
Used with tx resistant Sz, sometimes with success!
Treats negative symptoms including disorganization. Less extrapyramidal effect, less cognitive inhibition.
Oral absorption.
Expensive.
Blood levels (rarely, but potentially fatal).
Side (toxic) effects: sedation, weight gain, constipation, agranulocytosis (a rare, drug-induced blood disorder that is characterized by a severe reduction in the number of white blood cells), urinary incontinence, hypotention, esophagitiss, seizures, excessive drooling. Withdrawal symptoms (psychosis, hostility, paranoia, nausea, restlessness, agitation, confusion, sweating).

Atypical Antipsychotics
Risperdal (risperidone), 1993
Improved control of psychotic symptoms, with minimal extrapyramidal effects.
Well absorbed orally.
Reduces positive symptoms; less extrapyramidal effect.
Side (toxic) effects: decreased memory, sleep disorders, agitation, anxiety, headache, nausea, weight gain. Extrapyramidal effects are seen at high doses and in patients with new onset of Sz.

Atypical Antipsychotics
Zyprexa (olanzapine), 1996
Absorbed orally.
Improves positive & negative symptoms (per manufacturer). Reduces agitation and aggression.
Extrapyramidal effects are rare (per manufacturer).
Used to treat Bipolar Disorder, Pervasive Developmental Disorder
Side (toxic) effects: weight gain, sedation, orthostatic hypotention, dizziness.

Atypical Antipsychotics
Seroquel (quetiapine) 1998.
Reduces positive symptoms, sometimes reduces negative symptoms.
Low extrapyramidal side effects.
Used to treat drug-induced psychosis in Parkinson’s Disease, Bipolar Disorder, Schizoaffective Disorder.