Antipsychotic Drugs

Antipsychotic drug (AKA Neuroleptic Drugs)

Definition: drugs that diminish psychotic thought processes (e.g. hallucination, delusions, ideas of reference)

classified as either typical or atypical; atypical block 5-HT_2A receptors (5-hydroxytryptamine (5-HT) is serotonin)

Typical

D₂ (Dopamine) receptor antagonists

Cause extrapyramidal side effects (EPS)

Ý serum prolactin

induce tardive dyskinesia with chronic use

Prototype drug: Haloperidol

Atypical

5-HT_2A (serotonin) and D₁ receptor antagonists

minimal to no EPS

minimal to no Ý in serum prolactin

probably less/no propensity to induce tardive dyskinesia

Prototype drug: Clozapine

Typical Antipsychotic Drugs

Examples

Phenothiazines

Alipathic (Chlorpromazine) - commonly used
Piperidine (Thioridazine) - not commonly used due to side effects

side effects: can cause retinitis pigmentosa resulting in irreversable blindness; retrograde ejaculation

Piperazine (Fluphenazine) - commonly used as a slow-release depot form

Thioxanthines (Thiothixene)
Butyrophenones (Haloperidol) - commonly used in ER departments; available as a slow release depot form
Dibenzoxazepines
Indoles

Mechanism of Action - D₂ receptor antagonists (D₂ is one of five subclasses of Dopamine receptors)

Direct correlation between dose and affinity

Four Principal Dopamine Systems in the Human Brain:

(1) Nigrostriatal projection: substantia nigra Þ caudate-putamen

Blockade leads to: EPS and tardive dyskinesia

(2) Mesolimbic projections: midbrain tegmentum Þ cortex and limbic structures

Blockade leads to: therapeutic effects

(3) Mesocotical projections: midbrain tegmentum Þ mesial-prefrontal and temporal areas of the cerebral cortex

(4) Tubero-infundibular projection: hypothalamus Þ pituitary

Blockade leads to: elevated prolactin (remember that dopamine tonically inhibits prolactin release)

Depolarization Blockade refers to lack of spontaneous and evoked responses by dopaminergic neurons after acute (1 day) or chronic (4 week) treatment with antipsychotic drugs

typicals induce depolarization blockade of both substantia nigra and ventral tegmental area (VTA) DA neurons

atypicals induce depolarization blockade of only the VTA DA neurons; substantia nigra not affected Þ no EPS

Side Effects of Typical Antipsychotic Drugs

Acute Side Effects:

Sedation: histamine (H₁) receptor blockade is side effect of typicals

this occurs in atypcials as well - may be related to 5-HT_2A receptor blockade

Anticholinergic: effect inversely proportional to potency; ß potency Þ Ý anticholinergic side effects

Orthostatic Hypotension: due to a ₁-adrenergic blockade

Extra-pyramidal side effects

Parkinsonism: bradykinesia, tremor, gait disturbances - treated with anticholinergic medications (benztropine, trihexyphenidyl (symptoms of true Parkinson’s tend to be asymmetric; drug-induced Parkinsonism is symmetric)

Acute dystonias (spasm of voluntary muscle groups): treated with intramuscular benztropine

Akathisis: restlessness (objective/subjective); treated with hydrophobic b -blockers (propranolol)

Elevated Prolactin: galactorrhea (white discharge from the nipple)

Neuroleptic Malignant Syndrome - may occur at any time following typical/atypical antipsychotic drug administration

Characteristics: lead pipe rigidity (Parkinsonism-associated cogwheel rigidity), autonomic instability (Ý HR), fever, rhabdomyolysis (breakdown of skeletal muscleÞ Ý CPK and myoglobinuria/emia), altered mental status (coma)

Treatment: stop antipsychotic medication, transfer to ICU, aggressive hydration, Dantrolene (skeletal muscle relaxant) and Bromocryptine (D₂ agonist)

Risk Factors: Ý parenteral doses of antipsychotic drug over short period of time (uncommon now with ß dosing regimens), non-schizophrenia diagnosis, male, non-caucasian

Tardive Dyskinesia (TD): involultary mvts of any skeletal muscle in the body; often seen in face (oral-facial dyskinesia)

Risk Factors: female, non-schizophrenia diagnosis, diabetes, elderly, long-term typical antipsychotic drug treatment

Chronic Side Effects:

Tardive dystonia - acute dystonia which does not improve

Tardive akathisia - long term, does not improve; restlessnes

NOTE: all tardive syndromes may be lessened or even ameliorated by the atypical drug clozapine

Side Effect Profile of Typical Antipsychotic Drugs

Drug	Potency	Sedation/ Anti-cholinergic	a 1 -blockade	EPS
Thioridazine	Low	+++	+++	+/++
Perphenazine (Phenothiazine)	Medium	++	++	++
Haloperidol	High	+	0/+	+++

Potency inversely correlates with sedation/anticholinergic and hypotension and directly correlates with EPS

Atypical Antipsychotic Drugs

Examples:

Clozapine - binds to large number of neurotransmitter receptors (5-HT_2A, 5-HT_2c, 5-HT₆, 5-HT₇, D₃, D₄, m₁-m₅ muscarinic, a ₁-adrenergic, etc)

effective in treatment-resistant schizophrenia; no Ý in EPS; may ameliorate tardive syndromes in some patients

Side Effects: agranulocytosis (0.9%) (ß neutrophils), seizures, orthostatic hypotension, constipation, sialorrhea (drooling), low potency

Risperidone-most widely prescribed; Side Effects: orthostasis, sedation, more EPS than other atypicals, high potency

Olanzapine (structurally similar to Clozapine) - 2^nd most widely prescribed; Side Effects: orthostasis, sedation, high potency

Quietipine: Side Effects: sedation, anti-cholinergic side effects, no EPS, efficacy unknown

Sertindole/ziprasidone: not FDA approved; Side Effects: dry ejaculation and prolonged Q-T interval

Mechanism of Action

in general have higher affinities for 5-HT (particularly for 5-HT_2A) than for dopamine receptors

high 5-HT_2A/D₁ affinity ratio predicts atypicality

5-HT_2A receptors are concentrated in cortical regions: especially in limbic cortical regions (eg cingulate gyrus)
5-HT_2A receptors are located on apical dendrites of pyramidal neurons

LSD is a 5-HT_2A receptor agonist and is hallucinogenic