Wednesday, November 29, 2000



Wednesday, November 29, 2000 Scribe: Eric Chan

Pharmacology 8:00 a.m. Joe Roman

AntiPsychotic Agents I & II

Note: Dr. Roghani read straight from his notes, word for word, so why I am retyping this, I don’t know? Page 9 Roghani’s notes: Know that chart!

Introduction

Antipsychotic=neuroleptic

• Therapeutic benefit in psychosis: Patients become less withdrawn or less excited, less agitated, less hostile, less irritable. Some patients may be withdrawn without recurrence while others may require a lifetime of treatment.

• These drugs also relieve the manic phase of bipolar affective disorder.

• There is no proven difference in antipsychotic efficacy among the conventional antipsychotic drugs. However, atypical antipsychotic drugs may relieve symptoms in schizophrenic patients resistant to the other agents and may produce a better quality of response.

• Conventional antipsychotic drugs are those that were approved through 1975, they act primarily by antagonizing dopamine receptors.

• First atypical antipsychotic agent approved in the U.S. was Clozapine. There are now others to follow. They produce significant action on 5HT2 receptors as well as on dopamine D2 receptors.

Conventional Antipsychotics Atypical Antipsychotics

Phenothiazines Clozapine

Haloperidol Rispiridone

Miscellaneous Olanzapine

Quetiapine

Sertindole

Conventional Antipsychotics

A. Phenothiazines

1. Structure-Activity Relationships

• Phenothiazine structure forms the basic nucleus of this group.

• Substitution at position (2) imparts antipsychotic activity

• Substitution on the nitrogen at position (10) alters potency

Potency:

Aliphatic and piperidine substituted compounds are called low potency

Piperazine substituted compounds are high potency antipsychotics

Other effects:

*Aliphatic and piperidine compounds: more likely to cause sedation, orthostatic hypertension, hypersensitivity; less likely to induce parkinsonism

Recommended as a second-line drug in treatment of acute psychosis.

*Piperzine compounds: are more likely to cause extrapyramidal effects but cause less hypotension or sedation.

2. Pharmacological Effects

The phenothiazines are antagonists at various dopamine receptors (D1 and D2) and at adrenergic and muscarinic receptors. They have a high affinity for D2 receptors, and the degree of binding with D2 receptors correlates with clinical potency in alleviating schizophrenia.

a. Behavioral effects

• Antipsychotic action: reduce hallucinations, delusions

• Sedation: helps in agitated patients, but in not essential for antipsychotic activity

• Decreased spontaneous activity

• Mechanism of action: Dopamine receptor blockade in mesolimbic-mesocortical dopaminergic system.

• Inhibits adenylyl cyclase.

b. Lowered seizure threshold

c. Toxic confusional state due to central anticholinergic effects

d. Extrapyramidal effects

Parkinsonism-----------------------------Treatment: reduce dose or change drugs

Mechanism: Antipsychotic drug antagonism of dopamine D2 receptors in nigrostriatal system

Acute dystonia---------------------------Treatment: benztropineor diphenhydramine

Mechanism: Dopamine recptor blockade by antipsychotic drugs

Akathisia---------------------------------Treatment: reduce dose

Mechanism: uncertain

Tardive dyskinesia----------------------Treatment: gradual reduction of dose; avoid

(stereotyped by repetitive, anticholinergic drugs, switch to clozapine

involuntary movements switch to atypical drugs. of the mouth,lips) Mechanism: development of supersensitivity

of dopamine receptors as consequence of

long term blockade

Perioral tremor---------------------------Treatment:Responds to anticholinergic

(Rabbit Syndrome) antiparkinson drugs

Tardive Dyskinesia is a major problem with use of the anitpsychotic drugs

• should use the lowest effective dose

e. Antiemetic effect:

• Blockade of chemoreceptor trigger zone; blocks emesis induced by apomorphine, morpine, and other agents acting on the CTZ

• Pheothiazines in general are not effective against motion sickness, but promethazine (phenergen) is effective

f. Autonomic nervous system effects:

• Alpha-adrenergic receptor blockade: result-orthostatic hypotension

• Muscarinic receptor blockade: dry mouth, blurred vision

• Phenothiazine antipsychotic agents have antihistaminic and antiserotonergic activity

g. Cardiac effects:

• Anticholinergic and quinidine-like effects on the heart

• Depressed T-wave and prolonged Q-T interval which are reversible on discontinuation of the drug

h. Endocine effects:

• Dopamine receptor blockade results in increased prolactin secretion, producing lactation in females, gynecomastia in males

• Decreased secretion of gonadotropin, growth hormone and ACTH

i. Temperature regulation:

• Depression of temperature regulating and vasomotor mechanisms causes the pt. to tend to assume the temp. of the environment (poikilothermic effect)

3. Adverse effects:

• Central nervous system: Drowsiness, Parkinsonism, akathisisa, dystonia

• Autonomic: Hypotension, tachycardia

*Hypotension is more common with the aliphatic compounds

• Endocrine: Galactorrhea, gynecomastia, menstrual changes

• Hypersensitivity: Photosensitivity allergic rashes, blood dyscrasias

• Miscellaneous:

*Eye- Toxic retinopathy

4. Neuroleptic Malignant Syndrome:

• Fever diaphoresis, marked muscular rigidity, stupor

• Incidence is as high as 0.5-1% of pts. who receive high-potency neuroleptics

• Death from respiratory or renal failure, cardiovascular collapse, arrhythmias

• MUST stop drug

• Mechanism relates to sudden decrease in dopaminergic activity

• Bromocriptine effective for symptoms

• Levodopa-carbidopa and amantadine have also been used with some success.

• The pt. should not be re-exposed to a neuroleptic drug for at least 2 weeks.

• Maintain hydration

5. Drug Interactions:

• Potentiation of CNS depressants and opiods

• Synergistic depression with ethanol and inhibition of alcohol metabolism

• Reduced therapeutic effectiveness of levodopa in Parkinson’s disease.

• Additive anticholinergic effects and alpha blocking effects

• Interference with antihypertensive effect of guanethidine

• Thioridazine with drugs that have quinidine-like action may potentiate cardiotoxicity

• Inhibition of phenytoin metabolism

B. HALOPERIDOL (Haldol)

• Considered a high potency conventional antipsychotic drug

• Recommended as first-line drugs for treatment of schizophrenia

• Basic therapeutic effects are similar to the phenothiazines

• Extrapyramidal effects are common and are more frequent than with aliphatic or piperdine phenothiazines(chlorpromazine or thioridazine); has precipitated neuroleptic malignant syndrome.

• Potent dopaminergic D2 receptor antagonist

• Fewer autonomic effects but still causes orthostatic hypotension

• Lacks anticholinergic effects

• Particularly effective for acute mania

C. OTHERS

• Thiothixene-alternative to other agents. High Potency

• Loxapine—alternative for pts. refractory to others, but higher likelihood of oculogyric crisis and seizures.

• Molindone- Unlikely to cause weight gain. Low Potency

I. ATYPICAL ANTIPSYCHOTICS

Since clozapine, risperidone, olanzapine, quetiapine, and sertindole have been approved. All these agents are atypical antipsychotics which have in common high affinity for 5HT2 receptors as well as dopamine D2 antagonist activity. They bind less avidly to D2 receptors in the striatum and hypothalamus. Therefore, produce less extrapyramidal symptoms and endocrine disturbance. They reduce both positive and negative symptoms of Schizophrenia. They appear to improve cognitive function

A. Clozapine( Clozaril)

• Blocks dopamine receptors in the mesolimbic-mesocortical system while having less dopamine D2 receptor blocking activity in the extrapyramidal system. It is an effective antipsychotic agent which produces minimal extrampyramidal side effects, including an apparent lack of tardive dyskinesia

• Clozapine is characterized as an atypical antipsychotic agent since it produces minimal extrapyramidial effects.

• Conventional drugs have a much lower affinity for 5HT2 receptors than the new drugs.

• Is several times more potent in blocking 5-HT2 receptors than D2 receptors.

• High affinity for D4 dopamine receptors found in limbic areas

• Potent anticholinergic actions in the caudate

• Recommended only for pts. who have not responded adequately to standard antipsychotic drugs

• Clozapine treated patients are more animated and their behavior is more socially appropriate than pts. treated with other antipsychotics.

Adverse Effects:

• Agranulocytosis—most serious adverse effect of clozapine

• Onset is usually within the first six months of treatment, but the cell count can drop abruptly.

• If total white cell count falls below 3000/mm3 or the granulocyte count falls below 1500, treatment is interrupted.

• If the white cell count is less than 2000 or the granulocytes less than 1000, then the drug must be discontinued

• Seizures

• Withdrawal – rapid withdrawal may result in marked exacerbation of the patient’s psychosis. Schizophrenic patients who have responded well to clozapine should not be taken off without a valid reason.

• Other: Sedation, Tachycardia, Dizziness, and Hypotension.

Dosage

• To minimize hypotension, sedation and seizures, use low doses initially, followed by gradually increasing dose until maintenance level is achieved.

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