Typical antipsychotics

Typical antipsychotics
Typical antipsychotics, which include phenothiazines and nonphenothiazines, can be broken down into smaller classifications.
Different adverse reactions
Many clinicians believe that the phenothiazines should be treated as three distinct drug classes because of the differences in the adverse reactions they cause:
Aliphatics primarily cause sedation and anticholinergic effects. They’re low potency drugs that include chlorpromazine.
Piperazines primarily cause extrapyramidal reactions and include fluphenazine decanoate, fluphenazine enanthate, fluphena-zine hydrochloride, perphenazine, and trifluoperazine.
Piperidines primarily cause sedation and anticholinergic and cardiac effects; they include mesoridazine and thioridazine.
Different chemical structure

Based on their chemical structure, nonphenothiazine antipsychotics can be divided into several drug classes, including:

• butyrophenones, such as haloperidol and haloperidol decanoate
• dibenzoxazepines such as loxapine
• dihydroindolones such as molindone
• diphenylbutylpiperidines such as pimozide
• thioxanthenes, such as thiothixene and thiothixene hydrochloride.

Pharmacokinetics

Although phenothiazines are absorbed erratically, they’re very lipid-soluble and highly protein-bound. Therefore, they’re distributed to many tissues and are highly concentrated in the brain.

Like phenothiazines, nonphenothiazines are absorbed erratically, are lipid-soluble, and are highly protein-bound. They’re also distributed throughout the tissues and are highly concentrated in the brain.

Metabolism and excretion

All phenothiazines are metabolized in the liver and excreted in urine and bile. Because fatty tissues slowly release accumulated phenothiazine metabolites into the plasma, phenothiazines may produce effects up to 3 months after they’re stopped.

Nonphenothiazines are also metabolized in the liver and excreted in urine and bile.

Pharmacodynamics

Although the mechanism of action of phenothiazines isn’t fully understood, researchers believe that these drugs work by blocking postsynaptic dopaminergic receptors in the brain.

The mechanism of action of nonphenothiazines resembles that of phenothiazines.

Erecting a blockade

The antipsychotic effect of phenothiazines is due to receptor blockade in the limbic system. Their antiemetic effect is due to receptor blockade in the chemoreceptor trigger zone located in the brain’s medulla.

Sending a charge

Phenothiazines also stimulate the extrapyramidal system (motor pathways that connect the cerebral cortex with the spinal nerve pathways).

Pharmacotherapeutics

Phenothiazines are used primarily to:

• treat schizophrenia
• calm anxious or agitated patients
• improve a patient’s thought processes
• alleviate delusions and hallucinations.

Working overtime

Other therapeutic uses have been found for phenothiazines:

• They’re administered to treat other psychiatric disorders, such as brief reactive psychosis, atypical psychosis, schizoaffective psychosis, autism, and major depression with psychosis.
• In combination with lithium, they’re used in the treatment of patients with bipolar disorder, until the slower-acting lithium produces its therapeutic effect.
• They’re prescribed to quiet mentally challenged children and agitated geriatric patients, particularly those with dementia.
• The preoperative effects of analgesics may be boosted with their addition.
• They’re helpful in the management of pain, anxiety, and nausea in patients with cancer.

Solo solutions

As a group, nonphenothiazines are used to treat psychotic disorders. Thiothixene is also used to control acute agitation. Haloperidol and pimozide may also be used to treat Tourette syndrome.

Drug interactions

Phenothiazines interact with many different types of drugs and may have serious effects:

• Increased CNS depressant effects, such as stupor, may occur when phenothiazines are taken with CNS depressants.
• CNS depressants may reduce phenothiazine effectiveness, resulting in increased psychotic behavior or agitation.
• Taking anticholinergic drugs with phenothiazines may result in increased anticholinergic effects, such as dry mouth and constipation. By increasing phenothiazine metabolism, anticholinergic drugs may also reduce the antipsychotic effects of phenothiazines.
• Phenothiazines may reduce the antiparkinsonian effects of levodopa.
• Concurrent use with lithium increases the risk of neurotoxicity.
• Concurrent use with droperidol increases the risk of extrapyramidal effects.
• The threshold for seizures is lowered when phenothiazines are used with anticonvulsants.
• Phenothiazines may increase the serum levels of TCAs and beta-adrenergic blockers. Thioridazine can cause serious, even fatal, cardiac arrhythmias when combined with such drugs as fluvoxamine, propranolol, pindolol, and fluoxetine that inhibit the cyto-chrome P-450 2D6 isoenzyme, or drugs known to prolong the QTc interval. 

Warning!

Adverse reactions to typical antipsychotics

Neurologic reactions are the most common and serious adverse reactions associated with phenothiazines.

Extrapyramidal symptoms

Extrapyramidal symptoms (EPS) may appear after the first few days of therapy; tardive dyskinesia may occur after several years of treatment.

S.O.S.! Extreme EPS!

Neuroleptic malignant syndrome is a potentially fatal condition that produces muscle rigidity, extreme EPS, severely elevated body temperature, hypertension, and rapid heart rate. If left untreated, it can result in respiratory failure and cardiovascular collapse.

Little difference

Most nonphenothiazines cause the same adverse reactions as phenothiazines.

Special caution

Antipsychotics with anticholinergic properties should be avoided in elderly patients.

Fewer interactions

Nonphenothiazines interact with fewer drugs than phenothiazines. Their dopamine-blocking activity can inhibit levodopa and may cause disorientation in patients receiving both medications. Halo-peridol may boost the effects of lithium, producing encephalopathy (brain dysfunction).