Antipsychotics

Primarily used to treat schizophrenia, but can also be effective in psychotic/manic states. Wide variety of side effects. These drugs are not curative but can decrease severity of symptoms

Antipsychotic Drugs

1st generation (FGAs)

Competitive inhibitors at a variety of receptors but antipsychotic affect is due to the blockage of D2 receptors. Likely associated with extrapyramidal symptoms especially haloperidol which binds tightly. Those that don’t bind as tightly like chloropromazine. have less movement disorder association

Examples: chlorpromazine and thiordazine have low potency. High potency drugs include fluphenazine, haloperidol, loxapine, molindone, perphernazine, pimozide, prochlorperazine, thiothixene, trifluoperazine.

2nd Generations (SGAs)

Lower incidence of extrapyramidal symptoms than 1st gen but have high incidence of of metabolic ADRs. Block 5HT2 and D2 receptors. Generally 1st line, efficacy exceeds/equals 1st gen. 1/5 of patients have an insufficient response to 1st or 2nd gen or high suicide risk → use clozapine. Pimavanserin is only indicated for psychosis associated with Parkinson’s.

Mechanism of Action

Dopamine Antagonist: All of 1st and 2nd gen block the D2 receptors in the brain and periphery.

Serotonin receptor blocking: Most 2nd gen also block the 5HT2 receptors. Clozapine has a higher affinity for D1, D4, 5HT2, muscarinic, and alpha adrenergic - weak to D2. Risperidone and olanzapine blocks 5HT2a better than D2. Ariproprazole, brexpiprazole, and cariprazine are partial agonist for D2 and 5HT1a and 2a. Quetiapine has a weak block at D2 and 5HT2a resulting in a lower risk for extrapyramidal symptoms. Pimavanserin acts as an inverse agonist (does the opposite) and antagonist at the 5HT2a and 2c receptors with no affinity for dopamine receptors.

Actions

Clinical effects are due to a blockade at dopamine or serotonin receptors. Many antipsychotics also block cholinergic, adrenergic, and histaminergic receptors.

Block D2 in mesolimbic system→ decrease delusions and hallucination but causes a blunted affect, apathy, impaired attention, cognitive impairment these secondary affects can be amerliorated by some SGAs. Cognitive impairment and anxiety are difficult to treat.

If we block D2 in the chemoreceptor trigger zone→ we also have antiemetic effects

Pharmokinetics

When given orally antipsychotics have variable absorption. These agents pass the BBB and have a large volume of distribution. They are metabolized usually by the CYP450 enzyme system. Some metabolites are active. Some are available in a long-acting injectable (last 2-4 weeks or 6 months usually given IM). Asenapine is available SL and transdermal.

Therapeutic Uses

Schizophrenia → only efficacious treatment is antipsychotics (1st gen is better at getting the “good symptoms”).

Anti-emetic → older ones like prochlorperazine are useful in treating drug-induced nausea. Olanzapine may be affect with chemo associated N/V.

Risperidone and aripiprazole are used to manage disruptive behavior secondary to autism. Pimozide can help with tics associated with Tourette’s, however risperidone and haloperidol are commonly prescribed. Mania and bipolar disorder can be managed with lurasidone, cariprazine, and quetiapine. Schizoaffective can be treated with paliperidone. In treatment refractory depression we can use ariprprazole, brexpiprazole and quetiapine. With intractable hiccups you can use chlorpromazine.

Maintenance

Patients who have had 2 or more psychotic episodes secondary to schizophrenia should receive maintenance therapy for at least 5 years. Rate of relapse of SGAs.

ADRs

Clozapine: bone marrow suspension, seizures, orthostasis, severe agranulocytosis (watch WBCs), constipation

Extrapyramidal symptoms are due to the imbalance of ACh and dopamine in the nigrostriatal pathway. So if we also block cholinergic receptors we can regain the balance (beta blockers can also help). SGAs have less.

Tardive dyskinesia (involuntary movements usually of the tongue, lips, neck, trunk, limbs) can occur months to years after treatment. Stoping the medications for awhile and picking them back up later can help. SGAs have less. Cholinergic antagonist given for the EPS can worsen tardive dyskinesia. Tardive dyskinesia can be managed with vesicular monamine transporter inhibitors.

Drowsiness occurs within the first few weeks of treatment.

Anything that blocks alpha adrenergics will cause orthostatic hypotension. Poikiolthermia (conditions in which body temperature varies with the environment). Anything that blocks D2s in the dopaminergic tuberounfundibular pathway may cause an increase in prolactin release, which can cause adverse effects such as gynecomastia, amenorrhea, or galactorrhea. Sexual dysfunction and weight gain is common. Mild to significant QT prolongation (thioridazine has the highest risk).

Contraindications and red flags

May lower seizure threshold so watch your epileptic patients or those withdrawing from alcohol.

Increased mortality risk in elderly patients or those with dementia-related behavioral disturbance and psychosis. Use lower doses and titrate your doses.