First generation antipsychotics increase prolactin levels by blocking the inhibitory actions of dopamine on lactrophic cells in the anterior pituitary.

Know: Dopamine receptor stimulation of anterior pituitary inhibits prolactin secretion. DA agonists like DA, bromocryptine and apomorphine will inhibit prolactin secretion. Neuroleptics and other DA antagonists increase prolactin levels.

Three of the more important side-effects of antipsychotic medications are neuroleptic malignant syndrome, acute extrapyramidal symptoms, and serotonin syndrome. Explain the manifestation and treatment of these three side effects.

How often is NMS fatal?

 Who is more likely to get NMS?

Serotonin syndrome is potentially life threatening. It is a consequence of excess serotonergic activity at CNS and peripheral serotonin receptors. Symptoms range from barely perceptible to fatal. Treatment consists of discontinuing medication and in moderate to severe cases administering a serotonin antagonist. Another important adjunct treatment is controlling agitation with benzodiazepine sedation. Symptoms include cognitive effects (headache, hypomania, mental confusion, hallucinations, coma), autonomic effects (shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, diarrhea), and somatic effects (myoclonus, hyperreflexia, tremor).

Acute extrapyramidal symptoms include akinesia (inability to initiate movement) and akathisia (inability to remain motionless). They are various movement disorders such as acute dystonic reactions (torticollis, occulogyric crisis, muscular spasms of tongue or jaw), pseudoparkinsonism (drug induced parkinsonism), tardive dyskinesia (involuntary, irregular muscle movements, usually in the face). Anticholinergic drugs are used to control symptoms but akathisia may require beta blockers or benzodiazepines. Switching to an atypical antipsychotic may relieve symptoms. Other commonly used medications for EPS are benztropine (Cogentin), diphenhydramine (Benadryl), and trihexyphenidyl (Artane).

NMS is a life-threatening neurological disorder that presents with muscle rigidity, fever, autonomic instability and cognitive changes such as delirium, and is associated with elevated CPK. It is very unpredictable so there is no one set course of action to treat the syndrome but usually removal of the antipsychotic drug treatment along with medical management leads to a positive outcome. Some say there is a genetic risk factor for NMS. Males under 40 are at greatest risk and so are postpartum women. Another very important risk factor is dementia; neuroleptics should be used very cautiously. Ten percent of cases are fatal.

Note: NMS is triggered by D2 blockers. More powerful D2 blockers like typical (or first generation) antipsychotics are much more likely to cause this than weaker D2 blockers like atypical (or second generation) antipsychotics. Treatment of NMS is to discontinue meds and may use either dantrolene or bromocrytpine.

Aripiprazole (Abilify), Clozapine (Clozaril), Ziprasidone (Geodon), Paliperidone (Invega), Risperidone (Risperdal), Quetiapine (Saroquel), Olanzapine (Symbax), Olanzapine (Zyprexa)

What effects do typical and atypical antipsychotics have on: postive symptoms of schizophrenia, negative symptoms of schizophrenia, and cognitive impairment associated with schizophrenia? Describe these symptoms.

The positive symptoms of neuroleptics: reduce the hallucinations and delusions associated with schizophrenia by blocking dopamine receptors in the mesolimbic system of the brain.

The negative symptoms of atypical and typical neuroleptics: anhedonia (not getting pleasure from normally pleasurable stimuli), apathy,  and sexual dysfuntion .

Cognitive impairments of atypical and typical neuoleptics: confusion, sedation, altered mental status, stupor, and drowsiness

Typicals and atypicals block positive symptoms of schizophrenia (via DA receptor blockade).
Atypicals (but not typicals) block negative symptoms of schizophrenia (via 5HT receptor blockade).

Atypical antipsychotic medications block ~ 40 to 60% D2 receptors.

Typical (or first generation) antipsychotics: block D2 receptors very effectively, do not block serotonin receptors.

Atypical (or second generation) antipsychotics: block D2 receptors, but not as effectively as typicals + also block serotonin receptors.

 What are the three main classes of typical (or first-generation) antipsychotic medications?

Give examples of each class.

1. Butyrophenones: Example Haloperidol

2. Phenothiazines: Example Chlorpromazine

3. Thioxanthenes: Example Chlorprothixene

What percentage of D2-receptors are blocked by typical antipsychotic medications?

 What other receptors may be blocked by these medications?

Typicals block ~ 80% D2 receptors.

Atypicals block about 40 - 60% of D2 receptors + 5HT receptors.

Make sure you understand how this accounts for their actions and side effects.

Side effects with first generation antipsychotics include sedation, anticholinergic effects, extrapyramidal symptoms (EPS), orthostatic hypotension, weight gain, photosensitivity, and elevated prolactin levels.

EPS: Include muscle stiffness, rigidity, tremor, drooling, “masklike” face. These symptoms may be treated with antiparkinson agents. Akathisia is not treated with antiparkinson agents however a beta-blocker maybe beneficial. Dystonia is an EPS common with acute onset (sudden spasm of muscle in tongue, jaw, and neck) the patient needs to seek immediate medical attention as this can be rapidly reversed with an anticholinergic.

The low-potency first-generation antipsychotics have more anticholinergic activity than the high-potency agents. When antipsychotics are combined with other medications with significant anticholinergic activity, such as tricyclic antidepressants and antiparkinson agents, the anticholinergic action of the medications are additive.

Adverse reactions include: Neuroleptic Malignant Syndrome, heatstroke, Tardive Dyskinesia, seizures, and arrhythmia (QTc prolongation).

Also known as atypical antipsychotics, they block both serotonin & dopamine receptors (clozapine, risperidone).They have lower potential of causing extrapyramidal effects and have lower risk of tardive dyskinesia.This is not exactly correct. DA antagonists produce parkinsonian symptoms. Second-generation (atypical) antipsychotics are less likely to produce these effects (extrapyramidal effects/tardive dyskinesia) because they are less effective at blocking D2 receptors than first-generation antipsychotics.

Metaclopramide (Reglan) has central antidopaminergic and peripheral cholinergic properties.

 What are the side effects of metoclopramide and how would you treat them?

Serious side effects caused by metaclopramide are: EPS - Parkinsonism, akathisia, neuroleptic malignant syndrome, tardive dyskinesia. These are caused by DA receptor blockade and may be treated with diphenhydramine, benztopine (Cogentin), or trihexyphenidyl (Artane).

Other side effects are: seizures, diarrhea, loss of bladder control, depression/suicidal thoughts, hallucination. Many of these side effects are due to the peripheral cholinergic effects of metaclopramide and may be treated with anticholinergic agent.

For the Test:

 Neuroleptic agents may be used to treat nausea and vertigo. Drugs you might give during the perioperative period include droperidol (a butyrophenone) and prochlorperazine (Compazine, a phenothiazine).