Neuroleptics

Neuroleptic agents may be used to treat nausea and vertigo.

Drugs you might give during the perioperative period include:

1. droperidol (a butyrophenone)

2. prochlorperazine (Compazine, a phenothiazine).

What effect do these medications have on prolactin levels? Explain

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

2. Dopamine receptor stimulation of anterior pituitary inhibits prolactin secretion. DA agonists like DA, bromocryptine and apomorphine will inhibit prolactin secretion.

3. Neuroleptics and other DA antagonists increase prolactin levels.

Three of the more important side-effects of antipsychotic medications are

1. neuroleptic malignant syndrome

2. acute extrapyramidal symptoms

3. 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:

1. Potentially life threatening consequence of excess serotonergic activity at CNS and peripheral serotonin receptors.

2. Symptoms: cognitive effects (headache, hypomania, mental confusion, hallucinations, coma), autonomic effects (shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, diarrhea), and somatic effects (myoclonus, hyperreflexia, tremor).

3. Treatment: consists of discontinuing medication and in moderate to severe cases administering a serotonin antagonist.

4. Another important adjunct treatment is controlling agitation with benzodiazepine sedation.

Three of the more important side-effects of antipsychotic medications are

1. neuroleptic malignant syndrome

2. acute extrapyramidal symptoms

3. serotonin syndrome.

Explain the manifestation and treatment of these three side effects.

How often is NMS fatal?

Who is more likely to get NMS?

Acute extrapyramidal symptoms: 

1. Akinesia (inability to initiate movement) and akathisia (inability to remain motionless).

2. They are various movement disorders such as:

         *acute dystonic reactions (torticollis, occulogyric crisis, spasms of tongue or jaw)

         *pseudoparkinsonism (drug induced parkinsonism)

          *tardive dyskinesia (involuntary, irregular muscle movts, usually in the face).

3. Anticholinergic drugs are used to control symptoms but akathisia may require beta blockers or benzodiazepines.

4. Switching to an atypical antipsychotic may relieve symptoms.

5. Other commonly used medications for EPS are benztropine, diphenhydramine

Three of the more important side-effects of antipsychotic medications are

1. neuroleptic malignant syndrome

2. acute extrapyramidal symptoms

3. serotonin syndrome.

Explain the manifestation and treatment of these three side effects.

How often is NMS fatal?

Who is more likely to get NMS?

NMS

1. Life-threatening neurological disorder that presents with muscle rigidity, fever, autonomic instability and cognitive changes such as delirium

2. Associated with elevated CPK.

3. Treatment of NMS is to d/c meds and may use either dantrolene or bromocrytpine, along with medical management

3. Some suggest a genetic risk factor for NMS.

4. Risk group: Males under 40,  postpartum women, dementia. 10% of cases are fatal.
6. NMS is triggered by D2 blockers.

7. 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.

Name some early atypical (second-generation) antipsychotic medications

Clozapine

Risperidone

What effects do typical and atypical antipsychotics have on:

1. postive symptoms of schizophrenia

2. negative symptoms of schizophrenia

3. cognitive impairment associated with schizophrenia?

Describe these symptoms.

The positive symptoms of neuroleptics:

1. Reduce the hallucinations and delusions associated with schizophrenia by blocking dopamine receptors in the mesolimbic system of the brain.

2. Typicals/atypicals block (+) symptoms of schizophrenia (via DA receptor blockade).

The negative symptoms of atypical and typical neuroleptics:

1. Anhedonia (not getting pleasure from normally pleasurable stimuli), apathy, sexual dysfunction

2. Atypicals (not typicals) block (-) symptoms of schizophrenia (via 5HT blockade).

What is the mechanism of action of atypical antipsychotic mediations and how does this compare to the mechanism of action of typical antyipsychotic medications?

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

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

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

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

Give examples of each class.

1. Butyrophenones: Haloperidol

2. Phenothiazines: Chlorpromazine

3. Thioxanthenes: Chlorprothixene

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

What other receptors may be blocked by these medications?

1. Typicals block ~ 80% D2 receptors.

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

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

What are the main side-effects of first-generation antipsychotics?

1. Sedation, anticholinergic effects, EPS, ortho hypoTN, weight gain, photosensitivity, and elevated prolactin levels.

2. EPS: Include muscle stiffness, rigidity, tremor, drooling, “masklike” face. These symptoms may be treated with antiparkinson agents.

3. Akathisia is not treated with antiparkinson agents but beta-blocker maybe beneficial.

4. Dystonia is an EPS common with acute onset (sudden spasm of muscle in tongue, jaw, and neck) and can be rapidly reversed with an anticholinergic.
5. The low-potency 1st-gen antipsychotics have more anticholinergic activity than the high-potency agents.

6. Combination with other meds with significant anticholinergic activity (TCAs/antiparkinson), the anticholinergic action of the medications are additive.
7. Adverse reactions include: NMS, heatstroke, Tardive Dyskinesia, seizures, and arrhythmia (QTc prolongation).

What are the main side-effects of second-generation antipsychotics?

1. Also known as atypical antipsychotics, they block both serotonin & dopamine receptors (clozapine, risperidone).
2. They have lower potential of causing extrapyramidal effects and have lower risk of tardive dyskinesia.

3. DA antagonists produce parkinsonian symptoms.

4. 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?

1. Serious side effects caused by metaclopramide are: EPS - Parkinsonism, akathisia, neuroleptic malignant syndrome, tardive dyskinesia.

2. These are caused by DA receptor blockade and may be treated with diphenhydramine, benztopine (Cogentin), or trihexyphenidyl (Artane).
3. Other side effects are: seizures, diarrhea, loss of bladder control, depression/suicidal thoughts, hallucination.

4. Many of these side effects are due to the peripheral cholinergic effects of metaclopramide and may be treated with anticholinergic agents.