Antipsychotics

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a. The “typical” antipsychotic medications include

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dopamine D2 receptor antagonists.

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dopamine hypothesis

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that schizophrenic symptoms are the result of excess dopamine activity.

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This observation indicates that while the “dopamine hypothesis” has merit, it is too simplistic.

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b. Although dopamine antagonists result in anti-DA activity within hours, symptom improvement in schizophrenic patients on these medications takes weeks

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first typical antipsychotics

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phenothiazines

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phenothiazines have three families within the class of drugs that are based on structures that alter potency:

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i. Low potency: chlorpromazine (prototype)
ii. Intermediate potency: thioridazine
iii. High potency: fluphenazine
iv. The lower potency drugs cause more sedation and less extrapyramidal effects. The higher potency drugs cause less sedation and more extrapyramidal effects.
v. Although there are differences in potency and side effects of the different subfamilies, all of the drugs have roughly the same therapeutic efficacy.

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d. Pharmacologic actions/side effects of phenothiazines

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i. Histamine blockadesedation; tolerance develops in a few weeks
ii. Chemoreceptor trigger zone blockadeanti-emetic
iii. Dopamine blockadehyperprolactinemiaamenorrhea-galactorrhea
iv. Dopamine blockadeextrapyramidal dysfunction: Parkinsonism, akathisia, dystonia, tardive dyskinesia, neuroleptic malignant syndrome
v. Cholinergic blockadedry mouth, constipation, urinary retetion, blurred vision
vi. Alpha-adrenergic blockadepostural hypotension
vii. Decreased seizure threshold
viii. Abnormal temperature regulation
ix. Moderate weight gain

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e. Drug interactions of phenothiazines

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i. Potentiation of anticholinergic drugs
ii. Potentiation of other CNS depressants, benzodiazepines, opioids
iii. Potentiation of adrenergic-blocking antihypertensive drugs

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f. Haloperidol

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i. High-potency (non-phenothiazine) dopamine blocker

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Haloperidol side effects

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ii. High incidence of extrapyramidal side effects: Parkinsonism, akathisia, dystonia, tardive dyskinesia, neuroleptic malignant syndrome.
iii. Can also cause hyperprolactinemia due to dopamine blockade.
iv. Relatively free of cholinergic, alpha-adrenergic, and histamine-blocking side effects.

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typical antipsychotics include?

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phenothiazine
haloperidol
molindone
thiothixene

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efficacy and side effects of molindone and thiothixene?

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g. Molindone
i. Also high-potency with extrapyramidal side effects
h. Thiothixene
i. Less potent than phenothiazines, lower incidence of EP side effects

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2. Describe the time course and symptoms of antipsychotic drug-induced neuromuscular effects?

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a. Parkinsonism
i. Can occur within 5-30 days.
ii. Tremors, muscle rigidity, bradykinesia
b. Akathisia
i. 5-60 days
ii. Motor restlessness (unable to remain stationary in one position)
c. Dystonias
i. Also early complication
ii. Prolonged abnormal contractions of the neck, tongue, and mouth muscles
d. Tardive dyskinesia
i. Irreversible complication of long-term use that occurs more frequently in older patients. The disorder consists of rhythmic, involuntary movements of tongue, lip smacking, abnormal postures, and involuntary limb movements.
e. Neuroleptic malignant syndrome
i. Severe muscle rigidity and hyperthermia that occurs about 30 minutes after injection. Can treat with dantrolene and bromocriptine.
f. These are all thought to be due to dopamine blockade.

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3. Explain how atypical antipsychotics differ from classical antipsychotics

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a. The atypical antipsychotics have a greater occupancy at 5-HT2 receptors relative to D2 receptors. Several of these drugs have also been reported to selectively block dopamine receptors on mesolimbic neurons rather than nigrostriatal neurons. These drugs are typically now first-line agents for schizophrenia due to far fewer extrapyramidal side effects. However, all have been reported to induce severe hyperglycemia and obesity.

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what is now the frontline drugs used in treatment of schizophrenia?

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the atypical antipsychotics

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what are the atypical antipsychotics

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clozapine
Olanzipine
Risperidone
Quetaipine
Ziprasidone
Aripiprazole

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clozapine info

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i. Blocks 5-HT2, D2, and alpha receptors
ii. Side effects include somnolence, orthostatic hypotension, hyperglycemia, and obesity.
iii. Lowers seizure threshold.
iv. Agranulocytosis may occur.

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olanzipine info

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i. Blocks several 5-HT receptors, D2 receptors, and alpha receptors
ii. Side effects include somnolence, orthostatic hypotension, hyperglycemia, and obesity.

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risperidone info

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i. Blocks 5-HT and D2 receptors. Also blocks alpha-1, alpha-2, and H1 receptors with lower affinity.
ii. Sedation
iii. Dose-related hypotension/reflex tachycardia
iv. Hyperglycemia, obesity
v. May prolong QT interval with possibility of arrhythmias

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Quetiapine info

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i. Blocks DA, 5-HT, and H1 receptors
ii. Toxicity: marked somnolence, orthostatic hypotension, hyperglycemia, and obesity.

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ziprasidone info

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i. Blocks D2, 5-HT2, and alpha receptors
ii. Toxicity
1. Somnolence, orthostatic hypotension, hyperglycemia, obesity
2. May prolong QT interval. There is a risk of sudden death, so the use of this drug is restricted to patients who fail other drugs.

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aripiprazole inof

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i. Complex, unique mechanism that is thought to involve mixed agonist and antagonist activities at the D2 and 5-HT receptor subtypes.
ii. Toxicity
1. Somnolence, orthostatic hypotension, hyperglycemia, obesity
2. Weight gain may be less than other atypicals

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4. List the uses of phenothiazines

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i. Schizophrenia
ii. Mania, schizoaffective disorder, Tourette’s syndrome
iii. Treatment of agitation and other symptoms of dementia
iv. Anti-emetic

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4. List the uses of buterophenones(haloperidol)

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i. Schizophrenia
ii. Mania, schizoaffective disorder, Tourette’s syndrome