Adrenergic antagonist drug

Antipsychotic Drugs

First-Generation Antipsychotics: FGAS (Typical)

Low Potency

(Extrapyramidal symptoms; EPS, but more H1, α1 and muscarinic blocking effects)

·         Phenothiazines:

o   Chlorpromazine CPZ & Thioridazine

High Potency

(More extrapyramidal symptoms (EPS), but less H1, α1 and muscarinic blocking effects)

· Phenothiazines:

o   Fluphenazine, Perphenazine, Trifluoperazine, Mesoridazine & Prochlorperazine

· Butyrophenones:

o   Haloperidol & Droperidol

· Others:

o   Loxapine, Zuclopenthixol, Flupenthixol, Pimozide & Thiothixene

Second-Generation Antipsychotics; SGAS (Atypical)

v  Second-generation agents are generally used as first-line therapy for schizophrenia to minimize the risk of EPS associated with the first- generation agents.

v  Clozapine, Aripiprazole, Olanzapine, Paliperidone, Quetiapine, Risperidone, Lurasidone, lloperidone, Ziprasidone, Asenapine, Sertindole & Sulpiride

v  Haloperidol is the most widely used typical antipsychotic. Aripiprazole is the most widely prescribed antipsychotic agent.

v  Pharmacokinetics: Depot forms (Along-acting forms) of Haloperidol, Fluphenazine, Zuclopenthixol, Risperidone, Pallperidone, Olanzapine and Aripiprazole.

Mechanism of action:

1) Dopamine Antagonists; All of the first-generation and most of the second-generation antipsychotic drugs block D dopamine receptors in the brain and the periphery.

2) Serotonin Antagonists; Most of the second-generation agents appear to exert part of their unique action through inhibition of 5-HT receptors, particularly 5-HT2a receptors.

v  Differences in Second-Generation (Most Common Agents); Clozapine: Strong 5-HT2A antagonist, weak D; antagonist (Antipsychotic mechanism), it also acts as an antagonist at α, M, H1 and other D & 5-HT receptors.

v  Aripiprazole; D2 & 5-HTA partial agonist and 5-HT2A antagonist.

v  Risperidone & Olanzapine; 5-HT2A antagonist > D2 antagonist.

v  Quetiapine; D2 antagonist > 5-HT2A antagonist.

Pharmacological Action:

1) Antipsychotic Effects:

A) Positive Symptoms; All antipsychotic drugs can reduce Positive Symptoms.

B) Negative Symptoms; Not responsive to the first-generation agents, but many second-generation agents.

C) Cognitive Symptoms: Not responsive to all antipsychotic drugs

2) Antiemetic Effects: Most of the antipsychotic drugs (except Aripiprazole) have antiemetic effects, blocking D2 in CTZ

3) Anticholinergic Effects; Some of the antipsychotics (particularly, Thioridazine, Chlorpromazine, Clozapine and Olanzapine).

4) Extrapyramidal Symptoms (EPS); are drug-Induced movement disorders. R can occur with both acute and chronic treatment. Blocking of dopamine receptors in the nigrostriatal pathway may cause unwanted movement symptoms.

v  Conditions of EPS:

A) Dystonia:

·         Dystonia is a sustained muscle contractions or abnormal postures.

·         Muscular spasms of, neck, jaw, back, extremities, eyes (oculogyric crisis), throat (laryngospasm) and tongue.

·         Highest risk in young men.

·         This is also treated with anticholinergic.

B) Akathisia

·         Akathisia, A feeling of internal motor restlessness that can present as tension, nervousness, or anxiety (inability to stay still or calm).

·         Treatments; reducing the antipsychotic dose or switching to an agent with a lower incidence of Akathisia is the best options. B-blockers (lipophilic) such as Propranolol and Nadolol are effective and are the agents of choice, it poorly responds to anticholinergic.

C) Psoudoparkinsonism (Parkinson-like Symptoms)

·         Parkinson-like symptoms such as; bradykinesia, rigidity, tremor or akinesia.

·         Greater risk in the elderly.

·         It is usually responsive to anticholinergic agents such as Diphenhydramine, Trihexyphenidyl & Benztropine.

D) Tardive Dyskinesia

·         Characterized by abnormal involuntary movements that occur with long-term antipsychotic therapy.

·         It usually involves the orofacial muscles and is often insidious.

·         If treated early, it can be reversible, continued drug exposure, particularly at high doses, it is often irreversible.

·         Symptoms may decrease with lowering the dose of antipsychotic or switching to an agent that is associated with less tardive dyskinesia, (Clozapine has not been associated with tardive dyskinesia). Anticholinergic agents should not be given to treat tardive dyskinesia and may actually worsen the symptoms.

5) Antiadrenergic Effects;

·         Blockade of α-adrenergic receptors cause orthostatic hypotension and light-headedness.

6) Antihistamine Effects:

·         Sedation occurs with drugs that are potent antagonists of the H1 receptor (Chlorpromazine, Olanzapine, Quetiapine & Clozapine)

7) Neuroleptic Malignant Syndrome (NMS):

·         This is another serious complication after EPS.

·         It occurs with all agents but more common with high-potency drugs.

·         Symptoms; agitation, confusion, consciousness disturbance, fever, tachycardia, unstable blood pressure and sweating

·         Its mortality rate is high (should be taken seriously).

·         Treatments:

·         Discontinue the drug and give supportive therapy, including fluids and cooling.

·         Bromocriptine (dopamine agonist) and Dantrolene (direct skeletal muscle relaxant) may be helpful.

8) Endocrine Effects

·         Dopamine inhibits prolactin hormone from pituitary.

·         Dopamine antagonists can increase prolactin concentrations, can cause Hyperprolactinemia;

o   In female, menstrual disturbance (amenorrhea) & galactorrhea.

o   In male. Gynecomastia and impotence (erectile dysfunction).

Therapeutic Uses

A) Psychiatric Indications;

·         Schizophrenia; is the primary indication for antipsychotic agents.

·         Psychotic bipolar disorder (BP-1), psychotic depression and treatment-resistant depression.

·         Schizoaffective disorders; characteristics of both schizophrenia and affective disorders (depression, bipolar disorder & anxiety disorder).

·         Tourette's syndrome and disturbed behavior in patients with Alzheimer's disease.

B) Non-psychiatric Indications:

·         Prevention of nausea and vomiting; most of older typical antipsychotic drugs (except Thioridazine) have a strong antiemetic effect.

·         Neuroleptanalgesia in medical procedure, Droperidol (Butyrophenones, typical antipsychotic) is used in combination with Fentanyl (opioid) in neuroleptanalgesia.

Side Effects

A) Serious Side Effects;

1) Extrapyramidal Side Effects (EPSE).

2) Neuroleptic Malignant Syndrome (NMS)

B) General Side Effects

1) Sedation and drowsiness: Due to antihistaminic effects, particularly with Chlorpromazine, Olanzapine, Quetiapine & Clozapine.

2) Antimuscarinic Side Effects; Particularly, Thioridazine, Chlorpromazine, Clozapine and Olanzapine.

3) Orthostatic Hypotension and light-headedness: Due to block α-adrenergic receptors.

4) Hyperprolactinemia;

·         In female; (amenorrhea) and galactorrhea.

·         In male; Gynecomastia and impotence (erectile dysfunction).

5) Sexual Dysfunction; erectile problems occur in 23-54% of men. Loss of libido may occur in men and women.

6) Weight Gain; Due to histamine or serotonin receptors

C) Specific Side Effects for Typical Antipsychotics:

·         Low-potency agents (Thioridazine and Chlorpromazine) can cause pigmentary deposits on the retina and corneal opacity.

·         Many of the typical agents (Thioridazine, Pimozide, and IV Haloperidol) can cause serious QT interval prolongation.

D) Specific Side Effects for Atypical Antipsychotics:

·         Clozapine Serious Side Effects: Agranulocytosis: Reduction in white blood cell count and it increases the risk of serious or fatal infections.

·         It is occurs about 1-2% and is highest during the first 4-6 months of therapy.

Ziprasidone can cause serious QT interval prolongation.

References

Medscape

PubMed

drugbank

pharma guide

WebMD