1. Antipsychotics: chemistry and pharmacokinetics
Antipsychotics: chemistry and pharmacokinetics
Domina Petric, MD

2. Chemical types I.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

3. Antipsychotic drugs: relation of chemical structure to potency and toxicities
Chemical class
Drug
D2/5-HT2A ratio
Clinical potency
Extrapyramidal toxicity
Sedative action
Hypotensive action
Phenothiazines
Aliphatic
Chlorpromazine
High
Low
Medium
Piperazine
Fluphenazine
Very low
Thioxanthene
Thiothixene
Very high
Butyrophenone
Haloperidol
Dibenzodiazepine
Clozapine
Benzisoxazole
Risperidone
Thienobenzodiazepine
Olanzapine
Dibenzothiazepine
Quetiapine
Low to medium
Dihydroindolone
Ziprasidone
Dihidrocarbostyril
Aripiprazole
D2/5-HT2A ratio is ratio of affinity for D2 receptors to affinity for 5-HT2A receptors.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

4. Phenothiazine derivatives
Aliphatic derivatives (chlorpromazine) and piperidine derivatives (thioridazine) are the least potent.
These drugs produce more sedation and weight gain.
Piperazine derivatives are more potent (effective in lower doses), but not necessarily more efficacious.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

5. Phenothiazine derivatives
Piperazine derivatives are more selective in their pharmacologic effects.
Perphenazine (piperazine derivative) may be as effective as atypical antipsychotic drugs, with the modest exception of olanzapine.
Typical antipsychotic drugs may be the treatment of choice for schizophrenia when it comes to their lower cost.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

6. Butyrophenone derivatives
Haloperidol is the most widely used typical antipsychotic drug, despite its very high level of extrapyramidal syndrome (EPS) relative to typical antipsychotic drugs.
The butyrophenones and congeners are more potent and have fewer autonomic effects, but greater extrapyramidal effects, than phenothiazines.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

7. Miscellaneous structures
Pimozide and molindone are typical antipsychotic drugs.
There is no significant difference in efficacy between these newer typical and the older typical antipsychotic drugs.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

8. Atypical antipsychotic drugs
Clozapine, asenapine, olanzapine, quetiapine, paliperidone, risperidone, sertindole, ziprasidone, zotepine and aripiprazole.
Clozapine is the prototype.
Paliperidone is 9-hydroxyrisperidone, the active metabolite of risperidone.
Risperidone is rapidly converted to hydroxyrisperidone, except for about 10% of patients who are poor metabolizers.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

9. Atypical antipsychotic drugs
These drugs share a greater ability to alter 5-HT2A receptor activity than to interfere with D2-receptor action.
They act as partial agonists at the 5-HT1A receptor, which produces synergistic effects with 5-HT2A receptor antagonism.
Most are either 5-HT6 or 5-HT7 receptor antagonists.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

10. Atypical antipsychotic drugs
Sulpiride and sulpiride constitute have equivalent potency for D2 and D3 receptors, but they are also 5-HT7 antagonists.
They dissociate EPS and antipsychotic efficacy.
They also produce marked increases in serum prolactin levels.
They are not as free of the risk of tardive dyskinesia as are clozapine and quetiapine.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

11. Clinical potency High High Low Low Medium Quetiapine
Chlorpromazine
Quetiapine
Clozapine, Ziprasidone
Fluphenazine, thiothixene, haloperidol
Risperidone, olanzapine, aripiprazole
Katzung, Masters, Trevor. Basic and clinical pharmacology.

12. Extrapyramidal toxicity
Very high
High
Medium
Low
Very low
Clozapine, olanzapine, quetiapine, ziprasidone, aripiprazole
Risperidone
Chlorpromazine, thiothixene
Fluphenazine
Haloperidol
Katzung, Masters, Trevor. Basic and clinical pharmacology.

13. Sedative action Low High Low Medium Very low Aripiprazole
Fluphenazine, haloperidol, clozapine
Risperidone, ziprasidone
Thiothixene, olanzapine, quetiapine
Chlorpromazine
Katzung, Masters, Trevor. Basic and clinical pharmacology.

14. Pharmacokinetics
II.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

15. Absorption and distribution
Most antipsychotic drugs are readily, but incompletely absorbed.
Many undergo significant first-pass metabolism.
Oral doses of chlorpromazine and thioridazine have systemic availability of 25-35%.
Haloperidol (less first-pass metabolism) has an average systemic availability of about 65%.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

16. Absorption and distribution
Most antipsychotic drugs are highly lipid soluble and protein bound (92-99%).
They tend to have large volumes of distribution, usually more than 7 L/kg.
These drugs generally have a much longer clinical duration of action than would be estimated from their plasma half-lives.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

17. Absorption and distribution
Metabolites of chlorpromazine may be excreted in the urine weeks after the last dose of chronically administered drug.
Long-acting injectable formulations may cause some blockade of D2 receptors 3-6 months after the last injection.
Time to recurrence of psychotic symptoms is highly variable after discontinuation of antipsychotic drugs.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

18. Absorption and distribution
The average time for relapse in stable patients with schizophrenia who discontinue their medication is 6 months.
Clozapine is an exception: relapse after discontinuation is usually rapid and severe.
Clozapine should never be discontinued abruptly, unless clinically needed, because of adverse effects: myocarditis, agranulocytosis.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

19. Metabolism
Most antipsychotic drugs are almost completely metabolized by oxidation or demethylation, catalyzed by liver microsomal cytochrome P450 enyzmes.
CYP2D6, CYP1A2 and CYP3A4 are the major isoforms involved.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

20. Metabolism
Drug-drug interactions should be considered when combining antipsychotic drugs with various other psychotropic drugs or drugs that inhibit various cytochrome P450 enzymes (like ketoconazole).
At the typical doses, antipsychotic drugs do not usually interfere with the metabolism of other drugs.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

21. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Literature
Katzung, Masters, Trevor. Basic and clinical pharmacology.
Katzung, Masters, Trevor. Basic and clinical pharmacology.