Antipsychotic drugs & lithium

Question 1

Phenothiazines, thioxanthene

Answer 1

• Chloropromazine, fluphenazine, thioridazine
• Thiothixene
• MOA
• blockade of D₂ receptors>>5-HT_2A receptors
• Effects
• α blockade (fluphenazine least)
• M blcokade (esp chloropromazine and thioridazine)
• H₁ blockade (chloropromazine, thiothixene)
• CNS depression, decreased seizure threshold
• QT prolongation (thioridazine)
• Clinical
• schizophrenia (alleviate positive symptoms)
• bipolar disorder - manic phase
• antiemesis, preop sedation (promethazine), pruritus
• Kinetics, tox, int.
• oral, parenteral, long t_1/2 with metabolism-dependent elimination
• tox: extensions of α- and M receptor effects, D blockade may result in akathisia, dystonia, parkinsonism, tardive dyskinesia, hyperprolactinemia

Question 2

Butyrophenone

Answer 2

• Haloperidol
• MOA
• blockade of D₂ receptors>>5-HT_2A receptors
• Effects
• some α blockade, but minimal M blockade and much less sedation than phenothiazines
• Clinical
• schizophrenia (alleviates positive symptoms)
• bipolar disorder - manic phase
• huntington’s chorea, tourette’s syndrome
• Kinetics, tox, int.
• oral, parenteral, metabolism-dependent elimination
• tox: extrapyramidal dysfunction

Question 3

Atypical antipsychotics

Answer 3

• Aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone
• MOA
• blockade of 5-HT_2A receptors>>D₂ blockade
• Effects
• some α blockade (clozapine, risperidone, ziprasidone)
• M blockade (clozapine, olanzapine)
• variable H₁ blockade (all)
• Clinical
• schizophrenia (improve both positive and negative sympt.)
• bipolar disorder (olanzapine/risperidone adjunctive with lithium)
• agitation in alzheimer’s and parkinson’s patients (low doses)
• major depression (aripiprazole)
• Kinetics, tox, int.
• tox: agranulocytosis (clozapine), diabetes (clozapine, olanzapine), hypercholesterolemia (clozapine, olanzapine), hyperprolactinemia (risperidone), QT prolongation (ziprasidone), weight gain (clozapine, olanzapine)

Question 4

Lithium

Answer 4

• MOA
• uncertain
• hypothesis: supresses inositol signaling and inhibits GSK-3 (multifunctional protein kinase)
• Effects
• no significant antagonistic actions on ANS or CNS receptors, no sedative effects
• Clinical
• bipolar affective disorder - prophylactic use can prevent mood swings between mania and depression
• Kinetics, tox, int.
• oral absorption, renal elimination, t_1/2 20h, narrow therapeutic window
• tox: tremor, edema, hypothyroidism, renal dysfunction, dysrhythmias, pregnancy category D
• int: clearance decreased by thiazides and some NSAIDs

Question 5

Newer agents for bipolar disorder

Answer 5

• Carbamazepine, lamotrigine, valproic acid
• MOA
• unclear in bipolar disorder
• Effects - see anitseizure drugs
• Clinical
• valproic acid increasingly used as first choice in acute mania
• carbamazepine and lamotrigine used in acute mania and for prophylaxis in depressive phase
• Kinetics, tox, int.
• oral absorption, once-daily dosing, carbamazepine forms active metabolite, lamotrigine & valproic acid form conjugates
• tox: hematotoxicity, induction of P450 (carbamazepine), rash, tremor, liver dysfunction, weight gain, inhibition of P450 (valproic acid)