Chlorpromazine

talking about chlorpromazine with consideration of its antiemetic effect & doses in emesis
lecture at Al-Mahmoudiya G. Hospital 2/10/2019

1. Chlorpromazine HCL Alaa Fadhel Hassan Drug information centre

2. Pharmacodynamic 1 st G (Typical) antipsychotic phenoththiazine of low clinical potency. blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits a strong α -adrenergic, muscarinic & H1-receptor blocking effect and depresses the release of hypothalamic and hypophyseal hormones ( α1 = 5-HT 2A > D2 > D1). Its strong antiemetic effect due to dopamine-receptor blockade, both centrally (in the chemoreceptor trigger zone of the medulla) and peripherally (on stomach receptors).

3. Pharmacodynamics Its toxicity attributed to the effects on α and M receptors while blockade of dopamine receptors may result in akathisia, dystonia , parkinsonian symptoms, tardive dyskinesia , and hyperprolactinemia. Longacting injectable formulations may cause some blockade of D2 receptors 3–6 months after the last injection. They generally have a much longer clinical duration of action than would be estimated from their plasma half-lives, in parallel to the prolonged occupancy of D2 dopamine receptors in the brain. Time to recurrence of psychotic symptoms is highly variable after discontinuation of antipsychotic drugs. The average time for relapse in stable patients with schizophrenia who discontinue their medication is 6 months.

4. Indications Behavioral problems in children (1-12 yr ) marked by combativeness &/ or explosive hyperexcitable . Short-term treatment of hyperactive children with excessive motor activity accompanying conduct disorders. Manic episodes associated with bipolar disorder , schizophrenia & psychotic disorders. Management of nausea and vomiting , intractable hiccups & a cute intermittent porphyria.   Management of restlessness and apprehension prior to surgery.  Adjunctive therapy in the treatment of tetanus. [Off Label Uses] nausea and vomiting of pregnancy, psychosis/ agitation associated with dementia.

5. Pharmacokinetics Readily & incompletely absorbed, oral doses availability is (25–35%) & duration of 4-6 hr. Plasma half-life is biphasic, initial (children : 1.1 hr & adults: ~2 hr ); terminal (children : 7.7 hr & adults: ~30 hr ). Highly lipid soluble and protein bound (92–99 %), tend to have large volumes of distribution (usually < 7 l/kg) , crosses blood-brain barrier. Metabolism: extensively hepatic by demethylation (followed by glucuronide conjugation) & amine oxidation , catalyzed by liver microsomal CYP450 enz . [CYP2D6 , CYP1A2, & CYP3A4]. Excretion: urine (<1% as unchanged drug) within 24 hr., metabolites may excreted weeks after the last dose of chronic administration.

6. Dosage Psychotic disorders: minimum effective therapeutic dose 100 mg while usual range of daily dose 100-1000 mg. Nausea and vomiting: 10 to 25 mg every 4 to 6 hr (oral/prn) & 25 mg; initial then 25 to 50 mg every 3 to 4 hr (I.M./ prn until vomiting stops, if no hypotension occurs). During surgery: 12.5 mg; repeat in 30 min. if necessary & if no hypotension occurs &/ 2 mg per fractional injection at 2 min. intervals using a 1 mg/mL solution (I.V). Nausea and vomiting of pregnancy, refractory: 25 to 50 mg every 4 to 6 hr (I.M/I.V) & 10 to 25 mg every 4 to 6 hr (oral).

7. Dosage II Geriatric : in the lower range of recommended adult dosing. Nausea and vomiting, treatment for infants ≥6 months, children , & adolescents weighing ≤45.5 kg: (Oral , I.M , I.V): 0.55 mg/kg/dose q 6-8 hr as needed. Usual maximum daily dose (I.M , I.V) for children <5 yr / weighing <22.7 kg is 40 mg/day while for children ≥5 yrs & adolescents/ weighing 22.7 to 45.5 kg is 75 mg/day For Adolescents weighing >45.5 kg (Oral) 10-25 mg q 4 to 6 hr as needed/ & (I.M , I.V) 25 mg; if tolerated (no hypotension), then may give 25 to 50 mg q -6 hours as needed. Cyclic vomiting syndrome; abortive therapy:   infants ≥6 months, children , & adolescents(I.V ) 0.5-1 mg/kg/dose q 6 hr ; maximum dose 50 mg in combination with diphenhydramine (for possible dystonic reactions ).

8. Reconstitution & administration Its reconstituted with N/S to a maximum conc . of 1 mg/ml (direct I.V inj.) while diluting 25-50 mg of chlorpromazine with 500-1000 ml N/S is recommended for treatment of intractable hiccups [manufacturer]. Diluted solution administered slow I.V. at a rate not exceed 1 mg/min while given as a slow I.V inf. for intractable hiccups. [ To reduce the risk of hypotension, patients must remain lying down during and for 30 min. after the inj ]. I.M inj. Given slowly , deep into upper outer quadrant of buttock. Injection solution must be protected from light and freezing [A slightly yellowed solution does not indicate potency loss, but a markedly discolored solution should be discarded].

9. Adverse effects

10. Black box warning

11. Preganancy & lactation Jaundice or hyper- or hyporeflexia have been reported. U se during the third trimester of pregnancy has a risk for abnormal muscle movements (EPS) and withdrawal symptoms in newborns following delivery. Symptoms may include [agitation , feeding disorder, hypertonia, hypotonia , respiratory distress, somnolence, and tremor]. Pregnancy category C, a s an adjunctive treatment of nausea and vomiting in pregnant women would be reserved for women with dehydration with persisting symptoms. Lactation: Drug enters breast milk; not recommended.

12. Drug interactions Contra-indicated Serious - Use Alternative Monitor closely Procainamide Sotalol Amiodarone, quinidine Amitriptyline, clomipramine, imipramine Bromocriptine , cabergoline Carvedilol, metoprolol, propranolol Clarithromycin, erythromycin, moxifloxacin Dopamine, epinephrine Fentanyl, haloperidol Fluconazole, ketoconazole formoterol hydrocodone Levodopa, methyldopa Ondansetron, prochlorperazine tretinoin Albuterol, salmeterol Alprazolam, diazepam, lorazepam Amitriptyline, clomipramine, imipramine Anticholinergic/sedative, chlordiazepoxide , diphenoxylate hcl , hyoscyamine, metoclopramide Atropine, ipratropium, atracurium Azithromycin, ciprofloxacin, levofloxacin, Trimethoprim-sulfamethoxazole Baclofen, orphenadrine Caffeine, cigarette smoking Chlorpheniramine , cyproheptadine, phenylephrine Dobutamine, dopamine, phedrine , norepinephrine Ethanol, haloperidol, Ketamine, vecuronium, propofol, phenobarbital Insulin aspart , metformin meperidine, methadone, morphine, tramadol Risperidone, topiramate Hydroxyzine, itraconazole, melatonin, mifepristone, pralidoxime , quinidine,tamoxifen , tamsulosin ,

13. References Katzung basic & clinical pharmacology 2018 Drugs.com website Medscape website

14. Thank You