imipramine, therapeutic drug monitoring

1. Welcome To all By- Akhil kanekar

2. Therapeutic drug monitoring of imipramine Introduction Clinical pharmacology Clinical pharmacokinetics Pharmacodynamics Special populations Factors affecting DRC conclusion

3. Introduction Imipramine is a tricyclic antidepressant with well established therapeutic ranges. To judge effectiveness the patient must receive doses for minimum 2 to 4 weeks. Oral and systemic clearance of imipramine varies with age requiring to change dose. In diseased patient, the dose must be adjusted. Metabolism,protein binding of imipramine plays important role in activity and drug monitoring.

4. Clinical pharmacology Imipramine is CAD used to treat psychiatric disorders like depression,panic disorder,anxiety,OCD,enuresis in children. Imipramine mainly blocks high affinity reuptake mechanism in norepinephrine(NE),serotonin(5HT),dopamine(DA) Imipramine is a ter.amine antidepressant having high affinity for NE and 5HT more than dopamine. Upon acute administration it shows increased concentration of NE,5HT,DA in synapse. chronic administration leads to decrease in beta adren.receptor density,with less 5HT density. Adverse Effects may observed after binding with other receptor.

5. Clinical pharmacokinetics The study includes absorption,distribution,metabolism,elimination of imipramine - Imipramine is available in oral dosage forma like tablets capsules and also in oral solutions and parenteral dosage form. differnce in bioavailability may appear between generic and branded formulations with decrese in plasma concentration.

6. Absorption Imipramine is highly lipophilic basic compound ionisable at stomach pH. Rate of absorption-rapid with max,plasma conc.( Cmax ) occuring 2-8 hrs. Effect of food-no effect First pass effect-decreased bioavailability(F) upto 0.20-0.70 leading to decreased clearance and plasma conc. Extraction ratio- upto 0.3-0.75 Changes in hepatic blood flow,reduces cardiac output and subsequently incresed PC . Follows non linear kinetics

7. DISTRIBUTION Partition coefficint- 1000-100000 Volume of distribution-large upto 3 - 63 l/kg Highest concentration is found in lung,kidney,brain,liver,skeletal muscle, Lowest conc , found in plasma and adipose tissues.

8. Metabolism and excretion Clearance of IMI is entierly by hepatic metabolism,5% of drug excreted unchanged through urine. Major metabolic pathways are demethylation,hydroxylation followed by glucuronide conju . Minor pathways are N- oxidation,dealkylation Ring hydroxylation of parent compound or N- demethylation of side chain further excretion in urine or bile.

9. Special population AGE- Paediatrics -high proportion of lean body mass than fatty tissues leads to altered tissue stores. Also due to increased hepatic area shows increased metabolism. In neonates higher unboumd fraction is observed (26%) Geriatrics-low hepatic blood flow leads to decreased clearance showing ADRs changes in vol.of distribution leads to low clearance. decreased half life with no change in clearance Decreased renal flow leads to accumulation of metabolite

10. Hepatic diseases- hepatic impairment results in implication of P450 isoenzyme . alteration in clearance and PC Reduction in first pass effect Prolongation of elimination half life Renal failure- Accumulation of metabolite Cardiovascular diseases- Decrease in C.O. results in reduced hepatic blood flow(Q) with increase in bioavailability

11. pharmacodynamics Concentration and response relationship Sigmoidal relationship with therapeutic threshold of 180 mg/ml Conc. Below 150 ng/ml shows no response whereas above 450 ng/ml shows toxicity Higher doses leads to seizures,OCD,thus requires dose adjustment Concentration and toxicity- Mainly anticholinegic and cvs side effects Delirium at 450 ng/ ml,seizurs at 745 ng/ ml,overdose may lead to death

12. Factors affecting dose conc.and response relationship Active metabolite- Hepatic metabolism produces active metabolites having longer half life. Monitoring of hydroxy metabolite Protein binding- CADs bind to alfa-1 acid glycoprotein,lipids,cholesterol Unbound fraction for IMI-4.2 to 10.9 % Methods for TDM include ultrafiltration,equi.dialysisfree drug conc.assays

13. Drug interaction Pharmacodynamic and pharmacokinetic interactions Enzyme induction Increased hepatic clearance Cigarette smoking With antihistaminics Inhibition of P450IID isoenzyme,SSRI With other psychotropic drugs With ethanol

14. C onclusion Use of TDM is warranted for CAD’S with established therapeutic ranges .more complex patients who have concurrent illness ,receiving concomitants medication ,or suspected of having toxic effects ; the elderly may warrant TDM for IMI for which therapeutic range is less certain. Pharmacokinetic profile can facilitate dosing of those CAD’s that are potentially toxic,improving the bennefit -to-risk profile for these medication.

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