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By-Akhil kanekar

Therapeutic drug monitoring of imipramine1) Introduction

2) Clinical pharmacology

3) Clinical pharmacokinetics

4) Pharmacodynamics

5) Special populations

6) Factors affecting DRC

7) conclusion

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.

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.

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.

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

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.

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 glucuronideconju.

Minor pathways are N-oxidation,dealkylation

Ring hydroxylation of parent compound or N-demethylation of side chain further excretion in urine or bile.

Special population AGE-

Paediatrics-high proportion of lean body mass than fattytissues leads to altered tissue stores. Also due to increasedhepatic area shows increased metabolism.

In neonates higher unboumd fraction is observed (26%)

Geriatrics-low hepatic blood flow leads to decreasedclearance 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

Hepatic diseases-1. hepatic impairment results in implication of P450 isoenzyme.2. alteration in clearance and PC3. Reduction in first pass effect

4. Prolongation of elimination half life

Renal failure-

1. Accumulation of metabolite

Cardiovascular diseases-

1. Decrease in C.O. results in reduced hepatic blood flow(Q)

with increase in bioavailability

pharmacodynamics Concentration and response relationship

1. Sigmoidal relationship with therapeutic threshold of 180 mg/ml

2. Conc. Below 150 ng/ml shows no response whereas above 450 ng/ml

shows toxicity

3. Higher doses leads to seizures,OCD,thus requires dose adjustment

Concentration and toxicity-

1. Mainly anticholinegic and cvs side effects

2. Delirium at 450 ng/ml,seizurs at 745 ng/ml,overdose may lead

to death

Factors affecting dose conc.andresponse relationship Active metabolite-1. Hepatic metabolism produces active metabolites having longer half

life.

2. Monitoring of hydroxy metabolite

Protein binding-

1. CADs bind to alfa-1 acid glycoprotein,lipids,cholesterol

2. Unbound fraction for IMI-4.2 to 10.9 %

3. Methods for TDM include ultrafiltration,equi.dialysisfree drug conc.assays

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

Conclusion 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.

Thank you