2. Therapeutic drug
monitoring of imipramine
1) Introduction
2) Clinical pharmacology
3) Clinical pharmacokinetics
4) Pharmacodynamics
5) Special populations
6) Factors affecting DRC
7) 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-
1. hepatic impairment results in implication of P450 isoenzyme.
2. alteration in clearance and PC
3. 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
11. 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
12. Factors affecting dose conc.and
response 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
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. 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.
