imipramine HClamitriptyline HCl desipramine HCl

nortriptyline HCl

TRICYCLIC ANTIDEPRESSANT (TCA.)

Although they have been used clinically for about 40years, assay procedures for clinical monitoring have only become available recently.

There are lots of antidepressant agents, but the focus here will be on TCAs since there assay procedures are widely available &therapeutic ranges are established.

Most clinicians adjust TCAs doses by monitoring the drugs efficacy & side effects.*Plasma levels are only monitored in specific situations.

  Dose adjustment of TCA when used for other cases ; eg. (Enuresis, Attention Deficit Disorder ADD, other mood disorder…) based primarily on clinical observation & most clinicians tend to use same therapeutic ranges established for depression since only very little data available on target plasma concentration for alternative use.

Plasma monitoring for TCA is difficult:

Inability to establish clear therapeutic defined end point.

Complication or inability to relate measured plasma concentration to therapeutic response due to :                         Active metabolite.                         Altered plasma protein binding.

High first fast hepatic clearance of TCA leads to :                   Variability in plasma concentration.                   Low, variable bioavailability.*Parenteral dosage forms available but not commonly used

Maximum therapeutic effect is usually not apparent for several weeks following initiation of TCA.

Steady state plasma concentration is achieved within one weak.

THERAPUTIC & TOXIC PLASMA CONENTRATION Its difficult to interpret the plasma concentration of these basic compounds (TCA) due to their plasma protein binding to various blood elements:

They bind to plasma serum albumin.

Lipoproteins concentration may be important, since degree of binding for Amitriptyline and Nortriptyline has been associated with cholesterol & triglyceride concentration. 

They bind to α1-acid lipoproteins (AAG) with

relatively high affinity but low capacity. *AAG concentration are elevated in response to certain inflammatory process and this will alter plasma binding & potential therapeutic range for TCAs.

its difficult to determine the alternation of blood protein binding for TCA . this is attributed to either :                Patient variation.                Collection techniques & the assay methodologies used to determine the unbound drug concentration.

Plasma protein binding for TCA is not identical.

They all have the free fraction less than 10%• •For most ;about 5% of the drug in plasma is unbound or free. while higher free fractions have been reported ,but it's unclear weather these studies present:        -Actual variation in plasma protein binding.-Artifacts in the assay methodologies.

Therapeutic range:   Imipramine ===metabolized=====>desipramine (active compund)To date, no therapeutic difference between these 2 has distinguished.

Amirtiptiline ==metabolized====>noramitriptyline (active compund) For those drugs :Their therapeutic range are distinguished as summation of the 2 compounds(Parent & metabolite).

Drug Therapeutic range Comments

Imipramine + desipramine

150-240μg/L But most clinicians prefer wider range 180-350 μg/L

Amirtiptiline + noramitriptyline

Not clearly established:120-250 μg/L

Conc. Range >450 μg/L don't ↑response in-patients failed to develop response at lower conc. But may develop anticholinergic Side effects …

*One study said that:Concentration >115 μg/L strongly correlated to positive therapeutic out come.*Other study suggested that :Plasma concentrations as low as 75 μg/L were potentially therapeutic. 

Table. 1

BIOAVAILABILITY (F)GIT absorption of orally administered TCA is almost complete but since the drug passes through the liver & suffers from first-pass metabolism (FPM); the (F) is decreased to 50% in most patients.

For that (F) range is broad & difficult to estimate in any individual patient.

Rate of absorption is variable with peak concentrations occurring 2-8hr following a single dose.

In general different dosage forms of TCA are bioequivalent.

There are some differences between oral & parenteral dosage forms : For parentral administration less FPM affect or non-, compared with oral administration.This is important in case of compounds producing active metabolites, which have different therapeutic effect because ratio between parent drug & its metabolite product will differ according to the rout of administration (orally or parenteraly).

There is a little information suggesting that drug interaction or food alters their absorption.

CLEARANCE (CL)TCA are cleared exclusively by the liver

Less than 5% of them are eliminated by the kidney.

TCA's active metabolites should be considered while plasma level monitoring.

Clearances estimated for TCA varies 3 to 5 times.

Average values are in the range 10ml/kg/min(0.6/kg/hr)  

This wide range is due to:   Intra- &inter-individual variation in hepatic metabolism &drug reactions  Many compounds & liver diseases appear to ↑Cp. Levels of TCA. eg. of diseases: alcoholic liver or liver diseases. it's difficult to estimate the clinical significant of these drug-drug inter action when these drugs are added or deleted from the therapy regimen ,since in some patients may they exhibit either:                  Substantial change in metabolism.                  Relatively little change in TCA Cp.

These are due to:

    Differences In intrinsic metabolism among patients.

    Difficulties in prediction of the magnitude of drug inter action.

Patients should be carefully monitored when current drug therapy is changed.

Careful patient's clinical symptom observations are warranted.

DRUG-DRUG INTERACTION FOR TCA  1.MAO. Inhibitors:-MAO inhibitor + TCA contraindicated -There should be 2 weeks elapse between discontinuation of either one of them.-Symptoms: hyperpraxia, confusion, diaphoresis, myoclonus, rigidity, seizure, cardio vascular disturbance & coma.-Mechanism is unknown but attributed to excessive serotonergic activity in CNS.

 2.Hypotensive agents:-Clonidine, reserpine, guanabenz +TCA↓hypotensive action.The ↓ed. effect may occur within 1 or 2 weeks of TCA intake.-Mechanism: TCA blocks intake of guanathidine into adrenergic neurons.Blood plasma levels should be monitored in 1st several weeks of concurrent therapy.

 3.CNS depressant:-Sedatives, hypnotics, alchohols +TCApotentiation of CNS depressant.-Barbiturates + TCA          Potentiate adverse reactions eg. Respiratory depression.   ↑Metabolism of TCA ↓therapeutic response & Cp.-Ethchlorvynol + amitriptyline transient delirium should be use with caution.-Benzodiazepines +TCA CP not altered, possible impaired motor function.-Dizepam + amitriptylinemay ↑t.5 & ↑steady state-Manufacturer of protriptyline states that TCA may ↑the seizure risk in patients taking tramadol hydrochloride.

4.Antipsychotic Agents:-Phenothiazines, haloperidol ↓ metabolizm of TCA↑Cp of TCA.Their concomitant administration should be combined with careful dose adjustment. 5.Sympathomimetic and Anticholinergic Agents:Isoproterenol,Phenylephrine,Noradrenaline,Adrenaline,Amphetamines+TCA↑Sympathetic activity specially pressor & cardiac effect could be Fatal*Close drug monitoring in this case is must.-Anticholinergic + TCAhyperthermia (particularly in hot weather), paralytic ileus.*Concomitant administration needs careful adjustment.

6.Drugs Affecting Hepatic Microsomal Enzymes: - TCA are metabolized by various microsomal isoenzymes of Cytochrom-P450: CYP1A2 CYP2D26 CYP3A4 CYP2C . -Drugs ↓ activity of CYP2D26 may ↑ cp. of TCA.- Those drugs may be enzymes:             nonsubstares eg.( quinidine, cimetidine)              Substrates eg. (Flecainide, phenothiazines, propafenone, selective serotonin-reuptake inhibitors [SSRIs], other antidepressants).- - constant stabilized dose of TCA + CYP2D26 inhibitor TCA

toxic blood level. So in this case:               Dose of either TCA or CYP2D26 inhibitor should be ↓.

             TCA dose should be ↑when CYP2D26 inhibitors are

discontinued.             Cp. monitoring of TCA is recommended.

 U 7.Quinidine: - Quinidine + (Imipramine or Desipramine) ↓clearance. -Quinidine + Nortriptyline substantial:                             ↑Plasma t.5 .                             ↑Area Under the plasma concentration-time curve.                             ↓ Clearance. 8.Cimetidine: -It's CYP2D26 inhibitor.

-Cimetidine + (Imipramine, Desipramine, Amitriptyline)                             ↑ Clearance.                            ↑Bioavailability .                            ↑Elimination t.5 or peak plasma and/or steady-state.                         ↑ Adverse reactions especially Anticholinergic side effects. So in this case:                             ↓ Dose of TCA.                             ↑ Dose of TCA when Cimetidine is discontinued. Ranitidine appears to be less likely to interact with TCA than cimetidine.

9.Selective Serotonin-Reuptake Inhibitors (SSRI): -They are Cytochrom-P450 isoenzymes inhibitor but in variable extent. e.g.(citalopram, fluoxetine, paroxetine, sertraline) -The clinical importance depends on:                       extent of inhibition of the cytochrome isoenzymes                       pharmacokinetics of the concomitantly administered SSRI - Fluoxetine potent CYP1A2 inhibitor +TCA ↑Cp. of TCA about(1-8fold)     ↑Clinical toxic signs: (sedation, decreased energy, lightheadedness, and psychomotor retardation, dry mouth, constipation, memory impairment). So in this case; when TCA are used with SSRI:↓ Dose of TCA.                       At least 5 weeks should elapse before initiating TAC therapy in a patient being withdrawn from fluoxetine, given the long t.5 of fluoxetine and its active metabolite. 

OTHER DRUG-DRUG INTERACTIONS…

Drugs Event Comments

Levodopa & phenylbutazone

May be inactivated since they are absorbed from the intestine

Because TCA ↓ gastric emptying.Careful dosage monitoring is needed.

Dicumarol +(Nortriptyline ,amitriptyline)   

↑ Dicumarol Cp.  

Warfarin (patients stabilized on it.)

↑the prothrombin time due to↑ the time available for absorption of the anticoagulant.

This is due to either:↓Of anticoagulant metabolism.↓Intestinal motility.

Levothyroxine & liothyronine  

Accelerate the onset of therapeutic effects of TCA. May produce to cardiac arrhythmia.

TCA should be given cautiously to(Hyperthyroid or receiving thyroid agents) patients.

Methylphenidate ↓metabolism of TCA ↑TCA effectivness

They may also ↑their toxicity  

Chlorpropamide 250 mg daily +Initiation of nortriptyline 125 mg daily

Substantial hypoglycemia  

in one patient with type 2 diabetes mellitus  

Table.2

Table. 3

Drug Bioavailabilty

Imipramine 20-70 %

Desipramine 30-50 %

Amitriptyline

30-60 %

Nortriptyline 45-70%

VOLUME DISTRIBUTION (Vd) TCAs are widely distributed through the body, considering their extensive binding to plasma protein; their tissue binding is impressive. Estimation for Vd of TCA varies ,but values mostly used ranges between 15-20L\kg.It's a phrmacokinetic parameter, which is not used clinically since loading doses of TCA are not administered.Due to the large Vd & high protein binding it appears that hemodialysis is not likely to remove significant amounts of drug from the body.

HALF-LIFE (t.5) Because of ↑Vd & ↑Cl result average t.5 ≈ 20 hrs. But it also varies to wide range 9-50hrs as Vd & Cl. The wide range is attributed to either :  True alternation in pharmacokinetc parameters.    Limitation that exist when attempting to estimate a drug t.5 within the dosing interval that’s ≈ the drug's t.5 . But it's difficult to know which one of these 2 is exactly responsible for the wide range.Its unclear weather t.5 of the drug would be used clinically to establish dose interval for TCAs.Lag between onset of clinical response relative to Cp. Palateau suggested that therapeutic response is associated with either:     More slow equilibrating deep tissue compartment.     Some other biochemical change. Both associated with TCA therapy. So daily changes in blood level may not be important to therapeutic control of depression but could be an issue with regard to side effects of TCAs. 

TIME TO SAMPLEMost clinicians waits at least 2 weeks before obtaining Cp., unless there are overt signs of toxicity . Any samples obtained before achieving steady-state are not recommended since they are miss leading.Using steady-state conc. Adjustment in the dosing regimens can be made in proportional to the change in Cp. Appropriate time to obtain plasma sample with the dosing interval is a bit difficult.Since the rate of absorption is variable ; trough conc. are often inconvenient , that’s why peak conc. obtained a few hours after the dose is administered can be miss leading. TCA.s are dosed at bed time so clinicians attempt to standardize the sampling in the morning ≈ after about 12hrs. after oral dose. mid-interval plasma conc.s should approximate steady-state conc ; thus any revision of pharmacokinetc parameter will focus on estimate of Cl & F.

by utalizing the principle of mean residence time ;which recommnends measuring a Cp. Conc at specified point in a time (usually24-36hrs after an initial oral dose) ≈ 1.5 half-lives.Clinicians usually limit TCA level monitoring to specific circumstances & rely on clinical observasion.

Many clinicians believe that Cp. Should be measured only to support clinicaly abserved SE …………..Drg conc. may also used for diffrentiation between noncompliant patients from who are unresponsive .TCA.s levels are used to documentsuspected drug toxicity: Conc.>500µg/L asociated with SE.     Conc.>1000µg/L inappropriate & warrant withholding

*Table .3DOSAGE FORMS AVAILABLE  

Drug Tablet Capsul Injectable Oral solution

Imipramine

(10,25,50)mg (75,100,125,150)mg Tofranil-PM

(12.5mg\ml2ml)ampules

 

Desipramine

(10,25,50,75,100,150)mg

(25,50)mg    

Amitriptyline

(10,25,50,75,100,150)mg

  10mg/ml,10ml(multidose vial)

 

Nortriptyline

  (10,25,75)mg   10mg/2ml

*The usual maximum recommended adult daily dose is ≈ 300mg   

Table .4s

  KEY PARAMETER

Parameter

Imipramine Desipramine Amitriptyine Nortriptyline

Therapeutic range

180-350µg/L 100-250µg/L

120-250µg/L

50-150µg/L

Free fraction

< 0.1 < 0.1 < 0.1 < 0.1

F 0.4 0.4 0.4 0.5

Vd 20L/kg 20L/kg 15L/kg 20L/kg

Cl 0.9 L/kg/hr 0.6 L/kg/hr 0.7L/kg/hr 0.4 L/kg/hr

t.5 20hrs 20hrs 20hrs 30hrs

Case #1:A.R., a 39years-old, 65Kg female, is to be given desipramine for depression. She has no other significant medical history & takes acetaminophen or ibuprofen rarely for headaches. Describe a reasonable starting dose & schedule for increasing her maintenance regimen.

Answer:Because the bioavailability & intrinsic hepatic Cl of TCAs varies over a wide range, most clinicians start therapy with conservative doses in a divided daily schedule. Doses are increased only after the initial dose has achieved steady-state & SE. can be evaluated.since A.R. has no other concurrent illnesses or medication that would be expected alter her TCA metabolism ; a starting Desipramine dose of 25mg twice daily is reasonable. Given the expected t.5 ≈ 20 hrs. , Steady state should be achieved probably in ≈4 days, although most clinicians will prefer to wait 5-7 days before considering an ↑ in the her maintenance schedule. Although Cp. of desipramine can be expected to plateau relatively rapidly but full response will not be evident for several weeks. If at the end of the 1st week of therapy A.R. is having no SE, the dose may be ↑ed. 75-100mg, even though the full therapeutic benefit is from the initial dose is unlikely to be evident. Maintenance doses are ↑ed. before the full therapeutic effect is achieved because an excessively long titration period would accrue if the interval between dose escalation were a month or more. If A.R had significant SE. from the drug. eg. (CNS depression or anticholinergic SE), any dose ↑ would be withheld. With time if ES.s diminish …↑ing daily dose may be permitted

Case#2:After 3 weeks of titration, A.R. has been stabilized on 150mg/day of desipramine for 1 week. She has relatively few SE. but her depression has improved minimally would plasma levels of desipramine be useful? What would one expect the average steady-state disipramine concentration to be?

Answer:One wouldn't expect to see full therapeutic effects of the TCA within 3 weeks of initiating therapy. Some clinicians believe that early Cp monitoring may help identify those patients with low Cp. & therefore at higher risk for therapeutic failure.Depending upon therapy the severity of A.R.'s depression, one approach would be to continue her current regimen for another few weeks. If a satisfactory response is not obtained; the dose could be ↑ed. to ≈200mg/day in an attempt to achieve adequate control of her depression. It wouldn't be irrational, however, to obtain a Cp. From A.R. now to determine if it's anywhere near the therapeutic range (100-250 μg/L) if her Cp. is low & compliance could be assured it would be logical to escalate her dose at this time. This saves waiting the additional 3weeks to evaluate the full therapeutic response & diminishes the total time required to achieve the optimal dose titration.

S=1.o , Dose = 150,000µg F=0.4 , = 24 hrCl = (0.6L/Kg * 65Kg)=39 L/hr Cpss ave= (S)(F)(dose)

Cl*

= 1*0.4*150,000 = 64.1 µg/L

39 * 24

Case#3:

S.U., a 68 years-old, 68 Kg. Male, is in good health following a mild myocardial infraction (MI) two years ago. He has been treated intermittently for the past twenty years for endogenous depression and is now to be started on nortriptyline. His most frequent complaints have been a general lack of interest in usual activities. What would be a reasonable starting dose? Would Cp. Monitoring be useful?

Answer:S.U.'s age and history of cardiac disease place him at higher risk for TCA toxicity than other patient. Therefore, he should started on the lowest available dose (10-25 mg/day). Even though these low doses are unlikely to result in a therapeutic response, concern for both the cardiovascular and other SE effect in the elderly is sufficient to warrant caution. Most clinicians would carefully evaluate S.U. weekly and if no SE are observed eg. (changes in visual acuity, dry mouth, orthostatic hyptension, cardiac arrhythmias), ↑ the dose by approximately 10 to 25 mg until he is stabilized on a dose of a 50 to 75 mg/day has not responded adequately after a sufficient time interval and there are no obvious SE, it will be necessary to decide whether or not a further increase in dose is appropriate. Many clinicians feel that the elderly and patients with pre-existing cardiac disease are candidates for therapeutic dry level monitoring. Thus, it might be appropriate to obtain a plasma nortriptyline level at this point. If the plasma conc. are low and an adequate therapeutic response has been attained, the dose should not be increased. If, however, low conc. are associated with a poor therapeutic response, a further escalation of the dose is probably warranted. If nortriptyline conc. are within the usual therapeutic range (50-150µg/L) and there is an inadequate therapeutic response, a decision to increase the dose would be difficult. As an alternative drug with a lower toxicity profile could be considered. 

Case#4:N.H., a 27 year-old male, has been stabilized on imipramine 100mg/day (500mg BID) with good response to his depression. 2 week ago his physician prescribed 100mg capsules (tofranil PM) at bed time to simplify the regimen, unfortunately, N.H continued to take 2 doses a day (200mg) at bed time & now presents with confusion, dry mouth, blurred vision. Would a drug plasma level be useful to establish a course of action for N.H & apparent imipramine toxicity? s

Answer:Many clinicians believe that cases of suspected TCA. toxicity are indications for obtaining Cp.. plasma levels help the clinicians distinguish tricyclic- induced dementia from the potential causes. However, relationship between TCA conc. and SE. is variable and cannot be relied upon absolute indicator. Many clinicians believe that any Cp. > 500 µg/L is reason to withhold or reduce Dm. and that conc. >1000µg/L warrant withhold the drug and monitoring the patient for Cardiovascular SE. In N.H.'s case, the diagnoses is not in question; therefore, the use of Cp for this purpose is not warranted. If an imipramine Cp could be rapidly obtained, it might provide the clinician with enough information to determine if an N.H's side effect could be treated an outpatient setting. This would also depend upon the severity of the SE. Some clinicians obtain Cp for medical legal reason, even if it will not alter the immediate care of patient.

Case#5:O.N., a 38-year old, 60Kg. Female, is being titrated on increasing doses of desipramine and., for the past month, has been receiving 150 mg. HS. In the past she has complained of dry mouth; lately she doesn't feel this is a problem and has no other symptoms which might be considered SE. of desipramine. She takes no other concurrent medication except for Acetaminophen occasionally and smokes one pack of cigarettes a day. Estimate her desipramine concentration.

Answer:In order to calculate O.N.'s steady-state desipramine conc. , it will 1st be necessary to select a pharmacokinetic modle. Its calculated as follow: Cpss ave= (S)(F)(dose) S=1.o , Dose = 150,000µg Cl* F=0.4 , = 24 hr Cl = (0.6L/Kg/hr * 60Kg)=36 L/hr =1*0.4*150,000 = 69.44 ≈ 70 µg/L 36 * 24

since expected desipramine t.5≈20 & =24 , the continuous infusion model is not appropriate .the intermittent steady-state bolus dose model is appropriate when non-sustained release product is used & absorption occurs over a short time period relative to the drug t.5 .

Cpssmin = (S)(F)(dose)(℮-kd) S=1.o , Dose = 150,000µg

Vd (1-℮-kd) F=0.4 , = 24 hr

Vd= (20L/kg * 60kg ) = 1200 L

Cl = (0.6L/Kg/hr * 60Kg) =36 L/hr

kd=(0.693/20hr) =0.0347hr –1

= 1* 0.4 * 150,000 * ℮ - (0.0347 * 24) = 38.4 ≈ 40 µg/L

1200 * (1-℮ - (0.0347 * 24)

Note that while there is a differences in the calculate (Cpss ave) & trough conc. (Cpssmin), they are somewhat similar, if the measured conc. differs from the predicted levels, it would be difficult to explain. For example, if a measured (Cpssmin) reported to be 60µg/L , one could revise the (F),(Cl) or (Vd) ,since all these parameter can vary significantly. However, while Vd is a variable, it would require an exceedingly large Vd to ↑ the (Cpssmin ) to 60µg/L when the (Cpss ave) is expected to be 69.4µg/L . therefore the most common approach would be to adjust the Cl value since this parameter is thought to be removed to be more variable than either F or Vd for most of TCA.s . however, hepatic Cl & (FPM) effect are predominant reasons for the low F ;thus is a patient has a lower-than-average Cl ,one would should anticipate an ↑in her F.

Case#6:O.N. didn't respond well to her therapy and trough desipramine level was obtained, the laboratory reported a value of 68 ng/ml (μg/L) . Because she is not responding, the physician plans to increase O.N.'s desipramine concentration to 100 to 150 ng/ml (μg/L). What dose adjustment is likely to achieve this goal?

Answer:One approach is to calculated a new pharmacokinetic parameter ,it's by interpretation of plasma drug conc. : the peak conc. 1st estimated by adding the observed trogh conc. (Cpssmin) to the expected change associated with the dose DM(S)(F) = (Cpssmax*Vd )- (Cpssmin *Vd ) =rearrangement=>=>Cpssmax =[ Cpssmin] + [(S)(F)(dose)/Vd] = [68] + [(1)(0.4)(150,000)/ 1200] F=0.4 , Cpssmin = 68µg/L =118µg/L Vd= (20L/kg*60kg )=1200L S=1.0 , DM= 150,000µg

the revised elimination constant (Kd) can be calculated & also the t.5 : Kd = In (Cpmax / Cpmin ) = In (118/68) Kd = 0.023 hr -1

∆ 24 t.5 = 0.693 = 0.693 t.5=30 hrs Kd 0.023 hr This data can be used to calculate the dose needed to achieve the target plasma conc. assuming (Cpssmin) is the trough value… Cpssmin = 150µg/LCpssmin = (S)(F)(dose) (℮-kd) S=1.o , ?? Dose ??

Vd (1-℮-kd ) F=0.4 , = 24 hr

Vd= (20L/kg * 60kg ) = 1200 L

=↕rearrangement↕= kd=0.023 hr -1

dose= (Cpssmin ) (Vd) (1-℮-kd ) (S)(F) (℮-kd) =150 *1200 *(1-℮ - (0.023 * 24) ) = 331,25 ≈ 300 g

1 * 0.4 *℮ - (0.023* 24)

it's unlikley that the maintenance dose (DM) would be ↑ed. by this amount because it's a large % ↑ in the dose (thogh it will give us the desired ↑ in Cp.) & the new dose is exceeding the max. therapeutic recommended dose .while it may be necessary to ↑O.N.'s dose to the range of 300mg/day to achieve the Cp=150µg/L, most clinicians would↑ O.N.'s dose by ≈(25-50 mg/day) & observe her for clinical immprovment & SE. this step wise approach is more rational since some patients response at lower Cp.s & the chances of SE. are subsatntial with larger doses.