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CLINICAL PHARMACOKINETICS OF ANTIDEPRESSANTS

First tricyclic antidepressant (Imipramine) came into general use in 1957.

Chemical structure similar to Chlorpromazine: Imipramine was therefore introduced as an antipsychotic, but found to be antidepressant.

1. Mode of Action (Still Unproven:

(a) Monoamine theory:

Reserpine (depletes brain of noradrenaline and serotonin) - often causes depression.

Antidepressants:

Tricyclics (block reuptake of amine transmitters)
Monoamine oxidase inhibitors (increase concentration of amine transmitters within brain)

But, some newer antidepressants (eg. Mianserin) do not block amine uptake.

 

(b) Receptor regulation theory:

Supersensitivity of central -receptors in depression (increased feedback inhibition of noradrenaline release).

Antidepressants, with continued therapy, down-regulate -receptors, leading to an increase in central noradrenaline release.

 

TABLE: Actions of Tricyclic Antidepressants on Some Neurotransmitter Receptors
Beta-2-adrenoreceptor	Down-regulation due to increased presence of agonist, Norepinephrine.
5-HT-2 receptor	? down-regulation due to increased presence of agonist, Serotonin.
Alpha-2-adrenoreceptor	Down-regulation of inhibition by this receptor presynaptically leading to increased release of Norepinephrine.
Alpha-1-adrenoreceptor	Blocked, producing hypotension and sedation.
Muscarinic acetylcholine receptors	Antagonised; anticholinergic effects; sedation.
Histamine H-1 receptors	Antagonised, producing sedation, ? antidepressant action.
Histamine H-2 receptors	Antagonised, ? consequences.

 

TRICYCLIC AND RELATED ANTIDEPRESSANTS
Drug	Usual Daily Dose Range - Oral (mg)	Brand Name	Dose Form	Strengths
Amitriptyline	100-250	Amitrip M  Amitrip  Endep M Endep  Endep 50  Laroxyl  Saroten  Tryptanol	T  T T T  T  T  T  T	10mg  25mg  10mg  25mg  50mg  10, 25mg  25mg  10,25, 50mg
Clomipramine	100-250	Anafranil	T	25mg
Desipramine	100-250	Pertofran	T	25mg
Dothiepin	100-200	Prothiaden	C  T	25mg  75mg
Doxepin	100-300	Deptran 10  Deptran  Deptran  Sinequan  Sinequan	C  C  T  C  T	10mg  25mg  50mg  10, 25mg  50mg
Imipramine	100-250	Imiprin  Tofranil	T  T	10, 25mg  10, 25mg
Mianserin	30-120	Tolvon	T	10, 20mg
Nortriptyline	50-150	Allegron Nortab	T  L  T	10, 25mg  10mg/5mL  10, 25mg
Trimipramine	100-300	Summontil	T  C	25mg  50mg

 

RELATIVE PRICES OF ANTIDEPRESSANTS (Applicable to Hospitals only)
Drug	Brand Name	Relative Price
Tricyclic - Amitryptiline  - Clomipramine  - Desipramine  - Dothiepin  - Doxepin  - Imipramine  - Nortriptyline  - Trimipramine	Tricyclic Laroxyl, Saroten, Tryptanol  Amitrip, Endep  Anafranil  Pertofran  Prothiaden  Sinequan  Deptran  Imiprin  Tofranil  Allegron, Nortab  Surmontil	Tricyclic 1.0  0.7  3.3  1.4  1.1  1.0  0.7  0.7  1.0  1.0  1.0
Tetracyclic  - Mianserin	Tetracyclic Tolvon	Tetracyclic 3.2
Monoamine Oxidase Inhibitor - Isocarboxazid - Phenelzine  - Tranylcypromine	MAOI Marplan  Nardil  Parnate	MAOI 3.9  1.7  1.7

 

2. Side Effects:

- CNS:

Sedation, fatigue, impaired psychomotor performance.

- Anticholinergic:

Dry mouth, blurred vision, constipation, urinary hesitancy and retention, tachycardia, aggravation of glaucoma,

- Blockade:

Postural hypotension.

- Cardiovascular:

ECG abnormalities, delayed cardiac conduction, arrhythmias, sudden death.

- Miscellaneous:

Weight gain, tremor, cholestatic jaundice, seizures.

- NB Mainserin:

Agranulocytosis, fatal bone marrow aplasia - should report sore throat or fever.

The Selection of an Individual Tricyclic Antidepressant is Based Largely on Differences in Adverse Effects Profiles
Drug	Relative Frequency of Adverse Effects
	Sedation	Antichol	Postural Hypo	Arrhythmias
Amitriptyline	High	High	High	High
Nortriptyline	Mod	Mod	Low	Mod
Protriptyline	V. Low	Mod	Mod	High
Imipramine	Mod	Mod	High	High
Desipramine	Low	Low	Mod	Mod
Trimipramine	High	High	Mod	High
Doxepin	High	Mod	Low	Low
Dothiepin	High	Mod	Low	Low
Mianserin	Mod	Nil	Nil	Nil
Fluoxetine	Low	Nil	Nil	Nil

Examples:

- Use of a sedating TCA (eg. Amitriptyline, Doxepin, Dothiepin) in a patient with agitated depression and insomnia.

- Use of TCA with minimal anticholinergic effects (eg. Desipramine, Dothiepin) in a patient with prostatic hypertrophy.

- Use of a TCA with minimal cardiac effects (eg. Doxepin or the Tetracyclic, Mianserin) in a patient with ischaemic heart disease or suicidal tendencies.

 

3. Overdoses:

Tricyclics are extremely dangerous when taken in overdose.

Major symptoms include:-

(a) Coma with shock.

(b) Respiratory depression with a tendency to sudden apnoea.

(c) Agitation or delirium.

(d) Neuromuscular irritability and seizures.

(e) Bowel and bladder paralysis.

(f) A great variety of cardiac manifestations, including ventricular arrhythmias and conduction defects.

There is some evidence that therapeutic doses can produce cardiac arrhythmias in patients with heart disease, and recent (within 6 weeks) acute myocardial infarction is a contraindication for the use of tricyclics.

 

4. Pharmacokinetics and Therapeutic Drug Monitoring:

In general, the tricyclic antidepressants are highly lipid-soluble drugs. They are completely absorbed, but systemic bioavailability is markedly reduced by pronounced hepatic “first-pass” metabolism. The high lipid solubility and extensive tissue binding result in a large volume of distribution.

Pharmacokinetics of Heterocyclic Antidepressants
Antidepressants	Availability (Oral) (%)	Bound in Plasma	Vd (L/kg)	Half-life	Dosage Range	Plasma Level (mg/mL)
Tertiary Amines
Amitriptyline	37-59	95	12-16	10-22	75-300	60-220¶
Doxepin	17-37	ND	12-28	11-23	75-300	30-150¶, §
Imipramine	19-35	95	15-31	11-25	75-300	100-300¶
Secondary Amines
Protriptyline	77-93	92	21-23	67-89	15-60	100-200
Nortriptyline	46-56	92	14-22	18-44	50-200	50-150
Desipramine	51	90	26-42	12-24	75-300	40-160
Newer Agents
Amoxapine	ND	90	ND	8-30	100-600	180¶
Fluoxetine	100	94	12-97	24-72	20-80	ND
Maprotiline	37	88	23	27-57	150-300	200-300¶, §
Trazodone	ND	92	ND	10-12	50-600	ND
¶ Parent compound plus active metabolite.  § Optimal concentrations have not been defined.

A large variability in plasma concentrations among patients taking similar doses of tricyclics has been demonstrated.

Figure:

Variation in the plateau plasma concentration of Nortriptyline in 263 patients receiving 25mg orally, three times daily. Redrawn from Sjoqvist et al (1980).

Hence, it is possible that the application of pharmacokinetics and plasma level monitoring might assist in optimal dosage individualisation of these drugs.

 

TABLE: Pharmacokinetic Properties of Tricyclic Antidepressants
Drugs	Percent Bioavailable	t½, hr	VD L/kg	Cl ml/min	Fraction Bound
Imipramine	29-77	8-28	9.3-23	700-1700	.63-.96
Desipramine	33-51	12-28	24-60	1300-2800	.73-.92
Amitriptyline	30-60	9-46	6.4-36	320-630	.92-.97
Nortriptyline	46-70	18-56	15-23	290-1330	.87-.93
Doxepin	13-45	8-25	9-33	690-1020	----
Protriptyline	75-90	54-198	15-31	140-390	.90-.94

 

(i) Pharmacokinetic overview:

(a) Absorption:

- In general, absorption is rapid (peak levels: 2-4 hours post-dose).

- Bioavailability is variable (30-70%) due to “first pass” effect.

(b) Distribution:

- Highly lipophilic compounds which distribute widely in the body (Vd up to - 60L/kg).

- Concentrate in cerebral and cardiac tissue.

- Highly bound to - acid glycoprotein in plasma (70-95%).

(c) Elimination:

- Primarily cleared by metabolism:

Eg. Demethylation or Hydroxylation

then glucuronidation

- The rates of metabolism vary widely (eg. t½ : 12 - 190 hours). Consequently, the daily dose (mg/kg) is not a reliable guide to steady-state plasma levels.

- Active metabolites are important.

TABLE: Active Metabolites of Tricyclic Antidepressants
Administered Drug	Active Metabolites
Imipramine	2-hydroxy Imipramine Desipramine 2-hydroxy Desipramine
Desipramine	2-hydroxy Desipramine
Amitriptyline	Nortriptyline 10-hydroxy Nortriptyline
Nortriptyline	10-hydroxy Nortriptyline
Doxepin	Desmethyldoxepin (cis and trans isomers)

- Since their half-lives are long, tricyclics can be administered in a single daily dose.

 

(ii) Factors influencing pharmacokinetics:

- Differences in the pharmacokinetics (and steady-state plasma levels) of the tricyclics appear to be largely genetically determined.

- Several other social and environmental factors have been demonstrated to alter the metabolism of these agents:

Eg. 

Smoking - metabolic clearance

Advancing age - metabolic clearance

TABLE: Factors Reported To Affect Tricyclic Antidepressant Plasma Concentration
Lower	No Effect	Raise
Barbiturates	Benzodiazepines	Aging
Smoking	Fluphenazine	Methylphenidate
Chloral Hydrate	L-triiodothyronine	Chloramphenicol
Trihexyphenidyl		Haloperidol
Acidic Urine pH		Phenothiazines  Weight Loss  Basic Urine pH

 

TABLE: Factors Reported To Affect Cyclic Antidepressant Plasma Concentration
Factor	Effect on Plasma Concentration	Mechanism
Barbiturates	Decrease	Hepatic enzyme induction
Smoking	Decrease	Hepatic enzyme induction
Chloral hydrate	Decrease	Enzyme induction
Trihexyphenidyl	Decrease	Interference with absorption
Acidic Urine pH	Decrease	Reduces renal tubular reabsorption
Benzodiazepines	No Effect
L-triiodothyronine	No Effect
Aging	No effect or increase	Decreased metabolic clearance
Methylphenidate	Increase	Competitive enzyme inhibition of hydroxylation pathways
Chloramphenicol	Increase	Enzyme inhibition
Haloperidol	Increase	Enzyme inhibition
Phenothiazines	Increase	Mutual hepatic enzyme competition
Basic Urine pH	Increase	Increased urinary reabsorption
Cimetidine	Increase	Decreased hepatic blood flow and (or) hepatic enzyme inhibition
Alcoholic Liver Disease	Increase	Decreased metabolic capacity in advanced disease state
Renal Failure	Increase	Decreased excretion of conjugated metabolites
Oral Contraceptives	Increase	Enzyme inhibition

 

(iii) Plasma level monitoring:

- For most of the tricyclics, the relationship between plasma levels and therapeutic response remains poorly defined.

- For some, tentative therapeutic ranges of plasma levels have been proposed.

- Several problems hinder the examination of the relationship between plasma levels and response:-

(a) Must use steady-state plasma levels (equilibration with target tissue) - delay of 4 - 5 x t½ (> 1 week).

(b) The development of the full antidepressant effect often takes 3 or 4 weeks.

(c) Contributions of active metabolites must be taken into account.

Recommended Therapeutic Plasma Concentration Ranges For Antidepressant Treatment and Cyclic Antidepressants
Antidepressant	Plasma Concentration Ranges
Imipramine (+ Desipramine)	180-350ng/ml
Nortriptyline	50-150ng/ml
Amitriptyline (+ Nortriptyline)	120-250ng/ml
Desipramine	115-250ng/ml

 

(iv) Clinical application of pharmacokinetic data:

- dosage selection is largely empirical.

- The use of loading doses does not hasten the therapeutic response, and may be hazardous.

- Reduce dosage in elderly.

- Measurement of plasma levels may be useful in certain instances, Eg:-

(a) Patients at greatest risk of toxicity (elderly, heart disease).

(b) Over-dosage.

(c) Problem patients: Therapeutic failures, persistent side effects, suspected non-compliance, possible drug interaction.

- With further research, the application of pharmacokinetics and TDM should become a useful and routine component of the pharmacological management of depression.

- Maintenance dosage requirements can be estimated from the plasma level taken 24 hours after a single test dose (follows the report of good correlations between plasma concentrations at 24 hours and final steady-state concentrations).

TABLE 3: Dosage Regimen for Nortriptyline Based on 24hr Plasma Concentration Following a Single 50mg Dose
Blood Concentration ng/ml	Suggested Daily Dose
Below 12	50mg
13-19	100mg
20-24	75mg
25-34	50mg
35-40	30mg
Above 41	20mg
From Cooper and Simpson (19), with permission.

 

TABLE: Dosage Regimen for Nortriptyline Based on a 24 or 48hr Plasma Level Following a Single 100mg Dose
24hr Level (ng/ml)	48hr Level (ng/ml)	Daily Dose
7.5-10	5-7.5	200mg
10-15	7.5-10	150mg
15-25	10-15	100mg
25-35	15-20	75mg
35-50	20-32	50mg
Above 50	Above 32	25mg
From Montgomery et al. (40), with permission

 

 

5. Drug Interactions:

Relatively few of any clinical significance.

Interactions Between Heterocyclic Antidepressants and Other Substances
Effect	Interacting Drug	Mechanism	Onset	Significance
Increased Plasma Antidepressant Concentrations	Cimetidine  Antipsychotic agents  Oral contraceptives Phenylbutazone  Phenytoin  Aspirin	Enzyme inhibition  Enzyme inhibition  Decreased first pass  Protein displacement  Protein displacement  Protein displacement	Fast  Slow  Fast  Fast  Fast  Fast	Moderate  Minor  Minor  Minor  Minor  Minor
Decreased Plasma Antidepressant Concentrations	Barbiturates  Chloral hydrate  Smoking	Enzyme induction  Enzyme induction  Enzyme induction	Slow  Slow  Slow	Moderate  Minor  Minor
Increased Side Effects Anticholinergic	Antihistamines Antiparkinson drugs Antipsychotics  Meperidine	Additive effects	Fast	Minor
Sedation	Narcotics  Sedative hypnotics  Antipsychotics  Alcohol	Additive effects	Fast	Minor
Sympathetic stimulation	Norepinephrine  Epinephrine  Phenylephrine	Additive effects	Fast Fast  Fast	Major  Major  Moderate
Cardiotoxicity	Quinidine  Procainamide  Disopyramide	Additive cardiac conduction effects	Fast	Minor
Increased Therapeutic or Toxic Effects of Antidepressants	MAOI’s  Thyroid hormone  Methylphenidate	Additive effects at receptor level	Fast  Slow  Slow	Major  Moderate  Minor
Antidepressant Effects on Other Drugs	Clonidine  Guanethidine  Methyldopa  Warfarin	Decreased antihypertensive effect Increased anticoagulation effect	Fast  Fast  Slow  Slow	Moderate  Moderate  Moderate  Major

 

6. Clinical Use (Also See Appendix):

- At least 70% of patients respond satisfactorily to treatment with antidepressants.

- Takes 2-4 weeks before an antidepressant response occurs, though anxiety and sleep disturbance may not be helped within a few days.

- Many agents now available.

- Little evidence for any claimed differences in efficacy.

- Important differences, however, with regard to adverse effects, as previously discussed.

- Start in low dosage (eg. Amitriptyline or Imipramine 50mg nocte) and gradually increase