The cyclic antidepressants are named after their chemical structure, which consists of a three-ring central structure plus a side chain, thus the common term tricyclic antidepressants. Maprotiline is a tetracyclic (also termed a heterocyclic), with a four-ring central structure plus a side chain. Cyclic antidepressants are subdivided into two categories: tertiary and secondary amines. Tertiary amines have two methyl groups at the end of the side chain. The five tertiary amines—amitriptyline, clomipramine, doxepin, imipramine, and trimipramine—are generally more potent in blocking reuptake of serotonin compared with norepinephrine. Tertiary tricyclics also cause more anticholinergic side effects (e.g., constipation or blurred vision) and are also highly sedating because of their central effects on histamine receptors.
Secondary amines—desipramine, nortriptyline, and protriptyline—have one methyl group at the end of the side chain and are more potent in blocking reuptake of norepinephrine. Desipramine is the active (demethylated) metabolite of imipramine, and nortriptyline is the active (demethylated) metabolite of amitriptyline. The tetracyclic maprotiline has a side chain identical to that of the secondary amines; thus it is more potent in blocking reuptake of norepinephrine.
Amoxapine has a three-ring central structure and a side chain that differs from the other tricyclics. It is a potent norepinephrine reuptake inhibitor and also blocks postsynaptic dopamine receptors. Thus, it is the only antidepressant that has antipsychotic effects and can produce seizures with minimal warning and normal QRS complex.
Cyclic antidepressants are nonselective agents with multiple pharmacologic effects (Table 177-3) with considerable variation in potency at therapeutic dosages.4 However, these differences become less important at the higher plasma levels typically seen in overdose. Inhibition of amine reuptake (norepinephrine, serotonin) and antagonism of postsynaptic serotonin receptors are believed to produce the therapeutic effects of these agents. The remaining pharmacologic actions are seemingly without therapeutic benefit in treating major depression but significantly contribute to cyclic antidepressant–related adverse effects and overdose toxicity.
TABLE 177-3Pharmacologic Profile of Cyclic Antidepressants ||Download (.pdf) TABLE 177-3 Pharmacologic Profile of Cyclic Antidepressants
|Pharmacologic Activity ||Clinical Presentation |
|Antagonism of postsynaptic histamine receptors ||Sedation |
|Antagonism of postsynaptic muscarinic receptors ||Sedation, coma, agitation, confusion, hallucinations, ataxia, seizures, mydriasis, dry mucous membranes, dry skin, flushed skin, tachycardia, mild hypertension, hyperthermia, ileus, urinary retention, tremor |
|Antagonism of postsynaptic α-adrenergic receptors ||Sedation, miosis, orthostatic hypotension, reflex tachycardia |
|Inhibition of norepinephrine reuptake ||Agitation, mydriasis, diaphoresis, tachycardia, early hypertension |
|Inhibition of serotonin reuptake ||Sedation, mydriasis, myoclonus, hyperreflexia (see later discussion of inhibition of amine reuptake and chapter 178, "Atypical and Serotonergic Antidepressants") |
|Inhibition of voltage-gated sodium channels || |
Impaired conduction, wide QRS complex, other conduction abnormalities; impaired cardiac contractility; wide-complex tachycardia, Brugada pattern, ventricular ectopy
|Inhibition of voltage-gated rectifier potassium channels ||Prolongation of QT interval, ventricular ectopy, torsades de pointes |
Cyclic antidepressants are potent inhibitors of peripheral and central postsynaptic histamine receptors.4 Antagonism of central histamine receptors produces sedation and contributes significantly to the depressed level of consciousness and coma frequently seen in cyclic antidepressant overdose.
Cyclic antidepressants are competitive inhibitors of acetylcholine at central and peripheral muscarinic receptors but not at nicotinic receptors.4 Thus, they are antimuscarinic agents and not truly anticholinergic drugs. Central antimuscarinic symptoms vary from agitation to delirium, confusion, amnesia, hallucinations, slurred speech, ataxia, sedation, and coma. Peripheral antimuscarinic symptoms include dilated pupils, blurred vision, tachycardia, hyperthermia, hypertension, decreased oral and bronchial secretions, dry skin, ileus, urinary retention, increased muscle tone, and tremor. Antimuscarinic symptoms are especially common when cyclic antidepressants are combined with other medications that also have antimuscarinic activity, such as antihistamines, antipsychotics, antiparkinsonian drugs, antispasmodics, and some muscle relaxants. Antimuscarinic symptoms and signs are common findings in cyclic antidepressant overdose, making them an important clinical marker for toxicity, but these effects are not directly responsible for cyclic antidepressant–related deaths, and they do not require specific therapy other than supportive care.5
INHIBITION OF α-ADRENERGIC RECEPTORS
Inhibition of postsynaptic central and peripheral α-adrenergic receptors is a characteristic action of most cyclic antidepressants.4 Cyclic antidepressants have a much greater affinity for α1-adrenergic than for α2-adrenergic receptors. Inhibition of α1-receptors produces sedation, orthostatic hypotension, and pupillary constriction. This action frequently offsets pupillary dilatation induced by antimuscarinic activity. Thus patients with cyclic antidepressant toxicity can present with mid-sized or small pupils despite having other antimuscarinic signs. Orthostatic hypotension is often associated with reflex tachycardia. The antihypertensive effect of clonidine can be negated by cyclic antidepressants because of their ability to block the binding of clonidine to α2-receptors.
INHIBITION OF AMINE REUPTAKE
Inhibition of amine reuptake is believed to be the most important mechanism for treating depression.6 Cyclic antidepressants are potent inhibitors of norepinephrine and serotonin reuptake but produce little inhibition of dopamine reuptake, except for amoxapine, which does inhibit dopamine reuptake. Inhibition of neurotransmitter reuptake leads to increased synaptic levels and subsequent augmentation of the neurotransmitter response. Inhibition of norepinephrine reuptake is thought to produce the early sympathomimetic effects occasionally seen in some cyclic antidepressant overdoses and may contribute to the development of cardiac dysrhythmias. Myoclonus and hyperreflexia are attributed to increased serotonin activity. Serotonin syndrome results from increased serotonin brainstem activity that can be produced by cyclic antidepressants that are particularly potent serotonin uptake inhibitors, such as clomipramine and amitriptyline (see chapter 178). In general, cyclic antidepressants produce serotonin syndrome only when used in combination with other serotonergic agents.
Cyclic antidepressant–induced cardiotoxicity is the most important factor contributing to patient mortality.7 Cardiac conduction abnormalities occur during cyclic antidepressant poisoning because inhibition of the fast sodium channels in the His-Purkinje system and myocardium decreases conduction velocity, increases the duration of repolarization, and prolongs absolute refractory periods. Severe sodium channel blockade culminates in depressed myocardial contractility, hypotension, various types of heart blocks, cardiac ectopy, bradycardia, widening of the QRS complex, and/or the Brugada pattern. Mechanisms that contribute to hypotension during overdose include decreased contractility from reduced calcium release during depolarization within the ventricular myocytes and peripheral vasodilatation from blockade of α1-adrenergic receptors. Rapid influx of sodium is necessary for the release of intracellular calcium stores and subsequent myocardial contractility. Some of the negative chronotropic effects of sodium channel blockade can be attenuated by the sinus tachycardia secondary to antimuscarinic activity.
Cyclic antidepressant cardiotoxicity produces ECG changes, such as prolongation of the PR interval and QRS duration, frontal plane right axis deviation, and the Brugada pattern (incomplete right bundle-branch block with ST-segment elevation in leads V1 to V3).7,8 The right axis deviation is most pronounced in the terminal 40 milliseconds of limb leads, demonstrated by a terminal R wave in ECG lead aVR and an S wave in ECG lead I. The Brugada pattern is seen in approximately 10% to 15% of all patients with significant cyclic antidepressant overdose admitted to an intensive care unit but is rarely seen in other types of overdose.8,9 Therefore, the Brugada pattern strongly suggests a cyclic antidepressant overdose.
Slow electrical conduction can produce various types of heart blocks. Local changes in electrical conduction can predispose to ventricular dysrhythmias by establishing reentry loops. Bradycardia, when accompanied by QRS complex widening, indicates profound sodium channel blockade.
POTASSIUM CHANNEL ANTAGONISM
Cyclic antidepressants block myocardial potassium channels and inhibit the efflux of potassium during repolarization.7 This effect is seen on the ECG as QT interval prolongation, which is more pronounced at slower heart rates.10,11 Torsades de pointes is rarely seen in cyclic antidepressant overdoses in the presence of sinus tachycardia, which is partially protective against severe QT interval prolongation and after-potential generation.
All cyclic antidepressants share similar pharmacokinetic properties.4 They are highly lipophilic, readily cross the blood–brain barrier, and achieve peak plasma levels between 2 and 6 hours after ingestion at therapeutic doses. In overdose, GI absorption can be prolonged because of the antimuscarinic effect on gut motility. Bioavailability is only 30% to 70% because of extensive first-pass hepatic metabolism. Cyclic antidepressants are highly protein bound to α1-acid glycoproteins, with a large apparent volume of distribution, ranging from 10 to 50 L/kg. Tissue cyclic antidepressant levels are commonly 10 to 100 times greater than plasma levels, and only 1% to 2% of the total body burden of cyclic antidepressants is found in the blood. These pharmacokinetic properties explain why it is unproductive to attempt removal of cyclic antidepressants by hemodialysis, hemoperfusion, peritoneal dialysis, or forced diuresis.
Cyclic antidepressants are eliminated almost entirely by hepatic oxidation, which consists of N-demethylation of the amine side-chain groups and hydroxylation of ring structures. The removal of a methyl group from the tertiary amine side chain usually produces an active metabolite designated by the desmethyl prefix (Table 177-1). Clinical toxicity from cyclic antidepressants usually lasts longer than explained by the activity of the parent drug because of the production of active metabolites. These active metabolites often have different pharmacologic activities compared with the parent compounds. Secondary amines such as desipramine, nortriptyline, and protriptyline are not believed to have active metabolites. Amoxapine and maprotiline both have active metabolites. Some cyclic antidepressants undergo enterohepatic circulation prior to their eventual oxidation, conjugation, and renal elimination, but this does not significantly contribute to their toxicity.
The average elimination half-life of cyclic antidepressants is approximately 24 hours (range, 6 to 36 hours) at therapeutic dosages, but this can increase to 72 hours after overdose. Inhibition of cyclic antidepressant metabolism by other drugs that use the same hepatic enzymes can prolong the half-life of cyclic antidepressants.
Cyclic antidepressants undergo significant postmortem drug redistribution.12 Plasma levels can increase significantly after death as tissue binding sites release cyclic antidepressants back to the blood. This is a time-dependent process, and therefore, the diagnostic accuracy of postmortem cyclic antidepressant levels is inversely proportional to the time after death at which the measurement sample was obtained, among other factors.
Therapeutic dosages of cyclic antidepressants are variable, generally ranging from 1 to 5 milligrams/kg per day (Table 177-1). Ingestions of <1 milligram/kg are generally nontoxic.13 Life-threatening symptoms usually occur with ingestions of >10 milligrams/kg in adults, and fatalities are commonly associated with ingestions of >1 gram. Children are particularly susceptible to antimuscarinic effects and show clinical toxicity at lower dosages.5 The majority of adult intentional ingestions and pediatric accidental exposures of >2.5 milligrams/kg are expected to result in some clinical toxicity based on the low therapeutic index of cyclic antidepressants.13 In addition, patients at higher risk for cyclic antidepressant toxicity include patients who have co-ingested cardiotoxic or sedative-hypnotic medications, geriatric patients, and patients with underlying heart or neurologic disease.
Desipramine is the most potent sodium channel blocker among the cyclic antidepressants and is able to precipitate severe cardiotoxicity (e.g., wide QRS complex, hypotension) without producing significant antimuscarinic symptoms. It is associated with a higher case-fatality rate than the other cyclic antidepressants.14 Amoxapine and maprotiline have historically been associated with greater toxicity than other cyclic antidepressants, especially in regard to causing seizures.14
Quantitative measurement of plasma levels of cyclic antidepressants is helpful in monitoring long-term drug therapy, but results are rarely available during the time of patient evaluation. Patients with a combined plasma level of parent cyclic antidepressant and metabolite of >1000 nanograms/mL (>3500 nmol/L) are at greater risk for developing seizures and cardiotoxicity. However, the severity of clinical toxicity does not always correlate with the degree of plasma cyclic antidepressant elevation.7 Serious toxicity rarely develops at therapeutic levels, typically 75 to 300 nanograms/mL (300 to 1000 nmol/L) for most agents.