In tricyclic antidepressant overdose

Hoffman JR, McElroy CR. Bicarbonate therapy for dysrhythmia hypotension in tricyclic antidepressant overdose. West J Med 1981 134(l) 60-4. 

McAlpine SB, Calabro JJ, Robinson MD, Burkle FM Jr. Late death in tricyclic antidepressant overdose revisited. Ann Emerg Med 1986 15(ll) 1349-52. 

Toxicity. Serious medication-related adverse effects associated with actual or potential damage to tissues, organs, or the entire body system. Toxicity may be directly related to critically elevated blood levels of a drug and may be acute (as in tricyclic antidepressant overdose) or chronic (as in prolonged, moderately elevated lithium level). A drug may also produce "toxic effects" at therapeutic doses (such as phenothiazine s potential for inducing bone marrow damage, which in turn causes decreased production of white blood cells). 

Sodium bicarbonate administration for cardiac arrest is controversial because there are few clinical data supporting its use, and it may have some detrimental effects. Sodium bicarbonate can be used in special circumstances (i.e., underlying metabolic acidosis, hyperkalemia, salicylate overdose, or tricyclic antidepressant overdose). The dosage should be guided by laboratory analysis if possible. 

For many drugs, at least part of the toxic effect may be different from the therapeutic action. For example, intoxication with drugs that have atropine-like effects (eg, tricyclic antidepressants) reduces sweating, making it more difficult to dissipate heat. In tricyclic antidepressant intoxication, there may also be increased muscular activity or seizures the body s production of heat is thus enhanced, and lethal hyperpyrexia may result. Overdoses of drugs that depress the cardiovascular system, eg, 13 blockers or calcium channel blockers, can profoundly alter not only cardiac function but all functions that are dependent on blood flow. These include renal and hepatic elimination of the toxin and any other drugs that may be given. 

Once touted as the medication of choice to treat lethal tricyclic antidepressant overdoses, physostigmine (antilirium ) has very limited uses today in overdose management. Physostigmine is a cholinesterase inhibitor and finds its primary application in the treatment of severe anticholinergic poisoning. When indicated, physostigmine is administered preferably in small incremental doses of 2 mg mixed in 10 cc of saline by slow intravenous infusion over 10 min. 

Early signs of tricyclic antidepressant toxicity are due to anticholinergic effects and include tachycardia, mydriasis, dry mouth, low-grade fever, diminished bowel sounds, CNS excitation, and delirium. More serious toxicity is manifested by coma, respiratory depression, seizures, and cardiovascular toxicity including conduction disturbances, hypotension, ventricular arrhythmias, and asystole. Seizures cause hyperthermia, rhabdomyolysis, and metabolic acidosis. Clinical deterioration can be rapid and catastrophic in patients with tricyclic antidepressant overdose. Death most often occurs due to dysrhythmia and circulatory collapse. The typical therapeutic dose of a tricyclic antidepressant is 2-4 mg kg day Doses of 15-20 mg kg are potentially lethal. Therapeutic drug levels for most tricyclic antidepressants range from 100 to... 

The flow of saliva is largely under the control of the parasympathetic nervous system. Collection of saliva may therefore be difficult from individuals who experience anticholinergic symptomatology (e.g., dry mouth associated with tricyclic antidepressant overdose). In addition, salivary flow may be impaired in some alcoholics. 

The CNS manifestations of tricyclic antidepressant overdose may vary from mild agitation or drowsiness to delirium, coma, respiratory depression, or seizures. These manifestations are thought to result in part from central anticholinergic and antfliistaminic actions of these drugs. 

In addition to general supportive measures (gastric lavage, activated charcoal, and IV fluids), therapy for tricyclic antidepressant overdose includes administration of NaHCOs for dysrhythmias (alkahnization causes tricyclic antidepressants to dissociate from the membrane sodium channels and Na" provides a favorable gradient for Na" channel activated... 

Patients may deteriorate rapidly and progress from no symptoms to life-threatening cardiotoxicity or seizures within 1 hour. Major symptoms of tricyclic antidepressant overdose typically are manifest within 6 hours of ingestion. The principal effects of tricyclic antidepressant poisoning involve the cardiovascular system and the central nervous system and can result in arrhythmias, hypotension, coma, and seizures (see below). 

In severe tricyclic antidepressant overdose, it would NOT be of value to (A) Administer lidocaine (to control cardiac arrhythmias)... 

Hypercarbia results in acidosis, which may contribute to arrhythmias, especially in patients with tricyclic antidepressant overdose. 

A. Check blood pressure and pulse rate and rhythm. Perform cardiopulmonary resuscitation (CPR) if there is no pulse and perform advanced cardiac life support (ACLS) for arrhythmias and shock. Note that some ACLS drugs may be ineffective or dangerous in patients with dmg- or poison-induced cardiac disorders. For example, procainamide is contraindicated in patients with tricyclic antidepressant overdose, and atropine and isoproterenol are ineffective in patients with beta-blocker poisoning. 

For antichollnergic-induced tachycardia, give physostigmine, 0.01-0.03 mg/kg IV (see p 489) or neostigmine, 0.01-0.03 mg/kg IV. Caution Do not use these drugs in patients with tricyclic antidepressant overdose, because additive depression of conduction may result in asystole. 

In a tricyclic antidepressant overdose (see p 90), acidemia enhances cardiotoxicity. Maintain the semm pH at 7.45-7.5 with boluses of sodium bicarbonate. 

A small dose of physostigmine (see p 489), 0.5-1 mg IV in an adult, can be given to patients with severe toxicity (eg, hyperthermia, severe delirium, or tachycardia). Caution physostigmine can cause atrioventricular block, asystole, and seizures, especially in patients with tricyclic antidepressant overdose. 

D. Death from tricyclic antidepressant overdose usually occurs within a few hours of admission and may result from ventricular fibrillation, intractable cardiogenic shock, or status epilepticus with hyperthermia. Sudden death several days after apparent recovery has occasionally been reported, but in all such cases there was evidence of continuing cardiac toxicity within 24 hours of death. 

It may Induce seizures in patients with tricyclic antidepressant overdose. 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Tricyclic antidepressants (TCAs) are effective for all depressive subtypes, but their use has diminished because of the availability of equally effective therapies that are safer on overdose and better tolerated. In addition to inhibiting the reuptake of NE and 5-HT, they also block adrenergic, cholinergic, and histaminergic receptors. 

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