Tricyclic antidepressant overdose
Encyclopedia
Tricyclic antidepressant overdose is caused by excessive use or overdose of a tricyclic antidepressant
drug. It is a significant cause of fatal drug poison
ing. The severe morbidity and mortality associated with these drugs is well documented due to their cardiovascular
and neurological
toxicity. Additionally, it is a serious problem in the pediatric population due to their potential toxicity and the availability of these in the home when prescribed for bed wetting and depression.
, central nervous system
and the heart
are the main systems that are affected following overdose. Initial or mild symptoms typically develop within 2 hours and include tachycardia
, drowsiness, a dry mouth, nausea
and vomiting
, urinary retention, confusion, agitation, and headache
. More severe complications include hypotension
, cardiac rhythm disturbances, hallucinations, and seizures. Electrocardiogram
(ECG) abnormalities are frequent and a wide variety of cardiac dysrhythmias can occur, the most common being sinus tachycardia and intraventricular conduction delay resulting in prolongation of the QRS complex and the PR/QT intervals. Seizures, cardiac dysrhythmias, and apnea are the most important life threatening complications.
, i.e., the therapeutic dose
is close to the toxic dose. In the medical literature the lowest reported toxic dose is 6.7 mg per kg body weight. Although there are differences in toxicity with the drug class, ingestions of 10 to 20 mg per kilogram of body weight are a risk for moderate to severe poisoning, however, doses ranging from 1.5 to 5 mg/kg may even present a risk. Most poison control center
s refer any case of TCA poisoning (especially in children) to a hospital for monitoring. Factors that increase the risk of toxicity include advancing age, cardiac status, and concomitant use of other drugs. However, serum drug levels are not useful for evaluating risk of arrhythmia or seizure in tricyclic overdose.
effects, cause excessive blockade of norepinephrine
reuptake at the postganglionic synapse
, direct alpha adrenergic blockade, and importantly they block sodium membrane channels with slowing of membrane depolarization, thus having quinidine
like effects on the myocardium.
either orally or via a nasogastric tube. Activated charcoal is most useful if given within 1 to 2 hours of ingestion. Other decontamination methods such as stomach pumps
, ipecac
induced emesis, or whole bowel irrigation
are not recommended in TCA poisoning.
Symptomatic patients are usually monitored in an intensive care unit
for a minimum of 12 hours, with close attention paid to maintenance of the airways, along with monitoring of blood pressure, arterial pH, and continuous ECG monitoring. Supportive therapy is given if necessary, including respiratory assistance, maintenance of body temperature, and administration of intravenous sodium bicarbonate
as an antidote
, which has been shown to be an effective treatment for resolving the metabolic acidosis
and cardiovascular complications of TCA poisoning. If sodium bicarbonate therapy fails to improve cardiac symptoms, conventional antidysrhythmic drugs such as phenytoin
and magnesium
can be used to reverse any cardiac abnormalities. However, no benefit has been shown from lidocaine
or other class 1a and 1c antiarrhythmic drugs; it appears they worsen the sodium channel blockade, slow conduction velocity, and depress contractility and should be avoided in TCA poisoning. Hypotension is initially treated with fluids along with bicarbonate to reverse metabolic acidosis
(if present), if the patient remains hypotensive despite fluids then further measures such as the administration of epinephrine
, norepinephrine
, or dopamine
can be used to increase blood pressure. Another potentially severe symptom is seizures; often seizures resolve without treatment but administration of a benzodiazepine
or other anticonvulsive may be required for persistent muscular overactivity. There is no role for physostigmine
in the treatment of tricyclic toxicity as it may increase cardiac toxicity and cause seizures.
Tricyclic antidepressants are highly protein bound and have a large volume of distribution
; therefore removal of these compounds from the blood with hemodialysis
, hemoperfusion
or other techniques are unlikely to be of any significant benefit.
and the United Kingdom
showed that between 8 and 12% of drug overdoses were following TCA ingestion. TCAs may be involved in up to 33% of all fatal poisonings, second only to analgesics. Another study reported 95% of deaths from antidepressants in England and Wales between 1993 and 1997 were associated with tricyclic antidepressants, particularly dothiepin and amitriptyline
. It was determined there were 5.3 deaths per 100,000 prescriptions.
Sodium channel blockers such as Dilantin should not be used in the treatment of TCA overdose as the Na+
blockade will increase the QTI
.
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
drug. It is a significant cause of fatal drug poison
Poison
In the context of biology, poisons are substances that can cause disturbances to organisms, usually by chemical reaction or other activity on the molecular scale, when a sufficient quantity is absorbed by an organism....
ing. The severe morbidity and mortality associated with these drugs is well documented due to their cardiovascular
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
and neurological
Neurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
toxicity. Additionally, it is a serious problem in the pediatric population due to their potential toxicity and the availability of these in the home when prescribed for bed wetting and depression.
Signs and symptoms
The peripheral autonomic nervous systemAutonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
, central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
and the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
are the main systems that are affected following overdose. Initial or mild symptoms typically develop within 2 hours and include tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, drowsiness, a dry mouth, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
and vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, urinary retention, confusion, agitation, and headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
. More severe complications include hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, cardiac rhythm disturbances, hallucinations, and seizures. Electrocardiogram
Electrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...
(ECG) abnormalities are frequent and a wide variety of cardiac dysrhythmias can occur, the most common being sinus tachycardia and intraventricular conduction delay resulting in prolongation of the QRS complex and the PR/QT intervals. Seizures, cardiac dysrhythmias, and apnea are the most important life threatening complications.
Toxicity
Tricyclics have a narrow therapeutic indexTherapeutic index
The therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death or toxicity ....
, i.e., the therapeutic dose
Dose (biochemistry)
A dose is a quantity of something that may impact an organism biologically; the greater the quantity, the larger the dose. In nutrition, the term is usually applied to how much of a specific nutrient is in a person's diet or in a particular food, meal, or dietary supplement...
is close to the toxic dose. In the medical literature the lowest reported toxic dose is 6.7 mg per kg body weight. Although there are differences in toxicity with the drug class, ingestions of 10 to 20 mg per kilogram of body weight are a risk for moderate to severe poisoning, however, doses ranging from 1.5 to 5 mg/kg may even present a risk. Most poison control center
Poison control center
A poison control center is a medical facility that is able to provide immediate, free, and expert treatment advice and assistance over the telephone in case of exposure to poisonous or hazardous substances...
s refer any case of TCA poisoning (especially in children) to a hospital for monitoring. Factors that increase the risk of toxicity include advancing age, cardiac status, and concomitant use of other drugs. However, serum drug levels are not useful for evaluating risk of arrhythmia or seizure in tricyclic overdose.
Pathophysiology
Most of the toxic effects of TCAs are caused by four major pharmacological effects. TCAs have anticholinergicAnticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
effects, cause excessive blockade of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
reuptake at the postganglionic synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
, direct alpha adrenergic blockade, and importantly they block sodium membrane channels with slowing of membrane depolarization, thus having quinidine
Quinidine
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
like effects on the myocardium.
Treatment
Initial treatment of an acute overdose includes gastric decontamination of the patient. This is achieved by administering activated charcoal lavage which absorbs the drug in the gastrointestinal tractGastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
either orally or via a nasogastric tube. Activated charcoal is most useful if given within 1 to 2 hours of ingestion. Other decontamination methods such as stomach pumps
Gastric lavage
Gastric lavage, also commonly called stomach pumping or Gastric irrigation, is the process of cleaning out the contents of the stomach. It has been used for over 200 years as a means of eliminating poisons from the stomach. Such devices are normally used on a person who has ingested a poison or...
, ipecac
Syrup of ipecac
Syrup of ipecac , commonly referred to as ipecac, is derived from the dried rhizome and roots of the ipecacuanha plant, and is a well known emetic .-Preparation:...
induced emesis, or whole bowel irrigation
Whole bowel irrigation
Whole bowel irrigation is a medical process involving the rapid administration of large volumes of an osmotically balanced polyethylene glycol solution , either orally or via a nasogastric tube, to flush out the entire gastrointestinal tract.-History:Whole bowel irrigation was originally developed...
are not recommended in TCA poisoning.
Symptomatic patients are usually monitored in an intensive care unit
Intensive Care Unit
thumb|220px|ICU roomAn intensive-care unit , critical-care unit , intensive-therapy unit/intensive-treatment unit is a specialized department in a hospital that provides intensive-care medicine...
for a minimum of 12 hours, with close attention paid to maintenance of the airways, along with monitoring of blood pressure, arterial pH, and continuous ECG monitoring. Supportive therapy is given if necessary, including respiratory assistance, maintenance of body temperature, and administration of intravenous sodium bicarbonate
Intravenous sodium bicarbonate
Intravenous sodium bicarbonate is a solution for intravenous administration that increases plasma bicarbonate, buffers excess hydrogen ion concentration, raises blood pH and reverses the clinical manifestations of acidosis....
as an antidote
Antidote
An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....
, which has been shown to be an effective treatment for resolving the metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
and cardiovascular complications of TCA poisoning. If sodium bicarbonate therapy fails to improve cardiac symptoms, conventional antidysrhythmic drugs such as phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
and magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
can be used to reverse any cardiac abnormalities. However, no benefit has been shown from lidocaine
Lidocaine
Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
or other class 1a and 1c antiarrhythmic drugs; it appears they worsen the sodium channel blockade, slow conduction velocity, and depress contractility and should be avoided in TCA poisoning. Hypotension is initially treated with fluids along with bicarbonate to reverse metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
(if present), if the patient remains hypotensive despite fluids then further measures such as the administration of epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...
, norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, or dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
can be used to increase blood pressure. Another potentially severe symptom is seizures; often seizures resolve without treatment but administration of a benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
or other anticonvulsive may be required for persistent muscular overactivity. There is no role for physostigmine
Physostigmine
Physostigmine is a parasympathomimetic alkaloid, specifically, a reversible cholinesterase inhibitor. It occurs naturally in the Calabar bean....
in the treatment of tricyclic toxicity as it may increase cardiac toxicity and cause seizures.
Tricyclic antidepressants are highly protein bound and have a large volume of distribution
Volume of distribution
The volume of distribution , also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution of a medication between plasma and the rest of the body after oral or parenteral dosing...
; therefore removal of these compounds from the blood with hemodialysis
Hemodialysis
In medicine, hemodialysis is a method for removing waste products such as creatinine and urea, as well as free water from the blood when the kidneys are in renal failure. Hemodialysis is one of three renal replacement therapies .Hemodialysis can be an outpatient or inpatient therapy...
, hemoperfusion
Hemoperfusion
Hemoperfusion is a medical process used to remove toxic substances from a patient's blood. The technique involves passing large volumes of blood over an adsorbent substance. The adsorbent substance most commonly used in hemoperfusion are resins and activated carbon...
or other techniques are unlikely to be of any significant benefit.
Epidemiology
Studies in the 1990s in AustraliaAustralia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
and the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
showed that between 8 and 12% of drug overdoses were following TCA ingestion. TCAs may be involved in up to 33% of all fatal poisonings, second only to analgesics. Another study reported 95% of deaths from antidepressants in England and Wales between 1993 and 1997 were associated with tricyclic antidepressants, particularly dothiepin and amitriptyline
Amitriptyline
Amitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...
. It was determined there were 5.3 deaths per 100,000 prescriptions.
Sodium channel blockers such as Dilantin should not be used in the treatment of TCA overdose as the Na+
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
blockade will increase the QTI
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
.