TCA and Opioid Toxicity Management Quiz

Acute Intoxication with CNS Depressants (Opioids, Benzodiazepines, TCAs)

• CNS depressants slow brain activity, used to treat various conditions including insomnia, anxiety, pain, and seizures.
• Types of CNS depressants include sedatives, hypnotics, tranquilizers, alcohol, barbiturates, benzodiazepines, and opioids.

Opioids

• Opioids are derived from opium poppy plants or synthetic versions.
• Primarily used for pain relief and euphoria.
• Act on opioid receptors in the brain, spinal cord, and throughout the body.
• Include natural opioids (morphine, codeine), semi-synthetic opioids (heroin, apomorphine), and synthetic opioids (methadone, pethidine, oxycodone, hydrocodone, fentanyl).
• Accidental overdose is the most common route of exposure.
• Opioid-induced intolerance is a desensitization process where increasing doses are needed to achieve the same effect.
• "Drug idiosyncrasy" refers to unusual reactions to drugs.
• Opioids primarily act on mu receptors, but also affect delta and kappa receptors.
• Effects include analgesia, euphoria, respiratory depression, and physiological dependence.
• Opioids inhibit neuronal activity by postsynaptic hyperpolarization and reducing presynaptic Ca++ influx.
• Toxicological effects include depressed respiration, altered consciousness, cardiovascular suppression (especially affecting heart muscle contraction), gastrointestinal complications (constipation), and potential metabolic disturbances like hypoventilation and metabolic acidosis.
• CNS actions include mixed stimulation and depression, impacting centers like the CTZ, vagus nerve, cranial nerves, cerebral cortex (analgesia/sedation), cough center, respiratory center, and heat regulation center.
• Other effects include effects on blood vessels (causing shock), digestive tract (increasing motility, constipation), biliary tract (exacerbating biliary colic), genitourinary system (urine retention), bronchi (bronchospasm), skin (itching), and uncommon adverse effects like seizures, bad dreams, and hallucinations.

Diagnosis of Opioid Toxicity

• Circumstantial Evidence: Signs of acute intoxication in addicts, accidental poisoning in children or iatrogenic poisoning, recent opioid prescription/intake.
• History: Recent prescription or intake of opiates.
• Clinical Examination: Symptoms like decreased level of consciousness, pinpoint pupils, respiratory depression, hypotension, hypothermia, and other signs (e.g., bradycardia, coma, gastrointestinal tract motility problems). Needle track marks on skin can be a sign.
• Investigations: Toxicological tests (immunoassay screening, TLC) and non-toxicological investigations (radiographic images for cerebral bleeding, ECG, arterial blood gases, electrolytes, blood glucose, renal function tests) are needed.

Treatment of Opioid Overdose

• Hospitalization is mandatory.
• Focus on maintaining a patent airway, ensuring adequate oxygenation, supporting pulse and blood pressure, and monitoring for complications.
• Consider gastric decontamination (e.g., lavage, whole bowel irrigation, activated charcoal) if appropriate.
• Naloxone (opioid antagonist) is the drug of choice administered intravenously.
• Some precautions and notes are given regarding the treatment of bradycardia, if needed.

Benzodiazepines

• Remain a widely prescribed drug class.
• Overdoses typically not severe.
• Produce sedative, hypnotic, anxiolytic, and anticonvulsant effects by enhancing GABA's actions.
• Rapidly absorbed orally and parenterally.
• High lipophilicity facilitates blood-brain barrier penetration.
• Highly protein-bound in plasma.
• Metabolized in the liver to active metabolites (e.g., diazepam to nordiazepam).

Benzodiazepines Toxicokinetics

• Rapidly absorbed (orally and parenterally).
• Distribute widely throughout the body, including the brain.
• Highly lipophilic structure facilitates penetration of the blood-brain barrier.
• Highly protein-bound in plasma.
• Metabolized in the liver (e.g., diazepam to nordiazepam).
• Elimination sometimes prolonged in elderly or those with liver issues leading to possible prolonged elimination of some benzodiazepines.

Benzodiazepine Pathophysiology of Toxicity

• Stimulation of GABA release, causing CNS depression, sedation, and possible hypnosis.
• Respiratory depression with reduced alveolar ventilation, potentially leading to apnea.
• Cardiovascular effects potentially include coronary vasodilation, and reduced cardiac output with hypotension.
• Habituation or addiction is possible.
• Complications such as aspiration pneumonia and pressure necrosis of skin and muscles are also possible.

Benzodiazepine Clinical picture of Toxicity

• CNS symptoms (sleepiness, ataxia, impaired motor function,anterograde amnesia, slurred speech, anxiety, delirium, hallucinations, or aggression).
• Cardiovascular problems (hypotension, bradycardia, and cardiac arrest).
• Respiratory problems (apnea and hypoxemia).
• Gastrointestinal discomfort (nausea and vomiting).
• Allergic reactions (urticaria, and skin rash).
• Other symptoms (hypothermia and hypotension).
• Severe cases might involve rapid sleep and later coma due to vasomotor and respiratory depression.
• Benzodiazepines have a wide therapeutic index, and overdose rarely leads to severe complications.
• Elderly and those with chronic illnesses are particularly vulnerable to lethal overdose.

Benzodiazepine Management of Toxicity

• General supportive care (ABCs).
• Gastric lavage (if indicated) and charcoal administration.
• Avoiding the use of ipecac syrup as it may pose risks to patients with diminished gag reflex.
• Diuresis, peritoneal dialysis or hemodialysis are usually ineffective.
• Flumazenil (GABA inverse agonist) can be used, though it has no role treating addiction, or withdrawal.
• Patients with no further symptoms after 4–6 hours of careful observation may be discharged.
• Those with deliberate overdose need psychiatric consultation.

Benzodiazepine Withdrawal

• Can occur from abrupt withdrawal after prolonged administration.
• Syndrome develops within a few days to about a week after cessation of benzodiazepine use.
• Symptoms vary based on dosage and duration of use.
• Possible symptoms Include anorexia, nausea, vomiting, weight loss, insomnia, irritability, increased anxiety, palpitations, headaches, panic attacks, hand tremors, muscular pain/stiffness, and potentially seizures or psychotic symptoms in severe cases.
• Treatment generally involves gradual dose reduction.

Tricyclic Antidepressants (TCAs)

• Used as psychoanaleptics, primarily for the treatment of depression.
• Well absorbed by the digestive tract.
• Highly metabolized in the liver resulting in active metabolites.
• High volume of distribution causing a wide spread in plasma and tissues.

TCA Toxicokinetics

• Well absorbed from gastrointestinal tract (GIT), but anticholinergic effect can delay absorption.
• Metabolized by the liver into active metabolites.
• Primarily bound to plasma and tissue proteins.
• Largely not excreted unchanged in urine.
• Little gastric and biliary excretion with potential enterohepatic circulation.

TCA Mechanism of Action

• Inhibit the reuptake of neurotransmitters (norepinephrine, dopamine, and serotonin) at synapses.
• Block histamine receptors, leading to sedation.
• Block sodium channels, potentially causing cardiac arrhythmias.
• Block muscarinic acetylcholine receptors, resulting in anticholinergic effects (e.g., dry mouth, urinary retention).
• Several other actions involving alpha-adrenergic receptors and GABA receptors.

TCA Clinical Picture of Toxicity

• Cardiovascular: hypotension, potential cardiac arrhythmias (e.g., sinus tachycardia, ventricular dysrhythmia), ECG changes (e.g., widening of QRS complex, ST segment depression, abnormal T wave, prolonged PR and QT intervals).
• Central Nervous System (CNS): Stimulation followed by depression (e.g., seizures, altered mental status, delirium, disorientation, agitation, hallucinations, lethargy, and coma).
• Anticholinergic effects: can include dilated pupils, blurred vision, dry skin, tachycardia, hyperthermia, urinary retention, ileus, dry mouth, agitation, delirium, confusion, hallucinations, and slurred speech.

TCA Investigations of Toxicity

• Toxicological assessment of serum drug levels.
• Assessment of acid-base status including blood gases.
• ECG analysis.
• Chest X-ray.
• Glucose, electrolytes, and kidney function tests.

TCA Treatment of Toxicity

• Early intubation in case of CNS depression and/or hemodynamic instability.
• Cardiac monitoring.
• Treatment of hypotension.
• Management of any cardiac arrhythmias. Sodium bicarbonate is the first choice , with Lidocaine as a second choice.
• Avoid gastric emptying if there are seizures or coma.
• Decontamination may include lavage or use of cathartics (under careful supervision).
• Elimination of the drug is limited due to its large volume of distribution,
• Treatment of seizures and hyperthermia.