Tricyclic Antidepressants (TCAs) lecture 9 by Dr. Magdy M.Awny

Examples of TCA Clinical Uses Of TCAs .Pediatric enerusis .Severe depression .Panic disorders, phobia .Bulimia nervosa (uncontrolled constant eating followed by vomiting) .Pediatric enerusis TCA overdose: 60% likely intentional 90% of TCA suicides do not reach hospital but die at home Examples of TCA Imipramine Tofranil® Desipramine Trimipramine Clomipramine Anafranil® Amitriptyline Tryptizol® Nortriptyline protriptyline

Therapeutic mechanism At low therapeutic dose or at the beginning of toxicity…….TCAs Inhibit neuronal reuptake of catecholamines especially NE, 5HT so increase their level in synapse

At high toxic dose TCA can block -Histamine receptors……sedation -Muscarinic receptors…… antimuscarinic effects, -α adrenergic receptors …….VD (orthostatic hypotension) GABA-A receptor antagonist……..seizures Sodium channel blockage Potassium Channel Blockade

Pharmacokinetics Peak levels occur 2-6 hours post ingestion Lipophilic….easily crosses BBB Highly bound to plasma protein Hemodialysis, hemoperfusion and forced diuresis are ineffective Enter enterohepatic circulation Hepatic metabolism…..active metabolites Renal excretion Half life Therapeutic: on average 24 hours Overdose: up to 72 hours

Manifestations of TCA toxicity Peripheral anticholinergic CNS manifestations CVS effects

Anticholinergic Effects Due to muscarinic receptor blockade Eye….. GIT…… Heart…… Secretions…… Urinary tract ……. Body temp…….

CNS manifestations (due to central anticholinergic effects and H blockage ) Delirium Sedation Stupor Coma Respiratory depression Myoclonic twitching Seizures & hyperthermia Choreoathetoid movements (dancing movements of upper limbs)

CVS manifestations sympathomimetic effects: resulted in hypertension as TCAs at low dose or initially during toxicity they block neuronal reuptake of NE so ↑ NE in synapse→→ VC (α effect), ↑HR (sinus tachycardia “Beta effect”)→ ↑BP sympatholytic effects: resulted in hypotension as TCAs at high dose or later during toxicity they -block alpha-receptor →Vasodilation -Has direct depressant action on myocardium (Na+ channel blockade)→↓contractility→↓ cardiac output→ ↓BP

TCAs mediated Sodium Channel Blockade Impairs sodium entry Arrhythmogenic action due to (quinidine-like or anticholinergic effects) TCAs mediated Sodium Channel Blockade Impairs sodium entry into myocardial cells → Prolongs depolarization (Phase 0), ↓ contractility (-ve inotropy) ↓conduction velocity may →AV block Prolonged PR Widens QRS Bradycardia as TCA depress phase 4 (May be attenuated by antimuscarinic effect) Potassium Channel Blockade Prevents potassium efflux during repolarization QT interval prolongation More pronounced with bradycardia Tachycardia prevents severe QT prolongation

TCA induced acidosis causes arrhythmia (VT either monomorphic or polymorphic “torsades de-points”). where respiratory depression result in accumulation of CO2 (respiratory acidosis), ↓ utilization of O2 →hypoxia → Anerobic metabolism →metabolic acidosis Also hypotension causes tissue hypoperfusion →hypoxia On conclusion acidosis inhibit Na/K ATPase pump → hyperkalemia……arrhythmia

Toxicity Life threatening Ingestions greater than 10mg/kg in adults Pediatrics more susceptible to antimuscarinic effects Manifest symptoms within 6 hours High risk for TCA toxicity ▪ Co-ingestion with other cardiac or CNS depressants ▪ Prior heart disease ▪ Geriatrics Most fatalities ingest more than 1 gram Fatalities occur in initial hours usually before arrival to hospital

Clinical Features Mild/Moderate Toxicity Severe Toxicity Drowsiness Confusion Slurred speech Ataxia Dry skin/mucous membranes Tachycardia Urinary retention Myoclonus Hyperreflexia Hypertension Severe Toxicity Coma Conduction delays Hypotension Respiratory depression Ventricular tachycardia Seizures Pulmonary edema High degree AVB

Diagnosis ICU Suspect in: Rapidly presenting coma Cardiovascular collapse Anticholinergic toxidrome Generalized seizure Characteristic ECG findings ▪ 1st degree AVB ▪ Widened QRS ▪ Prolonged QT ICU

Treatment GI Decontamination Emesis not recommended in unconscious pt Gastric lavage within first few hours after toxic ingestion Activated Charcoal 1-2gm/kg PO, repeated dose (0.5-1g/kg) 2-4 hrs of first dose with cathartic Elimination enhancement …….. Not effective Lipophilic Highly distributed “vd 12-20 L/kg) Highly bound to plasma proteins up to 95% So TCAs elimination not affected by hemodialysis, hemoperfusion or even multiple doses of charcoal. Also urinary excretion of TCAs or their metabolites (demethylated cpd) is < 10% so enhancing renal excretion is not effective

Adjunctive Treatments Sodium Bicarbonate Therapy (1-3 mEq/kg, bolus injection as the initial management) Indications Widened QRS Refractory hypotension (trendlenburg, I.V saline,….) Ventricular dysrhythmias or conduction abnormality Improves ▪ Conduction ▪ Contractility ▪ correct acidosis Hypokalemia is an expected complication Supplementation usually required NaHCO3 →↑pH →↑non ionized fraction of TCAs→→ ↑protein binding→↓active free fraction→ facilitate dissociation of TCAs from !fast Na channel (recovered) also increased extracellular sodium reverses the effect on conduction velocity and QRS duration

Treatment Seizures Hypotension Benzodiazepines are drug of choice (diazepam 5-10mg i.v Hypotension Vasopressor e.g. Norepinephrine used with caution as TCA block amine pump so may increase Arrhythmogenic potential of theses agents

Treatment Dysrhythmias Antidotes Prolonged QRS or ventricular dysrhythmias 1st line drug is bicarbonate therapy 2nd line drug is lidocaine - torsade de pointes is best treated with overdrive cardiac pacemaker insertion Antidotes There are no readily available specific antidotes for the most serious manifestations.

Case study A.B is a 24-year- female with a 4 months history of depression who was found unresponsive at home. The paramedics discovered empty bottles of amitriptyline (Elavil)100 mg and trazodone (desyrel) 100mg. Vital signs was BP 80/55 mm Hg, pulse 160/min and irregular, respiration 6 /min and temperature 99.9˚ F. physical examination showed dry mucous membranes, dilated pupils, absent bowel sounds and a distended urinary bladder. During transport to hospital the patient had severe episodes of myoclonic jerking of her arms. 1-Characterize the toxicity of the antidepressant compounds. A.B has anticholinergic manifestations e.g. tachycardia, fever,…… CNS manifestations include coma, respiratory depression, fever and myoclonus 2-what initial management would you recommend for A.B? Emesis …….. hypotensive and unresponsive and should be admitted to ICU should be placed in trendlenburg position and resuscitated with saline to restore cardiac output

3-What antiarrhythmic treatment would be most appropriate for A.B? a-bolus injections of 1-3mEq/kg sod bicarbonate as the initial management of TCA-induced conduction abnormality and vent arrhythmia b-if no response after bicarbonate therapy or hyperventilation→ antiarrhythmic therapy is indicated 4-while in the emergency department, A.B had a tonic-clonic seizures, which lasted about one minute and spontaneously subsided. What treatment is indicated? If A.B develop persistent tonic clonic seizures, they may be controlled initially with 5-10 mg IV diazepam 5- 30 hrs after admission A.B. was alert and her vital signs were BP 110/70 mmHg, pulse 65/min, respiratory rate 20/min and temperature 98.6 F. her ECG has returned to normal 12 hrs after admission and remained stable. What is A.B’s risk for developing delayed arrhythmia? It is highly unlikely that she will develop arrhythmia following discharge since she is alert and her ECG has been stable for 12 hrs.