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Management of specific drug poisoning: Antidepressants Barbiturates Benzodiazepines Dr. Satya Pal University College of Medical Sciences & GTB Hospital, Delhi
Antidepressants drug poisoning Antidepressants most commonly divided into three categories: • Tricyclic antidepressants (TCAs) • Monoamine oxidase inhibitors (MAOIs) • Serotonergic drugs
Tricyclic Antidepressants • Amitriptyline • Amoxapine • Clomipramine • Desipramine • Dothiepin • Doxepin • Imipramine • Maprotiline • Nortriptyline • Protriptyline • Trimipramine
Tricyclic Antidepressants • 3rd most commonly ingested medications after analgesics & sedative-hypnotics. Also 3rd most common cause of overdose-related death. • Accounts for 20-25% of fatal drug poisoning in the U.K. & U.S. • Deaths normally occur outside of hospital. • Lethal dose: 15-20 mg/kg (Amitriptyline).
Tricyclic Antidepressantsmechanism of action • Blocking reuptake of norepinephrine and serotonin These effects are probably more important in combined overdose with selective serotonin reuptake inhibitors (SSRIs)
Tricyclic Antidepressants • These drugs are pharmacologically "dirty" and bind to many other receptors: • Histamine (H1 & H2) (sedation) • α1 & α2 (vasodilatation) • GABAA (seizures ) • Muscarinic receptors (anticholinergic effects )
Tricyclic Antidepressantsmechanism of action on heart • These drugs block sodium and other membrane ion channels. • The influx of sodium is the major event responsible for the zero phase of depolarisation in cardiac muscle and Purkinje fibres.
mv Cardiac Action Potential Phase 1 20 0 Phase 2 Repolarization (Plateau Phase) -20 Depolarization -40 Phase 3 Phase 0 -60 -80 Phase 4 Resting membrane Potential Na+ -100 Na+ Na+ ca++ ca++ Na+ Na+ ca++ Na+ K+ Na+ K+ m ca++ ATPase h K+ Na+ K+ K+ K+ K+ K+
Tricyclic Antidepressants • The duration of phase 0 in the heart as a whole is measured indirectly as the duration of the QRS complex on the ECG. • Thus, blockade of the Na+ channel can be indirectly measured by estimating QRS width.
Tricyclic Antidepressants • TCAs block voltage gated Na+ channels in a use dependent manner (i.e. block increases with heart rate). • As the degree of Na+ channel block increases with use, the QRS width will increase with increasing heart rates.
Tricyclic Antidepressants • Other cardiac effects: reversible inhibition of the outward potassium channels responsible for repolarisation giving a mechanism for QT prolongation and arrhythmia generation • Dose dependent direct depressant effect on myocardial contractility that is independent of impaired conduction • alter mitochondrial function and uncouple oxidative phosphorylation
Tricyclic Antidepressantspharmacokinetics • Highly lipid soluble. • Rapidly absorbed • Anticholinergic effects may prolong absorption. • High volume of distribution. • Protein binding > 95% • May get saturated, increasing free fraction • pH dependent • Toxicity increase with acidosis • Alkalinisation: significant decrease in % of free amitriptyline • P450 Hepatic metabolism • Long elimination half life: eg.Amitryptiline 16 hrs; Nortryptiline 30 hrs; Clomipramine 32 hrs • Active metabolites
Tricyclic AntidepressantsCLINICAL EFFECTS • Symptoms and signs at presentation depend upon the dose and the time since ingestion. • Patients who are asymptomatic at six hours post ingestion of normal release medication do not normally develop major toxicity.
Tricyclic Antidepressants • There are three major toxic syndromes. -Anticholinergic effects; -Cardiac toxicity; -CNS toxicity • Death in TCA overdose is usually due to CNS and cardiotoxiceffects.
Tricyclic Antidepressants • Anticholinergic Syndrome: • Hot as hell • Blind as a bat • Dry as a bone • Mad as a hatter • Thus, ask patients when they regain consciousness whether they're hearing or seeing anything strange • A sensitiveindicator for ingestion, but poor predictor for toxicity.
Tricyclic AntidepressantsCardiac effects • ECG changes: • Prolongation of QT interval • Prolongation of PR interval • Prolongation of QRS interval • Right bundle branch block • Right axis deviation • Atrioventricular block • Brugada wave (ST elevation in V1-V3 and right bundle branch block)
Tricyclic Antidepressants • ArrhythmiasSinus tachycardia due to anticholinergic activity and/or inhibition of norepinephrine uptake, heart blocks and ventricular tachycardia/ fibrillation. • Hypotension Blood pressure elevated in early stages after overdose, due to inhibition of norepinephrine uptake. Later on, • hypovolaemia, • decreased peripheral resistance due to alpha-adrenergic blockade • impaired myocardial contractility and cardiac output
Tricyclic AntidepressantsCNS effects • Rapid onset of decreasing consciousness and coma due to very rapid absorption of the drug • Hyperreflexia ,myoclonic jerks or seizure activity • TCAs (eg.dothiepin, desipramine, and amoxapine) cause seizures more frequently and at lower drug concentration. • Convulsions may lead to haemodynamic compromise.
Management of tca toxicity • Supportive • Resuscitation of patient. • ECG monitoring • GI Decontamination • If patient is alert and co-operative and have ingested > 5 mg/kg, charcoal may be administered orally at dose of 1-2 gm/kg€. • If the patient is unconscious , intubation to protect the airway and insert an orogastric tube, aspirate stomach contents then give single dose activated charcoal. €Frommer, DA, Kulig, KW, Marx, JA, Rumack, B. Tricyclic antidepressant overdose: A review. JAMA 1987; 257:521.
Tricyclic AntidepressantsTreatment of specific complications • Seizures • Diazepam 5-20 mg IV • Phenobarbitone 15-18 mg/kg IV • Phenytoin should be avoided ( sodium-channel blocking) • Anticholinergic delirium • Mild delirium : Reassurance +/- benzodiazepines • Neuroleptics should be avoided (most of which have significant anticholinergic activity).
Tricyclic AntidepressantsBicarbonate Both sodium loading and alkalinisation have been shown to be effective in reversing TCA induced conduction defects and hypotension Dose: 1-2 meq/kg Sodium bicarbonate is the drug of choice for the treatment of ventricular dysrhythmias and/or hypotension due to TCA poisoning Brown, TC, Barker, GA, Dunlop, ME, Loughnan, Anaesth Intensive Care 1971; 1:203.Brown, TC. Med J Aust 1976; 2:380.Brown, TC. Clin Toxicol 1976; 9:255
Tricyclic AntidepressantsIntravenousLipid emulsions A new antidote of tca toxicity • ILE decreased mortality from clomipramine toxicity by 80% when compared to placebo. * Yoav G, Odelia G, Shaltiel C. A lipid emulsion reduces mortality from clomipramine overdose in rats. Vet Hum Toxicol 2002; 44(1):30) ILE decreased the frequency of recurrent ventricular arrhythmia in a case of suspected imipramine overdose.
Monoamine oxidase inhibitors • Low therapeutic index and potential for food (tyramine reaction) and drug (serotonin syndrome) interactions. • Severe toxicity in overdoses. • Includes: • Isocarboxazid • Phenelzine • Selegiline • Tranylcypromine • Moclobemide
Used in refractory depression, social phobia disorder, panic disorder, PTST, OCD & bulimia. • MAO is intracellular enzyme bound to outer mitochondrial membrane which removes amine group from endogenous and exogenous biogenic amines (dopamine, norepinephrine and serotonin) by oxidative deamination. • Reduction in systemic bioavailability of absorbed dietery biogenic amines eg. Tyramine MAO- AMAO- B NorepinephrineDopamine Serotonin Tyramine
Mao inhibitors pharmacokinetics • Rapidly absorbed in 1-2 hrs with 1-3 lt volume of distribution • Bioavailability-50%, Protein binding-50% • Metabolism- hepatic P-450 • Plasma half life- 2-4 hrs • No significant active metabolite except selegiline
Mao inhibitors toxicityClinical presentation • Lethal dose : 4 - 6 mg/kg. • Symptoms delayed 6 to 12 hours after ingestion but may be till 24 hours. • Secondary to gradual accumulation of norepinephrine and serotonin in brain and peripheral sympathetic neurons leading to hyper adrenergic and hyperserotonergic state. • Initial symptoms: headache, agitation, irritability, tremor, nausea and palpitations.
Mao inhibitors toxicity • Signs : sinus tachycardia, hypereflexia, drowsiness, hyperactivity, mydriasis, fasciculations, hyperventilation, nystagmus, and generalized flushing. • In moderate toxicity, opisthotonus, muscle rigidity, diaphoresis, hypertension, chest pain, diarrhea, hallucinations, confusion, hyperthermia PING-PONG gaze. • Severe toxicity causes bradycardia, cardiac arrest, hypoxia, hypotension, papilledema, seizures, coma, and worsoning hyperthermia.
Mao inhibitors toxicityTyramine reaction • Dietary amine reaches more in MAO inhibited patients to systemic circulation and releases presynaptic stores of norepinephrine • Most commonly by tranylcypromine than phenelzine or isocarboxid or levodopa • More than 70 foods: eg.aged cheese, broad (fava) beans, non fresh meat or fish, concentrated yeast extract • Within 15-90 min after ingesting these foods.
Mao inhibitors toxicity tyramine reaction • Hallmark: severe occipital or temporal headache • Hypertension, palpitation, diaphoresis, mydriasis, neck stiffness, pallor, chest pain • Phentolamine is antiHT of choice. Avoid ß-blockers. Nitroprusside @ 1-4μg/kg/min • Rapidly resolves. Asymptomatic discharged after 4 hrs of observation.
Mao inhibitors toxicityManagement • History of MAO inhibitor ingestion and hyperadrenergic symptoms. • Identify : hypoxia, rhabdomyolysis, renal failure, hyperkalemia, metabolic acidosis, hemolysis and DIC. • I.V. line placement and cardiac monitoring. • Single dose activated charcoal 1g/kg with gastric lavage. • Phentolamine is antiHT of choice. 2.5-5.0 mg every 10-15 min; continuous infusion @ 1-5 mg/hr. Nitroprusside infusion @ 1 μg/kg/min
Mao inhibitors toxicity • Fenaldopam, short acting i.v. antiHT, acting as peripheral dopamine (D1 receptor) agonist, @ 0.05-0.1 μg/kg/min If hypotension, isotonic i.v. fluids 10-20ml/kg. Norepinephrine : vasopressor of choice • Sinus tachycardia: lidocaine, procainamide and phenytoin. Bradycardia: atropine, isoproterenol and dobutamine. • BZD : anticonvulsant of choice. • No role of hemodialysis
Serotonergic antidepressants • Referred to as atypical, heterocyclic,or second –generation antidepressants. • Heterogeneous group of drugs • GENERAL CHARACTERISTICS: 1. Less cardiotoxic than TCA. 2. Do not inhibit MAO and not associated with tyramine-like reaction. • 3. Have higher therapeutic index than MAO inhibitors and TCAs.
Serotonergic antidepressants 4. Mechanism of action: poorly understood but due to inhibition of neurotransmitter uptake (except mirtazapine). 5. Unlikely to be removed significantly by extracorporeal mechanisms. 6. May interfere with metabolism of other drugs due to hepatic enzyme inhibition. 7. Not detected by standard drug screening tests
Serotonergic antidepressantstrazodone • MOA: Combination of serotonin reuptake inhibition and antagonism of postsynaptic 5-HT2 receptors. • Moderately potent nonselective α1-adrenergic receptor blocker (five times affinity for α1 than α2) S/E. orthostatic hypotension • Rapid and completely absorbed, highly protein bound with intermediate volume of distribution. • Hepatic oxidation by CYT P50 with active metabolite, m-chlorophenylpiperazine(m-CPP).
Serotonergic antidepressants trazodone • Serious toxicity if ingested >2gm. • Most common sign: CNS depression. Other: ataxia, dizziness, coma, and seizures with marked improvement in 6 to 12 hrs. • In CVS, mostly orthostatic hypotension. Others are arrhythmias, conduction abnormalities or IHD. ECG : marked prolongation of QTC interval. • G.I : nausea, vomiting and nonspecific abdominal pain.
Serotonergic antidepressantsmanagement of trazodone toxicity • I.V. access and cardiac monitoring should be started. • Treat hypotension with fluids before initiating vasopressors. • G.I. decontamination with early gastric lavage followed by activated charcoal. • Coingested other drugs or ethanol leads higher incidence of coma, seizures and respiratory arrest.
Serotonergic antidepressantsnefazodone • Inhibits serotonin reuptake and antagonizes postsynaptic 5-HT2 receptors. • Rapidly absorbed, bioavailability of only 20%, 99% protein bound. • Inhibit metabolism of terfenadine, astemizole, pimozide:prolongation of QT interval and torsades de pointes. Symptoms includes drowsiness, nausea, dizziness and vomiting. • Relatively safe, supportive care alone is sufficient • Asymptomatic: discharged after 6 hrs of observation
Serotonergic antidepressantsbupropion • Inhibit reuptake of dopamine and to a lesser extent norepinephrine and serotonin. • Rapidly absorbed, readily crosses BBB. • Abrupt discontinuation – Neuroleptic malignant syndrome due to dopamine agonist activity. • Low therapeutic index, toxic dose more than 450mg/day.
Serotonergic antidepressants bupropion • Hallmark: seizures and sinus tachycardia. Mild hyperthermia and hypertension may be seen. • Peripheral I.V. line and cardiac monitoring • Supportive care and G.I. decontamination if large overdoses. • Benzodiazapines effective in stopping seizures. • Observe asymptomatic pts. for 8 hr on monitored bed.
Serotonergic antidepressantsmirtazapine • Instead blocks central α2-adrenergic receptor & postsynaptic 5-HT2 and 5-HT3. • Rapidly absorbed, 50% bioavailability due to significant 1st pass metabolism. • Presents with sedation, confusion, sinus tachycardia and mild hypertension. • Resolves over 24 hours with supportive care. Single dose activated charcoal for large overdose within 1 to 2 hours.
Serotonergic antidepressantsvenlafaxine • Nonselective inhibitor of serotonin, norepinephrine and dopamine reuptake. • Peaks in 2hrs with 27% protein bound and large volume of distribution, hepatic P-450 oxidation. • 50% pts. asymptomatic. M.C. symptom: drowsiness, progressed to coma. • Sympathetic stimulation: tachycardia, hypertension, diaphoresis, tremors and mydriasis
Serotonergic antidepressantsvenlafaxine • Immediate evaluation , I.V. line and cardiac monitoring. 8 hrs observation is required. • More aggressive G.I. decontamination with single dose activated charcoal within 1 to2 hrs. • Benzodiazepines are anticonvulsant of choice. • Sodium bicarbonate therapy if QRS widening >100msec.
Selective serotonin reuptake inhibitors • In CNS, serotonergic neurons found in brainstem – regulating mood, personality, temperature, wakefulness • 98% of body serotonin found peripherally – regulate vascular tone, peristalsis and platelet activation • SSRIs inhibit reuptake → increasing stimulation of receptors. • Includes: -Fluoxetine -Citalopram -Sertraline -Escitalopram -Paroxetine -Fluvoxamine
Ssripharmacokinetics • Rapidly absorbed, reach peak within 6 hr • High degree of protein binding • Long elimination half life, with sustained biochemical activity due to active metabolites • Metabolized in liver by cyt P-450, metabolites, renally excreted.
SSRI toxicity • Compared with other anti-depressants, rarely produce fatality or serious sequelae • Most fatalities reported with very high doses e.g x150 or because of coingestant. • Unlikely to cause CNS depression or seizures • Do not have significant cardiotoxicity (except citalopram, prolonged QTc)
SSRI toxicity • Do not typically cause anti-cholinergic symptoms, significant sedation or hypotension • May cause hyponatraemia (even at theraputic doses) • Serotonin syndrome is rare unless mixed serotonergic ingestion or changes made in theraputic SSRI dosing
Serotonin syndrome • Life-threatening • Classical triad of mental status changes, autonomic instability and increased neuromuscular tone • BUT actually spectrum from benign to lethal • Increased serotonergic activity in CNS • Seen with theraputic use, inadvertant interactions and intentional self-poisoning
Management of ssri toxicity • Supportive care. • Single dose activated charcoal • Use of sodium bicarbonate therapy; if QRS prolongation. • Administration serotonin antagonist Cyproheptadine – 12mg (PO)+2mg every 2 hr until clinical response ?Olanzapine, chlorpromazine • BZD anticonvulsant of choice.
Barbiturates poisoning • Originally introduced as sedative-hypnotics and anticonvulsants in early 1900s. • Highest risk of morbidity and mortality among all sedative-hypnotics . • Newer , relatively less toxic medication such as benzodiazepines largely supplanted its routine use.