1. به نام خدا گروه طب اورژانس دانشگاه علوم پزشکی اصفهان

2. Case Report1 Woman 34 years old Hx = negative Finding= confused, agitated, dry skin, pupil dilatated, hypotension,

3. Case Report2 Man, 42 years old Agitated with no problem No finding Hx of suicide

4. T.C.A POISONING Is the most common cause of death due to drug overdose Is the most common cause of death due to drug overdose High Mortality Rate High Mortality Rate

5. Antidepressants

6. USES: USES: Anxiolytic & Antidepressive Anxiolytic & Antidepressive Headach Headach Enuresis Enuresis Neuropathy Neuropathy Chronic Pain Chronic Pain

7. EPIDEMIOLOGY : EPIDEMIOLOGY : T.C.A Poisoning is common T.C.A Poisoning is common Poisoning is usually suicidal Poisoning is usually suicidal Toxic effects are typically moderate Toxic effects are typically moderate Severe toxicity or death may occur in large ingestion or co-ingestion Severe toxicity or death may occur in large ingestion or co-ingestion

8. THE CAUSES OF THE HIGH MORTALITY RATE USE BY DEPRESSIVE PATIENTS USE BY DEPRESSIVE PATIENTS SEVERE CARDIOVASCULAR TOXICITY SEVERE CARDIOVASCULAR TOXICITY SEVERE C.N.S TOXICITY SEVERE C.N.S TOXICITY LIMITED TREATMENT LIMITED TREATMENT

9. PHARMACODYNAMIC: PHARMACODYNAMIC: Serum peak 2-8 h Serum peak 2-8 h First pass hepatic metabolism: 20-70% First pass hepatic metabolism: 20-70% High v/d 10-20 l/kg High v/d 10-20 l/kg High Tissue Concentration: 100 times High Tissue Concentration: 100 times metabolism: Liver metabolism: Liver Elimination: Kidney Elimination: Kidney

10. MECHNISM MECHNISM T.C.A s Inhibit Reuptake of Neurotransmitters: T.C.A s Inhibit Reuptake of Neurotransmitters: Norepinephrine Dopamine Serotonin Antihistaminic Antihistaminic Anticholinergic Anticholinergic

11. AT TERAPEUTIC DOSE : AT TERAPEUTIC DOSE : Have Different Anticholinergic & Antihistaminic Effects Have Different Anticholinergic & Antihistaminic Effects AT TOXIC DOSE : AT TOXIC DOSE : Most Have Similar Effects Exceptions : Exceptions : Lofepramin : Minimum Toxicity Lofepramin : Minimum Toxicity Amoxapin : Max. Incidence of Seizure & Min. Cardiovascular Toxicity Amoxapin : Max. Incidence of Seizure & Min. Cardiovascular Toxicity Maprotiline : High Cardiovas. Toxicity Maprotiline : High Cardiovas. Toxicity

12. AFTRE OVERDOSE :  Onset of Toxicity is typically rapid  Gastric emptying become slow & absorption delayed  Most death occur within first 24 hrs  Tissues distribution is very rapid  Rapidly progression from no symptom to life- threatening cardiotoxicity or seizure occur in less than 1 hr

13. TOXIC EFFECTS: TOXIC EFFECTS: HEART : Myocardial Depression, Dysrhythmia, Conduction abnormality HEART : Myocardial Depression, Dysrhythmia, Conduction abnormality VASCULAR : Hypotention VASCULAR : Hypotention C.N.S : seizure, myoclonus, coma C.N.S : seizure, myoclonus, coma OTHERS : G.I.T,Urinary System, Hyperthermia, Metabolic Acidosis, Mydriasis, Dry Skin,... OTHERS : G.I.T,Urinary System, Hyperthermia, Metabolic Acidosis, Mydriasis, Dry Skin,...

14. CARDIOVASCULAR EFFECTS Conduction Delay ( QRS Prolongation ) Conduction Delay ( QRS Prolongation ) Sinus Tachycardia Sinus Tachycardia Ventricular Arrhythmias Ventricular Arrhythmias Severe Hypotension Severe Hypotension

15. ventricular bigeminy, right axis deviation, wide QRS complex, long Q-T interval, and right deviation of terminal 40-msec QRS vector in limb leads, with prominent R wave in aVR

16. C.N.S TOXICITY Loss of consciousness : Loss of consciousness : Confusion Confusion Drowsiness Drowsiness Lethargy & Coma Lethargy & Coma Dellirium: Agitation, Disorientation, Psychotic behaviour Dellirium: Agitation, Disorientation, Psychotic behaviour Seizure & Myoclonus Seizure & Myoclonus Hyperthermia Hyperthermia

17. MECHANISM OF C.N.S TOXICITY Block of cholinergic Receptors Block of cholinergic Receptors Block of GABA Receptors in Brain Block of GABA Receptors in Brain Inhibition of Fast Na Channel in Neurons Inhibition of Fast Na Channel in Neurons

18. ANTICHOLINERGIC EFFECTS Sinus tachycardia Sinus tachycardia Hyperthermia Hyperthermia Illeus Illeus Urinary retention Urinary retention Pupil dilatation Pupil dilatation Seizure & Coma Seizure & Coma * Alpha Blockade Vasodilation & Refractory Hypotension

19. HYPERTHERMIA Impaired Sweating Impaired Sweating Excessive heat generation Excessive heat generation Seizure Seizure Myoclonous Myoclonous Agitation Agitation

20. COMPLICATIONS : A.R.D.S A.R.D.S RESPIRATORY DEPRESSION RESPIRATORY DEPRESSION ASPIRATION PNEUMONIA ASPIRATION PNEUMONIA A.R.F (Rhabdomyolysis, Hypotension) A.R.F (Rhabdomyolysis, Hypotension)

21. TOXIC DOSE TOXIC DOSE As low as 100 mg in children As low as 100 mg in children Ingestion of 2-3 times the daily dose in adult Ingestion of 2-3 times the daily dose in adult Ingestion of more than 1 gr is lifethreatening Ingestion of more than 1 gr is lifethreatening Ingestion of 300-1000 mg Mild toxicity Ingestion of 300-1000 mg Mild toxicity 1-2 g Moderate 1-2 g Moderate 2-3 g Severe ( lethal) 2-3 g Severe ( lethal)

22. DIAGNOSIS DIAGNOSIS History Taking Physical Examination Dilated Pupil Dry Skin Seizure, Loss of consciousness Agitation, increased DTR, myoclonus Hyperthermia Serum Level ECG findings QRS Widening

23. B.L.S & A.L.S ( A, B, C, D ) B.L.S & A.L.S ( A, B, C, D ) Air way Management Air way Management Breathing Breathing Circulatory Support Circulatory Support Treatment of Shock & Hypotension Treatment of Shock & Hypotension Fluid & Electrolyte Correction Fluid & Electrolyte Correction Acid - Base disturbances Acid - Base disturbances Antidotal therapy Antidotal therapy

25. TREATMENT : Focused on aggressive airway management: Focused on aggressive airway management: Endotracheal intubation should be performed Endotracheal intubation should be performed if the patient is exhibiting a markedly decreased level of consciousness if the patient is exhibiting a markedly decreased level of consciousness if the level of consciousness is rapidly deteriorating. if the level of consciousness is rapidly deteriorating.

26. Gasteric Lavage Gasteric Lavage ( O.G.T, Char. - Lav. - Char ) Activated Charcoal Activated Charcoal ( M.D.A.C ) EMESIS is contraindicated EMESIS is contraindicated Dialysis is not effective Dialysis is not effective Flumazenil should not be used Physostigmine is contraindicated in CA overdose. Physostigmine is contraindicated in CA overdose. Seizures, cardiac arrest, and death have occurred when physostigmine has been used in CA overdose." Seizures, cardiac arrest, and death have occurred when physostigmine has been used in CA overdose."

27. Hypertension Hypertension is usually mild and transient and requires no treatment Hypotension Hypotension begins with isotonic crystalloids, 10 cc/kg Second line : sodium bicarbonate If hypotension does not resolve, third line : norepinephrine or dopamine is recommended.· High-dose dopamine (20 to 30 mic g/kg/min) norepinephrine (0.1 to 10 mic g/min) may be necessary for the direct α,- agonist effect. For inotropic support alone, dobutamine is controversial

28. Antidote Therapy : Sodium Bicarbonate Ventricular dysrhythmia Refractory hypotension Wide QRS > 100 ms R terminal > 3 mm in AVR

29. Antidote Therapy : Sodium Bicarbonate Serum alkalinization is clinically effective in decreasing CA-induced intraventricular conduction delays. The major effect of increasing pH seems to be increased sodium conductance through myocardial sodium channels rather than the increase in plasma protein binding.· NaHC03 is administered by intra- venous boluses of 1 to 2 mEq/kg NaHC03 is administered by intra- venous boluses of 1 to 2 mEq/kg until hypotension improves and the QRS narrows to 100 msec, or until serum pH increases to a maximum of 7.50 to 7.55. Speed of infusion : 2-3 cc/kg/min After obtaining the desired endpoint with intravenous NaHC0 boluses initiating continuous isotonic intravenous infusion by adding three ampules of 8.4% NaHC03 (50 mEq/ampule, 100 mOsm/ampule) to 1 L of 5% dextrose in water. For a hypertonic continuous intravenous solution, four ampules of 8.4% NaHC03 can be added to 1 L of 5% 3 dextrose in water.

30. serial measurements of arterial pH Repeat boluses and continuous intravenous infusion should be guided by serial measurements of arterial pH and QRS duration. Sinus tachycardia is usually well tolerated and does not require specific therapy. β-Receptor antagonists and fysostigmine are contraindicated. Determining the specific type of wide-complex rhythm is unnecessary because treatment in either case is intravenous NaHC03 Lidocaine has not been consistently effective. Phenytoin has been shown to increase the frequency and duration of episodes of ventricular tachycardia and is not recommended as an anti dysrhythmic agent

31. Type IA antidysrhythmics (quinidine, disopyramide, procainamide) and type IC antidysrhythmics (flecainide, moricizine, propafenone) are contraindicated because they also inhibit fast sodium channels. Type IA antidysrhythmics (quinidine, disopyramide, procainamide) and type IC antidysrhythmics (flecainide, moricizine, propafenone) are contraindicated because they also inhibit fast sodium channels. A transvenous pacemaker and over- drive pacing can be used for CA- associated polymorphic ventricular tachycardia (torsades de pointes) not responsive to magnesium. Bradydysrhythmias are rare and late in CA overdose. do not mandate specific therapy Q-T prolongation, PR prolongation, and rightward terminal 40-msec QRS axis deviation do not mandate specific therapy Treatment with NaHC03, hypertonic sodium chloride, and hyperventilation does not resolve completely Q-T prolongation, which involves not only sodium channel blockade, but also protracted depolarization from potassium efflux blockade.

32. Benzodiazepines should be used for agitation seizures usually respond to intravenous lorazepam or diazepam. ' Seizures refractory to other benzodiazepines have terminated with intravenous midazolam boluses of 2.5 to 10 mg and continuous intravenous infusions." If benzodiazepines fail to terminate prolonged o repetitive seizures, phenobarbital may be administered in a loading dose of 20 mg/kg, given at a rate of up to 50 mg/min in adults or up to 1 mg/kg/min in children. Propofol also has been used to treat refractory seizures successfully. A loading dose of 2.5 mg/kg is followed by continuous infusion of 25 to 200 µg/kg/min. Phenytoin may cause more and longer episodes of ventricular tachycardia. If maximal doses of benzodiazepines, phenobarbital, or propofol are ineffective, neuromuscular blockade and general anesthesia with continuous electroencephalogram monitoring are recommended to prevent rhabdomyolysis and hyperthermia caused by excessive muscle activity.

33. Life-threatening hyperthermia (rectal temperature >40° C) is best treated with control of seizures and neumuscular blockade. A nondepolarizing neuromuscular blocker (e.g., rocuronium) is recommended if rabdomyolysis and hyperkalemia with ECG changes present. Evaporative cooling should be used until ore temperature reaches 38.5° C.,

34. Treatment of Neurologic Complications Treatment of Neurologic Complications of Antidepressant Poisoning

35. Disposition Patients with known or suspected CA overdoses require 6 hours of observation with continuous cardiac monitoring and pulse oximetry. do not After 6 hours of obser vation, patients may be discharged for psychiatric evaluation if they do not develop : (1) ventilatory insufficiency, (2) desaturation on pulse oximetry, (3) QRS greater than 100 msec, (4) sinus tachycardia greater than 120 beats/min, (5) dysrhythmias, (6) hypotension, (7) decreased level of consciousness, (8) seizures, (9) abnormal or inactive bowel sounds. Patients who exhibit any of these findings should be admitted to an lCU Patients who exhibit any of these findings should be admitted to an lCU