Selected Toxicological Antidotes PowerPoint Presentation

Slide 1 -

Selected Toxicological Antidotes Joel Turner, CCFP, FRCP (R5) Dept. of Emergency Medecine McGill University

Slide 2 -

Selected Toxicological Antidotes Present 3 cases Epidemiology, pathophysiology Conventional treatment of each. Their limitations Specific antidotes Mechanism of action Indications Dosing instructions Benefits and side effects

Slide 3 -

Case 1. “Lub/Dub………………………… Lub/Dub” 65 year old male found comatose at home En route: BP 80/s HR: 30 RR: 10 On arrival, he is intubated.

Slide 4 -

1. Atropine 1 mg given  no response 2. Bolus 500 cc NS  no response Atropine – 2mg  no response Pacing Paddles placed  BP drops 5. Dopamine infusion started (at 20 ug/kg/min) HR at 40 Case 1. “Lub/Dub………………………… Lub/Dub”

Slide 5 -

Case 1. “Lub/Dub………………………… Lub/Dub” Finally, family member brings in an empty bottle of propranalol (~ 5 grams missing) Diagnosis: Beta Blocker overdose

Slide 6 -

Beta Blockers Beta Blocker overdose - epidemiology 2000: 1. U.S - 11,064 exposures (3.6:100,000) - 2,829 < 6yrs (25%) - 2,491 intentional (22%) 2. Quebec - 247 exposures (3.5:100,000) - 30 in < 6yrs (12 %) - 121 intentional (49%)

Slide 7 -

Beta Blockers

Slide 8 -

Beta Blockers ABC’s Treatment of Bradycardia: ACLS guidelines: hypotension: fluids, dopamine bradycardia: atropine, pacers, dopamine Circulatory support

Slide 9 -

Atropine: limited effects (bradycardia is not due to increased vagal tone) Beta Blockers  Increases HR only 22% of the time

Slide 10 -

Beta Blockers -blocker Catecholamines (epi, dobutamine, dopamine) often are ineffective in treating -blocker effect. Catecholamines  Dopamine: 25% effective, Epi: 67% effective Therefore, must find something that will bypass this blocked receptor

Slide 11 -

Beta Blockers Glucagon -blocker Secreted by pancreas secondary to hypoglycemia Glucagon Receptors found in heart muscle Acts by stimulating adenylate cyclase. independent of -receptor glucagon + Glucagon receptor Drug of choice for -blocker (& CCB) O.D.

Slide 12 -

Beta Blockers The final outcome: positive chronotropic and inotropic effects despite -adrenergic blockade. Onset within minutes, peak levels in 5-7 minutes, duration of action of 10-15 minutes. Glucagon

Slide 13 -

Glucagon - evidence. Beta Blockers Many animal studies of Glucagon’s cardiac effects Human Studies About 15-20 case reports of glucagon benefit, when other modalities failed. Only two case reports of glucagon benefit where glucagon was the sole agent used. About 5 cases of treatment failure No prospective studies exist

Slide 14 -

Beta Blockers Glucagon - How to give: Available as a 1-unit (1-mg) or 10-unit (10-mg) lyophilized powder accompanied by 1 cc or 10 cc diluent Initial dose (adults or pediatrics): 50ug/kg (3.5 mg in 70 kg) infused over 1 min. If ineffective, higher doses (up to 10 mg) can be tried. infusion: 2-5 mg/hr in D5W (0.1 mg/kg/hr – Peds). (“response dose”/hr)

Slide 15 -

Beta Blockers Glucagon - precautions Side effects from glucagon include: dose-dependent nausea and vomiting  aspiration hyperglycemia, hypokalemia (not clinically important) Some Reports of treatment failure Diluent contains 2 mg/ml phenol as preservative Max 10-h dose of phenol = 50 mg = 5mg glucagon Use sterile water instead of diluent

Slide 16 -

4. Insulin?? Shown to have positive inotropic effects on animal and human myocardium Beta Blockers

Slide 17 -

Insulin in Acute Beta Blocker OD. Kerns, et al. Ann Em Medicine. 1997. 29:748-757 24 dogs, anesthetized and infused with Inderal. Hemodynamics before & after treatment with: Normal Saline (n=6) Insulin (4IU/min) + glucose PRN (n=6) Glucagon (50 ug/kg) + infusion (n=6) Epinephrine (1ug/kg/min) + titrated (n=6) Beta Blockers

Slide 18 -

Results: 6/6 Controls died within 150 min 5/6 Epinephrine animals died after 240 min 2/6 Glucagon animals died “ “ “ 0/6 Insulin animals died “ “ “ Kaplan-Meier Survival Curve Insulin vs. Glucagon (p<0.05) Insulin vs. Epinephrine (p<0.02) Beta Blockers

Slide 19 -

1. May enhance catecholamine release 2. May enhance myocardial substrate use In normal myocardium, FFA are preferred substrate. In poisoned myocardium, glucose becomes 1o substrate 3. May increase cytosolic calcium Pathophysiology ?: Beta Blockers Insulin in Acute Beta Blocker OD.

Slide 20 -

Questions ??

Slide 21 -

35-year male, brought it to ED, with ataxic gait. Vomiting ++, c/o abdominal cramps - smells and looks drunk. Patient’s mental status quickly deteriorates – Vitals remain normal, Physical exam - WNL What tests do you order? Case 2. Saturday Night’s all right for drinking

Slide 22 -

ABG: 7.10/20/10/95 Ca: 2.3 mmol/L Anion Gap= 32 Ethanol: 1.1 mmol/L Osmolal Gap: 57 ! Imp: Toxic alcohol ingestion Case 2. Saturday Night’s all right for drinking ASA, APAP – neg ECG - normal

Slide 23 -

Ethylene Glycol Methanol Ethylene Glycol / Methanol

Slide 24 -

Toxic Alcohol overdose – the numbers 2000: U.S. - 5837 E.G. poisonings (2:100,000) - 2474 Methanol poisonings (0.8:100,000) - 1460 in age < 6yrs (18%) - 862 intentional (10%) Quebec - 311 E.G. intoxications (4.4:100,000) - 732 methanol intoxications (10:100,000) - 318 in age < 6 yrs (30%) - 46 intentional (4%) Ethylene Glycol / Methanol

Slide 25 -

Regional Distribution in Quebec Toxic Alcohol overdose – the numbers Ethylene Glycol / Methanol

Slide 26 -

Methanol Ethylene Glycol Alcohol dehydrogenase Formaldehyde Aldehyde dehydrogenase Formic acid Lactic Dehydrogenase Or Glycolic acid Oxidase Glyoxylic acid & Oxalic acid A-OH-B ketoadipic acid Glycine and benzoic acid Ethylene Glycol / Methanol Glycoaldehyde Glycolic acid Th B6 CO2 & H2O Folate

Slide 27 -

Case 2. Saturday Night’s all right for drinking Bedside pearls (ethylene glycol): i) hypocalcemia = suggests ethylene glycol ii) urine calcium oxalate crystals (50%) iii) urine fluorescence (w/in 30 min) NOT sensitive (some antifreezes do NOT contain fluorescein) (Do not put urine in glass container – false pos) iv) “normal” gap does NOT rule out toxicity

Slide 28 -

Ethylene Glycol / Methanol Initial management: ABC’s (remember the impending CNS depression) Initiate specific treatment if ingestion strongly suggested – Do NOT wait for lab values Untreated, lethal dose (apr. 100 cc) will cause death in about 24 hours.

Slide 29 -

Ethylene Glycol / Methanol Goal of Specific Treatment: Prevent further metabolism of toxic alcohol Eliminate alcohol from circulation Toxic Alcohol ADH Formic, glycolic or Oxalic acid X Eliminated (renal, dialysis)

Slide 30 -

Indications of specific treatment: Methanol levels > 6.3 mmol/L Ethylene Glycol > 3.2 mmol/L, or Suspicion of ingestion and metabolic acidosis. Ethylene Glycol / Methanol

Slide 31 -

Ethylene Glycol / Methanol 1. Ethanol Traditionally been used as antidote for Methanol and Ethylene Glycol (never approved) Historical Case series/reports only (1st report: 1959) Never prospectively/retrospectively studied Preferred substrate of alcohol dehydrogenase  therefore inhibits formation of NEW toxic substrate Toxic Alcohol ADH X Ethanol

Slide 32 -

What amount will completely block the metabolism of methanol/ethylene glycol? Objective (regardless of route): quickly achieve and maintain ethanol level  22 mmol/L or (100 g/dL) Ethylene Glycol / Methanol Can be given IV or PO. (each has its own advantages and disadvantages) Ethanol – How to give.

Slide 33 -

Ethanol (IV or PO) Loading Dose (over 1 hour) = [plasma] x Vd =1g/L (100 g/dl) x 0.8 g/kg =For 70 kg person  56 grams ethanol =280 cc of 20% ethanol: (4 cc/kg) 560 cc of 10% ethanol: (8 cc/kg) 1120 cc of 5% ethanol: (16 cc/kg) Ethylene Glycol / Methanol

Slide 34 -

Maintenance Dose  to replace what is being eliminated: 66-130 mg/kg/hr Using 10% Etoh, Average in 70 kg person = 5.6 g/hr = 56 cc/hr (double in alcoholic) ~ 10 g/hr = 105 cc/hour Ethanol (IV or PO) Ethylene Glycol / Methanol

Slide 35 -

Ethylene Glycol / Methanol Lots of problems with Ethanol!! Oral Absorption is erratic (and difficult) IV preparations rarely shelved Math is challenging (many reports of errors) Kinematics vary between pts. and in same pt. Causes even more profound CNS depression Need large volumes (1120 cc bolus of 5% etoh) Etoh intoxication can cause hypoglycemia, gastritis, pancreatitis Use of Ethanol mandates hourly ethanol and glucose checks in ICU Duration can take as long as 100 hrs (depending on dialysis)

Slide 36 -

Ethylene Glycol / Methanol 2. Fomepizole (4-methypyrazole) Competitive Inhibitor of Alcohol dehydrogenase (in vitro: 80,000 times affinity for ADH than methanol) Toxic Alcohol ADH Formic, glycolic or oxalic acid Introduced in 1986

Slide 37 -

Ethylene Glycol / Methanol 2. Fomepizole (4-methypyrazole) Competitive Inhibitor of Alcohol dehydrogenase (in vitro: 80,000 times affinity for ADH than methanol) Toxic Alcohol ADH - Fomepizole X Eliminated (renal, dialysis) Formic, glycolic or oxalic acid Introduced in 1986

Slide 38 -

Evidence: Fomepizole in E.G. poisoning: ~ 10 Cases: prevention or normalization of acidosis and renal failure (+/- dialysis) M.E.T.A. Study group: Brent, et al. NEJM 1999. 340:832 19 consecutive pts. with confirmed E.G. poisoning Treated with fomepizole (and dialysis if indicated*)  18/19 survived  prevented RF in 10/10 pts with initially normal Cr.  eventual normalization of Cr in 6/9 pts with ARF *Indications for dialysis: -pH<7.1, worsening acidosis -Cr>265, worsening ARF -E.G. [ ] > 8.1 mmol/L Ethylene Glycol / Methanol

Slide 39 -

Fomepizole in methanol poisoning:  Only 4 case reports (first one – 1997)  M.E.T.A. Study group: Brent, et al. NEJM 2001. 344:424 11 consecutive pts. with confirmed methanol poisoning Treated with fomepizole (and dialysis if indicated*) Outcomes followed: formic acid [ ], visual acuity, pH  9/11 patients survived visual deficits reversed in 7/7 patients Acidosis resolved in all 9 patients *Indications for dialysis: -pH<7.1, worsening acidosis -methanol [ ] > 15.6 mmol/L -Any visual symptoms Ethylene Glycol / Methanol

Slide 40 -

 Approved by FDA for E.G. poisoning in 1997, and for methanol poisoning in 2000 Fomepizole (4-methypyrazole) Ethylene Glycol / Methanol

Slide 41 -

No human studies comparing EtOH vs. Fomepizole Only 2 animal studies: In dogs, fomepizole increased urinary excretion of E.G. compared to ethanol (Toxicol Lett. 1987.35:307) In Cats, Fomepizole was less effective than Etoh in preventing ARF if given 2 hours after intoxication with E.G. (dosing issues) (Am J Vet Res. 1994. 55:1771) Ethylene Glycol / Methanol Ethanol vs. Fomepizole??

Slide 42 -

Ethylene Glycol / Methanol Fomepizole - How to Give Can be given PO or IV Loading Dose: 15 mg/kg Maintenance: 10 mg/kg bolus q12 h x 48 hrs Maintenance: 15 mg/kg bolus q12 h until end Endpoint: Methanol levels < 6.3 mmol/L Ethylene Glycol < 3.2 mmol/L

Slide 43 -

Ethylene Glycol / Methanol Change in dialysis recommendations with Fomepizole? Historical indications for dialysis with E.G. 1. pH<7.1, or worsening acidosis despite treatment 2. Cr>265, worsening ARF 3. E.G. [ ] > 8.1 mmol/L Borron S, et al. 1999 Lancet. 354:831 Following E.G. ingestion (Median [ ] = 16.5), 7 patients with initial normal Cr and no acidosis were treated with Fomepizole and NOT dialyzed  No adverse effects

Slide 44 -

Change in dialysis recommendations with Fomepizole? Ethylene Glycol / Methanol For E.G. intoxication,  In the absence of metabolic acidosis, patients who present with normal renal function would not be expected to require hemodialysis, regardless of the EG concentration. Sivilotti, et al. 2000, Ann Em Med. 36:114

Slide 45 -

Ethylene Glycol / Methanol Historical indications for dialysis for Methanol 1. pH<7.1, or worsening acidosis despite treatment 2. Any visual symptoms 3. Methanol [ ] > 15.6 mmol/L Megarbane, et al. 2001. Int. Care Med. 27:1370 Following methanol intoxication ([ ] > 15.6)= 4 patients without visual impairment or acidosis recovered fully after fomepizole (no dialysis) Change in dialysis recommendations with Fomepizole?

Slide 46 -

Fomepizole – Advantages: Does not require separate preparations Therapeutic levels are reliably achieved No Change in mental status No risk of hypoglycemia, hepatotoxicity Hemodialysis not needed in subgroup of patients Main Disadvantage: Cost! Apr. $1000 US per 1500 mg vial Suggested shelf life of drug ~ 3 yrs U.S. Manufacturer (Orphan Medical) will replace drug at no charge Ethylene Glycol / Methanol

Slide 47 -

Questions ??

Slide 48 -

Case 3. Gimme Sugar 54 year old male brought in by police because of extreme agitation. While being subdued, patient becomes lethargic, and begins to show bizarre focal neurological deficits. Vitals: BP: 120/80 HR: 110 RR: 20 T=37.5 gluc: 1.3 After 1 amp of D50, patient’s neuro findings resolve, and he becomes more alert.

Slide 49 -

Case 3. Gimme Sugar But… After an hour on a dextrose drip, patient again becomes lethargic and agitated. Repeated gluc: 1.7 Another D50 given with resolution of Sx This cycle of hypoglycemia-induced symptoms returns several times

Slide 50 -

Inside patient’s pocket is an empty bottle of glipizide XL Diagnosis: Sulfonylurea overdose Case 3. Gimme Sugar

Slide 51 -

Mechanism of action Sulfonylureas Lower blood sugar by stimulating pancreatic islet cells and facilitating the release of preformed pancreatic insulin

Slide 52 -

Sulfonylureas

Slide 53 -

Sulfonylurea overdose – the numbers 2000: U.S - 6910 O.H. poisonings (2.3:100,000) - 2493 in age < 6yrs (36%) - 1284 intentional (19%) Quebec - 73 intoxications (1:100,000) - 15 in < 6yrs (20 %) - 30 intentional (40%) Sulfonylureas

Slide 54 -

Initial Managements Sulfonylureas Dextrose Initial management for all hypoglycemia. BUT: Glucose itself stimulates release of insulin. Results in recurrent, rebound hypoglycemia. Requires ICU monitoring, blood glucose measurements q 20-60 minutes Duration of treatment can be very long (>2-4 days)

Slide 55 -

Sulfonylureas Diazoxide Direct inhibitor of insulin release Increases hepatic glucose output Effective in several case reports and chart review Cumbersome, may cause hypotension, hypernatremia Glucagon Raises glucose levels by stimulating gycogenolysis. Effective only if sufficient glycogen present, has no effects in starvation, chronic hypoglycemia. Since it stimulates Insulin secretion, it is detrimental and contraindicated in Sulfonylurea O.D.

Slide 56 -

Octreotide: Long-acting somatostatin analogue suppresses hormone release GH, gastrin, glucagon, and, most interestingly, INSULIN Sulfonylureas

Slide 57 -

Sulfonylureas Octreotide to treat sulfonylurea overdose: Case reports and case series About 9 isolated case reports - Intoxications - Insulinomas - PHHI

Slide 58 -

Sulfonylureas 1. Boyle PJ. J Clin Endocrin Metab. 1993 8 normal subjects received O.D. of glipizide on 3 occasions. D50 + dextrose infusion D50 + octreotide (30 ng/kg/min) D50 + diazoxide (300 mg q4h) Number of patients with hypoglycemic episodes Frequency of rebound hypoglycemia after treatment end Dextrose requirement significantly lower in octreotide group (p<0001) Rebound hypoglycemia occurred in all patients receiving dextrose or diazoxide, but only 2/8 in octreotide group.

Slide 59 -

2. McLaughlin, et al Ann Em Med, Aug. 2000 9 patients treated with Octreotide for sulfonylurea-induced hypoglycemia Before Octreotide therapy: Number of rebound hypoglycemic events (<3.5): 28 Number of amps of D50 given: 25 Following the administration of Octreotide (SC): Number of hypoglycemic events: 2 Number of amps of D50 given: 2 NO MAJOR SIDE effects reported!! Sulfonylureas

Slide 60 -

Sulfonylureas Octreotide - How to give: Can be given IV or SQ Initial dose: 50 g q 6 hours (Infusion doses: 100 g /hr) Pediatric dose: 1.0 g /kg (single case report) End point: 24-48 hrs (remember: PO intake is the optimal glucose source)

Slide 61 -

Sulfonylureas Octreotide: Advantages/Side effects: Can be given both IV or SC. Very inexpensive,  $11 for a 100 ug vial Highly efficacious and safe in multiple studies argued that the use of octreotide can prevent admission to the ICU NO MAJOR SIDE effects reported

Slide 62 -

Summary Beta Blocker Overdose: Bradycardia may not respond to usual ACLS Glucagon – drug of choice Insulin – novel antidote? Toxic Alcohol overdose: Must prevent metabolism of benign alcohol into toxic metabolite. Do not wait for levels to start specific Rx Ethanol is efficient but very difficult to use Fomepizole very efficient and reliable, and may avoid need for dialysis; - but expensive.

Slide 63 -

Sulfonylurea overdose: Dextrose treatment will cause recurrent rebound hypoglycemia Glucagon is contraindicated Octreotide is simple, inexpensive and reliable (can prevent ICU admission) Summary

Slide 64 -

Questions ??

Slide 65 -

Thank you.

Slide 66 -

Beta Blockers

Slide 67 -

Beta Blockers Brief Review: 3 types of Beta receptors: 1, 2, 3 1: found in heart muscle Stimulation causes increase contractility, conduction velocity and automaticity 2: Smooth muscle of lung Stimulation causes bronchodilation and secretion Beta blockers are classified as selective or non-selective

Slide 68 -

Beta Blockers

Slide 69 -

Beta Blockers Airway protection, and ventilation GI decontamination: Activated Charcoal: effective Emesis +/- lavage are contrainidicated increase vagal tone and worsen bradycardia pretreat with atropine Treatment of Bradycardia: ACLS guidelines: hypotension: fluids, dopamine bradycardia: atropine, pacers, dopamine

Slide 70 -

Case 2. Saturday Night’s all right for drinking Bedside pearls (ethylene glycol): i) hypocalcemia = suggests ethylene glycol ii) urine calcium oxalate crystals (50%) iii) urine fluorescence (w/in 30 min) NOT sensitive (some antifreezes do NOT contain fluorescein) (Do not put urine in glass container – false pos) iv) “normal” gap does NOT rule out toxicity

Slide 71 -

Ethylene Glycol / Methanol Pathophysiology/Clinical effects: Initial clinical effects of all alcohols are similar Ethylene Glycol and Methanol are themselves not toxic – therefore goal is to minimize metabolism Methanol: Formic acid formation causes severe acidosis and retinal toxicity (snowstorm vision) Ethylene Glycol: Glycolic Acid formation causes severe acidosis. Oxalic Acid formation causes calcium oxalate deposits in all tissue (esp kidney)

Slide 72 -

Evidence: Ethylene Glycol / Methanol No randomized controlled trials Consistent results in Case Reports and Multicentred Case Series – All prevent toxic sequelae of Toxic alcohol ingestion May avert need for dialysis in EG intoxication who have no acidosis () Pediatrcs: isolated case reports – similar results

Slide 73 -

Isoniazid Clinical Findings: Asymptomatic pts. should be observed for at least 6 hr (toxicity usually develops by then) Initial s/sx: n+v, dizzyness, Temp, BP Generalized seizures will occur within 2 hours Ingestions of: ~20mg/kg usually associated with seizures, ~140 mg/kg usually fatal Metabolic acidosis secondary to Lactic acid accumulation (type B)

Slide 74 -

Case 4. A whole lot of Shakin’ Going On. 24 year old woman brought in to ED, unconscious Found unconscious in apartment by brother. On the way to hospital, she had tonic-clonic seizure On arrival, 130/90, 100, 12, 38.4 No trauma found, neck supple, PERL, GCS=6 Intubated for airway protection, IV, monitor, bloods sent… BUT…

Slide 75 -

Had another generalized seizure: Valium 5 mg IV  No response Valium 5 mg IV  No response Phenobarbital 500 mg  No response Chemstrip = 5.7 ABG: 7.32/32/90 Case 4. A whole lot of Shakin’ Going On. Anion Gap = ECG=NST (QRS n) 30

Slide 76 -

Case 4. A whole lot of Shakin’ Going On. We have a patient with: Repeated seizures refractory to normal anticonvulsants. Coma Metabolic Acidosis These are hallmarks of toxicity to:

Slide 77 -

Isoniazid Introduced in 1952, cornerstone for therapy and prophylaxis of tuberculosis Use of INH dramatically increased in past 10 years. With increase use, comes increase abuse. U.S 1996: - 507 cases of INH-related poisonings Among 5 most common causes of drug-induced seizures in U.S.

Slide 78 -

Isoniazid Isoniazid overdose – the numbers 2000: Quebec - 8 exposures - 1 < 6yrs (12 %) - 4 intentional (50%)

Slide 79 -

Pyridoxal 5’-Phosphate INH PPK INH Urinary elimination INH Pyridoxine (Vit B6) Isoniazid End Result = Severe Pyridoxine Deficiency

Slide 80 -

Isoniazid Why should we care about a vitamin deficiency?

Slide 81 -

Isoniazid Treatment: As with all seizing patients, ABC’s (airway protection, IV fluids) BDZ (Valium, 5-10 mg iv) initial approach. BUT… BDZ’s and Barb’s when used alone, often not effective They require presence of GABA to be effective

Slide 82 -

Isoniazid Treatment: Dilantin (Na-channel blocker), not effective and not recommended. Problem is NOT inadequate GABA channel activation, but inadequate GABA

Slide 83 -

Isoniazid PYRIDOXINE (VIT B6) IS THE ONLY ANTIDOTE FOR INH TOXICITY Pyridoxine reverses the INH process by activating glutamic acid decarboxylase and increasing formation of GABA

Slide 84 -

Isoniazid Pyridoxine - How to give: Actively seizing patients should immediately be given pyridoxine IV – in a gram-to-gram dose. If ingested amount not known, start with 5 grams pyridoxine Rate of 1 gram q 2-3 minutes

Slide 85 -

Isoniazid Repeated dosing for persistent seizures If iv form not available, can be given as a slurry using crushed tablets via NG Pyridoxine - How to give: Pediatric dose: 70 mg/kg (IV or PO) max dose – 5 g

Slide 86 -

Isoniazid Side Effects: Very little Reports of irreversible sensory loss when given in mega doses (> 130 g) Recommendations: 10-15 g of Vit B6 should be available in stock in hospital