PDP 406 CLINICAL TOXICOLOGY

Transcription

1 PDP 406 CLINICAL TOXICOLOGY Pharm.D Fourth Year

2 Toxicological Antidotes Mr.D.Raju.M.Pharm., Lecturer

3 Selected Toxicological Antidotes 1. Present 3 cases 2. Epidemiology, pathophysiology 3. Conventional treatment of each. a. Their limitations 4. Specific antidotes a. Mechanism of action b. Indications c. Dosing instructions d. Benefits and side effects

4 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.

5 Case 1. Lub/Dub Lub/Dub 1. Atropine 1 mg given no response 2. Bolus 500 cc NS no response 3. Atropine 2mg no response 4. Pacing Paddles placed BP drops 5. Dopamine infusion started (at 20 ug/kg/min) HR at 40

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

7 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 exposures (3.5:100,000) - 30 in < 6yrs (12 %) intentional (49%) Beta Blocker Overdose - by region Saguenay Quebec Montreal Outaouais Cote Nord Chaudiere Lanaudiere Laurentides Monteregie

8 Beta Blockers

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

10 Beta Blockers 1. Atropine: limited effects (bradycardia is not due to increased vagal tone) Increases HR only 22% of the time

11 Beta Blockers 2. Catecholamines (epi, dobutamine, dopamine) often are ineffective in treating β-blocker effect. Dopamine: 25% effective, Epi: 67% effective Catecholamines β-blocker Therefore, must find something that will bypass this blocked receptor

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

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

14 Beta Blockers Glucagon - evidence. Many animal studies of Glucagon s cardiac effects Human Studies About 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

15 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)

16 Beta Blockers Glucagon - precautions 1. Diluent contains 2 mg/ml phenol as preservative i. Max 10-h dose of phenol = 50 mg = 5mg glucagon ii. Use sterile water instead of diluent 2. Side effects from glucagon include: i. dose-dependent nausea and vomiting aspiration ii. hyperglycemia, hypokalemia (not clinically important) iii. Some Reports of treatment failure

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

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

19 Beta Blockers 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)

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

21 Ethylene Glycol / Methanol Methanol Ethylene Glycol Alcohol dehydrogenase Formaldehyde Glycoaldehyde Folate Formic acid CO 2 & H 2 O Aldehyde dehydrogenase Lactic Dehydrogenase Or Glycolic acid Oxidase Glycolic acid Th Glyoxylic acid & Oxalic acid B 6 A-OH-B ketoadipic acid Glycine and benzoic acid

22 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.

23 Ethylene Glycol / Methanol Goal of Specific Treatment: 1. Prevent further metabolism of toxic alcohol 2. Eliminate alcohol from circulation Toxic Alcohol Eliminated (renal, dialysis) ADH X Formic, glycolic or Oxalic acid

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

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

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

27 Ethylene Glycol / Methanol Ethanol (IV or PO) Loading Dose (over 1 hour) = [plasma] x V d =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)

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

29 Ethylene Glycol / Methanol Lots of problems with Ethanol!! 1. Oral Absorption is erratic (and difficult) 2. IV preparations rarely shelved 3. Math is challenging (many reports of errors) 4. Kinematics vary between pts. and in same pt. 5. Causes even more profound CNS depression 6. Need large volumes (1120 cc bolus of 5% etoh) 7. Etoh intoxication can cause hypoglycemia, gastritis, pancreatitis 8. Use of Ethanol mandates hourly ethanol and glucose checks in ICU 9. Duration can take as long as 100 hrs (depending on dialysis)

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

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

32 Ethylene Glycol / Methanol Evidence: 1. 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 : 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

33 Ethylene Glycol / Methanol 2. Fomepizole in methanol poisoning: Only 4 case reports (first one 1997) M.E.T.A. Study group: Brent, et al. NEJM : 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

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

35 Ethylene Glycol / Methanol Ethanol vs. Fomepizole?? 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 :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 :1771)

36 Ethylene Glycol / Methanol Fomepizole - How to Give Can be given PO or IV 1. Loading Dose: 15 mg/kg 2. Maintenance: 10 mg/kg bolus q12 h x 48 hrs 3. Maintenance: 15 mg/kg bolus q12 h until end Endpoint: Methanol levels < 6.3 mmol/l Ethylene Glycol < 3.2 mmol/l

37 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 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

38 Ethylene Glycol / Methanol Change in dialysis recommendations with Fomepizole? 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

39 Ethylene Glycol / Methanol Change in dialysis recommendations with Fomepizole? 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 Int. Care Med. 27:1370 Following methanol intoxication ([ ] > 15.6)= 4 patients without visual impairment or acidosis recovered fully after fomepizole (no dialysis)

40 Ethylene Glycol / Methanol Fomepizole Advantages: 1. Does not require separate preparations 2. Therapeutic levels are reliably achieved 3. No Change in mental status 4. No risk of hypoglycemia, hepatotoxicity 5. Hemodialysis not needed in subgroup of patients Cost! Main Disadvantage: 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

41 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.

42 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

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

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

45 Sulfonylureas Gen. Generic name Trade name Time to peak (hr) Duration of Action (hr) First Chlorpropamide Diabinase First Tolbutamide Orinase Second Glipizide Glucatrol (XL) 1-3 (6-12) (24) Second Glyburide Micronase DiaBeta Third Glimepiride Amaryl

46 Sulfonylurea overdose the numbers 2000: 1. U.S O.H. poisonings (2.3:100,000) in age < 6yrs (36%) intentional (19%) Sulfonylureas Quebec - 73 intoxications (1:100,000) - 15 in < 6yrs (20 %) - 30 intentional (40%) Sulfonylurea overdose - by region Saguenay Quebec Montreal Outaouais Cote Nord Chaudiere Lanaudiere Laurentides Monteregie Mauricie Laval

47 Initial Managements 1. Dextrose Sulfonylureas Initial management for all hypoglycemia. BUT: Glucose itself stimulates release of insulin. 1. Results in recurrent, rebound hypoglycemia. 2. Requires ICU monitoring, blood glucose measurements q minutes 3. Duration of treatment can be very long (>2-4 days)

48 Sulfonylureas 2. 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. 3. Diazoxide Direct inhibitor of insulin release Increases hepatic glucose output Effective in several case reports and chart review Cumbersome, may cause hypotension, hypernatremia

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

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

51 Sulfonylureas 1. Boyle PJ. J Clin Endocrin Metab normal subjects received O.D. of glipizide on 3 occasions 1. D50 + dextrose infusion 2. D50 + octreotide (30 ng/kg/min) 3. 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.

52 Sulfonylureas 2. McLaughlin, et al Ann Em Med, Aug 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!!

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

54 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

55 Summary 1. Beta Blocker Overdose: Bradycardia may not respond to usual ACLS Glucagon drug of choice Insulin novel antidote? 2. 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.

56 Summary 3. Sulfonylurea overdose: Dextrose treatment will cause recurrent rebound hypoglycemia Glucagon is contraindicated Octreotide is simple, inexpensive and reliable (can prevent ICU admission)

57 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

58 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

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

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