Selected Antidotes

Jon B Cole, MD

Department of Emergency Medicine

Objectives

• Discuss the treatment of carbon monoxide poisoning, including hyperbaric oxygen

• Discuss the treatment of organophosphate poisoning, including the value of oxime treatment

• Review old and new treatments of cyanide toxicity

• Review the indications and uses of some classic antidotes

Background

• Antidote: any substance which can counteract a form of poisoning.

• Derived from the Greek “anti didonai,” which literally translates as “given against.”

• Different mechanisms:– Animal antibodies– Enzyme inhibitors– Cofactor – Competitive inhibition– “Universal” antidotes

Oxygen (O2)

Oxygen (O2)

• The treatment of choice for carbon monoxide (CO) poisoning

• Normobaric (NBO) vs. Hyperbaric (HBO)

• HBO also used to treat:– Cyanide (CN)

– Hydrogen sulfide (H2S)

– Carbon tetrachloride (CCl4)

– Methylene chloride (Ch2Cl2)

– Methemoglobinemia

– Decompression sickness

– Air embolism

– Necrotizing fasciitis

Carbon Monoxide (CO)

• Binds hemoglobin with 230-270 times the affinity of oxygen

• Also binds myoglobin, cytochrome P450, and cytochrome aa3

– Note: CYP450 is named after the peak absorption of light at 450nm when the enzyme is 50% saturated with CO

• Transforms the hemoglobin binding curve from a sigmoid to an asymptotic shape

Carboxyhemogloin (COHb)

Hyperbaric Oxygen (HBO)

• Physiologic goal is elevation of partial pressure of O2

• Outcome goal is restoration/preservation of normal CNS function as well as reduction in mortality

• Much controversy exists regarding the benefit of HBO– 6 prospective studies have been done to date,

all with mixed results• 2 of these studies are fairly recent

Carboxyhemoblobin – half-life

HBO – Scheinkestel et al (AUS)

• 191 CO-poisoned patients of different severity

• High flow O2 (for 3 or 6 days) vs. HBO (3.0 ATA for 60 minutes daily)

• Outcome measured was neuropsychiatric testing 1 month after treatment

• No benefit shown, but…

HBO – Scheinkestel et al (AUS)

• Controversies:– 69% of cases were suicide attempts– 50% of patients co-ingested EtOH or other drugs– Both the NBO and HBO regimens deviated from

standard regimens and were potentially toxic– Many patients had active depression or CNS-

affecting drugs on board at 1 month during their neuro-psych testing

– Only 46% of the patients completed the follow-up test

HBO – Weaver, et al (USA)

• 152 patients, stratified by age (<40 or >40), time to end of CO exposure, start time of treatment (< 6 hrs or > 6hrs), hx of LOC.

• Patients treated 3 times at 6-12 hr intervals in a monoplace chamber

• Outcomes measured by CO poisoning questionnaires, functional outcome evaluations, neuropsychological test battery given at 2 weeks, 6 weeks, 6 months, and 12 months

HBO – Weaver, et al (USA)

• NBO group did have a higher incidence of cerebellar dysfunction, but this was accounted for

• HBO group had a lower incidence of cognitive sequelae

• Risk factors for which HBO therapy was recommended were:– LOC

– COHb ≥ 25%

– Age 50 ≥ years

– Base excess ≤ 2mEq/L

• Patients without any of these characteristics did not have improved outcomes

HBO - Indications

• Definite:– AMS/Abnormal Neuro Exam

– LOC or near-syncope

– Coma

– Hypotension at any time

– MI

– “Prolonged” exposure

– Pregnancy and COHb ≥ 15%

• Relative:– Persistent Neurologic Sxs (including HA or dizzy) after 4hrs NBO

– Persistent acidosis

– Concurrent thermal or chemical burns

– Pregnancy regardless of COHb level

HBO - Contraindications

• Paraquat poisoning• General HBO contraindications (relative)

– Middle ear surgery

– Thoracic surgery

– Untreated pneumothorax

– Seizure disorder

– Severe sinusitis

HCMC Hyperbaric Chamber

HCMC HBO Indications (non-pregnant)

• LOC

• COHb ≥ 40%

• “Serious” toxicity including:– Lethargy, confusion or disorientation on arrival to med facility

– Hx of seizures

– Focal neuro deficit

– Ischemic chest pain

– New dysrhythmias or ECG changes

– Hypotension

• COHb ≥ 25% plus:– Hx of CAD

– Age ≥ 60 yrs or ≤ 2 years

– HGB ≤ 10

– Exposure duration ≥ 2 hours

HCMC HBO Indications (pregnant)

• Patients meeting any of the previous indications

• COHb ≥ 20%

• Exposure duration ≥ 5 hrs

• Any signs of fetal distress

HCMC HBO protocol

• Non-pregnant– 100% O2 by non-rebreather mask until HBO

– 100% O2 at 2.4 ATA for 90 min

– 100% O2 by non-rebreather until pt without sxs and COHb ≤ 3

– Dispo as appropriate, f/u w/ Neurology in 1 month

• Pregnant (as above, plus)– Check for fetal distress prior to HBO

– L&D fetal monitoring if gestation ≥ 28 weeks

– Dispo as appropriate, same Neurology follow-up

– F/u w/ OB/GYN in 1 week

N-Acetylcysteine (NAC)

• The mainstay of treatment for acetaminophen (APAP) overdose

• Other uses include treatment of:– Chloroform

– CCl4– 1,2-dicloropropane

– Acrylonitrile

– Doxorubicin

– Cyclophosphamide

– Radiographic contrast exposure

APAP metabolism

Glutathione (GSH) metabolism

NAC

• Provides a substrate for sulfation

• Regenerates glutathione (reduced form - GSH)

• GSH reduces NAPQI, allowing it to be cleared via the kidneys

APAP and NAC metabolism

• NAC allows safe metabolism of the directly hepatotoxic metabolite NAPQI.

• NAC is itself an antioxidant, which may be more useful in late-presenting overdoses

Rumack-Matthew Nomogram

• Published 1975• Based on a

retrospective analysis of previous APAP overdoses and their clinical outcomes

• Original line at 200mcg/mL, but moved to 150 at urging of FDA

• 200 still the treatment threshold in Europe

NAC – additional indications

• Consider NAC if patients are on any CYP 2E1 inducers– Isoniazid– Chronic alcohol use/abuse

• Signs of liver toxicity past 24 hours and still-measurable APAP level

• Note: pregnancy is NOT a contraindication

NAC – oral vs. IV

NAC - oral

• Advantages:– reduced anaphylactoid reaction risk– Safer in asthmatics

• Disadvantages:– Horrible smell– Vomiting common (may need antiemetics)– Dosing is over 72 hours

• 140mg/kg load• 70mg/kg dose q 4 hrs thereafter for 17 does

IV NAC - Acetadote®

IV NAC - Acetadote®

• Advantages:– Shorter treatment course – 21 hours

• 150mg/kg loading dose over 1 hr (instead of 15 min)• 50mg/kg in 500mL D5W over 4 hrs• 100mg/kg in 1000mL D5W over 16 hrs

– New dosing guidelines for < 40kg patients now available– Decreased GI effects– Actually studied in hepatic failure

• Disadvantages:– Increased anaphylactoid reactions– More costly (debatable)– Difficult Peds dosing

• Initial reports of hyponatremia from increased water infusion

Allergic reactions – What to do

• Stop the IV infusion immediately• Treat accordingly

– Diphenhydramine, steroids, epi if indicated

• Once the reaction resolves, infusion can be re-started

• If the reaction persists or worsens, stop the IV infusion and either switch to oral or re-evaluate the need for NAC– Oral has been proven very safe in patients who have had

severe reactions to the IV perparation

Physostigmine (Antilirium®)

• The antidote for anti-cholinergic toxicity

• A carbamate that reversibly inhibitis cholinesterases in both the CNS and PNS

• Derived from the plant Physostigma venenosum Balfour, from Nigeria

Physostigmine

• Originally used as a miotic agent to treat glaucoma, and in the treatment of myasthenia gravis

• Also used as an antidote to atropine toxicity, and as an insecticide

• Structure is tertiary amine (other “stigmines” are quaternary), which allows better CNS penetration.

Tertiary vs. Quaternary Amines

Physostigmine• Uncharged

Neostigmine• Charged

Physostigmine

• Available only as an IV preparation

• Dose: 1-2mg infused over at least 5 min (0.02mg/kg in peds).

• Onset of action is within minutes

• Dose can be repeated q 10-15 min

• T1/2 is 16 minutes, but duration of action is usually much longer

Physostigmine and TCA OD

• Physostigmine was used often in the 1970s to treat undifferentiated delerium

• Case report by Pentel in 1980 re: 2 patients who suffered asystole after receiving physostigmine for TCA overdoses

• Since then the antidote has greatly fallen out of favor

Physostigmine - Indications

• Peripheral or Central anti-cholinergic manifestations without evidence of QRS or QTc prolongation, such as:– Agitation

– Hypertheria

– Hallucinations

– Delerium

– Seizures

– coma

• The patient to use this in is a known non-TCA anti-cholinergic overdose

Physostigmine - contraindications

• Definite contraindications:– Suspicion of TCA ingestion

– Widened QRS on ECG

• Relative contraindications:– History of asthma

– Concomitant use of succinylcholine

– Parkinsonism

– AV block

• Beware “evidence based medicine” such as uptodate.com

Opioid Antagonists

• Primarily μ-antagonists, some secondary antagonism of κ and δ receptors.

• 3 options available:– naloxone (Narcan®)– nalmefene (Revex®)– naltrexone (Revia®)

• The primary difference between the three drugs is their duration of action

Opioid Antagonists

• Naloxone– Duration of action 1-2 hours– Can be started as a drip– Re-assess for respiratory distress

• Nalmefene– Duration of action up to 4 hours– More expensive

• Naltrexone– Duration of action up to 24 hours– Oral preparation only

Opioid Antagonists

• Used primarily in the treatment of opioid overdose, though naloxone is used to treat other overdoses such as:– Clonidine– Ethanol– Benzodiazepines– Valproic acid– captopril

• No major contraindications

Opioid Antagonists - Structure

Agonist Antagonist

Naloxone Dosing

• “Waking up” vs. withdrawal – different approaches

• Usual dosing is to start low and titrate up– 0.4mg, then 2mg, then 10mg– If no response, consider another cause of coma

• Remember, naloxone can be given via the endotraheal tube, but dosing should be 2-3x.

Flumazenil (Romazicon®)

• A competetive benzodiazepine receptor antagonist.

• Unlike naloxone, flumazenil is NOT indicated as part of the “coma cocktail,” as it has potentially serious side-effects and minimal benefit

Flumazenil

• Flumazenil precipitates seizures in benzodiazepine dependent patients, and in patients with underlying seizure disorders– The “zero setpoint” of intrinsic CNS activity

may be influenced by GABA activity and chronic benzo use

• Flumazenil can also unmask dysrhythmias in patients who co-ingest pro-arryhthmic drugs

Flumazenil - Indications

• Known benzo ingestion in benzo-naïve patients, e.g.– Iatrogenic exposure

– Toddler ingestion

– Paradoxic benzo response

• Postoperative or postprocedure sedation reversal

• CNS depression from hepatic encephalopathy

Flumazenil - dosing

• Start with 0.2mg IV over 30 seconds (0.01mg/kg in children)

• If no response, then 0.3mg over 30 seconds

• If still no response give 0.5mg every 30 seconds up to 3 mg

Atropine

• A competetive anti-muscarinic drug that acts both centrally and peripherally

• Derived from the plant Atropa belladonna

• Similar to physostigmine it has a teritiary amine structure, whereas other anti-muscarinic drugs such as glycopyrrolate are quaternary amines

Tertiary vs. Quaternary Amines

Atropine Glycopyrrolate

Atropine - Indications

• Organophosphate poisoning

• “Nerve Gases”

• Carbamate poisoning

• Bradycardia from:– Beta blockers– Calcium antagonists– Digitalis– Other AV node-blockers

Atropine - Contraindications

• All are relative– Angle-closure glaucoma– Myasthenia gravis– Obstructive uropathy– Obstructive GI diseases (severe ulcerative colitis)– Hypertension– Thyrotoxicosis– Tachyarrhythmias– CAD– Valvular disease

Atropine Dosing in Organophosphates

• Based on work by Eddelstein, et al, J Clin Tox, 2004

• Starting dose is 0.5-2mg, then doubling every 5 minutes until “endpoint” is achieved– Pediatric starting dose is 0.02mg/kg

• Goal is “atropinization”– Clear chest on auscultation

– Increased heart rate > 80

• Each poisoned patient may need as much as 75mg of atropine, so be prepared to mobilize stores

Pralidoxime (2-PAM® or Protopam®)

• Used in the treatment of organophosphate (OP) poisoning

• OPs exert their effects by phosphrylating cholinesterases, inactivating them

• Cholinestereases break down acetylcholine (ACh), so ACh builds up in synapses and causes a cholinergic or muscarinic crisis

Pralidoxime

Quaternary oxime

Pralidoxime - mechanism

• Bound (inactive) undergo one of three processes:– Endogenous hydrolysis and recovery (as with carbamates,

such as physostigmine)– Reactivation by a strong nucleophile (e.g. 2-PAM)– “Aging,” which involves biochemical changes to the enzyme

that result in permenant dysfunction

• Oximes work to prevent aging by exerting a nucleophilic attack on the phosphate moiety, releasing it from the enzyme and preventing aging

Pralidoxime

• Believed to work synergistically with atropine

• Can be used in severe carbamate poisonings

• Some evidence the drug should be used within 48 hrs – by this time aging may be inevitable

• A mainstay of OP poisoning treatment, but…

Pralidoxime – benefit?

• There is now evidence that oximes may not only not improve mortality, they may be harmful.– Buckley, et al (2005) Cochrane Database

• Two published RCTs, one abstract RCT

• Insufficient evidence for harm or benefit of oximes

– Peter, et al (2006) Crit Care Med• Two published RCTs, 5 controlled trials

• Oximes either ineffective or harmful

– Rahimi, et al (2006) Human Exp Toxicol• Six clinical trials

• Oximes are not effective and can be dangerous

Pralidoxime

• For now, it is the standard of care• Always use with atropine• Field Dosing

– 600mg IM from the autoinjector, up to 3 doses

• Hospital Dosing is– 1-2g IV over 15-30min as initial dose

• 25-50mg/kg in children

– Continuous infusion of 200-500mg/hr thereafter• 5-10mg/kg in children

The Mark I Nerve Agent Antidote Kit

• 600mg IM of pralidoxime

• 2mg IM of atropine

Treatment of cyanide (CN)

• CN is toxic because it binds the ferric (Fe3+) ion in cytochrome oxidase, uncoupling oxidative phosphorylation and causing chemical asphyxia.

• Treatment involves – creating other sources of Fe3+, – inducing the enzyme that clears CN, and– providing another oxidized ion (Co+) for the CN to bind with

Nitrites

• Nitrites (-NO2) oxidize the iron in hemoglobin from Fe2+ to Fe3+ to create methemoglobin

• Since CN reversibly binds the Fe3+ in cytochrome oxidase, it now has a new competetive pool of Fe3+ to bind

Amyl Nitrite

• A volatile (and flammable) gas• Comes in 0.3mL ampules• Administered by breaking open the

ampule and holding it in front of the patient’s mouth for 15 seconds on, then 15 seconds off, etc.

• Should be discontinued as soon as an IV can be established

• This is a stop-gap solution

Sodium Nitrite

• Comes in a 10mL vial, 300mg

• Administered IV at 2.5-5mg/min

• Should be followed immediately with IV sodium thisulfate

Nitrites

• Indications– Symptomatic cyanide poisoning

– Hydrogen sulfide (H2S) poisoning < 30 min ago

• Contraindications– Significant (>40%) pre-existing

methemoglobinemia– Severe hypotension– Concomitant CO poisoning/smoke inhalation

Sodium Thiosulfate (Na2S2O3)

• This relatively non-toxic CN antidote works to regenerate the mitochondrial enzyme rhodanese.

• Rhodanese metabolizes CN to thiocyante (SCN-) by using a unique sulfur bond on the enzyme known as a sulfane group

• This is the only type of sulfur that reacts with CN

Sodium Thiosulfate (Na2S2O3)

• Comes in 50mL bottles containing 12.5

• Given IV as a bolus or over 10-30 min depending on severity of illness

• No significant contraindications

Nitrites and Thiosulfate - Summary

Taylor Pharmaceuticals Cyanide Antidote Kit

• 12 ampules of amyl nitrite

• 2 ampules of sodium nitrite

• 2 vials of sodium thiosulfate

• Cost: $317.18 each

hydroxycobalamin (Cyanokit®)

• Hydroxycobalamin is a direct precursor to cyanocobalamin (a member of the vitamin B12 family)

• FDA approved in 2007

• Very safe

Hydroxycobalamin - metabolism

Hydroxycobalamin Cyanocobalamin

Hydroxycobalamin

• Dosing:– 5g IV given over 15 minutes

• Side effects:– Turns body fluids bright red within minutes

• Interactions:– Do not administer in the same line as

sodium thiosulfate, as they will bind each other rendering them both ineffective

References• Pentel, P, et al, “Asystole Complicating Physostigmine Treatment of Tricyclic

Antidepressant Overdose,” Ann Emerg Med, Nov 1980, pp 588-590

• Cocuzza, et al, “Inappropriate Use of Physostigmine in TCA Toxicity: An Online Medical Reference May Be Partially Responsible,” Clinical Toxicology, Vol 46, No 7, Aug 2008

• Goldfrank, L, et al, “Goldfrank’s Toxicologic Emergencies,” McGraw-Hill, Mar 2006, pp 1-22, 544-549, 614-619, 794-797, 1112-1117, 1513-1518, 1519-1522, 1705-1711, 1725-1727, 1728-1730, 1731-1733

• Dart, RC, “Medical Toxicology,” Ch. 5, “Antidote Stocking,” Lippincott, Wilkens, & William, December, 2003, pp 159-163

• Weaver, LK, et al, “Hyperbaric Oxygen for Acute Carbon Monoxide Poisoning,” NEJM, Oct. 3, 2002, pp 1057-1067

• Scheinkestel, CD, et al, “Hyperbaric or normobaric oxygen for acute carbon monoxide poisoning: a randomised controlled clinical trial,” Medical Journal of Australia, 1999, 170: 203-210

• HCMC Guidelines for Treatment of Carbon Monoxide Poisoning, current as of August 2008

• Olson, KR, et al, “Poisoning & Drug Overdose,” Lange Medical Books/McGraw-Hill, 2004, pp406-519

• Cyanokit manufacturer’s package insert, current as of August 2008

• Acetadote manufacturer’s package insert, current as of August 2008