alcohols and opioids tintinalli 6th edition chapters 166 & 167 february 9, 2006
TRANSCRIPT
ETHANOL
Unique drug of abuse b/c legal and socially accepted
most medical morbidity assoc. with acute intoxication is not direct drug effect but from secondary injuries
most frequently used and abused in the U.S.
Nearly 3/4 of adult Americans consume at least 1 alcoholic drink yearly
Beer ranks as fourth most popular beverage in terms of volume consumed
Etoh use in the U.S. costs $185 billion (in 1998) and contributes to approx. 100,000 deaths yearly
40% of motor vehicle fatalities are related to etoh (15,000/yr)
Etoh abuse as reported by injured women is the strongest predictor for acute injury related to domestic violence
Prevalence and lifelong risk of etoh abuse or dependence are 7% and 13%, respectively
From a 1995 Nat’l Hospital Ambulatory Medical Care survey, 2.7% of all ED visits are related to alcohol use
Etoh is detected in the blood of 15-40% of ED patients, depending on location
ER doctors and inpatient specialists fail to recognize 50% of pts with ethanol dependence
One drink...
Considered to be 0.5 oz or 15 gm of Etohequivalent to:
12 oz. (335 cc) of beer 5 oz. (148 cc) of wine 1.5 oz. (44cc) of 80 proof spirits
Remember etoh is also in mouthwashes (up to 75% volume), colognes (40-60%), and medicinal preparations (0.4-65%)
Pathophysiology of Ethanol
CNS depressant which inhibits neuronal activity
Alcohol intoxication is assoc. with: depression of the glutamate (excitatory
neurotransmitter) increases GABA and glycine (inhibitory
neurotransmitters)
Absorption
Absorption of ethanol: mouth and esophagus= small amt stomach and large bowel= moderate
amt proximal portion of small bowel= lg.
Amt
Elimination
Approx. 2-10% of Etoh is excreted by lungs, in urine, or in sweat (proportion excreted dependent on BAL)
Remainder in metabolized by the Liver into acetaldehyde
Gender related differences in metabolism of Etoh explains higher BAL in women vs. men after same amount ingested
Elimination
Unhabituated pts eliminate etoh from the blood at 15-20 mg/dL per hour
Alcoholics average 25-35 mg/dL per hour
Note: Most states adopt 80 or 100 mg/dL as the legal definition of intoxication
Clinical Features
Slurred speechnystagmusdisinhibited
behaviorCNS depressionDecr motor
coordination and control
Hypotension d/t decr in total peripheral resistance or volume loss
syncope
Tolerance
Because of tolerance, BAL correlate poorly with degree of intoxication
Death from respiratory depression can occur at levels of 400-500 mg/dL yet some individuals with a high tolerance
can appear minimally intoxicated at levels of 400.
Impairment may be seen with levels as low as 5mg/dL unhabituated individuals
Labs
Mild lactic acidosis may be seen in Etoh intoxication
However, significant acidosis should never be attributed to ethanol intoxication
Ethanol does causes an osmolar gap If an anion gap metabolic acidosis is
present, search for a co-ingestion
Treatment
Etoh levels are not required for mild or moderate intoxication when no other abnormality is suspected check levels in altered mental status
D5NS is the most appropriate fluid to use, give thiamine, folate, and MVI with IVF Fluids do not hasten alcohol elimination, so
in uncomplicated cases may not be needed
Ethanol doesn’t bind to charcoalSerial observation is crucial
the majority improve over a few hours Mental status that fails to improve and any
deterioration should prompt a search for another cause of altered MS
Note: Resp depression is due to carbon dioxide retention; patient may need airway secured
Question concomitant drug useCocaine and Alcohol
become the most common combination forms a metabolite, Cocaethylene, which
is less potent than cocaine but has longer half life (3-5X longer)
risk of sudden death increases to as high as 20 times than with cocaine use alone
Disposition
Acute ethanol intoxication alone rarely requires hospitalization
Medical judgment of mental competence should not be confused with any particular BAL
Discharge the patient when… intoxication has resolved to the extent
they are no longer a danger to themselves or others
Another individual (not impaired) is going to take the responsibility for the care of the patient
Pts BAL is near zero (if driving self home) not just below the legal limit.
ISOPROPANOL
Commonly found in rubbing alcohol, solvent, disinfectant, skin/hair products, jewelry cleaners, detergents, paint thinners, anti freeze
Poisoning can occur from ingestion, inhalation, or dermal exposure
Principal metabolite= acetonedoes not cause eye, kidney, cardiac, or metabolic
toxicity like methanol or ethylene glycol metabolites
Twice as potent as ethanol in causing CNS depression
Duration is 2-4 times longer than ethanol
After ethanol, it is the second most ingested alcohol
Pathophysiology of Isopropanol
Clear, volatile liquid with bitter taste and aromatic odor
80% of oral dose absorbed after 30 min and complete absorption with 2 hrs
kidneys excrete 20-50% of absorbed dose unchanged
Majority of the metabolism occurs in the liver by alcohol dehydrogenase to acetone
Acetone is then primarily excreted by the kidneys and to a lesser extent by the lungs
Hallmark of isopropanol toxicity ketonemia and ketonuria without
elevation of blood glucose or glucosuriaPresence of ketones differentiates
isoprop ingestion from methanol or ethylene glycol
Follows concentration dependent (first order ) kinetics Half life of isoprop is the absence of Etoh is 6-
7 hrs half life of acetone is 22-28 hrs.
Dose of 0.5mL/kg can cause symptoms in children, 3 swallows can be toxic
Toxic dose of 70% isoprop is 1mL/kgLethal dose is 2-4mL/kg
Clinical Features
Similar to ethanol intoxicationDuration of s/s is longer & CNS
depression may be more profound b/c of acetone
Nystagmus usually presentSevere poisoning= early onset of coma,
resp depression, and hypotensionSerious dysrhythmias are rare
Massive ingestion may cause hypotension due to peripheral vasodilation &/or from hemorrhagic gastritis
Hemorrhagic gastritis is feature of isopropanol ingestions results in N/V, abd pain, UGI bleeding
Hypoglycemia occurs due to depression of gluconeogenesis
Less common complications: hepatic dysfunction, ATN, myoglobinuria, hemolytic anemia, rhabdo, myopathy
Fruity odor of acetone or smell of rubbing alcohol is usually present on the breath
Treatment of Isopropanol intoxication
Check blood glucose at bedsideGive thiamine and naloxoneNo use in gastric lavage b/c of its
rapid absorptionActivated charcoal binds isoprop
poorly thus is not necessary
LABS: CMP, CBC, glucose, acetone, type and screen (if necessary) If significant acidosis is present, look for
another cause of intoxicationHemodialysis (HD) is indicated
1. hypotension is refractory to conventional tx2. hemodynamic instability3. when predicted peak isoprop level is > 400
HD eliminates both isoprop and acetone
Disposition
Prolonged CNS depression or lethargy should be hospitalized
Patients asymptomatic for 6-8 hours in the ED may be discharged, referred to substance abuse counseling, or referred psych eval
METHANOL
Referred to as methyl alcohol, wood spirits, and wood alcohol
Used in commerical, industrial, and marine solvents Also present in measurable but smalll amts
in wine and distilled spirits, thus may be detectable in blood after binge drinking
Methanol’s toxic metabolites: formaldehyde and formic acid
Pathophysiology of Methanol
Well absorbed from GI tract peak levels attained 30-90 min after
ingestionToxicity can occur after oral ingestion,
along w/ exposure via the lungs and skinAmount of methanol required to cause
toxicity variesHalf life after mild toxicity is 14-20 hrs
increases to 24-30 hrs after severe toxicity
Following ingestion, highest conc found in the kidney, liver, and GI tract high levels also found in the vitreous
humor and optic nerve90-95% of methanol is eliminated by
the liverIn overdose situations, elimation
follows saturation (zero-order) kinetics
Formaldehyde and formic acid
Formaldehyde in the retina causes optic papillitis and retinal edema severe cases can lead to blindness
Folate is a co-factor in the breakdown of formic acid therefore alcoholics already deficient in
folate are highly susceptible to methanol toxicity via formic acid accumulation
Clinical Features of Methanol
Symptoms may not appear for up to 12-18 hrs after ingestion delay in symptoms may be longer if ethanol
is co-ingested and competing with methanol for the alcohol dehydrogenase
Cardinal manifestations: CNS depression, visual disturbances, abd pain, n/v, wide anion gap metabolic acidosis (with wide or nml osmolar gap)
Visual disturbances seen in approx. 50% of patients diplopia, blurred vision, decreased visual
acuity, photophobia, descriptions of “looking into a snow field”, constricted visual fields, blindness
Clinician may find nystagmus, retinal edema, fixed/dilated pupils, optic atrophy or hyperemia of optic disk
Hypotension and bradycardia are late findings and suggests a poor prognosis
Prognosis is best correlated to severity of acidosis than serum methanol level
Serum Methanol Levels
Normal methanol levels from endogenous sources is 0.05mg/dL
In asymptomatic individuals, levels usually peak at 20 mg/dL Serous poisoning indicated by levels >50 Symptoms
CNS-- levels >20Eye-- levels >50Risk of fatality rises with levels > 150-200 mg/dL
Wide Anion Gap Metabolic Acidosis
Differential Diagnosis methanol ethylene glycol DKA paraldehyde INH Salicylates iron lactic acidosis uremia
phenformin carbon monoxide cyanide alcoholic
ketoacidosis toluene
Treatment ofMethanol Intoxication
Initially, establish IV access, bedside blood glucose, thiamine, and narcan
General measures in treatment are: 1. Supportive care 2. Correction of acidosis 3. Admin. Fomepizole or ethanol to
decr conversion to toxic metabolites 4. Dialysis to eliminate methanol
Gastric aspiration or lavage of no benefit unless pt presents immediately after ingestion
activated charcoal ineffective unless other absorbable substances ingested
LABS (minimum): CMP, CBC, glucose, Etoh, methanol
Secure airway when necessary
Administer Sodium Bicarbonate goal is to maintain near normal pH correction of acidosis inhibits some of
the toxic effects, especially with visual impairment
Prevention of Methanol’s Toxic Metabolites
Ethanol and fomepizole competitively inhibit alcohol dehydrogenase
Fomepizole is superior drug to ethanol has an affinity for alcohol dehydrogenase
that is 8000 times that of ethanol doesn’t produce CNS depression or
metabolic toxicity doesn’t require monitoring of levels and
dosage adjustments
Fomepizole
Loading dose of 15 mg/kgThen 10 mg/kg every 12 hrs for 4 doses
given as infusion over 30min
Dosing is increased to every 4 hours when patient is also getting hemodialysis fomepizole is dialyzable
Fomepizole
Considered Drug of Choice Ethanol is considered DOC if a known allergy
to fomepizole existCase reports suggest fomepizole is safe
in childrenCosts: loading dose alone is $1000
compared to a few dollars for ethanolUse of fomepizole (or ethanol) doe not
alter the indications for dialysis
Ethanol
Has affinity for alcohol dehydrogenase 10-20 times of methanol
Blood ethanol levels should be maintained b/w 100-150 mg/dL to completely inhibit formation of metabolites
Administered po, IV, or via NG oral admin uses 20-30% conc (higher conc can
lead to gastritis and/or alterations of MS)
Ethanol
IV admin of ethanol is preferred can result in superficial thrombophlebitis solution contains 10% ethanol in D5W
Loading dose is 10cc/kg Maintenance is 1.5cc/kg/hr If dialysis is initiated, maintenance infusion
starts at 0.24gm/kg/hrMust check ethanol levels frequently and
adjust gtt to maintain BAL of 100-150
Further Treatment
Folic Acid-- 50mg IV every 4 hrs for several days is recommended especially in folate deficient individuals
Dialysis Indications 1. Signs of visual or CNS dysfunction 2. Peak methanol levels > 20 mg/dL 3. pH< 7.15 4. History of ingesting >30 mg/dL
Hemodialysis is more effective than peritoneal but if HD is not available start peritoneal dialysis when indicated
Disposition
Asymptomatic patients with any ingestion of methanol should be admitted and treatment initiated, even if no acidosis is evident
**Remember there is a delayed onset of symptoms
ETHYLENE GLYCOL (EG)
Used in antifreeze, preservatives, polishes lacquers, glycerine substitutes, cosmetics, detergents
In 2001, EG Accounted for 4938 poison exposures and 16 deaths in the U.S. as reported by poison control centers
EG’s toxicity is from the formation of 2 toxic metabolites: glycoaldehyde and glycoxalic acid
Pathophysiology of Ethylene glycol
Colorless, odorless, sweet tasting substance
highly water soluble and rapidly absorbed when ingested orally no absorption via lungs or skin
Peak blood levels occur within 1-4 hrs of ingestion
Half life is 3-5 hours
Metabolized by the liver and kidneys to toxic metabolites: aldehydes, glycolate, oxalate, and lactate
These metabolites are: toxic to the lungs, heart, and kidneys the cause of metabolic acidosis
associated with EG poisoning
Deficiency of either pyridoxal phosphate or thiamine may shift the metabolism of EG to metabolites
Oxalate crystalluria is found in the urine of about 50% of cases
Levels greater than 20 mg/dL are likely to result in toxicity
Potentially lethal dose: 2 mL/kg
Clinical Features of EG intoxication
Exhibits three phases (dependent on the amount ingested) 1. CNS phase 2. Cardiopulmonary phase 3. Nephrotoxicity phase
EG Phases
1. CNS Phase CNS depression within 1-12 after ingestion
appear inebriated but w/o the odor of ethanolhallucinations, coma, seizures, and death may
occur during this initial phaseCNS symptoms correlate with peak glycoaldehyde
production
Optic fundus is nml (differ from methanol), may have nystagmus & opthalmoplegia
LP: incr CSF pressure and protein, few polys
EG Phases
2. Cardiopulmonary Phase develops 12-24 hrs after ingestion tachycardia, mild HTN, tachypnea are
commonmay see CHF, ARDS, cardiomegaly,
circulatory collapse
EG Phases
3. Nephrotoxicity Phase occurs 24-72 hours after ingestion Early symptoms: flank pain and CVA
tenderness Oliguria renal failure and ATN develop
Complete anuria may occur, but most recover w/o renal damage if appropriate tx started
Nephrotoxicity caused by aldehyde metabolites and oxalic acide
More Clinical Features of EG
Hypocalcemia may develop secondary to precipitation of calcium as calcium oxalate may be severe enough to cause tetany and
prolonged QT intervalElevated CPK may accompany and explain
generalized myalgiasLeukocytosis is commonLook for wide anion gap metabolic acidosis
with osmolar gap
Treatment of Ethylene Glycol Intoxication
Similar to tx of methanol poisoning Indications for gastric emptying and bicarb
are the same as for methanolIf the pt is hypocalcemic, 10cc of calcium
glucanate 10% should be given IVpyridoxine(B12) 100mg and thiamine
100mg IV or IM should be administered daily
facilitates metabolism of EG to nontoxic pathways
Magnesium supplementation shown to be a cofactor in metabolism of
toxic metabolites may be deficient in alcoholics
LABS: CBC, CMP, acetone, Mg, CPK, Ca alcohol toxicology panel with ethanol,
isoprop, and methanol determinations serum ethylene glycol levels salicylate level UA (& HCG) ABG
Ethanol or Fomepizole should initiate in the ER if overdose is
suspected or confirmed Ethanol affinity for alcohol
dehydrogenase is 100x that of EG, thus prolonging EG half life to 17 hours
treatment and dosing for EG is same as for methanol intoxication
Indications for Dialysis in EG Poisoning 1. The triad of history, clinical
presentation, and lab results consistent with EG poisoning are present
2. Ethylene glycol >20 mg/dL 3. Signs of nephrotoxicity 4. Metabolic acidosis present
Disposition
Admit to the ICUAdmit to a facility that has
hemodialysis capabilitesPatient will be in the hospital until
lab testing are normal if they are initially asymptomatic
Opioids
Refers to all agonist, antagonist, endogenous, and exogenous substances that possess morphine-like activity
In the U.S., most commonly abused opioids are heroin and methadone
Pharmacology of Opioids
Modulate nociception in the terminals of afferent nerves in the CNS, PNS, and GI tract
Agonists at the mu, kappa, and theta receptors in the tissues receptors now called OP3, OP2, and
OP1, respectively--reflecting the order of discovery
OP3 Receptor
Subdivided into a and b: analgesia, respiratory depression, cough suppression, euphoria
Most of the analgesic effect of morphine is mediated via OP3a stimulation
All currently available opioids have some activity at the OP3b receptor, resulting in some degree of respiratory compromise
Other receptors
Stimulation of OP2 receptors results in spinal analgesia, miosis, and diuresis
Role of OP1 is clinically unknown
Pharmacokinetics
Most opioids more effective parenterally than orally due to significant first pass elimination
Opioids with good oral potency= codeine, oxycodone, levorphanol, methadone
In most opioids, metabolism is through the liver and creates pharmacologically active metabolites
Clinical Features of Opioids
Resp depressionmental status
changeanalgesiamiosis*orthostatic hypotnn/vurticariabronchospasm
Decr GI motilityurinary retention
*not universally present; may see mydriasis with co-ingestants or may signal cerebral hypoxia
Diagnosis
Diagnosis of opioid overdose or withdrawl remains clinical
Triad of coma, miosis, and respiratory depression strongly suggests opioid intoxication
Differential Diagnosis of Opioid Overdose
Effects of other agents: clonidine organophosphates
and carbamates phenothiazines sedative-hypnotic
agents carbon monoxide
Hypoglycemia hypoxiaCNS infectionspost-ictal statespontine
hemorrhages
Treatment
ABC’sNaloxoneGastric decontaminationAcetaminophen Level with Tox
ScreenObservation Disposition
Naloxone (Narcan)
pure antagonist at all OP receptors particular affinity for OP3
Binds to OP receptors without producing any effects (positive or negative)
Onset of action is rapid (1-2 min)Duration of action is 20-60 min
shorter than duration of action of most opioids
Naloxone
In patients with CNS depression without respiratory depression: in opioid dependent- 0.05 mg IV is
recommended in non-opioid dependent- 0.4mg IV is
recommendedIncremental dosing will avoid the
acute precipitation of opioid withdrawl
Give 2.0mg IV to the patient presenting with significant resp distress, regardless of drug history
Exposure to sustained release opioids may require larger doses of narcan to reverse the effects
Recent literature recommends the same dose ranges in the pediatric patient
Exception, the neonate in the immediate postpartum period, suggested dosage is 0.01 mg/kg IV
Gastric Decontamination
Syrup of ipecac and gastric lavage are not recommended
activated charcoal should be administered ideally within 1 hour after ingestion Dosage: 50 gm of activated charcoal po
followed by sorbitol 0.5-1.0gm po Delayed and multiple doses useful in:
1. hydrochloride-atropine sulfate (Lomotil) overdoses
2. Overdose of sustained release opioids
Meperidine
Active metabolite= Normeperidine largely renally excreted accumulates in pt with diminished renal
functionProconvulsive (esp. Normeperidine)
pts with drug induced seizure must be observed for 24-48 hours
treatment: benzos and avoid meperidine
Serotonin Sydrome
Example: Meperidine or Dextromethorphan plus MAOI
Characterized by disorientation, severe hyperthermia, hypo/hypertn, muscle rigidity
Treatment: benzos, cooling, avoid narcan
Propoxyphene
Active metabolite= norpropoxypheneCardiotoxic and neurotoxicOverdoses cause blockade of fast
sodium channels results in intraventricular conduction
disturbances, heart block, prolonged QT, ventricular bigemny
Treatment: Sodium Bicarb 1mEq/kg IV (can reverse cardiotoxic effects)
Tramadol (Ultram, Ultracet)
Overdoses associated with agitation, HTN, resp depression, seizure, and death (at levels > 500 mg)
Treatment: supportiveNarcan is ineffective in reversing
seizures
Acute Lung Injury
Rare complication assoc. with toxicity from certain drugs, including opioids
can occur immediately or be delayed up to 24 hours following use
Suspect in any pt with tachycardia, tachypnea, rales, or decr oxygen sat with nml CXR
pathophysiology poorly understoon
Opioid Withdrawal
Not life-threateningOnset within 12h of last heroin use and
within 30h of last methadone exposureClinical features:
anxiety, insomnia, yawning, lacrimation, diaphoresis, rhinorrhea, diffuse myalgias
followed by piloerection, mydriasis, nausea, profuse vomiting, diarrhea and abd cramping
Opioid Withdrawal
Symptoms more tolerable by giving: alpha 2 agonist (i.e. Clonidine) antiemetics (i.e. Reglan) antidiarrheal agents (i.e. Bentyl)
Questions??
1. A 36 yo M presents to the ER. Pt appears inebriated but does not smell of alcohol. Patients UA shows calcium oxalate crystals. Which of the following would be false?
a. Ingestion of ethylene glycol has occurredb. Pt most likely will have no anion gapc. Pt most likely will have an osmolar gapd. Pt will be admitted to the hospitale. Pt EKG may show prolonged QT intervals in
24 hours
2. True or False: Hemodialysis only removes the toxic metabolites formed in methanol poisoning.
3. True or False: Significant metabolic acidosis is found in all forms of alcohol intoxication
4. In propoxyphene overdoses, which therapy is most appropriate in reversing the cardiotoxic effects? a. Narcan b. Fluid restriction c. Sodium bicarbonate d. Normal saline infusion e. None of the above