Alcohols and Opioids

Tintinalli 6th editionChapters 166 & 167

February 9, 2006

ALCOHOLS

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

Mild contraction alkalosis and/or pre-renal azotemia may be noted if volume depletion is present

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

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

Special Considerations

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

True or False: Opioids are not as effective when given orally (vs. parenterally)

Answers: b, false, false, c, true