Alcohols and Opioids

Tintinalli 6th edition Chapters 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 Etoh  equivalent 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 speech  nystagmus  disinhibited behavior  CNS depression  Decr 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 charcoal  Serial 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 use  Cocaine 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= acetone  does 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 glucosuria  Presence 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/kg  Lethal dose is 2-4mL/kg

Clinical Features

 Similar to ethanol intoxication  Duration of s/s is longer & CNS depression may be more profound b/c of acetone  Nystagmus usually present  Severe poisoning= early onset of coma, resp depression, and hypotension  Serious 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 bedside  Give thiamine and naloxone  No use in gastric lavage b/c of its rapid absorption  Activated 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 intoxication  Hemodialysis (HD) is indicated  1. hypotension is refractory to conventional tx  2. hemodynamic instability  3. 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 ingestion  Toxicity can occur after oral ingestion, along w/ exposure via the lungs and skin  Amount of methanol required to cause toxicity varies  Half 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 nerve  90-95% of methanol is eliminated by the liver  In 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 >20  Eye-- levels >50  Risk 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 of Methanol 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/kg  Then 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 exist  Case reports suggest fomepizole is safe in children  Costs: loading dose alone is $1000  compared to a few dollars for ethanol  Use 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/hr  Must 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 ethanol  hallucinations, coma, seizures, and death may occur during this initial phase  CNS 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 common  may 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 interval  Elevated CPK may accompany and explain generalized myalgias  Leukocytosis is common  Look 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 methanol  If the pt is hypocalcemic, 10cc of calcium glucanate 10% should be given IV  pyridoxine(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 ICU  Admit to a facility that has hemodialysis capabilites  Patient 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 depression  mental status change  analgesia  miosis*  orthostatic hypotn  n/v  urticaria  bronchospasm  Decr GI motility  urinary 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  hypoxia  CNS infections  post-ictal states  pontine hemorrhages

Treatment

 ABC’s  Naloxone  Gastric decontamination  Acetaminophen Level with Tox Screen  Observation  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 recommended  Incremental 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 function  Proconvulsive (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= norpropoxyphene  Cardiotoxic and neurotoxic  Overdoses 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: supportive  Narcan 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-threatening  Onset within 12h of last heroin use and within 30h of last methadone exposure  Clinical 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 occurred  b. Pt most likely will have no anion gap  c. Pt most likely will have an osmolar gap  d. Pt will be admitted to the hospital  e. 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