Alcohols and Opioids

1
Alcohols and Opioids

• Tintinalli 6th edition
• Chapters 166 167
• February 9, 2006

2
ALCOHOLS
3
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.

4

• 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

5

• 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

6

• From a 1995 Natl 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

7
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)

8
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)

9
Absorption

• Absorption of ethanol
• mouth and esophagus small amt
• stomach and large bowel moderate amt
• proximal portion of small bowel lg. Amt

10
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

11
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

12
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

13
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

14
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

15

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

16
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

17

• Ethanol doesnt 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

18

• 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

19
Disposition

• Acute ethanol intoxication alone rarely requires
  hospitalization
• Medical judgment of mental competence should not
  be confused with any particular BAL

20

• 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.

21
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

22

• 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

23
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

24

• 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

25

• 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

26

• 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

27
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

28

• 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

29

• 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

30
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

31

• 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 gt 400
• HD eliminates both isoprop and acetone

32
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

33
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
• Methanols toxic metabolites formaldehyde and
  formic acid

34
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

35

• 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

36
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

37
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)

38

• 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

39

• Hypotension and bradycardia are late findings and
  suggests a poor prognosis
• Prognosis is best correlated to severity of
  acidosis than serum methanol level

40
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 gt50
• Symptoms
• CNS-- levels gt20
• Eye-- levels gt50
• Risk of fatality rises with levels gt 150-200 mg/dL

41
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

42
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

43

• 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

44

• 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

45
Prevention of Methanols 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
• doesnt produce CNS depression or metabolic
  toxicity
• doesnt require monitoring of levels and dosage
  adjustments

46
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

47
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

48
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)

49
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

50
Further Treatment

• Folic Acid-- 50mg IV every 4 hrs for several days
  is recommended
• especially in folate deficient individuals

51

• Dialysis Indications
• 1. Signs of visual or CNS dysfunction
• 2. Peak methanol levels gt 20 mg/dL
• 3. pHlt 7.15
• 4. History of ingesting gt30 mg/dL
• Hemodialysis is more effective than peritoneal
  but if HD is not available start peritoneal
  dialysis when indicated

52
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

53
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
• EGs toxicity is from the formation of 2 toxic
  metabolites glycoaldehyde and glycoxalic acid

54
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

55

• 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

56

• 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

57
Clinical Features of EG intoxication

• Exhibits three phases (dependent on the amount
  ingested)
• 1. CNS phase
• 2. Cardiopulmonary phase
• 3. Nephrotoxicity phase

58
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

59
EG Phases

• 2. Cardiopulmonary Phase
• develops 12-24 hrs after ingestion
• tachycardia, mild HTN, tachypnea are common
• may see CHF, ARDS, cardiomegaly, circulatory
  collapse

60
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

61
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

62
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

63

• Magnesium supplementation
• shown to be a cofactor in metabolism of toxic
  metabolites
• may be deficient in alcoholics

64

• 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

65

• 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

66

• 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 gt20 mg/dL
• 3. Signs of nephrotoxicity
• 4. Metabolic acidosis present

67
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

68
OPIOIDS
69
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

70
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

71
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

72
Other receptors

• Stimulation of OP2 receptors results in spinal
  analgesia, miosis, and diuresis
• Role of OP1 is clinically unknown

73
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

74
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

75
Diagnosis

• Diagnosis of opioid overdose or withdrawl remains
  clinical
• Triad of coma, miosis, and respiratory depression
  strongly suggests opioid intoxication

76
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

77
Treatment

• ABCs
• Naloxone
• Gastric decontamination
• Acetaminophen Level with Tox Screen
• Observation
• Disposition

78
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

79
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

80

• 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

81

• 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

82
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

83
Special Considerations
84
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

85
Serotonin Sydrome

• Example Meperidine or Dextromethorphan plus MAOI
  
• Characterized by disorientation, severe
  hyperthermia, hypo/hypertn, muscle rigidity
• Treatment benzos, cooling, avoid narcan

86
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)

87
Tramadol (Ultram, Ultracet)

• Overdoses associated with agitation, HTN, resp
  depression, seizure, and death (at levels gt 500
  mg)
• Treatment supportive
• Narcan is ineffective in reversing seizures

88
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

89
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

90
Opioid Withdrawal

• Symptoms more tolerable by giving
• alpha 2 agonist (i.e. Clonidine)
• antiemetics (i.e. Reglan)
• antidiarrheal agents (i.e. Bentyl)

91
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

92

• 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

93

• 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

94

• True or False Opioids are not as effective when
  given orally (vs. parenterally)
• Answers b, false, false, c, true