Transcript Slide 1
ALCOHOL OVERDOSE
Kobra Naseri
PharmD, PhD of Pharmacology
ETHANOL
POISONING
Ethanol (ethyl alcohol,C2H5OH)
- is derived from fermentation of sugars
in fruits, cereals, and vegetables.
Ethanol:
the
most frequently abused intoxicant
INTRODUCTION
PHARMACOLOGY OF ETHANOL
CNS depressant:
inhibits neuronal activity
behavioral stimulation at low blood level
Cross tolerance:
BZD & barbiturates
Absorption:
proximal small bowel
Excretion:
2% ~ 10% by lungs, in urine, in sweat
PHARMACOKINETICS
Ethanol is readily absorbed (peak30-120 min)
(Vd=0.5-0.7L/kg).
It is rapidly absorbed by diffusion across the
lipid membranes of the stomach and small
intestine.
Coingestion of food or decreased GI motility
produces a delay in absorption and
increases the gastric metabolism of ethanol.
Metabolism of ethanol
90% metabolized in the liver by one of the two
pathways:
1. cytosol:
– alcohol dehydrogenase
– aldehyde dehydrogenase
2. microsomal alcohol oxidizing system
Ethanol
Alcohol dehydrogenase
Acetaldehyde
Aldehyde dehydrogenase
Acetaldehyde Syndrome
Acetic
The mediator of liver toxicity
acid
Acetyl CoA
CO2 +
H 2O
METABOLIC PATHWAY
Adult : 6-10 mL/kg
Children : 4 mL/kg
SYMPTOMS OF INTOXICATION
• Slurred speech
• Disinhibited behavior
• CNS depression
• Decreased motor coordination & control
• Hypotension:
– decrease in total peripheral resistance
• Reflex tachycardia
HYPOTHERMIA
Depresses central thermoregulatory
mechanisms
Decreases shivering
Enhances heat loss through vasodilatation
Sedative effects:
lack of behavioral adjustment against
exposure to the cold environment
MANAGEMENT OF INTOXICATION
Airway protection
Adequate ventilation
IVF replacement
O2 supply
EKG monitoring
Thiamine (50 - 100 mg) IV
Glucose supply (if hypoglycemic)
Active charcoal (if co-ingestion is suspected)
Re-warming (if hypothermic)
Treatment is mainly supportive.
Protect the airway to prevent aspiration.
Glucose & thiamine administered.
Glucagon is not effective for alcohol induced
hypoglycemia.
Correct hypothermia with gradual rewarming.
Do not induced vomiting or activated charcoal and
gastric lavage in pure ethanol intoxication. Consider
gastric lavage only if the alcohol ingestion was massive
and recent( within 30-45 min.).
Hemodialysis efficiently removes ethanol
but enhanced removal is rarely needed
because supportive care is usually
sufficient.
Hemoperfusion and forced diuresis are
not effective.
BLOOD ALCOHOL CONC.
• Legal definition of ethanol intoxication:
BAC > 100 mg/dl
• BAC correlates poorly with degree of
intoxication
(because of tolerance)
BAC (mg/dl)
Effects
20 - 50
fine motor function
50 - 100
judgment, coordination
100 - 150
Difficulty with walking & balance
150 - 250
Lethargy
300
400 - 500
Coma
Respiratory depression,
Hypotension, Hypothermia
Convulsion, Death
EFFECTS IN NON-ALCOHOLICS
STAGE
ONSET
SYMTOMS
I
6 - 8 hours
Tremor, agitation,
nausea, vomiting
II
24 hours
Hallucinations
III
24- 48 hours
Grand mal seizures
IV
3 - 5 days
Delirium tremens
STAGING OF WITHDRAWAL
Rx : ALCOHOL WITHDRAWAL
• Hydration with D5NS (IV)
• Cross-reacting drugs:
– BZD or Phenobarbital
• Thiamine (IV)
• Magnesium sulfate (IV)
• Admission:
– fail to respond to 2 doses of sedative
Methanol
Physical Nature
Wood alcohol
CH3OH
Colorless liquid
Boiling point: 65°C
Source
Anti-freeze agents
Solvents
Cleaning agents
Industrial alcohol
Dye
Poisoning
Poisoning is common.
Adulterated beverages
(substituting methanol for ethanol)
Mis-swallowing accidentally
Suicide or homicide
Ingestion of just 0.15 mL/kg of 100% methanol may cause
toxicity.
Fatal dose : 60-240 mL
Pediatric cases are usually accidental.
Adult cases usually involve suicidal ingestion or
ingestion of methanol as an alcohol substitute.
Toxic effects are typically severe, if untreated.
Death may occur in untreated patients.
Inhalation or dermal absorption can produce toxicity.
Absorption
Gastrointestinal Tract
Skin
Respiratory Tract
Metabolic Pathway
Methanol
Alcohol dehydrogenase
Formaldehyde
Aldehydedehydrogenase
Formic acid
Tetrahydrofolate
CO2+ H2O
Methanol Metabolism
Enzyme Involved:
–Alcohol Dehydrogenase(Rate-Limiting)
–AldehydeDehydrogenase
Toxic Products:
–Formaldehyde
–Formic acid
Formic Acid Toxicity
Inhibition of mitochondrial cytochrome
oxidase:
–Histotoxic Hypoxia
–Metabolic Acidosis
Elimination
Liver (predominates)
Lung
Kidney
Elimination half life: 3 hours
Clinical feature
Incubation Time
12-72 hours
Factors influencing time to symptoms:
–Amount Ingested
–Concomitant Ethanol Intoxication
–The individual’s Folate Status
Premortal Vital Signs
Hyperpnea usually develops to compensate
metabolic acidosis(Kussmaul’s Respirations)
Sudden Respiratory Arrest
Tachycardia
Blood pressure is stable until death
Hypotension may develop late in severe cases.
Neurologic Toxicity
Neurologic Symptoms:
–Headache
–Dizziness
–Amnesia
–Restlessness
–Acute Mania
–Lethargy
–Confusion
–Coma
–Convulsions
–Parkinsonism may develop as a sequelae of severe intoxication.
Ophthalmologic Toxicity
Occur when serum pH drops below 7.2
Low pH → intracellular concentration of formate↑
Improvement of vision with correction of acidosis, because
formate moves out of the cell
Formate is an inhibitor of cytochrome oxidase, which could inhibit
ATP formation in the optic nerve leading to a stasis of axoplasmic
flow, axonal swelling, optic disc edema and finally loss of visual
function
Ophthalmologic Toxicity
Symptoms:
Blurred Vision
Photophobia
Eye Pain
Partial or complete loss of vision
Visual hallucinations (bright lights, snowstorm, dancing
spots, flashes)
Ophthalmologic Toxicity
Signs:
Optic discs hyperemia
Retinal edema
Retinal vessels engorgement
Papilledema
Papillary dilation
Loss of papillary reflex
Gastrointestinal Toxicity
Hemorrhagic Gastritis
Acute Pancreatitis
Symptoms:
•Abdominal Pain
•Nausea
•Vomiting
•Diarrhea
•Liver Function Impairment
Laboratory Tests
Essential Tests:
1.Serum Electrolytes (Hyperkalemia)
2.Leukocytosis
3.Amylase elevations
4.BUN and Creatinine
5.Glucose (Hyperglycemia)
6.Arterial Blood Gases
Elevated anion gap acidosis supports the diagnosis.
7.Osmolar gap
8.Elevated lactate levels
9.Serum Methanol Level (greater than 20 mg/dL)
Early diagnosis
History-taking
Increased osmolar gap
Blood methanol detection
Late diagnosis
Visual symptoms
Metabolic acidosis with increased anion
gap
History of alcohol consumption and
methanol contact
Treatment
Supportive Care
Antidotes
Hemodialysis
Sodium Bicarbonate
Folic acid
Supportive Treatment
Airway management in comatose patient
Intravenous Fluids
Cardiac Monitoring
Oxygen Supply
Ipecac is contraindicated (CNS depression)
Activated charcoal is not effective
Sodium bicarbonate
Antidotes
Fomepizole
Ethanol
Fomepizole
Fomepizole(Antizol)
Fomepizoleis the preferred agent
4-methylpyrazole (4-MP) “Fomepizole”:a more
potent inhibitor of alcohol dehyrogenase
No side effect of CNS depression as in ethanol
therapy
Fomepizole
Indications:
A history of ingestion when a serum level is
not immediately available
A Serum methanol level greater than 20
mg/dL
Unexplained metabolic acidosis with
elevated anion and osmolar gaps
Fomepizole
Metabolic acidosis with elevated anion gap
accompanied by visual signs and symptoms
Unexplained coma with a high osmolar gap
Clinical evidence of toxicity
Fomepizole
Contraindication
Disulfiram
Allergic reaction to fomepizole
Relative contraindication
Metronidazole
GI Ulceration
Child < 5 years
Severe Hepatic Disease
Fomepizole
L.D: 15mg/kg (IV)
M.D: 10mg/kg/12h for 4 doses then
15mg/kg/12h
Each dose is diluted in 100 mL normal
saline or D5W and infused over 30 minutes.
Ethanol
Ethanol is a preferential substrate for
alcohol dehydrogenase.
Once alcohol dehydrogenase metabolism is
blocked, methanol is eliminated slowly via
pulmonary and renal excretion.
Ethanol
Indications:
A history of ingestion when a serum level is
not immediately available
A Serum methanol level greater than 20
mg/dL
Unexplained metabolic acidosis with
elevated anion and osmolar gaps
Ethanol
Metabolic acidosis with elevated anion gap
accompanied by visual signs and symptoms
Unexplained coma with a high osmolar gap
Clinical evidence of toxicity
It may be used if fomepizole is not available
Ethanol
Loading Dose
Gram/kg of Ethanol 10% (Oral)
Non-Drinker/Child
0.88
Average Drinker
1.4
Chronic Drinker
2
Maintenance Dose
100 mg/kg/hour of Ethanol 10% (Oral)
Increase M.D. 2-3 times during hemodialysis
Ethanol Conc. to 100 -150 mg%
Enhanced Elimination
Hemodialysis effectively removes methanol and its
toxic metabolites
Elimination rates:
-142 ~ 286 ml/min (methanol)
-148 ~ 203 ml/min (formate)
Peritoneal dialysis also removes methanol but not as
effectively
Adjunctive Treatment
Folate or tetrahydrofolate(Leucovorin) to hasten
elimination of formic acid.
Leucovorin1mg/kg Max 50 mg/dose/IV/4-6 hours
until methanol becomes undetectable.
Folate 1mg/kg Max 50 mg/dose/P.O/4-6 hours until
methanol becomes undetectable.
Metabolic Pathway
Methanol
Alcohol dehydrogenase
Formaldehyde
Aldehydedehydrogenase
Formic acid
Tetrahydrofolate
CO2+ H2O
Overdose ETHYLENE GLYCOL
Ethylene glycol is a sweet,
odorless and colorless liquid.
Overdose ETHYLENE GLYCOL
Introduction
It is a common component of antifreeze used in:
Heating and cooling systems
Brake Fluid
Inks
It is used as an industrial solvent in:
Paints
Plastics
It is used in synthesis of:
Resins
Synthetic Fibers
Waxes
Epidemiology
Poisoning is uncommon.
Death occurs in patients who do not
receive medical care.
Poisoning most commonly occurs:
Accidental ingestion
Suicidal Attempt
Pathophysiology
E.G
ADH
Glycoaldehyde
ADH
Glyoxalate
Pyridoxine
Oxalate
Glycine
Itself is non-toxic
Toxicity being to…
Ethylene glycol
Fatal dose in adult : 100 mL
Clinical feature
The first phase: 3 min –12 hours
Resemble ethanol intoxication without alcohol smell
Nausea, Vomiting & hematemesis
The major effects are on the CNS
Coma
Seizure
Nystagmus
The second Phase: 12 –14 hours
Tachycardia
Mild Hypertension
Pulmonary edema
CHF
Due to deposition of calcium oxalate
within the vascular tree, myocardium
and lung parenchyma
The third phase: 24 –72 hours
Flank pain
CVA Tenderness (costovertebral angle)
Acute tubular necrosis
Treatment
Focus treatment:
Supportive care
Treatment with fomepizole
Treatment with ethanol
Hemodialysis as indicated.
Adjunctive Therapy
Pyridoxine and thiamine to hasten elimination
of toxic ethylene glycol metabolites.
Pyridoxine Dose
1 to 2 mg/kg administered intravenously every 6
hours until ethylene glycol level is undetectable.
Thiamine Dose
Adult dose is 100 mg/I.V. over 5 minutes every 6 hours until
ethylene glycol level is undetectable.
Pediatric dose is 50 mg/I.V. over 5 minutes every 6 hours
until ethylene glycol level is undetectable.
Sodium Bicarbonate
Sodium bicarbonate should not be used routinely but may
be used as a temporarily for life-threatening acidosis prior
to hemodialysis.