ALCOHOL OVERDOSEKobra Naseri

PharmD, PhD of Pharmacology

ETHANOL POISONINGETHANOL POISONING

INTRODUCTION INTRODUCTION

Ethanol (ethyl alcohol,C2H5OH) - is derived from fermentation

of sugars in fruits, cereals, and vegetables.

Ethanol: the most frequently abused intoxicant

PHARMACOLOGY OF ETHANOL 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

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.

PHARMACOKINETICS

90% metabolized in the liver by one of the two

pathways:

1. cytosol: – alcohol dehydrogenase– aldehyde dehydrogenase

2. microsomal alcohol oxidizing system

Metabolism of ethanol

C O 2 + H 2O

A c e ty l C o A

A c e tic a c id

A c e ta ld e hy d e

E tha n o l

Alcohol dehydrogenase

Aldehyde dehydrogenaseAcetaldehyde SyndromeThe mediator of liver toxicity

METABOLIC PATHWAYMETABOLIC PATHWAY

Adult : 6-10 mL/kg

Children : 4 mL/kg

• Slurred speech

• Disinhibited behavior

• CNS depression

• Decreased motor coordination & control

• Hypotension: – decrease in total peripheral

resistance

• Reflex tachycardia

SYMPTOMS OF INTOXICATION

HYPOTHERMIA 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 INTOXICATIONMANAGEMENT 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.

• Legal definition of ethanol intoxication:

BAC > 100 mg/dl

• BAC correlates poorly with degree of intoxication

(because of tolerance)

BLOOD ALCOHOL CONC.BLOOD ALCOHOL CONC.

EFFECTS IN NON-ALCOHOLICS

EFFECTS IN NON-ALCOHOLICS

BAC (mg/dl) Effects 20 - 50 fine motor function

50 - 100 judgment, coordination

100 - 150 Difficulty with walking & balance

150 - 250 Lethargy

300 Coma

400 - 500 Respiratory depression, Hypotension, Hypothermia Convulsion, Death

STAGING OF WITHDRAWALSTAGING OF WITHDRAWAL

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

Rx : ALCOHOL 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

Formaldehyde

Formic acid

CO2+ H2O

Alcohol dehydrogenase

Aldehydedehydrogenase

Tetrahydrofolate

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

Hemodialysis

Folic acid

Antidotes

Sodium Bicarbonate

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

FomepizoleEthanol

Antidotes

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 DoseGram/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

Formaldehyde

Formic acid

CO2+ H2O

Alcohol dehydrogenase

Aldehydedehydrogenase

Tetrahydrofolate

Ethylene glycol is a sweet, odorless and colorless liquid.

Overdose ETHYLENE GLYCOL

Overdose ETHYLENE GLYCOL

Introducti

on

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 Glycoaldehyde Glyoxalate

Pyridoxine Oxalate Glycine Itself is non-toxic Toxicity being to…

ADH

ADH

Fatal dose in adult : 100 mL

Ethylene glycol

Clinical feature

The first phase: 3 min –12 hours Resemble ethanol intoxication without alcohol

smell Nausea, Vomiting & hematemesis

The major effects are on the CNSComaSeizure 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 Dose1 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.