Toxicity of Alcohols

Metabolic Activation A common pathway Toxicity and its Management

A common industrial solvent: -used as antifreeze, screen wash and varnishes -Less potent in toxicity as compare to -Non-toxic in its parent from -requires for toxicity

Methanol Toxicity SIGNS AND SYMPTOMS

INITIAL INEBRIATION - ESPECIALLY IF ETHANOL COINGESTED

AFTER 12 - 24 HOUR DELAY - PROGRESSION TO ACIDOSIS AND OTHER SIGNS AND SYMPTOMS

MAY BE FURTHER DELAY WITH CONTINUED INGESTION OF ETHANOL

SIGNS AND SYMPTOMS

CNS - INEBRIATION ADVANCING TO COMA and CONVULSIONS

RETINAL - BLURRED VISION, PHOTOPHOBIA, VISUAL ACUITY LOSS, DILATED NON-REACTIVE PUPILS, OPTIC NERVE HYPERAEMIC - BECOMING OEDEMATOUS

GIT - NAUSEA, VOMITING

CARDIAC - TACHYCARDIA, HYPERTENSION PROGRESSING TO HYPOTENSION AND CARDIOGENIC SHOCK

RESPIRATORY - TACHYPNOEA  Time course ◦ 12-24 hours after ingestion ◦ Interval is correlated with the volume ingested and the amount of ethanol concomitantly ingested ◦ Minimal lethal dose is 1 mg/kg of body weight.  Neurologic manifestations ◦ Initial symptoms are similar to ethanol intoxication ◦ Headache, nausea, vomiting, or epigastric pain. ◦ Drowsiness may rapidly progress to obtundation and coma. ◦ Seizures ◦ Affect the basal ganglia, primarily the putamen  Vision loss ◦ Flashes of light and blurring which may progress to scotomas & scintillations ◦ Diminished visual acuity which progress to scotomata & scintillations ◦ Frank blindness may respond to immediate therapy; however, complete loss of vision is a common sequela.

Osmolar gap Osmolal Gap : Measured – Calculated Calculated Osmolality = (2xNa)+Urea+ Initial Biochemistry @ ~10:00h

Na 137 Alb 46 Glucose 6.0 pH 7.38 K 4.0 Prot 84 Ethanol < 2.2 H+ ion 42 Cl 101 Glob 38 Amylase 87 pCO2 5.7 HCO 27 ALP 81 pO2 12.2 3 Bili 20 Std.HCO 24.0 Urea 3.6 3 ALT 18 BE -0.8 Creat 102 GGT 23 (FiO2 21%) A.Gap 13

Osmo 335

(measured)

Osmo (calculated) 284  Osmolal Gap = 51

Metabolism of Alcohols Ethanol Methanol

Alcohol Dehydrogenase Acetaldehyde Formaldehyde Glycoaldehyde (hangover, flushing) (blindness, cerebral (CNS effects) oedema) Aldehyde Dehydrogenase Acetic Acid Formic Acid Glycolic Acid () (metabolic acidosis)

CO2 + H20 or glycolic acid oxidase Glycoxylate (lactic acidosis)

Lactate dehydrogenase or aldehyde oxidase Oxalate (cerebral & renal damage, hypocalcaemia) Methanol half-life during ethanol administration

MeOH t½ during:

• EtOH monotherapy 43.1h (30.3-52.0)

• EtOH & HD 3.5h dual therapy

“EtOH monotherapy greatly increased MeOH t½”

Palatnick et al. Methanol half-life during ethanol administration. Ann Emerg Med 1995; 26: 202-207 Treatment

• If the clinical suspicion of methanol poisoning is high, treatment should not be delayed pending the reporting of a blood level Differential Diagnosis

 Ethylene glycol -Usually no visual symptoms -Oxalate crystals in the -CNS excitation -Increase in muscle enzymes -Hypocalcemia  -Depressed central nervous system function -Unexplained osmolar gap -Does not cause severe -Acetonemia with a relatively low glucose

Thus visual symptoms, acidosis, and unexplained osmolar forces will lead to the clinical diagnosis of methanol poisoning.

INVESTIGATION

BLOOD METHANOL LEVEL!

ABC - METABOLIC ACIDOSIS

OSMOLAL GAP - INCREASED (METHANOL)

ANION GAP - INCREASED (FORMIC ACID, )

BLOOD ETHANOL

MAGNESIUM, , POTASSIUM Treatment

• Emesis can be induced if the patient is not comatose not having seizures has not lost the gag reflex

If contraindicated - endotracheally intubate and do gastric lavage Treatment

• Three major modalities of treatment Diminishing metabolic degradation to toxic products (4-methyl pyrazole) Dialysis to enhance removal of methanol and its toxic products Alkalinization to counteract the metabolic acidosis. Ethanol

• Has a higher enzyme affinity and is preferentially metabolized by alcohol dehydrogenase, so methanol is eliminated by nonmetabolic routes when ethanol is present • Concentrations of 100 to 200 mg/dl are optimal for saturating alcohol dehydrogenase

• With the initiation of dialysis procedures, ethanol requires alterations of the dose

Loading Dose and Infusion Rates

Loading Dose During After Dialysis Dialysis

Ethanol 42 gms 12-18 gms/hr 5-11 gms/hr

Intravenous (10%) 530 ml 150-230 60-140 ml/hr 7.9gm/dl ml/hr

Orally(43%) 125 ml 35-55 ml/hr 15-35 34gm/dl ml/hr

TREATMENT ETHANOL (REDUCES FORMATION OF TOXIC METABOLITES)

MAINTAIN BLOOD ETHANOL LEVEL OF 100 - 150 mg/dl

LOADING DOSE BEWARE OF EXISTING ETHANOL LEVEL

MAINTENANCE DOSE TITRATED AGAINST RATE OF ELIMINATION

NON-ALCOHOLIC 15 - 20 mg/dl/h CHRONIC ALCOHOLIC 30 - 40 mg/dl/h CHILD 30 mg/dl/h

Fomepizole

 Fomepizole/4-methylpyrazole  Acts similarly to ethanol  Stronger competitive inhibitor of ADH  Does not cause or sedation  Relatively easier to administer  Does not require monitoring of serum concentrations

 Clinical dose yet to be established:  However, 20 mg/kg/d can beused in small series

Folic Acid

• Folate-dependent systems are probably responsible for the oxidation of formic acid • Folic acid can be given • Not tested in clinical studies.

TREATMENT

HAEMODIALYSIS METHANOL

LOW MOLECULAR WEIGHT NOT PROTEIN BOUND LOW VOLUME OF DISTRIBUTION

THEREFORE IDEAL FOR HAEMODIALYSIS

Sodium

• Profound metabolic acidosis treated with bicarbonate therapy

• Acidosis does not causes damage or alters the outcome of the visual disturbances.

• Bicarbonate amount adjustment based upon cardiovascular status TREATMENT

FOLINIC ACID/FOLIC ACID:

-50 mg IV Every 4 hrs for 24 hrs, while formic acid may be forming and accumulating

MAGNESIUM:

-MgSO4 Titrated against Blood Mg levels

METHYLATED SPIRITS

METHYLATED SPIRITS: -5% METHANOL AND 95% ETHANOL

Acute ingestion will represent Ethanol rather than Methanol

METHANOL TOXICITYON IS CONCERNED WHEN METHYLATED SPIRSTS IS USED CHRONICALLY

METHYLATED SPIRITS

EXAMPLE:

IF 250 ml METHYLATED SPIRITS INGESTED:

BLOOD ETHANOL LEVEL = 450 mg/dl (LD50)

BLOOD METHANOL LEVEL = 24 mg/dl

Ethanol Ethanol Metabolism

Samir Zakhari, Alcohol Research & Health: Vol. 29, No. 4, 2006 ALCOHOL

ALCOPOPS 75% of High School Students report having tried alcohol at least once. 28% reported having an alcoholic beverage in the last month Male students more likely than female students to report episodic heavy drinking Effects of Alcohol • Heart/Blood Vessels –Short term •Perspiration increases and skin becomes flushed –Long Term •High blood pressure and damage to the heart muscle; blood vessels harden and become less flexible More Effects • Brain/Nervous System –Short Term • Speech is slurred and difficulty walking –Long Term • Brain cells are destroyed and unable to be replaced; damage to nerves in body resulting in numbness in hands and feet CNS Effect of ethanol

Inhibits L-Type Ca++ Channels: Reducing CNS Excitability -effects on vassopressin release -reduced water reabsorption (alcohol induced diuresis) CNS Effect of ethanol

…The Rest of Alcohol Effects • Liver –Short Term •Liver changes alcohol into water and carbon dioxide –Long Term •Liver is damaged possibly resulting in cirrhosis (scarring and destruction of the liver) Liver

• Can only oxidize about 1 serving of alcohol an hour • NO WAY to speed up this process • Until liver has had time to oxidize all of the alcohol ingested, it keeps circulating through the bloodstream Liver Damage • FATTY LIVER –alcohol interferes with body’s ability to break down fats. •Excess fat blocks flow in liver resulting in reduced oxygen and cell death •can be REVERSED when drinking stops Liver Damage • CIRRHOSIS –scarring of the liver –no blood flow in scarred area –liver cannot function –symptoms: high blood pressure, abdominal swelling, jaundice –IRREVERSIBLE Healthy Liver Alcoholic Liver …The Rest of Alcohol Effects • Stomach/ –Short Term •Stomach acids increase, which often results in nausea and vomiting –Long Term •Irritation occurs in the stomach lining, causing open sores called ulcers; pancreas becomes inflamed

Binge Drinking • 5 or more drinks in a sitting for men • 4 or more drinks in a sitting for women • May lead to Alcohol Poisoning • May lead to unplanned unprotected sex • May lead to drug use • Many high school/college students die from alcohol poisoning from binge drinking on the weekends. Dangers of Binge Drinking • Unintentional injuries (e.g. car crash, falls, burns, drowning). • Intentional injuries (e.g. firearm injuries, sexual assault, domestic violence). • Alcohol poisoning. • STD’s and/or Unintended pregnancy. • High blood pressure, stroke, and other cardiovascular diseases. • Liver Disease Factors affecting the amount of alcohol in a person’s blood • Gender • Metabolism • Amount of Alcohol (not # of drinks) • How much they weigh • How much time elapses after or between drinks Drinking and Driving • Drinking alcohol impairs vision, reaction time, and coordination. • DWI and DUI –leading cause of death among teens • Signs of intoxication can begin to appear as low as 0.02 • There is no acceptable BAC level for anyone under 21

SAFEST AMOUNT OF DRINKS = 0!!!

This is at any age!!!!

Alcohol Poisoning • Dangerous to just “sleep it off” • Signs –Mental confusion, stupor, coma, inability to be excited, vomiting, and seizures –Slow Respiration *Hypothermia *Dehydration *Irregular heartbeat –CALL 911 immediately if suspicious of poisoning Alcoholism • A disease in which a person has a physical or psychological dependence on drinks that contain alcohol. • Characterized as an impaired ability to study, work, or socialize normally. Alcohol Poisoning • Dangerous to just “sleep it off” • Signs –Mental confusion, stupor, coma, inability to be excited, vomiting, and seizures –Slow Respiration *Hypothermia *Dehydration *Irregular heartbeat –CALL 911 immediately if suspicious of poisoning The 3 Stages of Alcoholism • Early Stage (Stage 1) –to relax, relieve stress –leads to necessity to manage stress –begins to become intoxicated regularly –makes excuses and tries to rationalize drinking behavior • Middle Stage (Stage 2) –drinker denies or tries to hide problem –body develops tolerance –frequently absent from school or work –drinking is central event in a persons life –drinks when alone –drinks first thing in the morning –drinks daily • Final Stage (Stage 3) –person becomes aggressive & isolated –malnutrition occurs because drinker consumes alcohol and does not worry about food –body is addicted –try to quit=WITHDRAWAL –Delirium Tremens-hot/cold flashes, tremors, nightmares, hallucinations, fear of people and animals *****NO CURE---ONLY RECOVERY*****

Treatment •Cannot be cured •Can be treated •Counseling •Medication

Where to go for help • Alcoholics Anonymous • National Association for children of alcoholics • National drug and treatment referral routing service. Ethylene Glycol

• Molecular Weight 62 H

H-C-OH

• Low Volatility H-C-OH H • High boiling point Ethylene Glycol Ethylene Glycol

• Coolant/Antifreeze

• Solvents

• De-Icer Ethylene Glycol Metabolism

H O O H-C-OH ADH C-H ALDH C-OH H-C-OH H-C-OH H-C-OH

H H H Ethylene Glycol Glycoaldehyde Glycolic Acid

ADH = Alcohol dehydrogenase, ALDH = Aldehyde dehydrogenase Ethylene Glycol Metabolism Toxic metabolites of ethylene glycol Ethylene Glycol Toxicity

• Onset 4-6 hours

• Anion gap acidosis pH • Tachypnea

Ethylene Glycol Toxicity

• Abdominal pain

• Hypocalcemia

• oxalate crystals in urine

• Renal failure Identifying Patients for Treatment: Methanol/EG • Serum ethylene glycol or methanol level

• Action level for treatment: 25 mg/dL*

* Or any level with acidosis Treatment

• Limit absorption: NG Tube

• Prevent metabolism or parent ADH Inhibition compound to toxic metabolite

• Enhance elimination Substrates/Other – Parent – Metabolites Hemodialysis • Correct Derangements Limits of Serum Levels

• Useful prior to onset EG or Methanol of acidosis or in massive overdoses

• Parent compound not

directly toxic Anion Gap

Time • Levels not universally available

Arterial Blood Gas/Lactate

• Acidosis indicates advanced poisoning

• Lactate usually low*

• Patients with acidosis should receive treatment

*Some glycolates are misidentified as lactate Adjunctive Information:Ethanol

• Serum ethanol inhibits metabolism of EG and Methanol

• Onset of toxicity EG/Methanol may be delayed Adjunctive Information:

• Osmol Gap = Measured-Calculated Osmols

• Calculated: 2 Na + BUN + Glucose + Alcohol 2.8 18 N

• N = MW Alcohol/10 • Must use freezing point depression

Osmol Gap: Limitations • Normal Osmol gap in between – 14 ± 10 Osmol Gap

• Normal Osmol Gap in setting of poisoning does not rule out a treatable level Anion Gap

Time • Osmol Gap diminishes as parent compound is metabolized Adjunctive Information

• Ethylene glycol: – Limited utility of fluorescence of urine – May note crystals in urine

• Methanol – Hyperemia retina or visual complaints

Treatment: Methanol or Ethylene Glycol

• Level  25 mg/dL or

• Anion gap metabolic acidosis ( non-lactate) with strong suspicion EG or Methanol exposure

Treatment

Methanol ADH ALDH Ethanol -CHO -COOH Aldehyde Acid Ethylene Glycol

• Ethanol more avid for ADH – 6-8x more avid than ethylene glycol – 4x more avid than methanol