ALCOHOL POISONING

4th Year Clinical Pharmacology

Toxicology
Department of Pharmacy
School of Health Sciences UNZA
Andrew M Bambala
bambalaandrew@gmail.com

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Alcohol
• Most exposed to solvent – Ethyl alcohol and alcohol)

• Used industries;
• Petroleum industry – Additive in Gasoline
• Household domestic products
• Pharmaceutical industry- Additives and as API
• Consumed in intoxicating beverages

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Types of Alcohol

1. Ethanol (ethyl alcohol, grain alcohol)

2. Methanol (methyl alcohol, wood alcohol)

3. Isopropanol (isopropyl alcohol, rubbing alcohol)

4. Ethylene glycol

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 INTRODUCTION
What is ethanol ?
• Amphipathic
• Volatile, colorless and flammable liquid
• Chemical formula C2H6O, CH3−CH2−OH or EtOH

How it synthesize ?
• Fermentation
• Synthetic means

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Routes of Exposure

• Dermal

• Inhalation

• Intravenous injection

• Oral ingestion

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Factors affecting absorption Alcohol

• Concentration • Condition of stomach- Diseased

• Presence or absence of food in • Rate of emptying of stomach

stomach; • Rate and quantity of alcohol
• food delays absorption by slowing ingested
gastric emptying –Peak 2- 6hrs
• Tolerance
• Gender –Male or Female

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Fatal Dose
• No specific fatal dose.

• Blood alcohol concentration (BAC) that Specifies the lethality

• Dose. (>350mg)

• Fatal dose vary from person to person.

• Higher Fatal Dose in case of tolerance

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Fatal Dose
• Less Fatal Dose in: • Less Fatal Dose in:

• Fatal dose in case of: • Mentally unstable subjects

• Thin and lean person • Patients suffering from liver

disease, epilepsy, cerebral trauma
• Females
• Patients using barbiturates, anti
histamines, tranquilizers, hypnotic

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Absorption and Distribution

• Absorption of ethanol is by simple diffusion

• 25% of an ingested dose of ethanol is absorbed from the stomach

• 75% of an ingested dose of ethanol is absorbed from the small

intestine (Duodenum)
25%

75%

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 Distribution
• Alcohol is hydrophilic and distribute into fluids and tissues according to
water content
• Total body water (TBW) is dependent upon
• Sex - Females have a lower TBW content Distribute
Fast through out
• Age the body
• Body weight
• Alcohol can cross placental and blood brain barrier
5-7%
5-7%
• Distribution is rapid, VD = 0.6 L/kg Excretion

• 90% is oxidized in the liver; excreted in lungs and urine. Breathalyzer

metabolism
• The rate of oxidation follows zero-order kinetics

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Metabolism; Alcohol Dehydrogenase Pathway
• Two major pathways of alcohol metabolism to acetaldehyde

• Acetaldehyde is then oxidized to acetate

• Alcohol dehydrogenase (ADH), catalyze the conversion of alcohol to acetaldehyde.

• Located mainly in the liver and small amounts in brain and stomach.

• Some metabolism by ADH occurs in the stomach in men than in female due lower levels
of the gastric enzyme.
• Contributes to the sex differences in BAC

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Cytosolic Alcohol Dehydrogenase Pathway
• During conversion of ethanol by ADH to acetaldehyde,
• hydrogen ion is transferred from ethanol to the cofactor nicotinamide adenine
dinucleotide (NAD + ) to form NADH.
• Alcohol oxidation generates an excess of reducing agents in the liver, chiefly as
NADH.
• Excess NADH contributes to the metabolic disorders in chronic alcoholism and to
both the lactic acidosis and hypoglycemia that frequently accompany acute
alcohol poisoning.

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Microsomal Ethanol-Oxidizing System (MEOS)
• Also known as the mixed function oxidase

• NADPH as a cofactor and consists of cytochrome P450; 2E1, 1A2, and 3A4

• During chronic alcohol consumption, MEOS activity is induced.

• Results in significant increases in ethanol metabolism and clearance of other

drugs eliminated by the cytochrome P450s that constitute the MEOS system

• Generation of the toxic byproducts of cytochrome P450 reactions (toxins, free

radicals, H2O2 ).

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Acetaldehyde Metabolism
• Acetaldehyde is oxidized in the liver by mitochondrial NAD-dependent aldehyde
dehydrogenase (ALDH) to form Acetate

• Acetate metabolized to CO2 and water, or used to form acetyl-CoA.

• Oxidation of acetaldehyde is inhibited by disulfiram, used in alcohol dependence.

It causes acetaldehyde accumulation which causes unpleasant reaction of facial
flushing, nausea, vomiting, dizziness, and headache

• other drugs (eg, metronidazole, trimethoprim) inhibit ALDH and can cause a
disulfiram-like reaction if combined with ethanol

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Acetaldehyde Metabolism

• Some people, primarily of East Asian descent,

have genetic deficiency in the activity of the
mitochondrial form of ALDH leads Disulfiram
reaction

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 Mechanism of Acute Toxicity
• CNS is markedly affected in acute toxicity; sedation, relief of anxiety and, at higher
concentrations, slurred speech, ataxia, impaired judgment, and disinhibited behavior, a
condition called intoxication or drunkenness.

• Like other sedative-hypnotic drugs, it induces coma, respiratory depression, and death.
Affects a large number of membrane proteins that participate in signaling pathways

• including: neurotransmitter receptors for amines, amino acids, opioids, and

neuropeptides; enzymes such as Na + /K + -ATPase, adenylyl cyclase, phosphoinositide
specific phospholipase C; a nucleoside transporter; and ion channels.

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 Mechanism of Acute Toxicity
• Affects neurotransmission by glutamate and γ-aminobutyric acid (GABA), main excitatory and
inhibitory neurotransmitters in the CNS.

• Acute exposure enhances the action of GABA at GABA A receptors, GABA-mimetics to intensify many
of the acute effects of alcohol and of GABA A antagonists to attenuate some of the actions of ethanol.
inhibits the ability of glutamate to open the cation channel associated with the N -methyl-D-aspartate
(NMDA)

• NMDA receptor is involved in several cognitive function,

• including learning and memory.

• “Blackouts”—periods of memory loss that occur with high levels of alcohol—may result from
inhibition of NMDA receptor activation

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• Human
Metabolize one
UK unit per hour
ACUTE TOXICITY
• When the
metabolizing
enzymes is
saturated
Metabolites
Ethanol O2
• TOXICITY OCCURE H2O2 NADPH

ADH
Peroximal MEOS
catalase NAD+ NADH P450

Flushing , Nausea, headach Lactic acidosis, ketoacidosis ROS, and muscle

H2O2
andH2O
general discomfort and increase TG formation
Acetaldehyde weakness NADP+

ALDH

H2O + CO2 Peripheral tissue Acetate

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Toxic Effects
• B. Heart
• depression of myocardial contractility, BAC above 100 mg/dL.

• C. Smooth Muscle
• vasodilator, due to depression of the vasomotor center
• direct smooth muscle relaxation caused by its metabolite, acetaldehyde.
Severe overdose;
• hypothermia—caused by vasodilation
• Ethanol also relaxes the uterus

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 PHARMACO-KINETICS/DYNAMICS
• Blood Alcohol Concentration (BAC)
Total amount of alcohol

Total body water

• Alcohol Standard drink (alcohol unit):

around 10gm or 10ml

Regular beer can Wine glass Gin glass

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0.5 Unit 1.4 Unit 4.2 Unit
 ACUTE TOXICITY
Management
• Correct any deterioration in Vital signs
Airway IV fluid

• Increase ethanol clearance

Fructose Hemodialysis

• If the ingestion occurred within 1 hour of presentation

Nasogastric No benefit from
tube charcoal
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Chronic Alcohol Toxicity (CAT)
• Profoundly affects several vital organs— the liver—and the nervous, gastrointestinal,
cardiovascular, and immune systems.

• Due to low potency, it requires large concentrations higher than other misused drugs
(e.g., cocaine, opiates, amphetamines) to produce its intoxicating effects.

• Tissue damage in CAT is due;

• Combination of the direct effects of ethanol and acetaldehyde,

• Metabolic consequences of processing a heavy load of a metabolically active substance.

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Mechanism of Toxicity
• Specific mechanisms in Tissue damage Include:

• Increased oxidative stress coupled with depletion of glutathione,

• Damage to mitochondria,

• Growth factor dysregulation

• Potentiation of cytokine-induced injury.

• Chronic consumption of large amounts of alcohol increases risk of death.

• Deaths are caused by liver disease, cancer, accidents, and suicide.

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Liver
• Liver disease most common complication ; hepatitis to cirrhosis and liver failure.
• Women more susceptible to alcohol hepatotoxicity,
• hepatitis B or C virus increases the risk of severe liver disease.
• Poor Nutrition also increase the risk of severe liver disease
• The pathogenesis of alcoholic liver disease;
• metabolic repercussions of ethanol oxidation in the liver,
• dysregulation of fatty acid oxidation and synthesis
• activation of innate immune system by a combination of direct effects of ethanol and
its metabolites

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Gastrointestinal Tract
• Chronic alcohol ingestion most common cause of chronic pancreatitis

• Its direct toxic effect on pancreatic acinar cells; Pancreatitis : Acute and chronic

• Chronic Alcoholism alters pancreatic epithelial permeability

• Promotes the formation of protein plugs and calcium carbonate-containing stones.

• Bacterial endotoxins access the liver as a result of ethanol-induced changes in the

intestinal tract.

• Tumor necrosis factor-α, a pro-inflammatory cytokine, plays a pivotal role in the

progression of the disease and may be a fruitful therapeutic target

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 Gastrointestinal Tract
• Individuals with chronic alcoholism are prone to gastritis

• Increased susceptibility to blood and plasma protein contributes to anemia and

protein malnutrition.

• Alcohol also injures the small intestine, leading to diarrhea, weight loss, and multiple
vitamin deficiencies.

• Malnutrition from dietary deficiency and vitamin deficiencies due to malabsorption

• Malabsorption of water-soluble vitamins is especially severe.

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Tolerance and dependence
• Chronic withdrawal syndrome, indicates physical dependence.

• Symptoms consist of hyper excitability and seizures, toxic psychosis, and delirium tremens.

• Psychological dependence characterized by a compulsive desire to experience the rewarding

effects of alcohol

• Tolerance result from ethanol-induced up-regulation of pathway –NMDA Glutamate receptors

• Dependence from over activity same pathway after the ethanol effect dissipates and before the
system has time to return to a normal ethanol-free state.

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 CHRONIC TOXICITY
• Tolerance
Low response to alcohol
Metabolic Functional Psychological

• Withdrawal
Tremors GABA Glutamate Dopamine

Insomnia 15% death if

untreated
Hallucination
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CHRONIC TOXICITY
Central Nervous System ;
• Generalized symmetric peripheral nerve injury; distal paresthesia's of
the hands and feet.

• Degenerative changes resulting gait disturbances and ataxia.

• Dementia and demyelinating disease

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CHRONIC TOXICITY

• Increased homocysteine :

• withdrawal seizure,

• Brain atrophy and cognitive problems

• Disruption in memory learning and sleep patterns

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Wernicke-Korsakoff syndrome
• Characterized by paralysis of the external eye muscles, ataxia

• Confused state that can progress to coma and death.

• Associated with thiamine deficiency

• Thiamine is important in this pathologic condition

• Patients who present to the emergency department with altered consciousness, seizures, or both)
should receive thiamine therapy

• Often, the ocular signs, ataxia, and confusion improve promptly upon administration of thiamine

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Korsakoff's Psychosis
Wernicke's encephalopathy

• Chronic disabling memory disorder known as Korsakoff ’s psychosis.

• Alcohol may also impair visual acuity, with painless blurring
• That occurs over several weeks of heavy alcohol consumption.
• Changes are usually bilateral and symmetric and may be followed
• by optic nerve degeneration. Ingestion of ethanol substitutes such
• as methanol (see Pharmacology of Other Alcohols) causes severe
• visual disturbances

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CHRONIC TOXICITY
Cancer

Cardiovascular toxicity • Acetaldehyde

• Acetaldehyde : protein, • defect in aldehyde
Ca+ and actin myocin dehydrogenase
• Lipid peroxidation : ROS and
• GIT, liver cancer
others
Alcohol Induced
Hypertension

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 CHRONIC TOXICITY
Alcohol and pregnancy (Fetal alcohol syndrome)

• Physical, mental, and/or

behavioural problems

• Mental retardation

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 CHRONIC TOXICITY
Other toxicities

Skin Respiratory

Genitalia

Gouty arthritis

Immune Hormonal
Imbalance
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 CHRONIC TOXICITY
Management of chronic alcoholism

• Psychosocial treatment
• Long-term treatment of alcohol-
related diseases
• Nutritional supplements
• Antabuse (Disulfiram)

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 CHRONIC TOXICITY
Management of withdrawal symptoms

• Benzodiazepines

• Nitrous oxide

• Vitamins

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Dose beer truly give you a beer belly ?

The answer is

NO
drinking beer ALONE dose not cause a beer belly
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