Alcohols

Alcoholic beveragesA. Malted liquors : obtained by fermentation (conversion of

carbohydrates to alcohols) of germinating cereals; are undistilled ---- alcohol content is low (3-6%) e.g beers.

B. Wines : produced by fermentation of natural sugars as present in grapes and others fruits. These are also undistilled Like : light wines (9-12%); fortified wines (16-22%) distilled beverages are added from outside; effervescent wine (12-16%) bottle before fermentation is complete.

----- wines are called dry when all sugar present has been fermented and sweet when some sugar is left.

C. Spirits : distilled after fermentation; e.g. Rum, Gin, Whiskey, Brandy, Vodka etc.(40- 55%).

Others : absolute alcohol (ethanol – 99%); rectified spirit (ethyl alcohol – 90%) and proof spirit (50 – 57%)

Pharmacokinetics of ethanol :• small water-soluble molecule that is absorbed rapidly from the

gastrointestinal tract.• fasting state, peak blood alcohol concentrations are reached within 30

minutes.• presence of food : delays absorption by slowing gastric emptying.• Distribution is rapid• volume of distribution for ethanol approximates total body water (0.5–

0.7 L/kg)• women have a higher peak concentration than men (lower total body

water content).• In central nervous system, the concentration of ethanol rises quickly

(large proportion of blood flow and ethanol readily crosses biologic membranes).

• Metabolism : 90% by liver, rest excreted through the lungs and in the urine (7- 10 g/hour).

• the rate of oxidation follows zero-order kinetics.• Breath alcohol tests

Two major pathways of alcohol metabolism to acetaldehyde

1. Alcohol Dehydrogenase Pathway (ADH):• Found mainly in the liver, but also in the brain and

stomach.• significant amount of ethanol metabolism by gastric ADH

occurs in the stomach in men, but a smaller amount occurs in women, who appear to have lower levels of the gastric enzyme.

• During conversion, hydrogen ion is transferred from alcohol to the cofactor nicotinamide adenine dinucleotide (NAD+) to form NADH.

• net result, alcohol oxidation generates an excess of reducing equivalents in the liver, chiefly as NADH. The excess NADH production appears to underlie a number of metabolic disorders that accompany chronic alcoholism.

Metabolic disorder due to high NADH• Proper functioning of the cell, the ratio of NAD to NADH

must be controlled. Alcohol metabolism generates excess amounts of NADH. Altered NAD/NADH ratio lead to several metabolic disorders:

• Fatty liver is the earliest stage and the most common form of alcohol-induced liver disease (reduces the breakdown of fats in the liver).

• Metabolic acidosis (formation of abnormally high levels of lactic acid)

• Gout (reduce the capacity of the kidney to excrete uric acid).

Microsomal Ethanol Oxidizing System (MEOS)

• uses NADPH as a cofactor in the metabolism of ethanol, blood concentrations below 100 mg/dL, contributes little to the metabolism of ethanol.

• concentration of ethanol increases above 100 mg/dL, there is increased contribution from the MEOS system (the alcohol dehydrogenase system becomes saturated owing to depletion of the required cofactor, NAD+).

Acetaldehyde Metabolism

• acetaldehyde ----- oxidized in the liver, by mitochondrial NAD-dependent aldehyde dehydrogenase -----CO2 and water.

Aldehyde dehydrogenase inhibitors

• inhibited by disulfiram• When ethanol is consumed in the presence of

disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache.

• Other drugs:- metronidazole, trimethoprim inhibit aldehyde dehydrogenase and can cause a disulfiram-like reaction if combined with ethanol.

• Genetic deficiency of ALDH : disulfiram-like reaction and if less activity, protect against alcoholism.

Blood Alcohol Concentration (BAC) and Clinical Effects in Nontolerant Individuals.

Pharmacodynamics of Acute Ethanol Consumption

1. Central Nervous System : - sedation and relief of anxiety• at higher concentrations, slurred speech, ataxia, impaired judgment,

and disinhibited behavior, a condition usually called intoxication or drunkenness

• Chronic drinkers ---- high concentration (300 – 400mg/dl) ---- CNS effects.

• No specific receptor for ethanol. • affect a large number of membrane proteins that participate in

signaling pathways, including neurotransmitter receptors (GABA and glutamate, NMDA) for amines, amino acids, and opioids; enzymes such as Na+/K+ ATPase, adenylyl cyclase, phosphoinositide-specific phospholipase C; and ion channels such as those for Ca2+.

• Commonly glutamate and GABA receptor• "Blackouts"—periods of memory loss that occur with high levels of

alcohol—may result from inhibition of NMDA receptor activation.

Heart• blood concentration above 100 mg/dL : Significant

depression of myocardial contractility• Smooth Muscle : vasodilatation (due to central

nervous system effects ;depression of the vasomotor center) and direct smooth muscle relaxation caused by its metabolite, acetaldehyde)

• Severe overdose, hypothermia—caused by vasodilation—may be marked in cold environments.

• Ethanol also relaxes the uterus and was used intravenously for the suppression of premature labor.

Consequences of Chronic Alcohol ConsumptionLiver :-• 15-30% severe liver disease• Fatty liver (reversible condition) ----- alcoholic

hepatitis ----- cirrhosis --- liver failure.Gastrointestinal Tract :- • Chronic pancreatitis and pancreatic stones• Gastritis • Anemia and protein malnutrition (blood and plasma

protein loss)• Small intestine : diarrhea, weight loss and multi vitamin

deficiency• Malabsorption of water soluble vitamins.

Nervous System1. Tolerance and Physical Dependence : consumption of alcohol in

high doses over a long period results in tolerance and in physical and psychologic dependence

• Alcohol withdrawal symptoms : hyperexcitability in mild cases and seizures, toxic psychosis, and delirium tremens in severe ones.

• Psychologic dependence : a compulsive desire to experience the rewarding effects of alcohol and, for current drinkers, a desire to avoid the negative consequences of withdrawal

• Tolerance may result from ethanol-induced up-regulation of a pathway in response to the continuous presence of ethanol.

• Dependence may result from overactivity of that same pathway once the ethanol effect disappearing, and before the system has time to return to a normal ethanol-free state.

2. Neurotoxicity

• most common neurologic abnormality :- generalized symmetric peripheral nerve injury that begins with distal paresthesias of the hands and feet.

• Gait disturbance (due to degenerative change in CNS) and dementia.

• Impair visual acuity.• Wernicke – Korsakoff syndrome (due to thiamin

deficiency): characterized by paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death.

3 .Cardiovascular system : 1. cardiomyopathy and heart failure : Heavy alcohol

consumption of long duration :dilated cardiomyopathy with ventricular hypertrophy and fibrosis.

• number of changes in heart cells : membrane disruption, depressed function of mitochondria and sarcoplasmic reticulum, intracellular accumulation of phospholipids and fatty acids, and upregulation of voltage-dependent calcium channels.

2. arrhythmias : Heavy drinking causes both atrial and ventricular arrhythmias (release of catecholamines).

Cont……3. hypertension: 5% of cases (most common cause

of reversible HTN). Independent of obesity, salt intake, coffee drinking, or cigarette smoking.

4. coronary heart disease : moderate alcohol consumption actually prevents CHD and even reduces mortality because ethanol's raise serum levels of high-density lipoprotein (HDL) cholesterol, the form of cholesterol that appears to protect against atherosclerosis, its ability to inhibit some of the inflammatory processes that underlie atherosclerosis.

Blood • indirectly affects hematopoiesis through metabolic and

nutritional effects• directly inhibit the proliferation of all cellular elements

in bone marrow. • most common hematologic disorder : in chronic

drinkers is mild anemia (folic acid deficiency). • Iron deficiency anemia (gastrointestinal bleeding). • several hemolytic syndromes (hyperlipidemia and

severe liver disease).

Endocrine System and Electrolyte Balance

• gynecomastia and testicular atrophy (steroid hormone imbalance).

• Alcoholics with chronic liver disease; ascites, edema, and effusions (due to fluid and electrolyte imbalance decreased protein synthesis and portal hypertension)

• K+ imbalance : vomiting and diarrhea • Hypoglycemia (impaired hepatic gluconeogenesis)

Fetal Alcohol Syndrome• teratogenic effects, mental retardation and congenital

malformationFetal alcohol syndrome include: (1) intrauterine growth retardation,(2) microcephaly, (3) poor coordination, (4) underdevelopment of midfacial region (appearing as a

flattened face), and (5) minor joint anomalies---- severe cases : congenital heart disease

Immune function

• Inhibited in the lung (due to suppression of the function of alveolar macrophages, inhibition of chemotaxis of granulocytes, and reduced number and function of T) .

• Enhanced in liver, (enhanced function of Kupffer cells; leading to collagen synthesis and fibrosis due to carcinogenic agents TNFα --- cirrhosis, or hepatic failure) and pancreas .

Increased Risk of Cancer

• cancer of the mouth, pharynx, larynx, esophagus, and liver.

• Primary metabolite, acetaldehyde, damage DNA produced by increased cytochrome P450 activity.

Alcohol-Drug Interactions

• Acetaminophen : hepatotoxic due to increased P450-mediated conversion of acetaminophen to reactive hepatotoxic metabolites.

• acute alcohol inhibit metabolism: Phenothiazines, tricyclic antidepressants, and sedativehypnotic drugs due to decreased enzyme activity or decreased liver blood flow.

Management of Acute Alcohol Intoxication• most important goals : to prevent severe respiratory

depression and aspiration of vomitus.• For hypoglycemia and ketosis by administration of glucose.• Thiamine (Wernicke-Korsakoff syndrome).• Fluid and electrolyte (dehydration and vomiting)• Important is recognition of decreased serum concentrations

of phosphate, which may be aggravated by glucose administration.

• Low phosphate stores may contribute to poor wound healing, neurologic deficits, and an increased risk of infection.

Management of Alcohol Withdrawal Syndrome

• mildest form (tremor, anxiety, and insomnia occurs 6–8 hours after alcohol is stopped).

• more severe withdrawal (visual hallucinations, total disorientation, and marked abnormalities of vital signs occur).

• Alcohol withdrawal is one of the most common causes of seizures in adults.

• major objective of drug therapy in the alcohol withdrawal period is prevention of seizures, delirium, and arrhythmias.

Cont……• Potassium, magnesium, and phosphate balance should

be restored• Thiamine therapy is initiated in all cases• Specific drug treatment for detoxification in severe

cases : substituting a long-acting sedative-hypnotic drug for alcohol and then gradually reducing ("tapering") the dose of the long-acting drug.

• Long-acting benzodiazepines (chlordiazepoxide, clorazepate, and diazepam) have the advantage of requiring less frequent dosing because their pharmacologically active metabolites are eliminated slowly

Cont….• disadvantage of the long-acting drugs : their

pharmacologically active metabolites may accumulate, especially in patients with compromised liver function.

Benzodiazepines administration :• orally in mild or moderate cases, and• parenterally in more severe withdrawal

reactions.• Phenothiazine contraindicated for alcohol

withdrawal due to its serious adverse effects (eg, increasing seizures)

Why short acting benzodiazepines are useful in alcoholic patients with liver

disease ?

• Short-acting drugs (lorazepam and oxazepam): rapidly converted to inactive water-soluble metabolites that will not accumulate.

Cont…..• After treatment, sedative-hypnotic medications

must be tapered slowly over several weeks. • Complete detoxification is not achieved with just

a few days of alcohol abstinence. Several months may be required for restoration of normal nervous system function, especially sleep.

Pharmacotherapy of Alcoholism

• Treatment with counseling and drugs can help decrease the rate of relapse for alcoholic patients.

• Drugs : naltrexone, disulfiram and acamprosate

Naltrexone • orally active opioid receptor antagonist that blocks the

effects at mu opiods receptors.• Injection of small amounts of opioids was followed by an

increase in alcohol drinking, whereas administration of opioid antagonists inhibited self-administration of alcohol.

• It reduce craving for alcohol and to reduce the rate of relapse to either drinking or alcohol dependence.

• Dose : 50 gm x od

Combination of naltrexone and disulfiram

• Avoided because both are potential hepatotoxins.

• Administration of naltrexone to patients who are physically dependent upon opioids will precipitate an acute withdrawal syndrome so patients must be opioid free before initiating naltrexone therapy

Disulfiram• causes extreme discomfort to patients who drink

alcoholic beverages• nondrinkers has little effect; however, flushing, throbbing

headache, nausea, vomiting, sweating, hypotension, and confusion occur within a few minutes after drinking alcohol and last for 30 minutes in mild cases, or several hours in severe ones.

• acts by inhibiting aldehyde dehydrogenase• rapidly and completely absorbed from the

gastrointestinal tract• elimination rate is slow, so that its action may persist for

several days after the last dose.

Cont…

• Several other drugs, eg, metronidazole, certain cephalosporins, sulfonylurea hypoglycemic drugs, and chloral hydrate, have disulfiram-like effects on ethanol metabolism.

• Patients should be warned to avoid drinking ethanol while taking these drugs and for several days after they discontinue them

Clinical uses of ethanol

• As antiseptics• Rubbed into the skin to prevent bedsores• To treat methanol poisoning• Reflex stimulation in fainting/hysteria : 1 drop

in nose.

Methanol (methyl alcohol, wood alcohol)• absorbed through the skin or from the respiratory or

gastrointestinal tract and is then distributed in body water.

• Elimination : by oxidation to formaldehyde, formic acid, and CO2:

--- methanol toxicity is probably due to folate-dependent production of formate and not to methanol itself or to formaldehyde, the intermediate metabolite

Cont…• most characteristic symptom in methanol poisoning is a

visual disturbance, called "like being in a snowstorm’’.• severe cases, the odor of formaldehyde present on the

breath or in the urine• bradycardia, prolonged coma, seizures, and resistant

acidosis all imply a poor prognosis• death in fatal cases is sudden cessation of respiration.• concentrations in excess of 50 mg/dL (an absolute

indication for hemodialysis and ethanol treatment), • Formate blood levels (indication of clinical pathology).• Acidosis (due to production of formic acid)

Treatment for methanol poisoning

Three specific modalities of treatment for severe methanol poisoning:

1.suppression of metabolism by alcohol dehydrogenase to toxic products,

2.dialysis to enhance removal of methanol and its toxic products, and

3.alkalinization to counteract metabolic acidosis.

Cont…• Keep the patient in a quiet, dark room; and protect the

eyes from light.• Gastric lavage if brought within 2 hours of ingestion• Ethanol (higher affinity than methanol for ADH) 100

mg/dl through NG tube; loading dose 0.7 ml/kg is followed by 0.15 ml/kg/hour drip

• Often used i.v for methanol poisoning• Fomepizole : inhibitor of alcohol dehydrogenase• Loading dose : 15 mg/kg i.v followed by 10 mg/kg every

12 hrs till serum levels of methanol falls 20 mg/dl

Cont…

• Hemodialysis rapidly eliminates both methanol and formate.

• Sodium bicarbonate (acidosis)• Folate therapy (50 mg inj.) every 6 hrs –

decrease formate level by enhancing its oxidation.