ALCOHOLS AND PHARMACOTHERAPY OF ALCOHOLISM

INTRODUCTION
x When unqualified, 'alcohol' refers to ethyl alcohol or ethanol x Alcohol beverages have been used since recorded history x Alcohol is known for intoxication. Rather than as a drug x Alcohol is the most commonly abused drug in the world

x Alcohol abuse: inability to limit alcohol consumption - becomes a health risk x Alcoholism: continued consumption of alcohol in spite of adverse medical or social consequences related directly to alcohol consumption

PHARMACOKINETICS
Rapidly absorbed from GIT x Peak levels in 30 min on empty stomach x Food delays absorption x Rapid distribution in total body water, tissue and blood levels almost similar x Women have higher peak concentrations x Concentration rises quickly in CNS

x Over 90% is oxidized in the liver; remainder is excreted through the lungs and in the urine x Metabolism follows zero-order kinetics; independent of time and conc. of the drug x A typical adult can metabolize 7 10 g/hr
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MAJOR PATHWAYS OF METABOLISM

#1 Alcohol Dehydrogenase (ADH) Pathway x The primary pathway, a cytosolic enzyme located mainly in the liver (also in stomach) x Reduced ADH activity - increased risk of alcoholism #2 Microsomal Ethanol Oxidizing System (MEOS) Pathway x Consists of cytochrome P450 2E1, 1A2, & 3A4 x Becomes important when levels are above 100 mg/dL

x During chronic alcohol consumption, MEOS activity is induced x Significant in ethanol metabolism and also in the clearance of other drugs x Increased generation of the toxic byproducts of cytochrome P450 reactions x Deficient activity of ALDH -disulifiram like effects; protective against alcoholism; risk of severe liver disease

PHARMACOLOGICAL ACTIONS
Local actions:
x Has mild rubefacient counterirritant and astringent action x Used as an antiseptic

CNS: x Alcohol is a neuronal depressant

x Higher areas are most sensitive (primarily inhibitory) - apparent excitation and euphoria at lower concentrations x Gradual CNS depression with increasing concentrations

x Alcohol can induce sleep x Increases pain threshold and also alters reaction to it x Effects are more marked when the blood concentration is rising x Cortex & RAS are most sensitive x Chronic alcoholism may lead to peripheral neuropathy, Wernicke-Korsakoff syndrome

CVS : dose & duration dependent effects

x Smaller doses cause cutaneous and gastric vasodilatation, BP not affected x Voderate doses: tachycardia and mild rise in BP due to sympathetic stimulation
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x Large doses cause fall in BP due to direct myocardial as well as VMC depression and direct smooth muscle relaxation x Chronic alcoholism contributes to hypertension, cardiomyopathy and arrhythmias

Blood :
x Consumption in moderation increase HDL x Megaloblastic anemia due to interference of folate metabolism (diminished hepatic storage)

Respiration :
x Transiently stimulate respiration reflexly x Directly depress respiratory centre

GIT:
x Directly and reflexly stimulate gastric secretion
x Higher conc. (>20%) inhibit gastric secretion cause vomiting, mucosal congestion & gastritis x Lower esophageal sphincter (LES) tone is reduced - Ted gastroesophageal reflux x Risk of chronic pancreatitis & stones

Liver :
x Reduced hepatic gluconeogenesis can lead to hypoglycemia (in acute intoxication) Chronic alcohol abuse leads to reversible fatty liver progressing to irreversible hepatitis, cirrhosis and liver failure

Body temperature :
x Produce a sense of warmth due to cutaneous and gastric vasodilatation x Temperature regulating centre depressed at higher dose

Skeletal muscle :
x Fatigue is allayed by small doses x Weakness and myopathy in chronic alcoholism

Endocrine effects:
x Moderate amounts - cause hyperglycaemia x Acute intoxication is associated with hypoglycaemia x Chronic alcoholism can produce impotence, testicular atrophy, gynaecomastia etc. (altered Steroid balance) x Reputed as an aphrodisiac

Kidney: x Can induce diuresis (ADH inhibition)

Fetal Alcohol Syndrome:

x Chronic maternal alcohol abuse during pregnancy is associated with teratogenic effects (leading cause of mental retardation and congenital malformation)

Immune System:
x Immune function in some tissues is inhibited (e.g, the lung), whereas pathologic, hyperactive immune function in other tissues is triggered (e.g, liver, pancreas)

Neoplasia: chronic use increase risk of GI cancers and also risk of breast cancer

MECHANISM OF ACTION
x Ethanol affects a large number of membrane proteins Neurotransmitter receptors Enzymes Transporter and ion channels

x Enhancement of the action of GABA at GABA A receptors x Inhibits the ability of glutamate to open NMDA receptors x Action of 5-HT on 5-HT 3 inhibitory autoreceptor is augmented x Can indirectly reduce neurotransmitter release by inhibiting voltage sensitive neuronal Ca 2+ channels

x Blockade of adenosine uptake contribute to synaptic depression x Increased turnover of NA, in brain through an opioid receptor dependent mechanism important in the pleasurable effects of alcohol and in the genesis of alcohol dependence

x Activity of membrane bound enzymes like Na+K+ATPase and adenylyl cyclase may be altered
x The activity and translocation of channel / enzyme proteins in the membrane could also be affected

DRUG INTERACTIONS
x Increases the risk of hepatotoxicity with acetaminophen x Additive CNS depression when combined with other CNS depressants x Disulfiram-like reactions with chlorpropamide, cefoperazone, cefotetan, moxalactam, cefamandole, metronidazole, trimethoprim etc. x Acute alcohol use may inhibit metabolism of sedative-hypnotics, TCAs, phenothiazines

ALCOHOL TOLERANCE & DEPENDENCE

x Tolerance - due to changes in the nervous system (upregulation of pathways) & changes in metabolic clearance x Dependence - both psychological & physical x Physical - responsible for "withdrawal reaction" x Psychological one is characterized by compulsive desire to experience rewarding effects and in current drinkers - desire to avoid negative effects of withdrawal

ACUTE ALCOHOL INTOXICATION

Sign and symptoms :
x Vomiting, hypotension, tachycardia, gastritis, hypoglycaemia, respiratory depression & coma Treatment: x Prevent respiratory depression & aspiration of
vomitus x Add adequate respiratory & CV support

x Treatment of hypoglycemia and ketosis by administration of glucose infusion x Thiamine: 100 mg in 500 ml of glucose solution infused intravenously x In case of dehydration and vomiting - give electrolyte solutions x Administer potassium and phosphate depending on the situation

ALCOHOL WITHDRAWAL SYNDROME

x Characterized by motor agitation, anxiety, insomnia; seizure & hallucinations (severe)

Treatment:
x Aim is to prevent seizure, delirium & arrhythmia 2 x Restore electrolyte balance (K+, mg + and phosphate) x Administer thiamine in all cases

In severe cases substitute alcohol with BZD followed by gradually tapering of BZD dose over several weeks x Long acting BZD in those with normal liver function (e.g. chlordiazepoxide/ diazepam) x Short acting BZD in impaired liver function (oxazepam/ lorazepam) x Can be administered orally/ parenterally

TREATMENT OF ALCOHOLISM
x Started after successful detoxification x Drugs are helpful in maintaining abstinence and reducing craving (adjunctive therapy) Naltrexone:

x Long acting opioid receptor antagonist

x Avoid giving with disulfiram - hepatotoxicity x Patient should be opioid free
x Dose: 50 mg

OD orally/ IM inj every 4 wks

Acamprosate :
x Weak NMDA-receptor antagonist and a GABA A-

receptor activator x Administered as 1-2 enteric coated tablets (333 mg) three times a day x Should not be used in patients with severe renal dysfunction x GI adverse effects are important

DISULFIRAM
Acts by inhibiting "Aldehyde dehydrogenase" x Flushing, throbbing headache, nausea, vomiting, sweating, hypotension, and confusion occur within a few minutes after alcohol x No effect in non-drinkers x For full effect 12 hrs are required x Action persist several days after last dose x May impair liver function tests x Adherence to therapy is poor

METHANOL POISONING & TREATMENT

x Methanol is a CNS depressant x Toxic effects are largely due to formic acid Blood levels >50mg/di associated with severe poisoning
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Manifestations of methanol poisoning: x Vomiting, headache, dyspnoea, bradycardia and hypotension x Acidosis is prominent
x Visual disturbances (like being in a snowstorm) progressing to blindness

x Death is due to respiratory failure

x Maintain respiration and BP x Suppression of metabolism by ALD to toxic products by ethanol (i.v.) or fomepizole (15mg/kg iv followed by 10 mg/kg/12hr till methanol level falls below 20 mg/dL) x Na-bicarbonate infusion to counteract acidosis x Hemodialysis to enhance removal of methanol and formate in severe case x Administration of folio acid (Ca-leucovorin 50 mg/6 hrly)

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