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ALCOHOL & DISULFIRAM - PHARMACOLOGY
The document provides an overview of alcohol's pharmacology, effects on the body, and the use of disulfiram as a deterrent for alcohol consumption. It details the various types of alcohol, their actions on the central nervous system, cardiovascular and gastrointestinal effects, and the implications of chronic alcoholism. Disulfiram is explained as an aldehyde dehydrogenase inhibitor that causes distressing symptoms when alcohol is consumed, reinforcing the desire to abstain from drinking.
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ALCOHOL & DISULFIRAM - PHARMACOLOGY
- 1. ALCOHOL & DISULFIRAM By-Dr.S.Kameshwaran
- 2. ALCOHOL: • Alcohols arehydroxy derivatives of aliphatic hydrocarbons. • Pharmacology of alcohol is important for its presence in beverages • Alcohol is manufactured by fermentation of sugar ALCOHOLIC BEVERAGES – Malted liquors – Wines – Spirits
- 3. Other forms ofalcohol • Absolute alcohol 99% w/w ethanol (dehydrated alcohol). • Rectified spirit 90% w/w ethyl alcohol produced from fermented mollases, by distillation. • Proof spirit - 100% proof spirit is 49.29% w/w or 57.1% v/v alcohol. • Methylated spirit Also called ‘denatured spirit’ is produced by adding 5 parts of wood naphtha (methyl alcohol) to 95 parts of rectified
- 4. PHARMACOLOGICAL ACTIONS LOCAL ACTIONS •Ethanol is a mild rubefacient (redness of the skin) and counterirritant (An externally applied substance that causes irritation or mild inflammation of the skin for the purpose of relieving pain in muscles, joints and viscera distal to the site of application) when rubbed on the skin. • Applied to delicate skin (scrotum) or mucous membranes it produces irritation and burning sensation. • When Injected in s.c. route it causes intense pain, inflammation and necrosis followed by fibrosis. • When Injected around a nerve it produces permanent damage. • Applied to the surface, alcohol is an astringent—precipitates surface proteins and hardens the skin. • By precipitating bacterial proteins it acts as an antiseptic. • The antiseptic action increases with concentration from 20 to 70%, remains constant from 70 to 90% and decreases above that.
- 5. CNS • Alcohol isa neuronal depressant. • They are primarily inhibitory • Excitation and euphoria are experienced at lower plasma concentrations (30–60 mg/dl). • Hesitation, caution, self-criticism and restraint (control) are lost first. • Mood and feelings are altered; anxiety may be allayed. • With increasing concentration (80 – 150 mg/dl) mental clouding, disorganization of thought, impairment of attention, memory, alteration of gait and perception. • At 150–200 mg/dl the person is sloppy (careless and unsystematic), ataxic (loss of coordination of the muscles, especially of the extremities )and blackouts (a temporary loss of consciousness) • 200–300 mg/dl result in stupor (a state of near-unconsciousness or insensibility) and above this unconsciousness, medullary centres are paralysed and death may occur. • Though, alcohol can produce anaesthesia, margin of safety is narrow. • ‘Hangover’ (headache, dry mouth, laziness, disturbed mood, impaired performance) may occur the next morning.
- 6. • Alcohol raisespain threshold and also alters reaction to it, but is not a dependable analgesic • alcohol is acting on brain, it exerts anticonvulsant action, • Chronic alcohol abuse damages brain neurones, cause shrinkage of brain.
- 7. Mechanism of action •Alcohol was believed to produce CNS depression • Alcohol has been shown to enhance GABA release at GABA A sites in the brain. • It also inhibits NMDA and kainate type of excitatory amino acid receptors • Action of 5-HT on 5-HT3 inhibitory autoreceptor is increased. • It also activates specific type of K+ channels in certain brain areas. • Release and turnover of DA in brain is enhanced • Activity of membrane bound enzymes like Na+ K+ ATPase and adenylyl cyclase is also altered.
- 8. CVS: • The effectsare dependent on dose. • Small doses: produce only cutaneous (especially on the face) and gastric vasodilatation. • BP is not affected. • Moderate doses: cause tachycardia and a mild rise in BP due to increased muscular activity and sympathetic stimulation. • Large doses: cause direct myocardial as well as vasomotor centre depression and there is fall in BP. • Chronic alcoholism contributes to hypertension and can lead to cardiomyopathy and cardiac arrhythmias
- 9. Blood Regular intakeof small to moderate amounts of alcohol has been found to raise HDL-cholesterol levels and decrease LDL oxidation. This may be responsible for the 15–35% lower incidence of coronary artery disease in such individuals. Risk reduction is greatest in high risk subjects and protection is lost if > 3 drinks are consumed daily. Mild anaemia is common in chronic alcoholics. Note: 1 drink = 50 ml of spirits 150 ml of wines 400 ml of beer
- 10. • One StandardDrink Equals: • 341 ml of 5% alcohol beer, cider or cooler. • 43 ml of 40% hard liquor (vodka, rum, whisky, gin etc.) • 142 ml of 12% wine.
- 11. Body temperature • Alcoholis reputed to combat cold. It does produce a sense of warmth due to cutaneous and gastric vasodilatation, • High doses depress temperature regulating centre. Respiration Brandy or whiskey are reputed as respiratory stimulants They irritate buccal and pharyngeal mucosa which stimulate respiration.
- 12. GIT • Dilute alcohol(10%) put in the stomach by Ryle’s tube is a strong stimulant of gastric secretion • Higher concentrations (above 20%) inhibit gastric secretion, cause vomiting, mucosal congestion and gastritis. • Alcoholism is an important cause of chronic gastritis • Bowel movements may be altered • Acute pancreatitis is a complication of heavy drinking.
- 13. Liver • intake ofsmall-to-moderate amounts cause significant liver damage, • it mobilize peripheral fat and increases fat synthesis in liver in a dose-dependent manner. • Proteins may also accumulate in liver because their secretion is decreased. • Chronic alcoholism exposes liver to oxidative stress and causes cellular necrosis (Death) followed by fibrosis (Thickening). • Acetaldehyde produced during metabolism of alcohol appears to damage the hepatocytes and induce inflammation, especially on chronic ingestion of large amounts. • Increased lipid peroxidation and glutathione depletion occurs. • These combined with vitamin and other nutritional deficiencies may be responsible for alcoholic cirrhosis.
- 14. Kidney • Diuresis isoften noticed after alcohol intake. This is due to water ingested along with drinks as well as alcohol induced inhibition of ADH secretion. • It does not impair renal function. Sex • Alcohol is reputed as an aphrodisiac (a food, drink, or other thing that stimulates sexual desire.) • Aggressive sexual behaviour is due to loss of restraint (control) • performance of the sexual act is often impaired. • Chronic alcoholism can produce impotence, testicular atrophy, gynaecomastia and infertility in both men and women.
- 15. PHARMACOKINETICS • Rate ofalcohol absorption from the stomach is dependent on its concentration, presence of food, and other factors, but is generally quite slow. • Absorption from intestines is very fast; peak levels are attained after ~30 min. • Alcohol gets distributed widely in the body , crosses blood brain barrier efficiently • concentration in brain is very near blood concentration. • Metabolized in liver • Excretion of alcohol occurs through kidney and lungs,
- 16. CO2 + H2O METABLOISMOF ALCOHOL
- 18. CONTRAINDICATIONS Intake of alcoholshould be avoided by 1. Peptic ulcer 2. Epileptics 3. Severe liver disease patients. 4. Unstable personalities: they are likely to abuse it and become excessive drinkers. 5. Pregnant women
- 19. TOXICITY • A. Sideeffects of moderate drinking Nausea, vomiting, flushing, hangover, traffic accidents. • B. Acute alcoholic Unawareness, unresponsiveness, stupor, hypotension, gastritis, hypoglycaemia, respiratory depression, collapse, coma and death.
- 20. CHRONIC ALCOHOLISM • Onchronic intake, tolerance develops but is generally of a low degree. • Psychic dependence often occurs even with moderate drinking; depends a lot on individual’s likings and attitudes. • Physical dependence occurs only on heavy and round-the- clock drinking Heavy drinking is often associated with nutritional deficiencies, because food is neglected and malabsorption may occur • In addition to impaired mental and physical performance, neurological afflictions are common—tremors, seizures, loss of brain mass, psychosis and megaloblastic anaemia. • Alcoholic cirrhosis of liver, hypertension, cardiomyopathy, CHF, arrhythmias, stroke, acute pancreatitis, impotence, gynaecomastia, infertility and skeletal myopathy are other complications. • Incidence of oropharyngeal, esophageal and hepatic malignancy and respiratory infections is high; immune function is depressed.
- 21. CLINICAL USES • Asantiseptic • Rubefacient and counterirritant for sprains, joint pains, etc. • Spirit is generally used as vehicle for other ingredients. • Rubbed into the skin to prevent bedsores. • Astringent action of alcohol is utilized in aftershave lotions. • Alcoholic sponges to reduce body temperature in fever. • Intractable neuralgias (trigeminal and others), severe cancer pain. • As appetite stimulant
- 22. ALDEHYDE DEHYDROGENASE INHIBITOR DISULFIRAM •It inhibits the enzyme aldehyde dehydrogenase probably after conversion into active metabolites. • When alcohol is ingested after taking disulfiram, the concentration of acetaldehyde in tissues and blood rises and a number of highly distressing symptoms (aldehyde syndrome) are produced. • These are—flushing (Skin – red), burning sensation, throbbing (pain), headache, perspiration (sweat), uneasiness, tightness in chest, dizziness, vomiting, visual disturbances, mental confusion, postural fainting and circulatory collapse. • Duration of the syndrome (1–4 hours) depends on the amount of alcohol consumed. Because of risk of severe reaction, • disulfiram is to be used with great caution, only in well- motivated subjects.
- 23. MECHANISM OF ACTIONOF DISULFIRAM
- 24. • Disulfiram aversiontherapy is indicated in subjects who sincerely desire to leave the habit. After making sure that the subject has not taken alcohol in the past 12 hours, • Disufiram is given at a dose of 500 mg/day for one week followed by 250 mg daily. • Sensitization to alcohol develops after 2–3 hours of first dose, • Reaches its peak at ~12 hours and lasts for 7–14 days after stopping it • The subject’s resolve not to drink is reinforced by the distressing symptoms that occur if he drinks a little bit.
- 25.