THE ALCOHOLS pharmacologyyyyyyy PPT.pptx

Alcohol pharmacology

1. THE ALCOHOLS BY DR OGBUAGU O.E MB,BS, MSc, PhD. DEPARTMENT OF PHARMACOLOGY & THERAPEUTICS

2. DEFINITION Alcohols are hydroxyl (OH) derivatives of aliphatic hydrocarbons. When unqualified alcohol refers to ethyl alcohol or ethanol.

3. IMPORTANCE Pharmacology of alcohol is important for its presence in beverages. for alcohol intoxication, rather than as a drug.

4. PRODUCTION Alcohol is manufactured by fermentation of sugars . C 6 H 12 6 zymase 2CO 2 + 2C 2 H 5 OH or CH 3 CH 2 O (Glucose ) ( in yeast) (ethanol) Fermentation proceeds till alcohol content reaches 15%. Then the reaction is inhibited by alcohol itself. Distillation can further increase the alcohol concentration greatly, and the law sets limit on the content which may be sold. Examples: Ethanol ( ethylalochol ) Methanol ( methylalcohol ) Propanol etc

5. ETHANOL (ETHYLALCOHOL) P-kinetics : Ethanol is water soluble and is rapidly and almost completely absorbed in the GIT. The rate of absorption is determined by the quantity of ethanol consumed , the concentration of ethanol in the beverages, the rate of consumption and the composition of the gastric content.   Absorption from an empty stomach occurs within 30 – 60mins. Absorption from an adult skin is minimal, but may be significant in infants given alcohol sponges.   Ethanol is well distributed, crosses the BBB ( concn . in brain near blood concn ), and placenta freely. Test for drunkenness generally involve an analysis of blood, the expired air, or urine for their alcohol content .   Metabolism takes place in the liver majorly (90-98% of ingested dose). Most of the remaining 2 – 10% is excreted unchanged in the urine and exhaled air.

6. Ethanol Acetaldehyde Acetate Acetyl coenzyme A CO 2 + H 2 O Alcohol dehydrogenase Aldehydedehydrogenase (NAD) (NAD) Microsomaloxidase (NADPH) Formepezole Catalase CH 2 O 2 - - Disulfiram - 2 3 METABOLISM OF ETHANOL Metabolic P – W of ethanol oxidation

7. METABOLIC P – W OF ETHANOL OXIDATION Over 90% of the alcohol consumed is completely oxidized in the liver. Rate of oxidation follows zero order kinetics, which means that a constant amount of alcohol is metabolized irrespective of time and concentration of the drug. The breakdown reaction in the liver consists of three (3) steps.

8.   Hepatic oxidation of alcohol to acetaldehyde (alcohol dehydrogenase pathway), using the hydrogen acceptor nicotinamide adenine dinucletoide (NAD) as coenzyme. This reaction is slow and determines the speed at which alcohol is removed from the body, and is termed as rate limiting step.   In addition, alcohol is metabolized to acetaldehyde by the microsomal enzymes using NADPH as cofactor and a minor pathway involving catalase which oxidize ethanol in the presence of a hydrogen peroxide generating system.   Conversion of acetaldehyde to acetate is catalyzed by the enzyme aldehydedehydrogenase .   The acetate formed enters the Kreb’s tricarboxylic acid cycle producing energy. (7Kcal per gram of ethanol). Later it is converted to carbon dioxide and water. Co2 leaves the body in the exhaled air.   An increase in alcohol oxidation is observed in chronic alcoholic due to an induction of microsomal ethanol oxidation activity.

9. MODE OF ACTION Ethanol auguments GABA – mediated synaptic inhibition and fluxes of chloride.

10. PHARMACOLOGICAL EFFECTS Local actions (topical application) Cools skin through evaporation Acts as an astringent (shrink or constricts body tissue eg . alum) Counter irritant or rubifacient (produces erythema or mild burning) Prevents bed sores or decubitus ulcers in bedridden patients – serves as gen antibacterial agent. When injected around a nerve neuritis and nerve degeneration (used to treat pain of trigeminal neuralgia).

11. SYSTEMIC ACTIONS CNS – alcohol is primarily a CNS depressant. The degree depression is directly proportional to quantity of ethanol consumed.   Increased and progressive depressant effect → euphoria, talkativeness, aggressiveness, loss of behavioural control, sedation, anxiety, ataxia, slurred speech, altered judgment, coma and death.   Chronic ingestion may→ serious neurological disorders like memory loss, reduced perceptual activity, emotional and sleep disorders to psychotic behaviours .   Can induce sleep, but not a dependable hypnotic.

12. CVS Vasodilatation of cutaneous vessels in moderate quantity. ↓ d myocardial contractility (from cardiomyopathy ) Congestive heart failure (from excessive ingestion) Cardiotoxic effect (partly from nutritional def. + acetaldehyde) Elevated triglyceride levels in chronic alcoholics, however small to moderate amount may elevate HDL, which is protective and enhances clearance of cholesterol.

13. GIS Stimulate secretion of gastric juice and HCL acid. High concentration (for a long time )→ inflammation of the gastric mucosa → gastritis Can provoke GI bleeding→ blood loss → anaemia . Impaired absorption of nutrients and vitamins (especially water soluble vitamins )→ malnutrition → vitamin deficiencies Megaloblastic anemia (due to interference with folate metabolism). Chronic alcohol ingestion→ ↑d risk of pancreatitis → Fatty liver→ alcoholic hepatitis→ cirrhosis→Liver damage.

14. Endocrine Gynaecomastia and testicular atrophy Aggressive sexual behaviour (from loss of inhibition and restraint ) Impotence and sterility (from prolonged consumption ).  

15. MSS Impairs psychomotor performance and blunts reflex motor activity. As a smooth muscle relaxant of the uterus, it may be used to suppress premature labor.   Renal system Has a diuretic effect proportional to blood alcohol level (due to inhibition of ADH release from posterior pituitary).

16. Others Risk of certain cancers oropharyrgeal, laryngeal , oesophageal, hepatic and possibly pancreatic. Excess consumption during pregnancy (1 st trimester ) may lead to f etal abnormalities (fetal alcohol syndrome) Depression of temperature regulating centre (from high dose)

17. THERAPEUTIC USES External Uses As skin disinfectant prior to injection, phlebotomy and surgery. Rubefacient and counter irritant for sprains and joint pain. Rubbed into skin to prevent bed sores. Not to be applied on already formed sores. As an ingredient of anhidrotic and astringent lotions to decrease sweating. Alcoholic sponges to reduce body temperature in case of fever. However, cold water/ice may be better

18. Local Uses Injection of dehydrated alcohol around the nerves or ganglia is used for relief of chronic, intractable pain e.g pain of trigeminal neuralgia or inoperable carcinoma. Inhalation of ethanol mist has been used as an antifoaming agent to collapse the foam obstructing the tracheobronchial tree in acute pulmonary oedema secondary to left heart failure.

19. Systemic Uses As an appetite stimulant and carminative (relief of flatulence).30-50ml of 7-10% alcohol may be taken as beverage or tincture before meal. Reflex stimulation in fainting/hysteria (1 drop in the nose). Methanol poisoning Has limited application as sedative, hypnotic, analgesic/antipyretic.

20. DRUG INTERACTION Ethanol can interact with other drugs in four distinct ways. Produce additive pharmacological action of CNS depression. Inhibit the metabolism of another co administered drug. Have its own metabolism inhibited by a co administered compound. Induce a cross tolerance with other drugs especially after chronic use.

21. Drugs Effects of simultaneous use in alcohol Anticoagulants Increase likelihood of bleeding Anticonvulsants Decrease antaiconvulsant effectiveness Antidepressants Decrease antidepressant action, increase BP Antihistamines Increase drowsiness Antihypertensives Increase BP lowering action, reduced drug effectiveness in chronic alcoholics Diuretics Increase hypotension and diuresis CNS stimulants (e.g. caffein) Reduced stimulatory effect Hypoglycaemics Interference with control of diabetes, increased hyperglycaemia Narcotic anelgesics Increase drowsiness, respiratory depression, and motor impairment Sedative hypotics Increase CNS depression Salicylate and other anti inflammatory drugs Increase GI distress and bleeding Vitamins Decrease utilization of most vitamins

22. ADVERSE REACTION This may manifest as acute or chronic ethanol intoxication.  

23. ACUTE ETHANOL INTOXICATION Clinical Features Disturbances in sensorium depending on blood alcohol level Residual hangovers. Hypothermia especially in the elderly. Hypostatic pneumonia if coma cont. Increase intracranial pressure 8 – 10hrs Cold and clammy skin Pupils normal or dilated Respiration is depressed and noisy

24. TREATMENT Is especially supportive and consists of maintaining respiration, BP, and body temperature until the ethanol has been removed by metabolism or haemodialysis. No effective remedy for hangover. Pharmacological Intervention Administer hypertonic mannitol solution intravenously if intracranial pressure is raised. Regulate fluid and electrolyte balance Phenothiazines or butyrophenones may be needed to control psychotic behaviour .  

25. CHRONIC ETHANOL ABUSE Clinical Features Psychological and physical dependence. Withdrawal syndrome – begins 6 – 8hrs following sudden cessation of drinking or reduction in amount consumed

26. STAGES OF WITHDRAWAL SYNDROME Stage 1: Onset of nausea, vomiting, sweating, tremors and hyperactivity.   Stage 2: Increase severity of above + auditory or visual hallucination + seizures (grand mal or non focal).   Stage 3: Delirum tremens (DTs ), profound confusion, disorientation and extreme autonomic hyperactivity.

27. OTHER FEATURES OF CHRONIC ALCOHOL USE ( RESULT OF DIRECT CYTOTOXIC ACTION) Hepatic fatty infiltration and cirrhosis. Cancer may develop in advanced stages of hepatic disease. Progressive malnutrition and vitamin deficiency. Alcoholic cardiomyopathy , cardiomegaly and heart failure Chronic gastritis and constipation. Pancreatitis, peripheral neuropathy and gonadal failure in both men and women → ↓ d levels of sex hormones. Wernicke’s encephalopathy and korsakoff’s psychosis. Foetal alcohol syndrome with microcephaly , prenatal growth deficiency and short palpebral fissures.

28. TREATMENT The immediate concern is often detoxification and management of the withdrawal syndrome. Complete abstinence. Psychiatric treatment and support from organization like the Alcoholic Anonymous (AA ).

29. PHARMACOLOGICAL INTERVENTION Multivitamin supplements are helpful in combating dietary deficiencies. Benzodiazepines are drug of choice for suppressing the withdrawal symptoms. Use of alcohol deterrent drugs (for aversion therapy of alcoholism ).

30. NALTREXONE An inhibitor of opioid receptors. It alters the responses to alcohol by decreasing the cravings of abstinent alcoholics for alcohol or by blunting the pleasurable high that comes with renewed drinking. Dose 50mg daily for treatment of alcoholism.

31. DISULFIRAM Is an inhibitor of aldehydedehydrogenase→accumulation of acetaldehyde → unpleasant symptoms such as nausea, sweating, thirst, thrombing headache, dyspnoea , weakness, vertigo, blurred vision, confusion and syncope. With large amount of alcohol can have congestive heart failure, arrhythmias, respiratory, depression, convulsions and even death. This scenario is called DISULFIRAM REACTION or ACETALDEHYDE SYNDROME or MALROUGE. Dose – 500mg daily x 1 – 2weeks then 125-500mg/daily until appetite for alcohol disappears.

32. CITRATED CALCIUM CARBIMIDE It is a mixture of 1 part calcium carbimide and 2 parts of citric acid . It has similar actions to disulfiram , although milder and of a short duration.   Alcohol deterrents are dangerous drugs, and should be used with extreme caution and under strict supervision.

33. METHANOL Methanol ( methylalcohol , wood alcohol, CH 3 OH) is the simple aliphatic alcohol. It has no therapeutic use, but is widely used commercially as an industrial solvent ,ethanol denaturant, and as a fuel.   Methanol has pharmacological properties similar to ethanol.   Unscrupulous mixing of methylated spirit with alcohol beverages or its inadvertent ingestion results in “METHANOL POISONING

34. Methanol is readily absorbed and distributed throughout the body. it is metabolized to formaldehyde and formic acid by alcohol and aldehydedehydrogenases respectively, but its rate is 1/7 th that of ethanol. It follows zero order kinetics with a t½ of 20-60hrs.   Methanol toxicity appears to be primarily due to the formation of formic acid and direct toxic action of formaldehyde. Blood concn . > 50mg/dl is associate with severe poisoning. 15ml of methanol has caused blindness . 30ml has resulted to death 75-100ml is regarded as fatal dose .  

35. CLNICAL FEATURES Vomiting, H eadache , U neasiness , D yspnoea , B radycardia , H ypotension , D elirium , C oma , A cidosis (due to production of formic acid), R etinal damage (specific toxicity of formic acid) →blurring of vision →congestion of optic disc →blindness. Death (due to respiratory failure)

36. TREATMENT Keep the patient in a dark and quiet room. Protect the eye from light. Gastric lavage with sodium bicarbonate, supportive measures to maintain ventilation and BP. Combat acidosis by IV sodium bicarbonate infusion the most important measure to prevent retinal damage and other symptoms. Potassium chloride infusion is needed only when hypokalemia occurs due to alkali therapy.

37. Ethanol 100mg/dl in blood, saturated alcohol dehydrogenase and retards methanol metabolism. This helps by reducing the generation of toxic metabolites. Haemodialysis – clears methanol as well as formate and hastens recovery. Formepizole (4-methylpyrazole) is a specific inhibitor of alcohol dehydrogenase . It retards methanol metabolism. Folate therapy – calcium leucovorin injected repeatedly has been shown to reduce blood levels by enhancing its metabolism.

38. OTHER ALCOHOLS Isopropanol ( isopropylalcohol ) – used as rubbing alcohol Butanols and pentanols – are more toxic than ethanol, but are rarely involved in poisoning. Dihydroxyalcohol (glycol) – like propylene glycol, are used as solvents for many drugs and cosmetics. Ethylene glycol – was formerly used as a solvent for drugs but caused deaths. Hence it is not employed medicinally. Death has occurred from ingestion of anti freeze mixture containing ethylene glycol.

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