Unit 3: Drug Therapy and Neurologic Drugs

1. Unit 3: Drug Therapy and Neurologic Drugs 11 days

2. February 19th and 24th: Drugs that Depress Brain Function

3. Sedative-hypnotics • CNS depressants affect neurons and alter the brain’s functioning • The observed behaviors are dose related • Resulting in the relief of anxiety, release from inhibitions, sedation, sleep, unconsciousness, general anesthesia, coma, and eventually death from respiratory and cardiac depression

4. Sedative-hypnotics • Most of these drugs have a high potential for toxicity, dependency, and/or abuse • The terms sedative, tranquilizer, anxiolytic, and hypnotic can be applied to any CNS depressant

5. Sedative-hypnotics • CNS depressants have a uniformity of action, and therefore any CNS depressant will potentiate the effects of any other CNS depressant • Sometimes the depressant effect can be supra-additive • Depressant drugs should never be used in combination for this reason

6. Sedative-hypnotics • All sedative-hypnotic drugs carry the potential for physiological dependence, psychological dependence, and tolerance • Physiological dependence is characterized by withdrawal signs and symptoms when the drug is withheld • Psychological dependence is due to positive reinforcement effects of taking the drug • Tolerance occurs as a result of increased metabolism by the liver and adaptation of neurons in the brain

7. Sedative-hypnotics • A large amount of cross-tolerance can occur which is where tolerance to one drug results in lessened response to another similar drug • Cross-dependence may also be exhibited, in which one drug can prevent the withdrawal symptoms of another drug • This is used to help moderate alcohol withdrawal symptoms with benzodiazepines

8. Ethyl Alcohol • In the English language the term alcohol is used to refer to ethyl alcohol or ethanol • Ethyl alcohol is unique of all the sedative-hypnotic drugs because it is used primarily for recreational purposes, and has virtually no medicinal uses in modern medicine • It is the 2nd most widely used drug (after caffeine) and has created a multitude of individual and societal problems

9. Pharmacokinetics of Alcohol Absorption: • Rarely drunk in its pure form • ~12% in wines, ~3-5 in beers, and ~40-50 in hard liquors • Expressed in ‘proof’ which is twice the alcohol percent by volume (i.e. 40 proof = 20% abv)

10. Pharmacokinetics of Alcohol • Alcohol is soluble in both water and fat, and diffuses easily within the body • It crosses all biological membranes • After it is drunk, it completely and rapidly absorbed through the gastrointestinal tract • The maximum blood concentration occurs between 30 and 90 minutes after alcohol is drunk

11. Pharmacokinetics of Alcohol • Alcohol can be directly absorbed from the stomach • Food quantity in the stomach may slow the absorption of alcohol into the blood stream

12. Pharmacokinetics of Alcohol Distribution: • Alcohol is distributed to all body tissues evenly • It easily crosses the blood-brain barrier • It easily crosses the placental barrier • A fetus’s blood alcohol level is virtually the same as the mother’s • This can lead to Fetal Alcohol Syndrome

13. Pharmacokinetics of Alcohol Metabolism and Excretion: • ~95% of the alcohol a person drinks is metabolized by alcohol dehydrogenase • The other ~5% is excreted unchanged, primarily through the lungs • Alcohol quantity in exhaled air compared to blood has a ratio of 1:2300

14. Pharmacokinetics of Alcohol • ~85% of alcohol metabolism occurs in the liver • The other ~15% is processed by gastric alcohol dehydrogenase (this is an example of first pass metabolism) • Drinking on an empty stomach increases gastric emptying time, which reduces the amount of time the alcohol is susceptible to first pass metabolism, which ultimately increases the blood alcohol level

15. Pharmacokinetics of Alcohol • Women are also more susceptible to alcohol for 3 main reasons: • They have ~50% less gastric metabolism due to a lower level of enzymes – which results in ~7% higher BAC (blood alcohol concentration) • They have a higher body fat ratio, which has little vascularization, so men have more blood, and therefore the alcohol is diluted more • They concentrate the alcohol into their plasma, as opposed to their body tissues (fatty)

16. Pharmacokinetics of Alcohol • The breakdown of alcohol is a 3 step process: 1. 3. 2.

17. Pharmacokinetics of Alcohol • 1. alcohol dehydrogenase functions to convert alcohol to acetaldehyde. NAD is required as a coenzyme. The availability of NAD is the rate-limiting step, and because of this the maximum amount of alcohol that can be metabolized in 24hrs is 170 grams. • 2. the enzyme aldehyde dehydrogenase converts acetaldehyde to acetic acid. • 3. Acetic acid is broken down into CO2 and H2O which releases energy (calories).

18. Pharmacokinetics of Alcohol • An average person can metabolize between 6 and 8 grams of pure alcohol per hour • This rate does not change depending on the BAC or the genetic variation of the individual • This is called a zero-order metabolism because it is concentration independent • Virtually all other drugs are 1st order, and their rate changes based on the amount of drug present

19. Pharmacokinetics of Alcohol • An average person will process the following in 1 hour: • 1 ounce glass of 80-proof liquor • 4 ounce glass of wine • 12 ounce bottle of 3.5% beer • 6 ounce glass of 7% microbrew beer • These quantities can be used by most people to predict level of drunkenness as well as time after drinking until the alcohol has cleared the body

20. Pharmacokinetics of Alcohol • Most states define a BAC of 0.08 grams percent (g%) as intoxication • Driving above this level is prohibited • This does not mean that a person with 0.07g% is a safe driver, since the effects of alcohol are not all-or-none • Like all sedatives the symptoms progressively impair a person’s ability to function

21. Pharmacokinetics of Alcohol • A BAC of 0.15g% makes a person 25 times more likely to be involved in a serious automobile accident

22. Pharmacodynamics of Alcohol • The exact mechanism was not fully understood for a long time • It was thought to be a general depressant on nerve membranes and synapses • This would result in a nonspecific and indirect depression of neuronal function

23. Pharmacodynamics of Alcohol • This explains the high-dose or anesthetic properties of alcohol, but new research indicates that there are other mechanism at work as well • Alcohol may disturb the synaptic activity of various neurotransmitters (especially glutamate and GABA) • May suppress calcium ion currents, and alter ATP-activated ion channels

24. Glutamate Receptors: • Ethanol is a potent inhibitor of NMDA type glutamate receptors • Reduces the glutamate release, and results in compensatory up-regulation of NMDA receptors • Therefore, upon withdrawal, these excess excitatory receptors may result in symptoms such as seizures

25. GABA Receptors: • Ethanol activates the GABA-mediated increase in chloride ion flow, resulting in neuronal inhibition • Results are sedation, muscle relaxation, and inhibitionof cognitive and motor skill • Helps alleviate panic and the anxiety associated with panic , and abuse is commonly seen in people with panic disorders

26. GABA Receptors: • Chronic alcohol abuse can affect gene expression • This causes several other neurotransmitter systems to be affected • Dependent people and their offspring may demonstrate a deficit in brain opioid activity • Ethanol may induce opioid release and trigger brain dopamine reward systems

27. Pharmacological Effects • The graded, reversible depression of CNS function is the main pharmacological effect of alcohol • Respiration is depressed and this depression is typically the cause of death at very high doses • Seizure activity peaks approximately 8 to 12 hours after the last drink

28. Pharmacological Effects • The effects of alcohol are additive with other sedative-hypnotic compounds • Alcohol dilates the blood vessels in the skin, causing a warm flush and decrease in body temperature • Long-term use is also associated with disease of the heart tissue which can result in heart failure

29. Pharmacological Effects • Small quantities of alcohol consumed daily may reduce the risk of coronary artery disease • This effect is lost on people who also smoke cigarettes

30. Pharmacological Effects • 1 to 2 drinks per day have also been shown to reduce the risks of ischemic strokes, but greater than 5 drinks per day increased this stroke risk

31. Pharmacological Effects • Alcohol exerts a diuretic effect on the body by increasing the excretion of fluids as a result of its effects on renal function • It does not appear to harm the structure or function of the kidneys

32. Pharmacological Effects • Alcohol is NOT an aphrodisiac • It causes behavioral inhibition, which may increase sexual activity, but actually impairs motor function and sexual performance • “It provokes the desire, but it takes away the performance.” MacBeth Shakespeare

33. Psychological Effects • In low doses the effect of alcohol on the CNS leads to a mixture of stimulant and depressant behaviors • This is determined largely by the individual, his or her mental expectations, and the environment • At high doses the effect becomes increasingly standardized and sedative

34. Psychological Effects • Alcohol intoxication with its resulting disinhibition plays a major role in a large percentage of violent crimes • More than 50% of crimes and highway accidents are alcohol related • More than 10 million people in the U.S. suffer from alcohol abuse • Also, more than 10 million people in the U.S. are alcohol dependent

35. Psychological Effects • Alcohol has lots of calories but few nutrients • Alcoholism leads to vitamin deficiencies and nutritional diseases • It also leads to a wide variety of issues with a wide variety of organ systems • About 10% of the U.S. population is affected by alcoholism in one way or another

36. Tolerance • Tolerance to alcohol develops in a similar manner to other CNS depressants • Moderate of infrequent use does not lead to tolerance • Heavy and frequent use leads to marked tolerance in individuals

37. Tolerance • 3 Types: • Metabolic tolerance, the liver increases its amount of drug metabolizing enzymes (~25% of tolerance) • Tissue or functional tolerance, neurons in the brain adapt to the amount of alcohol present (can have a BAC 2x higher than what would be behaviorally predicted) • Associative, contingent, or homeostatic tolerance, which are environmental manipulations that counter the effects of alcohol

38. Dependence • When physical dependence develops, withdrawal of alcohol results within several hours • Alcohol abuse is one of the most common causes of adult onset seizures • ~10% of adults in alcohol withdrawal exhibit seizures, these seizures usually last for a period less than or equal to 6 hours • Alcohol withdrawal is the only drug withdrawal that can be fatal

39. Side Effects and Toxicity • Many side effects occur with alcoholism: • Disorientation • Impaired insight • Impaired judgment • Antegrade amnesia (black outs) • Diminished intellectual capabilities • Delusions • Hallucinations • Confabulations

40. Side Effects and Toxicity • Liver damage: • Most serious long term physiological consequence • Irreversible • Changes in both structure and function • ~75% of alcoholic deaths are due to cirrhosis • Cirrhosis is the 7th most common cause of death in the U.S.

41. Side Effects and Toxicity • May cause destruction of nerve cells: • Permanent brain syndrome • Dementia • Korsakoff’s Syndrome • Digestive system: • Pancreatitis • Chronic gastritis • Peptic ulcers

42. Side Effects and Toxicity • Alcoholism is a major risk factor for cancer: • Ethanol is not itself carcinogenic • May be a co-carcinogen or tumor promoter • Metabolism of ethanol leads to acetaldehyde and free radical production • Shown to promote tumor growth • Stomach, intestines, and oral pharynx • Has an immunosuppressive effect • Augments the effects of other cancer causing agents (like cigarettes)

43. Teratogenic Effects • Birth defects • Both a physical and behavioral teratogen • Alterations occur in brain structure and/or function • Fetal Alcohol Syndrome (FAS) affects as many as 30 to 50% of babies born to alcoholic women • About 5 in every 1,000 births (and increasing)

44. Teratogenic Effects • Exact amount of alcohol required to cause FAS is unknown • Generally believed that more than 3 ounces of absolute alcohol per day • Especially high rates associated with binge drinking • No ‘safe’ level of alcohol consumption during pregnancy has been established

45. Teratogenic Effects • FAS: • CNS dysfunction • Low intelligence • Microcephaly (reduced cranial circumference) • Mental retardation • Behavioral abnormalities • Hyperactivity • Difficulty with social integration • Retarded body growth rate

46. Teratogenic Effects • FAS: • Facial abnormalities • Short palpebral fissures • Short nose • Wide-set eyes • Small cheekbones • Other anatomical abnormalities • Congenital heart defects • Malformed eyes • Malformed ears

47. Teratogenic Effects • ~2.6 million babies are born annually with significant intrauterine alcohol exposure • Birth defects range from FAS to more mild symptoms (ARND) • About 9 out of 1,000 births have alcohol-related neurodevelopmental disorder (ARND) • 3rd leading cause of birth defects with mental retardation – the only one that is preventable

48. Teratogenic Effects • Structural and growth effects are well documented and described, but the behavioral and cognitive effects are often underappreciated • Affected aspects include: • Intelligence (IQ), activity, attention, learning, memory, language, and motor activities • Also sensory problems involving: • Ocular, auditory, and speech and language development

49. Teratogenic Effects • The mechanism responsible for FAS and ARND are unclear • One hypothesis involves the interaction of vitamin A and ethanol • Another involves the production of reactive oxygen species (free radicals) that cause lipid peroxidation • All women who are, could be, or are trying to become pregnant should ABSTAIN from alcohol

50. Pharmacological Treatment • The recognition of alcoholism as a disease is relatively recent • In 1935 Alcoholics Anonymous was founded and treats patients based of a moral model of alcoholism • Offers spiritual and behavioral framework for understanding, accepting, and recovering from the compulsion to use alcohol