physiological effects of nicotine and ethanol

1. Physiological Effects of Nicotine and Ethanol Rebecca B R Milholland I have been asked to speak to you about the toxicities of nicotine and ethanol today. Both of these chemicals produce effects in a wide variety of body organs but the mechanism by which these two drugs produce their effects is very different. I have been asked to speak to you about the toxicities of nicotine and ethanol today. Both of these chemicals produce effects in a wide variety of body organs but the mechanism by which these two drugs produce their effects is very different.

2. Tobacco Plant Grown for its nicotine containing leaves which are smoked, chewed, or sniffed As I�m sure you all know, the tobacco plant is grown for its nicotine containing leaves which are smoke, chewed, or sniffed.As I�m sure you all know, the tobacco plant is grown for its nicotine containing leaves which are smoke, chewed, or sniffed.

3. Nicotine Nicotine is an alkaloid found naturally in tobacco plants, tomatoes, potatoes, eggplant and green peppers Nicotine itself is an alkaloid (refers to the 5 membered nitrogenous ring) found naturally in tobacco plants as I already mentioned, but also in tomatoes, potatoes, eggplant, and green peppers.Nicotine itself is an alkaloid (refers to the 5 membered nitrogenous ring) found naturally in tobacco plants as I already mentioned, but also in tomatoes, potatoes, eggplant, and green peppers.

4. Nicotine Nicotine is an alkaloid found naturally in tobacco plants, tomatoes, potatoes, eggplant and green peppers Nicotine itself is an alkaloid (refers to the 5 membered nitrogenous ring) found naturally in tobacco plants as I already mentioned, but also in tomatoes, potatoes, eggplant, and green peppers.Nicotine itself is an alkaloid (refers to the 5 membered nitrogenous ring) found naturally in tobacco plants as I already mentioned, but also in tomatoes, potatoes, eggplant, and green peppers.

5. Many of the effects of nicotine result from its effects on the neuromucular system which is made up of the brain and muscle. In order to understand the physiological response to nicotine, I would like to review with you some of the physiology of the neuromuscuar system. The neuromuscular system is consists of the connections between the brain and muscle. The brain connects to the muscle fiber by a special neuron called the motoneuron. The place of contact between the motoneuron and the muscle is called the NEUROMUSCULAR JUNCTION. Many of the effects of nicotine result from its effects on the neuromucular system which is made up of the brain and muscle. In order to understand the physiological response to nicotine, I would like to review with you some of the physiology of the neuromuscuar system. The neuromuscular system is consists of the connections between the brain and muscle. The brain connects to the muscle fiber by a special neuron called the motoneuron. The place of contact between the motoneuron and the muscle is called the NEUROMUSCULAR JUNCTION.

6. Normally, a signal from the brain stimulates a signal in the motorneuron. The signal travels down the motorneuron to the nerve terminals (the ends of the neuron).Normally, a signal from the brain stimulates a signal in the motorneuron. The signal travels down the motorneuron to the nerve terminals (the ends of the neuron).

7. Neuromuscular System A chemical called acetylcholine is then released from the motorneuron terminal and binds to proteins called receptors on the muscle fiber. A chemical called acetylcholine is then released from the motorneuron terminal and binds to proteins called receptors on the muscle fiber.

8. Neuromuscular System Binding of acetylcholine to its receptor results in muscle contraction. Normally, folowing its release and action at its receptor, acetylcholine is broken down and can no longer exert its effects allowing the muscle to relax. Binding of acetylcholine to its receptor results in muscle contraction. Normally, folowing its release and action at its receptor, acetylcholine is broken down and can no longer exert its effects allowing the muscle to relax.

9. Neuromuscular System Nicotine, however is not broken down but is able to mimic the effects of acetylcholine at its receptor thus it is as if acetylcholine is always in the synapse and the muscle remains is unable to relax. Nicotine, however is not broken down but is able to mimic the effects of acetylcholine at its receptor thus it is as if acetylcholine is always in the synapse and the muscle remains is unable to relax.

10. The neuromuscular system controls the muscle in many body organs via the acetylcholine receptor. Thus, nicotine produces effects in multiple body organs but the response is different depending on length of exposure. Acute exposure to high dose nicotine produces a syndrome or set of specific symptoms called the nicotinic syndrome. The nicotinic syndrom is characterized by...The neuromuscular system controls the muscle in many body organs via the acetylcholine receptor. Thus, nicotine produces effects in multiple body organs but the response is different depending on length of exposure. Acute exposure to high dose nicotine produces a syndrome or set of specific symptoms called the nicotinic syndrome. The nicotinic syndrom is characterized by...

11. Increases in heart rate or tachycardia and blood pressure due to nicotine�s action in the branch of the neuromuscular system called the sympathetic nervous system or the fight or flight system which controls heart rhythm. Increases in heart rate or tachycardia and blood pressure due to nicotine�s action in the branch of the neuromuscular system called the sympathetic nervous system or the fight or flight system which controls heart rhythm.

12. Acute action of nicotine in the enteric branch of the neuromuscular system which controls muscle tone in the GI tract results in loss of appetite. Acute action of nicotine in the enteric branch of the neuromuscular system which controls muscle tone in the GI tract results in loss of appetite.

13. paralysis and asphyxiation due to nicotine�s action on the diaphragm and skeletal muscle (muscle attached to the bone). paralysis and asphyxiation due to nicotine�s action on the diaphragm and skeletal muscle (muscle attached to the bone).

14. Chronic exposure to low dose nicotine also effects the neuromuscular system but leads to a different set of consequences. Chronic exposure to low dose nicotine also effects the neuromuscular system but leads to a different set of consequences.

15. Chonic action of nicotine on the sympathetic nervous system results in coronary artery disease and hypertension.Chonic action of nicotine on the sympathetic nervous system results in coronary artery disease and hypertension.

16. Chronic action of nicotine in the enteric neurvous system results in peptic ulcer disease and esophageal reflux. Chronic action of nicotine in the enteric neurvous system results in peptic ulcer disease and esophageal reflux.

17. Finally, chronic exposure to nicotine enhances learning and memory through its direct action in the brain. Finally, chronic exposure to nicotine enhances learning and memory through its direct action in the brain.

18. You may be asking yourself why don�t we just put ourselves on the nicotine patch to improve our memory? Because, chronic exposure to nicotine also produces physical addiction due to nicotine�s direct action on the brain. You may be asking yourself why don�t we just put ourselves on the nicotine patch to improve our memory? Because, chronic exposure to nicotine also produces physical addiction due to nicotine�s direct action on the brain.

19. Most Likely Avenues for Exposure Tobacco Products Insecticides Anti-AChE (Acetylcholine Esterase) nAChR activators (like nicotine) As I said before, one major avenue for exposure to humans is via tobacco products and other plants. Additionally, many insecticides produce their effects by binding to the nAChR of insects. High dose exposure of instecticides to humans such as those encountered by crop dusters could result in nicotinic syndrome. Other insecticides act by inhibiting the enzyme responsible for the breakdown of acetylcholine called Acetylcholine esterase and can thereby produce a nicotinic syndrome in high doses especially in small children and animals. With that I would now like to move one to talk about the physiological effects and toxicity of alcohol if there are no questions. As I said before, one major avenue for exposure to humans is via tobacco products and other plants. Additionally, many insecticides produce their effects by binding to the nAChR of insects. High dose exposure of instecticides to humans such as those encountered by crop dusters could result in nicotinic syndrome. Other insecticides act by inhibiting the enzyme responsible for the breakdown of acetylcholine called Acetylcholine esterase and can thereby produce a nicotinic syndrome in high doses especially in small children and animals. With that I would now like to move one to talk about the physiological effects and toxicity of alcohol if there are no questions.

20. Alcohol The alcohol available in alcoholic beverages is a member of the family of chemicals called alcohols characterized by� The alcohol available in alcoholic beverages is a member of the family of chemicals called alcohols characterized by�

21. Factors which Influence Ethanol Movement Though the Body Absorption Ethanol absorption by the GI tract is directly dependant on the concentration of ethanol present, the higher the ethanol concentration, the greater the absorption. Food in the gut decreases the ethanol concentration and hence decreases the absorption. Ethanol absorption by the GI tract is directly dependant on the concentration of ethanol present, the higher the ethanol concentration, the greater the absorption. Food in the gut decreases the ethanol concentration and hence decreases the absorption.

22. Factors which Influence Ethanol Movement Though the Body Absorption Distribution and Solubility Body Fat Percentage Additionally, ethanol is extremely water soluble and as such, once absorbed, distributes to the body water - in other words distributes to every organ. Conversely, ethanol is highly insoluble in fat and as such a higher fat percentage will result in a higher blood concentration of ethanol. Increases in blood alcohol results in a decreased response (because ethanol not reaching target) such as in a person that is obese. Although ethanol distributes to every body organ, the major toxicities which pose a health risk occur in the liver, the CNS (central nervous system), and kidney. I�ll just mention here, ethanol acts as a diuretic and as such increases urine production in the kidney producing dehydration. The dehydration produces the �hang-over�. Like nicotine, ethanol produces different effects depending on dose and length of exposure. Additionally, ethanol is extremely water soluble and as such, once absorbed, distributes to the body water - in other words distributes to every organ. Conversely, ethanol is highly insoluble in fat and as such a higher fat percentage will result in a higher blood concentration of ethanol. Increases in blood alcohol results in a decreased response (because ethanol not reaching target) such as in a person that is obese. Although ethanol distributes to every body organ, the major toxicities which pose a health risk occur in the liver, the CNS (central nervous system), and kidney. I�ll just mention here, ethanol acts as a diuretic and as such increases urine production in the kidney producing dehydration. The dehydration produces the �hang-over�. Like nicotine, ethanol produces different effects depending on dose and length of exposure.

23. A dose response curve for CNS response to acute administration of ethanol is shown in this slide. As you can see, as the dose increases the response changes from giddiness to sleep and as CNS depression increases and the response becomes deep sleep, unconsciousness (10 drinks), labored breathing, and finally death at very high doses. In order to understand the effects (both acute and chronic) of ethanol on the liver, it is important to understand the normal metabolic pathway for ethanol. Ethanol is metablized primarily in the liver and normally, this is a detoxification or deactivation process. A dose response curve for CNS response to acute administration of ethanol is shown in this slide. As you can see, as the dose increases the response changes from giddiness to sleep and as CNS depression increases and the response becomes deep sleep, unconsciousness (10 drinks), labored breathing, and finally death at very high doses. In order to understand the effects (both acute and chronic) of ethanol on the liver, it is important to understand the normal metabolic pathway for ethanol. Ethanol is metablized primarily in the liver and normally, this is a detoxification or deactivation process.

24. Chronic CNS Effects of Ethanol Korsacoff�s Syndrome Loss of short term memory Due to a Thyamine Defficiency Chronic intake of high dose alcholol (usually seen in alcholics) can result in Korsicoff�s syndrome through an indirect mechanism. Korsicoff�s syndrom is characterized by the loss of short term memory due to neuronal cell death in the brain. This disorder is thought to be due to a thyamine vitamin difficiency resulting from an inhibition of thiamine absorption by ethanol over a long period of time. In order to understand the effects (both acute and chronic) of ethanol on the liver, it is important to understand the normal metabolic pathway for ethanol. Ethanol is metablized primarily in the liver and normally, this is a detoxification or deactivation process. Chronic intake of high dose alcholol (usually seen in alcholics) can result in Korsicoff�s syndrome through an indirect mechanism. Korsicoff�s syndrom is characterized by the loss of short term memory due to neuronal cell death in the brain. This disorder is thought to be due to a thyamine vitamin difficiency resulting from an inhibition of thiamine absorption by ethanol over a long period of time. In order to understand the effects (both acute and chronic) of ethanol on the liver, it is important to understand the normal metabolic pathway for ethanol. Ethanol is metablized primarily in the liver and normally, this is a detoxification or deactivation process.

25. Ethanol is first converted by alcohol dehydrogenase to acetaldehyde which is in turn converted...Ethanol is first converted by alcohol dehydrogenase to acetaldehyde which is in turn converted...

26. To acetate by aldehyde dehydrogenase. To acetate by aldehyde dehydrogenase.

27. Acetate is then used by the cell for the citric acid cycle to produce energy. Now that we have a basic framework, we can delve a little further into ethanol�s effects on the liver. As you may have noticed, both alcohol dehydrogenase and aldehyde dehydrogenase use NAD as a cofactor and convert it to NADH.Acetate is then used by the cell for the citric acid cycle to produce energy. Now that we have a basic framework, we can delve a little further into ethanol�s effects on the liver. As you may have noticed, both alcohol dehydrogenase and aldehyde dehydrogenase use NAD as a cofactor and convert it to NADH.

28. Conversion of NAD to NADH results in an increase in lipid synthesis and results in Fatty liver even at low doses of ethanol. Fatty live is easily eliminated by the liver following acute administration of alcohol and usually produce permanent damage however, chronic induction of lipid synthesis due to chronic high dose alcohol can lead to liver fibrosis and cirrosis. Conversion of NAD to NADH results in an increase in lipid synthesis and results in Fatty liver even at low doses of ethanol. Fatty live is easily eliminated by the liver following acute administration of alcohol and usually produce permanent damage however, chronic induction of lipid synthesis due to chronic high dose alcohol can lead to liver fibrosis and cirrosis.

29. Many of ethanol�s effects occur due to its ability to inhibit the metabolism of other drugs. In addition to alcohol dehydrogenase, the first step in ethanol metabolism can be performed by an enzyme called cytochrome P450 or CYP. CYP 450 is responsible for the metabolism of throusands of chemicals in the liver and as such is extremely important for drug metabolism. Many of ethanol�s effects occur due to its ability to inhibit the metabolism of other drugs. In addition to alcohol dehydrogenase, the first step in ethanol metabolism can be performed by an enzyme called cytochrome P450 or CYP. CYP 450 is responsible for the metabolism of throusands of chemicals in the liver and as such is extremely important for drug metabolism.

30. Ethanol Interaction with P 450 Acute Administration - ? P 450 Chronic Administration - ? P 450 Ethanol is not only a substrate (is metabolized by) CYP 450 but following acute administration ethanol acts as a competative inhibitor of CYP 450. In other words, the metabolism of ethanol by CYP 450 occurs slowly and therefor renders CYP 450 unavailable to metabolize other chemicals. Thus, toxic response to a chemical detoxified by CYP 450 might be prolonged. Alternatively, chonic adminsitration of ethanol produces an increase in gene expression of CYP 450 and therefor an increase in CYP 450 activity. Induction of CYP 450 is especially important for acetominophen toxicity. Ethanol is not only a substrate (is metabolized by) CYP 450 but following acute administration ethanol acts as a competative inhibitor of CYP 450. In other words, the metabolism of ethanol by CYP 450 occurs slowly and therefor renders CYP 450 unavailable to metabolize other chemicals. Thus, toxic response to a chemical detoxified by CYP 450 might be prolonged. Alternatively, chonic adminsitration of ethanol produces an increase in gene expression of CYP 450 and therefor an increase in CYP 450 activity. Induction of CYP 450 is especially important for acetominophen toxicity.

31. Acetominophen (or tylenol) is metabolized in the liver via two different pathways. One pathway detoxifies acetominophen via sulfation or glucuuronidation and promotes extretion by the kidney or in the bile.Acetominophen (or tylenol) is metabolized in the liver via two different pathways. One pathway detoxifies acetominophen via sulfation or glucuuronidation and promotes extretion by the kidney or in the bile.

32. The other pathway converts acetominophen to a toxic metabolite called a quinoneimine free radical. Free radicals bind proteins and DNA to produce damage. Thus, the quinoneimine form of acetominophen induces liver and kidney damage. The other pathway converts acetominophen to a toxic metabolite called a quinoneimine free radical. Free radicals bind proteins and DNA to produce damage. Thus, the quinoneimine form of acetominophen induces liver and kidney damage.

33. The activation of acetominophen occurs via P450. Normally, there is an excess of enzymes which detoxify the acetominophen. The activation of acetominophen occurs via P450. Normally, there is an excess of enzymes which detoxify the acetominophen.

34. Additionally, as I stated before, chronic ethanol intake both produces inhibition induction of P450. The danger comes when a chronic drinker suddenly abstains from ethanol consumption and takes a high dose of acetominophen. The ethanol is not longer present to inhibit P450 but the extra molecules induced by ethanol are still present. Thus, an increase in the production of the quinoneimine occurs and liver and kidney damage can occur. Finally, I just wanted to mention the toxicities associated with two other alcohols, methanol and ethylene glycol (antifreeze). Additionally, as I stated before, chronic ethanol intake both produces inhibition induction of P450. The danger comes when a chronic drinker suddenly abstains from ethanol consumption and takes a high dose of acetominophen. The ethanol is not longer present to inhibit P450 but the extra molecules induced by ethanol are still present. Thus, an increase in the production of the quinoneimine occurs and liver and kidney damage can occur. Finally, I just wanted to mention the toxicities associated with two other alcohols, methanol and ethylene glycol (antifreeze).

35. Other Alcohols Methanol Both methanol and ethylene glycol are metabolized by the same enzymes as ethanol but the products are toxic. Both methanol and ethylene glycol are metabolized by the same enzymes as ethanol but the products are toxic.

36. Other Alcohols Methanol Induces blindness and death due to formic acid production Methanol induces blindness and death due to the formation of formic acid Methanol induces blindness and death due to the formation of formic acid

37. Other Alcohols Methanol Induces blindness and death due to formic acid production Ethylene Glycol Ethylene glycol induces�.Ethylene glycol induces�.

38. Other Alcohols Methanol Induces blindness and death due to formic acid production Ethylene Glycol Kidney damage due to oxalic acid production and crystal formation in the renal tubules Kidney damage due to the formation of oxalic acid crystals in the renal tubules (kidney)Kidney damage due to the formation of oxalic acid crystals in the renal tubules (kidney)

39. Other Alcohols Methanol Induces blindness and death due to formic acid production Ethylene Glycol Kidney damage due to oxalic acid production and crystal formation in the renal tubules The interesting thing about treatment for both of these alcohols is that you treat them with ethanol�ethanol out competes methanol or ethylene glycol for the alcolhol dehydrogenase thereby preventing the formation of the toxic metabolite. The interesting thing about treatment for both of these alcohols is that you treat them with ethanol�ethanol out competes methanol or ethylene glycol for the alcolhol dehydrogenase thereby preventing the formation of the toxic metabolite.

40. Conclusions: Nicotine Acute

41. Conclusions: Nicotine Acute Acts at acetylcholine receptor in muscle Produces asphyxiation and paralysis

42. Conclusions: Nicotine Acute Acts at acetylcholine receptor in muscle Produces asphyxiation and paralysis Chronic

43. Conclusions: Nicotine Acute Acts at acetylcholine receptor in muscle Produces asphyxiation and paralysis Chronic Acts at acetylcholine receptors in the sympathetic nervous system to coronaroy artery disease and high blood pressure Acts at acetylcholine receptors in the brain to induce physical addiction.

44. Conclusions: Ethanol Acute

45. Conclusions: Ethanol Acute Fatty Liver CNS Depression

46. Conclusions: Ethanol Acute Fatty Liver CNS Depression Chronic

47. Conclusions: Ethanol Acute Fatty Liver CNS Depression Chronic Korsacoff�s Syndrome Cirrosis of the Liver