Pharmacology: Test 2 Alcohol/alcoholism Lec 27

Front 1

Alcohol major metabolism

Back 1

via ADH (NAD+ dependant) in the liver via oxidation where acetalaldehyde is generated, which is then further oxidized by Ald. dehydrogenase into acetate.

Front 2

Minor Alchol Metabolism pathway?

Back 2

via CYP2E1, which is NADPH dependant. Also metabolizes acetaminophin, methanol, and ethylene glycol.

Front 3

Why is Alcohol metab. zero-order kinetics of elimination?

Back 3

because NAD+ is in limited supply so ADH is saturated.//

saturation reached once in excess of 0.1 mg/ml.

Front 4

Avg metabolic rate in adults?

Back 4

7 gm/hr

Front 5

ADH inhibitor

Back 5

Fomepizole: Used in delaying metabolism of toxic alcohols such as methanol, and ethylene glycol which also use ADH.

Front 6

Alcohol Effects: Liver

Back 6

NAD+ depletion > fatty acid synthesis increased, FA oxidation decreased, free FA in plasma increased, TG accumulation in liver. All due to altered redox potential from increased NADH:NAD+ ratio.

Front 7

Alcohol Effects: GI Tract

Back 7

stim. gastric acid secretion > ulcers. Intestines > reduces absorption causing diarrhea and pancreatitis.

Front 8

Alchol Effects: CVS

Back 8

peripheral vasodilatin, flushing, feeling of warmth, body heat loss, hypothermia. //

To compensate, sympathetic tone increased > tachycardia and arrhythmais.// Also, cardiomyopathies and increase risk of strokes.

Front 9

Alcohol effects; Brain

Back 9

CNS depression causing the sx of intoxication. Done via release of dopamine by disinhibition causing euphoria

Front 10

Where does the release of DA occur via inhibition by Eth?

Back 10

in Nucleus Accumbens which leads to activation of the reward pathways. CNS effects are related to [Eth] in blood.

Front 11

Eth action in Brain: Mechanism?

Back 11

Eth disrupts or alters function of neuronal receptors and enzymes >> causing reduction in firing of neurons.

Front 12

What receptors are altered by Eth in CNS?

Back 12

Glu (NMDA-R): reducing synaptic transmission.//

GABA mediated increase in Cl- conductance through action at an allosteric site.

Front 13

Eth effects on ADH?

Back 13

inhibits ADH, leads to diuresis, dehydration. Done by inhibition of SON and PVN neurons in HT.

Front 14

Eth effect on LHRH?

Back 14

depress reproductive function by inhibition of LHRH secretion in HT. Done via CB1-R indirectly via release of endogenous endocannabinoids.

Front 15

Mgmt of acute Eth toxicity?

Back 15

Remove Eth from stomach, supportive, antacid or H2 blockers to decrease gastric secretions, Thiamine. //

AVOID CNS stimulants OR depressnts. //

Front 16

Methanol Toxicity?

Back 16

less potent CNS depressant than CNS, metabolic acidosis, blindnes and death. Acidosis is due to formatin of formic acid

Front 17

Cause of blindness due to Methanol tox?

Back 17

It's the formaldehyde toxicity at the retina because of high local acitivity of retinol dehydrogenase, a homolog of ADH.

Front 18

Treatment of Methanol Tox?

Back 18

use alchol of Fomepizole to occupy or inhibit respectively the ADH and retard formation of formaldehyde.

Front 19

Higher Alcohols upto decanol

Back 19

more potent as CNS depressants than Ethanol. Very toxic. Ethylene glycol results in renal failure and uremia. Fomepizole can also be used to inhibit ADH.

Front 20

Benefits of Alcohol at moderate 3-7 drinks per week?

Back 20

yes beneficial at reducing risks of cardiac infarcts and cognitive decline in elderly probably due to reduced incidence of small strokes.

Front 21

How is alchol benifical at small quantities?

Back 21

Resveratrol: in red wine, antioxidant.//

Procyanidins: enhance vascular health in red wines esp from SW France.//

Also, Alcohol induced elevation of HDL cholesterol. //

Front 22

Metabolic tolerance in alcohol

Back 22

CYP2E1 increased resulting in increase rate of metabolism. Affects metabolism of other drugs metabolized by P450 enzymes.

Front 23

Pharmacodynamic tolerance of alcohol?

Back 23

Dose-Response curve shifts to the right, requiring higher doses. Also, cross tolerance with other CNS depressants incl. barbiturates and general anesthetics. Less tolerant to acute lethal effects.

Front 24

Physical dependance on alcohol.

Back 24

True withdrawal aka abstinence syndrome; sx slow in onset 12-24 hrs. Sx include tremors, hyperreflexia, vomiting, visual hallucinations, DELIRIUM TREMENS (DT) about day 3-4; hyperthermia, VC collapse, grand mal seizures.

Front 25

Other effects of chrnonic alcohol:

Back 25

Peripheral neuropathy, pellagra due to thiamine deficiency.// Wernicke's encephalopathy (thiamine def.)// Korsakoff's psychosis, cerebellar degeneration.//

Front 26

Chronic alcohol: GI

Back 26

gastritis, ulcers, pancreatitis

Front 27

Chronic Alcohol: Liver

Back 27

accumulation of acetaldehyde, CYP2E1 induction resluting in toxicity of precursors of hepatotoxicins and carinogens. Results in necrosis, fibrosis, and cirrhosis. Eventually causing liver failure.

Front 28

Alcohol drug interraction

Back 28

Acute: inhibition of drug metabolism by P450 enzymes.

Chronic: induction of CYP2E1, increasing metabolism rates of acetaminophen, halothane and other anesthetics.

Front 29

Teratogenesis due to alcohol?

Back 29

most frequent cause of mental deficiency in the west. Cause of Fetal Alcohol Syndrom: facial abnormalities, small head, low IQ, low weight, prenatal and postnatal stunting of growth.

Front 30

Tx of Alcohol: withdrawal syndrome

Back 30

reduce sx with benzodiazepine to supress seizures, fluid, electrolyte and vitamin esp. Thiamine supplementations.

Front 31

Alcohol Tx: maintaining alcohol-free state

Back 31

Disulfiram (antabuse): Ald. dehydrogenase inhibitor > acetalaldehyde accumulation >> unpleasant sxs. //

Naltrexone: opiate antagonist, reduces reinforcing effects of alcohol.//

Acamprosate: GABA analog, reduce hyperexcitability, reduce cravings.//