ALCOHOL MEDPHARM 03/24/2010

Saitz R. N Engl J Med 2005;352:596-607

The Spectrum of Alcohol Use

UNHEALTHY ALCOHOL USE

THE PROBLEM 8.2 million in US are alcohol

dependent Dependence =“ lack of control” 85,000 Deaths Disability-medical & psychiatric Secondhand effects-MVCs Cost $ 185 billion

UNHEALTHY ALCOHOL USE

EPIDEMIOLOGYPREVALENCE Outpatients 7-20% ED patients 30-40% Trauma patients 50%

ALCOHOL DEPENDENCEALCOHOLISM

• Clinically significant impairment or distress

with 3 or more:

Tolerance Continued use in spite of

Withdrawal psychological/physical

Time spent disability

Change in lifestyle

Desire to cut back

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Hasin, D. S. et al. Arch Gen Psychiatry 2007;64:830-842.

Hazard rates for age at onset of DSM-IV alcohol abuse and alcohol dependence

100 30 60 90 120 150

120 25 50 75 100 125

140 22 44 66 88 110

160 19 39 58 78 97

180 17 34 52 69 86

200 16 31 47 62 78

Drinks in one hour

Bod

y w

eig

ht

(pou

nds)

1 2 3 4 5

Blood alcohol concentration (BAC) mg/dl

Factors Affecting Ethanol Absorption

1. Concentration of ethanol 2. Blood flow at site of absorption

3. Irritant properties of ethanol 4. Rate of ingestion

5. Type of beverage

Absorption of ethanol from the duodenum and jejunum is much more rapid than from the stomach; hence the rate of gastric emptying is an important determinant of the rate of absorption of orally administered ethanol.

DISTRIBUTION: To body water. Women Men

General Scheme for Ethanol Oxidation

3. Most of this ethanol oxidation occurs in the liver

4. Ethanol cannot be stored in the liver

5. No major feedback mechanisms to pace the rate of ethanol metabolism to the physiological conditions of the liver cell

6. Kinetics are zero-order

OH + NAD+

ADHO + NADH + H+

O + NAD+ALDH

O

OH+ NADH + H+

O

OH

O

SCoACO2

Fatty acidsKetone bodiesCholesterol

1. < 10% ethanol excreted in breath, sweat and urine

2. ~ 90% ethanol removed by oxidation

METABOLISM OF ETHANOL

Alcohol dehydrogenase

Aldehyde dehydrogenase

Acetaldehyde

CH3CH2OH Ethanol

CH3C=O|H

AcetateCH3C=O|OH

Acetyl-CoA

CoAATP

NAD

NADH

NAD

NADH

Citric acidcycle

CO2 + H2O + Calories

Women have less ADH than men

Asians may have an inactive ALDH

CYP2E1

FOMEPIZOLE

ALCOHOL AND CARBOHYDRATE

METABOLISM

• Alcoholic hypoglycemia• Alcoholic ketoacidosis• Lactic acidosis

CONSEQUENCES OF INCREASED NADH/NAD RATIO

KETONEMIAKETONEMIA

LIVER

BLOOD

KIDNEY

LACTICACIDEMIA

LACTICACIDEMIA

HYPER-URICEMIA

HYPER-URICEMIA

Ethanol

Pyruvate

Lactate

Acetoacetate

-Hydroxybutyrate

Acetone

UrateGout ?

UrineSecretion

NAD

NADH

NAD

MECHANISM OF ALCOHOLIC HYPOGLYCEMIA

Liver Glycogen – Depleted by fasting

BLOODGLUCOSE Glucose

DHAP

Gluco- neogenesis

PEP

OAA

Pyruvate

-glycero- P

NAD NADHLactate

NADH NAD

NADH NAD

AlanineMalate

CONCENTRATIONDECREASED

BYETOH OXIDATION

MECHANISM FOR DECREASEDFATTY ACID OXIDATION

NADOAA

NADC18-FA-CoA + + FAD AcCoA + C16-FA-CoA+

NADH+

FADH2

TCA cycle+

respiratory chain

CO2 + H2O

LIVER TRIGLYCERIDE SYNTHESISINCREASED BY ETHANOL OXIDATION

ETHANOL OXIDATION

Acetyl-CoADihydroxyacetone

phosphate

Fatty Acids

NADP NADH

NADPH NAD

-glycerophosphate

Triglycerides

DISORDERS ASSOCIATED WITHINCREASING BLOOD ALCOHOL LEVELS:

DIRECT TOXIC EFFECTS

Adverse Effects on the Nervous System

• Intoxication • “Blackouts”• “Pathologic intoxication • Coma

Alcohol and Alcoholism

Nutritionaldeficiency

Pharmacologic Direct WithdrawalToxic effect Syndromes

LiverDisease

Unknown

ALCOHOL & THE BRAIN

GABA & GLUTAMATE

• STIMULATION

• SEDATION

• INTOXICATION

• WITHDRAWAL Sx

Low doses stimulate the gluta-

mate system with arousal &

increased energy

High doses inhibit glutamate ,

augment GABA suppressing

dopaminergic for sedation

DOPAMINE & OPIATE

• REINFORCEMENT,REW-ARD, & PLEASURE

• CRAVING

• SUSTAINED USE

• RELAPSE AFTER LONG ABSTINENCE

Endogenous opioids released

Inhibit GABA pathways and

enhance dopaminergic signals

Anton R. N Engl J Med 2008;359:715-721

Neurochemical Circuits Involved in Alcohol Dependence and Craving

ALCOHOL INTOXICATION

BEHAVIORAL SYNDROME• Exhilaration, excitement• Loquacity, assertiveness• Loss of behavioral inhibitions• Progresses to stupor and coma

CEREBELLAR SYNDROME• Dysarthria• Ataxia of gait and limbs• Progresses to marked generalized

loss of coordination

“ALCOHOLIC BLACKOUTS”

• Intoxicated but not drowsy or stuporous

• New memories not recorded during intoxication

• Duration of a few hours• Permanent retrograde amnesia for

period of intoxication• Mechanism not understood• No implications regarding prognosis

of alcoholism

ALCOHOLIC COMA: CLINICAL FEATURES

• Life threatening: not well appreciated• Often complicated by other drug

ingestion• Kills by respiratory depression or by

complicating states:- subdural hematoma - hypoglycemia- meningitis - pancreatitis- pneumonia - UGI hemorrhage- hypothermia - hepatitis

- portosystemic encephalopathy

ALCOHOL

• Polyneuropathy• Cerebellar atrophy• Pontine myelinolysis• WKS

• Wernicke - Korsakoff Syndrome (WKS)

• Wernicke’s

confusion

cranial nerve palseys

incoordination• Korsakoff’s

amnesia

confabulation

ALCOHOL: THE MAJOR CAUSEOF LIVER CIRRHOSISIN DEVELOPED NATIONS

Alcoholic cirrhosis(80%)

All other(20%)

Pathogenesis of Alcoholic Liver Injury

Theories Centrilobular hypoxia PMN infiltration & activation Inflammatory cell infiltration &

activation Antigenic adduct formation Injurious cytokines & endotoxin

ALCOHOL

• Heart - Cardiomyopathy• Peripheral vascular system- hypertension• Protective effect with moderate doses

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Sokol, R. J. et al. JAMA 2003;290:2996-2999.

Child With Facial Characteristics of Fetal Alcohol Syndrome

TOLERANCE TO CHRONIC ALCOHOL

METABOLICTOLERANCE

NEURONALTOLERANCE

INCREASEDCONSUMPTION

Decreasedblood level

Decreasedeffect

Increasedmetabolism

Increasedmetabolism

Kosten T and O'Connor P. N Engl J Med 2003;348:1786-1795

Medication Treatment for Alcohol Withdrawal

ALCOHOL WITHDRAWAL

• Benzodiazepines (lorazepam or others)

Decreased severity of withdrawal Sx

Reduced risk of seizures and DTs

LATE WITHDRAWAL: DELIRIUM TREMENS

• Profound confusion, disorientation, misperceptions

• Hallucinations, paranoid delusions• Motor hyperactivity: Tremor, restlessness,

agitation, hyperreflexia• Autonomic hyperactivity: Tachycardia,

profuse sweating, mydriasis• Leads to dehydration, hypotension, shock,

hyperthermia• Mortality: Inadequately treated10-15%

adequately treated 2-4%

ALCOHOLISM TREATMENT

• DISULFIRAM - ALDH INHIBITOR

• NALTREXONE - OPIOID ANTAGONIST

• ACAMPROSATE – MECHANISM ?

DrugsLI

VE

RB

LOO

D

AlcoholDehydrogenase

Acetaldehyde

Microsomes

Metabolites

Alcohol Drugs

LIV

ER

BLO

OD

AlcoholDehydrogenase

Acetaldehyde

Microsomes

Metabolites

Alcohol

Drugs

LIV

ER

BLO

OD

AlcoholDehydrogenase

Acetaldehyde

Microsomes

Metabolites

Alcohol Drugs

LIV

ER

BLO

OD

AlcoholDehydrogenase

Acetaldehyde

Microsomes

Metabolites

Alcohol

A B

C D

Lee, W. M. N Engl J Med 2003;349:474-485

The Role of Ethanol in the Formation of N-acetyl-p-benzoquinone-imine (NAPQI), the Toxic Metabolite of Acetaminophen (APAP), and the Dynamics of Enzyme Induction