Download Ethanol

ALCOHOL MEDPHARM
03/24/2010
The Spectrum of Alcohol Use
Saitz R. N Engl J Med 2005;352:596-607
UNHEALTHY ALCOHOL USE
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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
EPIDEMIOLOGY
PREVALENCE
Outpatients 7-20%
ED patients 30-40%
Trauma patients 50%
ALCOHOL DEPENDENCE
ALCOHOLISM
• 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
Hazard rates for age at onset of DSM-IV alcohol abuse and alcohol dependence
Hasin, D. S. et al. Arch Gen Psychiatry 2007;64:830-842.
Copyright restrictions may apply.
Body weight (pounds)
Drinks in one hour
1
2
3
4
5
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
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
1. < 10% ethanol excreted in
breath, sweat and urine
2. ~ 90% ethanol removed by
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 +
O
OH
+ NAD +
ADH
ALDH
O + NADH + H+
OH
+ NADH + H+
O
SCoA
CO2
O
O
Fatty acids
Ketone bodies
Cholesterol
METABOLISM OF ETHANOL
CH3CH2OH Ethanol
Women have less
ADH than men
NAD
Alcohol dehydrogenase
NADH
H
|
CH3C=O Acetaldehyde
NAD
Asians may have
Aldehyde dehydrogenase
an inactive ALDH
OH
|
CH3C=O Acetate
NADH
CoA
ATP
Acetyl-CoA
Citric acid
cycle
CO2 + H2O + Calories
CYP2E1
FOMEPIZOLE
ALCOHOL AND CARBOHYDRATE
METABOLISM
• Alcoholic hypoglycemia
• Alcoholic ketoacidosis
• Lactic acidosis
CONSEQUENCES OF INCREASED NADH/NAD RATIO
Ethanol
NAD
NADH
Acetoacetate
LIVER
Pyruvate
NAD
Lactate
-Hydroxybutyrate
Acetone
BLOOD
KIDNEY
KETONEMIA
LACTIC
ACIDEMIA
Urine
Secretion
HYPERURICEMIA
Urate
Gout ?
MECHANISM OF ALCOHOLIC HYPOGLYCEMIA
 Liver Glycogen
 BLOOD
GLUCOSE
Glucose
– Depleted
by fasting
NADH
DHAP
 Gluconeogenesis
NAD
NAD
-glycero- P
PEP
NADH
Pyruvate
NADH
Lactate
OAA
Malate
NAD
Alanine
MECHANISM FOR DECREASED
FATTY ACID OXIDATION
C18-FA-CoA +
NAD
+ FAD
CONCENTRATION
DECREASED
BY
ETOH OXIDATION
CO2 + H2O
AcCoA + C16-FA-CoA
+
NADH
+
NAD
FADH2
OAA
TCA cycle
+
respiratory chain
LIVER TRIGLYCERIDE SYNTHESIS
INCREASED BY ETHANOL OXIDATION
ETHANOL OXIDATION
Acetyl-CoA
NADP
NADH
NADPH
NAD
Dihydroxyacetone
phosphate
-glycerophosphate
Fatty Acids
Triglycerides
DISORDERS ASSOCIATED WITH
INCREASING BLOOD ALCOHOL LEVELS:
DIRECT TOXIC EFFECTS
Alcohol and Alcoholism
Pharmacologic
Direct
Withdrawal
Toxic effect Syndromes
Nutritional
deficiency
Liver
Disease
Unknown
Adverse Effects on the Nervous System
• Intoxication
• “Pathologic intoxication
• “Blackouts”
• Coma
ALCOHOL & THE BRAIN
GABA & GLUTAMATE
• STIMULATION
• SEDATION
• INTOXICATION
• WITHDRAWAL Sx
Low doses stimulate the glutamate system with arousal &
increased energy
High doses inhibit glutamate ,
augment GABA suppressing
dopaminergic for sedation
DOPAMINE & OPIATE
• REINFORCEMENT,REWARD, & PLEASURE
• CRAVING
• SUSTAINED USE
• RELAPSE AFTER LONG
ABSTINENCE
Endogenous opioids released
Inhibit GABA pathways and
enhance dopaminergic signals
Neurochemical Circuits Involved in Alcohol Dependence and Craving
Anton R. N Engl J Med 2008;359:715-721
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
•
•
•
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Polyneuropathy
Cerebellar atrophy
Pontine myelinolysis
WKS
• Wernicke - Korsakoff
Syndrome (WKS)
• Wernicke’s
confusion
cranial nerve palseys
incoordination
• Korsakoff’s
amnesia
confabulation
ALCOHOL: THE MAJOR CAUSE
OF LIVER CIRRHOSIS
IN DEVELOPED NATIONS
All other
(20%)
Alcoholic cirrhosis
(80%)
Pathogenesis of Alcoholic Liver
Injury
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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
Child With Facial Characteristics of Fetal Alcohol Syndrome
Sokol, R. J. et al. JAMA 2003;290:2996-2999.
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TOLERANCE TO CHRONIC ALCOHOL
METABOLIC
TOLERANCE
Decreased
blood level
NEURONAL
TOLERANCE
Decreased
effect
Increased
metabolism
Increased
metabolism
INCREASED
CONSUMPTION
Medication Treatment for Alcohol Withdrawal
Kosten T and O'Connor P. N Engl J Med 2003;348:1786-1795
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 treated
10-15%
adequately treated
2-4%
ALCOHOLISM TREATMENT
• DISULFIRAM - ALDH INHIBITOR
• NALTREXONE - OPIOID ANTAGONIST
• ACAMPROSATE – MECHANISM ?
Alcohol
Dehydrogenase
Microsomes
Acetaldehyde
Metabolites
BLOOD
Drugs
LIVER
BLOOD
LIVER
Alcohol
Alcohol
Dehydrogenase
Microsomes
Acetaldehyde
Metabolites
Drugs
Alcohol
Dehydrogenase
Microsomes
Acetaldehyde
Metabolites
C
BLOOD
Alcohol
LIVER
LIVER
Drugs
B
BLOOD
A
Alcohol
Alcohol
Drugs
Alcohol
Dehydrogenase
Microsomes
Acetaldehyde
Metabolites
D
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
Lee, W. M. N Engl J Med 2003;349:474-485