Transcript Alcohol-Pharma

By: Dr Alia Alshanawani
Dr. Ishfaq A. Bukhari
Dep of Medical Pharmacology, KSU
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Currently Alcohol ( Ethyl alcohol or ethanol) is the
most commonly abused drug in the world.
Alcohol in low-moderate amounts relieves anxiety &
fosters a feeling of well-being/ euphoria.
Alcohol abuse and alcoholism cause severe
detrimental health effects such as alcoholic liver and
heart disease, increased risk for stroke,chronic
diarrhoea and alcohol dementia
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Pharmacokinetic of Alcohol
water-miscible molecule, completely absorbed from
GIT
Peak blood ethanol conc after po doses: 30 -75 min,
absorption is delayed by food .
Volume of distribution = Total Body Water
Metabolism (in gastric mucosa & liver).
1- Oxidation of ethanol to acetaldehyde via
A- ADH;; reduction of NAD+ to NADH. Mainly in
liver. OR
B- via microsomal ethanol oxidizing system
2- Acetaldehyde is converted to acetate via AlDH, w
also reduce NAD+ to NADH.
Acetate ultimately is converted to CO2 + water.
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ADH
ALDH
CH3CH2OH  CH3CHOCH3COOH
Ethanol
Acetaldehyde
Acetic Acid
Acetaldehyde in more toxic than ethanol
EtOH
Peroxisome
H2O2
CAT
H2O
Aminotriazole
Cytosol
O2
NADPH
NADP+
ER
MEOS
P450
NAD+
ADH
NADH
Pyrazole
Acetaldehyde
NAD+
Mitochondrion
AlDH
NADH
Disulfiram
(antabuse)
Acetate
Extra-hepatic tissue
Chlorpropamide
(diabetes)
ADH
RATE-LIMITING STEP
Alcohol
Acetaldehyde
NAD+
NADH
Chronic intake→ induction of
CYP2E1
NAD+
AlDH
NADH
Acetyl CoA
Acetate
Citric Acid Cycle
Fatty Acid synthesis
Energy
Fatty liver
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Genetic variation in alcohol metabolizing
enzymes Aldehyde Dehydrogenase .(ALDH)
Acute acetaldehyde toxicity in individuals with
an inactive form of the ALDH2*2
(mitochondrial aldehyde dehydrogenase 2).
Associated with the ‘flushing reaction’
immediately following alcohol intake (due to
increased acetaldehyde)
Mostly Asian populations have ALDH2*2 allele .
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Chronic ethanol consumption induces cytochrome
P450 2E1, whic leads to ! generation of ROS + a
deficiency of oxygen in ! tissues (hypoxia).
Chronic ethanol use: NAD & of NADH by !
liver.
All of these biochemical changes have been
proposed to contribute to DNA damage,
hepatocyte injury & liver disease.
Pyruvate is reduced to lactate to generate NAD &
metabolic acidosis
This will cause hypoglycemia in malnurished
alcoholics
Lactate also inhibit uric acid excretion;;
hyperuricemia.
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Hyperlipidemia & fat deposition are common in
chronic alcohol use because of excess acetate & FA
synthesis + direct oxidation of ethanol for energy
instead of using body fat stores.
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Effects of alcohol greatly depends on dose and
frequency of use.
In order of increasing dose (or number of
drinks),alcohol is anxiolytic
moodenhancing sedative
slows reaction time
produces motor incoordination
impairs
judgment (making it dangerous and illegal to
drive a car).
At very high doses alcohol produces loss of
consciousness
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Medical complications of chronic alcoholism:
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Liver disease: ! most common medical complication.
Accumulated acetaldehyde: hepatotoxicity.
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Fatty liver/ alcoholic steatosis (common, reversible,
hepatomegaly, slight elevation in liver enzyme)
Followed by: steatohepatitis (fat, inflammation, &
injury),
then hepatic cirrhosis (jaundice, ascites, bleeding &
encephalopathy) &
liver failure & death within 10 yrs.
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Alcoholic Liver Disease
Steatosis
Steatohepatitis
Normal
Cirrhosis
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@AMSP 2010
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@AMSP 2010
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Hematological complication:
 Iron deficiency anemia; inadequate dietary intake
& GI blood loss
 Hemolytic anemia; liver damage
 Megaloblastic anemia; folate deficiency in chronic
alcoholism,, malnutrition, impaired folate abs, &
hemolysis.
 Thrombocytopenia & prolong bleeding times;
suppressing platelet formation
 Alcohol can diminish ! production of Vit-K
dependent clotting factors; due to hepatotoxic
action
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Alcohol effects on Central NTs:
Alcohol causes:
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inhibition of NMDA (Glutamate)
&
activation of GABAA receptors (Rs) in brain this will
lead to:
- Sedative effect & CNS depression
- Disruption in memory, consciousness, alertness &
learning by alcohol. “Blackouts”
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Chronic use of alcohol leads to UPREGULATION of NMDA-Rs & voltagesensitive Ca Channels ;;
1- increased NMDA activity significantly Ca
influx to ! nerve cells, Ca excess can lead to cell
toxicity & death. (Ca related brain damage).
2- This also contribute to alcohol tolerance &
withdrawal symptoms (tremors, exaggerated
response & seizures).
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Ethanol interactions e NTs release
•
Ethanol enhances Dopamine (DA) release in ! “pharmacological
reward” pathway
• Ethanol appears to release DA from ! VTA & NAC via interactions
e multiple NT Rs
• Ethanol has direct excitatory actions on DA containing neurons in
the VTA
Ventral Tegmental Area (VTA)
Nucleus accumbens (NAC)
Control
Dopamine
Ethanol
+
+
Dopamine
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Alcohol effects:
Acute, DA in NAC
Chronic,  DA in NAC 
tolerance
Activation of mesocorticolimbic system
Cont’ NTs release:
Alcohol increases release of:
-- DA: role in motivational behavior/ reinforcement,
i.e. rewarding stimuli & contribute to addiction
-- Serotonin: alcohol rewarding effects, tolerance &
withdrawal
5-HT system modulates the DAergic activity of the
VTA and the NAC.
-- Opioid peptides; feeling of euphoria & increase !
rewarding effect of alcohol.
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Cardiovascular:
- Chronic alcohol abuse can lead to alcohol
cardiomyopathy; cardiac hypertrophy, lowered
ejection fraction, compromised ventricular
contractility ; heart failure & degeneration.
- It is a type of dilated cardiomyopathy. Due to !
direct toxic effects of alcohol on cardiac muscle,
!unable to pump blood efficiently, leading to heart
failure.
results from:
1- alterations in contractile functions of ! heart
2- membrane disruption
3- up-regulation of voltage-dependent Ca2+ channels
4- function of mitochondia & sarcoplsmic reticulum
5- FA ethyl ester & oxidative damage.
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Alcoholic Cardiomyopathy
Control
Alcoholic
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Cardiovascular:
Arrhythmia: premature ventricular/ atrial
contractions, atrial & ventricular tachycardia, atrial
fibrillation & flutter.
result from: cardiomyopathy, electrolyte imbalance &
conduction delays induced by alc & its metabolites.
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CHD:
Moderate alcohol consumption: prevent CHD ( HDL)
Excess drinking is associated e higher mortality risk
from CHD.
 HTN: ( Ca & sympathetic activity).
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Fetal Alc Syndrome: IRREVERIBLE
Ethanol rapidly crosses placenta
 Pre-natal exposure to alcohol causes:
- intrauterine growth retardation, congenital
malformation (wide-set eyes, microcephaly,
impaired facial development) & teratogenicity
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fetal growth by inducing hypoxia.
- More severe cases include congenital heart defects &
physical + mental retardation.
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Fetal Alcohol Syndrome ( FAS )
Gastritis & ulcer diseases, Alcohol causes:
- Malabs of water-soluble vit
- Acute/ chronic hemorrhagic gastritis
- Gastroesophageal reflux disease, esophageal
bleeding (reversible).
 Cancer
- Excessive consumption of alc ! risk of developing
cancers (tongue, mouth, oropharynx, esophagus,
liver, & breast).
Due to chronically irritating membranes Acetaldehyde
can damage DNA
& cytochrome P450 activity + stimulate
carcinogenesis.
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Pancreatitis:
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Occur in heavy drinkers
Presented as severe pain + elevated amylase &
lipase
Due to hyperlipidemia
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Tr: parenteral analgesics, hydration & nutrition.
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Endocrine: hypogonadism
In women: amenorrhea, anovulation, luteal phase
dysfunction, hyperprolactinemia & ovarian
dysfunction, infertility & spontaneous abortion +
impairment fetal growth.
In men: hypogonadism, loss of facial hair,
gynecomastia, muscle & bone mass, testicular
atrophy & sexual impotence.
.. Also alc may testesterone & inhibit pituitary
release of LH.
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Wernicke-Korsakoff syndrome
is a manifestation of thiamine deficiency, usually as a
secondary effect of alc abuse (severe alcoholism).
Result from: (inadequate nutritional intake; uptake of
thiamine from GIT, liver thiamine stores are due
to hepatic steatosis or fibrosis).
! syndrome is a combined manifestation of 2
disorders:
Wernicke's encephalopathy is ! acute neurologic
disorder & is characterized by CNS depression
(mental sluggishness, confusion, Coma), ocular
disorder (impairment of visual acuity & retinal
hge), ataxia & polyneuropathy.
Korsakoff's Psychosis main symptoms are amnesia &
executive dysfunction .
Tr: thiamine + dextrose-containing IV fluids.
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Acute ethanol intoxication:
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CNS depression: sedation, relief anxiety, higher
conc: slurred speech, ataxia, & impaired judgment
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Resp depression leading to resp acidosis & coma
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Death can occur from resp depression + aspiration
of vomitus.
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Significant depression of myocardial contractility
Vasodilation due to depression of vasomotor center
& direct smooth muscle relaxation caused by
acetaldehyde.
Volume depletion, hypothermia & Hypotension
Hypoglycemia occur in conjunction e reduced CHs
intake & malnourished alcoholics.
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Supportive therapy
till metabolism clear
body to low levels
Hypotension/hypo
volumia → IV fluids
Artificial respiration
Intoxication
Mild signs
Ethanol level
<500 mg/L
(0.05%)
≤ 1000 mg/L
(0.1%)
Frequent
Psychomotor
Impairment
Hypoglycmia:IV
Psychomotor
1500
gluc
Impairment in
mg/L(0.15%)
Coma: lavage,
everyone
naloxone (opioid
Severe/ anesthe2500 mg/L
antagonist)
sia & coma
(0.25%)
Death (respiratory 5000 mg/L
depression)
(0.5%) 33
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Elevated acetaldehyde during ethanol intoxication
causes:
N & headache
Sensitivity rxs, Vasodilation & facial flushing
Increase skin temperature,
Lower BP
Sensation of dry mouth & throat
Bronchial constriction & allergic-type rxs
Euphoric effects that may reinforce alcohol
consumption.
Increase incidence of GI & upper airway cancers
Liver cirrhosis.
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! person must drink progressively > alcohol to
obtain a given effect on brain function
Tolerance develops e steady alcohol intake via:
Metabolic tolerance, hepatic enzyme induction
Functional tolerance, change in CNS sensitivity
(Neuro-adaptation )
Faster alc absorption
Tolerance appear to involve NMDA R, GABA R, 5HT, DA in brain reward & reinforcement.
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Alc Withdrawal occurs > 2/3 Alcohol Dependence
patients
Symptoms:
Autonomic hyperactivity & craving for alcohol
Hand tremor
Insomnia, anxiety, agitation
vomiting & thirst
transient visual/ auditory illusions
Grand mal seizures (after 7-48 hr alc cessation)
Rebound supersensitivity of glutamate Rs &
hypoactivity of GABAergic Rs are possibly involved
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Chronic wks-months intake followed by stop leads
to two-stage severe withdrawal:
 Aforementioned symptoms after few hours
 After ≥2 days delirium tremens” stage starts fatal;
profuse sweating, delirium & hallucinations, intense
Vasodilation, fever, severe tachycardia
Possible causes:
 rebound β-adrenoceptor super-sensitivity
 hyperactivity of neural adaptive mechanism
(neuroadaptation) no longer balance by ! inhibitory
effect of alcohol & upregulation of NMDA Rs .
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withdrawal symptoms depend upon severity, rate
& duration of preceding drinking period
In mild cases: hyperexcitability
In severe cases: seizures, toxic psychosis & delirium
tremens.
Begin after 8 hours, Peak at day 2, Diminish at day
5, Disappear 3 - 6 months.
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in the Figure! zero line represents ! excitability of !
brain.
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Short-term alcohol intake produces a depression of
! inhibitory centers of ! cerebral cortex, which
results in ! initial symptoms of intoxication
(euphoria, exaggerated feelings of well-being, &
loss of self-control followed by sedation).
Long-term alcohol intake causes ! initial decrease e
tolerance that occurs during continued exposure to
alc.
Removal of alcohol causes a rebound stimulatory
effect, increasing excitability in ! nervous system.
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Substituting a long-acting sedative hypnotic drug
for alc & then tapering ! dose.
- Such as BDZs (chlor-diazepoxide, diazepam) OR
short acting are preferable (lorazepam)
- Efficacy: IV/ po
manage withdrawal symptoms & prevent irritability,
insomnia, agitation & seizures.
! dose of BDZs should be carefully adjusted to
provide efficacy & avoid excessive dose that causes
respiratory depression & hypotension.
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Cont’ Management:
Clonidine; inhinbits enhanced symp NT release
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Propranolol; inhibits ! action of exaggerated symp
activity
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Naltrexone; po, an opioid antagonist, e weak partial
agonist activity, reduce psychic craving for alcohol
in abstinent patients & reduce relapse
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Acamprosate; a weak NMDA-R antagonist & GABA
activator, reduce psychic craving.
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Transient reduction in drinking
Reduction in drinking in alcoholics with a
family history of Alcohol Dependence
5-HT and Human Alcohol Consumption ---Reduced 5-HIAA levels
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For adjunctive Tr of alc dependence: Disulfiram
therapy: 250 mg daily
Disulfiram blocks hepatic AlDH, this will increase
bld acetaldehyde conc.
If alc + disulfiram = extreme discomfort &
disulfiram ethanol rx: VD, flushing, hotness,
cyanosis, tachyC, dyspnea, palpitations & throbbing
headache.
Disulfiram-induced symptoms render alcoholics
afraid from drinking alc.
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Chronic uses of alcohol induces liver enzymes
and increase metabolism of drugs such as
propranolol and warfarin etc
Acute alcohol us causes inhibition of liver
enzyme and incraeses toxicity of some drugs
such as bleeding with warfarin
Alcohol suppresses gluconeogenesis, which
may increase risk for hypoglycemia in diabetic
patients
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Increase in the risk of developing a major GI
bleed or an ulcer when NSAIDs are used with
alcohol
Increases hepatotoxicity when
Acetaminophen and alcohol used concurrently
(chronic use).
Alcohol increases the risk of respiratory and
CNS depression effects of narcotic drugs
(codeine and methahdone).
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