Download Alcohol

Alcohol
By: Dr Alia Alshanawani
Dep of Medical Pharmacology, KSU
1
Today, alc is widely consumed
Alc, like other sedative/ hypnotic drugs, in lowmoderate amounts relieves anxiety & fosters a
feeling of well-being/ euphoria.
It is ! most commonly abused drug in ! world.
2
Alcohol:
- Ethyl alcohol (ethanol)
• PK:
Alc is a water-soluble molecule, complete absorbed
from GIT
Peak bld ethanol conc after po doses: 30 -75 min,
delayed by food.
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.
3
Hepatic Cellular Processing
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)
Hepatic Ethanol Metabolism
ADH
RATE-LIMITING STEP
Alcohol
Acetaldehyde
NAD+
NADH
Chronic intake→ induction of
CYP2E1
NAD+
AlDH
NADH
Acetyl CoA
Acetate
Citric Acid Cycle
5
Fatty Acid synthesis
Energy
Fatty liver
• Chronic ethanol consumption induces cytochrome
P450 2E1, w leads to ! generation of ROS & RNS +
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.
6
• Hyperlipidemia & fat deposition are common
in chronic alc use bec of excess acetate & FA
synthesis + direct oxidation of ethanol for
energy instead of using body fat stores.
7
• Medical complications of chronic alcoholism:
- Liver disease: ! most common medical
complication. Accumulated acetaldehyde:
hepatotoxicity.
- Fatty liver/ alcoholic steatosis (common,
reversible, hepatomegaly, slight elevation in
liver enz)
- Followed by: steatohepatitis (fat, inflammation,
& injury),
- then hepatic cirrhosis (jaundice, ascites,
bleeding & encephalopathy) &
- 8liver failure & death within 10 yrs.
Alcoholic Liver Disease
Steatosis
Normal
Steatohepatitis
9
Cirrhosis
Hematological complication:
Iron deficiency anemia; inadequate dietary
intake & GI bld loss
Hemolytic anemia; liver damage
Megaloblastic anemia; folate deficiency in
chronic alcoholism,, malnutrition, impaired
folate abs, & hemolysis.
Thrombocytopenia & prolong bleeding times;
suppressing platelet formation
Alc can diminish ! production of Vit-K
dependent clotting factors; hepatotoxicity.
10
• Alcohol effects on Central NTs:
Alc causes inhibition of NMDA (Glutamate) &
activation of GABAA Rs in brain this will lead to:
- Sedative effect & CNS depression
- Disruption in memory, consciousness, alertness &
learning by alc. “Blackouts”
Chronic use of alc leads to UP-REGULATION of
NMDA-Rs & voltage-sensitive Ca Ch ;;
1- increased NMDA activity significantly Ca influx to !
nerve cells, Ca excess can lead to cell tox & death.
(Ca related brain damage).
2- This also contribute to alc tolerance & withdrawal
symptoms (tremors, exaggerated response &
seizures).
11
Ethanol interactions e NTs release
•
Ethanol enhances 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
12
+
+
Dopamine
Cont’ NTs release:
Alc also increase release of:
-- DA: role in motivational behavior/
reinforcement, i.e. rewarding stimuli &
contribute to addiction
-- Serotonin: alc rewarding effects, tolerance &
withdrawal
-- Opioid peptides; feeling of euphoria &
increase ! rewarding effect of alc.
13
Cardiovascular:
- Chronic alc abuse can lead to alc cardiomyopathy
that leads to cardiac hypertrophy, lowered ejection
fraction, compromised ventricular contractility &
COP;; heart failure & degeneration.
- It is a type of dilated cardiomyopathy. Due to ! direct
toxic effects of alc on hrt muscle, ! hrt is unable to
pump bld efficiently, leading to hrt failure.
results from:
1- alterations in contractile functions of ! hrt
2- membrane disruption
3- up-regulation of voltage-dependent Ca2+ chs
4- function of mitochondia & sarcoplsmic reticulum
5- FA ethyl ester & oxidative damage.
14
Alcoholic Cardiomyopathy
Control
Alcoholic
15
• Arrhythmia: premature ventricular/ atrial
contractions, atrial & ventricular tachyC, atrial
fibrillation & flutter.
result from: cardiomyopathy, electrolyte
imbalance & conduction delays induced by alc
& its metabolites.
• CHD:
Moderate alc consumption: prevent CHD ( HDL)
Excess drinking is associated e higher mortality
risk from CHD.
• HTN: ( Ca & sympathetic activity).
16
• Fetal Alc Syndrome: IRREVERIBLE
• Ethanol rapidly crosses placenta
• Pre-natal exposure to alc causes:
- intrauterine growth retardation, congenital
malformation (wide-set eyes, microcephaly,
impaired facial development) & teratogenicity
-
fetal growth by inducing hypoxia.
- More severe cases include congenital hrt
defects & physical + mental retardation.
17
•
-
Gastritis & ulcer diseases, Alc 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
18
carcinogenesis.
• Pancreatitis:
- Occur in heavy drinkers
- Presented as severe pain + elevated amylase
& lipase
- Due to hyperlipidemia
- Tr: parenteral analgesics, hydration & nutrition.
19
• 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.
20
• 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.
21
• Acute ethanol intoxication:
- CNS depression: sedation, relief anxiety,
higher conc: slurred speech, ataxia, & impaired
judgment
- Resp depression leading to resp acidosis &
coma
- Death can occur from resp depression +
aspiration of vomitus.
22
• Significant depression of myocardial
contractility
• VD 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.
23
Acute Ethanol Intoxication
• Supportive therapy till
metabolism clear
body to low levels
 Hypotension/hypovol
umia → IV fluids
 Artificial respiration
Intoxication
Mild signs
Ethanol level
<500 mg/L
(0.05%)
≤ 1000 mg/L
(0.1%)
Frequent
Psychomotor
Impairment
 Hypoglycmia:IV gluc
Psychomotor
1500
 Coma: lavage,
Impairment in
mg/L(0.15%)
naloxone
everyone
Severe/ anesthe2500 mg/L
sia & coma
(0.25%)
Death (respiratory 5000 mg/L
24
depression)
(0.5%)
• Elevated acetaldehyde during ethanol intoxication
causes:
- N & headache
- Sensitivity rxs, VD & facial flushing
- Increase skin temperature,
- Lower BP
- Sensation of dry mouth & throat
- B.constriction & allergic-type rxs
- Euphoric effects that may reinforce alc consumption.
- Increase incidence of GI & upper airway cancers
- Liver cirrhosis.
25
Alcoholism Tolerance
• ! person must drink progressively > alc to
obtain a given effect on brain function
• Tolerance develops e steady alc 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, 5-HT, DA in brain reward & reinforcement.
26
Alcoholism withdrawal
Alc Withdrawal occurs > 2/3 Alc Dependence patients
Symptoms:
 Autonomic hyperactivity & craving for alc
 Hand tremor
 Insomnia, anxiety, agitation
 N, V & 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
27
Alcoholism withdrawal
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
VD, fever, severe tachyC
Possible causes:
 rebound β-adrenoceptor super-sensitivity
 hyperactivity of neural adaptive mechanism
(neuroadaptation) no longer balance by ! inhibitory
effect of alc & upregulation of NMDA Rs .
28
Alc withdrawal symptoms
In conclusion, degree of 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.
29
! zero line represents ! excitability of ! brain.
• Short-term alc intake produces a depression of !
inhibitory centers of ! cerebral cortex, w results
in ! initial symptoms of intoxication (euphoria,
exaggerated feelings of well-being, & loss of
self-control followed by sedation).
• Long-term alc intake causes ! initial decrease e
tolerance that occurs during continued exposure
to alc.
• Removal of alc causes a rebound stimulatory
effect, increasing excitability in ! nervous system.
30
Schematic representation of ! effects
of alc exposure & withdrawal.
31
Management of alcoholism withdrawal
- 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
32causes respiratory depression & hypotension.
• Cont’ Management:
- Clonidine; inh enhanced symp NT release
- Propranolol; inh ! action of exaggerated symp
activity
- Naltrexone; po, an opioid antagonist, e weak
partial agonist activity, reduce psychic craving
for alc in abstinent patients & reduce relapse
- Acamprosate; a weak NMDA-R antagonist &
GABA activator, reduce psychic craving.
33
• 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.
34