1 alcohol by: dr alia alshanawani dep of medical pharmacology, ksu
Post on 19-Dec-2015
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Today, alc is widely consumed
Alc, like other sedative/ hypnotic drugs, in low-moderate amounts relieves anxiety & fosters a feeling of well-being/ euphoria.
It is ! most commonly abused drug in ! world.
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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.
ORB- via microsomal ethanol oxidizing system2- Acetaldehyde is converted to acetate via AlDH, w
also reduce NAD+ to NADH. Acetate ultimately is converted to CO2 + water.
Mitochondrion
Peroxisome
Hepatic Cellular Processing
EtOH
Acetaldehyde
Acetate
CytosolER
ADHNAD+
NADH
CATH2O2
H2O
AlDHNAD+
NADH
MEOS
NADP+
NADPHO2
P450
Extra-hepatic tissue
Pyrazole
Disulfiram(antabuse)
Chlorpropamide(diabetes)
Aminotriazole
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Hepatic Ethanol Metabolism
ADHADH
Acetaldehyde
AcetateAcetyl CoA
Citric Acid Cycle
Fatty Acid synthesis
Energy
AlcoholAlcohol
NAD+ NADH
AlDHAlDH
NAD+
NADH
RATE-LIMITING STEPRATE-LIMITING STEP
Chronic intake→ induction of CYP2E1
Fatty liver
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• 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.
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• 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.
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• 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) &
- liver failure & death within 10 yrs.
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Hematological complication:Iron deficiency anemia; inadequate dietary
intake & GI bld lossHemolytic anemia; liver damageMegaloblastic 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.
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• 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).
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Control
• 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
• 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
Nucleus accumbens (NAC)
Ethanol interactions e NTs releaseEthanol interactions e NTs release
Ethanol ++
Ventral Tegmental Area (VTA)
Dopamine
Dopamine
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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.
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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.
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• 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).
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• 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.
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• 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 carcinogenesis.
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• Pancreatitis:
- Occur in heavy drinkers
- Presented as severe pain + elevated amylase & lipase
- Due to hyperlipidemia
- 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 syndromeis 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:
- 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.
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• 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.
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Acute Ethanol Intoxication• Supportive therapy till
metabolism clear body to low levels
Hypotension/hypovolumia → IV fluids
Artificial respiration
Hypoglycmia:IV gluc Coma: lavage,
naloxone
IntoxicationIntoxicationEthanol levelEthanol level
Mild signsMild signs<500 mg/L <500 mg/L (0.05%)(0.05%)
Frequent Psychomotor Impairment
≤ 1000 mg/L (0.1%)
Psychomotor Impairment in
everyone
1500 mg/L(0.15%)
Severe/ anesthe-sia & coma
2500 mg/L (0.25%)
Death (respiratory Death (respiratory depression)depression)
5000 mg/L 5000 mg/L (0.5%)(0.5%)
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• 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.
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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 inductionFunctional 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.
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Alcoholism withdrawalAlc Withdrawal occurs > 2/3 Alc Dependence patientsSymptoms: 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 Rshypoactivity of GABAergic Rs are possibly involved
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Alcoholism withdrawalChronic wks-months intake followed by stop leads to
two-stage severe withdrawal:Aforementioned symptoms after few hoursAfter ≥2 days delirium tremens”delirium tremens” stage starts fatal;
profuse sweating, delirium & hallucinations, intense VD, fever, severe tachyC
Possible causes: rebound ββ-adrenoceptor super-sensitivity-adrenoceptor super-sensitivity hyperactivity of neural adaptive mechanism
(neuroadaptation) no longer balance by ! inhibitory effect of alc & upregulation of NMDA Rs .
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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.
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! 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.
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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 causes respiratory depression & hypotension.
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• 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.
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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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