By: Dr Alia AlShanawaniDep of Medical Pharmacology, KSU

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May2011

Currently, alcohol (alc): is the most commonly abused drug in the world.

Alc in low-moderate amounts relieves anxiety & fosters a feeling of well-being/ euphoria.

Alc abuse & alcoholism cause severe detrimental health effects such as:

alcoholic liver & heart diseases, increased risk for stroke, chronic diarrhea & alc dementia.

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Alc: Ethyl alcohol (ethanol)

PK:water-soluble molecule, complete absorbed

from GIT Peak blood ethanol conc. after po doses: 30 -75

min, absorption is 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, which also reduce NAD+ to NADH. Acetate ultimately is converted to CO2 + water. 3

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Alc Metabolism; 90-98% metabolized in liver

ADH AlDH

CH3CH2OH CH3CHO CH3COOH

Ethanol Acetaldehyde Acetic Acid

Mitochondrion

Peroxisome

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EtOH

Acetaldehyde

Acetate

CytosolER

NADH

CATH2O2

H2O

AlDHNAD+

NADH

MEOS

NADP+

NADPHO2

P450

Extra-hepatic tissue

Pyrazole

Disulfiram(antabuse)

Chlorpropamide(diabetes)

Aminotriazole

Hepatic Ethanol Metabolism

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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

Healthy Liver vs Fatty Liver

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Chronic ethanol consumption induces cytochrome P450 2E1, which leads to ! generation of ROS & RNS + hypoxia.

Chronic ethanol use: NAD & of NADH by ! liver.

All 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. 8

Hyperlipidemia & fat deposition are common in chronic alc use bec of excess acetate & fatty acid (FA) synthesis + direct oxidation of ethanol for energy instead of using body fat stores.

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Effects of alc greatly depends on dose & frequency of use.

In order of increasing dose (or number of drinks), alc is anxiolytic mood-enhancing sedative slows reaction time produces motor incoordination impairs judgment (making it dangerous & illegal to drive a car).

At very high doses alc produces loss of consciousness.

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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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Alcoholic Liver DiseaseSteatosis

Steatohepatitis Cirrhosis

Normal

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Your Healthy Liver

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Liver on Alcohol

inhibition of NMDA (Glutamate) Rs &

activation of GABAA Rs in brain this will lead to:

- Sedative effect & CNS depression - Disruption in memory, consciousness,

alertness & learning by alc “Blackouts”.

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Alcohol effects on Central NTs

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, excess Ca can lead to cell toxicity & death

(Ca related brain damage).

2- This also contribute to alc tolerance & withdrawal symptoms (tremors, exaggerated response & seizures).

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Cont’ Alc effects on Central NTs:

Control

• Ethanol enhances DA release in ! “pharmacological reward” pathway

• Ethanol appears to release DA from ! VTA & NAC via interactions with 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 with multiple NT Rs

• Ethanol has direct excitatory actions on DA containing neurons in the VTA

Nucleus accumbens (NAC)

Ethanol interactions with NTs releaseEthanol interactions with NTs release

Ethanol ++

Ventral Tegmental Area (VTA)

Dopamine

Dopamine17

Alcohol as a Reinforcer: Neural Systems

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Activation of mesocorticolimbic system

Alcohol effects: Acute, DA in NAC

Chronic, DA in NAC tolerance

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

5-HT system modulates the DAergic activity of the VTA & the NAC.

-- 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. 20

AlcoholicControl

Alcoholic Cardiomyopathy

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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.

Coronary Heart Disease: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 (FAS): IRREVERIBLE

Ethanol rapidly crosses placentaPre-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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Fetal Alcohol Syndrome ( FAS ) Fetal Alcohol Syndrome ( FAS )

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Gastritis & ulcer diseases, Alc causes: - Malabsorption of water-soluble vitamins- 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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Hematological complication:Iron deficiency anemia; inadequate dietary

intake & GI bld lossHemolytic anemia; liver damageMegaloblastic anemia; folate deficiency in

chronic alcoholism,, malnutrition, impaired folate absorption, & hemolysis.

Thrombocytopenia & prolong bleeding times; suppressing platelet formation

Alc can diminish ! production of Vit-K dependent clotting factors; hepatotoxicity.

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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 & excutive dysfunction.

Tr: thiamine + dextrose-containing IV fluids. 29

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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Cont’ Acute ethanol intoxication:

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 with reduced CHs intake & malnourished alcoholics.

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Acute Ethanol IntoxicationSupportive 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%) 32

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. 33

Alcoholism Tolerance

! person must drink progressively > alc to obtain a given effect on brain function

Tolerance develops with steady alc intake via:Metabolic tolerance, hepatic enzyme inductionFunctional tolerance, change in CNS sensitivity

(Neuro-adaptation ) Faster alc absorptionTolerance 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 alcHand tremorInsomnia, anxiety, agitation N, V & thirst transient visual/ auditory illusionsGrand mal seizures (after 7-48 hr alc cessation) Rebound supersensitivity of glutamate Rs &

hypoactivity of GABAergic Rshypoactivity of GABAergic Rs are possibly involved. 35

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 Withdrawal symptoms depend upon severity,

rate & duration of preceding drinking period

In mild cases: hyperexcitabilityIn 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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Schematic representation of ! effects of alc exposure & withdrawal.

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! zero line represents ! excitability of ! brain.

Short-term alc 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 alc intake causes ! initial decrease with 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; inhibits enhanced sympathetic NT

release that occurs during withdrawal

- Propranolol; inhibit ! action of exaggerated sympathetic activity

- Naltrexone; po, an opioid antagonist, with 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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Alcohol & drug interactionsChronic uses of alc induces liver enz & increase

metabolism of drugs such as propranolol & warfarin etc

Acute alc use inhibits liver enz & incraeses toxicity of some drugs such as bleeding with warfarin

Alc suppresses gluconeogenesis, which may increase risk for hypoglycemia in diabetic patients.

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Cont’ Alc & drug interactionsIncrease in the risk of developing a major GI

bleed or ulcer when NSAIDs are used with alc

Increases hepatotoxicity when Acetaminophen & alc used concurrently (chronic use).

Alc increases the risk of respiratory & CNS depression effects of narcotic drugs (codeine & methadone).

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