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By: Dr Alia AlshanawaniDr. Ishfaq A. Bukhari

Dep of Medical Pharmacology, KSU

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. 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.3

Acetaldehyde in more toxic than ethanol

ADH ALDH

CH3CH2OH CH3CHOCH3COOH Ethanol Acetaldehyde

Acetic Acid

Mitochondrion

PeroxisomeEtOH

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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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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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 .

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. 9

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 mood-enhancing 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:

- Liver disease: ! most common medical complication. Accumulated acetaldehyde: hepatotoxicity.

- 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

SteatohepatitisCirrhosis

Normal

@AMSP 2010 14

@AMSP 2010 15

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:

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 UP-REGULATION of NMDA-Rs & voltage-sensitive 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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Control

• 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

• 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

Nucleus accumbens (NAC)

Ethanol interactions e NTs releaseEthanol interactions e NTs release

Ethanol ++

Ventral Tegmental Area (VTA)

Dopamine

Dopamine

Activation of mesocorticolimbic system

Alcohol effects: Acute, DA in NAC

Chronic, DA in NAC tolerance

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. 22

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AlcoholicControl

Alcoholic Cardiomyopathy

Cardiovascular:

Arrhythmia: premature ventricular/ atrial contractions, atrial & ventricular tachycardia, atrial fibrillation & flutter.

result from: cardiomyopathy, electrolyte imbalance & conduction delays induced by alc & its metabolites.

CHD:Moderate alcohol consumption: prevent CHD

( HDL)Excess drinking is associated e higher mortality

risk from CHD. HTN: ( Ca & sympathetic activity). 24

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

- fetal growth by inducing hypoxia.

- More severe cases include congenital heart defects & physical + mental retardation.

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Fetal Alcohol Syndrome ( FAS ) 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:

- 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

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/hypovolumia → IV fluids

Artificial respiration

Hypoglycmia:IV gluc

Coma: lavage, naloxone (opioid antagonist)

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%) 33

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,

5-HT, 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 Rshypoactivity 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”delirium tremens” stage

starts fatal; profuse sweating, delirium & hallucinations, intense Vasodilation, fever, severe tachycardia

Possible causes: rebound ββ-adrenoceptor super-sensitivity-adrenoceptor super-sensitivity hyperactivity of neural adaptive mechanism

(neuroadaptation) no longer balance by ! inhibitory effect of alcohol & upregulation of NMDA Rs . 37

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.

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

- Propranolol; inhibits ! action of exaggerated symp activity

- Naltrexone; po, an opioid antagonist, e weak partial agonist activity, reduce psychic craving for alcohol in abstinent patients & reduce relapse

- 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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