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Alcohol

By: Dr Alia AlshanawaniDep of Medical Pharmacology, KSU

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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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Alcoholic Liver DiseaseSteatosis

Steatohepatitis Cirrhosis

Normal

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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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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.

• 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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Schematic representation of ! effects of alc exposure & withdrawal.

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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.