Alcohol and the brain

Objectives:Ø DescribethepharmacologicalactionsofalcoholØ DescribethepharmacokineticprofileofalcoholØ DescribethedevelopmentofintoxicationsymptomsofalcoholØ Describehowalcoholaffectsvariousneurotransmittersinthebrain.Ø IdentifyvarioustoxicityofalcoholsatdifferentorganslevelØ DescribetheaddictivenatureofalcoholanditsmechanismØ Identifyalcoholwithdrawalsymptomsandtheirmanagement.Ø IdentifyclinicallyrelevantdruginteractionswithalcoholØ Hazardsofalcoholinpregnancy

extrainformationandfurtherexplanation

important

doctorsnotes

Drugsnames

Mnemonics

Color index:

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ItisthemostcommonlyabuseddrugintheworldPh

armacok

inetics • Smalllipophilic(lipid soluble)molecule→ readilycrossesallbiologicalmembranes.

• Rapidly&completelyabsorbedfromGIT.

• Hashighvolumeofdistribution(distributedtoallbodytissues).→Volumeofdistribution=

Totalbodywater(0.5-0.7L/kg).“multicompartmentdistribution” (plasma+ESF+ICF)

• Crossesplacenta(can easilyreachthefetus)andexcretedinmilk.

Metab

olism

(ingastricm

ucosaan

dliver)

• Oxidationofethanol toacetaldehyde viaalcoholdehydrogenase (major) or2-CYT-p450(minor)(CYP-2E1).

• OxidationofAcetaldehydeisconvertedtoacetateviaaldehydedehydrogenase. whichalsoreducesNAD+toNADH.

• Acetate ultimatelyisconvertedtoCO2+water.

• Atlowethanolconcentration→minormetabolismbyMEOS(microsomalethanol-oxidizingsystem)mainlycyt-p450(CYP2E1).→Uponcontinuous(chronic)alcoholuse,thisenzymeisstimulatedandcontributesignificantlytoalcoholmetabolism&tolerance.

• Acutealcoholconsumptioninhibits CYP450especially 2E1 (liverenzyme)→↓metabolismofotherdrugstakenconcurrentlyas(warfarin,phenytoin).

• ChronicalcoholconsumptioninduceslivermicrosomalenzymeCYP4502E1,whichleadstosignificantincreasesinethanolmetabolism(Tolerance)&metabolismofotherdrugsaswarfarin(Druginteractions).

• Themicrosomalenzymeswilltaketheupperhandinmetabolismofalcoholinthiscase.

Alcoholmetabolism(major pathway)

CH3CH2OH(Ethanol) CH3CHO(Acetaldehyde)

CH3COOH(AceticAcid)Co2+water

NAD+ NADHNAD+

NADH

AlcoholdehydrogenaseOxidationreaction

Aldehyde(acetaldehyde)dehydrogenase

mitochondrialenzyme

Acetaldehydeinmoretoxicthanethanol

AlcoholMetabolism;90-98%metabolizedinliverDependsoncytosolicenzyme(alcoholdehydrogenase)

CH3CH2OH(ethanol)

Acetaldehyde

ER(EndoplasmicReticulum)

Mitochondrion

Acetate

Aldehydedehydrogenase

Extrahepatictissue

CYP450

Thesameeffectofalcoholdehydrogenase,

Convertalcoholacetaldehyde

cytosol

Alcoholdehydrogenase

Lowconc.alcoholintake Minorpathwaystartfunction

Prolongedalcohol

intake(eveniflowconc.)

Chronicalcoholabuse

Inductionofliver

enzymes

Toleranceisdeveloped

Upregulationofmicrosomalenzymes

Addiction(psychological

andphysiologicalsymptoms)

Hepaticcellularprocessingof(minor pathway)

O2NADPH

NADP+

NAD+*

NADH

NAD+

NADH

Dependsonthemicrosomalenzymes

Hepaticethanolmetabolism

Alcohol Acetaldehyde

AcetateAcetylCoA

NAD+ NADH NAD+

NADH

CitricAcidCycle

FattyAcidsynthesis

Energy

Fattyliver

Alcoholdehydrogenase

Alcoholdehydrogenase

*IfNAD+islowinthebody,thebodywillbedestroyedbythehugeamountoffreeradicals.

Nausea Vomiting

Dizziness Vasodilation

Headache Facialflushing

AldehydeDehydrogenasepolymorphism

Asianpopulations(includingChinese,Japanese,Taiwanese,Korean)havegeneticvariationinaldehydedehydrogenaseresultinginavariantalleleALDH2*2.Geneticvariationofalcoholmetabolism→WhichmeansthatacetaldehydecanNOTbeconvertedtoacetateduetoaldehydedehydrogenasedeficiency.Theymetabolizedalcoholatslower ratethanotherpopulations.Candevelop“Acuteacetaldehydetoxicity”afteralcoholintake→ithasabeneficialeffect→ThisStronglyprotectagainstalcohol-usedisordersandpreventthemfrombecomingalcoholic.*Polymorphismistheexistenceofonegeneindifferentforms.

Acuteacetaldehydetoxicityafteralcoholintakecharacterizedby:

Explanation:TheAsianpeoplewillhaveaccumulationofacetaldehydeSowhentheygetanotherdrinkofalcoholmoreacetaldehydewillbeformedsothefollowingcharacterswillstarttoappear(nausea,vomiting,…).Andthat’sonewaytotreatalcoholismpeopletoletthemstopdrinking(willbediscussedlater)

Excretion • Excretedunchanged inurine(2-8%).

• Excretedunchangedvialungs(basisforbreathalcoholtest). (usedasdrivingtest)• Rateofeliminationiszero-orderkinetic(notconcentration-dependent)i.e.rateof(amountof)eliminationisthesameatlowandhighconcentration.

Mecha

nism

ofa

ction

Acutealcoho

l • CNSdepressant.1. Enhancement theeffectofGABA(inhibitoryNeurotransmitter)

causingCNSdepression.2. Inhibitionofglutamateaction(excitatoryNeurotransmitter)causing

disruptioninmemory,consciousnessandalertness.

Chronic

alcoho

l • Up-regulation* ofNMDAreceptorsandvoltagesensitiveCachannelsleadingtoalcoholtoleranceandwithdrawalsymptomsincludestremor,exaggeratedresponseandseizures.Chronicmeanslowdosesinprolongedtime.

Acuteactio

nsofA

lcoh

ol

Mild

tom

oderateam

ount

v On CNS:• Relievesanxietyandeuphoria(feeling of well-being).• Inhigherdoses:Nystagmus,slurredspeech,impairedjudgmentand

ataxia.• Alittlebithigherdose:Sedation,hypnosisandlossofconsciousness.

v OnCVS:• Myocardialcontractilitydepression.• Vasodilatation dueto:

1. Vasomotorcenterdepression.2. DirectsmoothmusclerelaxationcausedbyAcetaldehyde.

Severa

mou

nts

• SevereCNS depression.• Nausea,vomitingandaspirationofvomitus.• Respiratorydepressionandacidosis.• CVSdepression.• Volumedepletion.• Hypotension.• Hypothermia.• comaanddeath.

Chronica

ctionsof

alcoho

l

• Tolerance, dependence, addiction and behavioral changes.• Liver: Hepaticcirrhosisandliverfailure.• CVS: hypertension(regardingepithelialcellsdamage),myocardial infarction.• CNS: cerebral degeneration, and peripheral neuropathy. Wernicke

encephalopathy or Korsakoff psychosis may occur. (explainedlaterinslide8)• GIT: irritation, inflammation, bleeding and nutritional deficiencies.• Endocrinesystem: gynecomastia(Enlargedbreastsinmen)and testicular atrophy.• hematology: hematological disorders, neoplasia.

*↑NMDAreceptorsamount→theybecomemoresensitive→begintobetoleranceandifthedrinkerdidn’t↑thedose→withdrawalsymptomswillstarttoappear

Organ/system Complications

Liver

v Themost commoncomplicationsincludes:1. Reductioningluconeogenesis.à Hypoglacemia2. AlcoholicFattyliver/Alcoholsteatosis.Reductionofgluconeogenesis

→accumulationofAcetylcoA→energyproductionfromalcoholratherthanfromfat→accumulationoffat→(fattyliver)

3. Hepatitis. jaundice,Ascites,bleeding,encephalopathy.(livermetabolismnotgoingproperly→accumulationammonia→enterbrain→encephalopathy)

4. Hepaticcirrhosis:jaundice,ascites,bleedingandencephalopathy.5. Irreversibleliverfailure.• AcetateconvertedtootherproductAcetylcoA“otherthanCO2+H2O”.Inover

drinking→depletionofNADwillbeinreducedform→allenzymesdependonNADwillnotwork→ThatleadtoaccumulationofAcetylcoA→convertedintofattyacid→depositioninliver→firststepinjuryhappeninliverondrinkingalcohol.

v Hypoglycemiaandketoacidosisduetoimpairedhepaticgluconeogenesisandexcessivelipolytic factorsespeciallyincreasedcortisolandgrowthhormone.

v Acetaldehyde ismoretoxicthanalcohol→causinginflammation andfatcellproliferationv AlcoholicLiverDisease:NormalLiverSteatosis(infiltrationoflivercellswithfat)

Steatohepatitis (inflammationoftheliverwithconcurrentfataccumulationinliver)Cirrhosis (achronicdiseaseofthelivermarkedbydegenerationofcells,inflammation,andfibrousthickeningoftissue)

v Fattyliver→inflammation→hepatitis→fibrosis“livernotfunctioning”→cirrhosis

GIT

v Gastritis,hemorrhagicesophagitis,ulcerdiseasesandpancreatitisduetodirecttoxicactiononepithelium.

v Diarrhea..v Deficiencyofvitamins.→decreasetheabsorptionintheintestine→duetodiarrheav Exacerbatesnutritionaldeficiencies.v Weightlossandmalnutrition.(duetomalabsorption)v Inheavydrinkers:increasedriskoforalandesophagealcancer

CVS

v Chronic alcoholabusecanleadtocardiomyopathy including:1. Cardiachypertrophy.2. Congestiveheartfailure.3. Arrhythmias duetoK+ andMg2+depletionas well as enhanced release of

catecholamine.4. Hypertensionduetoincreasedcalciumandsympatheticactivity alsobyproducing

substancesthatattackthevascularepithelialcells.• Alcoholisthemostcommoncauseofreversiblehypertension.

HealthyliverLiverinchronicalcoholicsNormalliver Fattyliver

Organ/system Complications

Hematology

1. Irondeficiencyanemia (microcyticanemia)duetoinadequatedietaryintakeandGITbloodloss.

2. Megaloblasticanemiaduetofolatedeficiency,malnutritionandimpairedfolateabsorption.

3. Hemolyticanemia.(Destructionofredbloodcells)4. Bonemarrowsuppression.5. Thrombocytopenia (suppressingplateletformationandprolongbleeding

time).6. Impairedproductionofvitamin-Kdependentclottingfactorsleadingto

prolongedprothrombintime.(Vit Kisanimportantprecursortoclotifthereweredeficiencythrombocytopeniawillhappen)

Endo

crine Hy

pogona

dism

Inwom

en ovariandysfunction,amenorrhea(abnormalabsenceofmenstruation) ,anovulation,hyperprolactinemia(highprolactin) associated withlowestrogen→infertility.

Inm

en

Gynecomastia,decreasedmuscleandbonemass,testicularatrophyandsexualimpotenceduetoinhibitionofluteinizinghormone(LH),decreasedintestosterone,estradiolandprogesterone.

Hypo

glycem

ia&

ketoacidosis duetoimpairedhepaticgluconeogenesis&excessivelipolytic factors,

especiallyincreasedcortisolandgrowthhormone.Ketoacidosiscan beseenin2conditioniftheglucoseis:- Low:alcoholismpatient(fattyliver)- High:diabeticpatient

CNS

1. Tolerance.2. Physiologicalandpsychologicaldependence.

• Physiologicaldependence:Changesinphysiologicalaction accordingtothesubstancethepatient’saddictedtoit.

• Psychologicaldependence:Nochangesinthephysiologybutthepersonjustwanttoshowoff.

3. Addiction:dopamine,serotoninandopioids areinvolved4. Neurologicaldisturbances.5. Wernicke-Korsakoff syndrome. Vitaminsdeficiency→A,D,B”B1”→Wernicke

encephalopathyorKorsakoff psychosismayoccur

Wernicke-Ko

rsakoffsyndrom

e Itisacombinedmanifestationof2disorders:

Wernicke'sencephalopathycharacterizedby:1. oculardisturbances2. unsteadygait3. changesinmentalstateasconfusion,

delirium ataxia, )ھذیان(

Korsakoff's psychosis:1. Impairedmemoryespecially

inelderly.2. Cognitiveandbehavioral

dysfunction.

Cause:thiamine(vitaminB1)deficiency(rarelyseenwithabsenceof alcoholism)dueto:

• inadequatenutritionalintake.• decreased uptakeofthiaminefromGIT.• decreased liverthiaminestores.

Treatedby:thiamine +dextrose-containingIVfluids. (becauseofdehydration).

Fetalalcoh

olsy

ndrome(FA

S)

v areagroupofconditionsthatcanoccurinapersonwhosemotherdrank alcohol during pregnancy.

v Problemsmayincludeanabnormalappearance,shortheight,lowbodyweight, smallheadsize,poorcoordination,lowintelligence,behaviorproblems,and problemswithhearing or seeing.

v Irreversible syndromev Ethanolrapidlycrossesplacentaandit’sprohibitedinallpregnancytrimesters.v Prenatalexposuretoalcoholcauses:

1. Intrauterinegrowthretardation(reductioninbodyweight)duetohypoxia.2. Congenitalmalformation(Teratogeniceffects)suchas:

• Microcephaly.(smallbrain)• Impairedfacialdevelopment.• Congenitalheartdefects.• Physicalandmentalretardation.

Alcoho

lismTo

lerance ChronicconsumptionofalcoholleadstotoleranceThatdevelopsdueto:

Metabolictolerance(pharmacokinetic)

Due toinduction (increase)oflivermicrosomalenzymes(e.g.CYP450)inchronicuse.

Functionaltolerance(Pharmaco-dynamic)

Changes inCNSsensitivityofreceptorstodopamineandGABAmainly.

Alcoho

lismwith

draw

al

symptom

sTheresymptomsresultfromhighsympatheticactivity&upregulationofthereceptors• Autonomichyperactivity &craving foralcohol• Vomiting,thirst• Profusesweating,severetachycardia• Vasodilatation,fever• Delirium,tremors,anxiety,agitation,insomnia(CNSeffectsandneed tobecontrolled)• transientvisual/auditoryillusions,violentbehavior,hallucinations.• Grandmalseizures (after7-48hours of alcoholcessation) Duetosuper-sensitivityofglutamate

receptors&hypo-activityofGABAreceptors arepossibly involved.

Man

agem

ento

falcoh

olismwith

draw

al Substitutingalcoholwithalong-actingsedativehypnoticdrug(depressantdrug)thentaperingthedose

Benzodiazepines

as(Chlordiazepoxide,diazepam)→longactingdrug.Orlorazepam thatispreferable (shorter durationofaction)

DoseofbenzodiazepinesshouldbecarefullyadjustedTo provideEfficacy:(IV/ po) &Managewithdrawal symptoms &preventirritability,insomnia,agitation&seizures. &avoidexcessive dose thatcausesrespiratorydepression&hypotension.

Fluoxetine • Serotonin reuptakeinhibitor(anti-depressantdrug).• Affectdopaminelevels.

Clonidine&Propranolol

Clonidine isa2agonistinhibits theactionofexaggeratedsympatheticactivity.

Acamprosate aweakNMDAreceptorantagonist&GABAactivator,reducepsychiccraving(reduceriskofrelapse)

Topreventalcoh

ol

relapse

Alcoho

land

druginteractions

Acutealcoholuse(largedose)

causesinhibitionoflivermicrosomal enzyme,decreasesmetabolismofsomedrugsandincreasestheirtoxicitiese.g.bleeding withwarfarin

Chronicalcoholuse(conti

nuous dose)

induces livermicrosomalenzymesandincreasesmetabolismofdrugssuchaswarfarin,propranolol andetc

other

• Acetaminophen +alcohol(chronicuse)=riskofhepatotoxicity.→duetoincreasedproductionoffreeradicalmetaboliteofacetaminophen→Highmetabolismofhighdosesofacetaminophen→highfreeradicals(resultfrommetabolismby microsomalenzymes)→hepatotoxicity

• NSAIDs +alcohol:IncreaseintheriskofdevelopingamajorGIbleedingoranulcer.Because NSAIDsmaycausesulcerandbleeding,sothecombinationincreasestheriskofulcer&bleeding

• Narcoticdrugs(codeine andmethahdone)+alcohol=riskofrespiratoryandCNSdepression

• Alcoholsuppressesgluconeogenesis,whichmayincreaseriskforhypoglycemiaindiabeticpatients.

.

Disulfiramtherapy:250mgdaily

.

Inhibitshepaticaldehydedehydrogenase

.

increasebloodlevelofacetaldehyde

Acetaldehydeproducesextremediscomfort,vomiting,diarrhea,flushing,hotness,cyanosis,tachycardia,dyspnea,palpitations&headache

Disulfiraminduced

symptomsrenderalcoholicsafraidfromdrinking

alcohol

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