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Alcohol and the brain
Objectives:Ø DescribethepharmacologicalactionsofalcoholØ DescribethepharmacokineticprofileofalcoholØ DescribethedevelopmentofintoxicationsymptomsofalcoholØ Describehowalcoholaffectsvariousneurotransmittersinthebrain.Ø IdentifyvarioustoxicityofalcoholsatdifferentorganslevelØ DescribetheaddictivenatureofalcoholanditsmechanismØ Identifyalcoholwithdrawalsymptomsandtheirmanagement.Ø IdentifyclinicallyrelevantdruginteractionswithalcoholØ Hazardsofalcoholinpregnancy
extrainformationandfurtherexplanation
important
doctorsnotes
Drugsnames
Mnemonics
Color index:
Kindlychecktheeditingfilebeforestudyingthisdocumenthttps://docs.google.com/presentation/d/1_-g1vol4eBWPet5xVCkuTGFvvnhFF3PJmU0tWtEEw_o/edit?usp=sharing
https://docs.google.com/presentation/d/1Z0Vf9oEOJSXo4JIA0mTCk5jB-OU9LP5TFCwz8iBgNac/edit?usp=sharing
Checkoutthemnemonicsfile:
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
:قادة فريق علم األدوية
عبدالرحمن ذكري &لي التميمي : الشكر موصول ألعضاء الفريق املتميزين
References:1- 436doctorsslides2-435teamwork
@pharma436
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