19

SalmaAdel

Hamza

AreejAlManaseer

❤ میكحلا میلعلا تنأ كنإ انتملع ام لاّإ انل ملع لا كناحبس

Alpha Adrenoceptor AntagonistsPharmacologicEffectsOfAlpha-ReceptorAntagonists:

1. miosis->alphareceptorsoftheiresmuscleareblocked2. nasalstuffiness(asifyouhavecommoncold)->alphareceptorsonnasal

mucosa

3. decreasesresistancetotheflowofurine(reduceurinaryurgency).*AslongasAlpha1receptorsareexpressedinthebaseofthebladderandtheprostate*Note:Alphablockersareusedforthetreatmentofurinaryretentionduetoprostatichyperplasialiketerazosin,doxazosin,prazosinandtomsulosin4.cardiovasculareffects:AlphareceptorantagonistsblockA1receptorsonvascularbeds—>Sothisremovesthesympathetictoneonthebloodvesselsandthiscausesvasodilation.🌸 vasodilation->↓peripheralvascularresistanceandbloodpressure.🌸 Preventthepressoreffectsofαagonists(byphentolamine)🌸 oftencauseorthostatichypotension(hypotensionwithin three minutes of standing when compared with blood pressure from the sitting or supine position)

è When you stand up your pressure goes down because A1 receptors on big veins on your legs are blocked —> this inactivates sympathetic reflex in legs —> blood pooling in legs —> decreasing the central blood volume —> less blood going to the brain causing dizziness and faintness

🌸 reflextachycardia;nonselective(α1=α2,)blockerscausetachycardiaifbloodpressureisloweredbelownormal.

:سكوبلا داھ اوأرقت مھم اھانللظ ةملك انلدع ١٠ ةحفص )１

اھوفوش رفصلأاب نیدیكأ شم ةربلإا مسا ٦ ةحفص )２

حضاو ناك ام روتكدلا ملاك ،ھنم (: ،،ریتك

*remember:nonselectivealphablockers—>blockalpha-1andalpha-2equally Effectsofselective&NonselectivealphablockersonHR

Prazosin(A1selective)blocksA1onbloodvessels->decreasesperipheralresistance:1)decreasebloodpressure2)evokesbaroreceptorsocardiovascularcenteractivatessympatheticnervetotheheart(theaimisproducingtachycardiainordertomaintainhomeostasisinthebody)But:InTheheartweseealittlebaroreceptorresponsebecausewhennorepinephrineisreleasedinexcess(duetotheincreasedsympathetictonetotheheart)itstimulatespresynapticalpha-2receptorsthatmaintainnegativefeedbackofreleasingNE,sonotachycardia.

Whilephentolamine(notselective):1) Blockingalphaonereceptorsdecreasestheperipheralresistanceand

evokesbaroreceptorssocardiovascularcenteractivatessympatheticnervestotheheart(excessnorepinephrine)

2) Butalpha-2receptorsareblockednowsononegativefeedbackforreleasingnorepinephrinewhichcausestachycardiasonotusefulforpatientswithhypertension.

Nowlet’sdiscuss:

Nonselectivealphablockers:Phenoxybenzamine,PhentolamineSelectiveα1blockers:Terazosin,Doxazosin,Prazosin,TamsulosinSelectiveα2blockers:Yohimbine

🐼 🐼 Nonselectivealphablockers:

1) Phenoxybenzamine:relatedtonitrogenmustard(mustardgas)**Blocksα1&tolessextentα2receptors**Bindscovalentlytoαreceptors,causingirreversibleblockadeoflongduration(14–48h)**InhibitsreuptakeofNEandblockshistamine(H1),ACh,andserotoninreceptors**CauseslittlefallinBPinnormalsupineindividuals,itreducesBPwhensympathetictoneishigh,e.g.,asaresultofuprightposture.

ھطغض لزنی حر ام صخشلا فقوی امل يلاتلاب ءاودلا داھ ببسب ضفخنم اسًاسأ مدلا طض نوكب ءاقلتسلاا ةلاح يفhypotensionorthostatic :هدنع ریصی حر ام ينعی ،ةأجف

**Absorbedpoorlybutusuallygivenorally.preoperativetocontrolhypertension**Uses:treatmentof:1)inoperableormetastaticpheochromocytoma,2)peripheralvasculardiseases

🌸 palpitationscanbefeltbythepatientasstrongheartbeat,buthecannotfeeltachycardia**Adverseeffects:

1)orthostatichypotension(mostcommon),3)tachycardia,4)nasalstuffiness,4)inhibitionofejaculation.

GermansuseditntheFirstWorldWarasifit'sgivenitchangesinthebodybloodandthenthenewformofit activelybindstoalphareceptorsthen:…

Pheochromocytoma is a tumor that usually starts in the cells of one of adrenal glands(chromophil cells: that produce NE and EPN), often cause the adrenal gland to make too many hormones. This can lead to: intermittent or sustained hypertension (vasoconstriction), headaches, palpitations & increased sweating

Peripheralvasculardisease=Raynaud'sphenomenon(excessivereversiblevasospasmintheperipheralcirculation).Duetovasoconstrictionofthearteriolesandarteriesofthehandsandfeetcausingpain,paleandcoldfingersPrazosinorphenoxybenzamineareusedbutcalciumchannelblockersarepreferableformostpatients

🌸 note that in inoperable or metastatic pheochromocytoma we also use Metyrosine (α -methyltyrosine) a competitive inhibitor of tyrosine hydroxylase (the rate limiting step in chatecolamines synthesis)Which decrease the releasing of EPN, NE from the tumer, but metyrosine decreases the releasing of dopamine also, and that can cause extrapyramidal effects (like parkinson disease) due to reduced dopamine levels

2) Phentolamine:

**Competitiveα1andα2antagonist.**Rapidlyactingαblockerwithshortdurationt½19min.**Reducesperipheralresistance(α1)andcausescardiacstimulation(α2receptorsblockadeenhancesreleaseofNE).**Minorinhibitoryeffectsat5HTreceptors (5-HT receptors = 5-hydroxytryptamine receptors, or serotonin receptors)

**Agonisteffectsatmuscarinicreceptors(salivary,sweat,lacrimal)andH1andH2receptorsinthestomach(Increaseacidsecretion). **Uses:Tocounteractvasoconstrictionduetoalphaagonists(Treatmentofoverdoseofα1agonist)+counteracthypertension:

1)Cheesereaction(+monoamineoxidaseinhibitors)->hypertnsion

2)Controlofhypertensionduetoclonidinewithdrawal(alpha-2receptoragonist->usingforalongtimecausesdepressioninsympatheticactivity),3)Diagnosticofpheochromocytoma:

:ھمھفی بحب ادح ازا سب ،حیضوت نودب قوف يللا رطسلا ركذ طقف روتكدلا��An acute attack of hypertension that can occur in a person taking a monoamine oxidase inhibitor (MAOI) drug who eats cheese, caused by an interaction of the MAOI with tyramine, formed in ripe cheese when bacteria provide an enzyme that reacts with the amino acid tyrosine in the cheese.

DuetothehighamountofcirculatingEPN,NE->patientswillhavesymptomsofhypertension,anxiety,arrhythmia..->it’sdifficulttodeterminethecauseofhypertensionaccordingtothesecommonsymptomssoweusephentolamine:

**Adverseeffects:severetachycardia,arrhythmias,andmyocardialischemia.Duetothepowerfulstimulationoftheheart.🐼 🐼 Selectiveα1blockers:1) Terazosin:

Highbioavailability.Thehalf-lifeis9–12hours.Reducesurinaryurgencyandimprovesurineflow

2) Doxazosin:Hasalongerhalf-lifeofabout22hours,apreferreddrug

accordingtoitslonghalflife,onedoseadayisenoughReducesurinaryurgencyandimprovesurineflow

3) Prazosin:

**Highlyselectiveα1blocker&lesspotentatα2receptors.**Relaxesbotharterialandvenousvascularsmoothmuscle&smoothmuscleintheprostate,duetoblockadeofα1receptorswithnoorlittletachycardia

**Extensivelymetabolized,only50%isavailableafteroraladministration.Thehalf-lifeis3hours.->shortactingdrug

**Favorableeffectonplasmalipids:increaseHDL/LDLratiowhichisgoodforhealth,whilebetablockersdotheoppositeHigh/Lowdensitylipoproteins**UsedasAntihypertensive(butnotverypopular,notrecommendedasmonotherapy,otherantihypertensiveagentsaremorepreferredbecausetheyprovideprotectionagainstheartfailure)

Remember:inpheochromocytomahypertensionhappensduetoalpha-1receptorsstimulation,soifyougivethepatient(phentolaminewithmesylate Injection),alphareceptorswillbeblockedandimmediatelyyouwillseedecreasingofhypertension,thisconfirmedthatthehypertensionwascausedbypheochromocytoma

**Usedinbenignprostatichyperplasia(BPH)commoninelderlymen:Blocksα1inbladdertrigone&prostate->reducedcontractionofsmoothmuscleinthebladderneckandprostaticcapsule->ReducesurinaryurgencyandImprovesurineflow.

**UsedintreatingPeripheralVascularDisease**Adverseeffects:Firstdosephenomenoni.e.posturalhypotensionwithinitialdoses->takingthefirstdosemakespatientsfeeldizzybecauseofthebloodpoolingtothelegs->sotheytakethefirstdose(alsothefirsttimeafterincreasingthedose)beforegoingtothebed

اومانی ام لبق ءاودلا اودخایب مھطغض لزنی ام ناشع ينعی

4) Tamsulosin:**Uroselectiveα1Ablocker.α1Aarepredominantinbladderbase&prostatesoitreducesurinaryurgencyandimprovesurineflow.preferredinpatientswhohaveorthostatichypotensionwithotherα1-receptorantagonists.

ناك ازا نكلو parazosinordoxazosinorterazosin مھیطعب ObstructionUrinary مھدنعلا ىضرملا ينعی tamsulosin مھیطعأ مزلا اھتعاس ،يبناج رثأك hypotensionorthostatic مھلببسب

🌸 uroselectivemeansthatit’seffectonprostateandbladderbaseishigherthanitsaffectonbloodvessel🌸 remember:alpha1receptorsubtypesare:Alpha1A,Alpha1B,Alpha1DWhile:alpha2receptorsubtypesare:Alpha2A,Alpha2B,Alpha2C**30timeshighaffinityforα1A**Highbioavailabilityandahalf-lifeof9–15hours.**ItisusedtotreatBPH.**NoeffectonBPandheartrate.**SideEffects:Dizziness&retrogradeejaculation(ejaculationintothebladder)NotethatnowwehavefourdrugsthatReduceurinaryurgencyandimproveurineflow:terazosin,doxazosin,prazosinandtamsulosin

🐼 🐼 Selectiveα2blockers:Yohimbine:

**Anindolealkaloid**Blocksotherreceptorsalso–5HT,DA5HT= 5-hydroxytryptamine receptors, or serotonin receptorsDA=dopaminereceptors**IncreasesADHrelease**Enhancessexualactivity–aphrodisiacWaswidelyusedtoimprovemaleerectiledysfunctionbuthasbeensupersededbyphosphodiesterase-5inhibitorslikesildenafil(viagra).**SometimesusedinthetreatmentoforthostatichypotensionbecauseitpromotesNEreleasethroughblockadeofpresynapticα2receptors.

β-AdrenoceptorAntagonists(lol)🌸 Firstgeneration:nonselective(β1andβ2)🌸 Secondgeneration:Cardioselective(β1)🌸 Thirdgeneration:Vasodilatorβblockers:additionaleffect->directlydilatebloodvesseleitherbyblockingalsoalphareceptors,orbyreleasingnitricoxidewhichisavasodilator.Theselectivityisdose-related;ittendstodiminishathigherdrugconcentrations.Othermajordifferencesrelatetotheir:🦜 localanesthetic(membrane-stabilizing)effects.However,theconcentrationinplasmawhentakingthedrugistoolowfortheanestheticeffects🦜 lipidsolubility

è Lipidsolubledrugshaveshorterhalflifethanwatersolubledrags.

ةحفص ١١ تیش اتیملاب هاندخأ يشإب طقف ریكذتلل( ةمھم ریتك شم ةظحلام��١٩( :

Howdoesviagrawork?ItinhibitsthephosphodiesteraseleadingtocGMPelevationandformusclerelaxation

Thefirstbetareceptorantagonistwassynthesizedinearly60slate50s

Mostdrugsarewellabsorbedafteroraladministration;peakconcentrations1–3hoursafteringestion.

•Lipophilicβblockers–readilyabsorbedfromGI,metabolizedinliver–largevolumeofdistribution,andpenetrateBBBwellreachingthebrainandhavingcentraleffectsorcentralsideeffects–hepaticfailureprolongstheirt1/2.🦜 metoprolol,🦜 oxprenolol,🦜 carevdilol,🦜 timolol:nolocalanestheticactivityusedtopicallytotreatglaucoma,nonselective🦜 propranolol:Prototype,nonselective,highlipidsolubledrug*Haslowanddose-dependentbioavailability(first-passmetabolism)->bioavailabilityimproveswithtime*First-passeffectvariesamongindividuals:sowestartwithaverylowdosethenincreaseitaccordingtothepatientresponse*Along-actingformofpropranololisavailable;prolongedabsorptionofthedrugmayoccurovera24-hourperiod.*NoeffectonαandMreceptorsbutmayblocksomeserotoninreceptorsinthebrain,thoughtheclinicalsignificanceisunclear.*Ithasnopartialagonistactionatβreceptors.•Hydrophilicβblockers–lessreadilyabsorbed,notextensivelymetabolized–longplasmahalf-liveswhichareprolongedinrenalfailure.🦜 acebutolol,🦜 atenolol,🦜 bisoprolol,🦜 nadolol:Hasaverylongdurationofaction,nonselective🦜 sotalol:exhibitsClassIIIantiarrhythmicproperties,Isacalciumchannelblocker,nonselective

1)EffectsontheCardiovascularSystem(propranolol)Veryvaluablein:hypertension,anginaandchronicheartfailureandfollowingmyocardialinfarction(MI).1)byblockingB1it:*decreasesheartrate,*decreasescontractility,*decreasescardiacoutputsodecreasesbloodpressure🌸 becauseofdecreasingHRtherewillbeareflexperipheralvasoconstrictionbyactivatingA1receptors(tomaintainhomeostasis)->whichcausevascularsmoothmusclecontraction->increasingperipheralresistanceandincreasingBPSubsequentlyBPwillremainconstant.🌸 aftercontinuoustreatment.:↓BPbothdiastolicandsystolicIfthepatientcontinuototakebetablockersforlongtime,peripheralresistancewilldecreasecausinglowBP

è Sobetablockersareeffectiveintreatinghypertention🌸 DonotcausehypotensioninhealthyindividualswithnormalBP.🌸 Heart:↓HR,↓SV(strokevolume),↓COP(cardiacoutput),↓AV(atrioventrecular)conduction,↓cardiacwork&O2consumption->thisisthebaseinusingbetablockersforanginaandischemicheartdisease2)byblockingB2:*bronchoconstriction(unusefulforbronchialasthmapatients)*vasoconstriction🌸 Nonselectiveandβ1-block→Inhibitrenin.Also,aninverseagonist(↓restingHeartRate)Inverseagonist:shiftsthereceptorformatintoitsactiveformat

CardioselectiveβBlockers(β1-selectiveantagonists)

*lesseffectsonbronchioles,carbohydratemetabolism,lipids->somorepreferredthannonselectivebetablockers

*LowerincidencesofColdhandsandfeet(whilenonselectivebetablockersblockvasodilatorbetareceptorinskeletalmusclesbloodvessels->cold)*Lessliabletoimpairexercisetolerancebecauseduringexerciseyouneedbeta-2receptorstobeactive->vasodilation->moreoxygentothemuscles*Saferinpatientswhoexperiencebronchoconstrictioninresponsetopropranolol,buttheirβ1selectivityismodest,sotheyshouldbeusedwithgreatcautioninpatientswithasthma.*Beta1-selectiveantagonistsarepreferredinpatientswithdiabetesorperipheralvasculardiseasesinceβ2receptorsareimportantinliver(recoveryfromhypoglycemiawhichdependsongluconeogenesisthatisblockedbybeta2receptorblockade)andbloodvessels(vasodilation)

2)EffectsontheRespiratoryTract

🌸 Increaseinairwayresistance,particularlyinpatientswithasthma->blockadeofbeta2.🌸 β1blockersaresaferthannonselectiveβblockers.🌸 β1-selectiveblockerarenotsufficientlyspecifictocompletelyavoidinteractionswithβ2receptors->it’sdosedependentConsequently,thesedrugsshouldgenerallybeavoidedinpatientswithasthma.Manypatientswithchronicobstructivepulmonarydiseasemaytoleratethesedrugs&thebenefitsmayoutweighorexceedtherisks.e.g.,inpatientswithmyocardialinfarction.e.g.inpatientswithconcomitantischemicheartdisease,angina

3)EffectsontheEye

Reduceintraocularpressureinglaucomabydecreasingaqueoushumorproduction.Glaucomaistreatedby:1-reductionofaqueoushumorsecretion.2-enhancementofaqueousout-flow.

Drugsusefulinreducingintraocularpressure:Cholinomimetics,αagonists,diuretics,βblockers,prostaglandinF2analogsProstaglandinanalogs&βblockersarethemostpopular

4)MetabolicandEndocrineEffects

🌸 Beta-receptorantagonistsincreasesLDL,triglycerides,↓HDLbyinhibitinglipolysis.—>whichisnotgoodforthebody🌸 β–blockersshouldbeusedwithcautionininsulin-dependentdiabeticpatients,fortowreasons:1)βblockersdelayrecoveryfromhypoglycemiaduetoinsulinandoralantidiabetics:Glycogenolysisintheliverisinhibitedafterβ2-receptorblockade.2)maskearlysymptomsofhypoglycemia(tremors,sweating&tachycardia).

انك ام بونذ نع انلغش نوكی ام لاإ سب ،�� انتقوب اھلمعن بحن انك ةولح تلاغش ریتك انم دخأ لصفلاھ طغض زوجب �� نییضاف انك امل اھكرتن نیرداق

��❤ مكیلع حتفی اللهThat’sit.Goodluck

Inpheochromocytomaweusebothphenoxybenzamin(whichprotectagainsthepertention)andbetablockers(protectagainstexcessivecardiacstimulation).ButphenoxybenzamineshouldbethefisrtonetousebecauseweneedtoestablishtheblockadebeforegivngthebetablockerBeta-receptorantagonistsusedtoreversethecardiaceffects.Shouldnotbeusedpriortoestablishingeffectiveα-receptorblockadeBlockingbeta2receptorsinthebloodvesselsinskeletalmusclescausesvasoconstrictionandhypertensionsowegivethepatientphenoxybenzaminetomakesurewedecreasetheBP,thenwegivebetablockerstoprotecttheheart❤

InHypertensiveEmergencies:Labetalol(αandβblocker)isused