SIMPATOMIMETIKASIMPATOLITIKJazanul Anwar_Hasanul ArifinDepartemen Farmakologi & Terapeutik Fakultas Kedokteran USU2009

SIMPATOMIMETIKA

syaraf pasca ganglionneurotransmitersintesapenimbunanpenglepasanperombakanreseptorperangsanganperangsanganSimpatomimetikaperangsangan

TYROSINE _METYLDOPA_> NA ___ NAAdrenalin COMTMAO

Adrenergik dan Penghambat AdrenergikNENENEDDDDDreseptorSimpatomimetik yang bekerja langsung/NENENENENEDDreseptorNENENEDNEDDreseptorABCSimpatomimetik yang bekerja tidak langsungSimpatomimetik yang bekerja campuranD : obat simpatomimetikE/NEamfetamine

Simpatomimetika langsungSimpatomimetika tak langsung

SIMPATOMIMETIKA (KIMIAWI)Endogen:adrenalinnoradrenalindopaminNonendogen:

1-adrenergik : phenylephrine, methoxamin 2-adrenergik : clonidine, oxymetazoline-adrenergik : adrenalin -adrenergik : isoprenaline1-adrenergik : dobutamine2-adrenergik : terbutaline, procaterolDopamin (D) : dopaminD1 : fenoldopamD2 : bromocriptinCATECHOLAMINENONCATECHOLAMINE : amfetamin, metamfetamin

1 Agonists

MethoxaminePenylpropranolaminePhenylephrineMephentermineMetaraminolMitodrine

1 Agonists Response utama & kegunaan klinikMethoxamine: i.v. hipotensi es paroxysmal takhikardiPhenylephrine: | vasokonstriksi nasal decongestantPhenylpropranolamine: vasokonstriksi nasaldecongestantMephentermine: direk & indirek, i.m. MetaraminolMitodrineResistens vaskuler perifer naik

1 AgonistsKontraindikasiHypertension Ischemic organ diseasesPembesaran Prostrat Pemberian bersama dg obat-obat jg menambah kadar NAMAO inhibitorssympathomimetika tak langsung

2 AgonistsPrototypeClonidineBrimonidine

2 Agonists Response utama & tempat kerjaResponseVasodilatasiProduksi cairan mata berkurangTempat kerjaPeripheralPrejunctional: mengurangi penglepasan NASome postjunctional sites (eye, pancreas, platelets)

SSP: mengurangi sympathetic outflow

2 Agonists Kegunaan klinikAntihypertensives

Menurunkan tekanan intraocular glaucoma sudut terbuka

2 AgonistsCara pemberianOral

Transdermal

Topical (to eye)

2 AgonistsEfek sampingBradycardia(kelambatan denyut jantung)SSP (50% of population) sedasi mulut keringDisfungsi Sexual

1 AgonistsPrototype Dobutamine

Response utama - KardiostimulasiKegunaan klinikGagal jantungShock CardiogenicEfek tak diinginkanArrythmias(variasi irama normal denyut jantung, meliputi kelainan frekuensi,regularitas,lokasi asal impuls)

2 AgonistsPrototypesAlbuterolSalbutamolSalmeterolRitodrine

2 Agonists ResponsesBronchodilationAlbuterolSalbutamolSalmeterol Terbutalin

Uterine dilationRitodrine

2 AgonistsClinical usesBronchodilatasiAsthmaCOPD

Tocolytic agents Late term gestation

2 AgonistsEfek tak diinginkanSymptoms stimulasi 1 TachycardiaWidening pulse pressure (systolic pressure rise)Symptoms of 2 stimulationWidening pulse pressure (diastolic pressure drop)Drop in serum K+ (skeletal muscle uptake)Skeletal muscle tremor

2 AgonistsAdverse Effects (Cont.)CNSAnxietyRestlessnessApprehension

Tolerance to bronchodilationWithout tolerance to adverse effect such as tachycardia.

2 AgonistsContraindicationsCardiac diseaseCoronary artery diseaseArrhythmiasDiabetesHyperthyroidismCo-administration MAO inhibitorsIndirect-acting sympathomimetics

Obat-obat adrenergik /simpatomimetik

AdrenergikReseptorPemakaian dalam klinikEpinefrin (Adrenalin)1, 1, 2Anafilaktik syok, asma akut, henti jantungEfedrin1, 1, 2Hipotensi, bronkospasme, kongesti hidungNE 1, 1Syok vasokonstriktor kuatPseudoefedrin1, 1DekongestanFenilefrin1DekongestanFenilpropanolamin (PPA)1, 1DekongestanDopamin1HipotensiIsoproterenol1, 2Payah jantung kongestif aliran darah miokardium dan curah jantungMetaproterenol1, 2Bronkospasme, blok jantung akutAlbuterol2BronkospasmeTerbutalin2Relaksasi uterus

SIMPATOLITIKA

syaraf pasca ganglionneurotransmitersintesapenimbunanpenglepasanperombakanreseptorperangsanganpenghambatan perangsanganpenghambatanSimpatomimetikaSimpatolitikaperangsanganpenghambatanpenghambatan penghambatanpenghambatan

PENGHAMBAT SINTESABlokade penimbunanBLOKADE PENGLEPASANBLOKADE RESEPTOR

NT inhibition On presynaptic endingDrug affecting NT synthesisDrug affecting NT storageDrug affecting NT release

On postsynaptic endingDrug affecting parasympathetic receptorsDrug affecting sympathetic receptors

SIMPATOLITIKAPRASINAPSPASCASINAPSPENGHAMBAT SINTESA-METHYL DOPABLOKADE PENIMBUNANRESERPINEPENGHAMBAT PENGLEPASAN NAGUANETHIDINEBLOKADE RESEPTOR BLOKADE RESEPTOR

BLOKADE PENYIMPANAN NA RESERPINE (RAUWOLFIA SERPENTINE)KEGUNAAN KLINIK: HIPERTENSIEFEK SAMPING: ssp- DEPRESI SEDASI PERIFERI NASAL CONGESTIPENGHAMBAT PENGLEPASAN NAGUANETHIDINE

Selectivity of AntagonistsSelective antagonistsNonselective (1/2) antagonistsSelective 1 antagonistsUroselective 1A antagonistsSelective antagonistsNonselective (2) antagonistsSelective 1 antagonists

Nonselective adrenergic ( antagonists

Nonselective AntagonistsClinical Uses: LimitedPheochromocytomaBenign prostatic obstruction(Phenoxybenzamine)Autonomic hyperreflexiaAdverse EffectsMigraine headache(Ergot alkaloids)CardiovascularTachycardia (reflex)Orthostatic hypotentionNasal congestionNon cardiovascularGI (Phentolamine)Impotence (Phenoxybenzamine)Potential mutagen (Phenoxybenzamine)

Selective 1 AntagonistsAdvantage over non-selective agentslack 2 componentless prejunctional control (less reflex tachycardia)

less CNS component of actionUses HypertensionCongestive heart failureBenign prostatic hyperplasiaPrazosin (BID dosage)Doxazosin &Terazosin (QD dosage)Pheochromocytoma

Selective 1 AntagonistsAdverse EffectsOrthostatic hypotensionUsually becomes toleratedGive first dose at nightNasal congestion

Uroselective 1A AntagonistTamsulosinQD dosageClinical UseBenign Prostatic HyperplasiaAdverse EffectsRetrograde ejaculationNOTE: Avoids orthostatic hypotension in most

Selective 2 AntagonistsYohimbineApparent Mechanism of Actionmajor mechanism of action appears to be increasing sympathetic outflow from CNSClinical Uses - (limited):ImpotencyDiabetic neuropathy painOrthostatic hypotension

AntagonistsIn hypertensive (hyperkinetic heart-induced)Decrease blood pressureIn heart failureDecrease heart work & protect against arrythmiasAsthma or other bronchospasmcause bronchoconstrictionDiabetesmask symptoms of insulin-induced hypoglycemiaaugment insulin-induced hypoglycemia

AntagonistsPrototype - PropranololPure antagonist, no Intrinsic Sympathomimetic Activity(ISA) (i.e. not a partial agonist)

Nonselective to subtypes

High lipid solubility - Enters gut & CNS

High first pass metabolism - causing low bioavailability

Has membrane-stabilizing activityQuinidine-like effects, Na+ channel blockade, (local anesthetic)

AntagonistsNonselectivePropranolol

Nadolol: long half-life

Timolol: use in glaucoma

Pindolol: ISA

Selective1 Metoprolol

Atenolol: limited entry

Esmolol: short half-life

Acebutolol: ISA

Bisoprolol

Uses of AntagonistsCardiovascularHypertensionAnginaArrhythmiasMyocardial infarctionHeart failureCV Symptoms ofHyperthyroidism PheochromocytomaAortic aneurysmMigraine headacheNon-cardiovascularGlaucoma

Somatic symptoms of anxiety (e.g. stage fright)

Fine muscle tremors

Nonselective Adrenergic AntagonistsLabetalol: and 1 antagonist Partial 2 agonistCarvedilol and 1 antagonistAntioxidantAnti-ischemic agentRecent report supports it improves cardiac performance > than metoprolol in chronic heart failure

AntagonistsAdverse EffectsCardiovascularInduce CHF or bradycardial arrhythmiaSudden withdrawal - in anginal patients may cause sudden death (due to receptor supersensitivity)

Bronchospasm

CNS - sleep disturbance, depression

Lacking recognition of hypoglycemia

Penghambat Adrenergik / Simpatolitik

Penghambat AdrenergikReseptorPemakaian dalam klinikTolazolinHipertensiFentolaminHipertensiPrazosinHipertensiPropanolol 1, 2Hipertensi, aritmia, angina pectoris, pasca infark miokardiumNadolol1, 2Hipertensi, anginaPindolol1, 2 HipertensiTimolol1, 2 Hipertensi, pasca infark miokardiumMetoprolol1Hipertensi, angina, pasca infark miokardiumAtenolol 1Hipertensi, anginaAsebutolol1Hipertensi, aritmia ventrikel

Thank you

Benign prostatic hyperplasia (BHP)Incidence 50% of age >60 90% of age >85Definition: Nonmalignant enlargement of prostate due to growth of Epithelia/glandular (mechanical obstruction)Smooth muscle (dynamic obstruction - urethra)Symptoms: hesitancy, urgency, frequency, dysuria, nocturia, straining, dribbling, etc.

AntagonistsMechanism & Sites of ActionsCardiovascular - vascular smooth musclecontractionReversal adrenalinePrejunctional 2 negative feedback on NE releaseNon-cardiovascular sitesBladder

AntagonistsNonselectivePhentolamine (reversible, competitive)Phenoxybenzamine (irreversible, noncompetitive)Ergot alkaloids (dirty drugs with multiple sites of action)Selective 1 antagonists Prazosin Uroselective 1A antagonistsTamsulosin

AntagonistsResponse in normal person during stressShort-term effectBlock heart sympathetic response rate and contraction - decrease CO block of sympathetic control of rhythm & automaticityIncrease TPR (block vascular 2 & increased reflex sympathetic tone)Long term effectCO remains downTPR returns to normal

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