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Bagian Farmakologi & Terapeutik Bagian Farmakologi & Terapeutik Fakultas Kedokteran Fakultas Kedokteran USU USU 1 FARMAKOLOGI OBAT-OBAT GAGAL JANTUNG KONGESTIF Dr.Datten Bangun,MSC,SpFK Dr.Zulkarnain Rangkuty,MKes.

K20- Farmakologi- Obat Gagal Jantung Dan Diuretik

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JANTUNG DAN PEMBULUH DARAHFiled under: PATOFIS — Leave a comment 2010/08/10JANTUNGJantung merupakan suatu organ otot berongga yang terletak di pusat dada.Bagian kanan dan kiri jantung masing masing memiliki ruang sebelah atas (atriumyang mengumpulkan darah dan ruang sebelah bawah (ventrikel) yang mengeluarkan darah.Agar darah hanya mengalir dalam satu arah, maka ventrikel memiliki satu katup pada jalan masuk dan satu katup pada jalan keluar.Ruang & katup jantungFungsi utama jantung adalah menyediakan oksigen ke seluruh tubuh dan membersihkan tubuh dari hasil metabolisme (karbondioksida).Jantung melaksanakan fungsi tersebut dengan mengumpulkan darah yang kekurangan oksigen dari seluruh tubuh dan memompanya ke dalam paru-paru, dimana darah akan mengambil oksigen dan membuang karbondioksida; jantung kemudian mengumpulkan darah yang kaya oksigen dari paru-paru dan memompanya ke jaringan di seluruh tubuh.FUNGSI JANTUNGPada saat berdenyut, setiap ruang jantung mengendur dan terisi darah (disebutdiastol); selanjutnya jantung berkontraksi dan memompa darah keluar dari ruang jantung (disebut sistol).Kedua atrium mengendur dan berkontraksi secara bersamaan, dan kedua ventrikel juga mengendur dan berkontraksi secara bersamaan.Darah yang kehabisan oksigen dan mengandung banyak karbondioksida dari seluruh tubuh mengalir melalui 2 vena berbesar (vena kava) menuju ke dalam atrium kanan.Setelah atrium kanan terisi darah, dia akan mendorong darah ke dalam ventrikel kanan.Darah dari ventrikel kanan akan dipompa melalui katup pulmoner ke dalam arteri pulmonalis, menuju ke paru-paru.Darah akan mengalir melalui pembuluh yang sangat kecil (kapiler) yang mengelilingi kantong udara di paru-paru, menyerap oksigen dan melepaskan karbondioksida yang selanjutnya dihembuskan.Darah yang kaya akan oksigen mengalir di dalam vena pulmonalis menuju ke atrium kiri.Peredaran darah diantara bagian kanan jantung, paru-paru dan atrium kiri disebut sirkulasi pulmoner.Darah dalam atrium kiri akan didorong ke dalam ventrikel kiri, yang selanjutnya akan memompa darah yang kaya akan oksigen ini melewati katup aorta masuk ke dalam aorta (arteri terbesar dalam tubuh).Darah kaya oksigen ini disediakan untuk seluruh tubuh, kecuali paru-paru.Potongan melintang jantungJantung tampak depanPEMBULUH DARAHKeseluruhan sistem peredaran (sistem kardiovaskuler) terdiri dari arteri,arteriola, kapiler, venula dan vena.Arteri (kuat dan lentur) membawa darah dari jantung dan menanggung tekanan darah yang paling tinggi.Kelenturannya membantu mempertahankan tekanan darah diantara denyut jantung.Arteri yang lebih kecil dan arteriola memiliki dinding berotot yang menyesuaikan diameternya untuk meningkatkan atau menurunkan aliran darah ke daerah tertentu.Kapiler merupakan pembuluh darah yang halus dan berdinding sangat tipis, yang berfungsi sebagai jembatan diantara arteri (membawa darah dari jantung) dan vena (membawa darah kembali ke jantung).Kapiler memungkinkan oksigen dan zat makanan berpindah dari darah ke dalam jaringan dan memungkinkan hasil metabolisme berpindah dari jaringan ke dalam darah.Dari kapiler, darah mengalir ke dalam venula lalu ke dalam vena, yang akan membawa darah kembali ke jantung.Vena memiliki dinding yang tipis, tetapi biasanya diameternya lebih besar daripada arteri; sehingga vena mengangkut darah dalam volume yang sama tetapi dengan kecepatan yang lebih rendah dan tidak terlalu dibawah tekanan.PASOKAN DARAH KE JANTUNGOtot jantung (miokardium) sendiri menerima sebagian dari sejumlah volume darah yang mengalir melalui atrium dan ventrikelSuatu sistem arteri dan vena (sirkulasi koroner) menyediakan darah yang kaya akan oksigen untuk miokardium dan kemudian mengembalikan darah yang tidak mengandung oksigen ke dalam atrium kanan.Arteri koroner kanan dan arteri koroner kiri merupakan cabang dari aorta; vena kardiak mengalirkan darah ke dalam sinurskoroner, yang ak

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  • Bagian Farmakologi & Terapeutik Fakultas KedokteranUSU1FARMAKOLOGI OBAT-OBAT GAGAL JANTUNG KONGESTIFDr.Datten Bangun,MSC,SpFK Dr.Zulkarnain Rangkuty,MKes.

  • Weight of the heart 300gWork: 75/min, 10000 beats /day35 million beats /year, 2.5 billion beats/life70ml/beat, 7200 l/dayThe work of the heart in one life is equivalent to lifting 30 tons to the Mount EverestThe busy and hard working heart!

  • Congestive heart failure:Inability of the heart to keep up with the demands on it, with failure of the heart to pump blood with normal efficiency. When this occurs, the heart is unable to provide adequate blood flow to other organs, such as the brain, liver and kidneys.

  • NYHA Classification of heart failureClass I: No limitation of physical activityClass II: Slight limitation of physical activityClass III: Marked limitation of physical activityClass IV: Unable to carry out physical activity without discomfort2

  • Classification of Heart Failure: ACC/AHA Stage vs NYHA Class

  • Peny. JantungPre-loadAfter loadOedemaAldosteroneAngiotensin IIRenin releaseRenal blood flowSympath.toneAdrenalin /noradrenalinTissue perfusionVasoconstriction /Heart rateRetensi Na+ /H2OCardiac Output

  • Neurohormonal changes

    N/H changesFavorable effectUnfavor. effect Sympathetic activity HR , contractility, vasoconst. V return, fillingArteriolar constriction After load workload O2 consumption Renin-Angiotensin Aldosterone Salt & water retention VRVasoconstriction after load VasopressinSame effectSame effect interleukins &TNFMay have roles in myocyte hypertrophy Apoptosis EndothelinVasoconstriction VR After load

  • Pharmacotherapeutic approaches in heart failureReduction of volume overload (reduce preload)diureticsVentricular unloading (reduce afterload)Acute: nitroglycerin, sodium nitroprussideChronic: inhibit renin-angiotensin-aldosterone system, diuretics, ACE inhibitors, angiotensin antagonistsBeta-blockers (also reduce sympathetic activation)Inotropic interventions (improve Starling function)Acute: dobutamineChronic: phosphodiesterase inhibitors, digitalis

  • Non-Pharmacological approach (Diet and Activity)

    Salt restrictionFluid restrictionDaily weight (tailor therapy)Gradual exertion programs

  • Essential to control symptomssecondary to fluid retention Prevent progression from HT to HF Spironolactone improves survival New research in progressDiuretics

  • Nephron sites of action of diuretics

  • LOOP DIURETICSChemistry-Sulfonamide derivatives, kecuali ethacrynic acid.Ex.-Sulfonamide :-furosemide(20-80 mg)-bumetanide(0.5-2 mg)-torsemide(2.5-20 mg)-Non sulfonamide :-Ethacrynic acid (50-200 mg)

  • Mechanisms of Action: Loop diureticsNo transport systems in descending loop of HenleAscending loop contains Na+ - K+ - 2Cl- cotransporter from lumen to ascending limb cellsLoop diuretic blocks cotransporter Na+, K+, and Cl- remain in lumen, excreted along with water

  • Loop diureticsGenerally cause greater diuresis than thiazides; used when they are insuffficientCan enhance Ca2+ and Mg2+ excretionEnter tubular lumen via proximal tubular secretion (unusual secretion segment) because body treats them as a toxic drugDrugs that block this secretion (e.g. probenecid) reduces efficacy

  • PHARMACOKINETIC-Rapidly absorbed orally :Duration of effect~torsemide:1 hour4-6 hrs~furosemide:2-3 hour2-3 hrs-Excretion via renal secretion.11

  • Mekanisme kerja1.Reduce the reabsorption of NaCl water excretion.2.menurunkan lumen positive potential that derives from K+ recycling.3. meningkatkan Mg2+ excretion hypomagnesemia.4. meningkatkan Ca2+ excretion tapi tidak menyebabkan hypocalcemia karena Ca2+ secara actif di reabsorb di distal convoluted tubule.

  • Thiazide Diuretics - ActionsActs on early part of distal tubules Inhibit Na+-Cl- symporter and reabsorptionIncrease NaCl excretion (5-10% Medium efficacy)Na exchanges with K+ in the DT K+ loss HypokalemiaNot effective in very low GFR of < 30ml/min, may reduce GFR furtherMetolazone additional action on PT, effective at low GFR, can be tried in refractory edema

  • Thiazide Diuretics - Other actionsHypotensive actionreduce Ca++ excretion may ppt hypercalcemia in patients of hyperparathyroidism, bone malignancy with metastasisIncrease Mg++ excretionHypochloremic alkalosisHyperuricemia Hyperglycemia (inhibit insulin release ?)Hyperlipidimia (Cholesterol and TG)

  • Thiazides Preparations

    Drug NameDose (oral)Duration (hr)Chlorothiazide (1957)500-20006-12Hydrochlorothiazide25-1008-12Benzthiazide25-10012-18Hydroflumethiazide25-10012Chlorthalidone50-10048Metolazone5-2018Xipamide, Clopamide20-4012-24Indapamide (No CAI) 2.5-524-36

  • Thiazides - UsesHypertension (Hydrochlorothiazide, Indapamide)Edema : Cardiac, Hepatic RenalLess efficacious than loop diureticUseful for maintainence therapyHypercalciuria and renal Ca stonesDiabetes Insipidus (DI) (Nephrogenic responds better)Paradoxical use,MOA - ? Reduce GFR, ? More complete reabsorption in PTConvenient, Cheaper than Desmopressin in Neurogenic DIAmiloride is the DOC for Lithium induced nephrogenic DIMetolazone useful even when GFR is as low as 15ml/min

  • Thiazides -Adverse EffectsHypokalemiaMay ppt renal failureHyperuricemiaHyperglycemiaHyperlipidemiaHypomagnesemiaHypohloremic alkalosisHypersensitivityppt. HypercalcemiaNot safe in pregnancy (all diuretics)

  • Comparison of loop and thiazide diuretics

  • Potassium-sparing diureticsHave most downstream site of action (collecting tubule)Reduce K loss by inhibiting Na/K exchangeNot a strong diuretic because action is furthest downstreamOften used in combination with thiazide diuretics to restrict K loss

  • POTASSIUM SPARING DIURETICSChemistry :-Spironolactone-EplerenoneSynthetic steroidAntagonist competitive to aldosterone.-Amiloride-TriamtereneAct by inhibition of Na+ influx through ion-channels in the luminal membrane.

  • Pharmacodynamic=reduce Na+ absorbtion in the collecting tubule and ducts (regulated by aldosterone). Spironolactone eplerenone=amiloride=triamtereneBlock the cytoplasmic aldosterone receptors.Block sodium channelsK+ secretion is coupled with Na+ entry in that segment K+ sparing=actions of spironolactone and triamterene depend on renal prostaglandin synthesis NSAIDs will inhibite the action of the diuretics.

  • SpironolactoneAldosterone antagonist, K-sparing diureticPrevention of aldosterone effects on distal tubule and collecting ductAldosterone inappropriately elevated in CHFMobilizes edema fluid in heart failurePrevention of hypokalemia induced by loop diuretics and thiazideDecrease the risk of digitalis toxicity.Prolongs life in CHF patients= a steroid,chemically related to mineralocorticoid aldosterone

  • Clinical Indications -Mineralocorticoid excess-Secondary aldosteronism , from:-heart failure-hepatic cirrhosis-nephrotic syndrome

  • Adverse Drug Reactions -hyperkalemia:-mild -moderate -life-threatening hati-hati dengan interaksi obat : --blocker,NSAIDs,ACE-I, - ARB- hyperchloremic metabolic acidosis - gynecomastia,DE,BPH- acute renal failure (with indomethacine)- triamterene is poorly soluble------ kidney stone

  • Neurohormonal activation Rebound Na+ uptake after volume loss Hypertrophy of distal nephron Reduced tubular secretion (renal failure, NSAIDs) Decreased renal perfusion (low output) Altered absortion of diuretic Noncompliance with drugsBrater NEJM 1998;339:387 Kramer et al. Am J Med 1999;106:90Diuretic Resistance

  • BradykininogenAngiotensinogenBradykininAngiotensin IBradykinin(inactive)ACE B.P B.P.Angiotensin IIAldosterone Renin ACE-Inhibitor: Mechanism of Action

  • ACE-IBradykininogenAngiotensinogenBradykininAngiotensin IBradykinin(inactive)ACE B.P B.P.Angiotensin IIAldosterone Renin ACE-Inhibitor: Mechanism of Action

  • ACE-I. Clinical Effects Improve symptoms Reduce remodelling / progression Reduce hospitalization Improve survival

  • ACE-I. Practical UseStart with very low doseIncrease dose if well toleratedRenal function & serum K+ after 1-2 wAvoid fluid retention / hypovolemia (diuretic use)Dose NOT determined by symptomsCombine to overcome resistanceDo not use alone

  • Side effects of ACE inhibitorsAngioedemaHypotensionRenal insuffiencyRashCough---- captopril

  • Inotropik Positif Digitalis : Berasal dari tanaman Digitalis ( Foxglove) Struktur kimia; cincin steroid dan lakton Bekerja dengan menghambat kerja ensim Na+-K + ATP ase kontraktilitas jantung meningkat Saturated dulu dalam tubuh baru timbul efek 1/3 lethal dose

  • William WutheringWilliam Wuthering35

  • Mechanism of Cardiac Muscle Excitation, Contraction & RelaxationFigure 14-11: Excitation-contraction coupling and relaxation in cardiac muscle

  • Digitalis Glycosides (Digoxin, Digitoxin)The role of digitalis has declined somewhat because of safety concernRecent studies have shown that digitals does not affect mortality in CHF patients but causes significant Reduction in hospitalizationReduction in symptoms of HF

  • Digitalis (cont.)Mechanism of Action+ve inotropic effect by intracellular Ca & enhancing actin-myosin cross bridge formation (binds to the Na-K ATPase inhibits Na pump intracellular Na Na-Ca exchangeVagotonic effectArrhythmogenic effect

  • Digitalis ToxicityNarrow therapeutic to toxic ratio ( < 2 ) I. Non cardiac manifestations:- Anorexia,nausea,vomitting- Headache, Xanthopsia scotoma, - Disorientation

    II.Cardiac manifestation: - Sinus bradicardia and arrest - A-V block (usually 2nd degree - Atrial tachycardia with A-V block - Development of junctional rhythm in patient with fibrillation - Ventr,tachycardia/fibrillation

  • Digitalis ToxicityTreatmentHold the medicationsObservationIn case of A/V block or severe bradycardia atropine followed by temporary PM if neededIn life threatening arrhythmia digoxin-specific fab antibodies (Digibind)Lidocaine and phenytoin could be used Try to avoid D/C cardioversion in non life-threatening arrhythmia

  • Vasodilators Mechanism of action: reduce preload (via venodilation and afterload (arteriolar dilationDrugs used: Sodium nitroprusside Hydralazine Ca2+ channel blockers Prazosin Side-effects: - reflex tachycardia - hydralazine------ SLE40

  • Phosphodiesterase Inhibitors amrinone milrinoneMechanism of Action inhibition of type III phosphodiesterase intracellular cAMP activation of protein kinase A Ca2+ entry through L type Ca channels inhibition of Ca2+ sequestration by SR

    cardiac output

    peripheral vascular resistance

  • Phosphodiesterase Inhibitors: Therapeutic Useshort term support in advanced cardiac failure long term use not possibleAdverse Effects of Phosphodiesterase Inhibitors= Cardiac arrhythmias = GI: Nausea and vomiting = Sudden deathamrinonemilrinone

  • b-Adrenoceptor and Dopamine Receptor Agonists Dobutamine Dopamine

  • Mechanism of Action: Stimulation of cardiac b1-adrenoceptors: inotropy > chronotropy peripheral vasodilatation myocardial oxygen demand DobutamineDopamine:=Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors=Splanchnic and renal vasodilatation

  • Therapeutic Use Dobutamine: management of acute -failure only - cardiac stimulantsDopamine: restore renal blood in acute failure

    Agent 1 2 1 2 D1

    Dopamine + ++ ++ ++Dobutamine +/- ++ + Adrenaline ++ ++ ++ ++

    Note : D1: low dose vasodilate renal vessels

  • Adverse Effects Dobutamine Tolerance TachycardiaDopamine tachycardia arrhythmias peripheral vasoconstriction

  • -adrenergic blockers: Dasar pemikiran: Digitalis tidak meningkatkan survival Penambahan diuretik seperti spironolakton meningkatkan survival 27 % ACE-I survival rate hanya 50 % Peneliti Swedia memulai dengan Beta bloker pada 1975,dg pemikiran/observasi: = -blocker will oppose the increase of simpa thetic in CHF = mengembalikan sensitivitas -adrenergic di jantung.

  • Beta adrenergic blockers:

    decrease renin release and afterload (and decrease sympathetic activation of heart)Carvedilol (Coreg)decreases afterload in part by alpha adrenoceptor antagonism

    Use of beta-blockers in carefully monitored patients CHF may be beneficial. Until recently, beta blockers were considered to be contraindicated in CHF.

  • Carvedilol : Tidak beta selektif Memblok reseptor alfa dan beta Efek anti oxidant Anti proliferatif Menurunkan kadar endothelin

  • PEDOMAN PENGGUNAAN BETA-BLOKER PADA GJK :Hanya diberikan pada pasien yang sudah stabil dengan obat.Tidak ada kontra indikasiDimulai dengan dosis kecil, awasi paling tidak selama satu jam untuk gejala oyong / pusing Dosis didoublekan setiap dua minggu, asal saja : - T.D. > 85 mmHg - H.R > 55 / menit - Pasien asimtomatikEFEK SAMPING : - Efek samping sama dengan Beta-Bloker lain

  • CYTOKINES INHIBITORSCytokines meningkat kadarnya pada GJK misalnya: - Endotelin - TNF alfa - ANF - Interleukin 1,2,6 dan 10ACE-I dan Beta-Bloker yang diketahui menurunkan jumlah cytokines pada GJK Nesitiride:Recombinant-type natriuretic peptide---- digunakan pada acute decompensated HF

    Masih membutuhkan penelitian lebih lanjut

  • KESIMPULAN :Digitalis bergeser dari first- line therapy ACE I meningkatkan survival bersama dengan diuretikaPenambahan Beta adrenergik bloker menurunkan mortalitas penderita GJK

  • **Slide ID: 7753The American College of Cardiology/American Heart Association (ACC/AHA) writing committee decided to take a new approach to the classification of heart failure one that emphasized the evolution and progression of the disease. Only Stages C and D qualify for the traditional clinical diagnosis of heart failure. This classification is intended to complement, but not replace, the New York Heart Association (NYHA) Functional Classification.ACC/AHA Heart Failure StageStage A: patients who are at high risk for developing heart failure but have no structural disorder of the heart.Stage B: patients with structural disorders of the heart who have never had symptoms of heart failure.Stage C: patients with past or current symptoms of heart failure associated with underlying structural heart disease.Stage D: patients with end-stage disease who require specialized treatment strategies such as mechanical circulatory support, continuous IV inotrope infusions, cardiac transplantation, or hospice care.NYHA Functional ClassificationAssigns patients to 1 of 4 functional classes depending on the degree of effort needed to elicit symptoms. Patients with very low LV ejection fractions may be asymptomatic, whereas patients with preserved LV systolic function may have many symptoms. The apparent discordance between severity of systolic dysfunction and the degree of functional impairment is not well understood.Class I: symptoms of heart failure only at levels that would limit normal individuals (asymptomatic).Class II: symptoms of heart failure on ordinary exertion.Class III: symptoms of heart failure on less-than-ordinary exertion.Class IV: symptoms of heart failure at rest.

    ReferencesHunt SA et al. J Am Coll Cardiol. 2001;38:2101-2113.Farrell MH et al. JAMA. 2002;287:290-297.*****************Treatment of Heart Failure.Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of actionACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion. It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition.

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