17. Obat obat hipertensi.pptx

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FARMAKOTERAPI ANTIHIPERTENSI Jimmy Posangi Bagian Farmakologi dan Terapi FAKULTAS KEDOKTERAN UNIERSITAS SA! RATULAN"I !ANADO #$ !ei #%&#

Transcript of 17. Obat obat hipertensi.pptx

PowerPoint Presentation

FARMAKOTERAPI ANTIHIPERTENSIJimmy Posangi

Bagian Farmakologi dan TerapiFAKULTAS KEDOKTERAN UNIVERSITAS SAM RATULANGIMANADO 24 Mei 2012

Klasifikasi obat antihipertensiA. Golongan DiuretikaB. Golongan AdrenergikC. Golongan VasodilatorD. Golongan Sistim Renin-AngiotensinE. Golongan Penghambat KalsiumSites of action

Spironolactone,TriamtereneMANNITOLTHIAZIDESFUROSEMIDE

Late Distal Convulated Tubule and Collecting Duct (Distal Nephron)Proximal Convulated TubuleEarly Distal Convulated TubuleThick Segment Ascending Limb of Henles Loop65%10%1%-5%20%

Diuretics

Neurotransmitter

REffectors cellR

RCell Signaling

adrenergic

b 1Effectors cellPropranololNoradrenaline- Blockerb1

adrenergicPrazosin

a 1Effectors cellNoradrenaline- Blockera1

a 1Effectors cella2 - Agonist

adrenergica2NoradrenalineClonidine

cholinergic

adrenergicSympathetic GangliaTrimethaphanAcetylcholine

Ganglia Blocker

aEffectors cell

b

SympatholiticReserpinAcetylcholineEndothel CellsCa 2+ CalmodulinArginine + O2 Citrulline + NONO SYNTHASESmooth Muscle CellsGuanylateCyclaseNOGTPcGMPRelaxationFeSmooth Muscle CellsGuanylateCyclaseGTPcGMPRelaxationFeVasodilatorNONitroprusside Extracellular15ACE - inhibitor dan Renin InhibitorAngiotensinogenAngiotensin IAngiotensin II+ Renin ACEBradykininePeptide inaktifXCaptoprilQuinapril, etcEnalkirenRemikirenXpropranololAngiotensin II BlockerLosartan

AT 1Effectors cellAngiotensin IIVoltage-gated Ca2+ ChannelMyosin light-chain kinaseActin and myosin interactionPhosphorilationMEMBRANEEndoplasmic reticulumcalmodulinCytosolExtra cellCa 2+Ca 2+Physiology of Calcium ChannelMEMBRANEVoltage-gated Ca2+ ChannelEndoplasmic reticulumcalmodulinCytosolExtra cellNIFEDIPINECa2+Calcium Channel BlockerGolongan Obat Antihipertensi dan Prototip ObatKeunggulan

Efek Samping dan Kerugian Lain Diuretik TIAZIDMurah, tak ada rebound phenomenaK+ depletion.Mg++ dan Ca++ naik .Glukosa dan LDL naik.Perlu replacement K+.BENEFIT-RISK OBAT ANTIHIPERTENSIGolongan Obat Antihipertensi dan Prototip ObatKeunggulan

Efek Samping dan Kerugian LainBloker Beta PROPANOLOLEfektif, frekuensi jantung turun.Menentramkan, renin turun.Bronhospasme.Kongesti nasal. Kelelahan.Bradikardi.Gangguan hantaran A-V, Raynauds phenomena. Impotensi, inhibisi glukoneogenesis. rebound + BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)Golongan Obat Antihipertensi dan Prototip ObatKeunggulan

Efek Samping dan Kerugian LainBloker AlfaPRAZOSINEfek vasodilatorTerpilih bagihipertensi + gagal jantung kongestif.Memperbaiki rasio HDL/LDL.

Hipotensi ortostatik.Adanya toleransi bila pakai lama.Palpitasi, mulut kering, diare.Kongesti nasal. Disfungsi seksualBENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)Golongan Obat Antihipertensi dan Prototip ObatKeunggulan

Efek Samping dan Kerugian Lain2-Agonis

KLONIDINOrtostatik efek kurang.Baik untuk hipertensi resisten, dikombinasi dgn diuretika dan dilator

Ada rebound effectSedasi, mulut kering.Disfungsi seksual.Mual, konstipasi.BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)Golongan Obat Antihipertensi dan Prototip ObatKeunggulan

Efek Samping dan Kerugian LainPenghambat adrenergik RESERPINOrtostatik kurang.Murah.Efek hanya berobah sedikit walau pasien tak patuh.Masa kerja panjang.Rebound effect relatif tak ada.Efek samping depresi.Dapat terjadi ulkus peptikum.Kongesti nasal.Disfungsi seksual.Dampak Ekstra-Piramidal.Ginekomasti.BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)Golongan Obat Antihipertensi dan Prototip ObatKeunggulan

Efek Samping dan Kerugian LainVasodilator arterioleHIDRALAZINDipakai pada krisishipertensi dan EklamsiSakit kepala.Tahikardi.GIT intolerance.BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)Golongan Obat Antihipertensi dan Prototip ObatKeunggulan

Efek Samping dan Kerugian LainCa-channel blocker

NIFEDIPIN

Fungsi seksual relatif normal.Baik pakai pada usia lanjut.Boleh dipakai padaEmergency.Sakit kepala.Edema, konstipasi.Palpitasi dan Bradikardi.

BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)Golongan Obat Antihipertensi dan Prototip ObatKeunggulan

Efek Samping dan Kerugian LainACE-inhibitor KAPTOPRIL

Efektif bagi hipertensi berat.Fungsi seks relatif normal.Dapat dipakai pada gangguan ginjal.Skin rash, alergi , batuk.Gangguan Pengecap (disgeusia)Mual,muntah,diaresakit kepala.BENEFIT-RISK OBAT ANTIHIPERTENSI (Sambungan)Obat/GolonganDosis/caraMula KerjaLama KerjaKeteranganNitroprusid Vasodilator 0,5-10 gr/kgbb/mnt i.v dripsBebera-pa detik

3-5 menitBeri bersama b-Blocker bila ao.disekansDiazoksid Vasodilator 15-30 mg/mnt-300 mg i.v drips1-5 menit

4-12 jam

Bahaya pada penyakit koronerTrimetafan

Bloker ganglion 1-5 mg/mnt i.v

1-3 menit10 menitBaik pada ao. DisekansOBAT BAGI KEDARURATAN HIPERTENSI

Obat/GolonganDosis/caraMula KerjaLama KerjaKeteranganEsmolol b-Blocker

500 gr/kg load + 25-200 gr/mnt maintenance i.v1-2 menit10-30 mntBahaya pada asma dan CHFLabetalol a & b blockers20-300 mg/10 mnt parenteral5 menit

3-6 jam

Bahaya pada asma & CHF

Hidralazin Vasodilator5-20 mg i.v/i.m10-30 menit2-6 jam

Bahaya pada p. KoronerEnalaprilat ACE inhibitor1,25 mg/6 jam i.m15 menit6 jamBaik + diuretikOBAT BAGI KEDARURATAN HIPERTENSI (Samb.)

Obat/GolonganDosis/caraMula KerjaLama KerjaKeteranganFurosemide

Diuretik10-80 mg i.v/i.m

15 menit

4 jam

Hipokalemi

Nifedipin

Ca-blocker10 mg ulangi tiap 30 mnt/oral15 menit2-6 jam

Awas anginaKlonidin

Simpatolitik0,2 mg lalu + 0,1-0,8 mg/jam/oral -1 jam6-8 jamAwas reboundKaptopril

ACE inhibitor6,25-25 mg oral15-30 menit4-6 jamHipotensi berlebihanOBAT BAGI KEDARURATAN HIPERTENSI (Samb.)

Strategi Pengobatan Hipertensi The stepped careTahap 1. Terapi satu obatTahap 2. Terapi dua obatTahap 3. Terapi tiga obatTahap 4. Terapi empat obatStepped careKakuKurang akomodatif terhadap:- Respons individu- Reaksi individuIndividualized approach(mempertimbangkan)UmurRasPenyakit penyertaObat lain yang dipakaiGaya hidupStatus sosial-ekonomiKesimpulan- Mengurangi mortalitas dan morbiditas- Aksi farmakologi: volume, arus, dinding- Penggunaan seyogianya:rasionalefektifamanekonomisTERIMA KASIHTekanan Darah Tinggi dan StrokeProf. dr. Iwan Darmansjah, Ahli Farmakologi Klinik

Mengapa banyak orang meninggal karena stroke dalam usia yang relatif muda di Indonesia? Salah satu penyebab ialah karena banyak penderita tekanan darah tinggi yang tidak diobati/diturunkan tekanan darahnya. Tekanan darah tinggi memang tidak bisa dirasakan dengan sakit kepala. Sebagian besar masih berjalan tanpa keluhan apa-apa. Tekanan darah tinggi hanya bisa dipastika dengan alat yang disebut tensi-meter. Normal ialah tekanan darah yang tidak lebih tinggi dari 120 mm air raksa sistolik (tanpa mempersoalkan tekanan diastolik. Kriteria ini berlaku bila diperiksa dalam keadaan istirahat atau setelah duduk sekitar 7-10 menit. Inipun ada caracara pemeriksaan yang standard. Semakin melebihi tekanan sistolik 120, semakin tinggi hipertensinya dan semakin besar risiko terkena stroke. Stroke bisa disebabkan oleh perdarahan atau penggumpalan darah. Sekitar 50% penderita stroke berakibat kematian, karena itu tekanan darah tinggi harus diobati dan dijaga berat badannya,. Pengobatan bertujuan untuk memperkecil risiko stroke. Semakin tinggi tekanan darah, semakin besar risiko ini, karena itu pengobatan ialah sepanjang umurnya pasien. Pengobatan juga memerlukan pengertian pasien dengan informasi. Sayangnya tidak banyak dokter yang memberi informasi. Tidak banyak dokter mengerti benar cara mengobati penyakit TD tinggi. Di bawah ini saya jelaskan dg sederhana: Kita memiliki sekitar 200 jenis obat antihipertensi dalam nama generik. Sebagian besar sudah memenuhi syarat utk diberi hanya satu kali (pagi) sehari. Hal ini penting karena obat harus bisa bertahan efeknya sepanjang 24 jam. Masih ada yang lama kerjanya hanya 5-6 jam , dan obat jenis ini harus diberi 2-3 kali sehari. Jenis terakhir ini sebaiknya tidak dipakai, karena tidak praktis. Prosedur: umum: hari pertama dimulai dengan memakai 1 jenis obat yang terpilih oleh dokter, dan diteruskan sedikitnya 1-2 mg untuk dicek apakah TD turun. Bila tidak turun, maka ditambah dg obat ke dua yang cocok, dan TD-nya dicek lagi setiap hari. Bila efeknya memuaskan , maka 2 obat diteruskan bersamaan selama 1-2 mg dan seterusnya bila penurunan TD cukup baik. Bila di mg ketiga TD naik lagi, maka boleh ditambah obat ke tiga. Bila hasilnya memuaskan, maka 2 atau 3 obat itu diteruskan sambil observasi. Ini merupakan prosedur yang, bila TD bandel, boleh dikombinasi sampai maksimal 4 obat (semua dengan dosis kecil dan tidak dibenarkan memakai dosis besar. Cara ini bertujuan supaya kita tidak menaikkan dosis obat sebelumnya dan mengharapkan terjadi sinergisme dan menjaga dosis tetap rendah, sehingga lebih aman. Pilihan campuran diserahkan dokter yang menilai. Semua obat biasanya diberi bersamaan pagi hari. Mengontrol TD dg cara demikian lebih baik daripada terserang stroke. Dengan metode ini, sebagian besar pasien biasanya tertolong dengan 2-3 kombinasi. Juga dalam perjalanan pengobatan, bisa saja salah satu obat dikurangi, sambil dicek. Juga pasien terlindungi oleh risiko stroke.Beyond Blood Pressure Lowering Effect of ARBs: Are They All the Same?Budi Yuli Setianto, MD, FIHA, FINASIMDepartment of Cardiology and Vascular Medicine Faculty of Medicine Gadjah Mada University Sardjito Hospital, YogyakartaHypertensionMore Than Just High BPA complex syndrome in which neurohumoral and metabolic abnormalities influence development and progression of vascular disease and clinical events Hypertension SyndromeA complex inherited syndrome of cardiovascular risk factorsGiles,TD, JCI Suppl,200538DecreasedArterial ComplianceEndothelial DysfunctionAbnormal Glucose MetabolismNeurohormonal DysfunctionRenal-Function ChangesBlood-Clotting Mechanism ChangesObesityAbnormal Insulin MetabolismLV Hypertrophyand DysfunctionAccelerated AtherogenesisAbnormal Lipid MetabolismHypertensionKannel WB. JAMA.. Weber MA et al. J Hum Hypertens. 1991;5:417-423. Dzau VJ et al. J Cardiovasc Pharmacol. 1993;21(suppl 1):S1-S5. 1996;275:1571-1576High Blood Pressure is a Late Manifestation of the Hypertension SyndromeNeutel JM et all, Am J Hypertens, 1999; 12:215-22339DIABETES and HEART DISEASE Framingham Study Diabetes Mellitus doubles risk of Cardiovascular disease in men and triples risk in women

Multiple Risk Factor Intervention Trial (MRFIT) Cardiovascular death three times higher in diabetic men as compared to men without diabetesCardiovascular death five times higher in diabetic men as compared to men without diabetes when optimal risk factor status is obtained Primary defects in type 2 diabetes1 Lebovitz HE. Diab Rev 1999; 7: 139-153. 2 Ward W, et al. Diab Care 1984; 7: 491-502. 3 Yki-Jarvinen H. Endocrine Revs 1992; 13: 415-431.

The development of type 2 diabetes is the result of a combination of -cell dysfunction and insulin resistanceGLUCOSE TOXICITYPrimary defects in type 2 diabetes1-3-celldysfunctionLoss of early phaseinsulin releasePostprandialglucose spikesInsulin signalling defectInsulin resistanceIncreased basalglucose levelsHyperglycaemiaAdapted from Lebovitz, Ward and Yki-Jrvinen41Seperti kita ketahui, pada diabetes tipe 2 didapatkan 2 defek yaitu insulin resisten dan pada sisi lain juga terjadi disfungsi sel beta yg terutama mengakibatkan hilangnya sekresi insulin fase awal

As we know, there are 2 defects in DM type 2 which are resistant insulin and also beta sel dysfunction that cause loss of early phase insulin secretionAntihypertensive AgentBlood pressure lowering effectNon blood pressure lowering effect insulin sensitivity microalbuminuria endothelial dysfunction arterial compliance LV hypertrophy and dysfunction atherogenesis+42ANTIHYPERTENSIVE TREATMENT IN DIABETICS Goal BP should be 130/80 mm Hg and treatment may be started already when BP is in the high normal range.

To lower BP, all effective and well tolerated drugs can be used. A combination of two or more drugs is frequently needed.

A blocker of the RAAS should be a regular component of combination treatment and the one preferred when monotherapy is sufficient.

Microalbuminuria should prompt the use of AHD treatment also when initial BP is in the high normal range. Blockers of the RAAS have a pronounced antiproteinuric effect ESC and ESH Guidelines 2007 Persistence with BP-lowering theraphy after 1 year UK data

(sample n= 5,505,875)Persistence with therapy after 1 year (%) What are the main mechanism responsible for the anti-diabetic effects of ACEIs and ARBs ?ACEIs

ALL inhibit the renin-angiotensin system+ALL bradykininARBs

ALL inhibit the renin-angiotensin system+Some PPARg(Telmisartan)Angiotensin IIAngiotensin IAngiotensinogenAngiotensin II ReceptorsACEReninCAGECathepsin GChymaset-PACathepsin GToninDzau VJ et al. J Hypertens. 1993;11(suppl):S13-S18.Angiotensin II Formation46Non-Hemodynamic Stress oxidative / inflammation TGF - & ECM PAI 1 Aldosterone Symphatic Activity

HemodynamicVasocontriction RBF P gc Wiecek A et al. NDT 2003;18(suppl 5):v16-v20AT1 receptor Angiotensin II AT2 receptorVasodilatationNatriuresisGrowth Inhibition

ARBsConstantly expressed Expressed only after injury47Composite CV risk = cardiovascular mortality, non-fatal myocardial infarction, hospitalisation for congestive heart failure, non-fatal strokeThe ONTARGET Investigators. N Engl J Med 2008;358:15471559Reduction in composite CV riskTelmisartan 80mg is as protective as Ramipril 10mg in terms of CV protection

4848Key point: Telmisartan (80 mg/day) alone is as effective as ramipril in reducing composite CV risk in high-risk patients. It is the only ARB to have proven to be as effective as the gold standard in reducing CV risk in this broad CV high-risk population.

Time to composite CV endpointTelmisartan (n=8542) and ramipril (n=8576) did not differ in the time to occurrence of the primary composite CV outcome (CV mortality, non-fatal MI, hospitalisation for congestive heart failure, and non-fatal stroke) in patients followed for up to 5.5 years (median, 56 months). Thus, telmisartan and ramipril are similarly effective in reducing composite CV risk in high-risk patients.

At median follow-up, the primary outcome had occurred in 16.5% of the ramipril group and 16.7% of the telmisartan group (relative risk, 1.01; 95% CI 0.94 to 1.09).

Reference1. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:15471559.

Telmisartan 80mg added to Ramipril 10mg : as effective as Ramipril aloneComposite CV risk = cardiovascular mortality, non-fatal myocardial infarction,hospitalisation for congestive heart failure, non-fatal strokeThe ONTARGET Investigators. N Engl J Med 2008;358:15471559

Reduction in composite CV risk

4949Key point: Telmisartan added to ramipril was shown to be as effective as ramipril alone in reducing composite CV risk. This result provides strong evidence that the theoretical additional benefit of dual RAS blockade does not translate into real improvements in clinical outcome for the majority of CV high-risk patients.

Time to composite CV endpointThe time to occurrence of the primary composite CV outcome (CV mortality, non-fatal MI, hospitalisation for congestive heart failure, and non-fatal stroke) was similar between the telmisartan combination therapy (n=8502) and ramipril (n=8576) groups followed for up to 5.5 years (median, 56 months). In this large population of patients at high CV risk, this finding provides irrefutable evidence that the theoretical additional benefit of dual RAS blockade does not translate into real improvements in clinical outcome for the broad CV high-risk population in this trial. The benefit of dual RAS blockade still needs to be clarified for some specific sub-populations (e.g. proteinurea patients, congestive heart failure)

Reference1. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:15471559.

Telmisartan is superior to Ramipril in 24 hour ABPM reduction

DBP change from baseline (mmHg)PRISMA II Time after closing (h)

Is there a differences between ARBs on non blood pressure lowering effect?53SOME ARB POSSES PARTIAL AGONIST PPAR ACTIVITY, DUE TO STRUCTURAL SIMILARITY WITH THE THIAZOLIDINEDIONES (FULL AGONIST PPAR ACTIVITY)

Scheen AJ. Diabetes Metab. 2004;30:498-505TELMISARTAN > IRBESARTAN > LOSARTAN METABOLITES54Telmisartan has a different structure which explains its unique pharmacology

Chemical structures of the most widely used angiotensin receptor blockers (ARBs), illustrating the unique nature of telmisartan. The circle encloses the biphenyl tetrazole moiety that is common to losartan and its related ARBs. ARBs Comparison of pharmacological propertiesOlmesartanLosartanCandesartanIrbesartanTelmisartanEprosartanValsartanProdrugYesYesYesNoNoNoNoReceptor antagonismNon-competitiveCompetitive (active metabolite is non-competitiveNon-competitiveNon-competitiveNon-competitive

CompetitiveNon-competitiveAT1:AT2 affinity12,5001,000>10,0008,500>3,0001,00020,000t1/2 (hours)10-156-9911-15245-99Tmax (hours)1-23-43-41.5-20.5-11-22-4Vd (L)16-29340.1 L/kg53-93500 ~13~23Bioavail-ability (%)25.6~331460-805013235656Olmesartan has an elimination half-life of 10-15 hours and a smaller volume of distribution in comparison to most other ARBs.

Olmesartans binding affinity for angiotensin II receptors is highly selective for AT1 receptors, demonstrating a binding affinity 12,500-fold stronger than for AT2 receptors.Olmesartan displays noncompetitive antagonism at AT1 receptors, ie, an insurmountable blockade.Peak plasma concentration of olmesartan is reached within 2 hours following dosing, which is consistent with other ARBs.Also consistent with the class, olmesartan is extensively bound to serum albumin.

(continued in next slide)ARBs Comparison of pharmacological properties (cont.)OlmesartanLosartanCandesarta

IrbesartanTelmisartanEprosartanValsartanFaecal elimination (%)50-65606780989083Urinary elimination (%)35-50353320