AntiHypertensive Drugs dr. Ave Olivia Rahman, MSc. Bagian farmakologi FKIK UNJA Tujuan Pembelajaran : Kompetensi 4A • • • • Memahami penggolongan obat antihipertensi Memahami mekanisme kerja obat antihipertensi Memahami efek samping obat antihipertensi Memahami pemilihan obat antihipertensi dengan co morbid tertentu • Memahami algoritma terapi hipertensi JNC 7 • Memahami terapi hipertensi emergensi • Menulis resep obat antihipertensi Hypertension High Blood Pressure, Persistently What is Normal Blood Pressure? Classfication of Blood Pressure Normal • SBP < 120 mmHg • DBP < 80 mmHg Prehypertension • SBP 120 -139 mmHg • DBP 80-89 mmHg Hypertension stage 1 • SDP 140-159 mmHg • DBP 90-99 mmHg Hypertension stage 2 • SDP ≥ 160 mmHg • DBP ≥ 100 mmHg Hypertensive Crisis • SDP > 180 mmHg • DBP > 120 mmHg Blood Pressure Arterial Blood Pressure Contractility Cardiac Output Heart Rate X Peripheral Resistance Arteriolar Volume Filling Pressure Blood Volume Venous Tone Groups of Antihypertensive Drugs Diuretics Ca Channnel Blockers ACE Inhibitors Angiotensin II Receptor Blockers β Blockers α1 Blockers Centrally α2 agonist Direct Vasodilator others Diuretics Trigger the excretion of water and electrolytes from the kidneys Sodium water retention Blood Volume Peripheral Retention Cardiac Output Decrease Blood Pressure Diuretics I. Thiazide& Thiazide-like diuretics : – Thiazide diuretics include: bendroflumethiazide, chlorothiazide, hydrochlorothiazide (HCT), hydroflumethiazide, methyclothiazide, polythiazide. – Thiazide-like diuretics include: chlorthalidone, indapamide, metolazon II. Loop diuretics : bumetanide, ethacrynic acid, and furosemide Continue... III. Potassium Sparing Diuretic • Diuretics that do not promote secretion of potassium in the urine. • As adjunctive drugs, combination with other drugs • Actions : – – Aldosterone antagonis : spironolactone, eplerenone Block sodium channel : amiloride, triamteren Thiazide Diuretics • Diuretic that most widespread use. Derived from sulfonamides. • Thiazide diuretics are absorbed rapidly but incompletely from the GI tract. Cross the placenta and are secreted in breast milk. • Therapeutic Uses : long-term treatment of hypertension. Particularly useful in the treatment of black or elderly. Also used to treat edema. • Not effective in patient with inadequate kidney function (Cr Cl < 50 mL/min). • Decrease the level of calcium in urine prevent the development and recurrence of renal calculi. Continue... • Side effects : hyperurecemia (70%), hyperglycemia (10%), hypomagnesemia. Increase the excretion of chloride, potassium, and bicarbonate electrolyte imbalance • Potassium levels should be monitored closely in patient who are predisposed to arrhythmias or using digitalis glycosides. Loop Diuretics • Highly potent diuretics. Loop diuretics, with the exception of ethacrynic acid, contain sulfa. • Act on proximal tubule the thick, ascending loop of Henle. • Cause decreased renal vascular resistance, increase renal blood flow, increase Ca2+ content of urine. • Used to treat edema, hypertension (usually with a potassium-sparing diuretic or potassium supplement to prevent hypokalemia) CALCIUM CHANNEL BLOCKERS Blocking the slow calcium channel in myocardial and vascular smooth muscle cell membranes Inhibits the influx of extracellular calcium ions Have intrinsic natriuretic effect No Contraction = Dilatation Decrease Blood Pressure Pharmacokinetics • When administered orally, calcium channel blockers are absorbed quickly and almost completely. • Because of the first -pass effect, however, the bioavailability of these drugs is much lower. • The calcium channel blockers are highly bound to plasma proteins. 3 classes of CCB • Diphenylalkylamine : verapamil. • Benzothaizepines : diltiazem. • Dihydropyridines : • 1 st generation : nifedipine • 2nd generation : amlodipine, felodipine, isradipine, nicardipine, nisoldipine. Differences Classes /Drugs Verapamil Diltiazem Nifedipine etc Properties Has significant effect on both cardiac and vascular smooth muscle Affect both cardiac and vascular smooth muscle, but less pronounced negative inotropic effect compare to verapamil Much greater affinity for vascular smooth muscle Continue...CCB • Useful in the treatment of hypertensive (mildmoderate) who also have asthma, diabetes, angina, peripheral vascular disease. • Side effects: constipation (10%), dizzines, headache, feeling fatique. Verapamil contraindication for congestive heart failure due to its negative inotropic effects. ACE INHIBITORS • • • • • • • • • • Benazepril Captopril Enalapril Enalaprilat (the only ACE inhibitor that’s administered I.V.) Fosinopril Lisinopril Moexipril Quinapril Ramipril Trandolapril Actions • ACE inhibitors prevent the conversion of angiotensin I to angiotensin II. Continue... • ACEI slow progression of diabetic nephropathy and decrease albuminuria. • Side effect : dry cough (10%) , rash, fever, altered taste, hypotension, hyperkalemia (must be monitored). Angioedema (rarely) • Combination with potassium supplement, spironolactone is contraindicated • Fetotoxic ANGIOTENSIN II RECERPTOR BLOCKERS • • • • • • • Candesartan cilexetil Eprosartan Irbesartan Losartan Olmesartan Telmisartan Valsartan Actions • Block the binding of angiotensin II to the AT1 receptor This prevents angiotensin II from exerting its vasoconstricting properties and from promoting the excretion of aldosterone lowered blood pressure. Continue... • Valsartan may also be used for the management of heart failure. • Decrease nephrotoxicity of diabetes therapy in hypertensive diabetics (Irbesartan and losartan). • Losartan is also used to reduce the risk of stroke in high-risk patients with hypertension and left ventricular hypertrophy. • Side effect similar with ACEI, but risk of cough and angiodema sigificantly decrease β Blockers Continue... • Selective β1 Blockers : metoprolol, atenolol • Non selective β Blockers (block β1 & β2) : Propanolol • May take several (1-2) weeks to develop full effects Continue... • Side effect : bradycardia, fatique, insomnia, hallucination, hypotension, decrease libido, cause impotence, disturb lipid metabolism, decreasing HDL, increasing Trigliseride, drug withdrawl (rebound hypertension should be tapering off) • Caution in obstructive lung disease, chronic congestive heart failure, severe symptomatic occlusive peripheral vascular disease, acute heart failure, diabetes. α1 Blocker • Actions : competitive block α1 adrenoceptor relaxation arterial and venous smooth muscle decrease peripheral vascular resistance and lower arterial blood pressure. • Have minimal change in cardiac output, renal blood flow, glomerular filtration rate. • Cause short term effect of reflex tachycardia to blunt this effect concomitant use of β blocker may be needed. • Prazosin, doxazosin, terazosin. • Side effect : postural hypotention, reflex tachycardia, first dose syncope. α-1 and β Blockers • Actions : blocking both α-1 and β receptors in the body lowers blood pressure. • Carvedilol, labetalol • Contraindication : heart block, heart failure, asthma, obstructive airway disease, severe slow heartbeat, severe low blood pressure Clonidine • It is α2 presinaptic agonist, work centrally • Action: inhibit the released of noradrenaline from symphatetics nerves. • Does not decrease renal blood flow & GFR Useful in the treatment of hypertention complicated by renal disease. • Causes sodium and water retention usually used in combination with diuretic. • Side effect : sedation, drying nasal mucosa, rebound hypertention in abrupt withdrawal (should be withdrawn slowly) α methyldopa • It Inhibits dopa decorboxylase and deplete norepinephrine • Also valuable in treating hypertensive patient with renal insufficiency. • Reduce total peripheral resistance and decreased blood pressure. • Cardiac output not decreased Does not decrease renal blood flow & GFR • Side effect : sedation, drowsiness. Direct Vasodilators • Actions : act on arteries, veins, or both. • Include : – Diazoxide – Hydralazine – Minoxidil – Nitroprusside Continue...Indications • They’re usually combined with other drugs to treat the patient with moderate to severe hypertension (hypertensive crisis). • Hydralazine and minoxidil are usually used to treat resistant or refractory hypertension. • Diazoxide and nitroprusside are reserved for use in hypertensive crisis. • Hydralazine monotherapy accepted method for controlling blood pressure in pregnancy-induced hypertension. Continue... Side effect • Produce reflex stimulation of heart increased myocardial contractility, heart rate, oxygen consumption may prompt angina pectoris, MI, cardiac failure in predisposed individuals. • Increase plasma renin concentration sodium and water retention • Those undesirable side effects can be blocked by concomitant use of diuretic and β blocker. Others : Reserpin • Actions : Norephinefrine depletors. Sediaan dan Dosis Nama Obat Sediaan Dosis Awal Hydrochlorthiazide (HCT) tablet 12.5; 25; 50 mg 1 x 12,5 mg Furosemide Tablet 40 mg, Ampul 2 ml, 10mg/ml, 2 x 20 mg Spironolakton Tablet 25 mg, 100 mg 1-2 x 25 mg Clonidin Tab 0,075; 0,15; 0,25 mg Injeksi 0,15 mg/ml 2 x 0,075 mg Metildopa Tab 125; 250 mg 2 x 125 mg Bisoprolol Tab 5 mg 1 x 5 mg propanolol Tab 10,40 mg 2 x 20 mg Asebutolol Tab 200; 400 mg 2 x 100 mg Atenolol Tab 50, 100 mg 1 x 25 mg Metoprolol Tab 50; 100 mg 1-2 x 50 mg Nama Obat Sediaan Dosis Awal Captopril Tablet 12,5; 25; 50 mg 2 x 12,5 mg Ramipril tab 1,25 ; 2,5; 5 mg 1x 1,25 mg Lisinopril Tab 5, 10 mg 1x 5 mg Amlodipin Tab 5, 10 mg 1x 2,5 mg Felodipin Tab 5 ; 10 mg 1 x 5 mg Nikardipin Tab 20 mg Ampul 2; 10 mg 3 x 20 mg Nifedipin Tab 5;10 mg 3 x 5 mg Losartan Tab 50 mg 1 x 50 mg Irbesartan Tab 75;150;300 mg 1 x 150 mg Kandesartan Tab 8;16 mg 1 x 4 mg Telmisartan Tab 40;80 mg 1 x 40 mg Olmesartan Tab 20;40 mg 1x 20 mg Valsartan Tab 80 ; 160 mg 1 x 80 mg Causes of Resistant Hypertension • • • • Improper BP measurement Excess sodium intake Inadequate diuretic therapy Medication: – Inadequate doses – Drug actions and interactions (e.g., nonsteroidal antiinflammatory drugs (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives) – Over-the-counter (OTC) drugs and herbal supplements • Excess alcohol intake • Identifiable causes of hypertension Recommendations for initiating and modifying pharmacotherapy for patients with elevated blood pressure (BP) : "2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8), published online Dec. 18 by JAMA: The Journal of the American Medical Association Initiation pharmacologic treatment (1) Population In the general population aged ≥60 years In the general population <60 years In the population aged ≥18 years with chronic kidney disease (CKD) Blood Pressure SBP ≥150 mm Hg or DBP ≥90 mm Hg SBP ≥140 mmHg or at DBP ≥90 mmHg SBP ≥140 mmHg or DBP ≥90 mmHg Initiation pharmacologic treatment (2) Population In the general nonblack population, including those with diabetes In the general black population In the population aged ≥18 years with CKD Drugs a thiazide-type diuretic, calcium channel blocker (CCB), angiotensinconverting enzyme inhibitor (ACEI), or angiotensin receptor blocker (ARB). a thiazide-type diuretic or CCB. ACEI or ARB Evaluation Initiate with 1 drugs for 1 month If goal BP cannot be reached , increase the dose of the initial drug or add a second drug . Do not combine together ACEI and an ARB Referral to a hypertension specialist may be indicated for patients in whom goal BP cannot be attained using the above strategy or for the management of complicated patients If goal BP cannot be reached with 2 drugs, add and titrate a third drug . CRISIS HYPERTENSIVE • Rarely but life threatening situation (emergency) • DBP > 150 mmHg in healthy person; DBP >130 mmHg in individual with preexixting complication (encelopathy, cerebral hemorrhage, left ventricular failure, aortic stenosis) • Therapeutic goal : Rapidly reduce blood pressure choose drugs with rapid onset Sodium Nitroprusside. • Administered IV • Cause reflex tachycardia • Acting equally in arterial and veous smooth muscle can reduce cardiac preload. • Metabolized rapidly require continuous infusion to maintain hypotensive action. • Metabolit : cyanide ion • Labetalol – α and βblocker – Administered by IV bolus or infusion. – Does not cause reflex tachycardia • Fenoldopam – Peripheral dopamine- 1 receptor agonist. – Administerd by IV infusion – Lower blood pressure and also increase renal perfusion – Contraindicated in patient with glucoma. • Nicardipne – Can be given as intravenous infusion. • Minoxidil – Dilatation of arteriole but not venules. – For severe to malignant hypertention that is refractory to other drugs. – Concomitant with other drug to diminish side effect. – Side effect : hypertrichosis, water nad sodium retention. Post Test 1. 2. 3. 4. 5. Candesartan adalah obat antihipertensi golongan .... Lisnopril adalah obat antihipertensi golongan .... Furosemid adalah obat antihipertensi golongan .... Amlodipine adalah obat antihipertensi golongan .... Penderita hipertensi denngan penyakit ginjal kronis, maka pilihan obat antihipertensinya adalah .... 6. Untuk hipertensi emergensi dipilih obat antihipertensi yang ........, contoh : ..... 7. Efek samping kaptopril antara lain ... 8. Seorang pasien hipertensi derajat 1 dengan riwayat asma bronkiale, golongan obat antihipertensi yang harus dihindari adalah ... 9. Seorang pasien terdiagnosis hipertensi dan edema pretibial. Obat antihipertensi yang juga dapat menurunkan edemanya adalah .... 10. Seorang pasien 50 tahun dengan riwayat hipertensi, pada pemeriksaan tekanan darah didapatkan 200/150 mmHg. Obat antihipertensi pilihan untuk pasien tersebut adalah .... Tuliskan Resep • Ny. T, 50 tahun. Hasil pemeriksaan tekanan darah masih tinggi setelah dilakukan modifikasi gaya hidup. Tekanan darah terakhir : 150/90 mmHg. Tidak ada penyakit komorbid lainnya. Berikan resep obat antihipertensi untuk Ny. T. Tugas : Buat Artikel Rumusan Masalah : 1. Bagaimana pedoman pemilihan obat antihipertensi yang akan diberikan kepada pasien yang terdiagnosis hipertensi ? 2. Apakah ada golongan obat antihipertensi yang lebih superior dibandingkan golongan antihipertensi lainnya?
