*Antihypertensive DrugsDR. Dr Umi Kalssum Mkes

*Hypertension is defined as systolic blood pressure (SBP) of 140 mmHg or greater, diastolic blood pressure (DBP) of 90 mmHg or greater, VI I JNC, (The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)

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Drugs Used in HypertensionObjectives:Untuk meninjau etiologi hipertensiUntuk membahas penentu utama tekanan darahUntuk memahami strategi terapi yang digunakan dalam pengobatan tekanan darah tinggiUntuk menggambarkan kelompok utama obat yang digunakan dalam pengobatan tekanan darah tinggi. To review the etiology of hypertensionTo discuss the major determinants of blood pressureTo understand the therapeutic strategies used in the treatment of high blood pressureTo describe the major classes of drugs used in the treatment of high blood pressure.

*Hypertensive CrisisBP = 210/150Drugs that may be used:Sodium NitroprussideDilates arterial and venous smooth muscleDiazoxidevasodilatorLabetolol- and -blockerDrug of choice

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*1999 WHO Guidelines :Definitions and Classifications of BP Levels SBP DBP Category* (mm Hg) (mm Hg) Optimal < 120 < 80Normal < 130 < 85High-normal 130-139 85-89Grade 1 hypertension (mild) 140-159 90-99 Borderline subgroup 140-149 90-94Grade 2 hypertension (moderate) 160-179 100-109Grade 3 hypertension (severe) > 180 > 110

*What Determines Arterial Pressure?Arterial PressureCardiac OutputPeripheralResistance~~XResist p.dVisk darah

* Heart Rate = Chronotropy

2) Contractility = Inotropy

3) Venous Return = Preload

4) Total Peripheral Resistance = AfterloadFaktor yang menentukan Cardiac Output

*Penyakit yang dihubungkan dengan HypertensiHYPERTENSIONGangrene of the Lower ExtremitiesHeart FailureLeft Ventricular HypertrophyMyocardial InfarctionHypertensive EncephalopathyAortic AneurymBlindnessChronic Kidney FailureStrokePreeclampsi/EclampsiaCerebral HemorrhageCoronary Heart Disease

*Types of hypertensionEssential hypertension90%Tidak diketahui penyebabnyaSecondary hypertensionDisebabkan oleh penyakit tertentu

*Causes of Secondary HypertensionRenalParenchymalVascularOthersEndocrineNeurogenicMiscellaneous Unknown

*Hypertension: Predisposing factorsAge > 60 yearsSex (men and postmenopausal women)Family history of cardiovascular diseaseSmokingHigh cholesterol dietCo-existing disorders such as diabetes, obesity and hyperlipidaemiaHigh intake of alcoholSedentary life style

*Life style modificationsLose weight, if overweightLimit alcohol intakeIncrease physical activityReduce salt intakeStop smokingLimit intake of foods rich in fats and cholesterol

*Approaches For High Blood Pressure TreatmentNon-Pharmacological:Obesity, diet, stressful lifestyle, cigarette smoking, exercisePharmacological therapy: Antihypertensive Drugs

*TUJUAN TERAPI MENGHILANGKAN GEJALA

MEMPERPANJANG HIDUP

MENCEGAH KOMPLIKASI

*Antihypertensive DrugsThe Problem:Sustained diastolic pressure can lead to CHF, infarction, end-organ damagePossible Solutions:Mild Htn can be treated with a single drugSevere Htn treated with several drugs, choice of which depends on patient needs

*Some Examples of Antihypertensive DrugsBeta BlockersAtenolol, Metoprolol , Acebutolol

DiureticsHydrochlorothiazide, spironolactoneACE InhibitorsCaptoprilCalcium Channel BlockersNifedipine, Amlodipin , Nifedipin , verapamil

Centrally-Acting DrugsClonidine , Methyldopa VasodilatorsHydralazine , Minoxidil

*Beta blockersExample: AtenololBlock b1 receptors on the heartBlock b2 receptors on kidney and inhibit release of reninDecrease rate and force of contraction and thus reduce cardiac outputDrugs of choice in patients with co-existent coronary heart diseaseKelemahan Adverse effects: lethargy, impotency, bradycardiaNot safe in patients with co-existing asthma and diabetesHave an adverse effect on the lipid profile

*-adrenoceptor blocker (propranolol, atenolol, metoprelol)-blockers and/or diuretics are currently recommended as first-line drug therapy for hypertension.Their main effect is CO, also they inhibit the release of renin from the kidneys.Side effects: CNS (fatigue-lethargy-insomnia) - sexual dysfunction - rebound hypertension

*Rebound PhenomenaPenghentian mendadak beta blocker memicu timbulnya myocardial infarctionKontra Indikasi :AsthmaPeripheral Vascular DiseaseRelative contraindicationHeart failureBradycardia / Heart block

*Adverse Drug ReactionsfatigueLethargyImpotenceBradycardiaBronchospasm

*VasodilatorsHow do they work? Mechanism 1:ACE converts Angiotensin I to Angiotensin IIAngio II has effects as shownACE inhibitors decrease A IIEnd Results:Decrease fluid retention, afterloadExamples:Enalapril, Captapril

Angiotensin IACE SympatheticOutputConstrictVascular SmoothMuscle Na+/H20Retention Bradykinin

*Renin/Angiotensin/Aldosterone System afterloadCardiacPerformance

*Direct Smooth Muscle Relaxants (Nitrovasodilators)

*Other Vasodilators:Mechanism 2: Direct smooth muscle relaxantsNitratesVenous dilatorsReduce preloadEg: sodium nitroprusideCalcium channel blockersAmlodipine, felodipene

*DiureticsBottom line: they decrease fluid volumesAda 4:Carbonic anhydrase inhibitorsLoop diureticsThiazide diureticsK+-sparing

*DiureticsExample: HydrochlorothiazideAct by decreasing blood volume and cardiac outputDecrease peripheral resistance during chronic therapyDrugs of choice in elderly hypertensivesKELEMAHAN :HypokalaemiaHyponatraemiaHyperlipidaemiaHyperuricaemia (hence contraindicated in gout)Hyperglycaemia (hence not safe in diabetes)Not safe in renal and hepatic insufficiency

*Therapeutic Agents that Alter Cardiac Contractility (Inotropy) - Agonists - AntagonistsCardiac GlycosidesCalcium Channel BlockersPhosphodiesterase Inhibitors (?)

*Renin, Angiotensin, Aldosterone System(RAAS)() Renal Perfusion() RAAS() TPR (A-II: direct & indirect)() Na+/H20 retention (Aldosterone)() Blood Volume

*Calcium Channel Blockers:Phenylalkylamine: VerapamilBenzothiazipine: DiltiazemDihydropyridines: Nifedipine, et al.

*Calcium Channel Blockers

*Love - Hate Triangle :

*Calcium channel blockersExample: AmlodipineBlock entry of calcium through calcium channelsCause vasodilation and reduce peripheral resistanceDrugs of choice in elderly hypertensives and those with co-existing asthmaNeutral effect on glucose and lipid levelsDrawbacksAdverse effects: Flushing, headache, Pedal edema

*ACE inhibitorsExample: Lisinopril, EnalaprilInhibit ACE and formation of angiotensin II and block its effectsDrugs of choice in co-existent diabetes mellitusDrawbacksAdverse effect: dry cough, hypotension, angioedema

*Angiotensin II receptor blockersExample: LosartanBlock the angiotensin II receptor and inhibit effects of angiotensin IIDrugs of choice in patients with co-existing diabetes mellitusDrawbacksAdverse effect: dry cough, hypotension, angioedema

*Alpha blockersExample: DoxazosinBlock a-1 receptors and cause vasodilationReduce peripheral resistance and venous returnExert beneficial effects on lipids and insulin sensitivityDrugs of choice in patients with co-existing hyperlipidaemia, diabetes mellitus and BPHDrawbacksAdverse effects: Postural hypotension

*Peripheral 1-receptor antagonists (Prazocin - Terazocin)Competitive blockers of 1-adrenoceptorsThey decrease TPR BPThey are used in combination with -blockers or diuretics for additive effectsSide effects: Reflex tachycardia - postural hypotensionPenggunaan -blocker diperlukan mengurangi efek jangka pendek reflex tachycardia

*Antihypertensive therapy:Side-effects and ContraindicationsClass of drugsMain side-effects Contraindications/ Special PrecautionsDiuretics Electrolyte imbalance, Hypersensitivity, Anuri(e.g. Hydrochloro- total and LDL cholesterol thiazide) levels, HDL cholesterol levels, glucose levels, uric acid levelsb-blockersImpotence, Bradycardia,Hypersensitivity, (e.g. Atenolol)FatigueBradycardia, Conduction disturbances, Diabetes, Asthma, Severe cardiacfailure

*Class of drugMain side-effectsContraindications Calcium channel blockers Pedal edema, Headache Non-dihydropyridine (e.g. Amlodipine, CCBs (e.g diltiazem) Diltiazem) Hypersensitivity, Bradycardia, Conduction disturbances, Congestive heart failure Left ventriculardysfunction. Dihydropyridine- Hypersensitivity

a-blockersPostural hypotensionHypersensitivity (e.g. Doxazosin)

ACE-inhibitorsCough, Hypertension,Hypersensitivity, (e.g. Lisinopril) Pregnancy, Angioneurotic edemaBilateral renal artery stenosis

Angiotensin-II receptorHeadache, DizzinessHypersensitivity, Pregnancy, blockers (e.g. Losartan)Bilateral renal artery stenosisAntihypertensive therapy: Side-effects and Contraindications

*Keuntungan Terapi Kombinasi Better blood pressure controlLesser incidence of individual drugs side-effectsNeutralisation of side-effectsIncreased patient complianceLesser cost of therapy

*Fixed-dose combinations as recommended byJNC-VI (1997) guidelines and 1999 WHOguidelinesCalcium channel blocker and b-blocker (e.g. Amlodipine and Atenolol)Calcium channel blocker and ACE-inhibitor (e.g. Amlodipine and Lisinopril)ACE-inhibitor and Diuretic (e.g. Lisinopril and Hydrochlorothiazide)b-blocker and Diuretic (e.g. Atenolol and Hydrochlorothiazide)

*Drugs in special conditionsConditionPregnancy Coronary heart diseaseCongestive heart failurePreferred DrugsNifedipine, labetalol, hydralazine, beta-blockers, methyldopa, prazosinBeta-blockers, ACE inhibitors, Calcium channel blockersACE inhibitors, beta-blockers1999 WHO-ISH guidelines

*Atrioventricular and Semilunar Valves

*ValvesSEMILUNAR VALVES Ventricle contracts: openVentricle relaxes: closed

Cardiac CycleSystole: contraction.Diastole: relaxation.

*Heart DiseaseArrhythmias = abnormal heart rhythms.Bradycardia = slowerTachycardia = faster (exercise!)Flutter: extremely rapidFibrillation:Contractions of different groups of myocardial cells at different times.Ventricular fibrillation is life-threatening.

*Drug -Drug InteractionsPrimarily PharmacodynamicHypotension when used with other hypotensive agentsBradycardia when used with other rate limiting drugs such as verapamil or diltiazemCardiac failure when used with negatively inotropic agents such as verapamil, diltiazem or disopyramideNSAIDs antagonise antihypertensive actions

*Calcium Channel BlockersDILTIAZEM, VERAPAMIL, AMLODIPINEPrevent calcium influx into myocytes and smooth muscle lining arteries and atrerioles by blocking the voltage dependent L-Type calcium channelRate limiting CCBs like diltiazem and verapamil also reduce heart rateCCBs like nifedipine or amlodipine may produce a reflex tachycardia

*Mechanism of ActionIncreased free calcium in the cytoplasm of vascular smooth muscle cells leads to vasoconstriction.

The calcium ion, after binding to calcium-binding proteins, activates a myosin light-chain kinase (MLCK), causing phosphorylation of myosin filaments followed by an interaction of these filaments with actin filaments and finally cell contraction.

*The calcium ion can enter the vascular smooth muscle cell by two main channels. The receptor-regulated channels cause, upon activation with an agonist (eg, angiotensin II, norepinephrine, endothelin), the formation of inositol trisphosphate (IP3).This intracellular messenger triggers the release of calcium from the sarcoplasmic reticulum (SR). The rapid calcium mobilization by this pathway stimulates then sustains entry of calcium through the channel.Calcium antagonists block voltage-dependent channels. These channels allow the entry of calcium in response to cell depolarization.

*Renin-Angiotensin Aldosterone SystemAngiotensinogenNon-ACE Pathways (e.g., chymase)VasoconstrictionCell growthNa/H2O retentionSympathetic activationreninAngiotensin IAngiotensin IIACECough, AngioedemaBenefits? BradykininInactive FragmentsVasodilationAntiproliferation (kinins)AldosteroneAT2AT1

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*Akibat apabila tek. Darah tinggi tidak diobatiIncrease morbidity and mortality due to accelerated atherosclerosis (sudden death, aortic aneurysm, stroke, renal insufficiency)The higher the blood pressure the higher the risk of cardiovascular diseases (CHF, coronary disease)

*HERDITYENVIRONMENTPREHYPERTENSION (AGE 0-30)INCREASED CARDIAC OUTPUTEARLY HYPERTENSION (AGE 20-40)INCREASED PERIPHERAL RESISTANCEESTABLISHED HYPERTENSION (AGE 30-50)ACCELERATED ATHEROSCLEROSISCOMPLICATED HYPERTENSION (AGE 40-50)CARDIACEnlargementFailure, InfarctionAORTICAneurysm, embolizationRENALArteriosclerosis,InsufficiencyCEREBRAL Thrombosis, hemorrhage,embolization

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*Angiotensin Converting Enzyme Inhibitors (e.g., captopril)Angiotensin-II type 1 (AT1) receptor blockers (e.g., losartan)captoprillosartan

*CNS 2-agonists(Clonidine - -methyldopa)Stimulation of 2-receptors in the medulla sympathetic outflow TPR BPGenerally used as second-line agents, after diuretics, in the treatment of hypertension-methyldopa is converted to -methyl-nor epinephrineSides effects include sedation, dry mouth and bradycardiaRebound hypertension occurs following abrupt withdrawal of these drugs.

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*****Angiotensin-receptor blockers, or ARBs, provide an opportunity to inhibit the renin-angiotensin system directly at the angiotensin II type 1 receptor level, which has been postulated to provide more complete inhibition of the deleterious effects of angiotensin. Alternatively, because ACE inhibitors (kininase II inhibitors) also reduce bradykinin breakdown, the combination of an ACE inhibitor plus an ARB may result in incremental clinical benefits. These assumptions must be rigorously tested as direct comparisons of these three modes of inhibiting the renin-angiotensin system to provide the quantitative data needed to guide clinical practice.