Pengelolaan Hipertensi

dr. Wuryanto, SpPD-KGH

Topik
Latar Belakang; Mengapa harus diturunkan? CV Assessment Definisi hipertensi Compelling indication Target tekanan darah Algoritme Pengobatan non-farmakologik Pilihan obat hipertensi

Mengapa tekanan darah harus diturunkan ?

Cardiovascular Mortality Risk Increases as Blood Pressure Rises*

8

8x

Cardiovascular Mortality Risk

7 6 5 4 3 2 1 0

4x 2x

115/75 135/85 155/95 175/105 Systolic/Diastolic Blood Pressure (mm Hg)

*Measurements

taken in individuals aged 4069 years, beginning with a blood pressure of 115/75 mm Hg.
Slide Source Hypertension Online www.hypertensiononline.org

Lewington S, et al. Lancet. 2002;360:1903-1913; Chobanian AV, et al. JAMA. 2003;289:2560-2572.

Impact of High-Normal Blood Pressure on Risk of Major Cardiovascular Events* in Men

Cumulative Incidence of Major Cardiovascular Events (%)
16 14 12 10 8 6 4 2 0 0 2 4 6 8 10

Blood Pressure:
High-Normal 130139/8589 mm Hg Normal
120129/8084 mm Hg

Optimal

<120/80 mm Hg

12

Time (Years)
*Defined as death due to cardiovascular disease or as having recognized myocardial infarction, stroke, or congestive heart failure.
Vasan RS. N Engl J Med. 2001;345:1291-1297.
Slide Source Hypertension Online www.hypertensiononline.org

From Lewington S, Clarke R, Qizilbash N, et al: Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective Slide Source Hypertension Online studies. Lancet 360:19031913, 2002
www.hypertensiononline.org

Complications of Hypertension: End-Organ Damage

Hypertension
Hemorrhage, Stroke LVH, CHD, CHF

Retinopathy
CHD = coronary heart disease CHF = congestive heart failure LVH = left ventricular hypertrophy

Peripheral Vascular Disease

Renal Failure, Proteinuria

Slide Source Hypertension Online www.hypertensiononline.org

Chobanian AV, et al. JAMA. 2003;289:2560-2572.

Antihypertensive Treatment Can Reduce Cardiovascular Events in Diabetic Patients

Hypertension Optimal Treatment Study
Target DBP
(mm Hg)

Achieved SBP*
(mm Hg)

Achieved DBP*
(mm Hg)

Events Per 1000 Patient-Years

Patients with Diabetes

30 25 20 15 10 5 0

P = 0.005

90 85 80
*Mean

143.7 141.4 139.7

85.2 83.2 81.1

501 501 499

of all blood pressures for all study patients in the blood pressure subgroups from 6 months of follow-up to the end of the study.

DBP = diastolic blood pressure

SBP = systolic blood pressure Events include all myocardial infarctions, all strokes, and all other cardiovascular deaths.
Hansson L, et al. Lancet. 1998;351:17551762.

Slide Source Hypertension Online www.hypertensiononline.org

Absolute and relative risk for a cardiovascular disease event in a high- and low-risk 55-year old man by systolic blood pressure. See text. (From Lewington S, Clarke R, Qizilbash N, et al: Agespecific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data Slide Source for one million adults in 61 prospective studies. Lancet 360:19031913, 2002.)
Hypertension Online www.hypertensiononline.org

Oxidative Stress: Endothelial Dysfunction and CAD/Renal Risk Factors

Hypertension
Diabetes Smoking LDL Homocysteine Estrogen deficiency

O2 Endothelial Cells and H2O2 Vascular Smooth Muscle

Endothelial Dysfunction
Apoptosis Leukocyte adhesion Lipid deposition Vasoconstriction VSMC growth Thrombosis

Slide Source Hypertension Online www.hypertensiononline.org

Assessment of the overall cardiovascular risk

Over 90% of hypertensive have other cardiovascular
risks

Assess and manage hypertensive patients for

dyslipidemia, dysglycemia (e.g. impaired fasting glucose, diabetes) abdominal obesity, unhealthy eating and physical inactivity

2009 Canadian Hypertension Education Program Recommendations

Slide Source Hypertension Online www.hypertensiononline.org

Assessment of the overall cardiovascular risk

Search for target organ damage
Cerebrovascular disease - transient ischemic attacks - ischemic or hemorrhagic stroke - vascular dementia Hypertensive retinopathy Left ventricular dysfunction Left ventricular hypertrophy Coronary artery disease - myocardial infarction - angina pectoris - congestive heart failure Chronic kidney disease - hypertensive nephropathy (GFR < 60 ml/min/1.73 m2) - albuminuria Peripheral artery disease - intermittent claudication - ankle brachial index < 0.9

2009 Canadian Hypertension Education Program Recommendations

Slide Source Hypertension Online www.hypertensiononline.org

Assessment of the overall cardiovascular risk

Search for exogenous potentially modifiable factors that can induce/aggravate hypertension
Prescription Drugs:
NSAIDs, including COXIBS (e.g. celecoxib)

Corticosteroids and anabolic steroids

Oral contraceptive and sex hormones Vasoconstricting/sympathomimetic decongestants Calcineurin inhibitors (cyclosporin, tacrolimus) Erythropoietin and analogues Monoamine oxidase inhibitors (MAOIs) Other sympathomemetics e.g. Midodrine

Other:
Licorice root Stimulants including cocaine

Salt
Excessive alcohol use

Sleep apnea 2009 Canadian Hypertension Education Program Recommendations

Slide Source Hypertension Online www.hypertensiononline.org

ESH/ESC Definition and Classification of Blood Pressure Levels (mm Hg)

Category Systolic 120 120-129 130-139 140-159 160-179 180 140 and and/or and/or and/or and/or and/or and Diastolic 80 80-84 85-89 90-99 100-109 110 90

Optimal Normal
High Normal Grade 1 Hypertension Grade 2 Hypertension Grade 3 Hypertension Isolated Systolic Hypertension

Mancia G, et al. J Hypertens 2007;25:1105-1187

Slide Source Hypertension Online www.hypertensiononline.org

Cardiovascular Risk Stratification

Blood pressure (mm Hg) Other risk factor, organ damage, or disease No other risk factors 1-2 risk factors 3 risk factors, mets, organ damage, or diabetes Established CV or renal disease High normal Average risk Grade 1 HT Low added risk Moderate added risk High added risk Very high added risk Grade 2 HT Moderate added risk Moderate added risk High added risk Very high added risk

Normal Average risk

Grade 3 HT High added risk Very high added risk Very high added risk Very high added risk

Low added Low added risk risk Moderate added risk Very high added risk High added risk Very high added risk

HT: hypertension; mets: metabolic syndrome; CV: cardiovascular

Mancia G, et al. 2007 ESH/ESC Guidelines for the Management of Arterial Hypertension. J Hypertens 2007;25:1105-1187

Target Pengobatan

A gradual reduction in blood pressure is desirable in hypertensive patients in general, particularly in elderly patients,
Target control level should be achieved within a few weeks in high-risk patients, such as those with grade III hypertension and multiple risk factors.
Japan Society of Hypertension 2009

Current Blood Pressure Targets for Various Chronic Conditions

Uncomplicated Hypertension

140
90

Systolic Blood Pressure

Chronic Kidney Disease Coronary Artery Disease Diabetes

130
80

Diastolic Blood Pressure

mm Hg

American Diabetes Association. Diabetes Care. 2003;26:S80-S82; Hansson L, et al. Lancet. 1998;351:1755-1762; National Kidney Foundation. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-S266; Rosendorff C, et al. Circulation. 2007;115:2761-2788.

Slide Source Hypertension Online www.hypertensiononline.org

TERAPI HIPERTENSI
Non-farmakologik
Farmakologik JNC VII 2004: berjenjang dan compelling indications BHS-NICE 2006 : terapi sekuensial Pengobatan awal dan kombinasi :
ESH-ESC 2009, CHEP 2009, JHS 2009

Modifikasi gaya hidup untuk pengendalian Hipertensi

Modifikasi Rekomendasi
Pelihara berat badan normal (BMI 18.5-24.9) Konsumsi makanan kaya buah, sayur, susu rendah lemak dan rendah lemak jenuh Penurunan Tekanan Darah Sistolik kurang lebih

Menurunkan berat badan

Menjalankan menu DASH Mengurangi asupan garam/sodium Meningkatkan aktifitas fisik
Kurangi konsumsi alkohol

5-20 mm Hg utk setiap penurunan 10 kg BB 8-14 mm Hg

Kurangi natrium sampai tidak 2-8 mm Hg lebih dari 2.4 g/hari atau NaCl 6 g/hari

Berolahraga erobik teratur seperti misalnya berjalan kaki (30 men/hari 4-5 hari seminggu)

4-9 mm Hg

Batasi konsumsi alkohol,jangan 2-4 mm Hg lebih dari 2 /hari utk pria dan 1 /hari utk perempuan. Source: The Seventh Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure JNCVII. JAMA. 2003;289:2560-2572.

The BHS recommendations for combining blood pressure-lowering drugs

<55 years aaaaaaaaaa
Step 1 A A + C or A + D

55 years or black patients at any age

C or D

Step 2

Step 3

Step 4

Add: further diuretic therapy or alpha-blocker or beta-blocker

Consider seeking specialist advice

A: ACE inhibitor or ARB, if ACE inhibitor intolerant C: Calcium-channel blocker D: Diuretic (thiazide)
BHS, British Hypertension Society; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker
National Collaborating Centre for Chronic Conditions. Hypertension: management in adults in primary care: partial update. London: Royal College of Physicians, 2006

2006 update

Hypertension treatment strategy: ESH/ESC 2007

Mild BP elevation Low/moderate CV risk Conventional BP target

Choose between:

Marked BP elevation High/very high CV risk Lower BP target

Single agent at low dose If goal BP not achieved

Two-drug combination at low dose

Previous agent at full dose

Switch to different agent at low dose

Previous combination at full dose

Add a third drug at low dose

If goal BP not achieved Two- to three-drug combination

BP, blood pressure

Full-dose monotherapy

Two-three-drug combination at effective doses

ESH/ESC Guidelines 2007 European Heart Journal. 2007;28:1462-1536

Follow-up of blood pressure above targets

Patients with blood pressure above target are
recommended to be followed at least every 2nd month

Follow-up visits are used to increase the intensity of

lifestyle and drug therapy, monitor the response to therapy and assess adherence

History of antihypertensive drugs

Effectiveness and general tolerability

1940s 1950 Direct vasodilators Peripheral sympatholytics Ganglion blockers Veratrum alkaloids 1957 1960s 1970s Alphablockers 1980s 1990s 2000 2007

ARBs ACE inhibitors

DRI

Thiazide diuretics

Central 2 agonists

Calcium antagonistsnon-DHPs

Calcium antagonistsDHPs

Betablockers
DHP, dihydropyridine; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker

Main classes of antihypertensive drugs

Diuretics
Inhibit the reabsorption of salts and water from kidney tubules into the bloodstream

Calcium-channel antagonists
Inhibit influx of calcium into cardiac and smooth muscle

Beta-blockers
Inhibit stimulation of beta-adrenergic receptors

Angiotensin-converting enzyme (ACE) inhibitors

Inhibit formation of angiotensin II

Angiotensin II receptor blockers (ARBs)

Inhibit binding of angiotensin II to type 1 angiotensin II Receptors

Vasodilators Direct renin inhibitors

JAPAN HYPERTENSION SOCIETY 2009 Treatments of Hypertension

1. The antihypertensive drug to be first administered alone or
concomitantly with other drugs should be selected from Ca channel blockers, angiotensin-receptor blockers (ARBs),angiotensin-converting enzyme (ACE) inhibitors, diuretics and b-blockers.

2. Appropriate antihypertensive drugs should be selected considering positive indications, contraindications, conditions that require the careful use of drugs and the presence or absence of complications. 3. Administered once a day, but as it is more important to control the BP over 24 h, splitting the dose into twice a day is desirable in some situations.

2007 ESH/ESC Guidelines

Diuretics

-blockers

AT1-receptor blockers

1-blockers

CCBs

ACE inhibitors

Treatment of hypertension

Each drug class has contraindications as

well favorable effects in specific clinical settings. The choice of drug(s) should be made according to this evidence.

The traditional ranking of drugs into first,

second, third, and subsequent choice, with an average patient as reference, has now little scientific and practical justification and should be avoided

Mancia et al. Reappraisal of ESH-ESC Guidelines 2009

Thiazide Diuretics
Veins Mechanism: inhibit Na/K pumps in the distal tubule

Examples:
Hydrocholorthiazide 12.5-25 mg daily

Thiazides

Chlorthalidone 12.5-50 mg daily

Effective first line agent and provides synergistic benefit

As single agent more effective if CrCl >30 ml/min Compelling indications: HF, High CAD risk, Diabetes, Stroke, ISH

Loop Diuretics
Veins Mechanism: Inhibit Na/K/Cl ATPase in ascending loop of henle

Examples:
Furosemide 20 mg BID

Thiazides Loops

Typically only beneficial in patients with resistant HTN and evidence of fluid; effective if CrCl <30 ml/min MUST be dosed at least twice daily (Lasix = Lasts six hours) Administer AM and lunch time to avoid nocturia

Aldosterone Receptor Antagonists

Veins Mechanism: inhibit aldosterones effect at the receptor, reducing Na and water retention Examples: Thiazides Loops Aldosterone Ant.
Spironolactone 25 mg daily

Can provide as much as 25 mmHg BP reduction on top of 4 drug regimen in resistant hypertension Monitor SCr and K Compelling indications: HF
Am J Hypertension. 2003; 16:925-930.

Beta Blockers
Heart Mechanism: Competitively inhibit the binding of catecholamines to beta-adrenergic receptors Examples: Beta Blockers
Atenolol 25-100 mg QD, Metoprolol 25 100 mg BID, Bisoprolol 2.5 10 mg QD Carvedilol 6.25-50 mg (alfa+Beta)BID

Monitor: HR, Blood Glucose in DM Not contraindicated in asthma or COPD but use caution Compelling indications: HF, post-MI, High CAD risk, Diabetes

Calcium Channel Blockers Non-Dihydropyridine: Diltiazem and Verapamil

Arteries Heart

Mechanism: Decrease calcium influx into cells of vascular smooth muscle and myocardium Examples:
Diltiazem Long acting; CD 100 -400 mg

Diltiazem Verapamil

Verapamil 60-480 mg, long acting SR

Monitor: HR Verapamil causes constipation Relatively contraindicated in heart failure Compelling indications: Diabetes, High CAD risk

Calcium Channel Blockers: Dihydropyridine

Arteries

Mechanism: Decrease calcium influx into cells of vascular smooth muscle

Examples:
Dihydropyridine CCBs
Amlodipine 2.5-10 mg PO daily Felodipine 2.5-10 mg PO daily OROS/GITS. Do not use immediate release nifedipine

Monitor: Peripheral edema, HR (can cause reflex tachycardia) Good add on agent if cost is not an issue

ACEI
Veins
Arteries Mechanism: Inhibit vasoconstriction by inhibiting synthesis of angiotensin II; provides balanced vasodilation

Examples:
ACEI
ACEI: Captopril 12.5 -50 BID, Enalapril 2.540 mg daily BID, Lisinopril 5 40 mg daily, Imidapril 5-10 QD, Perindopril 4-8 mg QD, Ramipril 2.5-20 mg

Monitor: S Cr, K Compelling indications: HF, post-MI, High CAD risk, Diabetes, CKD, Stroke

Renin-Angiotensin Cascade
Angiotensinogen
Non-renin (eg tPA)

Renin Bradykinin

Angiotensin I
Non-ACE (eg chymase)

ACE
Inactive peptides
Slide Source Hypertension Online www.hypertensiononline.org

Angiotensin II
AT1 AT2

ATn

ARBs
Veins
Arteries Mechanism: Inhibit vasoconstriction by blocking action of angiotensin II; provides balanced vasodilation

Examples:
ARB
ARB: Irbesartan 150-300 mg QD, Losartan 25-100 mg BID, Olmesartan 20-40 mg, Telmisartan 20-80 mg, Valsartan 90-160 mgQD

Monitor: S Cr, K Compelling indications: HF, post-MI, High CAD risk, Diabetes, CKD, Stroke

Angiotensin II (Ang II) generated in the afferent arteriole interacts with AT1 receptors on cellular components of the nephron

Angiotensinogen

Ang I

ACE

Ang II

Renin

AT1R

= AT1 Receptor
Slide Source Hypertension Online www.hypertensiononline.org

Pathologic Processes Leading to Glomerular Injury and Proteinuria

Glucose
Glycoxidation (glycation)

Urinary protein

AGEs

=angiotensin AT1 receptor

Increased glomerular pressure

Efferent arteriolar constrictio n

Ang II

Ang II

Slide Source Hypertension Online www.hypertensiononline.org

Alpha1 Blockers
Arteries

Mechanism: Inhibit peripheral postsynaptic alpha1 receptors causing vasodilation Examples:

Terazosin 1 20 mg daily Doxazosin 1 16 mg daily

Alpha1 Blockers

Cause marked orthostatic hypotension, give dose at bedtime Consider only as add on therapy Can be beneficial in patients with BPH

Central Acting Agents

Heart

Mechanism: false neurotransmitters reduce sympathetic outflow reducing sympathetic tone

Examples:
Clonidine 0.75-0.6 mg bid, Methyldopa 250 mg-1000 mg BID (Pregnancy), Reserpin 0,1 -0,25 mg QD

Central Acting Mechanism: Clonidine

Monitor: HR (bradicardia)
Side effects often limiting: Dry mouth, orthostasis, sedation

Withdrawal/Rebound effect

Vasodilators
Arteries

Mechanism: Direct vasodilation of arterioles via increased intracellular cAMP

Examples:
Dihydropyridine CCBs Hydralazine Minoxidil
Hydralazine 20-400 mg BID-QID Minoxidil 2.5-40 mg PO daily-BID

Monitor: HR (can cause reflex tachycardia), Na/Water retention Hydralazine is an alternative in HF if ACEI contraindicated Consider minoxidil in refractory patients on multi-drug regimens

NEW ANTIHYPERTENSIVE AGENTS

Direct Renin Inhibitor; ALISKIREN Monotherapy effective in lowering SBP and DBP in hypertensive patients Effective also in combination with a thiazide diuretic, a CCB and an ACE inhibitor or an ARB Protect against subclinical organ damage when combined with an ARB
= the available evidence justifies its use in hypertension, in combination with other agents.
Mancia et al.Reappraisal of ESC Hypertension Guidelines 2007

Aliskiren reduces Ang I, Ang II and PRA

Direct renin inhibitor
Angiotensinogen Renin

Ang I
Non ACE pathways

ACE

Feedback Loop
Ang II

ACEIs ARBs
AT1 Receptor

Ang I ACEI

Ang II

Renin

PRA

ARB
Aliskiren

Azizi M et al. 2006; Adapted from: Mller DN & Luft FC. 2006