Current Concepts in Pharmachotherapy in

Hypertension

Army Cardiac Centre Lahore Pakistan

Brig Afsar Raza

FCPS (Medicine), FCPS( Cardiology), MRCP(UK),CCST Cardiology (UK)

Commandant Army Cardiac Centre

Consultant Cardiologist & Physician

Hypertension : High Prevalence & Growing Incidence in Pakistan

• Accounts for over 100,000 deaths a year or 12% of all cause mortality .

• Overall 18% of adults in Pakistan suffer from hypertension: 21.5% in urban areas and 16.2% in rural areas.

• One in every 3 adults over age 45 suffer from hypertension.

• Very few Pakistanis with hypertension (<3%) have their B.P controlled.

PROCOR: 7/25/99 The National Health Survey in Pakistan published in 1998 by (PMRC)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

US CanadaAustralia Pakistan**IndiaFinland Scotland EnglandGermany Spain

*

* Controlled defined as <140/90 mm Hg; other countries <160/95 mm Hg

Percent of Patients Controlled

J Hum Hypertens 1997;11(4):213-220 ** 3% controlled: Data from Pakistan Hypertension League

Levels of blood-pressure control in different countries: Only 3% controlled in Pakistan

Benefits of Lowering BP

Average Percent Reduction

Stroke incidence 35–40%

Myocardial infarction 20–25%

Heart failure 50%

5

Benefits of Lowering BP

Ref : EWPHE, LANCET, 1985; 1349-1954 SHEP, JAMA’ 1991; 265: 3255-3264Ref : EWPHE, LANCET, 1985; 1349-1954 SHEP, JAMA’ 1991; 265: 3255-3264

To Prevent Target Organ Damage

Heart• Left ventricular hypertrophy• Angina or prior myocardial infarction• Prior coronary revascularization• Heart failure

Brain• Stroke or transient ischemic attack

Chronic kidney disease

Peripheral arterial disease (PVD) Eye: Retinopathy

Benefits of Lowering BP

In stage 1 HTN and additional CVD risk factors, achieving a sustained 12 mmHg reduction in SBP over 10 years will

prevent 1 death for every 11 patients treated.

8

Goals of Therapy

Reduce CVD and renal morbidity and mortality.

Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients with diabetes or chronic kidney disease.

Achieve SBP goal especially in persons >50 years of age.

Blood Pressure Classification

Normal <120 and <80

Prehypertension 120–139 or 80–89

Stage 1 Hypertension 140–159 or 90–99

Stage 2 Hypertension >160 or >100

BP Classification SBP mmHg BP mmHg

TreatmentOverview

Goals of therapy

Lifestyle modification

Pharmacologic treatment• Algorithm for treatment of hypertension

Followup and monitoring

Traditional Treatment Approach

Hypertension systemic disease

Hemodynamics altered

Treat Blood Pressure

New Treatment Approach

Hypertension disease of blood vessels

Vascular biology altered

Control BP & Treat vasculature

(Endothelium)

Is it just BP control which is required or ......

CV Risk Factors affect Prognosis & Guide Treatment(JNC 7 Report)

>95% of hypertensives haveOther CV risk factors*

•Cigarette smoking•Obesity•Physical inactivity•Dyslipidemia•Diabetes mellitus•Microalbuminuria or estimated GFR <60 mL/min•Age (>55 years for men, >65 years for women)•Family history of premature CVD

High-risk Hypertension

95%

*Stern N, et al. J Intern Med. 2000;203-210JNC 7 Report JAMA, May 21, 2003- Vol 289, No. 19Hypertension with CV risk factors: Patients highly vulnerable for target organ damage

Identifiable Causes of Hypertension

Sleep apnea Drug-induced or related causes Chronic kidney disease Primary aldosteronism Renovascular disease Chronic steroid therapy and Cushing’s syndrome Pheochromocytoma Coarctation of the aorta Thyroid or parathyroid disease

Lifestyle Modification

Modification Approximate SBP reduction(range)

Weight reduction 5–20 mmHg/10 kg weight loss

Adopt DASH eating plan 8–14 mmHg

Dietary sodium reduction 2–8 mmHg

Physical activity 4–9 mmHg

Moderation of alcohol consumption/Smoking

2–4 mmHg

Classification and Management of BP for adults

BP classification

SBP* mmHg

DBP* mmHg

Lifestyle modification

Initial drug therapy

Without compelling indication

With compelling indications

Normal <120 and <80 Encourage

Prehypertension 120–139 or 80–89 Yes No antihypertensive drug indicated.

Drug(s) for compelling indications. ‡

Stage 1 Hypertension

140–159 or 90–99 Yes Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.

Drug(s) for the compelling indications.‡

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.

Stage 2 Hypertension

>160 or >100 Yes Two-drug combination for most† (usually thiazide-type diuretic and ACEI or ARB or BB or CCB).

*Treatment determined by highest BP category.†Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.‡Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.

Special Considerations

Compelling Indications

Other Special Situations

•Obesity and the metabolic syndrome• Peripheral arterial disease• Hypertension in older persons• Postural hypotension• Hypertension in women•Hypertension urgencies and emergencies

Compelling Indications

Compelling Indications for Individual Drug Classes

Compelling Indication Initial Therapy Options Clinical Trial BasisACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES

ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS

ALLHAT, HOPE, ANBP2, LIFE, CONVINCE

THIAZ, BB, ACEI, ARB, ALDO ANT

BB, ACEI, ALDO ANT

BB, ACE, CCB

Heart failure

Postmyocardialinfarction

High CAD risk

Diabetes

Chronic kidney disease

Recurrent stroke prevention

Compelling Indications for Individual Drug Classes

Compelling Indication Initial Therapy Options Clinical Trial Basis

NKF-ADA Guideline, UKPDS, ALLHAT

NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

PROGRESS

ACE, ARB, CCB , THIAZ,

ACEI, ARB, CCB

ACEI,ARBs, THIAZ,

Other Special Situations

Hypertension in OlderPersons

More than two-thirds of people over 65 have HTN.

This population has the lowest rates of BP control

Threshold for treatment Diastolic > 90mm Hg and systolic > 150-160 mm Hg over 3-6 months observation(despite life style intervention)

Lower initial drug doses may be indicated to avoid symptoms

Thiazide or CCB(Dihydroyridine). ACE or ARB may be added

Postural Hypotension

Decrease in standing SBP >10 mmHg, when associated with dizziness/fainting, more frequent in older SBP patients with diabetes, taking diuretics or venodilators drugs.

BP in these individuals should be monitored in the upright position.

Avoid volume depletion and excessively rapid dose titration of drugs.

Hypertension in Women

Oral contraceptives may increase BP, and BP should be checked regularly. In contrast, HRT does not raise BP.

Development of HTN—consider other forms of contraception.

Pregnant women with HTN should be followed carefully. Methyldopa, BBs, and vasodilators, preferred for the safety of the fetus. ACEI and ARBs contraindicated in pregnancy.

Hypertension in Pregnancy

May be due to pre existing essential HTN or pre-eclampsia.

Methyl dopa is safe

B Blockers are effective & safe in 3rd trimester

Modified release prep of Nifedepine

IV Labetalol for hypertensive crises

ACE and ARBs best avoided

Accelerated Hypertension (Diasstolic >140 mm Hg)

Requires hospitalization.

IV not necessary

Rapid reduction not recommended can reduce organ perfusion; cerebral or myocardial ischemia

Long acting CCB(Amlodipine or modified release Nifedipine) or B Blocker to start with to reduce BP 100-110 mm Hg. Then ACE/ARB

may be added

Na Nitroprusside by infusion is the drug of choice if IV necessary

Pheochromocytoma

Long term remedy is surgery.

Alpha Blockers(Phenoxybenzamine) for short term management of episodes

Tachycardia can be controlled with careful use of BBs

Phentolamine for short term during surgery

Causes of Resistant Hypertension

Improper BP measurement Excess sodium intake Inadequate diuretic therapy Medication

• Inadequate doses• Drug actions and interactions (e.g., nonsteroidal anti-inflammatory

drugs (NSAIDs), illicit drugs, sympathomimetics, oral contraceptives)• Over-the-counter (OTC) drugs and herbal supplements

Excess alcohol intake Identifiable causes of HTN

ESH/ESC & ADA Guidelines

ADA Treatment Recommendations for Diabetic Patients with Hypertension

Recommended target blood pressure

• Systolic <130 mm Hg

• Diastolic <80 mm Hg

Drug therapy mandatory above 140 mm Hg systolic and 90 mm Hg diastolic

Recommended first-line agents for patients with microalbuminuria or clinical albuminuria

• ARBs and ACE-IsARBs and ACE-Is

American Diabetes Association. Diabetes Care. 2002;25(Suppl 1):S71-S73.

ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker.

ADA Treatment Recommendations for Diabetic Nephropathy

Both ACE-Is and ARBs are first-line agents for treatment of albuminuria/nephropathy

Initial choice in diabetic nephropathy for hypertensive and nonhypertensive patients with type 1 diabetes

• ACE-Is

Initial choice in diabetic nephropathy for hypertensive patients with microalbuminuria or clinical albuminuria and type 2 diabetes

• ARBsARBs

If one class is not tolerated, the other should be substitutedAmerican Diabetes Association. Diabetes Care. 2002;25(Suppl 1):S85-S89.

ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker.

ACE Inhibition

Beyond Hypertensive Control

Endothelium-Focus of New Research

Largest organ of the human body

Arteriole lumen

Endothelium

Vasospasm(coronory, cerebral)

Reocclusion

Hypertension

Reperfusion injury

Peripheral arterydisease

Inflammatory disease

Immunereaction

Hyperlipidemia

Hyperhomocystenemia

Diabetes

Heart failure

Atherosclerosis

Endothelialdysfunction

Causes and consequences of EndothelialDysfunction

Adopted from Rubanyi GM. J Cardiovasc Pharmacol. 1993;22(suppl 4):S1-S4

Additional Considerations in Antihypertensive Drug Choices

Potential favorable effects

Thiazide-type diuretics useful in slowing demineralization in osteoporosis.

BBs useful in the treatment of atrial tachyarrhythmias/fibrillation, migraine, thyrotoxicosis (short-term), essential tremor, or perioperative HTN.

CCBs useful in Raynaud’s syndrome and certain arrhythmias.

Alpha-blockers useful in prostatism.

Spironlactone in Conn,s syndrome

Additional Considerations in Antihypertensive Drug Choices

Potential unfavorable effects

Thiazide diuretics should be used cautiously in gout or a history of significant hyponatremia.

BBs should be generally avoided in patients with asthma, reactive airways disease, or second- or third-degree heart block.

ACEIs and ARBs are contraindicated in pregnant women or those likely to become pregnant.

ACEIs should not be used in individuals with a history of angioedema.

Aldosterone antagonists and potassium-sparing diuretics can cause hyperkalemia.

Conclusion

According to baseline BP and presence or absence of complications, therapy can be initiated either with a low dose of a single agent or with a low-dose combination of 2 agents

Most patients with hypertension will require 2 or more antihypertensive drugs to achieve BP goals

Choice of therapy has to be individualized keeping in view the associated co morbid conditions

Chobanian AV et al. JAMA. 2003;289:2560-2572.Guidelines Committee. J Hypertens. 2003;21:1011-1053.

Thank You

Trends in Awareness, Treatment, and Control of Hypertension in the US*

10%

31%

51%

29%

55%

73%

27%

54%

68%

0

10

20

30

40

50

60

70

80

90

100

AwareAware TreatedTreated ControlledControlled†

Percentage of Population

*Data for 1999-2000 were computed (M. Wolz, unpublished data, 2003) from the National Heart, Lung, Blood Institute and data for National Health and Nutrition Examination Surveys II and III (phases 1 and 2) are from The Sixth Report of the Joint National Committee on Prevention Detection, Evaluation and Treatment of High Blood Pressure . High blood pressure is systolic blood pressure of 140 mm Hg or diastolic blood pressure 90 mm Hg, or taking antihypertensive medication.†Systolic blood pressure <140 mm Hg and diastolic blood pressure <90 mm Hg.

Chobanian AV et al. Chobanian AV et al. JAMA. JAMA. 2003;289:2560-2572.2003;289:2560-2572.

70%

59%

34%

1999-2000

1976-1980

1988-1991

1991-1994

Adapted from Neaton JD, Wentworth D. Adapted from Neaton JD, Wentworth D. Arch Intern MedArch Intern Med. 1992;152:56-64. . 1992;152:56-64. 

Effect of Systolic and Diastolic Blood Pressure on Coronary Heart Disease Mortality: MRFIT

<120<120120-139120-139

140-159140-159160+160+

Systolic BP

Systolic BP

(mm Hg)

(mm Hg)

Diastolic BP

Diastolic BP(mm Hg)

(mm Hg)

CAD Death Rate per

CAD Death Rate per

10,000 Person-Years

10,000 Person-Years

100+100+

80-8980-89

70-7470-74<70<70

75-7975-79

90-9990-99

48.348.3

37.437.434.734.7 43.843.8

38.138.1

80.680.631.031.0

25.525.524.624.6

25.325.325.225.2

24.924.9

23.823.8

16.916.913.913.9

12.812.812.612.6

11.811.8

20.620.6

10.310.311.811.8

8.88.88.58.5

9.29.2

CVD Risk Factors

Hypertension* Cigarette smoking Obesity* (BMI >30 kg/m2) Physical inactivity Dyslipidemia* Diabetes mellitus* Microalbuminuria or estimated GFR <60 ml/min Age (older than 55 for men, 65 for women) Family history of premature CVD

(men under age 55 or women under age 65)

*Components of the metabolic syndrome.

CVD Risk

HTN prevalence ~ 50 million people in the United States.

The BP relationship to risk of CVD is continuous, consistent, and independent of other risk factors.

Each increment of 20/10 mmHg doubles the risk of CVD across the entire BP range starting from 115/75 mmHg.

Prehypertension signals the need for increased education to reduce BP in order to prevent hypertension.

ESH/ESC 2003: Cardiovascular Risk Stratification

Guidelines Committee. J Hypertens. 2003;21:1011-1053.

Very highadded risk

Very highadded risk

Very highadded risk

Very high added risk

Highadded risk

Associated clinical conditions

Very highadded risk

Highadded risk

Highadded risk

Highadded risk

Moderate added risk

≥3 risk factors,target organ damage, or diabetes

Very highadded risk

Moderateadded risk

Moderateadded risk

Lowadded risk

Lowadded risk

1-2 risk factors

Highadded risk

Moderateadded risk

Lowadded risk

Averagerisk

Averagerisk

No other risk factors

Grade 3SBP ≥180

or DBP ≥110

Grade 2SBP 160-179

or DBP 100-109

Grade 1SBP 140-159or DBP 90-99

High-NormalSBP 130-139or DBP 85-89

NormalSBP 120-129or DBP 80-84

Other Risk Factors and Disease History

Blood Pressure (mm Hg)

Category Systolic Diastolic

(mmHg) (mmHg)

Optimal <120 and <80

Normal <130 and <85

High-normal 130-139 or 85-89

Hypertension

Stage 1 140-159 or 90-99

Stage 2 160-179 or 100-109

Stage 3 >180 or 110

JNC Classification of Blood Pressure for adults age 18 and older

In hypertension With Controlled BP Mortality Risk is Still Higher Than in Normotensive

1 1 1.36 1.3 1.82 1.97

0

0.5

1

1.5

2 Male

Female

Normotensives Hypertensives,treated andcontrolled

Hypertensivestreated and

not controlled

Re

lati

ve

ris

k o

f d

eath

Hawlk RJ et al, Hypertension. 1989;13(suppl):1-20-1-32.

High risk of mortality in patients with controlled BP points out to other causes of target Organ damage (e.g endothelial dysfunction)

Algorithm for Treatment of Hypertension

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)

as needed.

With Compelling Indications

Lifestyle Modifications

Stage 2 Hypertension (SBP >160 or DBP >100 mmHg)

2-drug combination for most (usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 1 Hypertension(SBP 140–159 or DBP 90–99

mmHg) Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB,

or combination.

Without Compelling Indications

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved.

Consider consultation with hypertension specialist.

ACE InhibitorsBenefits Beyond Anti Hypertensive Effects

“ Data collected from various studies suggested that treatment of hypertension with ACE Inhibitors

could prevent endothelial dysfunction independent of systemic anti hypertensive effect.”

Medical clinics of North America 1998

Circulating ACE (endocrine)•Plasma

Tissue ACE (autocrine/paracrine)•Vasculature (endothelium)•CNS•Adrenal•Heart •Kidney•Reproductive organs•Lung

Circulating vs tissue ACE

Circulating ACE10%

Tissue ACE90%

Dzau VJ.Arch Intern Med. 1993;153:937-942

Tissue ACE Mainly Responsible For Target Organ Damage

ACE Inhibition Vasculoprotective Effect

Angiotensinogen

Angiotensin I

Renin

Angiotensin II

ACE Inhibition

Kininogens

Bradykinins

ACE Inhibition

Inactive Peptides

Kallikreinin

ACE Inhibition in vascular endothelium

Ang II; Bradykinin; NO

Laboratory Tests

Routine Tests• Electrocardiogram • Urinalysis • Blood glucose, and hematocrit • Serum potassium, creatinine, or the corresponding estimated GFR,

and calcium• Lipid profile, after 9- to 12-hour fast, that includes high-density and

low-density lipoprotein cholesterol, and triglycerides

Optional tests • Measurement of urinary albumin excretion or albumin/creatinine ratio

More extensive testing for identifiable causes is not generally indicated unless BP control is not achieved

(JNC 7)

Importance of Endothelium in Vascular Damage

In patients with hypertension permeability of endothelium is altered

Endothelium - Source of a host of Vaso-active Substances & growth regulating peptides

• Angiotensin II

• Bradykinin

• Endothelin

• Nitric Oxide

• Insulin Growth Factor

• Platelet Derived Growth Factor

Many of these factor have been incriminated in the pathogenesis of Vascular Damage

Medical Clinics of North America Vol 18, # 5, 1997 -1117

Healthy Endothelium

Damaged Endothelium

Endothelial Function / Vascular Health

Healthy endothelium maintains a balance between opposing states :

• Dilation vs constriction• Growth inhibition vs growth promotion• Antithrombosis vs prothrombosis• (antifibrinolysis vs profibrinolysis)• Anti-inflammation vs pro-inflammation• Antioxidation vs pro-oxidation

Lusher TF, Barton M. Clin Cardiol. 1997;10 (supplII):11-3-11-10.Vane JR et al.N Eng J Med. 1990;323:27-36.Harrison DG. Clin Cardiol. 1997;10(suppl):II-11-II-17