Post on 17-Dec-2015
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 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,
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
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.
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.
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
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