Hypertension: A Pharmacological Approach

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HypertensionA Pharmacological Approach

• Robert J. DiDomenico, Pharm.D

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Hypertension
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JNC 7 Express. NIH publication No 03-5233.
http//www.nhlbi.nih.gov/guidelines/hypertension/e
xpress.pdf. May, 2003.
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Percent Decline in Age-Adjusted Mortality Rates
for Stroke by Sex and Race U.S. 1972-1994
The decline in age-adjusted mortality for stroke
in the total population is 59.0. Age-adjusted
to the 1940 U.S. census population.
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Percent Decline in Age-Adjusted Mortality Rates
for CHD by Sex and Race U.S. 1972-1994
The decline in age-adjusted mortality for stroke
in the total population is 59.0. Age-adjusted
to the 1940 U.S. census population.
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Incidence of Reported End-Stage Renal Disease
Therapy, 1982-1995
253
Provisional data. Adjusted for age, race, and
sex.
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Prevalence of Heart Failure,by Age, 1976-80 and
1988-91
1988-91
1976-80
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Hypertension Blood Pressure

• Hypertension is a condition in which the blood
  pressure is persistently higher than normal
• Measurement is indirect
• Blood pressure is silent
• Hypertensive crisis acute, life threatening rise
  in blood pressure associated with acute end-organ
  damage.

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Risk Stratification

• Major Cardiovascular Risk Factors
• Hypertension
• Smoking
• Obesity (BMI 30)
• Physical inactivity
• Dyslipidemia
• Diabetes mellitus
• Microalbuminuria or GFR
• Advanced age
• Men 55, women 65
• Family history of premature CV disease

• Target Organ Disease
• Heart
• Left ventricular hypertrophy
• CAD
• Angina and/or prior MI
• Prior coronary revascularization
• Heart failure
• Brain
• Stroke or TIA
• Chronic renal insufficiency
• Peripheral arterial disease
• Retinopathy

NHBPEP Coordinating Committee. The JNC 7 Report.
JAMA 20032892560-72.
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JNC 7 Treatment RecommendationsInitial Drug
Therapy
JNC 7 Express. NIH publication No 03-5233.
http//www.nhlbi.nih.gov/guidelines/hypertension/e
xpress.pdf. May, 2003.
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Hypertension

• Therapeutic Treatment Options
• Diuretics
• Beta blockers
• ACE inhibitors
• Angiotensin II receptor blockers
• Calcium channel blockers
• Alpha blockers
• Centrally acting alpha agonists
• Direct vasodilators
• Peripheral adrenergic blockers

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Hypertension

• Selection of Initial Therapy
• Demographics
• Concomitant Diseases and Therapies
• Quality of Life
• Cost
• Drug Interactions

Arch Inter Med 1997
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Hypertension
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Hypertension
Functional Aspects of the Sympathetic NS
Organ
Sympathetic Response
Heart Increased contractility
(beta-1)
Increased HR
(beta-1)
Arterioles Vasoconstriction (skin/viscera)
(alpha-1)
Vasodilation (skeletal muscle/liver) (beta-2)
Lung Bronchodilation
(beta-2)
Kidney Increased renin
(alpha-1, beta-1)
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Hypertension

• Therapeutic Options Beta Blockers
• Inhibit sympathetic stimulation
• Beta-1 receptors ? heart
• Beta-2 receptors ? blood vessels, lungs
• Cardioselective vs. Nonselective
• Intrinsic sympathomimetic activity (ISA)

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Hypertension

• Beta Blockers CV Pharmacodynamics
• Reduced heart rate
• Reduced force of heart contraction
• Reduced cardiac output
• Reduced blood pressure
• Decreased renin

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Hypertension

• Beta Blockers Potential Adverse Effects
• Glucose intolerance, masked hypoglycemia
• Bradycardia, dizziness
• Bronchospasm
• Increased triglycerides and decreased HDL
• CNS Depression, fatigue, sleep disturbances
• Reduced C.O., exacerbation of heart failure
• Impotence
• Exercise intolerance

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Hypertension

• Beta Blockers Precautions
• Bronchospastic disease
• Heart Block
• Sick sinus syndrome
• Diabetes
• Dyslipidemia
• Depression

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Hypertension

• Beta Blockers Specific Indications
• Myocardial Infarction?
• Congestive Heart Failure?
• Essential Tremors
• Hyperthyroidism
• Angina
• Supraventricular tachycardias
• Perioperative Hypertension
• Migraine Headaches
• Beta blockers are underused!!!

?Compelling indications
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Hypertension

• Therapeutic Options Alpha-Beta Blockers
• Work by binding to both alpha-1 and beta-1 and/or
  beta-2 adrenergic receptors consequently
  preventing their activation by sympathetic
  neurotransmitters.
• Carvedilol alpha-1 beta-1 beta-2 blockade
• Labetalol alpha-1 beta-1 beta-2 blockade

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Hypertension
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Hypertension

• Therapeutic Options Diuretics
• Promote sodium and water excretion at various
  sites of the nephron
• Loop diuretics
• Thiazide/Thiazide-like diuretics diuretics
• Potassium-sparing diuretics
• Carbonic Anhydrase Inhibitors

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Hypertension
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Hypertension
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Hypertension
Carbonic anhydrase inhibitors
Thiazide diuretics
Potassium-sparing diuretics
Loop diuretics
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Hypertension

• Diuretics Pharmacodynamics
• Decreased intravascular (blood) fluid volume
• Decreased extravascular (edema) fluid volume
• Decreased blood pressure

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Hypertension

• Diuretics Potential Adverse Effects
• Electrolyte disturbances
• potassium, magnesium, sodium, calcium
• Hyperglycemia
• Hypotension, orthostasis
• Lipid abnormalities
• Photosensitivity
• Ototoxicity
• Hyperuricemia, gout flare

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Hypertension

• Diuretics Compelling Indications
• Isolated Systolic Hypertension
• Congestive Heart Failure
• Diuretics Possible Favorable Effects
• Osteoporosis (thiazides)
• Diuretics Possible Unfavorable Effects
• Diabetes
• Gout
• Renal Insufficiency

? Unless contraindicated
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Hypertension

• Diuretics Considerations
• Useful for patients with ISH, African Americans,
  CHF
• Different diuretic classes can be combined for
  additive, or possible synergistic effects
• Work well in combination with other
  antihypertensives
• Efficacy drops when renal function becomes
  seriously impaired

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Hypertension

• Therapeutic Options ACE Inhibitors
• ACE inhibitors inhibit the conversion of
  angiotensin I to angiotensin II, a potent
  vasoconstrictor
• Therapeutic Options Angiotensin II Receptor
  Blockers (ARBs)
• ARBs block the effects of angiotensin II by
  competing for binding sites at the receptor

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Hypertension
Low Blood Pressure
Angiotensinogen
(liver)
bradykinin
Renin
(kidney)
Angiotensin I
ACE inhibitor site of action
ACE
Vasoconstriction ? PVR
?Aldosterone ? ?Na retention
Angiotensin II
ARB site of action
Angiotensin II receptors
? Blood Pressure
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Hypertension
Renin
Angiotensinogen
Angiotensin I
Non-ACE alternate pathways (eg, chymase)
ACE
Angiotensin II
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Hypertension
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Hypertension

• ACE inhibitors and ARBs Pharmacodynamics
• Vasodilation
• Reduced peripheral resistance
• Increased diuresis
• Reduced BP
• No change in HR
• No reduction in cardiac output

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Hypertension

• ACE Inhibitors/ARBs Potential Adverse Effects
• ACE inhibitors
• Hyperkalemia
• Cough
• Hypotension, dizziness
• Headache
• Angioedema
• ARBs
• Same as ACE inhibitors but cough is uncommon

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Hypertension

• ACE inhibitors and ARBs Potential Drug
  Interactions
• Medications which promote hyperkalemia
• Medications that have activity which is sensitive
  to changes in serum K
• Medications that may cause additive
  antihypertensive effects
• NSAIDs

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Hypertension

• Therapeutic Options ACE inhibitors
• Compelling Indications
• Diabetes Mellitus (Type 1) with proteinuria
• Heart Failure
• Post MI with systolic dysfunction
• Possible Favorable Effects
• Diabetes Mellitus (Type 1 or 2) with proteinuria
• Renal Insufficiency

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Hypertension

• ACE inhibitors/ARBs should be carefully
  considered
• Pre-existing kidney dysfunction (degree of
  impairment, response to therapy)
• Renal artery stenosis (degree of stenosis)
• ACE inhibitors/ARBs are contraindicated
• Pregnancy
• History of angioedema
• Hyperkalemia

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Hypertension

• Therapeutic Options Calcium Channel Blockers
  (CCBs)
• Calcium channel blockers work by blocking calcium
  channels through which calcium ions enter muscle
  fibers, controlling hypertension.
• Calcium Channel Blockers
• Dihydropyridine
• Non-dihydropyridine

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Hypertension
Calcium Channel Blocking Agents
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Hypertension
Calcium Channel Blocking Agents
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Hypertension

• Calcium Channel Blockers Pharmacodynamics
• The activation of calcium channels can increase
• blood pressure by increasing heart rate
• stroke volume
• cardiac output
• total peripheral resistance
• Calcium channel blocking reduces these parameters

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Hypertension

• CCBs Potential Side Effects
• Dihydropyridines
• Peripheral edema
• reflex tachycardia
• flushing/headache
• hypotension
• Nondihydropyridines
• constipation
• conduction abnormalities

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Hypertension

• Calcium Channel Blockers Specific Indications
• CCBs Compelling Indications
• Isolated Systolic Hypertension (long-acting)
• CCBs Possible Favorable Effects
• angina
• atrial tachyarhythmias
• Cyclosporine-induced HTN
• Diabetes Mellitus Type 1 and 2 with proteinuria

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Hypertension The Diagnosis and Treatment Process
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JNC 7 Express. NIH publication No 03-5233.
http//www.nhlbi.nih.gov/guidelines/hypertension/e
xpress.pdf. May, 2003.
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Why the More Aggressive BP Classifications?High-N
ormal BP as CV Risk Factor
Vasan RS, et al. N Eng J Med 20013451291-7.
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Outcomes Studies in High-Risk PatientsALLHAT
Study Optimal 1st Line Agent
ALLHAT Investigators. JAMA 20022882981-7.
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Outcomes Studies in High-Risk PatientsHOPE
Study Ramipril vs Placebo
HOPE Investigators. N Eng J Med 2000342145-53.
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Outcomes Studies in High-Risk PatientsLIFE
Study Losartan vs Atenolol
LIFE Investigators. Lancet 2002359995-1003.
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Outcomes Studies in High-Risk PatientsEUROPA
Study Perindopril vs Placebo
EUROPA Investigators. Lancet 2003362782-8.
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(No Transcript)
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Algorithm for Treatment of HTN
NHBPEP Coordinating Committee. The JNC 7 Report.
JAMA 20032892560-72.
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Hypertension Treatment CostsPatient Perspective
Most patients require 2 antihypertensive
drugs ALLHAT Investigators. JAMA 20022882981-7.
www.walgreens.com. Accessed 4/8/05
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Algorithm for Treatment (continued)
Initial Drug Choices
Not at Goal Blood Pressure (No response or troublesome side effects
Inadequate response but well tolerated
Substitute drug from different class
Add second agent from different class (diuretic
if not already used)
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Drug Therapy

• Dose-effect curve
• Variation in a population
• Length of therapy
• Counter-regulation
• Absorption
• Elimination

No Effect
Effect
Effect
Toxic
Dose
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Special Populations

• African Americans
• Response to diuretics CCB response to ACEI,
  ARB, beta-blockers
• Angioedema 2 4-fold higher
• Left ventricular hypertrophy
• Aggressive BP control regresses LVH
• but hydralazine minoxidil DO NOT!

• Elderly
• (Isolated Systolic HTN)
• Same general principles
• Thiazide or CCB may be better tolerated
• Pregnancy
• Methyldopa, beta-blockers, vasodilators
  (hydralazine)
• Avoid ACEI ARBs
• Children/adolescents
• Avoid ACEI ARBs in pregnant or sexually active
  girls

NHBPEP Coordinating Committee. The JNC 7 Report.
JAMA 20032892560-72.
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Finally Quality of Life

• Hypertension is often silent
• Depression
• Urinary frequency
• Sexual dysfunction
• Male
• Female
• Fatigue
• Cough
• Cost