Download Hypertension : A Pharmacological Approach

Hypertension:
A Pharmacological Approach
Robert J. DiDomenico, Pharm.D
Hypertension
Hypertension
Hypertension
JNC 7 Express. NIH publication No 03-5233. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. May, 2003.
Rate per Million Population
Incidence of Reported End-Stage Renal
Disease Therapy, 1982-1995
253*
250
200
150
100
50
1983
1985
1987
1989
Year
*Provisional data.
Adjusted for age, race, and sex.
Hypertension
1991
1993
1995
Prevalence of Heart Failure,
by Age, 1976-80 and 1988-91
10%
1988-91
8%
6%
4%
1976-80
2%
0%
30
35
45
55
Age (Years)
Hypertension
65
75
80
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.
Hypertension
Risk Stratification
Major Cardiovascular Risk Factors
• Hypertension
• Smoking
• Obesity (BMI > 30)
• Physical inactivity
• Dyslipidemia
• Diabetes mellitus
• Microalbuminuria or GFR <
60ml/min
• 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 2003;289:2560-72.
Hypertension
JNC 7 Treatment Recommendations
Initial Drug Therapy
JNC 7 Express. NIH publication No 03-5233. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. May, 2003.
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
Hypertension
Hypertension
Functional Aspects of the Sympathetic NS
Sympathetic Response
Organ
Heart
Increased contractility
Increased HR
Arterioles
Vasoconstriction (skin/viscera)
(alpha-1)
Vasodilation (skeletal muscle/liver) (beta-2)
Lung
Bronchodilation
(beta-2)
Kidney
Increased renin
(alpha-1,
beta-1)
Hypertension
(beta-1)
(beta-1)
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)
Hypertension
Hypertension

Beta Blockers: CV Pharmacodynamics
•
•
•
•
•
Reduced heart rate
Reduced force of heart contraction
Reduced cardiac output
Reduced blood pressure
Decreased renin
Hypertension
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
Hypertension
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
Hypertension
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
Hypertension
Hypertension
Drug
Acebutolol (Sectral)
Atenolol (Tenormin)
Betaxolol (Kerlone)
Bisoprolol (Zebeta)
Carteolol (Cartrol)
Carvedilol (Coreg)
Esmolol (Brevibloc)
Labetalol (Trandate, Normodyne)
Receptor
Activity
1
1
1
1
1, 2
1, 1, 2
1
1, 1, 2
Metoprolol (Lopressor, Toprol XL)
Nadolol (Corgard)
Pindolol (Visken)
Propanolol (Inderal)
Timolol (Blocadren)
1
1, 2
1, 2
1, 2
1, 2
Hypertension
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
Hypertension
Hypertension
Thiazide/Thiazide-like Diuretics
Potassi um Sparing Diuretics
Chlorothiazide (Diuril)
Hydrochlorthiazide (HCTZ, Oretic)
Indapamide (Lozol)
Metolazone (Zaroxolyn , Mykro x)
Chlorthalidone (Hygroton)
Triamterene (Dyrenium )
Triamterene/HCTZ (Ma xzide, D ya zide)
Amiloride (Midamor)
Spironolactone (Aldactone)
Loop Diuretics
Carbonic Anhydra se Inhibitors
Furosemide (Lasix)
Bumetanide (Bumex)
Ethacrynic Acid (Edecrin)
Torsemide (Demadex)
Aceta zolamide (Diamox)
Methazolamide (Neptazane)
Hypertension
Hypertension
Hypertension
Hypertension
Carbonic anhydrase inhibitors
Thiazide diuretics
Potassium-sparing diuretics
Loop
diuretics
Hypertension
Hypertension

Diuretics: Pharmacodynamics
• Decreased intravascular (blood) fluid volume
• Decreased extravascular (edema) fluid volume
• Decreased blood pressure
Hypertension
Hypertension

Diuretics: Potential Adverse Effects
• Electrolyte disturbances
– potassium, magnesium, sodium, calcium
•
•
•
•
•
•
Hyperglycemia
Hypotension, orthostasis
Lipid abnormalities
Photosensitivity
Ototoxicity
Hyperuricemia, gout flare
Hypertension
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
Hypertension
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
Hypertension
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 (ARB’s)
• ARB’s block the effects of angiotensin II by
competing for binding sites at the receptor
Hypertension
Hypertension
Low Blood Pressure
Angiotensinogen
(liver)
Renin
(kidney)
Angiotensin I
ACE inhibitor site of
action
ACE
Aldosterone

Na retention
Angiotensin II
Angiotensin II receptors
 Blood Pressure
Hypertension
bradykinin
Vasoconstriction
+
 PVR
ARB site of action
Hypertension
Renin
Angiotensinogen
Angiotensin I
ACE
X
X
Aldosterone
secretion
Renal tubular
reabsorption of
sodium and water
Angiotensin II
Non-ACE alternate
pathways (eg, chymase)
ARB
Vasoconstriction
AT1 receptors
Catecholamine
secretion
Antidiuretic hormone
(vasoprressin)
secretion
X
Hypertension
X
X
X
Stimulation of thirst center
 BP
Hypertension
ACE-INHIBITORS
ANGIOTENSI N II ANTAGONISTS
Captopril (Capoten)
Enalapril (Vasotec)
Benazepril (Lotensin)
Lisinopril (Zestril, Prinivil)
Fosinopril (Monopril)
Quinapril (Accupril)
Ramipril (Altace)
Moexipril (Univasc)
Trandolapril (Mavik )
Perindopril (Aceon)
Losartan (Cozaar)
Valsartan (Diovan)
Irbesartan (Avapro)
Telmisartan (Micardis)
Candesartan (Atacand)
Eprosartan (Teveten)
Hypertension
Hypertension

ACE inhibitors and ARB’s: Pharmacodynamics
•
•
•
•
•
•
Vasodilation
Reduced peripheral resistance
Increased diuresis
Reduced BP
No change in HR
No reduction in cardiac output
Hypertension
Hypertension
ACE Inhibitors/ARB’s: Potential Adverse
Effects
 ACE inhibitors

•
•
•
•
•

Hyperkalemia
Cough
Hypotension, dizziness
Headache
Angioedema
ARB’s
• Same as ACE inhibitors but cough is uncommon
Hypertension
Hypertension

ACE inhibitors and ARB’s: 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
Hypertension
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
Hypertension
Hypertension

ACE inhibitors/ARB’s should be carefully
considered:
• Pre-existing kidney dysfunction (degree of
impairment, response to therapy)
• Renal artery stenosis (degree of stenosis)

ACE inhibitors/ARB’s are contraindicated:
• Pregnancy
• History of angioedema
• Hyperkalemia
Hypertension
Hypertension

Therapeutic Options: Calcium Channel
Blockers (CCB’s)
• Calcium channel blockers work by blocking
calcium channels through which calcium ions
enter muscle fibers, controlling hypertension.

Calcium Channel Blockers
• Dihydropyridine
• Non-dihydropyridine
Hypertension
Hypertension
Calcium Channel Blocking Agents
MEDICATION
SUGGEST ED U SES
Dihydropyridines
Nifedipine (Procardia XL, Adalat CC)
Amlodipine (Norvasc)
Felodipine ( Plendil)
Isradipine (Dynacirc)
Nicardipine (Cardene)
Nimodipine (Nimotop)
Nisoldipine (Sular)
Hypertension
HTN, angina
HTN, angina, CHF
HTN, CHF
HTN
HTN, chronic stable angina
Subarachnoid Hemorrhage
HTN, angina
Hypertension
Calcium Channel Blocking Agents
MEDICATION
Phenylalkylamines
Verapamil (Calan, Verelan,Isoptin
Covera HS)
SUGGESTED USES
HTN, SVT’s, unstable,
vasospastic, and chronic
angina
Benzothiazepines
Diltiazem (Cardizem,Dilacor XR,
Tiazac)
HTN, vasospastic and
chronic stable angina,
SVT's
Other Agents
Bepridil (Vasocor)
Hypertension
Chronic stable angina
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
Hypertension
Hypertension

CCB’s: Potential Side Effects
• Dihydropyridines
–
–
–
–
Peripheral edema
reflex tachycardia
flushing/headache
hypotension
• Nondihydropyridines
– constipation
– conduction abnormalities
Hypertension
Hypertension
Calcium Channel Blockers: Specific
Indications
 CCB’s: Compelling Indications

• Isolated Systolic Hypertension (long-acting)

CCB’s: Possible Favorable Effects
•
•
•
•
angina
atrial tachyarhythmias
Cyclosporine-induced HTN
Diabetes Mellitus Type 1 and 2 with proteinuria
Hypertension
Hypertension: The Diagnosis and
Treatment Process
Hypertension
JNC 7 Express. NIH publication No 03-5233. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. May, 2003.
Why the More Aggressive BP Classifications?
High-Normal BP as CV Risk Factor
Hypertension
Vasan RS, et al. N Eng J Med 2001;345:1291-7.
Outcomes Studies in High-Risk Patients
ALLHAT Study: Optimal 1st Line Agent
Chlor
Amlod
Lisin
C vs A
CHD
11.5
11.3
11.4
0.98
0.99
Mortality
17.3
16.8
17.2
0.96
1.00
Stroke
5.6
5.4
6.3
0.93
1.15
CHF
7.7
10.2
8.7
1.38
1.19
Hosp for
CHF
6.5
8.4
6.9
1.35
1.10
Hypertension
C vs L
ALLHAT Investigators. JAMA 2002;288:2981-7.
Outcomes Studies in High-Risk Patients
HOPE Study: Ramipril vs Placebo
Hypertension
HOPE Investigators. N Eng J Med 2000;342:145-53.
Outcomes Studies in High-Risk Patients
LIFE Study: Losartan vs Atenolol
Hypertension
LIFE Investigators. Lancet 2002;359:995-1003.
Outcomes Studies in High-Risk Patients
EUROPA Study: Perindopril vs Placebo
Peridopril
Placebo
N=6110
N=6108
Nonfatal MI or
CV death
8%
9.95
20%
p=0.003
CV death
3.5%
4.1%
14%
p=0.107
Nonfatal MI
4.8%
6.2%
22%
p=0.001
All-cause mortality
6.1%
6.9%
11%
p=0.1
Death, MI,
unstable angina, or
cardiac arrest
14.8%
17.1%
14%
p=0.0009
Hypertension
Risk Reduction
EUROPA Investigators. Lancet 2003;362:782-8.
Hypertension
Algorithm for Treatment of HTN
Compelling
Indications
Diuretic B-Blocker
Heart Failure
X
Post-MI
High CAD
risk
X
Diabetes
X
ACE
Inhibitor
ARB
X
X
X
X
X
X
X
CCB
Aldosterone
antagonisst
X
X
X
Non-DHP
X
X
X
X
Non-DHP
Chronic renal
disease
2° Stroke
prevention
Hypertension
X
X
X
X
NHBPEP Coordinating Committee. The JNC 7 Report.
JAMA 2003;289:2560-72.
Hypertension Treatment Costs
Patient Perspective
$80.00
Brand
Generic
Price per Month ($)
$70.00
$60.00
$50.00
$40.00
$30.00
$20.00
$10.00
$0.00
ACE I
ARB
BB
Loop
HCTZ
CCB
Hydralazine
Medication C lass
* Most patients require ~ 2 antihypertensive drugs
ALLHAT Investigators. JAMA 2002;288:2981-7.
www.walgreens.com. Accessed 4/8/05
Algorithm for Treatment (continued)
Initial Drug Choices
Not at Goal Blood Pressure (< 140/90 mm Hg)
No response or
troublesome side effects
Substitute drug from
different class
Inadequate response but
well tolerated
Add second agent
from different class
(diuretic if not already used)
Hypertension
Drug Therapy

Dose-effect curve
• Variation in a population
• Length of therapy
• Counter-regulation
Absorption
 Elimination

Effect
No
Effect
Effect
Toxic
Dose
Hypertension
Special Populations


African Americans
• Response to diuretics & CCB
• Same general principles
• Thiazide or CCB may be
> response to ACEI, ARB,
beta-blockers
• Angioedema 2 – 4-fold
higher

Elderly
(Isolated Systolic HTN)
better tolerated

• Methyldopa, beta-blockers,
Left ventricular hypertrophy
vasodilators (hydralazine)
• Avoid ACEI & ARBs
• Aggressive BP control
regresses LVH
• …but hydralazine & minoxidil
DO NOT!
Pregnancy

Children/adolescents
• Avoid ACEI & ARBs in
pregnant or sexually active
girls
Hypertension
NHBPEP Coordinating Committee. The JNC 7 Report.
JAMA 2003;289:2560-72.
Finally: Quality of Life

Hypertension is often silent
• Depression
• Urinary frequency
• Sexual dysfunction
– Male
– Female
• Fatigue
• Cough

Cost
Hypertension