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Hypertension:Hypertension:A Pharmacological A Pharmacological

ApproachApproachRobert J. DiDomenico, Pharm.DRobert J. DiDomenico, Pharm.D

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HypertensionHypertension

JNC 7 Express. NIH publication No 03-5233. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. May, 2003.

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Incidence of Reported End-Stage Incidence of Reported End-Stage Renal Disease Therapy, 1982-1995Renal Disease Therapy, 1982-1995

50

100

150

200

250

1983 1985 1987 1989 1991 1993 1995

Year

Rat

e p

er M

illi

on

Po

pu

lati

on

253*

*Provisional data.Adjusted for age, race, and sex.

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Prevalence of Heart Failure,Prevalence of Heart Failure,by Age, 1976-80 and 1988-91by Age, 1976-80 and 1988-91

0%

2%

4%

6%

8%

10%

30 35 45 55 65 75 80

Age (Years)

1988-91

1976-80

HypertensionHypertension

Hypertension & Blood Hypertension & Blood PressurePressure

Hypertension is a condition in which the Hypertension is a condition in which the blood pressure is persistently higher than blood pressure is persistently higher than normalnormal• Measurement is indirectMeasurement is indirect

• Blood pressure is silentBlood pressure is silent Hypertensive crisis: acute, life threatening Hypertensive crisis: acute, life threatening

rise in blood pressure associated with acute rise in blood pressure associated with acute end-organ damage.end-organ damage.

HypertensionHypertension

Risk StratificationRisk Stratification

Major Cardiovascular Risk Major Cardiovascular Risk FactorsFactors• HypertensionHypertension

• SmokingSmoking

• Obesity (BMI Obesity (BMI >> 30) 30)

• Physical inactivityPhysical inactivity

• DyslipidemiaDyslipidemia

• Diabetes mellitusDiabetes mellitus

• Microalbuminuria or GFR < Microalbuminuria or GFR < 60ml/min60ml/min

• Advanced ageAdvanced age– Men > 55, women > 65Men > 55, women > 65

• Family history of premature CV Family history of premature CV diseasedisease

Target Organ DiseaseTarget Organ Disease• HeartHeart

– Left ventricular hypertrophyLeft ventricular hypertrophy

– CADCAD– Angina and/or prior MI

– Prior coronary revascularization

– Heart failureHeart failure

• BrainBrain

– Stroke or TIAStroke or TIA

• Chronic renal insufficiencyChronic renal insufficiency

• Peripheral arterial diseasePeripheral arterial disease

• RetinopathyRetinopathy

NHBPEP Coordinating Committee. The JNC 7 Report. JAMA 2003;289:2560-72.

JNC 7 Treatment JNC 7 Treatment RecommendationsRecommendations

Initial Drug TherapyInitial Drug Therapy

JNC 7 Express. NIH publication No 03-5233. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. May, 2003.

HypertensionHypertension

HypertensionHypertension

Therapeutic Treatment OptionsTherapeutic Treatment Options• Diuretics Diuretics

• Beta blockersBeta blockers

• ACE inhibitorsACE inhibitors

• Angiotensin II receptor blockersAngiotensin II receptor blockers

• Calcium channel blockersCalcium channel blockers

• Alpha blockersAlpha blockers

• Centrally acting alpha agonistsCentrally acting alpha agonists

• Direct vasodilatorsDirect vasodilators

• Peripheral adrenergic blockersPeripheral adrenergic blockers

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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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Therapeutic Options: Beta BlockersTherapeutic Options: Beta Blockers• Inhibit sympathetic stimulation Inhibit sympathetic stimulation

– Beta-1 receptors Beta-1 receptors heart heart– Beta-2 receptors Beta-2 receptors blood vessels, lungs blood vessels, lungs

• Cardioselective vs. NonselectiveCardioselective vs. Nonselective

• Intrinsic sympathomimetic activity (ISA)Intrinsic sympathomimetic activity (ISA)

HypertensionHypertension

HypertensionHypertension

Beta Blockers: CV PharmacodynamicsBeta Blockers: CV Pharmacodynamics• Reduced heart rateReduced heart rate

• Reduced force of heart contractionReduced force of heart contraction

• Reduced cardiac outputReduced cardiac output

• Reduced blood pressureReduced blood pressure

• Decreased renin Decreased renin

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HypertensionHypertension

Beta Blockers: Potential Adverse EffectsBeta Blockers: Potential Adverse Effects• Glucose intolerance, masked hypoglycemiaGlucose intolerance, masked hypoglycemia

• Bradycardia, dizzinessBradycardia, dizziness

• BronchospasmBronchospasm

• Increased triglycerides and decreased HDLIncreased triglycerides and decreased HDL

• CNS: Depression, fatigue, sleep disturbancesCNS: Depression, fatigue, sleep disturbances

• Reduced C.O., exacerbation of heart failureReduced C.O., exacerbation of heart failure

• ImpotenceImpotence

• Exercise intoleranceExercise intolerance

HypertensionHypertension

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Beta Blockers: Specific IndicationsBeta Blockers: Specific Indications• Myocardial InfarctionMyocardial Infarction• Congestive Heart FailureCongestive Heart Failure

• Essential TremorsEssential Tremors

• HyperthyroidismHyperthyroidism

• AnginaAngina

• Supraventricular tachycardias Supraventricular tachycardias

• Perioperative HypertensionPerioperative Hypertension

• Migraine HeadachesMigraine Headaches

Beta blockers are underused!!!Beta blockers are underused!!!Compelling indications

HypertensionHypertension

HypertensionHypertension

Therapeutic Options: Alpha-Beta BlockersTherapeutic Options: Alpha-Beta Blockers• Work by binding to both alpha-1 and beta-1 Work by binding to both alpha-1 and beta-1

and/or beta-2 adrenergic receptors consequently and/or beta-2 adrenergic receptors consequently preventing their activation by sympathetic preventing their activation by sympathetic neurotransmitters.neurotransmitters.– Carvedilol: alpha-1 + beta-1+ beta-2 blockadeCarvedilol: alpha-1 + beta-1+ beta-2 blockade– Labetalol: alpha-1 + beta-1 + beta-2 blockadeLabetalol: alpha-1 + beta-1 + beta-2 blockade

HypertensionHypertension

Drug ReceptorActivity

Acebutolol (Sectral) 1

Atenolol (Tenormin) 1

Betaxolol (Kerlone) 1

Bisoprolol (Zebeta) 1

Carteolol (Cartrol) 1, 2

Carvedilol (Coreg) 1, 1, 2

Esmolol (Brevibloc) 1

Labetalol (Trandate, Normodyne) 1, 1, 2

Metoprolol (Lopressor, Toprol XL) 1

Nadolol (Corgard) 1, 2

Pindolol (Visken) 1, 2

Propanolol (Inderal) 1, 2

Timolol (Blocadren) 1, 2

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HypertensionHypertension

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Therapeutic Options: DiureticsTherapeutic Options: Diuretics• Promote sodium and water excretion at various Promote sodium and water excretion at various

sites of the nephronsites of the nephron– Loop diureticsLoop diuretics– Thiazide/Thiazide-like diuretics diureticsThiazide/Thiazide-like diuretics diuretics– Potassium-sparing diureticsPotassium-sparing diuretics– Carbonic Anhydrase InhibitorsCarbonic Anhydrase Inhibitors

HypertensionHypertension

HypertensionHypertension

Thiazide/Thiazide-like Diuretics Potassium Sparing Diuretics

Chlorothiazide (Diuril) Triamterene (Dyrenium)

Hydrochlorthiazide (HCTZ, Oretic) Triamterene/HCTZ (Maxzide, Dyazide)Indapamide (Lozol) Amiloride (Midamor)

Metolazone (Zaroxolyn, Mykrox) Spironolactone (Aldactone)

Chlorthalidone (Hygroton)

Loop Diuretics Carbonic Anhydrase Inhibitors

Furosemide (Lasix) Acetazolamide (Diamox)Bumetanide (Bumex) Methazolamide (Neptazane)

Ethacrynic Acid (Edecrin)

Torsemide (Demadex)

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Loop diuretics

Thiazide diuretics

Potassium-sparing diuretics

Carbonic anhydrase inhibitors

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Diuretics: PharmacodynamicsDiuretics: Pharmacodynamics• Decreased intravascular (blood) fluid volumeDecreased intravascular (blood) fluid volume

• Decreased extravascular (edema) fluid volumeDecreased extravascular (edema) fluid volume

• Decreased blood pressureDecreased blood pressure

HypertensionHypertension

HypertensionHypertension

Diuretics: Potential Adverse EffectsDiuretics: Potential Adverse Effects• Electrolyte disturbancesElectrolyte disturbances

– potassium, magnesium, sodium, calciumpotassium, magnesium, sodium, calcium

• HyperglycemiaHyperglycemia

• Hypotension, orthostasisHypotension, orthostasis

• Lipid abnormalitiesLipid abnormalities

• PhotosensitivityPhotosensitivity

• OtotoxicityOtotoxicity

• Hyperuricemia, gout flareHyperuricemia, gout flare

HypertensionHypertension

Unless contraindicated

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Diuretics: Compelling Indications*Diuretics: Compelling Indications*• Isolated Systolic HypertensionIsolated Systolic Hypertension

• Congestive Heart FailureCongestive Heart Failure Diuretics: Possible Favorable EffectsDiuretics: Possible Favorable Effects

• Osteoporosis (thiazides)Osteoporosis (thiazides) Diuretics: Possible Unfavorable EffectsDiuretics: Possible Unfavorable Effects

• DiabetesDiabetes

• GoutGout

• Renal InsufficiencyRenal Insufficiency

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Diuretics: ConsiderationsDiuretics: Considerations• Useful for patients with ISH, African Americans, Useful for patients with ISH, African Americans,

CHFCHF

• Different diuretic classes can be combined for Different diuretic classes can be combined for additive, or possible synergistic effectsadditive, or possible synergistic effects

• Work well in combination with other Work well in combination with other antihypertensivesantihypertensives

• Efficacy drops when renal function becomes Efficacy drops when renal function becomes seriously impaired seriously impaired

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Therapeutic Options: ACE InhibitorsTherapeutic Options: ACE Inhibitors• ACE inhibitors inhibit the conversion of ACE inhibitors inhibit the conversion of

angiotensin I to angiotensin II, a potent angiotensin I to angiotensin II, a potent vasoconstrictorvasoconstrictor

Therapeutic Options: Angiotensin II Therapeutic Options: Angiotensin II Receptor Blockers (ARB’s)Receptor Blockers (ARB’s)• ARB’s block the effects of angiotensin II by ARB’s block the effects of angiotensin II by

competing for binding sites at the receptorcompeting for binding sites at the receptor

HypertensionHypertension

HypertensionHypertension

Renin

ARB site of actionAngiotensin II receptors

Angiotensin II

Angiotensin I

Angiotensinogen

ACE

Low Blood Pressure

(liver)

(kidney)

Vasoconstriction + PVR

Aldosterone Na retention

ACE inhibitor site of action

Blood Pressure

bradykinin

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Renin

Angiotensinogen

ACEAngiotensin I

Angiotensin II

Non-ACE alternatepathways (eg, chymase)

ARB

AT1 receptors

VasoconstrictionAldosterone

secretion

Renal tubularreabsorption of

sodium and water

Antidiuretic hormone(vasoprressin)

secretion

Stimulation of thirst center

Catecholaminesecretion

XX

XX

XX BP

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ACE-INHIBITORS ANGIOTENSIN II ANTAGONISTSCaptopril (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)

HypertensionHypertension

HypertensionHypertension

ACE inhibitors and ARB’s: PharmacodynamicsACE inhibitors and ARB’s: Pharmacodynamics• Vasodilation Vasodilation

• Reduced peripheral resistanceReduced peripheral resistance

• Increased diuresisIncreased diuresis

• Reduced BP Reduced BP

• No change in HRNo change in HR

• No reduction in cardiac outputNo reduction in cardiac output

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HypertensionHypertension

ACE Inhibitors/ARB’s: Potential Adverse ACE Inhibitors/ARB’s: Potential Adverse EffectsEffects

ACE inhibitorsACE inhibitors• HyperkalemiaHyperkalemia• CoughCough• Hypotension, dizziness Hypotension, dizziness • HeadacheHeadache• AngioedemaAngioedema

ARB’sARB’s• Same as ACE inhibitors but cough is uncommonSame as ACE inhibitors but cough is uncommon

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ACE inhibitors and ARB’s: Potential ACE inhibitors and ARB’s: Potential Drug InteractionsDrug Interactions• Medications which promote hyperkalemiaMedications which promote hyperkalemia

• Medications that have activity which is sensitive to Medications that have activity which is sensitive to changes in serum K+changes in serum K+

• Medications that may cause additive Medications that may cause additive antihypertensive effectsantihypertensive effects

• NSAIDsNSAIDs

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Therapeutic Options: ACE inhibitorsTherapeutic Options: ACE inhibitors Compelling IndicationsCompelling Indications

• Diabetes Mellitus (Type 1) with proteinuriaDiabetes Mellitus (Type 1) with proteinuria

• Heart FailureHeart Failure

• Post MI with systolic dysfunctionPost MI with systolic dysfunction Possible Favorable EffectsPossible Favorable Effects

• Diabetes Mellitus (Type 1 or 2) with proteinuriaDiabetes Mellitus (Type 1 or 2) with proteinuria

• Renal InsufficiencyRenal Insufficiency

HypertensionHypertension

HypertensionHypertension

ACE inhibitors/ARB’s should be carefully ACE inhibitors/ARB’s should be carefully considered:considered:• Pre-existing kidney dysfunction (degree of Pre-existing kidney dysfunction (degree of

impairment, response to therapy)impairment, response to therapy)

• Renal artery stenosis (degree of stenosis)Renal artery stenosis (degree of stenosis) ACE inhibitors/ARB’s are contraindicated:ACE inhibitors/ARB’s are contraindicated:

• PregnancyPregnancy

• History of angioedemaHistory of angioedema

• HyperkalemiaHyperkalemia

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HypertensionHypertension

Therapeutic Options: Calcium Channel Therapeutic Options: Calcium Channel Blockers (CCB’s)Blockers (CCB’s)• Calcium channel blockers work by blocking Calcium channel blockers work by blocking

calcium channels through which calcium ions calcium channels through which calcium ions enter muscle fibers, controlling hypertension.enter muscle fibers, controlling hypertension.

Calcium Channel BlockersCalcium Channel Blockers• DihydropyridineDihydropyridine

• Non-dihydropyridine Non-dihydropyridine

HypertensionHypertension

MEDICATION SUGGESTED USESDihydropyridinesNifedipine (Procardia XL, Adalat CC) HTN, anginaAmlodipine (Norvasc) HTN, angina, CHFFelodipine (Plendil) HTN, CHFIsradipine (Dynacirc) HTNNicardipine (Cardene) HTN, chronic stable anginaNimodipine (Nimotop) Subarachnoid HemorrhageNisoldipine (Sular) HTN, angina

Calcium Channel Blocking Agents

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MEDICATION SUGGESTED USESPhenylalkylaminesVerapamil (Calan, Verelan,IsoptinCovera HS)

HTN, SVT’s, unstable,vasospastic, and chronicangina

BenzothiazepinesDiltiazem (Cardizem,Dilacor XR,Tiazac)

HTN, vasospastic andchronic stable angina,SVT's

Other AgentsBepridil (Vasocor) Chronic stable angina

Calcium Channel Blocking Agents

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Calcium Channel Blockers: Calcium Channel Blockers: PharmacodynamicsPharmacodynamics• The activation of calcium channels can increase:The activation of calcium channels can increase:

– blood pressure by increasing heart rateblood pressure by increasing heart rate– stroke volumestroke volume– cardiac outputcardiac output– total peripheral resistancetotal peripheral resistance

• Calcium channel blocking reduces these Calcium channel blocking reduces these parametersparameters

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CCB’s: Potential Side EffectsCCB’s: Potential Side Effects• DihydropyridinesDihydropyridines

– Peripheral edemaPeripheral edema– reflex tachycardiareflex tachycardia– flushing/headacheflushing/headache– hypotensionhypotension

• NondihydropyridinesNondihydropyridines– constipationconstipation– conduction abnormalitiesconduction abnormalities

HypertensionHypertension

HypertensionHypertension

Calcium Channel Blockers: Specific Calcium Channel Blockers: Specific IndicationsIndications

CCB’s: Compelling IndicationsCCB’s: Compelling Indications• Isolated Systolic Hypertension (long-acting)Isolated Systolic Hypertension (long-acting)

CCB’s: Possible Favorable EffectsCCB’s: Possible Favorable Effects• anginaangina

• atrial tachyarhythmiasatrial tachyarhythmias

• Cyclosporine-induced HTNCyclosporine-induced HTN

• Diabetes Mellitus Type 1 and 2 with proteinuriaDiabetes Mellitus Type 1 and 2 with proteinuria

HypertensionHypertension

Hypertension: The Hypertension: The Diagnosis and Treatment Diagnosis and Treatment

ProcessProcess

JNC 7 Express. NIH publication No 03-5233. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. May, 2003.

HypertensionHypertension

Why the More Aggressive BP Why the More Aggressive BP Classifications?Classifications?High-Normal BP as CV Risk FactorHigh-Normal BP as CV Risk Factor

Vasan RS, et al. N Eng J Med 2001;345:1291-7.

HypertensionHypertension

Outcomes Studies in High-Risk Outcomes Studies in High-Risk PatientsPatientsALLHAT Study: Optimal 1st Line AgentALLHAT Study: Optimal 1st Line Agent

ALLHAT Investigators. JAMA 2002;288:2981-7.

Chlor Amlod Lisin C vs A C vs L

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

HypertensionHypertension

Outcomes Studies in High-Risk Outcomes Studies in High-Risk PatientsPatientsHOPE Study: Ramipril vs PlaceboHOPE Study: Ramipril vs Placebo

HOPE Investigators. N Eng J Med 2000;342:145-53.

HypertensionHypertension

Outcomes Studies in High-Risk Outcomes Studies in High-Risk PatientsPatientsLIFE Study: Losartan vs AtenololLIFE Study: Losartan vs Atenolol

LIFE Investigators. Lancet 2002;359:995-1003.

HypertensionHypertension EUROPA Investigators. Lancet 2003;362:782-8.

Peridopril N=6110

Placebo N=6108

Risk Reduction

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

Outcomes Studies in High-Risk Outcomes Studies in High-Risk PatientsPatientsEUROPA Study: Perindopril vs PlaceboEUROPA Study: Perindopril vs Placebo

HypertensionHypertension

HypertensionHypertension

Algorithm for Treatment of Algorithm for Treatment of HTNHTN

Compelling Compelling IndicationsIndications

DiureticDiuretic B-BlockerB-Blocker ACE ACE InhibitorInhibitor

ARBARB CCBCCB Aldosterone Aldosterone antagonisstantagonisst

Heart FailureHeart Failure XX XX XX XX XX

Post-MIPost-MI XX XX XX

High CAD High CAD riskrisk

XX XX XX XXNon-DHPNon-DHP

DiabetesDiabetes XX XX XX XX XXNon-DHPNon-DHP

Chronic renal Chronic renal diseasedisease

XX XX

22°° Stroke Stroke preventionprevention

XX XX

NHBPEP Coordinating Committee. The JNC 7 Report. JAMA 2003;289:2560-72.

$0.00

$10.00

$20.00

$30.00

$40.00

$50.00

$60.00

$70.00

$80.00

Pri

ce p

er M

onth

($)

ACE I ARB BB Loop HCTZ CCB Hydralazine

Medication Class

BrandGeneric

Hypertension Treatment Hypertension Treatment CostsCosts

Patient PerspectivePatient Perspective

www.walgreens.com. Accessed 4/8/05

* Most patients require ~ 2 antihypertensive drugsALLHAT Investigators. JAMA 2002;288:2981-7.

HypertensionHypertension

Algorithm for Treatment Algorithm for Treatment (continued)(continued)

Not at Goal Blood Pressure (< 140/90 mm Hg)

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)

Initial Drug Choices

HypertensionHypertension

Drug TherapyDrug Therapy

Dose-effect curveDose-effect curve• Variation in a populationVariation in a population

• Length of therapyLength of therapy

• Counter-regulationCounter-regulation AbsorptionAbsorption EliminationElimination Effect

Dose

Toxic

NoEffect Effect

HypertensionHypertension

Special PopulationsSpecial Populations

African AmericansAfrican Americans• Response to diuretics & CCB Response to diuretics & CCB

> response to ACEI, ARB, > response to ACEI, ARB, beta-blockersbeta-blockers

• Angioedema 2 – 4-fold Angioedema 2 – 4-fold higherhigher

Left ventricular hypertrophyLeft ventricular hypertrophy• Aggressive BP control Aggressive BP control

regresses LVHregresses LVH

• ……but hydralazine & minoxidil but hydralazine & minoxidil DO NOT!DO NOT!

Elderly Elderly (Isolated Systolic HTN)(Isolated Systolic HTN)

• Same general principlesSame general principles• Thiazide or CCB may be Thiazide or CCB may be

better toleratedbetter tolerated PregnancyPregnancy

• Methyldopa, beta-blockers, Methyldopa, beta-blockers, vasodilators (hydralazine)vasodilators (hydralazine)

• Avoid ACEI & ARBsAvoid ACEI & ARBs Children/adolescentsChildren/adolescents

• Avoid ACEI & ARBs in Avoid ACEI & ARBs in pregnant or sexually active pregnant or sexually active girlsgirls

NHBPEP Coordinating Committee. The JNC 7 Report. JAMA 2003;289:2560-72.

HypertensionHypertension

Finally: Quality of LifeFinally: Quality of Life

Hypertension is often silentHypertension is often silent• DepressionDepression

• Urinary frequencyUrinary frequency

• Sexual dysfunctionSexual dysfunction– MaleMale– FemaleFemale

• FatigueFatigue

• CoughCough CostCost