HypertensionHypertension
Hypertension:Hypertension:A Pharmacological A Pharmacological
ApproachApproachRobert J. DiDomenico, Pharm.DRobert J. DiDomenico, Pharm.D
HypertensionHypertension
HypertensionHypertension
JNC 7 Express. NIH publication No 03-5233. http://www.nhlbi.nih.gov/guidelines/hypertension/express.pdf. May, 2003.
HypertensionHypertension
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.
HypertensionHypertension
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
HypertensionHypertension
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)
HypertensionHypertension
HypertensionHypertension
HypertensionHypertension
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
HypertensionHypertension
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
HypertensionHypertension
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
HypertensionHypertension
HypertensionHypertension
HypertensionHypertension
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)
HypertensionHypertension
HypertensionHypertension
HypertensionHypertension
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Loop diuretics
Thiazide diuretics
Potassium-sparing diuretics
Carbonic anhydrase inhibitors
HypertensionHypertension
HypertensionHypertension
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
HypertensionHypertension
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
HypertensionHypertension
HypertensionHypertension
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
HypertensionHypertension
HypertensionHypertension
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
HypertensionHypertension
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
HypertensionHypertension
HypertensionHypertension
HypertensionHypertension
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
HypertensionHypertension
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
HypertensionHypertension
HypertensionHypertension
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
HypertensionHypertension
HypertensionHypertension
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
HypertensionHypertension
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
HypertensionHypertension
HypertensionHypertension
HypertensionHypertension
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
HypertensionHypertension
HypertensionHypertension
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
HypertensionHypertension
HypertensionHypertension
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