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  • 1

    Hypertension and Antihypertensive Agents

    Edward JN Ishac, Ph.D.

    Department of Pharmacology and ToxicologyMedical College of VirginiaCampus of Virginia Commonwealth University Richmond, Virginia, USA

    Smith Building, Room 742eishac@vcu.edu8-2127 8-2126

    Agents used in HT, CHF, Arrhythmia and Angina

    NO/cGMP, tolerance (off periods), flushing, dizziness, headache, reflex tachycardia, many forms

    aaaa

    aaNitrates

    Effects enhanced in depolarized, damaged tissue, Phase 0, CVaaaa

    Na+-Channel blockers

    Flushing, dizziness, headache, nausea, reflex tachycardia

    aaaaaVasodilators

    Many Rx interactions, [K+], use HFimportant, low K+toxicity,

    aaaCardiac glycosides

    GFR >30, hypokalemia (CG); diabetes (glucose tolerance)aaa

    aaaaa

    Diuretics

    Angioedema, hyperkalemia, cough (acei), tetrogenic, glossitis, tasteaaa

    aaaaa

    ACEI / ARBs

    HF, constipation, gingival hyperplasia, edema, reflex tachycardia

    aaaa

    aaaa

    aaaa

    Ca++-Channel blockers

    HF (CI: unstable HF, broncho-spasm, significant bradycardia, depression); Raynaud D. Caution in diabetes, asthma (use 1-)

    aaaa

    aaaaaaaaaa

    Beta-Blockers

    Contraindications/Cautions/Notes AnginaArrhythmia

    HFHyper-tension

    Drug Class

    Leading Causes of Death in the U.S

    0

    250,000

    500,000

    750,000

    1,000,000

    Heart Disease

    CancerRespiratory Disease

    AccidentsDiabetesInfluenzaAlzheimer's Disease

    Data NIH 2000

    Prevalence of Common Cardiovascular and Lung Diseases, U.S., 2005

    24,000,000COPD

    22,000,000Asthma

    1,000,000Congenital Heart Disease

    5,800,000Stroke

    5,300,000Heart Failure

    16,800,000Coronary Heart Disease

    73,000,000Hypertension**

    80,700,000Cardiovascular Diseases*

    NumberDisease

    * Includes hypertension, CHD, heart failure, and stroke. ** Hypertension is defined as systolic blood pressure 140 mm Hg, or diastolic blood pressure 90 mm Hg

    IntroductionBlood Pressure Regulation: Franks Formula

    BP = Cardiac output (CO) X Total peripheral resistance (TPR)CO = Stroke volume (SV) X Heart rate (HR)

    Fast acting

    Long acting

    120/80 mmHg70 bpm

    - oppose direct change in BP- bidirectional, responds to or in BP- not concerned with HR- not concerned with pulse pressure

    Baroreceptor Reflex Arc

    Increase stretch increase firing of baroreceptors

  • 2

    Systolic Diastolic Blood Pressure

    Normal: 120/80 mmhg

    Definition of Hypertension (HT)

    Sustained elevation of systolic and/or diastolic BP above an arbitrarily defined level

    systolic >139 mmHg and/or diastolic >89 mmHg

    General population (15-20%) hypertensive45 60 million in USA

    CV mortality risk x2 each 20/10 mmHg BP

    Secondary HT (10%): can be treated by surgical procedures (early diagnosis of cause, ie renal stenosis, pheochromocytoma)

    Primary (essential) HT (90%): is a lifelong disease, long-term control & treatment, cause unknown

    JNC VII Blood Pressure Classification (2003)

    160Stage 2 Hypertension

    DBP mmHgSBP mmHgBP Classification

    *Require three measurements (repeat visits)BP lowest in the morning during the day

    Previous Classification of Hypertension (119

    For accurate determination: requires three measurements (repeat visits)BP in general is lowest in the morning and increases during the day

    Hypertension (HT)Secondary HTs (10%)- neurogenic HT caused by brain damage- cortisol overproduction: hypophysis or adrenal gland tumor- aldosterone overproduction: adrenal gland tumor hyperplasia- renal artery stenosis or occlusion- adrenal medulla tumor: pheochromocytoma

    Primary (essential) HTs (90%)- primary cause(s) unknown, possibly multi-factorial defects

    - genetics - smoking - stress- salt intake - obesity - age- alcohol - caffeine - others

    Renal Stenosis

    Decreased renal blood flow- renal BP- renin release- aldosterone- Na+, water retention- systemic BP

    Primary cause of 2o HT

  • 3

    Rule of Ten10% Pheochromocytomas are:

    Malignant Bilateral Extra-adrenal In children Familial Recur (within 5 to 10 years) Present after stroke

    PheochromocytomaTumor: synthesis, release of NE & EPI into the circulation.Result: BP, HR hypertensive crisisTreatment: - surgical removal for solid tumor

    - - / -blocker ie. Labetatol- -blocker ie, phenoxybenzamine or phentolamine- inhibit tyrosine hydroxylase ie. -methyl-p-tyrosine- -blocker only after -blockade

    Exam Stress

    Normal BP: 120 / 80 mmHg HR: 72 bpm

    During exam: 179 / 149 mmHg HR: 110 bpm

    End of exam: 111 / 74 mmHg HR: 76 bpm

    Before exam: 140 / 99 mmHg HR: 97 bpm

    Hypertension (HT)Secondary HTs (10%)- neurogenic HT caused by brain damage- cortisol overproduction: hypophysis or adrenal gland tumor- aldosterone overproduction: adrenal gland tumor hyperplasia- renal artery stenosis or occlusion- adrenal medulla tumor: pheochromocytoma

    Primary (essential) HTs (90%)- primary cause(s) unknown, possibly multi-factorial defects

    - genetics - smoking - stress- salt intake - obesity - age- alcohol - caffeine - others

    BP Daily Fluctuation

    Franklin Roosevelt(1882-1945)

    FDR died unexpectedly, April 12, 1945 -less than six months after being elected to a fourth term. His arteries were so atherosclerotic that embalmers could not get a needle into them

    *Individuals aged 40-70 years, starting at BP 115/75 mm Hg.CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressureLewington S, et al. Lancet. 2002; 60:1903-1913. JNC 7. JAMA. 2003;289:2560-2572.

    CVmortality

    risk

    SBP/DBP (mm Hg)

    0

    1

    2

    3

    4

    5

    6

    7

    8

    115/75 135/85 155/95 175/105

    CV Mortality Risk Doubles withEach 20/10 mm Hg BP Increment

  • 4

    Retinopathy Renal failurePAD/PVD

    Consequences/Complications of Hypertension:

    LVH, CHD, HFTIA, stroke

    Hypertension is a risk factor

    - end organ damage, ie. retinopathy- failure in blood supply, renal failure (fibrinoid necrosis)- loss of microcirculation, PAD/PVD- aneurysms (rupture of blood vessels)- myocardial and/or cerebral infarction- increased risk of stroke, congestive heart failure

    Health Consequences - AgeUSA

    45-60 million HT Na+ rise rate

    Health Consequences Effective Treatment

    Better understanding, better treatments, better results

    Hypertension Treatment in the Elderly

    Morse, M. Hypertension Treatment and the Prevention of Coronary Heart Disease in the Elderly. AFP; March 1, 1999.

    1900 1983 2000

    % T

    op T

    en C

    ause

    s of

    Dea

    th

    DiabetesFlu/PneumoniaOther infectionsAccidentsCancerCardiovascular dsOther conditions

    Top Causes of Death (%), U.S. Non Drug Treatment Life Style Modification

    - salt intake (Japan, intake BP)2.5gm/day (250meq) 1gm/day (100meq)

    - calorie intake, weight loss- alcohol (low dose BP)- physical activity- stress factors- smoking- caffeine intake

    For mild moderate hypertensionLess side effects, cheap, improved lifestyle

  • 5

    Exercise, Diet & Lifestyle Hypertension Lifestyle Modification

    2 4 mmHgModeration of alcohol consumption

    4 9 mmHgPhysical activity

    2 8 mmHgDietary sodium reduction

    8 14 mmHgAdopt DASH eating plan

    5 20 mmHg/10 kg wt lossWeight reduction

    SBP reductionModification

    Main classes(frontline agents)

    Diuretics (1st)Beta-blockersCalcium blockersACE inhibitors / ARBs

    Sites of Action of Antihypertensive

    Agents

    Antihypertensive Agents (JNC VII, 2003)

    1. Diuretics (1st) eg. hydrochlorothiazide2. Renin / AgII (ACEI, ARBs) eg. lisinopril, losartan3. Calcium-antagonists eg. nifedipine, verapamil4. Beta-antagonists eg. propranolol5. Alpha-antagonists eg. prazosin6. Potassium sparing eg. spironolactone7. Vasodilators eg. hydralazine, nitroprusside8. Central acting alpha2-agonists: eg. clonidine, -methyl dopa9. Renin inhibitor eg. aliskiren (newest agent)10. Dopamine agonist eg. fenoldopam (acute HT)11. Inhibit/reduce NE release eg. guanethidine, reserpine12. Ganglionic blockers eg. mecamylamine

    Development of Antihypertensive Therapies

    VasodilatorVasodilatorHydralazineHydralazine

    Alpha1Alpha1--blockersblockersPrazosinPrazosin

    Renin Renin inhibitorsinhibitorsAliskirenAliskiren

    PeripheralPeripheralsympatholyticssympatholyticsGuanethidineGuanethidine

    ReserpineReserpine

    Ganglion Ganglion blockersblockers

    HexamethoniumHexamethonium

    BetaBeta--blockersblockersPropranololPropranolol

    AlphaAlpha--blockersblockersPhenoxybenzaminePhenoxybenzamine

    PhentolaminePhentolamine

    AlphaAlpha22--agonistsagonists--MethyldopaMethyldopa

    ClonidineClonidine

    NonNon--DHP DHP CCBsCCBsDiltiazemDiltiazemVerapamilVerapamil

    ThiazidesThiazidesChlorothiazideChlorothiazide

    Beta1Beta1--blockersblockersMetoprololMetoprolol

    DHP DHP CCBsCCBsNifedipineNifedipine

    AmlodipineAmlodipine

    ACEIACEICaptoprilCaptopril

    1940s1940s 19501950 19571957 1960s1960s 1970s1970s 1980s1980s 1990s1990s 20052005

    ARBsARBsLosartanLosartan

    Alpha/betaAlpha/beta--blockersblockersLabetalolLabetalol

    AAAASpiroSpiro

    Antihypertensive Usage (ACC, 2001)

    17.216.4Alpha-blocker

    15.38.4None (life-style)

    5.14.4Other class

    54.548.8Diuretics (thiazides)

    35.651.5Ca++-blocker

    50.257.9Beta-blocker

    57.571.6ACE inhibitor / ARB

    GP/FPCardiologist

    % Selecting each class

    For untreated patients with BP

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