N**-*** PCP Kit

Hypertension Update:

Focus on Pharmacotherapy

Robert J. Straka, Pharm.D. FCCP

Associate Professor

University of Minnesota

College of Pharmacy

Minneapolis, Minnesota

abqd3z@r.postjobfree.com

Learning Objectives:

At the end of the presentation, learners should be able to:

1) Describe and define several basic facts about the epidemiology and

pathophysiology of hypertension

2) Describe and explain fully the goals and overall approach to

managing patients with hypertension with an emphasis on

pharmacotherapeutic issues

3) Discuss current JNC 7 issues and evidenced-based support for

their recommendations (and modifications based on recent studies)

4) Outline salient features of pharmacotherapeutic agents commonly

used to treat patients with hypertension and be able to develop a

rationale for their selection for specific patients

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JNC 7 Guidelines for Hypertension

Goal: To reduce CV morbidity and mortality through

prevention and management of hypertension

JNC 7 Guidelines (2003)

Classification of Blood Pressure

Category SBP (mm Hg) DBP (mm Hg)

Normal 50%

JNC 7 Express. 2003. NIH Publication 03-5233.

Neal B et al. Lancet. 2000;356:1955-1964.

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JNC - 7

The Seventh Report

of the

Joint National Committee on Prevention, Detection, Evaluation, and

Treatment of

High Blood Pressure

JAMA 2003; 289 (19): 2560-2572 May 21, 2003

Web Site

http://www.nhlbi.nih.gov/guidelines/hypertension/index.htm

JNC 7 Highlights

For patients older than 50 years, SBP >140 mm Hg is a more important

CVD risk factor than DBP

Patients with pre-hypertension require health-promoting lifestyle

modifications to prevent CVD

Thiazide-type diuretics should be used in drug treatment for most patients

with uncomplicated hypertension, either alone or in combination with

drugs from other classes

High-risk conditions are compelling indications for the initial use of specific

antihypertensive drug classes

Most patients will require 2 or more antihypertensive agents to reach their

goal blood pressure

If BP is >20/10 mm Hg above goal, consideration should be given to

initiating therapy with 2 agents, one of which should usually be a thiazide-

type diuretic

JAMA 2003; 289 (19): 2560-2572 May 21, 2003

The JNC 7 report. JAMA. 2003;289:2560-2572.

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JNC 7 Guidelines for Hypertension

Goal: To reduce CV morbidity and mortality through

prevention and management of hypertension

JNC 7 Guidelines (2003)

Classification of Blood Pressure

Category SBP (mm Hg) DBP (mm Hg)

Normal 55 years for men, >65 for women)

Family history of premature CVD (men aged 50 years of age

Adapted from the JNC 7 Slide Deck. Available at: http://www.nhlbi.nih.gov.

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JNC 7: Lifestyle Modification

Modification Approximate SBP reduction (range)

Weight Reduction 5-20 mmHg/10Kg wt loss

Adopt DASH eating plan 8-14 mmHg

Dietary sodium reduction 2-8 mmHg

Physical activity 4-9 mmHg

Moderation of alcohol consumption 2-4 mmHg

.

Adapted from the JNC 7 Reference Card. Available at: http://www.nhlbi.nih.gov.

JNC 7 Algorithm for Treatment

Adapted from the JNC 7 Slide Deck. Available at: http://www.nhlbi.nih.gov

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JNC 7: Compelling Indications for

Individual Drug Classes

Compelling Indication Recommended Drug Classes

Heart failure THIAZ, BB, ACEI, ARB, ALDO ANT

Post-myocardial infarction BB, ACEI, ALDO ANT

High CVD risk THIAZ, BB, ACEI, CCB

Diabetes THIAZ, BB, ACEI, ARB, CCB

Chronic kidney disease ACEI, ARB

Recurrent stroke prevention THIAZ, ACEI

.

Adapted from the JNC 7 Reference Card. Available at: http://www.nhlbi.nih.gov.

Compelling Indications for

Individual Drug Classes: JNC 7

Compelling Indication Recommended Clinical Trial Basis

DIUR, BB, ACEI, ARB, ALDO- ACC/AHA Heart Failure Guideline,

Heart failure

ANT MERIT-HF, COPERNICUS, CIBIS,

SOLVD, AIRE, TRACE, ValHEFT,

RALES, CHARM

ACC/AHA Post-MI

Post-myocardial

BB, ACEI, ALDO ANT Guideline, BHAT, SAVE, Capricorn,

infarction

EPHESUS

ALLHAT, HOPE, ANBP2, LIFE,

High CAD risk

CONVINCE

DIUR, BB, ACE, CCB

Adapted from Chobanian et al. JAMA. 2003; Vol 289, No 19: 2560-2572.

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Compelling Indications for

Individual Drug Classes: JNC 7

Compelling Indication Recommended Clinical Trial Basis

NKF-ADA Guideline,

Diabetes DIUR, BB, ACE, ARB, CCB

UKPDS, ALLHAT

NKF Guideline, Captopril

Chronic kidney disease ACEI, ARB Trial, RENAAL, IDNT,

REIN, AASK

PROGRESS

Recurrent stroke prevention DIUR, ACEI

Adapted from Chobanian et al. JAMA. 2003; Vol 289, No 19: 2560-2572.

Studies Supporting the Guidelines

ALLHAT, ANBP2, VALUE ASCOT-BPL

MERIT-HF, VALHFT, CHARM

LIFE, LIFE Substudy

HOPE, Micro-HOPE

IDNT RENAAL

AASK

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Treatment Diabetes:

Diabetes Care 29;S4-S42:2006

Initial drug therapy for those with a blood pressure

>140/90 should be with a drug class demonstrated to

reduce CVD events in patients with diabetes (ACE

inhibitors, ARBs, -blockers, diuretics, calcium channel

blockers). (A)

All patients with diabetes and hypertension

should be treated with a regimen that includes

either and ACE inhibitor or ARB (E)

Hypertension Management in Adults with Diabetes (Diabetes Care, Vol 29 S4-S42,

Supplements Jan 2006)

Treatment Cont.

If ACE inhibitors or ARBs are used, monitor renal function and

serum potassium levels. (E)

While there are no adequate head-to-head comparisons of ACE

inhibitors and ARBs, there is clinical trial support for each of the

following statements:

In patients with type 1 diabetes with hypertension and any degree of albuminuria, ACE

inhibitors have been shown to delay the progression of nephropathy. (A)

In patients with type 2 diabetes, hypertension, and microalbuminuria, ACE inhibitors and

ARBs have been shown to delay the progression to macroalbuminuria. (A)

In those with type 2 diabetes, hypertension, macroalbuminuria (>300 mg/day), and renal

insufficiency, an ARB should be strongly considered. (A)

Hypertension Management in Adults with Diabetes (Diabetes Care, Vol 29, S4-S42, Jan 2006)

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Diagnostic Criteria for Albuminuria

Standard urine dipsticks are not sensitive enough to

detect microalbuminuria

Albuminuria Spot Spot 24-hr Timed

Specimen Specimen Specimen

(mcg/mL) (mcg/mg Cr) (mg)

Normo- 200

ADA Clin Practice Guidelines; Diabetes Care. 2002;25(1):S85-S89.

JNC 7: Goals for Prevention and

Management of Hypertension

Reduce morbidity and mortality by least intrusive means

possible

SBP 30 ml/min thiazide (all probably work equally well)

ClCr 2-4 wks before assessing benefit

- may take 3-6 months before max. benefit (CHF)

but 1-2 months for HTN

SE's Hypotension (monitor BP)

- Renal Insufficiency (monitor Scr)

- Potassium retention (monitor K)

- Cough

Contraindicated with RAS, angioedema

Conclusions:

- ACE I's represent a significant opportunity for

CHF, post-AMI, diabetic nephropathy and HTN

ACE Inhibitors

Non-renin ANGIOTENSINOGEN

Renin

Angiotensin I Bradykinin

ACE

Non-ACE

Inactive

ANGIOTENSIN II

peptides

ACEI

AT1 AT2

ATn

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Angiotensin Receptor Blockers (ARBs)

Non-renin ANGIOTENSINOGEN

Renin

Angiotensin I Bradykinin

ACE

Non-ACE

ANGIOTENSIN II Inactive

peptides

ARBs

AT1 receptor stimulates:

AT2

AT1 Vasoconstriction, Cell growth, ATn

Na+ retention, Sympathetic

activation

ANGIOTENSINOGEN

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Glu-Ser

Renin RENIN INHIBITORS

ANGIOTENSIN I

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu

Angiotensin

ACE INHIBITORS

Converting

Enzyme

ANGIOTENSIN II

Asp-Arg-Val-Tyr-Ile-His-Pro-Phe

AII ANTAGONISTS

AT1 Receptor

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Classification of Angiotensin II Receptors

AT1 AT2

Sensitive to blockade by: Sensitive to blockade by:

Losartan, Valsartan, etc. CGP 42112A, PD123177

Vasoconstriction Vasodilation

Aldosterone Release Antiproliferation

Cardiac Inotropic Effect Apoptosis

Vasopressin Release Bradykinin Release

Increase SNS Activity Nitric Oxide Release

Decrease Renin Release

Renal Na+ & H2O Reabsorption

Cell Growth & Proliferation

Angiotensin II Receptor Blockers

Drug Brand % Bio- Effect of T Protein

Name available Food (hrs) Bound

Cozaar

Losartan 33 No 2 99%

(Metabolite E-3174) - - 9 99%

Diovan

Valsartan 25 50% 6 95%

Avapro

Irbesartan 60 No 15 90%

Atacand

Candesartan 40 No - -

(Metabolite CV-11974) - 9 99%

Micardis

Telisartan 50 20% 13 99%

Teveten

Eprosartan 13 25% 9 98%

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Angiotensin II Receptor Blockers

Drug Brand % Bio- Effect of T1/2 Protei

Name available Food (hrs) n

Bound

Cozaar

Losartan 33 No 2 99%

(Metabolite E-3174) - - 9 99%

Diovan 50%

Valsartan 25 6 95%

Avapro

Irbesartan 60 No 15 90%

Atacand

Candesartan 40 No - -

(Metabolite CV-11974) - - 9 99%

Micardis 20%

Telmisartan 50 13 99%

Teveten 25%

Eprosartan 13 9 98%

Angiotensin II Receptor Blockers (ARBs)

Losartan (Cozaar Merck, 25 + 50 mg tabs qd-bid)

Valsartan (Diovan,Novartis, 80 and 160 mg caps qd)

Irbesartan (Avapro BMS, 150-300mg/d tabs qd)

Telmisartan (Micardis Boehring Ing, Glaxo Welcome, 20-80mg tabs qd )

Candesartan (Atacand,Astra Merck, 4, 8,16,32mg tabs (qd-bid))

All of available agents are approved for hypertension

Hyzaar is losartan 50 mg/HCT 12.5 mg tablet

Diovan HCT is valsartan + HCT 80/12.5 or 160/12.5 capsules

Avilide is irbesartan + HCT 12.5 or 25mg tablets

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Angiotensin II Receptor Blockers (ARBs)

Similar anti-HTN efficacy to ACE inhibitors and atenolol

(perhaps less SE s and D/C rates)

Advantages may be in reduced incidence of cough and

angioedema (vs. ACE inhibitors) although angioedema has

been reported

Apparently no effects on lipids, fasting glucose although

have a significant uricosuric effect

Hyperkalemia can occur to comparable level as with ACE

inhibitors

Angiotensin II Receptor Blockers in Patients

With Hypertension

Advantages Disadvantages

Decr. incidence of cough vs.

Limited data on long-term

ACE inhibitors

efficacy/safety in clinical

Alternative for ACE intolerant

practice

patients

Questions remain about

Sign. Uricosuric effect

efficacy vs ACE s in heart

Benefits in Type 2 Diabetics

failure (ELITE II, Val-HeFT,

Benefit in CHF patients

CHARM)

(CHARM)

Similar to ACE inhibitors wrt

K+ sparing

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Cough: ARBs vs Enalapril

Percent of patients experiencing cough

15.1*

16 16 16

13.1*

Patients Patients Patients 12 12 12

8 8 8

4.3

4 4 4

3.0

2.5

0.7

0 0 0

Enalapril Irbesartan Enalapril Losartan Enalapril Valsartan

n = 61 n = 121 n = 199 n = 200 n = 60 n = 137

* P

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