1.6.2 Pharmacologic Treatment

Hypertension with compelling indications

Stage 1 hypertension (SBP 140-159 or DBP 90-99 mmHg)

Thiazide-type diuretics for most

May consider ACE inhibitor, ARB, -blocker, CCB, or combination

Stage 2 hypertension (SBP ≥160 mmHg or DBP ≥100 mmHg)

2-drug combination for most (usually thiazide-type diuretic and ACE inhibitor or ARB or -blocker or CCB)

Drug(s) for compelling indications

Other antihypertensive drugs (diuretics, ACE inhibitor, ARB, -blocker, CCB) as needed

Not at goal BP

Lifestyle modifications

JNC 7 VII, Hypertens. 2003;42:1206-1252.

Not at goal BP (<140/90 mmHg or <130/80 mmHg for those with diabetes or chronic kidney disease)

Initial drug choices

Hypertension without compelling indications

Optimize dosages or add additional drugs until goal BP is achievedConsider consultation with hypertension specialist

JNC 7 - Algorithm for treatment of hypertension

For Internal Use Only

ESH/ESC guidelines Pharmacological Treatment of

HypertensionConsider :Blood pressure level before treatment

Absence or presence of TOD and risk factors

Two-drug combination at low dose

Choose between :

Single agent at low dose

If goal BP not achieved :

Previous agent at full dose

Switch to different agent at low dose

Previous combination at

full dose

Add a third drug at low dose

If goal BP not achieved :

Two-three drug combination Two-three drug combination

ESH/ESC Guidelines. J Hypertens 2003; 21: 1011-1053For Internal Use Only

“The major classes of antihypertensive agents

(diuretics, ß-blockers, calcium antagonists,

ACE inhibitors, angiotensin-receptor antagonists)

are suitable for the initiation and maintenance of

therapy”

Position statement: Choice of antihypertensive drugs

ESH/ESC Guidelines. J Hypertens 2003; 21: 1011-1053

ESH/ESC guidelines


Position statement: Choice of antihypertensive drugs


ESH/ESC guidelines

• The main benefits of antihypertensive therapy are due to lowering of

blood pressure per se

• There is also evidence that specific drug classes may differ in some

effect, or in special groups of patients

• Drugs are not equal in terms of adverse disturbances, particularly in

individual patients

• Emphasis on identifying the first class of drugs to be used is probably

outdated by the need to use two or more drugs in combination in order

to achieve goal BP



ESH/ESC guidelines• Recommendations for the role of ARBs:

– Type 2 diabetic nephropathy– Diabetic microalbuminuria– Proteinuria– LV hypertrophy– ACE-inhibitor cough

• Searching for microalbuminuria is recommended in all hypertensives – A continuous relation between urinary albumin excretion

rate and cardiovascular, as well as non-cardiovascular mortality has been found


Diabetic hypertension


ESH/ESC guidelines

• To reach diabetic hypertension goals, combination therapy is most often required

• Evidence indicates that combinations including an ACE inhibitor in Type 1 diabetes and an ARB in Type 2 diabetes provide renoprotection benefits


JNC 7: Goals and RecommendationsGoal: To reduce cardiovascular, renal morbidity and mortality

• For patients older than 50 years, SBP 140 mm Hg is a more important CVD risk factor than DBP

• 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 two agents, one of which should usually be a thiazide-type diuretic JNC 7 VII, Hypertens. 2003;42:1206-1252


JNC-7 Guidelines Diabetic hypertension

• Thiazide diuretics, ß-blockers, ACE inhibitors, ARBs and CCBs have been shown to reduce CVD and stroke incidence in diabetic hypertension

• In diabetic hypertension, combinations of 2 or more medications are usually needed to achieve target BP of < 130/80 mmHg

• ACE- and ARB-based treatments favourably affect the progression of diabetic nephropathy and reduce albuminuria

• ARBs have been shown to reduce progression to macroalbuminuria

Chobanian AV et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 2003;289:2560-72.


ESH/ESC guidelines Elderly Patients

• Cardiovascular events can be reduced by antihypertensive treatment also in older patients with isolated systolic hypertension

• BP lowering should be gradual particularly in frail patients• Measure BP also in the erect posture to evaluate

excessive postural effects• Tailor therapy on concomitant risk factors and disease

(frequent in the elderly)• Use two or more drugs, if necessary• In subjects aged > 80 years, evidence of benefit from

antihypertensive therapy is still weak ESH/ESC Guidelines. J Hypertens 2003; 21: 1011-1053



• Renal protection in diabetes requires strict BP control (to less than 130/80 mmHg), but also in patients with non-diabetic nephropathy it appears

• prudent to lower BP intensively• Proteinuria should be lowered to values as near to normal as

possible• To reduce proteinuria either an angiotensin receptor antagonist or

an ACE-inhibitor (or the combination of both) is required• To achieve the BP goal, combination therapy is usually required,

with the addition of a diuretic, a calcium antagonist and other antihypertensive agents

• Consider an integrated therapeutic intervention (antihypertensives, statins, antiplatelet therapy, etc.)

ESH/ESC guidelinesPatients with Renal Impairment


Compelling indication for

others

Compelling indication for

others

Compelling indication for others

-2 drug combo2 drug combo

Low dose Diuretics

Any of 5

(A,A,B,C,D)Thiazide-type

Diuretics

WHO-ISHESH-ESCJNC 7

First line therapy


JNC 7 Report. JAMA 2003; 289: 2560-2572ESH/ESC Guidelines. J Hypertens 2003; 21: 1011-1053Guidelines Sub-Committee. 1999 WHO/ISH. J Hypertens 1999; 17:151–183

Di

ACE I

CCB

ARB B

B

WHO-ISHESH-ESCJNC VII

Di + anyDi +

ACE I/

ARB/

CCB/

B


JNC 7 Report. JAMA 2003; 289: 2560-2572ESH/ESC Guidelines. J Hypertens 2003; 21: 1011-1053Guidelines Sub-Committee. 1999 WHO/ISH. J Hypertens 1999; 17:151–183

Recommended combinations

Resistant hypertension

• Look for reasons (drugs, alcohol, compliance, secondary HTN)

• ‘more diuretic’ vs ‘a fresh start’

(JNC 7) (ESH)


10604 M

FACET

Micro HOPE

CAPPP

INSIGHT

HOT

VALUE

STOP-2

UKPDS

LIFE

RENAAL

IDNT

IRMA

ABCD130

140

150

160

170

180

190

200mmHg

120

Diabetics

B T

ALLHAT 1

HOPE

PROGRESS

CAPPP

INSIGHT

NORDIL

HOT

STONE

STOP-2

LIFE

ALLHAT 2

ANBP2

INVEST

SCOPE

ASCOT

VALUE

All patients

130

140

150

160

170

180

190

200mmHg

B T

* Most patients under ≥ 2 drugs Mancia G and Grassi G, J Hypert 2002;20:1461-1464For Internal Use Only

SBP Control in Trials *

0 10 20 30 40 1009080706050

Average

VA

SYST-EUR

STOP-2

STOP-1

SHEP

NORDIL

MRC II

MRC I

MAPHY

INSIGHT

HOT 90

LIFE

EWPHE

COOPEANBP

62%100%

41%55%

66%45%

52%51%

34%48%

54%60%

90%35%

93%33%

%

ALLHAT 41%

INVEST 82%

Combination Therapy in Large Trials

Updated from Coca A. J Cardiovasc Pharmacol 1999; 34 (Suppl 3): 29-35For Internal Use Only

Multiple Antihypertensive Agents Are Often Needed to Achieve Target BP

1

No. of Antihypertensive Agents2 3 4

SBP 140/DBP 90ALLHAT7

SBP 135/DBP 85IDNT6

MAP 92AASK5

DBP 80HOT4

MAP 92MDRD3

DBP 75ABCD2

DBP 85 UKPDS1

Target BP (mm Hg)

Trial

DBP- diastolic blood pressure MAP - mean arterial pressure ; SBP- systolic blood pressure

1. UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713. 2. Estacio RO et al. Am J Cardiol. 1998;82:9R-14R.

3. Lazarus JM et al. Hypertension. 1997;29:641-650. 4. Hansson L et al. Lancet. 1998;351:1755-1762.

5. Kusek JW et al. Control Clin Trials. 1996;16:40S-46S. 6. Lewis EJ et al. N Engl J Med. 2001;345:851-860.

7. ALLHAT. JAMA. 2002;288:2998-3007.For Internal Use Only

Average number of daily pills

0

10

20

30

40

50

60

70

1 2 3 8

Complianceto

treatment(%)

Mancia G et al. Am J Hypertens 1997; 10: 153S-158SFor Internal Use Only

Compliance to Treatment Related to Daily Number of Pills Prescribed

Persistence rates of one pill of lisinopril/HCTZ in fixed-combination vs two separate pills of lisinopril and HCTZ

100 95 90 85 80 75 70 65 60 55 50

0 1 2 3 4 5 6 7 8 9 10 11 12

Months

Persistence(%) 68.7

57.8

18.8%

Lisinopril/HCTZ (1 pill)

Lisinopril and HCTZ (2 pills)

Fixed-dose Combination Therapy Increases

Compliance to Treatment

Dezii CM. Manag Care 2000; 9 (Suppl): s2-s6For Internal Use Only

JNC 7 Report. JAMA 2003; 289: 2560-2572

JNC 7 2003 Guidelines Pharmacological Treatment

• Most patients with hypertension will require 2 or more antihypertensive medications to achieve their BP goals...

• When BP is more than 20/10 mmHg above the goal, consideration should be given to initiating therapy with two drugs, either as separate prescriptions or in fixed-dose combinations

• Use of fixed-dose combination drugs should be considered to reduce prescription costs...



ESH/ESC 2003 Guidelines Pharmacological Treatment

• To reach target BP, it is likely that a large proportion of patients will require combination therapy...

• According to the baseline BP and the presence or absence of complications, it appears reasonable to initiate therapy with a low-dose combination of two agents

• Fixed low-dose combinations are available in Europe, allowing the administration of two agents within a single tablet, thus optimizing compliance


The 3 Classes of Diuretics and Their Primary Sites of Action in

the Nephron


Adapted from: Oparil S and Weber MA. Hypertension.Elsevier/Sanders 2nd ed. 2005; Lip G and Bakris G. Handbook Hypertension Management. CMG 2006

Thiazide Diuretics

• Duration of action of 12–24 hours• Blood pressure lowering effect with low doses• Additive blood pressure lowering effect when used in combination with

other antihypertensive drugs• Main side effects:

- hypokalemia- hyponatremia- hyperglycemia- altered plasma lipid concentration- hyperuricemia or gout- impotence (reversible on withdrawal of treatment)

Bendroflumethiazide 1.25-2.5 mg once dailyChlorthalidone 12.5-25 mg once dailyHydrochlorothiazide 12.5-25 mg once dailyIndapamide 2.5 mg once daily or 1.5 mg

of sustained release (SR) preparation

For Internal Use OnlyLip G and Bakris G. Handbook Hypertension Management. CMG 2006

Loop Diuretics• Bumetanide 0.5 – 2 mg/d• Furosemide 20 – 80 mg/d• Torsemide 2.5 – 10 mg/d

• Most commonly used for powerful diuresis (renal failure, severe heart failure with oedema)

• Rapid onset of action:• - 1 hour after oral administration• - peak at 30 min after intravenous administration

• Useful when blood pressure require extremely rapid lowering (brisk diuresis)

• Main side effects:- Hypokalemia- hyponatremia

Lip G and Bakris G. Handbook Hypertension Management. CMG 2006


Diuretics that Cause Potassium Retension• Triamterene 50 - 100 mg/d

• Amiloride 5 – 10 mg/d• Spironolactone 25 – 100 mg/d• Weak diuretics• Little effect on blood pressure• Cause retention potassium• Combined to thiazide or loop diuretics to prevent or remedy

hypokalemia• Main side effects:

- hyperkalemia

- hyponatremia

- rashesLip G and Bakris G. Handbook Hypertension Management. CMG 2006


The Mechanism of Calcium-Channel Blockade



Calcium-Channel Blockers

• Class I (phenylalkylamine): (e.g. verapamil) act as antihypertensive agents by causing vasodilation of peripheral blood vessels. They also depress sinoatrial and atrioventricular nodal conduction, slowing the heart rate.

• Class II (dihydropyridine): (e.g. amlodipine and nifedipine) primarily cause vasodilation of both coronary and peripheral arteries. They have little or no effect on the strength of cardiac contractions or electrical conduction through the heart.

• Class III (benzothiazepine): (e.g. diltiazem) have peripheral and coronary vasodilator properties, and also inhibit cardiac conduction.

Amlodipine 5-10 mg once dailyFelodipine 5-10 mg once dailyNifedipine LA 20-60 mg once dailyDiltiazem LA 120-540 mg once dailyVerapamil modified release (MR) 240 mg once to twice daily

Lip G and Bakris G. Handbook Hypertension Management. CMG 2006For Internal Use Only

Calcium-Channel Blockers• Main side effects:

- Flushing, headaches and dizziness (short-acting Class II)

- Reflex tachycardia (short-acting Class II)

- Peripheral edema (short-acting Class II)

- Bradycardia

* Class I (verapamil)

* Class II (diltiazem)

- Constipation (commonly occurs with verapamil)Adapted from: Oparil S and Weber MA. Hypertension.Elsevier/Sanders 2nd ed. 2005; Lip G and Bakris G. Handbook Hypertension Management. CMG 2006For Internal Use Only

The Mechanism of Beta-Blockade

Reduced cardiac output

Reducedblood

pressure

Impulse

Smooth muscle presynaptic sympathetic neurons

Cardiac tissue (contains beta1 receptors)

Increased bronchial resistance

and vasoconstriction

Impulse


Tissue of the peripheral blood vessels, smooth muscle cells or lungs (contains beta2 receptors)

Beta-blockerNonadrenaline or adrenaline

Beta1 receptorsBeta2 receptors

Reduced heart rate and force

of constriction

Beta1 receptor blocked by beta-blocker

Beta2 receptor blocked by beta-blockerAdapted from: Oparil S and Weber MA. Hypertension.Elsevier/Sanders 2nd ed. 2005; Lip G and Bakris G. Handbook Hypertension Management. CMG 2006


Beta-BlockersAtenolol 50-100 mg once daily (selective)Bisoprolol 5-10 mg once daily (selective)Metoprolol 50-100 mg twice daily (selective)Propranolol 40-160 mg twice daily (non selective)Carvedilol 25-50 mg twice daily (non selective)

• * They are effective antihypertensive drugs:- reduce cardiac output- alter baroreceptor reflex sensitivity- block peripheral beta-adrenergic receptors

• * Cardioselective beta-blockers- Act on beta1 receptors (found mainly in the heart) and results in:

* reduction of heart rate* reduction of myocardial contractility* reduction in the rate of conduction of impulses through the heart* reduction of blood pressure* suppression of adrenergic-induced renin release and breakdown of fat

• * Non-selective beta-blockers- Act on beta1 and beta2 receptors (found in bronchial tissue and peripheral blood vessels) and results in:

* increased bronchial resistance* inhibition of catecholamine-induced glucose metabolism* increased vasoconstriction.



Beta-Blockers

• Beta-blockers are effective antihypertensives• Beta-blockers can be combined with other antihypertensive

drugs with different modes of action for an additive effect• Main side effects:

- Peripheral vasospasm (Raynaud’s phenomenon)

- Bronchoconstriction

- Bradycardia

- Neuropsychological effects (fatigue, apathy, nightmares)

- minor adverse effects on plasma lipid profile and glycemia Adapted from: Oparil S and Weber MA.

Hypertension.Elsevier/Sanders 2nd ed. 2005; Lip G and Bakris G. Handbook Hypertension Management. CMG 2006


Total peripheral resistanceincreased

BloodPressure

rises

Constriction of blood vessel

Impulse


Vascular smooth muscle cell

Total peripheral resistancedecreased

Bloodpressure

falls

Blood vessel remains dilated

Impulse


Alpha1 receptor blocked so muscle cells do not contract

Alpha1 receptor blockerNonadrenaline or adrenaline

Alpha1 receptorsAlpha2 receptors

The Mechanism of Alpha-Blockade



Doxazosin 1-16 mg once dailyTerazosin 1-10 mg once daily

Alpha-Blockers

• Two classes of alpha-blockers:* selective: act only on alpha1 receptors

- produce vasodilation by blocking the action of noradrenaline at postsynaptic alpha1 receptors in both arterioles and veins. This causes a drop in peripheral resistance and thus blood pressure

- can be used in combination with other antihypertensive drugs- lead to modest improvement in plasma lipid profile and glucose

tolerance* non-selective: act on both alpha1 and alpha2 receptors.

- mainly used to treat pheochromocytoma• Main side effects:

- Postural hypotension- Dizziness, vertigo, fatigue- Urinary frequency and incontinence- Gastrointestinal disturbances (nausea, diarrhea)

Oparil S and Weber MA. Hypertension.Elsevier/Sanders 2nd ed. 2005; Lip G and Bakris G. Handbook Hypertension Management. CMG 2006For Internal Use Only

The Mechanism of Action of ACE-inhibitors

Angiotensin IBradykininACE

Inhibitor

ACE(from lungs)

Angiotensinogen(from liver)

Renin(from kidney)

Angiotensin IIInactive

kininsVasodilation

Blood pressuredecreases

Retention of saltand water

Increasedaldosterone

Increased bloodvolume

Increased totalPeripheral resistance

Vasoconstriction

Blood pressure increase

Bradykininpathway

RAASystem



Captopril 12.5 mg twice daily - 50 mg three times dailyEnalapril 5-40 mg once dailyLisinopril 2.5-40 mg once dailyRamipril 1.25-10 mg once dailyPerindopril 2-8 mg once dailyTrandolapril 1-8 mg once daily

• * ACE inhibitors are particularly indicated for hypertension in patients with type 1 diabetes and nephropathy.

• * ACE inhibitors may be used in patients with heart failure, evidence of left ventricular dysfunction or postmyocardial infarction.

• ACE inhibitors can be used with other antihypertensive drugs for an additive blood pressure lowering effect.

• Main side effects:- Persistent irritating dry cough (20% of patients)- Angiodema- First-dose hypotension- Hyperkalemia- Gastrointestinal effects (dyspepsia, nausea, diarrhea)

ACE-inhibitors

For Internal Use OnlyAdapted from: Oparil S and Weber MA. Hypertension.Elsevier/Sanders 2nd ed. 2005; Lip G and Bakris G. Handbook Hypertension Management. CMG 2006

Adapted from Unger T. Am J Cardiol 2002; 89 (suppl):3A-10A.

AT1 Receptor

Na reabsorption

Aldosterone release

Sympathetic outflow

Vasopressin secretion

Vasoconstriction

Vascular and cardiac hypertrophy

Angiotensinogen

Angiotensin I

Angiotensin II

Non-ACE enzymes (cathepsin, chymase)

Renin

Bradykinin

ACEInactive Fragments

AT2 Receptor

Vasodilation

Growth inhibition

Apoptosis

Blood Pressure

ARBs


Mechanism of Action of Angiotensin II Receptor Blockers (ARBs)

HTNHTN, post MI, CHF

HTNHTN, Nephropathy T2DM +

HTN, Morbi-Mortality reduction and stroke prevention in HTN with

LVH

HTNHTN, CHFHTN, Nephropathy T2DM +

HTN

Indications

DigoxinnonoRifampin, Fluconazole

nononoDrug interract

24h6h12-18h2h5-9h9h11-15hT1/2

MinimalyesnoneminimalyesnonenoneFood effect

0.5-1h2-4h1-2h3-4h3h3-4h1.5-2hTmax

42-58%25%26%33%13%15%60-80%Bioavail

Boeh IngelhNovartis/

BeaufourMenar/SankMSDSolvayAstZen/TakSA/BMSCompany

Telmisartan

(Micardis)

Valsartan

(Diovan)

Olmesartan

(Benicar)Losartan

(Cozaar)

Eprosartan

(Teveten)Candesartan

(Atacand)

Irbesartan

(Avapro/

Aprovel)

Pharmacologic Characteristics of ARBs

For Internal Use Only Oparil S and Weber MA. Hypertension.Elsevier/Sanders 2nd ed. 2005; Lip G and Bakris G. Handbook Hypertension Management. CMG 2006

ARBs SummaryActions of ARBs

- ARBs block the RAA system further downstream than ACE inhibitors- They block the actions of angiotensin II by binding to the AT1 receptor- They lower blood pressure by inhibiting the effects of angiotensin II

Uses of ARBs- All ARBs are indicated for the treatment of hypertension (HTN).- Aprovel and losartan are indicated for the treatment of renal disease in patients with HTN and type 2 diabetes- Losartan is indicated for stroke prevention in patients with HTN and LVH.- Valsartan is indicated postmyocardial infarction in patients with left ventricular failure or

left ventricular systolic dysfunction.- ARBs are usually prescribed in a once-daily regimen.- Candesartan is the only ARB licensed for the treatment of essential hypertension and for patients with heart failure and impaired left ventricular systolic function as add-on therapy to ACE inhibitors or when ACE inhibitors are not tolerated.

Tolerability of ARBs- ARBs have a good tolerability (comparable to placebo)- They don’t provoke persistent dry cough (no inhibition of bradykinin breakdown)- Occasionally: hypotension, hyperkalemia


Oparil S and Weber MA. Hypertension.Elsevier/Sanders 2nd ed. 2005; Lip G and Bakris G. Handbook Hypertension Management. CMG 2006

Other antihypertensive agents

• Centrally-acting drugs (methyldopa, moxonidine)

• Direct vasodilator (hydralazine, minoxidil)

Poorly tolerated - headache, palpitation, edema- drug-induced lupus syndrome (hydralazine)- hirsutism in women (minoxidil)

Used when other treatments have failedUsed in special conditions (pregnancy)

Moxonidine 200 mg once daily – 300 mg twice dailyHydralazine 25-5- mg twice dailyMinoxidil 2.5-50 mg in 1-2 doses



Health & Medicine

1.6.2 Pharmacologic Treatment