Lecture 17 - Treatment Of Hypertension

Learning Objectives 2. Define high blood pressure 2. Calssify blood pressure into 4 categories and list the systolic and diastolic pressures in each 3. Describe the ways to control and prevent hypertension 4. Identify various groups of antihypertensive drugs 5. Describe the algorithm for treatment of hypertension

Category

Systolic (mmHg)

Diastolic (mmHg)

Normal

<120

<80

Pre-hypertension

120 – 139

80 – 89

Stage 1 hypertension

140 – 159

90 - 99

Stage 2 hypertension

>160

>100

What is hypertension? Abnormally chronic high blood pressure (>140/90)

LIFESTYLE MODIFICATIONS )Not at Goal Blood Pressure )<140/90 mmHg )mmHg for patients with diabetes or chronic kidney disease 130/80<( INITIAL DRUG CHOICES Without Compelling Indications

With Compelling Indications

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

Stage 2 Hypertension )SBP >160 or DBP )mmHg 100>

Drug)s( for the compelling indications )See table 8(

Thiazide-type diuretics for most. May consider ,ACEI, ARB, BB, CCB .or combination

Two-drug combination for most )usually thiazide-type diuretic and ACEI, or .)ARB, or BB, or CCB

Other antihypertensive ,drugs )diuretics, ACEI ARB, BB, CCB( as .needed

NOT AT GOAL BLOOD PRESSURE Optimize dosages or add additional drugs until goal blood pressure is .achieved. Consider consultation with hypertension specialists

Why should we treat hypertension? Hypertension is called the “SILENT KILLER”

General Treatment Goals 1. To reduce cardiovascular morbidity and mortality 2. To prolong useful life

Treatment Goals 1. Normalization of pressure (below 140/90) 2. Prevention of complications: stroke, heart failure, renal disease and coronary events

How do anti-hypertensive pharmacological agents work? ♣ In regulation of blood pressure, there are factors that increase blood pressure and factors that decrease blood pressure.

Anti-hypertensive agents are used: 1. To antagonize the actions of factors that increase blood pressure. 2. To ‘potentiate’ the actions of factors that decrease blood pressure

1. Angiotensin-converting enzyme inhibitors (ACEI) Captopril, enalapril Angiotensin II is a peptide that increases blood pressure by causing vasoconstriction and stimulation of aldosterone.

Mechanism of action 1. ACEI inhibit angiotensin-converting enzyme and prevent the conversion of angiotensin I to angiotensin II.

Mechanism of action (cont’d) ♣ Inhibition of synthesis of angiotensin II results in decreased levels of angiotensin II in the circulation, and blood pressure decreases.

Mechanism of action (cont’d) 2. ACEI prevent the degradation (inactivation) of bradykinin and increase its levels. Bradykinin causes vasodilation.

♣ ACEI are very effective as monotherapy. ♣ BP decreases because of vasodilation and reduction in peripheral resistance

♣ If an ACE inhibitor is used as first-step monotherapy, small doses should be prescribed initially.

♣ If target blood pressure is not achieved with a minimal or moderate dose of an ACE inhibitor, one can add a small dose of another drug like a diuretic.

♣ Side effects of the ACE inhibitors are relatively uncommon, except for cough.

2. Angiotensin II Receptor Blockers (ARB) Losartan, valsartan

Mechanism of action: 1. Inhibit actions of angiotensin II by blocking angiotensin type-1 receptors.

Mechanism of action (cont’d): 2. Reduce vascular resistance without reducing cardiac output. Renal blood flow is maintained.

♣ These medications are as effective in lowering blood pressure as the ACE inhibitors. ♣ These drugs have no major side effect.

♣ The blood pressure-lowering effects of the ARBs are greatly increased when a diuretic is added.

3. Calcium Channel Blockers (CCB) Mechanism of action: Lower blood pressure by inhibiting the entry of calcium ions into vascular smooth muscle cells, which results in vasodilation, reduces peripheral resistance, and decreases blood pressure.

Types of calcium channel blockers: 1. The nondihydropyridines: * vasodilation – decrease peripheral resistance- decrease blood pressure * coronary vasodilation * decrease AV and SA nodal conduction * verapamil, diltiazem

2. The dihydropyridine: * vasodilation – decrease peripheral resistance- decrease blood pressure * coronary vasodilation * do not affect cardiac function * nifedepine, amlodipine, felodipine, isradipine nicardipine

4. DIURETICS Mechanism of action: 1. Initially, there is a decrease in plasma volume with a short-term decrease in cardiac output.

2. The long-term effect is one of vasodilation and decreased vascular resistance

Thiazide diuretics (hydrochlorothiazide) Thiazide diuretics are one of the preferred initial monotherapies.

♣ When used in combination with a small dose of a beta-adrenergic inhibitor, an ACEI, an ARB or a calcium channel blocker(CCB), response to normotensive levels is approximately 80%.

Potassium Sparing agents (amiloride) ♣ Potassium-sparing diuretics are not used by themselves because they are weak diuretics and are relatively ineffective in lowering blood pressure when used alone.

♣ They are used to reduce excessive potassium loss. Various combinations of thiazides and potassium-sparing agents can be used.

5. Beta-Adrenergic Receptor Blockers Mechanism of action: Lower blood pressure by decreasing cardiac output, inhibiting the release of renin, possibly reducing norepinephrine release from sympathetic neurons, and decreasing central vasomotor activity (Figure 4).

There are several types of beta-blockers available: 1. Beta-1 selective: atenolol and metoprolol 2. Non-selective: propranolol

Place in Therapy Beta-Blockers are recommended as one of the first-step drugs in the management of hypertension.

♣ When beta-blockers are used as monotherapy, about 40% to 50% of patients will respond.

♣ In combination with small doses of a diuretic, however, these agents are highly effective in all patient groups with relatively few side effects.

♣ A beta-blocker should be used in almost every post-myocardial infarction patient unless there is a contraindication to it.

♣ Beta-Adrenergic inhibitors have been shown to prevent a second myocardial infarction in patients with known ischemic heart disease and to reduce mortality

6. Alpha-1 Adrenergic Inhibitors Doxazosin, Prazosin, Terazosin

Mechanism of action: ♣ Block alpha1-receptors on vascular smooth muscle. Vasoconstriction is reduced, and peripheral vasodilation occurs without major changes in cardiac output.

7. Combined Alpha-1 and Beta Blockers Labetalol and carvedilol

Mechanism of action: 1. Their antihypertensive effect is due to their combined alpha-1 and beta-adrenergic blocking activity.

2. Blood pressure is reduced, mainly as a result of a decrease in peripheral resistance.

♣ Hemodynamically, unlike pure beta-blockers, which reduce heart rate and contractility, these compounds reduce total peripheral resistance, maintain cardiac output, and preserve peripheral blood flow, renal plasma flow and glomerular filtration rate.

8. Central sympatholytics alpha-Methyldopa, Clonidine, Guanabenz, Guanfacine

Mechanism of action: 1. They stimulate alpha-2 receptors on the adrenergic neurons located within the medulla, which controls sympathetic outflow

2. Their effects include: decrease in sympathetic activity, decrease in peripheral resistance, and decrease in blood pressure.

♣ They are particularly useful for patients who have hypertension with associated anxiety, especially that which is manifested by sympathetic over activity.

♣ Methyldopa is used to treat pregnancy-induced hypertension.

9. DIRECT VASODILATORS Hydralazine, minoxidil and nitrates like sodium nitroprusside (Figures 3 and 5)

Mechanism of action: 3. They act directly on the vascular smooth muscle cell to cause vasodilation.

2. They cause dilation of arterioles with a decrease in peripheral resistance and blood pressure.

SUMMARY (Figure 6) Problem

Solution

Increased volume

Diuretics

Increased sympathetic tone

Alpha & Beta-blockers, sympatholytics

Angiotensin

ACEI, ARB

Excessive vasoconstriction

CCB, direct vasodilators

APPROACH TO THERAPY Stepped-care implies that if blood pressure is not reduced to normal with one drug, it is appropriate to add small doses of another drug from another class.

The plan for initial medical therapy: ♣ A diuretic such as hydrochlorothiazide can be given in small doses to most patients unless there is a specific contraindication to its use or a specific indication for the use of another agent.

♣ A beta-blocker is also an acceptable choice for initial therapy, although this class of agents may not be the best choice for elderly patients.

♣ If goal pressures of < 140/90 mm Hg are not achieved with the diuretic alone, a second drug such as a beta-adrenergic inhibitor, an ACEI, an ARB, an alpha1-beta-blocker, or, in some cases, a long-acting CCB will be added.

♣ If a beta-blocker was used as initial therapy, a diuretic should be added unless there is a contraindication to its use.

♣ In the situation where a patient has been started on an ACEI or a CCB, a diuretic should also be added if normalization of blood pressure has not occurred.

♣ If no blood pressure-lowering effect is noted with initial therapy or if troublesome side effects occur, the first medication should be stopped and another agent substituted.

Multiple Drug Therapy ♣ Using small doses of two different classes of drugs makes good sense, rather than increasing the dosage of one drug to a maximum level.

♣ Blood pressure response is generally better; about 75% of patients will respond to a combination of two different agents, whereas only about 50% will respond even to full doses of one drug.

♣ In addition, certain homeostatic reflex mechanisms may be blocked and side effects minimized by this approach.

Combination Therapy ♣ Available combinations include diuretics and beta-blockers, diuretics and ACE inhibitors, diuretics and ARBs, and ACE inhibitors and CCBs.

Important issues to remember: 1. Keep dosages of medication as low as possible to minimize side effects. 2. Make all efforts to ensure that patients follow instructions properly.

Patient education is very important in gaining cooperation and helping patients to understand the reasons for therapy

3. Treat to a goal of below 140/90mmHg. 4. Avoid overdosing. 5. Ensure 24 hour coverage.

Algorithm for the Treatment of Hypertension  Begin life style modifications (Stop smoking and alcohol intake, reduce salt intake, exercise, etc)

Not at goal blood pressure (140/90 mmHg) [Lower goals for patients with diabetes or renal disease (lower than 130/85 mmHg) ]

Initial Drug Choice  Uncomplicated Hypertension: Diuretics, Beta-blockers  Diabetes mellitus (type 1) with proteinuria: ACE inhibitors  Heart failure:

ACE inhibitors, diuretics

 Isolated systolic hypertension (older patients): Diuretics (preferred), long-acting dihydropyridine calcium antagonists  Myocardial infarction: Beta-blockers, ACE inhibitors

Not at goal blood pressure  No response or troublesome side effects: Substitute another drug (different class)  Inadequate response but well tolerated: Add a second agent (different class)

Not at goal blood pressure Continue adding agents from other classes

Causes of Arterial Hypertension • Primary (Essential or idiopathic) Hypertension- ~80-90%  Unknown cause

2. Secondary Hypertension- ~10-20%  Renal disease, vascular disease, adrenal disease, other causes

Prognosis of Untreated Hypertension  There is an inverse relationship between blood pressure and longevity

Blood pressure regulation Factors that increase BP

Factors that decrease BP

Increased volume (Diuretics)

Bradykinin (ACEI)

Increased sympathetic tone Histamine Norepinephrine (Beta blockers) Angiotensin (ACEI, ARB)

Prostaglandins (ACEI)

vasopressin, endothelin Increased vascular reactivity (CCB, dilators) Increased baroreflex sensitivity

Nitric oxide (dilators, ACEI)

Case #1 A 76 year old female comes to her family doctor complaining of constipation and epigastric pain as well as weakness and painful cramps (due to hypokalemia).

History: She has a history of hypertension, for which she has been taking propranolol and hydrochlorothiazide for the past several months. Observation: Mild hypertension (BP 145/90);

Treatment: Potassium rich foods (chickpeas, bananas, papaya), potassium supplement, or switch to potassium-sparing diuretics such as spironolactone or triamterene.

Case #2 A 62 year old female is referred to a pulmonary specialist by her family physician because of a chronic dry cough that has been unresponsive to medications.

History: On careful questioning the specialist discovers that she had been taking captopril for hypertension for three years. Observation: Normal BP

Treatment: Consider alternate antihypertensive agents. Losartan would be a good choice.

Case #3 A 45 year old female news reporter is brought to the emergency room from work after she was found to be disoriented; she also complained of a splitting headache and ringing in the ears.

Observation: hypertension (BP 190/120).

Treatment: Nitroprusside; do not attempt to lower BP>30% in the first hour due to possible coma or MI.

Discussion: Nitroprusside (a potent arteriolar and venular vasodilator) reduces preload and afterload and has very rapid onset and end of action (easy titration in case of hypertensive emergencies), making it the first drug of choice.

Angiotensinogen Renin Angiotensin I ACE Angiotensin II AT1

AT2

 BP

 BP

low BP

Alternative Enzymatic Pathways

The Renin-Angiotensin System Angiotensinogen (α2 globulin) Non-Renin (tonin cathepsin)

Renin Bradykinin

Angiotensin I decapeptide

Non-ACE (chymase)

ACE Angiotensin II octapeptide

AT1 receptors

Inactive peptides

AT2 receptors Angiotensinases

Ang heptapeptide, hexapeptide, others

non ACE

Angiotensin I ACE Angiotensin II AT1

AT2

 BP

 BP

Pathways for Angiotensin II (AII) and Targets for Inhibition

*

* Biologically active

Angiotensin II AT1 Receptors Kidney

Adrenal Gland

Vascular Smooth Muscle

 BP

CNS

Myocardium

Factors involved in blood pressure control. Determinants of blood pressure are cardiac output, determined by heart rate and stroke volume

Renin-angiotensin-aldosterone system

The relationship between cerebral blood flow (CBF) and mean arterial pressure (MAP)

Number of antihypertensive prescriptions in the US, 1984-1989

Dose-response relationship for thiazide antihypertensive agents and blood Pressure (antihypertensive action) and as a diuretic (shown here as effect on K+ excretion, the kaliuretic action)

Antagonism at postsynaptic α1 adrenoceptors

β Adrenoceptor antagonists classified according to cardioselectivity and partial agonist activity

Presynaptic α2 agonism

α2 Agonism decreases sympathetic activity and consequently reduces blood pressure

Metabolism of α methyldopa to α methylnorepinephrine

Effects of angiotensin-converting enzyme (ACE) inhibitors

Changes of chronic hypertension in the blood vessel wall

Changes of accelerated hypertension in the blood vessel wall