Drugs for hypertension

A. Introduction

• Hypertension (HT) is defined as a sustained elevation of systemic arterial blood pressure.

• There are 2 components of blood pressure: systolic and diastolic:

• Systolic pressure: ventricles contract and eject blood, creating pressure in the arteries

• Diastolic pressure: ventricles relax, heart temporarily stops ejecting blood, pressure in arteries falls

• One in three adults in the U.S. have been diagnosed with HT, making this the most common of the cardiovascular diseases.

• HT is usually found incidentally by healthcare professionals, and it is estimated that up to 30% of people with HT do not know they have it.

B. Factors affecting blood pressure

• There are 3 major factors which affect blood pressure

• 1. directions from vasomotor center, based on input from baroreceptors

• 2. emotions• 3. hormonal/enzyme factors

1. Vasomotor center

• Vasomotor center: this is a cluster of neurons in the medulla oblongata which regulates blood pressure on a minute to minute basis

• Nerves travel from the medulla oblongata to the arteries and direct smooth muscle to constrict (↑ blood pressure) or relax (↓ blood pressure)

• Baroreceptors are clusters of neurons in the aorta and carotid artery that have the ability to sense blood pressure within these vessels and then provide the vasomotor center with this information

2. Emotions

• Emotions can affect an individual’s blood pressure

• Mental depression and lethargy may cause B.P. to decrease.

• Anger and stress may cause an increase in blood pressure, and if present for a long time may contribute to chronic hypertension.

3. Hormonal/Enzyme factors

a. Renin-angiotensin-aldosterone (RAA) pathway

• This is the primary homeostatic mechanism controlling blood pressure and fluid balance

• When there is a ↓ in blood pressure or blood volume (due to hemorrhage, dehydration, etc) the enzyme renin is released by the kidneys

• Renin acts on angiotensinogen (produced by liver) converting it to angiotensin I (inactive)

• In the lung capillaries, angiotensin converting enzyme (ACE) modifies angiotensin I to angiotensin II (active)

• Angiotensin II then:• a. stimulates secretion of aldosterone

which causes Na1+ retention and H2O reabsorption at kidneys

• b. stimulates the secretion of ADH (vasopressin) which is synthesized in the hypothalamus and stored in the posterior pituitary, leading to H2O reabsorption

• c. stimulates hypothalamus to activate the thirst reflex

b. atrial natriuretic peptide(ANP)

• An ↑ in blood pressure or blood volume leads to a stretching of the cardiac muscle fibers in the walls of the atria

• They release ANP, whose 3 effects are the opposite of angiotensin II:

• a. ANP enhances the secretion of Na1+ and H2O at kidneys

• b. ANP inhibits the secretion of aldosterone and ADH

• c. ANP suppresses thirst

C. Diagnosis of hypertension

• A new classification scheme was introduced in 2003:

• Category Systolic Diastolic• Normal < 120 <80• Pre HT 120-139 80-89• Stage 1 HT 140-159 90-99• Stage 2 HT ≥ 160 ≥ 100

• Optimal blood pressure is associated with the lowest cardiovascular risk.

• Those who fall into the pre HT category are at risk for developing HT unless life-style modification is instituted.

• Stages 1 and 2 are associated with increased risk for target organ disease events:

• MI• kidney disease• stroke

• Therefore, both Stage 1 and Stage 2 HT need effective long-term therapy.

D. Primary versus Secondary HT

• HT may also be classified as either primary or secondary.

1. Primary hypertension

• Primary HT is also known as idiopathic HT and accounts for 90-95% of cases.

• In primary HT there is no definitive cause.

• A combination of genetic and environmental factors is thought to be responsible for the development of primary HT including:

a. family history of HT

b. advancing age

c. gender/ethnicity

• Caucasian: 30.6% of males, 31.0% of females;

• Hispanic Americans: 27.8% of males, 28.7% of females;

• African Americans: 41.8% of males, 45.4% of females;

• (derived from the American Heart Association 2006).

d. high dietary sodium intake

e. cigarette smoking (nicotine is a vasoconstrictor)

f. heavy alcohol consumption

• This is considered to be more than 3 drinks per day, but moderate drinkers (2-4 drinks per week) appear to have lower blood pressure than either abstainers or heavy drinkers

g. obesity

• As you gain weight, the amount of blood circulating through your body increases, resulting in added pressure on your artery walls.

• In addition, excess weight often is associated with an increase in heart rate and a reduction in the capacity of your blood vessels to transport blood. All of these factors can increase blood pressure.

2. Secondary hypertension

• Secondary HT is caused by altered hemodynamics associated with a primary disease, such as renal disease

• Although many diseases can cause secondary HT, this form accounts for only 5-8% of all cases of HT.

Known causes for secondary HT include:

• a. diabetic nephropathy (the most common type of kidney failure)

• b. Polycystic kidney disease, an inherited condition, where cysts in the kidneys disrupt normal function and raise blood pressure.

• c. Cushing’s syndrome in which corticosteroid medications, a pituitary tumor or other factors cause the adrenal glands to produce too much of the hormone cortisol, which raises blood pressure.

• d. Aldosteronism where a tumor in the adrenal gland or other factors cause the adrenal glands to release an excessive amount of the aldosterone.

adrenal gland tumor, aka pheochromocytoma

• This leads to retention of Na1+ and H2O and loss of K1+ , which raises blood pressure.

• e. Hyperthyroidism can increase the activity of epinephrine and norepinephrine, which can increase blood pressure.

• f. Sleep apnea, a condition where breathing repeatedly stops and starts during sleep.

• The repeated episodes of oxygen deprivation may damage the cellular lining of the blood vessel walls, which may deprive blood vessels of the elasticity they need to regulate blood pressure.

E. Treatment

• HT is usually managed with both pharmacological and nonpharmacological methods.

• Treatment begins with life-style modifications to reduce or eliminate risk factors.

• Generally, weight loss and regular exercise are the first steps. Regular mild exercise improves blood flow, and helps to lower blood pressure.

• Discontinuing smoking does not directly reduce blood pressure, but is very important for people with HT because it reduces the risk of many dangerous outcomes, such as stroke and heart attack

From news.bbc.co.uk/2/hi/health/

• Brain of a smoker who had a stroke

• A diet rich in fruits and vegetables and fat-free or low fat dairy foods, and low in fat and sodium lowers blood pressure in people with HT.

• Dietary sodium (salt) causes HT in some people and reducing salt intake decreases blood pressure in a third of people.

• Evidence suggests that reduction of the blood pressure by 5-6 mm of Hg can decrease the risk of stroke by 40% and of coronary heart disease by 15-20%.

• Antihypertensives are classified into groups according to their site of action.

• They include:

• 1. diuretics• 2. drugs that decrease sympathetic activity • 3. vasodilators • 4. drugs that interfere with the RAA system

1. Diuretics

• These were the 1st class of drugs used to treat hypertension in the1950’s.

• Thiazide/thiazide-like drugs are the preferred diuretic in treating HT

• The anti-HT effect seen, immediately, is the lowering of blood pressure by increasing excretion of Na1+ (along with water) in the urine

• After several weeks of treatment, another anti-hypertensive effect occurs.

• The decrease of Na1+ in vascular smooth muscle cells reduces the sensitivity of these cells to the effects of the circulating, naturally occurring vasoconstrictors epinephrine, norepinephrine, and angiotensin II.

• This results in a decrease in peripheral resistance.

• For mild HT with no other complications, a thiazide or thiazide-like diuretic alone is recommended.

• Thiazides are cheap, effective, and recommended as the best first-line drug for HT by many experts.

• They are not prescribed as often as some newer drugs, possibly because they are off-patent and thus rarely promoted by the drug industry.

• For mild HT in patients with reduced kidney function, a loop diuretic is recommended.

• For moderate to severe HT, a diuretic is used along with another anti-hypertensive drug.

2. Drugs that decrease sympathetic activity

• a. drugs with actions on the vasomotor center

• Drugs in this class stimulate inhibitory α2 receptors in the vasomotor center in the medulla oblongata (they are α2 adrenergic agonists)

• This decreases the “sympathetic relay of messages” to the heart, kidneys, and blood vessels.

• The effects of this include:• ↓ heart rate• ↓ cardiac output• ↓ secretion of renin from the kidneys• vasodilation

• Drugs in this class include:• clonidine (Catapres): the preferred drug• guanabenz (Wytensin)• guanfacine (Tenex)• methyldopa (Aldomet)

• Adverse effects of these drugs include:• constipation• dry mouth• sleepiness

• b. drugs which block α1 receptors on vascular smooth muscle (they are α1 adrenergic antagonists)

• Vasodilation and decreased peripheral resistance are the main anti-hypertensive effects of these drugs

• drugs in this class include:• doxazosin (Cardura)• prazosin (Minipress)• terazosin (Hytrin)

• They tend to cause orthostatic hypotension (when quickly move from supine to upright position)

• They are no longer recommended as a 1st-line choice unless the patient also has benign prostatic hyperplasia (BPH)

• c. drugs which cause a selective blockade of β1 receptors at therapeutic dosages (They are selective β1 receptor antagonists, or selective beta blockers)

• (At increased doses they may also block β2 receptors)

• By blocking β1 receptors in the heart, they decrease cardiac output and decrease blood pressure

• By blocking β1 receptors in the kidney, they prevent the release of renin, and this shuts down the RAA pathway

• drugs in this class include:• acebutolol (Sectral): 400 – 800 mg• atenolol (Tenormin): 50 – 100 mg• bisoprolol (Zebeta): 5 – 20 mg • metoprolol (Toprol, Lopressor): 100 – 400

mg

• Adverse effects of these drugs include:• ↓ AV conduction• bradycardia

• d. drugs which cause a nonselective blockade of β1 and β2 receptors (they are non-selective beta blockers)

• These generally should not be used in hypertensive patients with asthma or COPD

• As they block β2 receptors they may cause bronchoconstriction

• drugs in this class include:• carvediol (Coreg): also blocks α1 receptors

• labetalol (Normodyne, Trandate): also blocks α1 receptors

• nadolol (Corgard)• pindalol (Visken)• propranolol (Inderal)

• Adverse effects of these drugs include:• ↓ AV conduction• bradycardia• bronchospasm

• e. adrenergic neuronal blockers• These drugs prevent the release of

norepinephrine. They also deplete norepinephrine from storage vesicles.

• As this inhibits ALL sympathetic activity, they are only indicated for severe hypertension that is unresponsive to other medications.

• drugs in this class include:• guanadrel (Hylorel)• guanethidine (Ismelin)

• Adverse effects of these drugs include:• bradycardia• orthostatic hypotension• impotentcy

3. Vasodilators

• Vasodilators cause a direct relaxation of the smooth muscle of arteries.

• Many drugs in this class produce reflex tachycardia (baroreceptors respond to a decrease in blood pressure by increasing heart rate in attempt to return blood pressure to its original level) and fluid retention.

• Therefore, they are generally prescribed as a component of triple therapy (with a beta blocker and a diuretic)

• Vasodilators commonly used in triple therapy include:

• a. hydralazine (Apresoline): used in moderate to severe HT; long term effects include rheumatoid arthritis, and a systemic lupus erythematosis like syndrome

• b. minoxidil (Loniten): more potent than hydralazine, so indicated for patients not responding to hydralazine triple therapy

•

• Vasodilators commonly used in hypertensive crisis

• a. nitroprusside (Nitropress): 3 mcg/Kg/min; duration 1 – 5 minutes

• b. diazoxide (Hyperstat): 300 mg bolus over 10 minutes; duration 6 – 12 hours

• Vasodilators that are calcium channel blockers (CCB’s):

• As their name implies, CCB’s prevent the movement of Ca2+ into the cells of both cardiac and smooth muscle

• Their use in the treatment of HT is arteriolar vasodilation, which decreases both peripheral resistance and blood pressure.

• There are, generally, 2 categories of CCB’s used in the treatment of HT:

• CCB’s prescribed to treat HT AND either coronary artery disease (CAD) or angina pectoris

• These CCB’s do not have direct actions on the heart, and include:

• a. amlodipine (Norvasc)• b. felodipine (Plendil)• c. clevidipine (Cleviprex)

• d. isradipine (DynaCirc)• e. mibefradil (Posicor)• f. nicardipine (Cardene)

• g. nifedipine (Procardia)• h. nisoldipine (Sular)

• CCB’s prescribed to treat HT AND supraventricular arrhythmias

• These will decrease: heart rate, AV conduction, and myocardial contractility

• They include:• diltiazem (Cardizem)• verapamil (Calan)

4. Drugs that interfere with RAA

• The enzyme responsible for the final step in the renin-angiotensin pathway is ACE (angiotensin-converting enzyme)

• a. ACE inhibitors (ACEI)• ACE inhibitors block the effects of

angiotensin II. They result in dilation of both arteries and veins, which decreases peripheral resistance and blood pressure.

• In addition, they prevent the inactivation of bradykinin, a vasodilator which is normally degraded by ACE.

• ACE inhibitors have been approved for treating HT since 1980’s.

• They are the drug of choice for diabetic patients with HT (they ↓ progression of kidney failure associated with the progression of diabetes).

• They are also recommended for patients with coronary artery disease or a history of a heart attack.

• ACE-inhibitors lower blood pressure and protect heart muscle, leading to reduced mortality.

• ACE inhibitors generally prescribed in the treatment of HT:

• benazepril (Lotensin)• captopril (Capoten)• enalapril (Vasotec)• fosinopril (Monopril)• lisinopril (Zestril)• moexipril (Univasc)

• perindopril (Aceon)• quinapril (Accupril)• ramipril (Altace)• trandolapril (Mavik)

• Adverse effects of ACEI include:• dizziness• headache• GI disturbances• hypotension• hyperkalemia

• allergic reaction• dry cough• These 2 adverse effects are believed to be

due to increases in bradykinin

• b. Angiotensin II receptor antagonists• Drugs in this class block the

vasoconstrictor and aldosterone-producing effects of angiotensin II at its receptor sites (i.e. vascular smooth muscle)

• Angiotensin II receptor antagonists approved by the FDA for the treatment of HT include:

• losartan (Cozaar) • valsartan (Diovan)• irbesartan (Avapro)• candesartan (Atacand) • telmisartan (Micardis)• olmesartan (Benicar)

• They are different from the ACEI in that they do not increase bradykinin

• Their adverse effects are generally the same as the ACEI, except, no cough or allergic reaction

• c. renin inhibitors• This newer class of drugs inhibits the

actions of the enzyme renin, thus blocking the conversion of angiotensinogen to angiotensin I, and angiotensin I to angiotensin II

• There is 1 drug approved in this category:• aliskiren (Tekturna)

• Overall results are similar to the ACEIs and ARBs

• Adverse effects of the renin inhibitors include:

• GI disturbances• peripheral edema• rash• increased levels of uric acid• increased formation of kidney stones