Once thought to merely represent an elevation of blood pressure, medical science is starting to recognize that hypertension is a systemic disorder involving many biochemical and physiologic abnormalities, including alterations in blood volume, cardiac output (the amount of blood the heart pumps each minute), kidney function, and cellular resistance to the effects of insulin. Whether there is one yet to be discovered cause of hypertension, or many, is unknown.
It is estimated that nearly 50 million Americans have hypertension, involving almost 20% of all adults and over 60% of all senior citizens. The frequency of hypertension increases with increasing age and body weight, and is higher in african-americans than Caucasians. Half of patients suffering their first heart attack are hypertensive and two thirds of patients suffering their first stroke are significantly hypertensive.
Whether a person's hypertension is graded as mild (140/90-159/99), moderate (160/100-179/109), or severe (180/110-209/109), there is an increased risk of "end-organ" damage (stroke, heart attack, and kidney failure) when compared to people with normal pressures.
Initial treatment must start with life style modification. Weight loss. Decrease in salt intake, cessation of smoking, participating in regular exercise, and decrease in alcohol consumption are all integral to successful blood pressure control. Even if life style modifications must be supplemented by medication, drug dosing can be minimized by successfully managing these aggravating factors.
Antihypertensive medications can be divided into several different categories, each working by a different chemical or physiologic mechanism. While general guidelines have been published by the National Institute of Health regarding the use of these various types of blood pressure lowering drugs, the ultimate goal of a physician is to successfully lower a patients blood pressure into the normal range, using a drug, or a combination of drugs, that are affordable, readily tolerable, and without side effect. Responses to various types of antihypertensive drugs varies greatly amongst individuals as to side effects. Concomitant medical problems will also influence a physician's choice of antihypertensive medication in a given individual.
The various drug categories of antihypertensive drugs are:
1. Diuretics
In a general sense, diuretics increase the elimination of sodium (salt) and water from the body via the kidney. Some of their antihypertensive effects are due to decreasing the circulating blood volume, thereby reducing the cardiac output, while additional effect is obtained by reducing the amount of bodily sodium. Diuretics are relatively inexpensive and are especially helpful in the primary treatment of very mild hypertension and also in adjunctive treatment in more severe forms of hypertension. The main side effects common to all diuretics are fluid and electrolyte imbalance (sodium, potassium, chloride, calcium and magnesium problems), and provocation of gout.. As long as kidney function is moderately well preserved, mild diuretics can by used (hydrochlorothiazide, chlorothiazide, triamterene, midamore, spironolactone). When kidney function is impaired, more potent diuretics may be needed (furosemide, bumetadine, torsemide, ethacrynic acid, metolazone).
2. Beta Adrenergic Blocking Agents
Adrenaline is
the most commonly recognized member of a group of drugs (catecholamines) which
have potent stimulatory effects throughout the body. Catecholamines stimulate
the heart to beat harder and faster, increase the blood pressure, dilate bronchial
tubes, dilate some blood vessels while contracting others, alter insulin secretion
and sweat production, and contract muscles at the base of the urinary bladder.
The varying effects of catecholamines occur because different types of chemical
catecholamine receptors are present in different organs. Two distinct types
of catecholamine receptors are recognized; alpha (
)
and beta (
),
and each group has several sub-groups.
Drugs that interfere with catecholamines varying effects work by blocking either the alpha or beta receptor sites, or both, and some may selectively block only one receptor subtype.
A large number
of beta blockers are presently clinically available. Some are highly subtype
selective (1
or 2)
while others are non-selective. Some are able to get into brain tissue - others
not, and some actually partially stimulate the beta receptor while simultaneously
blocking them. Whether selective or not, beta blockers lower blood pressure,
reduce heart rate, reduce cardiac energy requirements, reduce and control
certain heart rhythm disturbances, and have been definitively proven to reduce
death rates after heart attacks.
Commonly used
cardiac selective (1)
blockers include atenolol, betaxolol, bisoprolol, esmolol, and metoprolol.
Commonly used non-selective beta blockers include propranolol, nadolol, carvedilol,
sotolol, and timolol. Labetolol has combined non-selective beta and alpha
blocking activity, while acebutolol and pindolol are beta blockers with some
beta receptor stimulatory effect.
3. Alpha Adrenergic Blocking Agents
Stimulation
of alpha-1 (1) catecholamine receptors
constricts blood vessels thereby increasing blood pressure, and so drugs that
block these receptors are used to treat hypertension. Prazosin, terazosin
and doxazosin are the most commonly prescribed selective 1
blockers. As urinary bladder outlet smooth muscle is also rich in 1
receptors, the use of these drugs relaxes these muscles, resulting in improved
urinary flow, and better bladder emptying, especially in men.
Carvedilol is
a unique drug that has both potent beta blockade and 1
blockade and has been used to treat angina as well as hypertension. A recent
landmark study has proven this drug to reduce mortality risk in patients suffering
heart failure. 2 receptors found
in brain tissue, when stimulated result in relaxation of arterial wall smooth
muscle and lowering of blood pressure. Drugs that stimulate brain 2
receptors included methyldopa, clonidine, guanabenz, and guanfacine. The main
side effect of this class of drugs is sleepiness.
4. Vasodilators: Hydrazine
Hydralazine is the only presently used drug in this class. It is a potent drug that acts directly to relax the smooth muscle cells in the walls of arteries, causing arterial dilatation and a brisk reduction in blood pressure. Successful use of this drug usually requires aggressive dosing and because of the drugs rapid metabolism, it must be given three to four times daily. Fluid retention is commonplace as is tachycardia. As many as 20% of patients taking hydralazine chronically develop a lupus syndrome.
5. Renin - Angiotensin Inhibitors (ACE inhibitors)
Angiotensin II is one of the most potent naturally occurring constrictors of arteries in the body and is intimately involved in blood pressure regulation. The body manufactures angiotensin II by a series of chemical steps, one of the first of which is the creation of a precursor chemical, angiotensin I. This step requires the action of an enzyme - Renin, which is manufactured by the kidneys. Angiotensin I is then altered by a converting enzyme, that is predominantly locate in the lungs, into angiotensin II. Any drug that interferes with the production or activity of angiotensin II will lower blood pressure.
All beta blockers reduce the production of renin by the kidneys and thus secondarily reduce angiotensin production.
Angiotensin converting enzyme inhibitors (ACE inhibitors) prevent the conversion of angiotensin I to its active form, angiotensin II. ACE inhibitors are remarkably effective antihypertensive drugs and they have also been shown to reduce mortality after heart attacks and to reduce heart enlargement after heart attacks. The major differences between the various marketed ACE inhibitors are their duration of action and their routes of elimination from the body. The major side effects shared by all ACE inhibitors include a dry, irritative cough, elevation of blood potassium levels, decreased sense of taste, and these drugs are specifically contraindicated if the arteries to both kidneys are significantly blocked. The more commonly prescribed ACE inhibitors include: benazapril, captopril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramipril and trandolapril.
Drugs that block
the effect of angiotensin II on its arterial wall smooth muscle receptor (ARB
drugs) similarly reduce blood pressure and are effective in the control of
symptoms of heart failure. These drugs share nearly all of the side effects
of ACE inhibitors but do not appear to cause a cough. The most commonly prescribed
drugs in this class include: valsartan, candesartan, eprosartan, and irbesartan.
6. Calcium
Channel Antagonists The past 50
years have witnessed a growing appreciation of the importance of calcium in
the control and regulation of many cellular functions, especially in the cardiovascular
system. Cardiac muscle contraction, cardiac electrical activity, and blood
vessel wall smooth muscle contraction are all calcium dependent processes.
Calcium cannot simply diffuse across cellular membranes, but must pass through
highly specific and regulated passage ways ("calcium channels"). Different
tissues may have different calcium channels. The activity profile of the various
calcium channel blocking drugs is related to the specific channel being blocked.
Verapamil and
diltiazem, while chemically unrelated compounds, each block myocardial calcium
channels, cardiac electrical system calcium channels, and arterial wall smooth
muscle calcium channels. As such, these drugs are effective in lowering blood
pressure, treating angina, and controlling certain heart rhythm disturbances.
Their negative effects on heart muscle contractile strength means that heart
failure can be aggravated by their use. Many formulations of these two compounds
are currently available, but the only significant difference between formulations
is their rates of absorption from the intestines. Those formulations that
are slowly absorbed can be dosed once to twice daily, while those formulations
more rapidly absorbed must be dosed three to four times daily. Intestinal
and urinary bladder calcium channels are also affected by these two drugs
and so constipation and the slowing of urine flow can be annoying side effects.
The dihydropyridine
class of calcium channel antagonists (nifedipine, nisoldipine, nicardipine,
felodipine, isradipine and amlodipine) predominantly only block blood vessel
wall smooth muscle calcium channels and have their major utility in treating
hypertension. The different members of this class may vary in their affinity
for heart muscle and in their duration of action.
Beperidil is
a unique calcium channel antagonist, as its complex effect on the cardiac
tissues make it especially useful in treating angina, while its lack of effect
on blood vessel wall smooth muscle calcium channels makes it a poor antihypertensive
agent. Unlike all other available CCA, beperidil's effect on the cardiac electrical
system may predispose to the occurrence of dangerous heart rhythm abnormalities.
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