drugs for high blood pressure

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drugs for high blood pressure
drugs for high blood pressure
Before the development of drugs for hypertension (high blood pressure) in the
1950s, treatments for severe high blood pressure were few and ineffective. The
most severe form of hypertension, malignant hypertension, led to the death of 9
in 10 sufferers within 12 months. Annual deaths in the UK from hypertensive
disease were approaching 500 per million population. Bed rest, weight loss
through a low fat diet, restriction of salt intake, no smoking and the use of
sedatives to reduce stress were all recommended, but the drastic treatment of
removal of the adrenal glands (which necessitated life-long replacement therapy
with the hormone cortisone) was often the only option.
Ganglionic blocking drugs
The development of effective drugs to reduce hypertension was a major step
forward. The first class of drugs, the ganglionic blockers, arose directly from
study of the nervous system in animals. Activation of certain nerves was shown
to constrict blood vessels and raise blood pressure. After many experiments, it
was shown that chemical messengers from nerves produced this effect. Thus
drugs which acted as mimics or blockers of these chemical messengers would
modify the nerve activity. The ganglionic blocking drugs are compounds which
can block these nerve-to-nerve junctions where they are concentrated, at
swellings called ganglia.
The first drug, hexamethonium, was discovered by William Paton and Zaimis in
19481 during development of muscle relaxants using anaesthetised cats and
rabbits. Although it was effective in reducing blood pressure (and its knock-on
effects such as severe headache and enlargement of the heart), it had
undesirable side effects because of its action on many different nerve reflexes.
Better ganglionic blocking drugs followed2, after they were shown to be effective
and relatively safe in various animals including dogs, cats, rats and mice.
Beta-blocking drugs
The development of beta-blocking drugs using animals in the 1960s was initially
aimed at the treatment of angina and cardiac arrhythmias. In 1964, it was
observed that pronethalol, the first beta blocker used to treat patients with
angina, also reduced blood pressure.3 Pronethalol was later withdrawn because it
was shown to produce tumours in mice, but the beta blocker propranolol was
also shown to be effective in reducing blood pressure. This finding was confirmed
in tests on rats which naturally suffer from high blood pressure.4 Of course, had
propranolol been tested on these rats before it reached the clinic, its
antihypertensive properties would have been discovered earlier.
Ace inhibitors
The third class of drugs to be developed for hypertension were the ACE
(angiotensin converting enzyme) inhibitors. These prevent the formation in the
blood of a naturally occurring substance, angiotensin II, which raises blood
pressure. An ACE inhibitor called bradyknin potentiating factor (BPF), from the
venom of snakes, was found to reduce blood pressure in rats. When eventually it
could be purified, BPF was also shown to reduce blood pressure in patients.
Various synthetic preparations were tested in rats, resulting in the introduction of
captopril in 1977.5 Captopril was later shown also to be an effective treatment for
congestive heart failure.
Further treatments for hypertension may result from the basic studies in animals
which are leading to a greater understanding of the role of nitric oxide, a gas
released by many tissues in the body.
We now know that the treatment of less severe cases of raised blood pressure
can reduce the risk of stroke, coronary heart disease and kidney disease.
Antihypertensive drugs have reduced deaths from hypertensive disease from 500
to about 50 per million population in the UK.
References
1.
Paton W & Zaimis E (1948) Nature 162, 810
2.
3.
4.
5.
Dollery C (1987) Br Heart J 58 , 179
Prichard B (1982) Br J Clin Pharmac 13, 51
Garvey H & Ram N (1975) L Pharm Exper Ther 194, 220
Vane J (1992) in Animal Experimentation and the Future of Medical
Research, ed Botting J, Portland Press, London
ANTI- HYPERTENSIVE DRUGS
Prescription Drugs
Non-Prescription Drugs
Anti-Hypertensive Drugs are medicines that help lower blood pressure.
Purpose
Anti-Hypertensive Drugs are used to help control blood pressure in people whose blood pressure is too high. Blood pressure is a
measurement of the force with which blood moves through the body's system of blood vessels. Although everyone's blood pressure
goes up and down in the course of a typical day-getting higher when they are active and going down when they sleep. Some people
have blood pressure that stays high all the time. This condition is known as hypertension. Hypertension is not the same as nervous
tension. People who have high blood pressure are not necessarily tense, high-strung or nervous. They may not even be aware of their
condition.
Being aware of high blood pressure and doing something to control it are extremely important, however. Untreated, high blood pressure
can lead to diseases of the heart and arteries, kidney damage, or stroke, and can shorten life expectancy.
Treatments for high blood pressure depend on the type of hypertension. Most cases of high blood pressure are called Essential or
Primary Hypertension, meaning that the high blood pressure is not caused by some other medical condition. For most people with
primary hypertension, it is difficult to figure out the exact cause of the problem. However, such hypertension usually can be controlled by
some combination of anti-hypertensive drugs and changes in daily habits (such as diet, exercise, and weight control).
In people with Secondary Hypertension, the high blood pressure may be due to medical problems such as kidney disease, narrowing of
certain arteries, or tumors of the adrenal glands. Correcting these problems often cures the high blood pressure, and no further
treatment is needed.
Controlling primary hypertension, on the other hand, is usually a life-long commitment. Although people may be able to reduce the
amount of medicine they take as their blood pressure improves, they usually must continue taking it for the rest of their lives.
Description
Many different types of drugs are used, alone or in combination with other drugs, to treat high blood pressure. The major categories are:
·

Angiotensin-converting Enzyme Inhibitors: ACE inhibitors work by preventing a chemical in the blood, angiotensin I, from
being converted into a substance that increases salt and water retention in the body. These drugs also make blood vessels
relax, which further reduces blood pressure. ·

Angiotensin II Receptor Antagonists: These drugs act at a later step in the same process that ACE inhibitors affect. Like ACE
inhibitors, they lower blood pressure by relaxing blood vessels. ·

Beta blockers: Beta blockers affect the body's response to certain nerve impulses. This, in turn, decreases the force and rate
of the heart's contractions, which lowers blood pressure. ·


Blood Vessel Dilators (Vasodilators): These drugs lower blood pressure by relaxing muscles in the blood vessel walls. ·
Calcium Channel Blockers: Drugs in this group slow the movement of calcium into the cells of blood vessels. This relaxes the
blood vessels and lowers blood pressure. ·


Diuretics: These drugs control blood pressure by eliminating excess salt and water from the body. ·
Nerve Blockers: These drugs control nerve impulses along certain nerve pathways. This allows blood vessels to relax and
lowers blood pressure.
Drugs of Choice in the Treatment of Hypertension
(Part 1)
We are bombarded with suggestions as to what should be our drug of first choice in the
management of patients with documented elevated blood pressure. Is it appropriate to choose
randomly from the wide array of available drugs, or is there a way to rationally pick the drug
which is most likely to benefit our patients? By setting up a hierarchy of the issues which are
most important, and compiling and critically appraising the presently available evidence, it is
possible to narrow the choice to one or two drugs (see picture). The issues that are significant
in descending order of importance include: evidence of effectiveness in decreasing the
complications associated with hypertension, efficacy in lowering blood pressure, tolerability,
convenience of dosing, and cost.
What evidence do we have about the effectiveness of antihypertensive
drugs in preventing cardiovascular diseases?
Studies to answer this question must be randomized, controlled, and double-blind to prevent
bias and must be large and of sufficient duration. In 1990 a meta-analysis of the 14 trials
which met defined criteria was published.(1) This analysis (mean age 52 years, 53% male),
demonstrated that a 5-6 mm Hg decrease in diastolic blood pressure produced a 14%
reduction in coronary heart disease, and a 42% reduction in cerebrovascular accidents over a 5
year follow-up period. Since 1990, five additional trials have been published. These trials
have confirmed and strengthened the original meta-analysis, and demonstrated a greater
relative and absolute risk reduction, particularly for coronary artery disease in the elderly (2)
plus the benefit of treating isolated systolic hypertension.(3) Most of the patients in these
trials received thiazide diuretics as the only drug or as a component of the treatment. We
therefore have compelling evidence of the effectiveness of this class of drugs in reducing
morbidity and mortality in patients of all ages and types of hypertension. Beta blockers have
also been studied as a single agent, but have not consistently shown an equal benefit: in a trial
comparing atenolol with hydrochlorothiazide/amiloride, both drugs lowered blood pressure to
the same degree but only the thiazide was associated with a decreased risk of stroke and
coronary events. (4) We therefore cannot assume that an equal reduction in blood pressure
will be associated with an equal benefit. Other classes of antihypertensives have not been
assessed in effectiveness trials.
Are there differences in blood pressure lowering efficacy?
There are many trials comparing efficacy, but the most relevant trial is the TOMHS study. (5)
In this study with an average 4.4 years of follow-up 5 antihypertensive drugs and placebo
were compared in 902 patients with mild hypertension. The drugs and daily doses used were
thiazide-like diuretic, (chlorthalidone, 15 mg), beta-blocker, (acebutolol, 400 mg), ACE
inhibitor, (enalopril 5 mg), alpha1-antagonist, (doxazosin, 2 mg), and calcium antagonist,
(amlodipine, 5 mg). The blood pressure lowering efficacy of all the five drugs was similar and
greater than placebo. For chlorthalidone, but not for the other drugs, left ventricular mass
declined more than for participants given placebo.
Are there differences in tolerability or quality of life measures?
In the same trial a significant improvement in quality-of-life indexes was seen with acebutolol
and chlorthalidone but not with the other drugs. The incidence of impotence was greater in
men assigned to placebo than those assigned to drug treatment.
Are there differences in convenience or cost?
The preferred regimen for chronic preventive therapy is once daily dosing. All thiazide and
thiazide-like drugs should be prescribed only once daily in the morning. There are significant
cost differences.(see Table and Therapeutics Letter 8). Hydrochlorothiazide is the least
expensive of all antihypertensive drugs available in B.C.
What about the metabolic consequences of thiazide therapy?
Using recommended low-dose regimens (table) the incidence of hypokalemia is small (1% of
patients in the SHEP study had K+ below 3.2 meq/L).(3) In patients who develop
hypokalemia a K+-sparing diuretic should be added (see Table). Do not prescribe K+
supplements; they are inconvenient and expensive. The small increase in total cholesterol
(2.5%) and triglycerides seen in some studies was not seen in the TOMHS study (5) and has
not been proven to have any adverse consequences. The hyperglycemic effect is also small
and did not have any consequences in the SHEP study in which at least 10% of patients had
NIDDM on entry.3 Thiazides can be safely used for the treatment of hypertension in NIDDM,
except in patients where significantly worsened glucose control has been proven. Elevations
in uric acid seen with thiazides are innocuous; thiazides should not be used in patients who
develop recurrent gout with thiazide therapy.
What is the mechanism of antihypertensive action of thiazides?
Thiazides and indapamide have direct vasorelaxant effects on resistance vessels. The thiazides
are acting on calcium activated potassium channels and indapamide is acting as a calcium
antagonist. (6) Therefore indapamide cannot be used interchangeably with the thiazides. The
diuretic action of these drugs may have only minor importance in the overall antihypertensive
effect.
Conclusion
Based on the evidence available at this time and using criteria of effectiveness and cost,
thiazides are clearly the drug of first choice. Based on the criteria of efficacy, tolerability and
convenience, thiazides are equivalent to or better than all other drugs. Therefore, thiazides are
the drug of first choice for most uncomplicated hypertensive patients. There will be a
proportion of patients (20-25%) where thiazides are proven ineffective or inappropriate. In
these patients or in patients requiring more than one drug, other drugs must be substituted or
added. These other drugs will be discussed in Therapeutics Letter 8.
Table: Dosing and Cost of Diuretics for the Treatment of Hypertension
Diuretic
Hydrochlorothiazide 25 mg
Chlorthalidone 50 mg
Trade Name
Hydrodiuril®,
generic
Usual Dosage
Range
Daily
Cost*
12.5 - 25 mg daily
12.5 - 25 mg daily
0.3 - 0.6
1.2 - 2.4
(in cents)
Hygroton®, generic
Bendroflumethiazide 2.5 mg
Indapamide 2.5 mg
Naturetin®
Lozide®
1.25 - 2.5 mg daily
2.5 mg daily
6.6 - 13.3
55.5
Potassium sparing
HCTZ (25 mg)/triamterene (50 mg)
HCTZ (50 mg)/amiloride (5 mg)
HCTZ (25 mg)/spironolactone (25
mg)
Triamterene (50, 100 mg)
Amiloride (5 mg)
Spironolactone (25, 100 mg)
1/2 - 1 tablet daily
Dyazide®, generic
2.5 - 5.0
1/4 - 1/2 tablet
Moduret®, generic
5.9 - 11.9
daily
Aldactazide®, generic
5.6 - 11.2
1/2 - 1 tablet daily
Dyrenium®
9.9 - 13.1
25 - 50 mg daily
Midamor®
15.2 - 30.4
2.5 - 5 mg daily
Aldactone®, generic
8.8 - 27.6
25 - 100 mg daily
* Least expensive available formulation in BC, 1993
References
1. Collins R, Peto R, MacMahon S, et al. Epidemiology, blood pressure, stroke and coronary heart disease.
2.
3.
4.
5.
6.
Part 2: Short-term reductions in blood pressure: Overview of randomised drug trials in their
epidemiological context. Lancet 1990;335:827-38.
Thijs L, Fagard R, Lijnen P, Staessen J, Van Hoof R, Amery A. A meta-analysis of outcome trials in
elderly hypertensives. J of Hypertension, 1992;10:1103-9.
SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older
persons with isolated systolic hypertension: Final results of the Systolic Hypertension in the Elderly
Program (SHEP). JAMA, 1991;265:3255-64.
Medical Research Council trial of treatment of hypertension in older adults: Principal results. Br Med J.
1992;304:405-12.
Treatment of Mild Hypertension Study Research Group. Treatment of Mild Hypertension Study Final
Results. JAMA. 1993;270:713-724.
Calder JA, Schachter M, Sever PS. Ion Channel Involvement in the Acute Vascular Effects of Thiazide
Diuretics and Related Compounds. J. Pharmacol. Exp. Ther. 1993;265:1175-80.
Drugs of Choice in the Treatment of Hypertension
(Part 2)
After review of the long term hypertension studies, including the epidemiologic and
randomized placebo controlled drug trials, certain clinically important facts stand out:





Risk of cardiovascular events correlates better with systolic than diastolic blood
pressure.(1)
Risk correlates better with blood pressures taken outside the doctor's office than with
office blood pressures.(2)
Blood pressure consistently decreases with placebo treatment (10/8 mm Hg).(3)
The average additional blood pressure fall in the active treatment group is modest
(11/6 mm Hg).(3), (4)
The average blood pressure fall with treatment in trials using low doses of just one
drug (7-9.5/46.5mm Hg) (5), (6) is similar to that obtained from an overview of trials
using high doses of multiple drugs (11/6 mm Hg).(3), (4)
These facts suggest the following ways to assist in managing your patients with hypertension:



Put more emphasis on systolic and home blood pressures when making treatment
decisions.
Appreciate that some of the blood pressure lowering effect seen in the office is due to
the placebo effect. In other words, no matter what you are prescribing, it is likely to
appear efficacious.
Realize that pushing the dose seldom improves the antihypertensive effect. Likewise,
the dose can frequently be lowered in patients receiving high doses of antihypertensive
drugs without changing the antihypertensive effect.
In Part 1 we summarized the published evidence demonstrating that if we want to be certain
of reducing morbidity and mortality in our hypertensive patients, a low-dose thiazide diuretic
is the best choice. However, we obviously need the use of more than one class of
antihypertensive drugs. Beyond the thiazides, we have much less evidence of effectiveness in
decreasing cardiovascular events. We cannot assume that drugs which are equivalent in
lowering blood pressure will prove to be equally effective in reducing morbidity and
mortality.
What is the evidence that beta blockers decrease morbidity and
mortality in hypertensive patients?
There are only two trials in which the effectiveness of beta blockers (propranolol(3) and
atenolol(7)) can be compared with placebo. When the data from these trials are combined,
there is a trend towards a reduction in the incidence of total stroke, log odds ratio, 0.77 (0.591.04), but little effect on total coronary events, 0.89 (0.71-1.13). The lack of effectiveness of
atenolol based therapy in reducing coronary events corroborates that seen in other studies. (8),
(9) It may be that the high cardioselectivity of atenolol is not a desirable pharmacological
action.
There are three trials(3), (7), (10) in which the effectiveness of beta blockers can be compared
with thiazides. When the results of these trials are combined in a meta-analysis the patients
receiving thiazide had a non statistically significant reduction in the incidence of stroke, 0.81
(0.58-1.14)and coronary events, 0.92 (0.74-1.14). In post myocardial infarction trials, nonselective beta blockers and high dose beta-1 selective blockers, but not oxprenolol or pindolol,
beta blockers with high partial agonist (increased sympathomimetic) activity, reduce risk of
reinfarction and mortality.(11) With the evidence presently available, it is advisable when
prescribing beta blockers to use a non-selective beta blocker in the lowest dose required
to lower the blood pressure (see Table).
In what hypertensive patient is a beta blocker the drug of first choice?
To lower blood pressure in patients with angina pectoris a beta blocker is the drug of first
choice. Although we do not have the evidence, it also seems reasonable to use a beta blocker
as first choice in patients where the drug can be used to treat more than the hypertension, eg.
patients with frequent recurrent migraine or patients with sympathetic hyperactivity, resting
tachycardia, and palpitations. Beta blockers should not be used in patients with asthma or
other forms of obstructive airways disease.
Table 1: Beta Blockers
Beta Blockers
Trade Name
Usual Dosage Range Daily Cost (x)
Propanolol*
Inderal®, generic
Inderal® LA
20-120 mg BID
60-240 mg daily
$0.08-$0.24
$0.47-$1.66
Nadolol*
Corgard®, generic
20-160 mg daily
$0.15-$0.79
Timolol*
Blocadren®, generic
5-20 mg BID
$0.36-$1.05
Atenololº
Tenormin®, generic
25-100 mg daily
$0.20-$0.66
Metoprololº
Betaloc®, Lopressor®, generic 25-100 mg BID
Betaloc® SR, Lopressor® SR 100-200 mg daily
$0.26-$0.48
$0.41-$0.71
Acebutolol^
Sectral®, Monitan®, generic
100-400 mg daily
$0.44-$1.32
Oxprenolol^
Trasicor®
Slow Trasicor®
20-160 mg BID
80-320 mg daily
$0.31-$1.65
$0.83-$1.66
Pindolol*^
Visken®, generic
5-15 mg BID
$0.52-$1.31
Labetalol*ª
Trandate®
100-400 mg BID
$0.52-$1.82
* non-selective || º selective || ^ partial agonist || ª alpha blocker
(x) Average or lowest cost alternative (LCA) price in BC, 1994.
In what hypertensive patient is an ACE inhibitor the drug of first choice?
ACE inhibitors have been clearly shown to prolong survival in patients with congestive heart
failure.(12) They are therefore the obvious first choice in patients with hypertension and CHF.
It is not established at the present time whether ACE inhibitors have a unique renal protective
effect in diabetic nephropathy.(13)
A recent study suggests that ACE inhibitors increase the risk of hypoglycemia in treated
diabetic patients.(14) There are no proven therapeutic differences between the ACE
inhibitors; drug choice can be made based on convenience and cost. (see Table). The cost can
be minimized by prescribing 1/4 or 1/2 tablets whenever possible. (e.g.1/4 of a 20 or 40 mg
tablet of quinapril costs $0.23 a day).
Table 2: ACE Inhibitors
ACE Inhibitors
Trade Name
Usual Dosage Range Daily Cost (x)
Quinapril
Ramipril
Captopril
Accupril®
5-40 mg daily
Altace®
1.25-10 mg daily
Capoten®, generic 12.5-50 mg daily
$0.92 all tablets
$0.72-$1.01
$0.45-$1.19
Perindopril
Benazepril
Cilazapril
Coversyl®
Lotensin®
Inhibace®
2-8 mg daily
5-40 mg daily
1-10 mg daily
$0.68-$1.28
$0.61-$1.64
$0.65-$1.69
Lisinopril
Fosinopril
Enalapril
Prinivil®, Zestril
Monopril®
Vasotec®
5-40 mg daily
10-40 mg daily
5-40 mg daily
$0.70-$2.10
$0.84-$2.01
$0.82-$2.36
(x) Average or lowest cost alternative (LCA) price in BC, 1994.
In what hypertensive patient is a calcium antagonist the drug of first
choice?
At the present time there are no outcome studies which identify a group of patients who
would specifically benefit from a calcium antagonist. It is clear that post MI patients with left
ventricular dysfunction do worse with diltiazem than with placebo.(15) An overview of 31
placebo controlled trials submitted to the United States Food and Drug Administration (16)
reported that patients receiving calcium antagonists had a 63% excess of cardiac events, as
compared to placebo.
A recent unpublished but highly publicized study also suggests that patients receiving a
calcium antagonist for hypertension have a significantly increased risk of myocardial
infarction compared with patients receiving diuretics or beta blockers. Neither of these studies
are definitive. They do, however, reinforce the message in this and the previous letter, and
emphasize the need for prospective randomized controlled studies measuring morbidity and
mortality. These trials are under way, but we cannot expect any results for 4 - 5 years.
Table 3: Calcium Antagonists
Calcium Antagonists
Trade Name
Usual Dosage Range Daily Cost (x)
Cardizem®, generic 60-120 mg BID, TID $0.77-$2.32
Diltiazem
Cardizem SR®
60-180 mg BID
$1.50-$3.60
Cardizem CD®
120-300 mg daily
$1.35-$2.98
Isoptin®, generic 80-160 mg BID, TID $0.62-$1.85
Verapamil
Isoptin SR®
120-240 mg BID
$2.07-$3.08
Verelan®
120-480 mg daily
$0.88-$2.45
Adalat®, generic 5-30 mg BID, TID $0.55-$1.27
Nifedipine
Adalat PA®
10-30 mg BID
$0.99-$2.54
Felodipine
Amlodipine
Nicardipine
Adalat XL®
Plendil®, Renedil®
Norvasc®
Cardene®
30-90 mg daily
2.5-20 mg daily
5-10 mg daily
20-40 mg TID
$1.00-$2.56
$0.54-$2.12
$1.33-$1.94
$1.85-$3.70
(x) Average or lowest cost alternative (LCA) price in BC, 1994.
In what hypertensive patients are second drugs useful?
From the large controlled studies of the treatment of mild hypertension it is clear that in at
least 50% of patients the BP can be controlled with a thiazide alone. The additional drugs
used in these studies, for patients not controlled with a thiazide include reserpine in three
studies, methyldopa in two studies, hydralazine in two studies, and beta blockers in two
studies. We thus can have some confidence in the effectiveness of these drugs used in
combination with a thiazide. In patients with moderate to severe hypertension 3 to 4 drugs are
often required to adequately control the blood pressure. We, therefore, are fortunate to have a
wide armamentarium of drugs to choose from (see Tables).
Conclusion
It is up to the clinician, through systematic therapeutic trials, to identify the drug(s) which are
efficacious, well tolerated in low doses, convenient, and affordable to the patient and society.
We should use the drugs proven to reduce morbidity and mortality as much as possible,
but occasionally we are forced to individualize and choose based on other factors.
Table 4: Alpha 1 Blockers
Alpha 1 Blockers
Trade Name
Usual Dosage range Daily Cost (x)
Prazosin
Minipress®, generic 1-10 mg BID
$0.34-$1.32
Terazosin
Hytrin®
1-20 mg daily
$0.64-$2.94
Doxazosin
Cardura®
1-16 mg daily
$0.58-$3.60
(x) Average or lowest cost alternative (LCA) price in BC, 1994.
Table 5: Central and Peripheral Sympatholytics
Central and Peripheral
Usual Dosage
Trade Name
Sympatholytics
Range
Serpasil®,
0.0625-0.25 mg
Reserpine
generic
daily
Aldomet®,
Methyldopa
125 mg - 1 g daily
generic
Catapres®,
Clonidine
0.05-0.3 mg BID
generic
(x) Average or lowest cost alternative (LCA) price in BC, 1994.
Table 6: Direct Vasodilators
Daily Cost
(x)
<<$0.01
$0.08-$0.50
$0.20-$1.06
Direct Vasodilators
Trade Name
Usual Dosage Range Daily Cost (x)
Hydralazine
Apresoline®, generic 25-100 mg BID
$0.35-$1.08
Minoxidil
Loniten®
2.5-40 mg daily
$0.34-$2.96
* Average or lowest cost alternative (LCA) price in BC, 1994.
REFERENCES
1. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older
persons with isolated systolic hypertension: Final results of the Systolic Hypertension in the Elderly
Program (SHEP). J.Amer. Med Assoc. 1991;265:3255-64.
2. Verdecchia P, Porcellati C, Schillaci G, et al. Ambulatory Blood Pressure an independent predictor of
prognosis in essential hypertension. Hypertension 1994;24:793-801.
3. Medical Research Council Working Party. MRC trial of treatment of mild hypertension: principal
results. Br.Med. J. 1985;291:97-104.
4. Collins R, Peto R, MacMahon S, et al. Epidemiology, blood pressure, stroke and coronary heart
disease. Part 2: Short-term reductions in blood pressure: Overview of randomised drug trials in their
epidemiological context. Lancet 1990;335:827-38.
5. Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men. A comparison
of six antihypertensive agents with placebo. N Engl J Med 1993;328:914-21.
6. Treatment of Mild Hypertension Study Research Group. Treatment of Mild Hypertension Study Final
Results. JAMA 1993;270:713-724.
7. Medical Research Council trial of treatment of hypertension in older adults: Principal results. Br. Med.
J. 1992;304:405-12.
8. Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary
care. Br. Med. J.1986;293:1145-1151.
9. Kaplan NM. Critical comments on recent literature. SCRAAPHY about MAPHY from HAPPHY. Amer
J. Hypert. 1988;1:428-430.
10. HAPPHY Collaborative Group. Heart Attack Primary Prevention in Hypertensives (HAPPHY), J Clin
Hypertens, 1987;5:561-572.
11. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: An overview of
the randomized trials. Progress in Cardiovascular Disease, Vol XXVII, No.5, 1985:pp 335-371.
12. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on
mortality and morbidity in patients with heart failure. JAMA 1995;273:1450-1456.
13. Bauer JH. Diabetic Nephropathy: Can it be prevented? Are there renal protective antihypertensive
drugs of choice? South Med. J. 1994; 87:1043-1052.
14. Herings RMC, de Boer A, Stricker BHCh, et al. Hypoglycaemia associated with use of inhibitors of
angiotensin converting enzyme inhibitors. Lancet 1995;345:1195-98.
15. The Multicentre Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and
reinfarction after myocardial infarction. N Engl J Med 1988;319:385-92.
16. Glasser SP, Clark PI, Lipicky RJ et al. Exposing patients with chronic, stable, exertional angina to
placebo periods in drug trials. J. Amer. Med. Assoc. 1991;265:1550-1554.
Background: Hypertension is a major cause of morbidity and mortality in the United States
and many other countries. The prevalence of hypertension in the adult population of the
United States, defined by a single measurement of 140/90 mm Hg or more obtained under
nonstandardized conditions, is estimated to be 15-20%. This compares with a prevalence of
1.5-2.0% among children aged 4-15 years in whom hypertension was defined as a blood
pressure persistently greater than the 95th percentile for age. This figure, however, fails to
convey the observation that children with blood pressures within the upper percentiles of
normal range are at risk of becoming hypertensive later on in life.
Blood pressure standards
For children in the United States, extensive normative blood pressure data are not available.
Standards have been developed by a Task Force on Blood Pressure Control in Children
commissioned by the Heart, Blood, and Lung Institute of the National Institutes of Health,
using the results of 9 surveys of 70,000 infants and children. Approximately equal numbers of
boys and girls were surveyed. The percentile curves describing the age-specific distributions
of systolic and diastolic blood pressures in infants and children, with corrections for height
and weight, were published in 1987 and have been reproduced extensively in other
publications. Further details regarding the diagnosis and treatment of hypertension in infants
and children are provided in the third report of the task force, published in 1996.
In accordance with the recommendations of the task force, a blood pressure is considered
normal when the systolic and diastolic values are less than the 90th percentile. Average
systolic and/or diastolic values, corrected for body size, at or greater than this percentile level
but not exceeding the 95th percentile are considered high normal. Hypertension is defined as
average systolic and/or diastolic blood pressures greater than the 95th percentile. These
definitions allow construction of a table that can serve as a guide to the practicing physician
(see Table 1).
Table 1. The 95th Percentile of Blood Pressures (mm Hg) in Children and Adolescents*
Girls
Girls
Boys
Boys
Age, years
50th percentile
for height
75th percentile
for height
50th percentile
for height
75th percentile
for height
1
104/58
105/59
102/57
104/58
6
111/73
112/73
114/74
115/75
12
123/80
124/81
123/81
125/82
17
129/84
130/85
136/87
138/88
*Adapted from "Update on the 1987 Task Force Report on High Blood Pressure in
Children and Adolescents: a working group report from the National High Blood
Pressure Education Program"
Pathophysiology: The level of blood pressure is determined by the balance between cardiac
output and vascular resistance. A rise in either of these variables, in the absence of a
compensatory decrease in the other, increases mean blood pressure, which is the actual
driving pressure. Multiple factors regulate cardiac output and vascular resistance (see Table
2). In addition, some of these factors are affected by changes in electrolyte homeostasis,
particularly changes in sodium, calcium, and potassium. Under normal conditions, the amount
of sodium excreted in the urine matches the amount ingested, resulting in near constancy of
extracellular volume. Retention of sodium results in increased extracellular volume, which is
associated with an elevation of blood pressure. Through a variety of physical and hormonal
mechanisms, this triggers changes in both glomerular filtration rate and tubular reabsorption
of sodium, resulting in excretion of excess sodium and restoration of sodium balance.
A rise in intracellular concentration of calcium, brought about by changes in plasma calcium
concentration, increases vessel contractility. In addition, calcium stimulates the release of
renin, the synthesis of epinephrine, and the activity of the sympathetic nervous system. On the
other hand, increased potassium intake suppresses production and release of renin and induces
natriuresis, thus decreasing blood pressure. The complexity of the system explains the
difficulties encountered in identifying the mechanism that accounts for hypertension in a
particular patient. This explains why, in a large number of patients, treatment is designed to
affect regulatory factors rather than the cause of the disease.
Table 2. Factors Affecting Blood Pressure*
Cardiac Output
Baroreceptors
Extracellular volume
Effective circulating volume
Atrial natriuretic
hormones
Mineralocorticoids
Angiotensin
Catecholamines
Sympathetic nervous
system
Vascular Resistance
Pressors
Angiotensin II
Calcium (intracellular)
Catecholamines
Sympathetic nervous
system
Vasopressin
Depressors
Atrial natriuretic
hormones
Endothelial relaxing
factors
Kinins
Prostaglandin E2
Prostaglandin I2
*Modified from Gruskin AB et al
Frequency:

In the US: True incidence of hypertension in the pediatric population is not
known. This stems, in part, from the rather arbitrary definition of hypertension.
In adults, hypertension was defined on the basis of extensive studies that
allowed correlation of the level of blood pressure with detrimental outcomes,
such as heart failure or stroke. Such studies have not been performed in
children, although reports on small sample populations of children provide
compelling evidence of a relationship between hypertension and both
ventricular hypertrophy and atherosclerosis. The figure quoted above (ie, 1.52.5% of children having hypertension) is based on a compilation of studies.
How many of these children qualify as hypertensive and develop
complications during adulthood remains unknown.

Internationally: Because of differences in genetic and environmental factors,
incidence varies from country to country and even from region to region within
the same country.
Race: The task force noted no differences in blood pressure between black and white
children. However, black children of any age appear to demonstrate higher peripheral
vascular resistance and a greater sensitivity of their blood pressure to salt intake than white
children.
Sex: No significant differences in blood pressure exist between girls and boys younger than 6
years. From that age until puberty, blood pressure is slightly higher in girls than in boys. At
puberty and beyond, males have a slightly higher blood pressure than females.
Age: Blood pressure is affected by height and weight. However, these relationships do not
become evident until children are school-aged. The normative data published by the task force
in 1987 consider these factors. Numerous investigators have noted a correlation between the
blood pressure of parents and that of their offspring. The familial aggregation of blood
pressure is detectable early in life.
Indeling:
II.Diuretics:
- Thiazides
- Loop diuretics
- Potassium sparing diuretics
III.
Sympatholitics:
-
Central agents
Alfa-blockers
Beta-blockers
Alfa/Beta blockers
IV.
Calcium channel blockers:
- Dihydropiridines
- Phenylalkilamines
V.
Angiotensin converting enzyme inhibitors
VI.
Angiotensin receptor antagonists
VII.
Vasopeptidase inhibitors
VIII.
Endothelin antagonists
IX.
Other vasodilators
X.
Hybrids
The Ups and Downs of Hypertension
What's the most important number to know? Not your net worth, your age, or even the PIN number for your ATM card. It's
your blood pressure. You should know this number and what it means. Nearly one-third of people with high blood pressure
don't know they have it.
Why is blood pressure important? Because high blood pressure, also called hypertension, affects millions of people in the U.S.
and Canada. It is the major treatable risk factor for heart disease and stroke. Yet only half of those with hypertension are being
treated for it, and only half of those being treated have the disorder under control. In the past 20 years, deaths from coronary
artery disease in the U.S. have fallen by 53%, and from stroke by nearly 60%—in large part because of better detection of and
treatments for hypertension and heart disease. But recently the rate of improvement has slowed. Compared with 1991, a
smaller percentage of people are aware of the dangers of hypertension and are taking steps to prevent and control it. Here is
what everybody should know about hypertension, including the latest findings and recommendations from the Sixth Report of
the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure.
Note: Medications for hypertension are beyond the scope of this article and—if you need them—should be discussed with your
doctor.
How blood pressure turns into hypertension
Blood pressure is created by the pumping of your heart—a variable force that moves blood through the circulatory system.
When your heart contracts, blood flows into the arteries, and at the end of the contraction the pressure exerted on the walls of
the vessels is at its highest. Then as the heart relaxes, blood flows from the veins into the heart, and the pressure falls to its
lowest level. Thus blood pressure is expressed as two numbers: systolic (high point, during a contraction) and diastolic (low
point, between heart beats). A complex bodily system regulates blood pressure, which fluctuates normally according to your
activity level and many other factors. The main regulators of blood pressure are small blood vessels called arterioles, which
widen and constrict, causing pressure to fall and rise.
But when the regulatory system goes awry—for instance, if the arterioles stay constricted—blood pressure stays chronically
high. In most cases the cause of this condition is unknown—this is called "essential" hypertension. Untreated hypertension can
damage the arteries, resulting in damage to the brain, heart, and kidneys. The major risk factors are advancing age, a high
sodium and/or alcohol intake, being overweight, being sedentary, and a family history of hypertension. For reasons that remain
unclear, the incidence is also higher among black people, poor people, and those with lower educational levels. But anybody in
any walk of life can develop hypertension.
Everybody, at any age, should have a blood pressure check every two years. If you have elevated pressure, a family history of
heart disease, or other risk factors, you may need more frequent monitoring.
How can I prevent hypertension? Besides taking drugs, if that becomes necessary, how can I control it if I have it?
It's not certain that you can prevent it, but it's reasonable to think that the same practices that help control it might also
prevent or postpone it. Here's what to do:
• Maintain a healthy weight. Losing even a few pounds if you're overweight can reduce blood pressure. Weight loss
(achieved through diet and exercise) can sometimes bring hypertension under control without the need for drugs, or with lower
doses of drugs.
• Don't smoke. A person with high blood pressure who smokes is at serious risk. Every cigarette raises blood pressure.
Quitting lowers it.
• Exercise regularly. Exercise is useful in both preventing and treating hypertension. For one thing, it can help you lose
weight. It can also lower your blood pressure somewhat, though it's not understood exactly how this happens. There are other
benefits beyond blood pressure reduction: for instance, regular aerobic exercise reduces your risk of heart attack. If you are
sedentary and just beginning an exercise program to combat hypertension, remember that you may not see the effects for
months. But just 30 minutes of brisk walking four or five times a week can eventually make a difference.
If you already have high blood pressure and plan to exercise intensely, you should first discuss your program with your doctor.
Neither exercise nor any other life-style modification is a panacea, however, or a substitute for antihypertensive drugs if these
are needed.
• Eat a diet rich in fruits, grains, vegetables, and low-fat dairy products. For details the "DASH" diet.
• Keep your sodium intake low (below 2,400 milligrams daily). There's bitter dispute among scientists and others about this
recommendation, but we think it's a good one. There's plenty of evidence that a high sodium intake drives up blood pressure in
some people. A high-sodium diet has no advantages and many disadvantages. For instance, the typical salty diet is likely to
contain lots of processed foods, be low in vitamins and minerals, and be high in fat. Reducing sodium intake is often an
important step in treating high blood pressure.
• If you drink alcohol, do so in moderation: no more than one drink daily for a woman, or two for a man. (A drink is
defined as 1.5 ounces of 80-proof spirits, 5 ounces of wine, or 12 ounces of beer, all of which contain the same amount of
alcohol.)
What about vitamin supplements?
Researchers at the National Institutes of Health are currently studying the overall effects of diet on hypertension. It's difficult to
isolate one nutrient from another and assess the effects that each may have on hypertension. You can't go wrong by increasing
your intake of fruits, grains, and vegetables—these may have beneficial effects on blood pressure. Recent studies have shown
that as produce intake rises, stroke risk drops.
We recommend vitamin C and vitamin E supplements for their antioxidant potential. It's not clear that they help prevent high
blood pressure.
What about calcium, potassium, magnesium supplements?
These three minerals are important in blood pressure regulation. But there's no evidence that high doses of them from
supplements will lower blood pressure and help prevent hypertension. Calcium supplements are a good idea for
postmenopausal women, but we strongly suggest that you get some calcium and all your potassium and magnesium from
foods, which also contain other nutrients you need. Nonfat or low-fat dairy products are the best sources of calcium, though
some leafy greens are good, too. You need at least 800 to 1,000 milligrams of calcium daily; women over 50 and men over 65
should get 1,500 milligrams daily. Potassium is plentiful in most foods. Magnesium is plentiful in whole grains, leafy greens,
meats, milk, beans, bananas, and nuts.
We've recommended a multivitamin/mineral supplement for many older people (see WELLNESS LETTER, February 1998, or our
online Guide to Supplements). If you're on hypertensive medication, your doctor may recommend potassium supplements.
Will taking fish-oil capsules decrease blood pressure?
High doses of fish oil (which contains omega-3 fatty acids) may lower blood pressure on a short-term basis in some people, but
are not recommended for preventing or treating high blood pressure. High doses have potential adverse effects, including an
increased risk for one type of stroke (see WELLNESS LETTER, March 1999). Moderate doses have no effect on blood pressure.
Can coffee cause high blood pressure?
Any caffeine-containing beverage (tea, cola, or coffee) can temporarily raise blood pressure, especially if you are not used to
caffeine. But caffeine is not known to cause hypertension.
How blood pressure is defined
CATEGORY
SYSTOLIC/DIASTOLIC* RECOMMENDATIONS
Optimal
leass than 120/80
Recheck in 2 years
Normal
less than 130/85
Recheck in 2 years
High-Normal
130-139/85-8
130-139/85-89 Recheck in 1 year; begin
life-style modifications; if no change,
consider therapy
Stage 1
140-159/90-99
Confirm in 2 months; begin life-style
modifications
Stage 2
160-179/100-109
Medical evaluation; begin treatment
within one month
Stage 3
180/110 or higher
Medical evaluation; begin treatment
within one week
Hypertension
* When systolic and diastolic readings fall into different categories, the higher one is used to classify your blood pressure.
Article
Basic Research in Cardiology
Publisher: Dr. Dietrich Steinkopff Verlag, A Subsidiary of Springer-Verlag GmbH
ISSN: 0300-8428 (Paper) 1435-1803 (Online)
DOI: 10.1007/s003950050213
Issue: Volume 93, Number 8
Date: October 1998
Therapeutic advantages of AT1 blockers in hypertension
M.J. Kendall A1
A1
Department of Medicine, Queen Elizabeth Hospital, Birmingham B15 2TH, England, E-mail: [email protected]
Abstract:
Abstract Most antihypertensives have advantages and disadvantages. The ideal antihypertensive drug should be effective in
lowering blood pressure, well tolerated, safe in the long term, and easy to use. Ideally, it should be relatively inexpensive. Most
importantly it should reduce the risk of the adverse effects of high blood pressure, such as myocardial infarction, sudden death,
stroke, heart failure, renal damage, and retinal changes.
Most antihypertensive drugs effectively reduce blood pressure, are available as once daily preparations, and are safe long-term.
Unfortunately, most antihypertensive drugs cause adverse effects in some patients and for few drugs is there good evidence that
they protect the heart, the brain, the kidney, and the eye? Reducing the effects of Angiotensin II (using an ACE inhibitor) has been
shown to reduce the incidence of coronary events, sudden death, heart failure, renal damage, and fundal changes. AT1 blocking
drugs offer the same pharmacological advantages but also very good tolerability, in particular no cough. Therefore, they have the
potential to meet all the criteria for an ideal antihypertensive drug.
Keywords:
Key words Hypertension - ACE inhibitors - candesartan - AT 1 blockers - therapy

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