The rational for the use of combined drug therapy for hypertension in Kuwait
B.Pharm. MSc. Ayed Al-Shammari, Dr. I.L.Naylor (Bradford University UK)
Health services structure in Kuwait
Kuwait is an oil-rich country with an area of 17 818 km2 located at 30.27°N and 48.46°E. It is bordered on the north and west by Iraq, on the south by Saudi Arabia and on the east by the Arabian Gulf. The total population is about 2 million, however only about 700 000 of these are Kuwaiti citizens the others are mostly foreign contract workers [23]
Kuwait has 77 primary health centres, 4 PHC physicians for each 10 000 of population and 6-4 PHC nurses for each 10 000 population. Every hypertension patient has a complete medical file. Hypertension and obesity clinics are present in some PHC centres. Patients are provided with treatment cards and educational material. The prevalence of hypertension in 2003 is 7%, with a significant relationship to body mass index, physical inactivity and smoking. The mortality rate from cardiovascular diseases is 6.6% of total mortality among Kuwaiti and 4.2% of total mortality among non-Kuwaiti populations. Cardiovascular diseases are the leading cause of death followed by accidents, neoplasms and diabetes mellitus. [24]
Introduction
Hypertension is quite common in patients with diabetes mellitus. Overall, more than 60% of patients with diabetes mellitus are hypertensive. Hypertensive significant increases the risk of microvascular complications of diabetes mellitus (nephropathy, retinopathy and neuropathy. Hypertension is also a major risk factor for cardiovascular disease [25]. The risk of cardiovascular disease is doubled in diabetic patients who have hypertension. Most studies on hypertension to 1996 included no or only small number of diabetic patients. This is surprising, since up to 80% of deaths in diabetes mellitus are to due to cardiovascular causes. It seems that the focus in diabetes had been devoted mostly to the management of blood sugar in Kuwait. Studies have however not shown a clear relationship between the control of blood sugar and the macrovascular disease, while the evidence is overwhelming for the association between hypertension and cardiovascular disease. [8]
Hypertension increases the risk of diabetic microvascular and macrovascular diseases and is the cause of death in >80% of diabetic patients in Kuwait.
In Kuwait, Both JNC-7 and the American Diabetic Association define hypertension in diabetes as blood pressure of 130/80 mmHg and above.
Treatment of hypertension reduces the cardiovascular mortality more in diabetics than in nondiabetics.The target blood pressure in diabetics is less than 130/80 mmHg. The UKPDS trial proved that controlling blood pressure is more important in reducing cardiovascular events than controlling hyperglycemia. Generally, there is no advantage of one antihypertension drug over the other in managing hypertension in diabetics. Thiazides should be the drug of choice in most diabetic patients.
ACE indicators and ARBs are also fast line drugs in this condition. Multiple drug therapy is usually needed. In the United States, the JNC7 (The Seventh Report of the Joint National Committee on Prevention of Detection, Evaluation and Treatment of High Blood Pressure) [1] recommends starting with a thiazide diuretic if single therapy is being initiated and another medication is not indicated. This is based on a slightly better outcome for chlortalidone in the ALLHAT study versus other anti-hypertensives and because thiazide diuretics are relatively cheap. A subsequent smaller study (ANBP2) published after the JNC7 did not show this small difference in outcome and actually showed a slightly better outcome for ACE-inhibitors in older male patients.
Despite thiazides being cheap, effective, and recommended as the best first-line drug for hypertension by many experts, they are not prescribed as often as some newer drugs. Arguably, this is because they are off-patent and thus rarely promoted by the drug industry.
In the United Kingdom, the June 2006 "Management of hypertension in adults in primary care" guideline of the National Institute for Health and Clinical Excellence, downgraded the role of beta-blockers due to their risk of provoking type 2 diabetes.
Hypertension is the number one risk factor for congestive heart failure (CHF) is a serious condition in which the heart is unable to pump enough blood to supply the body's needs.
People with high blood pressure are twice as likely to get heart attacks and eight times as likely to get strokes as the normal population, especially if they are over fifty-five.
High blood pressure can lead to hypertensive heart disease. It makes the heart work harder to push blood through the vascular system. It can make the heart grow in size and cause cardiac failure with possible fatal consequences.
Study the advantages and disadvantage of combination treatment, by different patient prescription in chest hospital in Kuwait which receives many patients in OPD clinics.
|
year
|
No. of Heart diseases patient
|
|
2004
|
77011
|
|
2005
|
74116
|
|
2006
|
74774
|
|
2007
|
77763
|
|
2008
|
81947
|
Table 1. Department of statistic chest hospital
Current Available drugs in Kuwait : in Kuwait :
- Diuretics
- Adrenergic receptor antagonists
- Adrenergic receptor agonist
- Calcium channel blockers
- ACE inhibitors
- Angiotensin II receptor antagonists
- Aldosterone antagonists
- Vasodilators
- Centrally acting adrenergic drugs
Diuretics Help the kidneys eliminate excess salt and water from the body's tissues and blood.
· Loop diuretics: bumetanide - ethacrynic acid -furosemide
Beta blockers: (no longer 1st line therapy in many countries) Propranolol, the first beta-blocker to be successfully developed and has been followed by:-
atenolol - metoprolol - nadolol - oxprenolol - pindolol - propranolol - timolol
Although beta blockers lower blood pressure, they do not have as positive a benefit on endpoints as some other antihypertensives. In particular, atenolol seems to be less usefulin hypertension than several other agents. However, beta blockers have an important role in the prevention of heart attack in people who have already had a heart attack.
Despite lowering blood pressure, alpha blockers have significantly poorer endpoint outcomes than other antihypertensives, and are no longer recommended as a first-line choice in the treatment of hypertension. However, they may be useful for some men with symptoms of prostate disease.
Adrenergic receptor agonist
Calcium channel blockers Block the entry of calcium into muscle cells in artery walls.
ACE inhibitors ACE inhibitors inhibit the activity of Angiotensin-converting enzyme (ACE), an enzyme responsible for the conversion of angiotensin I into angiotensin II, a potent vasoconstrictor, the list includes:-
Angiotensin II receptor antagonist Valsartan, an angiotensin II receptor antagonist , Angiotensin II receptor antagonists work by antagonizing the activation of angiotensin receptors, the list includes:-
candesartan- eprosartan- irbesartan- losartan- olmesartan- telmisartan- valsartan
Aldosterone antagonists
Aldosterone antagonists are not recommended as first-line agents for blood pressure,[3] but spironolactone and eplerenone are both used in the treatment of heart failure.
Vasodilators
Vasodilators act directly on arteries to relax their walls so blood can move more easily through them; they are only used in medical emergencies.
Centrally acting adrenergic drugs
Central alpha agonists lower blood pressure by stimulating alpha-receptors in the brain which open peripheral arteries easing blood flow. Central alpha agonists, such as clonidine, are usually prescribed when all other anti-hypertensive medications have failed. For treating hypertension, these drugs are usually administered in combination with a diuretic.
Clonidine- Guanabenz- Methyldopa- Moxonidine
Adverse effects of this class of drugs include sedation, drying of the nasal mucosa and rebound hypertension.
Some adrenergic neuron blockers are used for the most resistant forms of hypertension
Guanethidine - Reserpine
Combinations in Antihypertensive Treatment in Kuwait
Their effects and adverse effects
Traditionally monotherapy in Kuwait, is recommended when initiating antihypertensive treatment except in patients in phase 3 (severe), for which a therapy with two drugs is recommended [1].
Hypertension is one of the most important pathologies in everyday practice due to its high prevalence and its status as a risk factor for stroke, coronary artery disease, heart failure and end stage renal disease (ESRD) in Kuwait. Although the available trials clearly show the benefits of blood pressure (BP) reduction, they do not define with precision the desired reduction in BP for a number of situations. In fact, due to the continuous relation between BP and risk, the goal of reducing BP to the greater extent possible seems appropriate, since different epidemiological studies demonstrated that, even at "normal" levels, a lower BP is associated with lower risk of stroke, renal function impairment or heart failure in KUWAIT. [3, 4]
Thus, in Kuwait ,the Joint National Committee (JNC) in its Sixth Communication as well as the World Health Organization (WHO) and the International Hypertension Society (ISH) [2]consider that a patient is "controlled" when BP is steadily below 140/90 mmHg (systolic/diastolic blood pressure, respectively . However, many doubts arise when trying to define "control" for patients with other associated risk factors, target organ damage or previous cardiovascular disease. In this context, a normal (< 130/85 mmHg) or optimal (120/80 mmHg) BP appears to be a desirable goal in young patients, middle-aged adults and in diabetics or patients with renal disease (particularly when they present with proteinuria), and at least a high-normal BP in the elderly (< 140/90 mmHg) considered in Kuwait. [5]
When a satisfactory control (sustained BP < 140/90 mmHg) is not achieved with monotherapy, one of the following alternatives is prescribed: maximum dose titration, drug change or addition of a second, complementary drug. This therapeutic plan would seem the logical choice to make, but bears important limitations.
Monotherapy requires drugs with an adequate dose-effect curve, because if a satisfactory response is not achieved with the initial dose, it must be increased. In addition, selected drugs should have a prolonged half-life (achieving optimal trough-peak index) to guarantee adequate therapeutic action over a 24 h period.
A single drug acts mainly on a single pathophysiological mechanism, whereas it is widely known that hypertension is a multifactor pathology, in which many mechanisms interact. It is also known that when a particular system is blocked, others systems are activated that reduce the initial therapeutic effect. For example, sodium retention induced by ß-blockers or vasodilators as minoxidyl causes pseudotolerance, with loss of antihypertensive effect and calls for the prescription of a diuretic in order to neutralize this mechanism. [10, 11]
Lately, stepped care approaches for the use of specific drugs have been abandoned; nowadays, physicians can select any of the following therapeutic options: diuretics, alpha, beta -blockers, calcium-channel blockers, and ACE inhibitor or angiotensin-II receptor antagonists, according to the specific needs of the patients. [2]
However, hypertension is a highly heterogeneous disease, and depends on the interplay of many pathophysiological factors ranging from genetics to environment; it is not surprising, then, that each patient responds differently to distinct antihypertensive drugs.
In everyday practice, normotension is only poorly attained with these recommendations. For example, only 27% of hypertensive are controlled in the USA, less than 6% in the UK, 16% in Canada and less than 13% in Argentina.[1] In all these cases, monotherapy is prescribed in 60% or more[9] of treated hypertensive. These insufficient outcomes are quite predictable since, as the WHO and the ISH indicate in their report [2]: "When drugs form the main classes available are used as monotherapy at the recommended doses, they produce very similar blood pressure reductions. In general, the sizes of the blood pressure reductions increase with the initial level of blood pressure, but typically, the placebo adjusted reductions average about 4-8% for both systolic and diastolic blood pressure. Thus for patients with blood pressure of about 160/95 mmHg, the usual reduction produced by monotherapy would be about 7-13 mmHg systolic and 4-8 mmHg diastolic. Clearly, for many patients with hypertension, such reductions in blood pressure would not restore optimal or even nonhypertensive blood pressure levels."
Combined therapy
Physicians seldom modify the therapeutic regimen in uncontrolled patients on monotherapy and many are reluctant to add a second or third drug when BP goals are not achieved. Trials in different countries have shown that physicians, in everyday practice, modify the treatment only in 1 of every 4-5 uncontrolled hypertensive patients, although they indicate more frequent control visits. [10, 11]
Some patients respond to any drug, others only to a single drug and it is not possible to predict the response in a particular patient. A study in the UK [12] demonstrated that in everyday practice, independently of the type of drug initially selected, the physician indicates a change in monotherapy in more than 50% percent of patients during the initial six months of therapy, without a successful control of BP. Thus, although a sequential approach for each patient may have good results, at the same time is troublesome and requires more visits over a number of months.
Even in studies in which initial monotherapy could be highly up-titrated; researchers added a second drug in 50-70% of cases, proving that seldom can normotension be obtained with monotherapy.
This situation requires alternative answers. First, to continue the search for new and more effective antihypertensive drugs than those presently used. Despite that nowadays important pharmaceutical research is being done, this process will take time and it cannot be assured whether they will succeed or not. The problem calls for a rapid implementation of alternative solutions.
If initial monotherapy fails to achieve normotension in a high number of patients, the option of therapy with two drugs at low doses seems adequate.
From a pharmacological standpoint, the association of drugs is optimal when they act through different mechanisms and are complementary. The use of this type of association is widely extended over a number of fields as oncology (chemotherapeutic combinations), infectious diseases (tuberculosis, AIDS, mixed infections, etc.), osteopathy (treatment of osteoporosis) and in cardiology (treatment of heart failure with different drugs). [6] In all cases, the use of more than one drug is accepted and fixed combinations are frequently used. On the contrary, despite that since 1960 fixed combinations with two antihypertensive drugs are available (Table 2), in this field the physician is still reluctant to use them; they are actually mere therapeutic instruments that naturally have its pros and cons.
(Table 2).Fixed combinations:
|
1
|
1960
|
a. Alphamethyldopa+hydrochlorothiazide
b. Reserpine+ hydrochlorothiazide
|
|
2
|
1970
|
a. hydrochlorothiazide+Amiloride
b. hydrochlorothiazide+Spironolactone
c. β-blockers+ hydrochlorothiazide
|
|
3
|
1980
|
a. Enzyme inhibitors+ hydrochlorothiazide
|
|
4
|
1990
|
a. Beta-blockers+Calcium-channel blockers
b. Enzyme inhibitors+Calcium-channel blockers
c. AT-1 antagonists+ hydrochlorothiazide
|
J of Hypertension 1986
Advantages of combined therapy Advantages are the overwhelming evidence about the higher therapeutic response to a combination of two antihypertensive drugs in Kuwait. In fact, recently issued international l recommendations indicate that: "Combination therapy of several of the available drug classes has been shown to produce blood pressure reductions that are greater than those produced by any group of individual agents used alone. The TRIAL in Kuwait study, [13] in which blood pressure was lowered to below 90 mmHg in over 90% of patients, demonstrated that combination therapy was necessary in 70% of participants. Combinations with fully additive hypotensive effects will deliver blood pressure reductions that are around twice as great as those obtained with a single drug, of the order of 8-15%, or 12-22 mmHg systolic and 7-14 mmHg diastolic for patients with blood pressure of 160/95 mmHg"
For example the Hot Trial (13) diastolic normotension (<90 mmHg) was attained in almost 90% of patients, but the combination of at least two drugs was necessary in 70% of participants. In a recent evaluation of the outcomes in a private clinic and a public hospital, diastolic normotension was achieved in 82% of all cases. Again, 69% of patients required at least two drugs. [14]
One of the major reasons for the combination of drugs is that, while reaching a superior clinical effectiveness, lower doses of both associated drugs can be used, and this results in a lower incidence of adverse effects and therefore, in better patient-adherence to treatment. (Table 3)
(Table 3): Collateral effects in patients with mild and moderate hypertension [7] on chronic treatment with a diuretic, a Beta-blocker or a combination of both.
|
|
Bendroflurnethiazide
|
propranolol
|
combination
|
|
Glucose intolerance
|
7.7
|
3.1
|
4.2
|
|
Increase in uricemia
|
10.2
|
2.0
|
5.1
|
|
Impaired sexual function
|
14.6
|
6.5
|
8.8
|
|
Cold extremities
|
.2
|
5.3
|
2.2
|
|
Cutaneous side-effects
|
.5
|
2.2
|
1.2
|
|
Dyspnea
|
.2
|
4.4
|
1.8
|
|
Constipation
|
1.4
|
1.4
|
0.9
|
|
Asteria
|
3.7
|
9.2
|
4.8
|
|
Nausea, dizziness or headaches
|
7.9
|
6.0
|
4.6
|
J. of hypertension 1986
For example, diuretics stimulate the angiotensin-renin system and allow through this mechanism an enhanced activity of ACE inhibitors as well as angiotensin receptor antagonists. Beta-blockers can also neutralize the reflex tachycardia that a number of vasodilators or dihydropyridinic calcium-channel blockers may induce. Effective combinations result from the association of different types of drugs that produce an additive BP lowering effect, minimizing compensatory mechanisms that limit the reduction of BP.[13,15]( table 4)
(Table 4).Effective and reasonable combinations of antihypertensive drugs
|
1
|
Diuretic+ Beta-blockers
|
|
2
|
Diuretic+ACE1 or angiotensinII antagonists
|
|
3
|
Calcium-channel blockers(dihydropridine)+beta-blocker
|
|
4
|
Alpha-blockers+Beta-blockers
|
Combinations are less expensive than separate prescription of drugs. This is a key component in the treatment of hypertension, which require medication over long periods or even for a lifetime.
Overall, fixed combinations make management easier for the physician when compared to free association of drugs. Also, it is well-known that the therapeutic regimen may influence patient-compliance, clearly indicating the superiority of single tablet administration in once-daily regimens. [15]
Target-organ damage associated with hypertension may be effectively prevented or reverted with combination therapy. Meta analyses [8] have shown that combination therapy regresses left-ventricular hypertrophy in a much greater extent than monotherapy.
In addition, in diabetics, the progression to ESRD is reduced with antihypertensive treatment. In FACET study [16], those hypertensive diabetics treated with lisinopril progressed to less ESRD than those treated with amlodipine, but the best result was obtained with a combination of both drugs, suggesting that a higher antihypertensive effect is associated with nephroprotection.
Disadvantages of combinations of drugs
Among the possible disadvantages of fixed combinations are:
Desired combinations or a variety of doses are not always available, although new ones are being offered continuously.
Concern about the consequences of over treatment. The potential risk of reducing DBP below 85 mmHg ("J" curve hypothesis) and a resultant higher risk of coronary events have not been confirmed, and were not observed in a number of studies. [17,18] In fact, these trials evaluated the results in hypertensive randomized to different DBP goals (< 90, < 85 or < 80 mmHg) and confirmed the absence of increased risk in the group with a goal of DBP <80 mmHg.
Moreover, there was a significantly lower risk of cardiovascular disease for diabetics randomized to a SBP < 80 mmHg. Similar results were observed in the UKPDS 38 study [19], which showed that diabetics with better BP control (144/82 mmHg) had a higher reduction of cardiovascular risk than those less controlled (154/87 mmHg). In elderly hypertensive, a higher morbidity and mortality could not be demonstrated with a DBP below 80 mmHg [3]. A reduction in BP of 10/5 mmHg (SBP/DBP) is equivalent to a decrease of 10 cardiovascular events / 1000 patients per year, whereas a greater reduction of 20/10 mmHg may reduce the risk in 17 events / 1000 patients per year in Kuwait.
In 1998, a survey was performed on 495 physicians from different specialties concerning diverse aspects of hypertension [20]. It was surprising that 74% were firmly against the use of fixed combinations in antihypertensive treatment, but only 29% were able to ground their decision. Even more surprising was the fact that all the physicians surveyed acknowledged the excellent results of using a product containing hydrochlorothiazide + amiloride in fixed combination. This evidences rigidity in therapeutic attitudes and disregards advances in clinical research.
Although personal experience is of great value, it is also limited. It should be remembered that any fixed combination available is a product of years of research in many centers, which have studied a number of possible doses before deciding which of them are more adequate. Moreover, before they become available, the approval of national and international regulating institutions is required.
In summary, despite significant progress in the knowledge of the pathophysiology of hypertension, its treatment and research methodologies, at least 3 of every 4 patients are poorly controlled and have an excess of 18/12 mmHg in systolic and diastolic BP, respectively in Kuwait. The myth of monotherapy has come to an end, opening the way for combination therapy with two complementary drugs at low doses, in free associations or in fixed combinations; the latter have proved to be an excellent choice for initial treatment of hypertension because of their lower costs and better tolerance, which accounts for a higher patient-adherence to treatment.[21,22] If high blood pressure is identified early enough, when it is still in its very mildest stages, the first line of defense is an attempt to modify the risk factors associated with it. Of course, we can't do anything about our heredity, age, race, or sex; but we can lose weight, exercise more, stop smoking, and improve our eating habits. We may even be able to alter our personality; your doctor can recommend programs intended to teach Type-A personalities (the hard-driven, success-oriented types who start blowing their horns before the traffic light has changed) how to become easy-going, Type-B personalities.
In most cases, the mainstay of treatment for hypertension is medication. It brings blood pressure down quickly and keeps it down. And although it doesn't cure the disease (if you haven't improved your diet and lifestyle, blood pressure almost always shoots back up when medication is discontinued), it does prevent the serious and even life-threatening complications that can result if high blood pressure is left untreated.
The first step is usually a prescription for one of five types of medication: a diuretic, a beta blocker, an ACE (angiotensin converting enzyme) inhibitor, an angiotensin II receptor antagonist, or a calcium channel blocker. If these drugs, either alone or in combination, fail to bring under control, other classes of drugs may be prescribed.
These drugs usually make no difference in the way you feel, so it's easy to forget about them. Nevertheless, it's important to take them faithfully according to the prescribed schedule. If they are not taken on a regular basis, they won't do their hidden, but lifesaving job. Here's a closer look at the various categories that are generally prescribed.
Diuretics, such as furosemide (Lasix), chlorothiazide (Diuril), hydrochlorothiazide (Esidrix, HydroDIURIL), and spironolactone (Aldactone), make it difficult for the kidneys to retain water and salt, which are then filtered out into the urine. Increasing the amount of urine reduces the amount of fluid in the bloodstream, and hence the pressure on artery walls. It's like turning on a second faucet in your house and watching the water pressure drop in the first -- not a subtle mechanism, to be sure, but it works. Because some important chemicals may be washed out along with the water and salt, a doctor may prescribe supplements -- most commonly a potassium supplement -- to go with the diuretic in Kuwait.
A potential Future treatment
Choice between the drugs
The choice between the drugs is to a large degree determined by the characteristics of the patient being prescribed for in Kuwait also for the drugs' side-effects, and finally their cost. For example, asthmatics have been reported to have worsening symptoms when using beta blockers. Most drugs have other uses; sometimes the presence of other symptoms can warrant the use of one particular antihypertensive, such as beta blockers in case of tremor and nervousness, and alpha blockers in case of benign prostatic hyperplasia. The JNC 7 report outlines compelling reasons to choose one drug over the others for certain individual patients
Blood pressure vaccine
One very recent development for the treatment of hypertension has been under trial; blood pressure vaccinations. Those may become a treatment option for high blood pressure in the future. Research on the vaccine CYT006-AngQb was published in The Lancet on the 8 March 2008 entitled, “Vaccination against high blood pressure: a new strategy” showed patients experienced a drop in systolic and diastolic blood pressure after taking the vaccine. Effective blood pressure vaccines would assist those people who forget to take their medication and, it would also help those who stop taking their medication due to side effects or falsely believing that they don't need them anymore once their blood pressure is lowered.
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