Hypertension: Drugs used to treat hypertension
There are three classes of diuretic drugs that are used to treat hypertension. Most commonly used are thiazide diuretics such as hydrochlorothiazide or chlorthalidone. There is not usually an increased urine flow after the first one or two days of taking these medications. Nevertheless, it is best to take them in the morning to prevent annoying urine production overnight. They are effective in lowering blood pressure in the great majority of patients, especially those over 60, African Americans, and those with diabetes. Diuretics increase the effectiveness of all other categories of antihypertensives. That is why they are an essential part of almost any multidrug regimen for hypertension.
Special Points: Diuretics are the original antihypertensives. Therefore, their efficacy and adverse effects are very well understood. No drug is more effective overall in reducing blood pressure than a diuretic when given with dietary salt restrictions. Adverse effects are usually slight, and can often be anticipated and prevented (see below). The recent large scale clinical trial, ALLHAT, compared outcomes amongst hypertensive subjects with cardiovascular risk factors who were randomized to receive either a diuretic (chlorthalidone), an angiotensin converting enzyme inhibitor (ACEI; ramipril) or an calcium channel blocker (CCB; amlodipine) reported that the more modern drugs were no more effective overall in preventing cardiovascular disease than the diuretic and no more effective in lowering blood pressure. For this reason, the Joint National Commission on Hypertension Detection Evaluation and Treatment (JNCVII) recommended thiazide diuretics as first line therapy for patients with hypertension, unless there were special reasons to select another type of drug.
Thiazide diuretics reduce calcium excretion and have beneficial effects in preventing bone loss and fractures, especially in elderly subjects.
Diuretics increase the effectiveness or all other classes of antihypertensive agents. Therefore, almost any subject, except those with a contraindication, should receive a diuretic if their blood pressure requires more than one drug for its management.
Adverse Effects: Diuretics increase the excretion of potassium and can lead to hypokalemia (low blood potassium concentration) which predisposes to irregular heart beats, and muscular weakness. However, a combination of a thiazide or loop diuretic with a distal, potassium sparing agent (such as in the combined medications, Maxzide or Moduretic), prevents potassium loss and obviates this problem. Diuretics lead to some increase in uric acid and should not normally to be used in patients with gout. They cause a small increase in blood glucose, but it is unclear whether this predisposes to diabetes in the long term. Over treatment with diuretics can lead to low blood pressure, orthostatic hypotension (weakness, dizziness and possibly fainting on standing) and a feeling of tiredness and lethargy, all of which can be prevented or reversed by holding the diuretic for a day or two and resuming, if necessary, at a lower dosage.
Different Drugs: Thiazide diuretics include: hydrochlorothiazide (usual starting dose 12.5 to 25 mg daily) or chlorthalidone (similar dose range). Loop diuretics include: furosemide (Lasix), bumetanide (Bumex), and torsemide (Demadex), torsemide has a rather longer duration and is preferred in patients with heart failure. Ethacrinic acid (Edecrin) is used in the rare patients who are allergic to diuretics. Loop diuretics are not as effective as thiazides in lowering blood pressure in patients with hypertension. They are used especially to treat edema (swelling of the ankles) or heart failure. However, unlike thiazides, they effective in patients with poor kidney function in lowering blood pressure or treating edema.
Distal, potassium retaining diuretics include: amiloride (Midamor) and Triamterene (Dyrenium), together with spironolactone (Aldactone) and eplerenone (Inspra). All these agents can raise serum potassium. This is usually beneficial in patients receiving thiazide or loop diuretics who have increased loss of potassium in the urine. Thus these drugs are often prescribed together. However an increase in serum potassium predisposes to cardiac arrhythmias and can be especially dangerous in patients with a thickened heart (left ventricular hypertrophy) or coronary artery disease. Spironolactone causes problems with sexual performance and sometimes breast swelling in males, but is free of these kinds of effects in females. Eplerenone does not have these adverse effects, but is more expensive.
ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEIs)
ACEIs are widely used to treat hypertension because they are effective, have relatively few side effects and in reduce the complications of hypertension such as heart attacks and strokes. They have a special use in patients with diabetes mellitus who have protein the urine (“diabetic nephropathy”) and in patients with chronic kidney disease (CKD) in whom they appeared to have beneficial actions in slowing the loss of kidney function above that achieved by other agents.
ACEIs block the action of the renin angiotensin system (RAS). Renin is released from the kidney during low blood pressure, low salt intake or diuretic usage and generates angiotensin II, which constricts blood vessels, retains salt and water by the kidneys and raises blood pressure. Therefore, these drugs target important hypertensive mechanisms. Younger and white subjects are particularly likely to have an activated RAS whereas elderly and African American subjects are less likely. Therefore, ACEIs are especially effective in the former. They interact very well with diuretics. Diuretics enhance the action of ACEIs, whereas ACEIs themselves act on the kidney to retain some potassium, thereby reducing the adverse affect of low blood potassium that can occur during diuretic therapy. Indeed, there are a number of combination drugs in which an ACEI and a diuretic are included in the same medication.
Individual Drugs: The following are examples of ACEIs in clinical practice: benazepril (Mylan), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), Lisinopril (Prinivil), moexipril (Univasc), quinapril (Accupril), ramipril (Altace) and trandolapril (Mavik). There are some small differences in how long these drugs act in the circulation, they are relatively small and, with the exception of the very short acting captopril, any of these agents are usually affective when given once or sometimes twice daily as antihypertensive agents.
Adverse Effects: The quality of life of patients receiving ACE inhibitors is not impaired. They do not affect concentration, sleep, exercise abilities, sexual performance or wellbeing. However, 10 to 20 percent of subjects develop an irritant cough. If this occurs, the drug should be withdrawn and the patient advised that they should not have long term therapy with an ACEI since this is an effect common to all drugs of this class. Very rarely, they can cause a dangerous swelling of the tongue, lips and throat, which, in extreme circumstances, can seriously interfere with breathing and requires emergent treatment. Patients with chronic kidney disease often have a temporary worsening of kidney function as shown by a rise in blood urea nitrogen (BUN) or creatinine concentration, but this is temporary and modest, and is not necessarily a contraindication to prolonged therapy. Indeed, ACEI treatment has been shown in some, but not all studies do delay the onset of end stage renal disease (ESRD). ESRD is the requirements for dialysis or renal transplant in patients with progressive kidney disease.
Biochemical changes with ACEIs are usually insignificant in patients with normal kidney function. However, in those with impaired kidneys, they can raise the serum potassium concentration to levels that are dangerous and require either a change in therapy, or increasing thiazide or loop diuretic dosage to promote potassium loss. Such patients should discuss with their physician or a nutritionist how to restrict of dietary potassium intake. Generally, ACEIs improve blood glucose and maybe beneficial in patients at risk for developing diabetes mellitus. These drugs can reduce the thickness of the heart (left ventricular hypertrophy), which occur after prolonged hypertension and predisposes to congestive heart failure (CHF). ACEIs are strongly indicated in patients who have congestive heart failure since numerous studies have shown that cardiac performance and life expectancy is improved in patients who receive these drugs even if they are not hypertensive.
Special Indications: As these include patients with chronic kidney disease (but see the adverse effects above), early diabetes mellitus, congestive heart failure, or left ventricular hypertrophy.
ANGIOTENSIN RECEPTOR BLOCKERS (ARBs):
ARBs also block the renin angiotensin system (RAS), similar to ACEIs, but have a different mechanism of action by blocking the actions of angiotensin II in the tissues rather than the generation of angiotensin II, which is the action of ACEIs. These drugs also have an excellent acceptability and preservation of quality of life. Moreover, they do not cause an irritant cough or the rare danger of swelling of the lips, tongue and throat, that can occur with ACEIs. In general, the indications for their use, their effectiveness and beneficial interactions with thiazides and loop diuretics are similar to ACEIs. Some studies have suggested they are particularly effective in preventing stroke and that they may have an additional action to diminish the progression of Alzheimer’s disease in those with early dementia, but this requires conformation.
Individual Drugs ARBs include: candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), olmesartan (Benicar), telmisartan (Micardis) and valsartan (Diovan). As with ACEIs, there are only minor differences between agents in this class of drugs. All are effective in lowering blood pressure when given once, or perhaps twice daily.
Adverse Effects: As discussed, these drugs do not cause irritant cough, but otherwise have a similar spectrum of adverse actions to ACEIs.
Special Indications: These are similar to ACEIs except that they have not been shown to be beneficial in patients with congestive heart failure and maybe particularly helpful in preventing stroke and progression of Alzheimer’s disease.
BETA BLOCKERS, ALPHA BLOCKERS AND SYMPATHOLYTIC DRUGS
This group of drugs was introduced next after diuretics, to be used for hypertension. They act on a part of the nervous system that controls blood pressure, known as the sympathetic nervous system. Blockade of the sympathetic nervous system reduces blood pressure by relaxing blood vessels, and decreasing the rate and force of contraction of the heart. Therefore, beta blockers and sympatholytics typically slow the heart rate which can occasionally cause problems in subjects with a slow heart rate.
The actions of these agents are enhanced in patients taking diuretic drugs and therefore are a good second or third line selection in those patients who are not controlled with a diuretic and an ACEI or ARB. Unfortunately, alpha blockers have been shown to be less affective than other groups of blood pressure lowering agents in preventing the complications of heart failure and heart attacks in hypertensive subjects. Therefore, they are not routinely used and so will not be discussed further.
Beta blockers are affective in lower blood pressure and reducing its complications. However, their popularity has diminished because of a large range of annoying adverse effects. Although these are rarely serious, they do adversely impact the quality of life of some patients, and this limits their popularity. Nevertheless, beta blockers have been shown in many trials to prevent the probability of a recurrence in patients who have had a heart attack. Therefore, they are strongly indicated in these patients even if they cause some side effects or the patient does not have high blood pressure.
Sympatholytic agents act in the brain to decrease the drive to the sympathetic nerves. In this sense, the effects are somewhat similar to beta blockers, but because of their action in the brain, they have a different, and often rather worse, spectrum of adverse effects.
Individual Agents: The following are some beta blockers that are in current use: nadolol (Corgard), propranolol (Inderal), atenolol (Tenormin), metoprolol (Toprol), carvedilol (Coreg) and labetalol.
There are significant differences between many of the drugs in this class. Some such as atenolol abd metoprolol work on a selective part of the sympathetic nervous system and do not have so many adverse effects regarding precipitating asthma. Others such as carvedilol and labetalol act on additional parts of the sympathetic nervous system and are therefore more potent. The physician may change therapy from one to another beta blocker if it is insufficient or producing adverse effects.
Adverse Effects: The most frequent adverse effects of beta blockers are: slow heart rate, depression and irritability, impaired sleep, decreased exercise capacity, wheezing and precipitation of asthma, sexual dysfunction, and an increase in serum potassium (hyperkalemia). These effects are mostly dose dependent and, if encountered, may be amendable to reduction in dosage.
Special Indications: Beta blockers have some additional effects that make them attractive therapy for certain of patients. Thus, they are effective in reducing the frequency of migraine attacks, their slowing of the heart can be beneficial in people who have fast and irregular heart rates or atrial fibrillation, they reduce the symptoms and bad outcome in patients who have angina (chest pain on exertion due to narrowed coronary arteries), they reduce tremor of the hands in patients with essential tremor and they are protective in patients who have had a prior heart attack. They are used increasingly in patients with congestive heart failure.
Central Sympatholytic Agent: These agents include the following: clonidine (Catapres), and alpha methyldopa (Aldomet). Catapres is available as a patch similar to a band-aid which provides slow release of the drug over the course of a week. This is especially beneficial in patients who have difficulty in remembering to take the medication, but often leads to allergic skin troubles after some months.
Adverse Effects of Central Sympatholytic Agent: These include many of the problems encountered with beta blockers. In addition, these agents can cause a dry mouth, difficulty in focusing the eyes, constipation, and sleepiness during the daytime.
CALCIUM CHANNEL BLOCKERS (CCBs)
These are very effective in lowering blood pressure. They act directly on the blood vessels to cause relaxation. They are used sometimes as first line therapy but more often with diuretics or ACEIs or ARBs as second or third line therapy. They are especially effective in lowering blood pressure in elderly, black, obese, and diabetic patients. They are excellent in preventing stroke but rather less effective than diuretics, ACEIs, and ARBs in preventing heart failure.
Individual drugs: They fall into two categories. The first are called dihydropyridine CCBs and include amlodipine (Norvasc), felodipine (Plendil), nifedipine (Procardia), and nicardipine (Cardene). The second, termed nondihydropyridine CCBs include two drugs, diltiazem (Dilacor, Cardizem, Cartia, and Tiazac), and verapamil (Calan, Covera, Isoptin, Verelan). Both groups are effective in lowering the blood pressure but have different effects on the heart and rather different adverse effects. Dihydropyridine drugs generally do not impair the function of the heart and do not cause much cardiac slowing but can cause swelling of the ankles. Nondihydropyridine drugs, especially verapamil, slow the heart, similar to beta blockers and cause constipation, especially in elderly subjects.
Adverse Effects: They are usually well tolerated, and most patients have few side effects. However, dihydropyridine CCBs do cause swelling of the ankles (edema), which is worse in hot weather and at higher dosage. This usually does not indicate a major problem such as heart failure but an increased passage of fluid from the plasma into the tissues of the skin. The only way to manage edema of this type is to reduce the dose or change to another agent, although occasionally, ACEI will be beneficial.
Non-dihydropyridine CCBs cause cardiac slowing. This typically reduces the heart rate by about 10%. It can be beneficial in some patients with a fast heart rate or who have irregular heartbeat (atrial fibrillation), but in those with a slow initial heart rate, it can cause symptoms of decreased cardiac output (tiredness, lethargy, and dizziness on exertion). This group of drugs also can cause constipation, especially in the elderly but rarely cause edema.
There are a number of other drugs available to treat hypertension, but they are either rather new and expensive or suffer from some particular adverse effects and therefore are usually reserved only for exceptional circumstance, for example, when patients remain hypertensive despite receiving 3 or 4 other drugs from established categories described above.
These drugs will not be discussed in detail since they are used infrequently.
NEW DEVELOPMENTS IN HYPERTENSION RESEARCH AT GEORGETOWN UNIVERSITY HYPERTENSION, KIDNEY AND VASCULAR RESEARCH CENTRE
This is a rapidly developing field with extensive research, both by Centre scientists in the laboratory and clinical investigators in patients with hypertension. The following outlines some of the areas of research conducted at the Centre at Georgetown.
Role of Oxidative Stress
Oxidative stress occurs in cells and tissues of the body when oxygen reacts to form toxic molecules called reactive oxygen species (ROS). These can inactivate the normal signaling pathways between cells, damage cell membranes and proteins, and alter the DNA that forms the basis of our genes. Therefore, oxidative stress has widespread effects in the body. Increasing evidence suggests that oxidative stress develops progressively as we age. Indeed, almost all the common conditions that afflict us in the second half of life have an origin in oxidative stress. Studies in animal models, and human subjects show that oxidative stress is increased in patients with hypertension, coronary artery disease, heart or kidney failure, dementia and Alzheimer’s disease, Parkinson’s disease, diabetes mellitus, high blood cholesterol, smokers, obesity, and in post menopausal women. Therefore, we have selected it as the key target for therapy. Unfortunately, clinical trials with “antioxidant vitamins” such as vitamin E and C have been disappointing and usually negative. This is explained because these vitamins are very weak antioxidants and have not been given in sufficient dose to affect oxidative stress in the body.
Research at the Hypertension, Kidney and Vascular Research Centre at Georgetown has focused on a different path, namely drugs related to a chemical termed tempol. This is a highly effective drug in animal models where it enters cells throughout the body and detoxifies the reactive oxygen species, thereby preventing or reversing the oxidative stress. In so doing, tempol lowers blood pressure in animals and protects the blood vessels, kidneys, heart, and brain from damage. It is being developed as a potential therapy by the Hypertension, Kidney, and Vascular Research Center in collaboration with the Georgetown Drug Development Program. Presently, tempol is not available as a drug for human subjects and will require significant development before it reaches that stage.
Genetic Basis of Hypertension
Research indicates that about half the risk of hypertension is due to genes inherited from our parents, but so far, the key genes have not been identified. Recently, small circulating fragments of genes called micro RNAs have been detected in the plasma of humans and animal models. These have been shown to regulate a host of different genes in cells around the body. Research at Georgetown is focusing on identifying specific micro RNAs that are activated by oxidative stress and may coordinate the adverse effects such as hypertension and its complications. The long-term goal is to devise strategies to reduce the circulating burden of detrimental micro RNAs and thereby redirect the genes and the processes they regulate in the body towards a healthy state. Again, the therapeutic application of this research requires much investment and further study.
Dietary Salt Intake
Amongst those factors that are under our control which influence the probability of developing hypertension, an excessive dietary salt intake is probably the most important. Research in animal models at Georgetown at the Center for Hypertension, Kidney, and Vascular Research has linked dietary salt intake with oxidative stress that may underlie the hypertension and adverse consequences that follow from a persistently increased salt intake in the diet.
Novel Treatment Strategies
In addition to drugs such as novel antioxidants, research in the center is focusing on a novel finding first reported by Australian scientists that patients with drug resistant hypertension have a substantial fall in blood pressure when the nerves running to the kidney are ablated. Remarkably, this can be achieved without the need for an operation. The technique involves the passage of a catheter from an artery in the groin up the aorta and into the arteries to the kidney. A radiofrequency pulse of energy is applied to the catheter tip, which damages the sensitive nerves running around the artery to the kidney and thereby denervates the kidney. The initial studies in approximately 100 patients have been very encouraging. Investigators at the Hypertension, Kidney, and Vascular Research Center are working with an American company which is producing a radiofrequency renal nerve ablation device that should be simpler to use and safer. It is hoped that clinical trials may start within 1-2 years.