Table of Contents
Pharmacological Treatment of Hypertension
The major group of drugs which are used in the treatment of hypertension includes:
- Thiazide-like diuretics
- Angiotensin-converting enzyme inhibitors
- Angiotensin II receptor blockers
- Calcium channel blockers
The drugs under each group work almost with equal efficacy in decreasing hypertension. In a meta-analysis in which 31 trials with 190,606 participants were included and the occurrence of a major cardiovascular event was taken as the primary outcome showed that the different classes of drugs have the same effect in both younger and older age groups.
But still the matter of concern lies in that there is variability in the extent to which the decrease in blood pressure occurs between individuals with the same medication.
The degree of hypertension control is the major factor that determines the decrease of cardiovascular risk in patients of all age groups and the use of various classes of medications doesn’t influence this risk.
Classification and mechanism of action
Thiazide diuretics include :
Chlorthalidone, indapamide, hydrochlorothiazide, chlorothiazide, and metolazone. Chlorthalidone and indapamide are thiazide-like diuretics and hydrochlorothiazide is thiazide-type diuretic. The difference between the two lies in that thiazide-like diuretics lack the benzothiadiazine in their structure but have the same physiological properties.
The nephron that is a functional unit of the kidney is composed of two main parts: renal corpuscle and a renal tubule, this tubule can be divided into many segments, according to its anatomical and physiological characteristics. Thiazide diuretics act at the level of the distal loop, especially by inhibiting the sodium–chloride transporter. So the reabsorption of sodium is hindered and it is lost in the urine. The loss of sodium and the consequent decrease in cardiac output causes a reduction in the blood pressure at the initial stages.
But on long-term therapy, the decrease in the vascular resistance rather than the reduction of cardiac output is responsible for reducing blood pressure. There is proposed a hypothesis, according to which the reason of decreased peripheral resistance are additional properties of blood pressure lowering medications such as the opening of the calcium-activated potassium channels, inhibition of vascular carbonic anhydrase and the indirect effect of sodium loss.
Main indication of thiazide diuretics
In the evaluation of cardiovascular outcomes and, the thiazide-like diuretics reduced the overall risk of cardiovascular events and heart failure in patients with hypertension, compared to the thiazide-type diuretics. So between these two the thiazide-like diuretics like chlorthalidone are preferred for the treatment of hypertension.
Some physicians recommend using a low dose of hydrochlorothiazide.
In the treatment of resistant hypertension, increasing the dose of hydrochlorothiazide (to as high as 50 mg) plays a very important role.
Adverse and side effects related to thiazide diuretics
The risks associated with thiazide diuretics are hypokalemia and metabolic alkalosis. The reason of hypokalemia is that the increased sodium concentration in the distal tubular system causes the exchange and loss of potassium and hydrogen ions for the re-absorption of sodium. This is mediated by the aldosterone-sensitive sodium channels. The risk hypokalemia is greater during the first two weeks of therapy and monitoring is warranted during this period.
The other side effects include gout (due to the hyperuricemia induced by these drugs, gout is an indication to change this class of drug), hypercalcemia (due to the inhibition of renal calcium excretion), erectile dysfunction, severe hyponatremia in some cases, increased risk of polymorphic ventricular tachycardia (due to potassium loss), alteration in the lipid levels and development of glucose in tolerance.
There are some studies showing sudden cardiac death to be associated with thiazide diuretics, especially at higher doses (greater than 25 mg daily dose of hydrochlorothiazide) but there is no conclusive evidence regarding to this. The postulated mechanism of sudden cardiac death is the increased risk of ventricular fibrillation associated with potassium loss.
Angiotensin-converting Enzyme Inhibitors (ACE) and Angiotensin II Receptor Blockers (ARB)
Classification and mechanism of action
The ACE inhibitors include captopril, enalapril, ramipril, fosinopril, perindopril, trandolapril and benazepril. This group of drugs inhibits the conversion of angiotensin 1 to angiotensin 2 (Figure 1). ACE inhibitors decrease blood pressure through decreasing: sympathetic activity, arteriolar vasoconstriction, aldosterone production and ADH secretion. The ARBs include drugs like Losartán, candesartan, valsartán, telmisartán, irbesartan, olmesartan, they block the receptors the Angiotensin II acts on.
Main indication of ACEIs and ARBs
Between these two, ACE inhibitor is prescribed first, in case of intolerance it is switched to ARB. According to the newest recommendations they shouldn’t be prescribed together. These drugs are used both as a monotherapy and combination therapy in the treatment of hypertension. ACE inhibitors and ARBs are the drugs of choice in patients suffering from hypertension and diabetes, as they decrease the progression of diabetic glomerulopathy.
These medications are also used in patients with heart failure, asymptomatic left ventricular dysfunction. Potassium loss in the urine characterized for thiazide diuretics decreases with addition of ACE inhibitors or ARBs (advantage of combination therapy).
Adverse and side effects related to ACE and ARB
ACE inhibitors can cause hypotension, acute renal failure, hyperkalemia (due to increase in Angiotensin II) and pulmonary side effects -cough, angioedema, anaphylactoid reaction (due to increased kinin production). ARBs have decreased risk of pulmonary side effects but increased risk of hypotension. Both the types of drugs are contraindicated in pregnancy.
Classification and mechanism of action
The drugs in this category include metoprolol, propranolol, atenolol, betaxolol, nadolol, nebivolol, penbutolol, carteolol, bisoprolol, penbutolol and esmolol. Beta blockers decrease heart rate, cardiac output and contractility of the myocardium. They also cause the reduction of renin secretion by blocking beta receptors present in the juxtaglomerular complex.
Generally beta blockers aren’t used as monotherapy for hypertension initially, unless there is present specific indication (patient with hypertension and atrial fibrillation or after myocardial infarction) they offer inferior protection against stroke; this is especially important as hypertension is one of the main risk factors of stroke.
Adverse and side effects related to beta blockers
The side effects include the nausea, bronchospasm, block of electrical impulse conduction in the heart, hair loss, fatigue, dizziness, reduction of heart rate, vivid dreams and nightmares. The nonselective beta blockers can precipitate an asthma attack, hypoglycemic episodes and they can increase the concentration of triglycerides along with the reduction of HDL cholesterol.
Calcium Channel Blockers
Classification and mechanism of action
Ca channel blockers include : Nisoldipine, Amlodipine, Isradipine, clevidipine. This group of drugs causes arteriolar muscle relaxation (resulting the decrease of peripheral resistance) by blocking the voltage-sensitive calcium channel. This blockage leads to a decreased transmembrane movement of calcium and thereby decreases the concentration of calcium required for contraction.
These drugs are used as monotherapy as well as in combination with other antihypertensive medications and there are no special indications.
Adverse and side effects
The side effects of calcium channel blockers include: headache, , dizziness, variation in heart rate, constipation, ankle and leg edema, gingival overgrowth. The short acting calcium channel blockers like Nifedipine sublingually are no longer used (evidence shows that they have
Direct renin inhibitors like Aliskiren
This medication directly inhibits renin. But due to the increased risk of nonfatal stroke and kidney diseases this medication is not recommended There is warning issued by the FDA in a package insert containing the Aliskiren.
Alpha 1 adrenergic blocker
This group includes alpha receptor antagonists like prazosin, terazosin, phentolamine, doxazosin, and phenoxybenzamine. They are not recommended as monotherapy and are used as an add-on for non-responding patients. Some studies showed an increased risk of developing congestive heart failure with the treatment of alpha 1 adrenergic blockers.
The phenomenon of first dose hypotension which occurs within 30 minutes after taking the initial dose of this class of drug is a major precaution to be taken care of during treatment. There develops the tolerance to this adverse effect on long-term treatment.
Combined alpha and beta blockers and centrally acting adrenergic blockers
The drugs with both alpha and beta blocking properties are labetalol (used in the treatment of hypertensive emergencies) and carvedilol. The drugs that are centrally acting adrenergic blockers include methyldopa, clonidine, guanfacine, and guanabenz.
Methyldopa is used in the treatment of hypertension in pregnancy. Some common side effects of methyldopa include sedation, depression, dryness of the mouth, hyperprolactinemia, decreased libido and signs related to Parkinson’s disease. Clonidine suppression test employs clonidine in order to diagnose pheochromocytoma, which is one of the differential diagnosis in hypertensive patients.
Reserpine comes under the category of adrenergic neuron blocking agents. These drugs prevent the storage and release of catecholamines from the nerve endings and results in pharmacological sympathectomy.
Lines of Therapy
The monotherapy is advised only in case if blood pressure is no more then 20/10 mmHg above the target blood pressure. As already described, all classes of antihypertensive medications have almost the same efficacy. The ARB/ACE inhibitors or calcium channel blockers are suggested as the initial monotherapy considering the potential of employing these two drugs in the combination therapy if needed, in the future.
If a diuretic is chosen, chlorthalidone should be the initial monotherapy because of its longer duration of action and better cardiovascular risk reduction, but some doctors recommend a low-dose hydrochlorothiazide for the initial treatmens in patients with mild hypertension.
Generally the treatment is started from half of the standard dose as defined in the pharmacopeia. The increase of the dose of a single drug in case of monotherapy would warrant no increase in efficacy with increasing side effect (due to flat dose-response curve).
The age and race are two factors influencing the efficacy of medications. The younger age group patients have more chance of responding to ACE inhibitors /ARBs and beta blockers while people of black race and older age group are more likely to respond to thiazide diuretics and calcium channel blockers.
When the blood pressure of the patient is above the target blood pressure by 20/10 mmHg, then consider adding a 2nd drug. A combination of ACE inhibitors/ARB along with long-acting calcium channel inhibitors is recommended in case of non-obese patients. In obese patients, the combination of thiazide and ACE inhibitors/ARB is recommended.
When a monotherapy has failed to control blood pressure, the sequential monotherapy is employed by some physicians. A different class of drugs given during the initial monotherapy will be tried for the treatment. This differs compared to the routine practice of increasing dose or employing combination therapy.
The practice of giving at least one anti-hypertensive agent used in combination therapy during the night shows better nocturnal control of hypertension and also decreased risk of cardiovascular mortality. The conclusive evidence regarding to this has yet to be achieved.