Hypertension is the rise in blood pressure beyond the defined set point (conventionally ≥ 140/90 mmHg). Hypertension is the known risk factor for a number of cardiovascular events like myocardial infarction, angina and heart failure, sudden cardiac death. The pharmacological therapy for hypertension is discussed in this section. The therapies have evolved over time and the current line of therapy offers tremendous response and decreases the morbidity and mortality associated with this condition. It should be noted that non-pharmacological therapy like exercise and healthy food habits also play an important part in controlling hypertension.
Main complications of persistent high blood pressure

Image: “Main complications of persistent high blood pressure” by Häggström, Mikael. "Medical gallery of Mikael Häggström 2014". Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008. ISSN 20018762. License: Public Domain

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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
  • Beta 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 class of drugs has the same effect in both younger and older age groups.

But still the matter of concern lies in that, there occurs variability in the extent to which the decrease in blood pressure occurs between individuals with the same drug. The degree of hypertensive control is the major factor determining the decrease in the cardiovascular risk in patients of all age groups and the use of the various classes of drugs does not influence the decrease in risk.

Thiazide Diuretics

Classification and mechanism of action

Chlorthalidone, indapamide, hydrochlorothiazide, chlorothiazide, and metolazone are the  drugs which fall under this category. Chlorthalidone and indapamide fall under thiazide-like diuretics, and hydrochlorothiazide falls under thiazide-type diuretics. The difference between the two lies in that thiazide-like diuretics lack the benzothiadiazine in their structure but have the same physiological properties.

The nephrons, which are the functional unit of the kidney, can be divided into many segments. 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 the sodium is lost in the urine. The loss of sodium and the consequent decrease in cardiac output causes a reduction in the blood pressure in the initial stages.

But on long-term therapy, the decrease in the vascular resistance rather than the reduction in cardiac output is responsible for the reduction in blood pressure. The proposed hypothesis behind the decrease in peripheral resistance include the additional properties with these drugs such as the opening of the calcium-activated potassium channels, inhibition of vascular carbonic anhydrase and the indirect effect of loss of sodium. 

Main indication of thiazide diuretics

In the evaluation of cardiovascular outcomes between thiazide-like diuretics and thiazide-type diuretics, the thiazide-like diuretics reduced the overall risk of cardiovascular events and heart failure in patients with hypertension. So the thiazide-like diuretics like chlorthalidone are considered the preferred choice for the treatment of hypertension when thiazide is decided as treatment.

But some physician recommends towards using the low dose hydrochlorothiazide. In the treatment of resistant hypertension, the increased dose of hydrochlorothiazide (as high as 50 mg) plays a very important role.

Adverse and side effects related to thiazide diuretics

These drugs have the risk of causing hypokalemia and metabolic alkalosis. The reason behind causing hypokalemia is that the increase in sodium concentration in the distal tubular system causes the exchange and loss of potassium and hydrogen ions for the re-absorption of the sodium. This is mediated by aldosterone-sensitive sodium channel. The risk of occurrence of 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 and the occurrence of gout is an indication of changing this class of drug), hypercalcemia (due to the inhibition of the renal calcium excretion), erectile dysfunction, severe hyponatremia in some cases and enhancement of risk of polymorphic ventricular tachycardia (due to potassium loss), alteration in the lipid levels, and development of glucose tolerance.

There are some studies showing sudden cardiac death to be associated with the thiazide diuretics, especially at higher doses (greater than 25 mg daily doses of hydrochlorothiazide) but there is no conclusive evidence regarding this. The postulated mechanism for the sudden cardiac death is because of the increased risk of ischemic 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, fosinoprilperindopril, trandolapril, and benazepril. This group of drugs inhibits the conversion of angiotensin 1 to angiotensin 2 (Figure 1). This drug also decreases with the increase in the level of aldosterone seen in the treatment of thiazide diuretic and thereby increase the potency of the combination. The ARB include drugs like Losartán, candesartan, valsartán, telmisartán, irbesartan, olmesartan, and block the receptor in which the Angiotensin II acts.

Renin-angiotensin-aldosterone system

Image: “Fig. 1: The renin-angiotensin system (RAS) or the renin-angiotensin-aldosterone system (RAAS).” by A. Rad (me) – Own work, License: CC BY-SA 3.0

Main indication of ACE and ARB

These drugs are used both as monotherapy and combination therapy in the treatment of hypertension. ACE inhibitors and ARB are the drug of choice in patients suffering from hypertension along with diabetes, as the drug decreases the progression of diabetic glomerulopathy.

They are also used in the patients with heart failure, dysfunction of the left ventricle which is asymptomatic. The loss of potassium in the urine, which is seen in the treatment of thiazide diuretic will be decreased with an addition of ACE inhibitors/ARB (advantage of combining in combination therapy).

Adverse and side effects related to ACE and ARB

ACE inhibitors cause hypotension, acute renal failure, an increase in the potassium level (due to increase in Angiotensin II) and cough, angioedema, anaphylactoid reaction (due to increase in kinin). ARB has a decreased side effect of cough and angioedema when compared to ACE but has increased risk of hypotensive effect. Both the types of drugs are contraindicated in pregnancy.

Beta Blockers

Classification and mechanism of action

The drugs in this category include metoprolol, propranolol, atenolol, betaxolol, nadolol, nebivolol, penbutolol, carteolol, bisoprolol, penbutolol, and esmolol. These groups of drugs cause reduction in the heart rate, cardiac output and decrease the contractility of the myocardium. They also cause a reduction of the secretion of renin by blocking the beta receptors present in the juxtaglomerular complex.

Main indication of the group

The beta blockers are generally not used for the initial monotherapy unless there is a specific indication present (patients of hypertension with atrial fibrillation or after myocardial infarction). The beta blockers offer inferior protection against stroke. This becomes especially important as hypertension is one of the important risk factors for stroke.

Adverse and side effects related to beta blockers

The side effects include the sensation of vomiting, bronchospasm, block in the conduction of the electrical impulse of the heart, hair loss, fatigue, dizziness, reduction of heart rate, vivid dreams, and nightmares. The nonspecific beta blockers can precipitate an attack of asthma, a risk of hypoglycemic episodes and increase the concentration of triglycerides along with the reduction of HDL cholesterol.

Calcium Channel Blockers

Classification and mechanism of action

Nisoldipine, Amlodipine, Isradipine, clevidipine, Felodipine are the drugs under this category. This group of drugs causes the relaxation of  the arteriolar muscle (resulting in a decrease in 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 the contraction.

Main indication of the group

These drugs are used as monotherapy as well as combination therapy in the treatment of hypertension and there is no special indication of this group.

Adverse and side effects related to calcium channel blockers

The side effects seen with this group include headache, dizzy feeling, variation in heart rate, constipation, edema over the ankle and the legs, overgrowth of the gingiva. The usage of shorter acting calcium channel blockers like Nifedipine sublingual has been completely stopped and abandoned (evidence shows that there is no role of a sudden reduction of blood pressure  and it is more deleterious).


Direct renin inhibitors like Aliskiren

The drug inhibits the renin directly. But as such the drug is not recommended due to the increased risk of nonfatal stroke and the associated risk of kidney disease. There are warning issued by the FDA in the package insert containing Aliskiren.

Sympatholytic drugs

Alpha 1 adrenergic blocker

This 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 in the treatment with alpha 1 adrenergic blockers.

The phenomenon of first dose hypotension which occurs within 30 minutes of the initial dose of this class of drug is a major precaution to be taken care during therapy. The tolerance develops to this adverse effect on long term.

Combined alpha and beta blockers and centrally acting adrenergic blockers

The drug, which is both alpha and beta are labetalol (used in the treatment of hypertensive emergencies) and carvedilol. The drugs which 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 mouthhyperprolactinemia, libido and occurrence of 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 the case that the blood pressure is less than 20/10 mmHg from the target blood pressure. As already described, all classes of antihypertensive drugs almost have the same efficacy. The ARB/ACE inhibitors or calcium channel inhibitor is suggested as the initial monotherapy considering the potential of employing these two drugs in the combination therapy if needed in the future.

When diuretic is decided, chlorthalidone should be the initial monotherapy because of its longer duration of action and better cardiovascular risk reduction, but some recommend low-dose hydrochlorothiazide as the initial therapy in patients with mild hypertension. The treatment is

The treatment is generally started at 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 the two factors recognised for influencing the efficacy of the drugs. The younger age group patients have more chance of responding to ACE/ARB inhibitors and beta blockers while the persons of the black race and older age group is more likely to respond to thiazide diuretics and calcium channel blocker.

Combination therapy

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.

Sequential monotherapy

When a monotherapy has failed to control blood pressure, the sequential monotherapy is employed by some physician. A different class of drugs than which was given during the  initial monotherapy will be tried as treatment. This is different when compared to the routine practice of increasing the dose or employing the combination therapy.

Night-time therapy

The practice of giving at least one anti-hypertensive agent used in combination therapy during the night is seen to have better nocturnal control of hypertension and also decreases the cardiovascular risk of mortality. The conclusive evidence regarding this is yet to be achieved.

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