Cardiovascular disease contributes to approximately one-third of all deaths globally. Hypertension is a major stakeholder in the morbidity and mortality of cardiovascular diseases. Therefore, there is an urgent need to revisit its management and treatment.

The increasing cases of hypertension and reducing patient compliance to the antihypertensive treatment trigger the urgent need to develop combinations that ensure better control of blood pressure while increasing patients compliance with therapy.

Therapeutic guides recommend five main pharmacological classes for the treatment of hypertension, namely, angiotensin enzyme converting inhibitors (AECIs), angiotensin II receptor blockers (ARBs - sartans), calcium channel blockers (CCB), beta-blockers (β-blockers), and diuretics (thiazide and thiazide-like).

The combination drugs work in the principle that more pharmaceutical substances are added in a single pharmaceutical formulation, with each drug typically working at a separate site, thus blocking different effector pathways.

Benefits of Fixed Drug Combinations (FDC)-

Among the several benefits rendered by the FDCs, some are-

• Increased patient compliance (two or more pills combined into one), 
• Control on adverse reactions (Calcium Channel Blockers, when combined with AECIs, prevents peripheral edema, because arteriolodilatation caused by blockage of calcium channels is compensated by the venodilation produced by the AECI),
• Renders synergistic/additive effects of the combined drugs,
• Use of lower doses of each drug,
• Simplified treatment,
• Combining drugs means targeting several mechanisms involved in hypertension, like renin-angiotensin system blockade and induction of vasodilation and / or diuresis, etc.,
• Faster control of blood pressure,
• Can prove economic too.

Also, the triple combinations, required in nearly 15-20% of hypertensive patients remarkably increase patient compliance. However, it is not recommended as an initial treatment and is reserved for a particular category of patients requiring quicker and effective pressure control, difficult to achieve with dual therapy.

Combination therapies available in the market-

An antihypertensive drug (ARB, AECI, CCB) combined with the diuretic drug, hydrochlorothiazide is available in the market. Hydrochlorothiazide acts on the distal convoluted tube, reducing the reabsorption of sodium, inducing natriuresis, concomitant water loss and intravascular volume depletion which can lead to an activation of the renin-angiotensin-aldosterone system, thus having an additive effect on the antihypertensive effect of ACEI.

Combining hydrochlorothiazide with ARB shows a potentiated antihypertensive effect. It blunts metabolic derangements, such as hypokalemia, hyperglycemia, hypercholesterolemia and hyperuricemia, which are often seen with the use of high-dose diuretic therapy. 

Apart from hydrochlorothiazide, a thiazide-like diuretic and ACEI combination and thiazide diuretic in combination with an ARB are also available. 

A CCB with a renin-angiotensin system blocker (ARB) and a CCB and a thiazide diuretic are considered to be the most effective combinations.  CCB sensitizes the renin-angiotensin-aldosterone system leading to an improvement of the renin state, thus enhancing the antihypertensive effects of ACEI and ARB. 

The combination of CCB and thiazide or thiazide-like diuretics are less preferred over CCB with ARB or ACEI and is reserved for patients in which renin-angiotensin system inhibition is not indicated.

Among the CCBs, amlodipine remains the first choice for fixed-dose combinations with ARB and ACEI.

So, due to their larger benefits, it is advantageous to use fixed drug combination in hypertensive patients even as the initial treatment.

REFERENCE:

Popescu GC, Hancu G, Stăcescu S, Barabás-Hajdu E. Fixed dosed combinations in the treatment of hypertension. Trends in Pharmaceutical Sciences 2020: 6(1): 57-64.