Antihypertensive Drugs

 

How Antihypertensive Drugs Work

High blood pressure (hypertension) is a complex condition influenced by multiple physiological systems: blood vessel tone, fluid volume, heart function, and neurohormonal signaling (renin-angiotensin, sympathetic nervous system, etc.). Because there is no single “cause” of hypertension, different drug classes target different parts of the system to lower blood pressure. 

Here are the main mechanisms by which antihypertensive agents act:

Vasodilation / relaxing blood vessels.

Many drugs reduce vascular resistance by relaxing smooth muscle in the walls of arteries and arterioles. This lowers the force the heart must pump against. ACE inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers all act (in part) via this mechanism. 

Reducing blood volume (diuresis / natriuresis).

Diuretics increase the excretion of sodium and water through the kidneys, reducing total circulating fluid volume and lowering blood pressure. 

Decreasing cardiac output / slowing the heart.

Some drugs (notably beta-blockers) reduce heart rate and the force of contraction, thereby reducing blood pressure. 

Blocking or modulating hormonal pathways.

A major regulatory system is the renin-angiotensin-aldosterone system (RAAS). Drugs that inhibit ACE (angiotensin converting enzyme) or block the angiotensin II receptor (ARB) reduce vasoconstriction and sodium retention. Others act centrally (in the brain) to modulate sympathetic outflow or block receptors for vasoconstrictive hormones. 

Direct vasodilators / other “bonus” mechanisms.

Some agents act more directly on vascular smooth muscle (e.g. hydralazine) or through newer, emerging targets (e.g. brain renin-angiotensin modulation) to lower blood pressure. 

Because combinations of these mechanisms often produce better results than a single approach, many patients end up on two or more classes of antihypertensive drugs. 

Major Classes of Antihypertensive Drugs

Below is an overview of the main drug classes, their mechanisms, common examples, and considerations.

1. Diuretics

These are often first-line agents because of cost-effectiveness and proven benefit.

Thiazide and thiazide-like diuretics (e.g. hydrochlorothiazide, chlorthalidone)

Mechanism: inhibit sodium reabsorption in the distal tubule, promoting sodium and water excretion

Effects: reduced plasma volume, lower cardiac preload, reduced peripheral resistance over time

Considerations: can cause electrolyte disturbances (low potassium, hyponatremia), metabolic side effects (e.g. elevated glucose, uric acid) 

Loop diuretics (e.g. furosemide)

Mechanism: inhibit the Na⁺-K⁺-2Cl⁻ transporter in the loop of Henle

Use: more powerful diuresis; often used in patients with concomitant conditions (e.g. heart failure, kidney impairment)

Considerations: more potent diuresis, risk of electrolyte imbalance, more dosing frequency 

Potassium-sparing diuretics / aldosterone antagonists (e.g. amiloride, spironolactone, eplerenone)

Mechanism: oppose sodium reabsorption in collecting ducts or block aldosterone effects

Use: often used in combination, especially in patients with low potassium

Considerations: risk of hyperkalemia, hormonal side effects (e.g. gynecomastia with spironolactone) 

2. ACE Inhibitors (Angiotensin-Converting Enzyme Inhibitors)

Examples: lisinopril, enalapril, ramipril, captopril

Mechanism: inhibit ACE, reducing the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor), thereby reducing vasoconstriction and aldosterone secretion

Effects: vasodilation, reduced sodium retention, decreased remodeling of blood vessels and heart

Benefits: proven reductions in cardiovascular events, beneficial effects on kidney disease (especially in diabetes)

Side effects/risks: cough (via bradykinin accumulation), angioedema, hyperkalemia, effects on renal function (especially in renal artery stenosis)

Notes: ACE inhibitors are often favored in patients with diabetes, heart failure, or chronic kidney disease unless contraindications exist 

3. ARBs (Angiotensin II Receptor Blockers)

Examples: losartan, valsartan, irbesartan, candesartan

Mechanism: block the binding of angiotensin II to the AT₁ receptor, preventing its vasoconstrictive and aldosterone-promoting effects

Effects: similar to ACE inhibitors in many respects (vasodilation, less sodium retention)

Benefits: lower incidence of cough/angioedema compared to ACE inhibitors

Considerations: still risk of hyperkalemia, monitor kidney function

Notes: ARBs are a good alternative when ACE inhibitors are not tolerated 

4. Calcium Channel Blockers (CCBs)

Two subtypes and slightly different profiles:

Dihydropyridines (e.g. amlodipine, nifedipine)

Mechanism: block L-type calcium channels in vascular smooth muscle more than in the heart, causing vasodilation

Effects: potent reduction of peripheral resistance

Side effects: edema, flushing, headache, reflex tachycardia

Notes: widely used as first-line therapy, especially in some populations (e.g. Black patients) 

Non-dihydropyridines (e.g. verapamil, diltiazem)

Mechanism: block calcium channels in both vascular smooth muscle and cardiac tissue

Effects: reduce heart rate and contractility (in addition to vasodilation)

Considerations: avoid in patients with heart block or reduced cardiac output

Side effects: constipation, bradycardia, heart block

Notes: used especially when control of heart rate is also desired 

5. Beta-Blockers

Examples: atenolol, metoprolol, bisoprolol, propranolol

Mechanism: block β₁ (and sometimes β₂) receptors, reducing heart rate, contractility, and renin release

Effects: lower cardiac output, blunted sympathetic effects

Benefits: useful when patients have concomitant cardiac disease (e.g. ischemic heart disease, arrhythmias, heart failure)

Considerations/side effects: fatigue, cold extremities, exacerbation of asthma or COPD (if non-selective), masking signs of hypoglycemia

Role today: sometimes not preferred as first-line in patients without cardiovascular disease, but still important in specific situations 

6. Alpha-Blockers (Alpha-1 Antagonists)

Examples: prazosin, doxazosin

Mechanism: block α₁-adrenergic receptors on blood vessels, leading to vasodilation

Use: less commonly used, sometimes in combination therapy

Side effects: orthostatic hypotension, dizziness, reflex tachycardia

Notes: sometimes used in patients with benign prostatic hyperplasia (because they also relax prostatic smooth muscle) 

7. Centrally Acting Agents / Miscellaneous

These act on the central nervous system or via other mechanisms:

Centrally acting sympatholytics (e.g. clonidine, methyldopa)

Mechanism: reduce sympathetic outflow from the brain

Side effects: sedation, dry mouth, rebound hypertension if stopped abruptly

Use: often secondary or adjunctive therapy

Direct vasodilators (e.g. hydralazine, minoxidil)

Mechanism: relax vascular smooth muscle directly

Use: reserved for resistant hypertension or specific settings

Side effects: reflex tachycardia, fluid retention, lupus-like syndrome (hydralazine)

Others / Emerging agents

Firibastat (brain aminopeptidase A inhibitor): a novel agent targeting the brain renin-angiotensin system (RAS). By inhibiting brain aminopeptidase A (preventing conversion of angiotensin II to angiotensin III in the brain), it may help reduce sympathetic tone, vasopressin release, and vascular resistance. Early trials show promise especially in populations that are salt-sensitive or less responsive to standard RAS blockers. 

Ongoing research seeks new targets, e.g. dual or multi-pathway agents with additional benefits (e.g. organ protection). 

How to Choose the Right Drug (or Combination)

Selecting an antihypertensive regimen is individualized. Some factors guiding choice:

1. Patient comorbidities / indications.

Diabetes, chronic kidney disease, heart failure, ischemic heart disease often favor use of RAS blockers (ACE inhibitors, ARBs). 

In Black patients or those with low renin hypertension, calcium channel blockers or diuretics may have better response. 

Coexisting conditions such as arrhythmias may favor beta-blockers or non-dihydropyridine CCBs.

2. Efficacy and outcomes data.

All major classes reduce blood pressure fairly reliably; differences lie more in side-effect profiles and benefit in specific outcomes. 

Some recent studies have explored whether longer exposure to particular classes correlates with better cardiovascular outcomes. 

3. Tolerability and side effects.

Individual differences in side effects (e.g. cough from ACE inhibitors, edema from CCBs, metabolic effects of diuretics) often guide switching or combining drugs. 

Renal function, potassium levels, electrolyte status must be monitored.

4. Cost, adherence, and convenience.

Fixed-dose combinations (two drugs in one pill) can improve adherence.

Dosing schedules, drug cost and availability in a region often matter more in practice.

5. Resistance and combination therapy.

Many patients will require two or more agents (from different classes) to reach blood pressure goals. 

Resistant hypertension may require additional agents (e.g. adding a mineralocorticoid receptor antagonist, direct vasodilator) and specialist evaluation. 

6. Monitoring and adjustment.

Regular follow-up is key to titrate doses, monitor side effects, and adjust therapy.

In some advanced approaches, dynamic treatment regimes are being developed (using patient data over time to optimize when and how to adjust therapy) 

Challenges, Side Effects, and Considerations

Even though antihypertensive therapy is highly effective, several challenges remain:

Adverse effects and tolerability.

Each class comes with potential side effects. For example, ACE inhibitors may cause cough or angioedema; diuretics may cause electrolyte disturbances; beta-blockers may cause fatigue or worsen asthma; calcium channel blockers can cause edema or GI effects. 

Inter-individual variability / pharmacogenomics.

Genetic differences influence how patients respond to medications and risk of adverse events. Some biomarkers are being studied to predict which patients will benefit most from particular drug classes. 

Adherence issues.

Many patients discontinue therapy because of side effects, costs, or forgetfulness. Using simpler regimens or fixed-dose combinations helps.

Combination complexity & drug interactions.

Using multiple drugs increases risk of drug–drug interactions, over-lowering blood pressure, or cumulative adverse effects.

Residual risk and organ protection.

Blood pressure control is necessary but not always sufficient to eliminate cardiovascular and renal risk. Some newer agents seek to provide extra organ-protective effects beyond pure blood pressure lowering. 

Underutilization of newer agents

Many emerging agents are still under clinical evaluation and not widely available. For example, firibastat is promising for specific subtypes of hypertension but is not yet a standard therapy. 

References / further reading

1. Antihypertensive Medications — StatPearls / NCBI Bookshelf (overview of drug classes and indications) 

2. Present and future of drug therapy in hypertension: an overview (review on new directions) 

3. Comparative Effectiveness of Antihypertensive Therapeutic Classes (comparative outcomes) 

4. Antihypertensive drugs and brain function: mechanisms underlying therapeutic benefits and metabolic‐vascular risks (mechanisms, especially central) 

5. Antihypertensives associated adverse events: a review (side effect profiles, molecular mechanisms) 

6. Impact of antihypertensive drug classes on cardiovascular outcomes (recent outcome study) 

7. Evolution of a New Class of Antihypertensive Drugs (on firibastat / brain RAS targeting) 

Antoinette NDACYAYISENGA

AN, BScN Candidate