Pharmacological Treatment of Hypertension

If blood pressure remains elevated after 3-6 months of lifestyle modifications, or if the patient is at moderate or high risk, pharmacological therapy is required.

The main classes of drugs used for blood pressure control are:

• ACE inhibitors (e.g., enalapril, lisinopril, ramipril) → Block the angiotensin-converting enzyme (ACE), reducing the production of angiotensin II (a vasoconstrictor) and the release of aldosterone, leading to antihypertensive and nephroprotective effects.
• Angiotensin II receptor blockers (ARBs) (e.g., losartan, valsartan, telmisartan) → Directly block the angiotensin II (AT1) receptor, preventing vasoconstriction and fluid retention without increasing bradykinin levels, reducing the risk of cough compared to ACE inhibitors.
• Dihydropyridine calcium channel blockers (e.g., amlodipine, nifedipine, felodipine) → Inhibit calcium entry into blood vessels, causing vasodilation and reducing peripheral resistance.
• Thiazide diuretics (e.g., hydrochlorothiazide, chlorthalidone, indapamide) → Inhibit sodium and chloride reabsorption in the distal tubule, reducing plasma volume and arterial stiffness, with long-term antihypertensive effects.
• Beta-blockers (e.g., bisoprolol, metoprolol, carvedilol, nebivolol) → Block β-adrenergic receptors, reducing heart rate, cardiac output, and renin activity, indicated in patients with ischemic heart disease or heart failure.
• Loop diuretics (e.g., furosemide, torsemide, bumetanide) → Inhibit the Na-K-2Cl cotransporter in the loop of Henle, reducing extracellular volume, indicated in renal failure or heart failure.
• Aldosterone antagonists (e.g., spironolactone, eplerenone) → Antagonize aldosterone in the renal tubules, increasing sodium and water excretion and reducing resistant hypertension.
• Non-dihydropyridine calcium channel blockers (e.g., verapamil, diltiazem) → Act on calcium channels in the heart and blood vessels, reducing heart rate and contractility, used in patients with tachyarrhythmias or angina.
• Alpha-blockers (e.g., doxazosin, prazosin, terazosin) → Block α1-adrenergic receptors, causing vasodilation, indicated in patients with benign prostatic hyperplasia and hypertension.
• Potassium-sparing diuretics (e.g., amiloride, triamterene) → Inhibit sodium channels in the distal tubule, reducing potassium loss, often used in combination with other diuretics.
• Central sympatholytics (e.g., clonidine, methyldopa, moxonidine) → Stimulate central α2 receptors, reducing sympathetic tone and lowering blood pressure, indicated in resistant hypertension and pregnancy (methyldopa).
• Direct vasodilators (e.g., hydralazine, minoxidil) → Relax arterial smooth muscle, reducing peripheral resistance, used in severe or refractory hypertension.
• Direct renin inhibitors (e.g., aliskiren) → Directly block renin, preventing the formation of angiotensin I and II, indicated in selected cases.
• Phentolamine → A non-selective α-adrenergic blocker used for hypertensive crises due to pheochromocytoma.

🚨 Fundamental Rule: Never combine an ACE inhibitor with an ARB due to the risk of renal failure and hyperkalemia.

Therapy Selection Based on Risk

The ACD scheme guides antihypertensive therapy in a practical way:

• ✅ A → ACE inhibitors or ARBs → First-line choice in younger patients (< 55 years) or those with renal disease.
• ✅ C → Calcium channel blockers → Indicated in patients over 55, African descent, or with angina.
• ✅ D → Thiazide diuretics → Preferred in elderly patients and those with isolated systolic hypertension.

Treatment starts with monotherapy, then progresses to dual therapy (A + C or A + D). If blood pressure remains uncontrolled, a third drug is added (A + C + D). If hypertension persists, spironolactone or beta-blockers are added in selected cases.

Hypertension treatment is not solely based on blood pressure values but on stratification of Cardiovascular Risk.

Low Cardiovascular Risk Patients

Lifestyle modifications for 3-6 months as the first therapeutic approach.
If blood pressure levels remain high after this period, a monotherapy is initiated, choosing from ACE inhibitors, sartans, calcium channel blockers, or thiazide diuretics, based on the patient’s characteristics.
If blood pressure is not adequately controlled within 1-3 months, the dosage of the initial drug is increased to the maximum tolerated dose.
If the response is insufficient, a drug switch is necessary (e.g., replacing an ACE inhibitor with a sartan or a calcium channel blocker with a diuretic).
If blood pressure remains high, dual therapy is initiated.

Moderate Risk Patients

Immediate initiation of pharmacological therapy, without waiting for lifestyle modifications to fail.
It is preferable to start with a dual therapy in a fixed combination, typically ACE inhibitor or sartan + calcium channel blocker or thiazide diuretic.
Follow-up after one month with potential adjustments. If target blood pressure is not achieved, the dosage of dual therapy is increased to the maximum tolerated dose.
If blood pressure is still not controlled, switching one component of the combination is considered (e.g., replacing the calcium channel blocker with a diuretic).
If hypertension persists, triple therapy is recommended.

High Cardiovascular Risk Patients

Dual therapy with two combined drugs from the outset, preferably in a fixed-dose combination.
The recommended combination is ACE inhibitor or sartan + calcium channel blocker or thiazide diuretic.
After one month, if blood pressure is not controlled, the dosage of dual therapy is increased to the maximum tolerated level.
If hypertension remains uncontrolled, one of the two drugs may be replaced with another from the same class.
If blood pressure is still elevated after three months, triple therapy is initiated, adding the missing drug between the thiazide diuretic and the calcium channel blocker.
If hypertension persists, the addition of spironolactone or other second-line drugs is considered (quadruple therapy).
Strict monitoring is essential to prevent organ damage.

Very High-Risk Patients

Immediate intensive treatment with a triple fixed-dose combination: ACE inhibitor or sartan + calcium channel blocker + thiazide diuretic.
If heart failure or renal insufficiency is present, a loop diuretic is considered instead of a thiazide diuretic.
Follow-up after one month and, if target blood pressure is not achieved, the dosage of triple therapy is increased.
If blood pressure remains uncontrolled, switching one drug should be considered before adding a fourth one.
If hypertension persists, a fourth drug is added, usually spironolactone, or a beta-blocker if indicated (e.g., for ischemic heart disease or atrial fibrillation).
In cases of resistant hypertension, renal denervation may be considered, a minimally invasive procedure that uses radiofrequency or ultrasound to ablate perirenal sympathetic nerve fibers.

Conclusion

Hypertension is a complex condition requiring a personalized approach.
Optimal management is based on a combination of lifestyle modifications and pharmacological therapy, with risk stratification to tailor treatment to patient characteristics.

Key strategies include:

• ✅ Precise blood pressure targets, differentiated by patient category.
• ✅ Early use of drug combinations to improve blood pressure control.
• ✅ Regular monitoring to adjust therapy and prevent complications.

An integrated and timely approach is essential to reduce mortality and improve the quality of life in hypertensive patients.
Pharmacological treatment should always be complemented by Non-Pharmacological Treatment, focusing on lifestyle and modifiable risk factors.

References
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4. Società Italiana dell’Ipertensione Arteriosa. Linee Guida ESH 2023 per il trattamento dell’Ipertensione Arteriosa. 2023.
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