Pharmacological Treatment of Hypertension

Lowering blood pressure in hypertensive patients is widely recognized to reduce the incidence of cerebrovascular and cardiovascular diseases, with a relatively greater effect in preventing stroke than coronary artery disease. The degree of blood pressure reduction primarily determines the preventive effect of antihypertensive drugs on these diseases. While all major antihypertensive drugs can serve as first-line treatments, each has specific indications and varying side effects among individuals, so doctors should select medications based on the patient’s condition. To improve patient adherence, simplify medication prescriptions, monitor side effects carefully, and encourage patients to actively participate in their treatment by measuring their blood pressure at home.

1. Principles of Prescribing Antihypertensive Drugs

To minimize the long-term morbidity and mortality of cerebrovascular diseases, modifiable risk factors should be corrected, aiming to control blood pressure below 140/90 mmHg.
Start with a low dose to avoid side effects when first administering the medication.
Select medications that have a 24-hour effect allowing once-daily dosing. When prescribing once-daily medications, it is preferable to choose those with a trough/peak ratio of 0.5 or higher. These medications enhance patient adherence by minimizing blood pressure fluctuations and help in maintaining stable blood pressure control. If blood pressure is not stably controlled with once-daily dosing, the medication can be divided into two or more doses.
Choose from ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, and diuretics as primary antihypertensive drugs, considering indications, contraindications, the patient’s comorbid conditions, and asymptomatic organ damage. In elderly patients, beta-blockers are used only when there is a specific indication due to controversy over their therapeutic benefits. The combination of beta-blockers and diuretics increases the risk of developing diabetes, so caution is needed in patients with a high risk of developing diabetes.
In cases where blood pressure exceeds 160/100 mmHg or is 20/10 mmHg above the target, combination therapy of antihypertensive drugs can be started to maximize the hypotensive effect and rapidly control blood pressure.
Fixed-dose combinations can enhance the hypotensive effect, reduce side effects, and increase patient adherence, thus helping prevent cerebrovascular diseases and asymptomatic organ damage.

Blood Pressure Classification

Category	Systolic Pressure (mmHg)	Diastolic Pressure (mmHg)
Normal	Less than 120	Less than 80
Elevated	120-129	Less than 80
Hypertension Stage 1	130-139	80-89
Hypertension Stage 2	140 or higher	90 or higher
Hypertensive Crisis	Higher than 180	Higher than 120

2. Selection of Antihypertensive Drugs

The choice of antihypertensive drugs should be based more on the patient’s clinical characteristics and comorbidities rather than on blood pressure levels alone. The currently available primary antihypertensive drugs, which are effective, safe, and have relatively mild side effects, are classified into five categories:

ACE inhibitors or angiotensin receptor blockers,
beta-blockers (including alpha-beta blockers),
calcium channel blockers,
thiazide or thiazide-like diuretics, and
other medications (loop diuretics, aldosterone antagonists, alpha blockers, vasodilators).

While these medications have similar hypotensive effects when adjusted for dosage, there can be individual differences in long-term cardiovascular prevention effects and side effect occurrence. When other diseases or risk factors are present, these should be considered when selecting an antihypertensive drug.

It is difficult to directly compare which drug is superior to another, so the choice of antihypertensive drug should consider side effects and be tailored to the individual characteristics of the patient for primary administration.

Recommended Antihypertensive Drugs by Disease

Disease/Condition	ACE inhibitors or Angiotensin blockers	Beta-blockers	Calcium Channel Blockers	Diuretics
Heart failure	O	O		O
Left ventricular hypertrophy	O		O
Coronary artery disease	O	O	O
Chronic kidney disease	O
Stroke	O		O	O
Isolated systolic hypertension in the elderly	O		O	O
Post myocardial infarction	O	O
Atrial fibrillation prevention	O
Diabetes	O	O	O	O

3. Types and Usage of Antihypertensive Drugs

(1) Diuretics

Diuretics promote the excretion of water and salt through the kidneys. Initially, they reduce sodium absorption in the kidney tubules to lower blood pressure, but long-term use decreases peripheral vascular resistance, enhancing the hypotensive effect. Physicians often choose diuretics as the first-line medication for stage 1 hypertension. These drugs work particularly well for elderly patients and those who need more salt restriction. Doctors prescribe diuretics alone for mild hypertension, but they frequently combine them with other antihypertensive agents to amplify their effect on reducing circulating blood volume. Patients must limit salt intake when taking diuretics. Reducing salt intake improves the drug’s effectiveness and minimizes side effects.

[Types of Diuretics]

Category	Characteristics
Thiazide series	The most commonly used diuretics Bendroflumethiazide Chlorothiazide Hydrochlorothiazide(Dichlozid®) Methyclothiazide Chlorthalidone Indapamide Metolazone
Loop diuretics	Very potent diuretics that remain effective even when renal function is impaired; important for treating hypertension in patients with cardiac or renal function decline Bumetanide Ethacrynic acid Furosemide (Lasix®) Torsemide
Potassium-sparing agents	Remove salt from the blood while preserving potassium; often prescribed in combination with thiazide or loop diuretics to prevent potassium loss in the urine Amiloride Spironolactone (Aldactone®) Triamterene

[Diuretics Side Effects]
Diuretics increase urine output. Thiazide and loop diuretics, in particular, cause potassium loss, so physicians often combine them with potassium-sparing agents. High doses of thiazide diuretics can lead to hypokalemia, impaired glucose tolerance, increased uric acid, arrhythmias, and lipid metabolism disorders, but these side effects rarely occur at low doses. Physicians typically prescribe up to 25 mg per day for antihypertensive treatment. When doctors combine diuretics with beta-blockers, the risk of diabetes and dyslipidemia increases, so they avoid using this combination for obese patients or those at high risk of developing diabetes. Loop diuretics can sometimes cause dehydration, while potassium-sparing diuretics can elevate potassium levels. If patients have severe kidney disease, doctors must use potassium-sparing diuretics cautiously. Elevated blood potassium levels can cause irregular heartbeats and, in severe cases, lead to death. Although diuretics can cause various biochemical side effects, these issues are generally mild and do not cause significant clinical problems.

(2) Adrenergic Blockers

Adrenergic nerves regulate the tension of blood vessels and the strength of heartbeats. These signals are transmitted at synapses by neurotransmitters, which bind to receptors, including alpha and beta types. Adrenergic blockers act on these alpha or beta receptors to block the effects of neurotransmitters, thus inhibiting the action of the sympathetic nervous system and lowering blood pressure.

[Types of Adrenergic Blockers]

Category	Characteristics
Beta-blockers	○ Advantages: Beta-blockers not only lower blood pressure but also protect the heart in conditions such as acute myocardial infarction. They exhibit antiarrhythmic effects, which leads physicians to widely use them as antihypertensive agents. ○ Side effects: Beta-blockers are more prone to causing side effects than other antihypertensive drugs. Patients may experience fatigue, reduced physical activity, cold hands, sleep problems, sexual dysfunction, high blood sugar, and elevated cholesterol levels. In the respiratory system, beta-blockers constrict the bronchi, worsening symptoms in patients with respiratory diseases like asthma. While they provide significant benefits for the heart, they also reduce the heart’s contractility and heart rate. This reduction can exacerbate heart failure in severe cases. Acebutolol* (Sectral®) Atenolol (Tenormin®) Betaxolol (Kerlone®) Bisoprolol (Concor®) Carteolol (Mikelan®) Celiprolol (Selectol®) Metoprolol (Betaloc®) Nadolol* (Corgard®) Propranolol (Inderal®) Timolol (Blocadren®)
Alpha-blockers	○ Advantages: In addition to lowering blood pressure, they reduce the tension of the prostate and bladder, making them particularly beneficial for hypertensive patients with prostate enlargement. Unlike beta-blockers, they do not inhibit physical activity and do not increase blood sugar or lipid levels. ○ Side effects: They can cause orthostatic hypotension leading to dizziness due to changes in posture. Therefore, these drugs are started at a low dose, increased gradually, and taken before bedtime. Other side effects include headaches, tachycardia, nausea, and weakness. Doxazosin (Cardura®) Prazosin (Minipress®) Terazosin (Hytrin®)
Alpha/beta-blockers Types (potassium-sparing agent)	Carvedilol (Dilatrend®) Labetalol (Trandate®)
Central nervous agents	Advantages: Block alpha receptors in the central nervous system, inhibiting the entire sympathetic nervous system and thus lowering blood pressure. Proven safe for use during pregnancy in hypertensive patients. Side effects: These drugs can cause extreme fatigue or sedative effects. Other side effects include sexual issues, dry mouth, headaches, weight gain, and emotional side effects such as depression. Stopping the medication suddenly can be very dangerous and cause blood pressure to rise to very high levels, so it should be discontinued gradually under a doctor’s guidance. Clonidine (Kapvay®) Guanabenz Guanadrel Guanethidine Guanfacine Methyldopa Reserpine Labetalol (Trandate®)

(3) Calcium Channel Blockers (CCBs)

Calcium channel blockers act on the calcium channels in the membranes of blood vessels and heart cells, expanding blood vessels, lowering blood pressure, and either inhibiting the heart’s contractility or reducing heart rate. Some drugs with a short half-life (e.g., nifedipine) can rapidly lower blood pressure and are used in emergency situations, but they can cause tachycardia and increase the burden on the heart, so they are not used for routine hypertension control.

[Types of Calcium Channel Blockers]

Calcium channel blockers are effective in treating stable angina, particularly variant angina caused by coronary artery spasms. They also slow the progression of carotid atherosclerosis and are effective in reducing cardiac hypertrophy. Non-dihydropyridine calcium channel blockers such as verapamil and diltiazem do not cause reflex tachycardia and are effective after myocardial infarction and improve diastolic filling, so they are recommended for patients with hypertrophic cardiomyopathy.

Side effects: Dihydropyridine calcium channel blockers commonly cause tachycardia, ankle edema, headaches, and facial flushing. Non-dihydropyridine calcium channel blockers can cause constipation, atrioventricular conduction disorders, and decreased myocardial contractility, so they should be used with caution in patients with atrioventricular block or systolic heart failure. Additionally, caution is needed when co-administering with beta-blockers in elderly patients.

(4) Angiotensin-Converting Enzyme (ACE) Inhibitors/Angiotensin Receptor Blockers

This class of drugs inhibits the renin-angiotensin-aldosterone system, which raises blood pressure and accumulates salt and water in the body, thereby lowering blood pressure.

[Renin-Angiotensin-Aldosterone System]

ACE Inhibitors	Angiotensin Receptor Blockers
Captopril (Capril®)	Losartan (Cozaar®)
Enalapril (Renitec®)	Valsartan (Diovan®)
Quinapril (Accupril®)	Irbesartan (Aprovel®)
Ramipril (Tritace®)	Telmisartan (Micardis®)
Perindopril (Acertil®)	Candesartan (Atacand®)
Lisinopril (Zestril®)	Eprosartan (Teveten®)
Benazepril (Cibacen®)	Olmesartan (Olmetec®)
Imidapril (Tanatril®)	Fimasartan (Kanarb®)
Trandolapril (Odrik®)
Cilazapril (Inhibace®)
Fosinopril (Fosiril®)

ACE inhibitors and angiotensin receptor blockers are effective in reducing mortality in heart failure patients and preventing the progression of kidney dysfunction. They inhibit left ventricular hypertrophy and atherosclerosis and have minimal impact on glucose and lipid metabolism. They improve endothelial cell function and have beneficial effects on vascular remodeling.

Care should be taken when administering to elderly patients or those in a dehydrated state, as low blood pressure can occur initially. Administering to patients with bilateral renal artery stenosis can cause severe hypotension and worsen renal function. If serum creatinine increases by up to 30% from baseline and blood potassium does not rise above 5.5 mEq/L, there is no need to discontinue the medication. Caution is needed in patients with a serum creatinine level above 3.0 mg/dL. Potassium and kidney function should be tested before administration and within 1 to 2 weeks after, then every 3 to 6 months thereafter.

ACE inhibitors can cause a dry cough, which usually disappears within a few days to weeks after discontinuation. Dry cough is more common in women and non-smokers. Angiotensin receptor blockers do not affect bradykinin and therefore have fewer incidences of cough. ACE inhibitors and angiotensin receptor blockers are harmful to the fetus and are contraindicated in pregnant women.

(5) Other Medications

The renin inhibitor aliskiren (Rasilez®) has been used alone or in combination with diuretics to effectively reduce hypertension and proteinuria, but its impact on improving the prognosis of cerebrovascular diseases has not yet been established.

Direct vasodilators (direct vasodilators) are potent drugs that act on the muscles of the vessel walls to lower blood pressure, such as hydralazine (Apresoline®) and minoxidil (Loniten®). They are limitedly used in the treatment of resistant hypertension, as fluid accumulation and an increase in heart rate can occur in response to the drop in blood pressure, necessitating the use of diuretics or adrenergic blockers.

4. Combination Therapy

More than two-thirds of hypertensive patients need two or more different antihypertensive drugs when one type fails to control their blood pressure. This tendency becomes more pronounced as hypertension treatment extends over time, particularly in clinically high-risk patients or those with lower target blood pressures.

When the initially prescribed primary drug does not work effectively, physicians replace it with another drug. If the medication shows some effect but fails to achieve the target blood pressure, doctors either increase the dose or add another drug with a different mechanism. Instead of increasing the dose, adding small amounts of drugs with different actions enhances the hypotensive effect, improves adherence, and minimizes side effects.

Single-drug therapy serves as the first step in treatment when blood pressure is uncontrolled, followed by combination therapy. Treating hypertension with two drugs that have different mechanisms produces better results than increasing the dose of a single drug. Physicians can choose from all types of combination therapies. Although research on the best long-term combination remains insufficient, combining a renin-angiotensin system inhibitor, a calcium channel blocker, and a diuretic consistently shows favorable outcomes and is recommended as a priority. Physicians can also combine beta-blockers with drugs that have different mechanisms. However, combining beta-blockers with diuretics raises the risk of diabetes and metabolic disorders, so healthcare providers should conduct regular monitoring. Combining angiotensin receptor blockers with ACE inhibitors, which have similar mechanisms, might slightly improve proteinuria but also increases the risks of end-stage kidney disease, strokes, and other cerebrovascular diseases. Therefore, doctors should avoid this combination.

※ References : Korean Hypertension Project website (http://www.hypertension.or.kr/index.php)