Detailed Explanation of β-blockers and Modulators: Individualized Blood Pressure Lowering Regimens for Complex Complications

Beta-blockers block myocardial beta₁ receptors, producing negative chronotropic, negative conductional, and negative inotropic effects, thus reducing cardiac output. They inhibit renin secretion, reduce central sympathetic activity and peripheral vascular resistance, thereby effectively controlling hypertension and angina. They can also reduce the size of acute myocardial infarction and decrease the incidence of sudden death and re-infarction. Beta-blockers are more suitable for young people and patients with high renin activity and high dynamic hypertension. These patients respond sensitively to beta-blockers and can quickly achieve the effects of slowing heart rate, reducing cardiac output, and lowering blood pressure. It is generally believed that the sensitivity of the elderly to beta-blockers tends to decrease, and the renin levels of elderly hypertensive patients are mostly normal or decreased. Therefore, the efficacy of beta-blockers alone is not very ideal, with an effectiveness rate of only 20%-60%. However, the efficacy can be greatly improved when used in combination with diuretics and/or vasodilators.

Beta-blockers are particularly suitable for patients with hypertension and arrhythmias, sinus tachycardia, coronary heart disease, angina (excluding variant angina), left ventricular hypertrophy, hyperthyroidism, and anxiety. Several issues should be noted when using beta-blockers:

Individual variability in beta-blocker use is significant: Plasma concentrations of the same drug at the same dose can vary by 10-20 times among different patients. This is mainly related to significant differences in first-pass effect and bioavailability. These differences are due to factors such as race, genetics, diseases (especially liver diseases such as hepatitis and fatty liver) leading to decreased hepatic hydroxylation function, lifestyle habits such as alcohol consumption, medication use such as sedatives and hypnotics, and individual constitution.

Avoid "withdrawal syndrome": Patients who have used beta-blockers for a long period (more than 2 weeks) and need to discontinue use must gradually reduce the dosage over two weeks, and should not stop abruptly. Sudden discontinuation generally occurs within 1-10 days, peaking on day 6, and can lead to frequent angina attacks, acute myocardial infarction, or even sudden death. This may be related to the feedback-induced increase in β-receptor density during medication, followed by hypersensitivity to catecholamines from excessive β-receptors after sudden discontinuation. The incidence is approximately 6%.

Be alert to the potential "first-dose syndrome": Elderly individuals often have poor tolerance to β-blockers, especially those who have never used β-blockers before. Caution should be exercised, starting with the minimum dose and closely monitoring for 2-3 hours to prevent serious adverse reactions such as severe bradycardia or shock.

Avoid adverse reactions to β-blockers: There are four common types of adverse reactions: First, inhibition of β2 receptors in bronchial and vascular smooth muscle, causing smooth muscle contraction, more common with non-selective β-blockers, which can lead to bronchospasm and worsen asthma attacks; second, increased peripheral vascular resistance causing cold extremities, with an incidence of 5%-10%, contraindicated in conditions such as intermittent claudication and Raynaud's disease. Secondly, there are adverse cardiac reactions, mainly due to the negative chronotropic, tracing, and inotropic effects of these drugs, leading to sinus bradycardia, atrioventricular block, hypotension, and heart failure.

Thirdly, adverse neurological reactions include insomnia, depression, dizziness, headache, and lightheadedness, with an incidence of approximately 10%. Fourthly, other adverse reactions include fatigue (incidence approximately 5%), nausea (10%), vomiting, myalgia, rash, and impotence. They can also interfere with blood glucose and lipid metabolism, causing increases in blood glucose, cholesterol, triglycerides, and low-density lipoprotein, especially when used in combination with thiazide diuretics, which can significantly raise blood lipid levels and adversely affect the long-term prognosis of cardiovascular disease.

Angiotensin-converting enzyme inhibitors (ACEIs) primarily work by inhibiting the activity of angiotensin-converting enzyme, preventing the conversion of angiotensin I into ANGII, which has a strong vasoconstrictive and pressor effect, thereby causing systemic arteriolar dilation. They also reduce aldosterone secretion, facilitating sodium excretion; decrease sympathetic nerve excitability and increase parasympathetic nerve activity; inhibit kininase II, increasing prostaglandin synthesis, further reducing peripheral vascular resistance, thus lowering blood pressure, reducing cardiac afterload, reversing left ventricular hypertrophy, and improving cardiac function. ACEIs can also specifically dilate glomerular efferent arteries, reducing intraglomerular pressure, increasing renal blood flow, and improving renal function. Recent studies have found that ACEIs can improve insulin sensitivity, lower plasma insulin levels, and improve insulin resistance.

Angiotensin II receptor blockers (ARBs) are a new class of antihypertensive agents that were introduced in the mid-to-late 1990s. These drugs specifically block ATI receptors in the renin-angiotensin-aldosterone system (RAS), exhibiting a good antihypertensive effect. They also inhibit and reverse target organ damage caused by hypertension, such as reversing left ventricular hypertrophy and reducing atherosclerosis and renal function impairment. These drugs do not bind to receptors of other cardiovascular regulatory hormones, do not inhibit ACE, and do not affect bradykinin and substance P in the body, thus avoiding the dry cough and other side effects caused by ACEIs. Patient tolerance and compliance are significantly better than with ACEIs. It is worth noting that ACEI/ARB drugs are gradually gaining prominence in the prevention and treatment guidelines for coronary heart disease and cerebrovascular disease in various countries. These guidelines generally recommend that patients with multiple risk factors or high-risk coronary heart disease, or ischemic cerebrovascular disease, should take ACEIs or ARBs as long as they do not have symptomatic hypotension, which can reduce the incidence of cardiovascular and cerebrovascular events by about 20%.

There are techniques for changing antihypertensive drugs. Rebound effect when switching medications: One characteristic of modern antihypertensive drugs is their gentle and gradual effect on blood pressure. Traditional antihypertensive drugs, however, often have short half-lives, leading to severe rebound in blood pressure when switching or discontinuing them. New drugs have a slow onset of action, and the rebound effect upon discontinuation of old drugs is significant, causing fluctuations and confusion in the patient's blood pressure when switching medications. Therefore, when starting a new antihypertensive drug, do not abruptly stop the old drug. Instead, gradually reduce the dosage over several days. This transition, with simultaneous use of the new drug, allows for a smoother transition until the antihypertensive effect of the new drug becomes apparent, facilitating the replacement of the old drug with the new one.

The following situations should be considered when treating hypertension:

Hypertension combined with dyslipidemia: ARBs/ACEIs or alpha-blockers are the first choice, as they have a positive effect on lipid metabolism regulation; calcium channel blockers are the second choice (no effect); beta-blockers and thiazide diuretics should be used with caution, and if necessary, the dosage should be small. Hypertension complicated by metabolic syndrome: First-line considerations should be ARBs/ACEIs, which have positive effects on glucose and lipid metabolism, and angiotensin II receptor blockers (ARBs) with strong insulin sensitivity-enhancing effects; secondly, calcium channel blockers. However, when using beta-blockers and thiazide diuretics long-term, their negative effects on glucose and lipid metabolism should be considered, and the dosage should be low.

Hypertension complicated by diabetic nephropathy or chronic kidney disease: ARBs/ACEIs have a renal protective effect, and long-term treatment can significantly prevent or slow the progression of kidney disease. In cases of diabetic nephropathy, the target blood pressure should be <120/75 mmHg. Hypertension complicated by diabetes: Blood pressure treatment for diabetic patients should begin when blood pressure is >130/80 mmHg. For diabetic patients with ischemic heart disease, blood pressure should be lowered to below 120/80 mmHg. For hypertensive patients with diabetes, ARBs/ACEIs are the first-line initial treatment, followed by calcium channel blockers. To achieve target blood pressure, combination therapy is often necessary for patients with moderate to severe hypertension. Hypertension complicated by stroke: ARBs/ACEIs or dihydropyridine calcium channel blockers are the first-line treatment, reducing the risk of stroke by about 25% more than other antihypertensive drugs; most patients require two or more medications to achieve target blood pressure as quickly as possible. Hypertension complicated by coronary artery disease: In cases of stable angina, if there are no contraindications, beta-blockers should be used, as they can relieve angina symptoms and prevent myocardial infarction and heart failure.