There are six classes of first-line antihypertensive drugs, namely angiotensin converting enzyme inhibitors (ACE I), angiotensin II receptor blockers or antagonists (ARB), beta-blockers (B: beta-blockers), calcium antagonists (C: calcium antagonists), diuretics (D: diauretics), and alpha 1 receptors. (ARB), beta-blockers (B: beta-blockers), calcium antagonists (C: calcium antagonists), diuretics (D: diauretics), and alpha 1 receptor blockers. Indopamine is a diuretic with calcium antagonist effect. α1-blockers have been decreasing in clinical use and have faded out of the category of first-line antihypertensive drugs because they do not significantly reduce mortality in hypertensive patients (especially in combination with heart failure and coronary artery disease), and even tend to increase. At present, the most used first-line antihypertensive drugs in clinical practice are mainly the first five categories, which can be simply expressed as AB/CD. The principles of antihypertensive drug selection should take into account four aspects, namely antihypertensive effect, clinical situation, quality of life and drug cost. The selection method of antihypertensive drugs is basically individualized. According to the different conditions of hypertensive patients, all six categories of drugs can be used as the preferred drugs. However, only 30% of patients with hypertension can control their blood pressure to the target level with only one drug, while 70% of patients need a combination of two or more drugs to achieve ideal blood pressure control. In order to control blood pressure more effectively without producing significant adverse effects, small-dose combinations have become one of the principles of modern hypertension treatment. In addition to its general principles, the combination of drugs must take into account a variety of individual patient factors to truly obtain the best combination. Individualization, small doses, attainment of optimal combination, and reduction of total risk are the current principles of antihypertensive therapy.
1. Principles of antihypertensive drug combinations
1. 1 Enhance the efficacy – reduce adverse reactions principle This is the core principle of the combination of antihypertensive drugs. The combination of ACE I and thiazide diuretics can reduce the hypokalemia caused by the former and counteract the sympathetic activation caused by the latter, and the relative reduction of blood volume brought by the latter can enhance the antihypertensive effect of the former. ACEI, ARB and β-blockers inhibit the activity of the renin-angiotensin-aldosterone system, while calcium antagonists and diuretics stimulate the activity of this system, so the combination of the first three classes of drugs with the latter two classes of drugs is reasonable. Beta blockers can antagonize the effect of diuretics in increasing renin secretion and plasma renin activity. beta blockers in combination with alpha 1 blockers can also enhance the efficacy, and the former can offset the adverse effects of tachycardia caused by the latter. It is generally believed that diuretics can be used in combination with various antihypertensive drugs, which can not only enhance the antihypertensive effect, but also reduce the water and sodium retention caused by some other antihypertensive drugs (such as β-blockers and α1-blockers), and the mild potassium retention effect of ACE I and ARB can counteract the adverse effects of diuretics in reducing blood potassium. The diuretics can be considered the best “supporting role” in the combination of antihypertensive agents. If three or more antihypertensive drugs are combined, one of them should be a diuretic, otherwise it is difficult to achieve the desired antihypertensive effect. However, because beta blockers and diuretics have certain adverse effects on lipid and glucose metabolism, and can also cause sexual dysfunction, so they should not be used in combination for a long time.
1. 2 small dose combination principle about the dose of antihypertensive drugs, except for β-blockers, α1 blockers, other antihypertensive drugs generally do not use more than three dosage forms (such as fosinopril 1 tablet for 10mg, this is a dosage form), because all antihypertensive drugs have certain adverse effects, if you keep increasing the dose of a drug to increase the efficacy, the cost may be to increase the adverse effects of the drug This is because all antihypertensive drugs have certain adverse effects. At present, it is recognized that the combination of antihypertensive drugs should be taken in small doses, most antihypertensive drugs with a dosage form, a few necessary cases can be used in two or three dosage form doses, dihydrocotrimoxazole only with half or a dosage form dose. In addition, the effectiveness and safety of foreign imported antihypertensive drugs are better, but the price is still relatively high, and many patients in China still can not afford the long-term application of these drugs. Therefore, in the actual clinical work sometimes requires us to consider this factor rather than the dose of imported drugs with large.
1. 3 Doubling the amount – drug plus the principle of sequential species When a preferred drug of a dose does not make blood pressure fall to the target level, the dose can be increased by 1 times, or add a second drug; if blood pressure still does not fall to the target level, the dose of the second drug can be increased by 1 times, or add a third drug; if blood pressure still does not fall to the target level, the dose of the third drug can be increased by 1 times, or add a fourth drug; if blood pressure If the blood pressure still does not fall to the target level, the cause should be analyzed (whether it is secondary hypertension, whether it is combined with serious target organ damage such as renal insufficiency, whether the drug used has not yet been able to target the pathogenesis of hypertension, or whether it is intractable hypertension) and the corresponding treatment should be taken or the type of antihypertensive drug adjusted. The initiation of antihypertensive drugs should start with one to three drugs depending on the blood pressure level, i.e., the level of hypertension, and then “fine-tune” the drug type and dose according to the efficacy. The number of antihypertensive drugs needed to achieve the target level of blood pressure control in a specific hypertensive patient depends on the degree of hypertension. Many large international clinical trials have found that: the number of antihypertensive drugs needed = the number of hypertension levels ± 1. For example, hypertension levels 1, 2, and 3 often require 0 to 2, 1 to 3, and 2 to 4 antihypertensive drugs. Hypertensive emergencies also require intravenous use of antihypertensive drugs.
1. 4 Other factors with the control principle Hypertensive patients are often combined with other risk factors such as coronary heart disease, such as smoking, dyslipidemia, diabetes and obesity, etc. Whether or not to treat these risk factors also seriously affect the prognosis of hypertension, and therefore must be controlled at the same time. In addition, more than 50% of hypertensive patients have a combination of various other medical conditions or hypertension itself has led to target organ damage, and these factors must be taken into account when choosing antihypertensive drugs. Comprehensive interventions to reduce the overall risk of cardiovascular disease.
2. Common protocols for antihypertensive drug combinations
It is generally accepted that the combination of drugs on different sides of the slash is appropriate for the five classes of AB /CD antihypertensive drugs. Commonly used combination schemes are: ACE I + diuretics, ACEI + calcium antagonists, ARB + diuretics, ARB + calcium antagonists, β blockers + diuretics, β blockers + dihydropyridine calcium antagonists. β blockers + α1 blockers are also one of the available schemes. β blockers and diuretics can be combined, but because of the concern that long-term combined use may have adverse effects on metabolism, it is currently not favored in academic circles. The combination of β-blockers and diuretics can be combined, but due to the concern of long-term combined use may have adverse effects on metabolism, it is currently not favored in academic circles.
3. Contraindications to the combination of antihypertensive drugs
For example, metoprolol and bisoprolol are both beta blockers and should not be combined. However, if necessary, nifedipine can be used in combination with verapamil, which is an exception, but do not use this combination clinically, because there are many effective and excellent antihypertensive drugs, and this combination is not an excellent combination, but only a non-contraindicated combination. Diuretics with different mechanisms of action can be combined.
3. 2 AB / CD drugs on the same side of the slash do not need to be combined In theory, among the five classes of AB / CD antihypertensive drugs, drugs on the same side of the slash are generally not necessary to be combined for the treatment of hypertension, partly because their antihypertensive mechanisms are similar, so drugs on the same side of the slash should not be used as the preferred combination. However, the drugs on the same side of the slash are not contraindicated combinations, and such combinations are common in actual clinical applications for patients whose blood pressure is difficult to control, such as ACE I + beta blockers, diuretics + calcium antagonists, and even the combination of ACE I and ARB.
3. 3 β-blockers should not be combined with the following drugs Combining with colistin may aggravate bradycardia, and sudden discontinuation of colistin may lead to rebound hypertension induced by β-blockers, or even cardiovascular accidents. Combination with guanethidine may induce heart failure and postural hypotension because both of them can reduce cardiac blood output. Combination with prazosin is prone to prazosin first dose reaction, so the two should not be combined at the beginning of hypertension treatment. Combination with verapamil and thioridone can aggravate bradycardia, heart block and heart failure, and even cardiac arrest.
3. 4 Several other combinations are contraindicated The combination of guanethidine with prazosin and diazoxide with furosemide can cause severe postural hypotension. The combination of colistin with methyldopa can aggravate the respective drowsiness and bradycardia adverse effects. the combination of ACEI with potassium conserving diuretics can lead to hyperkalemia. The combination of thiazide diuretics and diazepam can increase blood sugar, so it is not recommended for diabetic patients.
4. Compounding of antihypertensive drugs
Some people have summarized a law in the process of antihypertensive treatment – “10 law”, that is, every 10 mmHg blood pressure on average should increase a kind of antihypertensive drugs, in order to achieve the target blood pressure often need more than three antihypertensive drugs combined, so the choice of daily oral once and drug interactions between the antihypertensive drugs Therefore, it is particularly important to choose antihypertensive drugs that are taken orally once a day and have fewer interactions. In order to meet the needs of the majority of hypertensive patients and improve compliance, the compounding of antihypertensive drugs came into being.
In China, the development of compounded antihypertensive drugs began as early as the 1960s, and a variety of compounded formulations have been developed and applied, but most of them choose centrally acting drugs or diuretics as matching drugs. Combination of central action drugs and diuretics as the main compound preparations: compound antihypertensive tablets, compound antihypertensive tablets, compound antihypertensive capsules, compound blood pressure tablets, compound colistin, compound deserpine tablets (antihypertensive le, an descending le), compound hypotensive tablets, compound antihypertensive tablets (Beijing antihypertensive 0), regular medicine antihypertensive tablets, pulse Shujing tablets, antihypertensive static tablets, vizipran tablets, an descending tablets. Combination of centrally-acting drugs with vasodilators: Andazepine (Adafin). Combination of ACEI and diuretic: Compound Captopril Tablets (Keflex). Combination of alpha-blocker with diuretic: Fupiperazine. Combination of diuretics and diuretics: compound aminopterin (Lidipine), compound amiloride tablets (Vuduli, Mundacin). Combination of Chinese and Western medicines: Xinjiang descending tablets, compound rooibos tablets, Zhenju antihypertensive tablets (Ju Le Ning antihypertensive tablets), Anshu antihypertensive tablets. Foreign compound antihypertensive preparations started later than ours, but the selection of drugs is newer than ours (Table 1). The biggest shortcoming of our compound antihypertensive preparations is the lack of large clinical trials.
In recent years, more and more attention has been paid to the research of compounded antihypertensive preparations, which is not only reflected in the improvement of dosage forms and the updating of formulations, but also in the emergence of new drug delivery systems. What is even more refreshing is that the composition of compounded formulations has taken on a new concept, no longer just a reasonable combination of several antihypertensive drugs, but taking into account the comprehensive prevention and treatment of the entire cardiovascular and cerebrovascular diseases. The United Kingdom has developed a new compound, including a lipid-lowering drugs, three antihypertensive drugs, folic acid and aspirin, and the United States has also developed a “multi-pill” for the prevention and treatment of cardiovascular disease. Although the effectiveness of these combinations has yet to be validated by evidence-based medicine, the concept of comprehensive control of multiple cardiovascular risk factors has gained widespread acceptance in the cardiovascular medical community.
Table 1 Foreign antihypertensive combination regimens
Combination regimen Combined drugs Trade names
ACEI + calcium antagonist Benazepril, amlodipine Lotrel
Enalapril, Felodipine Lexxel
Gundopril, verapamil Tarka
Enalapril, Diltiazem Teczem
ACEI + diuretics Captopril, hydrochlorothiazide Capozide
Benazepril, hydrochlorothiazide Lotensin HCT
Enalapril, hydrochlorothiazide Vaseretic
Lenopril, hydrochlorothiazide Prinzide
Moxepril, hydrochlorothiazide Uniretic
Quinapril, hydrochlorothiazide Accuretic
ARB + diuretics Candesartan, hydrochlorothiazide Atacand HCT
Eprosartan, hydrochlorothiazide Teveten HCT
Irbesartan, hydrochlorothiazide Avalide
Cilsartan potassium, hydrochlorothiazide HYZAAR
Telmisartan, hydrochlorothiazide Micardis HCT
Valsartan, hydrochlorothiazide Diovan HCT
Beta blocker + diuretic Atenolol, chlorothiazide Tenoretic
Bisoprolol, hydrochlorothiazide Ziac
Long-acting propranolol, hydrochlorothiazide Inderide
Metoprolol, hydrochlorothiazide Lop ressor HCT
Nadolol, hydrochlorothiazide Corzide
Timolol, hydrochlorothiazide Timolid
Centrally acting drug + diuretic Methyldopa, hydrochlorothiazide Aldoril
Risperdal, hydrochlorothiazide Diup res
Risperdal, hydrochlorothiazide Hydrop res
Diuretic + diuretic Amiloride, hydrochlorothiazide Moduretic
Spironolactone, hydrochlorothiazide Aldactone
Aminopterin, hydrochlorothiazide Dyazide