First, antihypertensive drugs that mainly affect blood volume.
Diuretics are usually used to treat hypertension. Mild hypertension should be treated alone and often combined with other antihypertensive drugs to treat moderate and severe hypertension. It is generally believed that the initial hypotensive mechanism of diuretics is sodium excretion and diuresis, which leads to the negative balance between Na+ and water in the body and reduces the extracellular fluid and blood volume. After long-term use of diuretics, when blood volume and cardiac output have gradually returned to normal, blood pressure can still continue to decrease. The possible mechanisms are as follows: ① Na+ content in arterial wall cells decreases due to sodium excretion, and intracellular Ca2+ content decreases through Na+-Ca2+ exchange mechanism. ② Decrease the reactivity of vascular smooth muscle to vasoconstrictors such as norepinephrine. ③ substances that induce arterial wall to produce vasodilation, such as kinin and prostaglandin.
Intake of a large amount of NaCl can antagonize the hypotensive effect of diuretics, while restriction of NaCl intake can enhance its hypotensive effect, indicating that Na+ excretion is an important reason for the hypotensive effect of diuretics.
The clinical treatment of hypertension is mainly thiazide diuretics, but long-term application often leads to adverse reactions, such as the decrease of blood potassium, sodium and magnesium, the increase of blood total cholesterol, triglyceride and low density lipoprotein cholesterol, and the increase of uric acid and plasma renin activity. High-dose thiazide diuretics can also aggravate hyperlipidemia and reduce glucose tolerance. However, the use of low-dose hydrochlorothiazide can avoid metabolic side effects, and others such as furosemide and triamterene can also be used.
Generally speaking, high-efficiency diuretics are not used as first-line drugs for mild hypertension, but for patients with hypertensive crisis and hypertension complicated with chronic renal failure, because they do not reduce renal blood flow and have strong Na+ benefits.
Second, beta blockers.
Beta blockers have a good antihypertensive effect. Now take propranolol as an example, as follows:
After several days of "antihypertensive effect" of propranolol, the systolic blood pressure can be reduced by 65,438+05% ~ 20%, and the diastolic blood pressure can be reduced by 65,438+00% ~ 65,438+05%. The antihypertensive effect of diuretics combined with drugs is more significant. Intravenous propranolol can slow down the heart rate and decrease the cardiac output, but the blood pressure only slightly decreases or does not decrease, which is the result of the increase of peripheral resistance caused by baroreceptor reflex.
After a few people use beta blockers, the total peripheral resistance increases, presumably activating the alpha receptor of blood vessels, so this drug is prohibited for those with peripheral vascular diseases.
The "mechanism" of propranolol in lowering blood pressure is secondary to its β receptor blocking effect, and there are several views on its further mechanism.
1. Reduce cardiac output Propranolol blocks cardiac β 1 receptor, inhibits myocardial contractility, slows down heart rate, thereby reducing cardiac output and lowering blood pressure. After administration, this effect appears rapidly, but the hypotensive effect appears slowly.
2. Inhibition of Renin Secretion Renal sympathetic nerve promotes the secretion and release of Renin in neighboring organs through β 1 receptor, and propranolol can inhibit it, thus lowering blood pressure. Indolol has a strong endogenous activity, which does not affect the plasma renin activity when lowering blood pressure.
3. Reducing peripheral sympathetic nerve activity Propranolol can also block some β2 receptors in the presynaptic membrane of norepinephrine-dominated blood vessels, inhibit their positive feedback and reduce the release of norepinephrine.
4. Central antihypertensive effect It is known that there are β receptors in hypothalamus and medulla oblongata. A small amount of propranolol central administration can lower blood pressure, but the same amount of intravenous injection is ineffective. Contrary to the evidence, beta blockers that cannot enter the central nervous system have antihypertensive effects. Therefore, the significance of central β receptor in blood pressure regulation remains to be clarified.
The mechanism of action of β -blockers is complex. One mechanism may play a leading role in the development of one disease, while the other plays a leading role in the process of another disease.
"Clinical Application" Beta blockers have been widely used in the treatment of hypertension, which is effective for mild to moderate hypertension and can also reduce the attack of hypertension with angina pectoris. In addition, for patients with high cardiac output and renin activity, the curative effect is also good for patients with cerebrovascular diseases. The dosage of propranolol varies from person to person. Generally, it is advisable to start with a small dosage and gradually increase it later, but the daily dosage should not exceed 300mg. Among β-blockers, metoprolol and atenolol, which are selective β 1 blockers, are more effective than propranolol. At low dose, it mainly acts on the heart, but has little effect on the bronchus, so it is relatively safe for patients with obstructive pulmonary disease.
Third, calcium antagonists.
Calcium antagonists can inhibit the influx of extracellular Ca2+, relax smooth muscle, relax blood vessels and lower blood pressure. Lowering blood pressure does not reduce the blood flow of important organs, and does not cause changes in lipid metabolism and glucose tolerance.
nifedipine
Nifedipine has antihypertensive effect on patients with mild, moderate and severe hypertension, but has no antihypertensive effect on those with normal blood pressure. Take it orally for 30-60 minutes for 3 hours, and the t 1/2 is about 3-4 hours. In vitro vascular experiments, it can obviously inhibit the contraction response caused by high potassium depolarization, but it has a weak inhibitory effect on the contraction response caused by norepinephrine, but it has a significant inhibitory effect on the contraction response caused by norepinephrine in vascular samples of spontaneously hypertensive rats, which seems to explain why nifedipine has no antihypertensive effect on normotensive people. In addition, it can also inhibit the renal vascular contraction caused by endothelin.
When nifedipine lowers blood pressure, with the increase of reflex heart rate and cardiac output, plasma renin activity also increases. Combined with beta blockers, this reaction can be avoided and its antihypertensive effect can be increased.
Clinically, it can be used to treat mild, moderate and severe hypertension, and can be used alone or in combination with diuretics and beta blockers.
Common adverse reactions include headache, facial flushing, dizziness, palpitation and ankle edema. The edema of ankle caused by it is caused by the dilation of anterior capillaries rather than the retention of water and sodium.
Similar drugs, such as verapamil, diltiazem, nitrendipine and nimodipine, have also been used to treat hypertension and achieved good results. Among them, calcium antagonists have diuretic effect, which can inhibit the reabsorption of Na+ by renal tubular cells, selectively dilate renal afferent arterioles and increase glomerular filtration rate.
Tetrandrine powder
Tetrandrine is an alkaloid contained in the root of tetrandrine. Tetrandrine has obvious antihypertensive effect on spontaneously hypertensive rats and hypertensive patients, which is caused by its calcium antagonism. It has been proved that tetrandrine can inhibit T and L-type calcium channels. Generally oral administration, patients with severe hypertension and hypertensive crisis can be injected intravenously.
The drug has no serious adverse reactions, and a few patients have mild nausea and epigastric discomfort.
4. An antihypertensive drug that affects the formation of angiotensin II-angiotensin I converting enzyme inhibitors.
Renin-angiotensin-aldosterone system (RAAS) plays an important role in blood pressure regulation and hypertension.
In recent years, a series of angiotensin converting enzyme inhibitors (ACEI) have been synthesized, such as captopril, enalapril, ramipril, lisinopril and perindopril. They can effectively lower blood pressure, and also have a good effect on cardiac insufficiency and ischemic heart disease.
Modern molecular biology research has proved that there are mRNA of renin and angiotensinogen in cardiovascular, brain, kidney and other tissues, and related genes are expressed locally. Therefore, it is suggested that there is an independent RAAS (local synthesis) in tissues, which regulates cardiovascular and nervous system functions and even structures in a paracrine and autocrine way. Angiotensin Ⅱ (AT Ⅱ) produced locally in blood vessels can increase the contractility of blood vessels, promote the release of norepinephrine, lead to vasoconstriction and increase blood pressure. Experiments show that ATⅱ can promote the growth and proliferation of cultured vascular smooth muscle cells, and increase protein synthesis and cell volume.
The role of AT ⅱ in promoting the growth of vascular smooth muscle can cause vascular proliferation and vascular wall thickening.
"Pharmacological Action and Mechanism" ACEI can relax blood vessels and lower blood pressure, and its mechanism is as follows:
1. Restrict RAAS in a loop
ACEI mainly plays a role by inhibiting the formation of angiotensin ⅱ, which has a direct impact on blood vessels and kidneys. And it has an indirect effect by sensing the secretion of nervous system and aldosterone. This is the main factor to change hemodynamics, and it is also the reason for the decrease of peripheral vascular resistance in the early stage of medication.
2. Inhibition of RAAS in local tissues
Tissue RAAS plays an important role in the stability of cardiovascular system. Angiotensin I converting enzyme (ACE) in tissues has a long-lasting binding effect with drugs, so inhibiting ACE for a longer time can reduce the release of norepinephrine and the effect of sympathetic nerve on cardiovascular system, which is helpful to lower blood pressure and improve heart function. This is related to the long-term antihypertensive effect of drugs. The combination mode of drugs and ACE is shown in Figure 26- 1. Taking captopril as an example, three groups of captopril can bind to three active sites of the enzyme. Firstly, the carboxyl group of proline is bound to the positive charge site (arginine) of the enzyme by ionic bond. Secondly, the carbonyl group of the peptide chain is hydrogen bonded to the hydrogen donor site of the enzyme; Thirdly, sulfhydryl groups combine with Zn2+ of the enzyme, which finally makes the enzyme lose its activity.
3. Reduce the degradation of bradykinin When ACE (that is, kallikrein II) is inhibited by drugs, the degradation of bradykinin (BK) in tissues decreases and the concentration of BK in local blood vessels increases. BK is an important activator of vascular endothelial L- arginine -NO pathway, which acts on endothelial β2 receptor, causing the release of EDHF (vascular endothelial hyperpolarization factor) and NO, thus playing a powerful role in dilating blood vessels and inhibiting platelet function. In addition, BK can also stimulate cell membrane phospholipids to release arachidonic acid (AA), promote prostaglandin synthesis and increase vasodilation, as shown in Figure 26-2.
Compared with other antihypertensive drugs, ACEI has the following characteristics:
1. Suitable for all types of hypertension. While lowering blood pressure, it is not accompanied by reflex heart rate increase, which may be due to the cancellation of AT ⅱ' s facilitation of sympathetic nerve transmission
2. Long-term application is not easy to cause electrolyte disorder and lipid metabolism disorder, and can reduce the possibility of glomerular damage in patients with renal parenchymal damage such as diabetes and nephropathy. For example, captopril can not only effectively lower blood pressure, but also increase the body's sensitivity to insulin.
3. It can prevent and reverse vascular wall thickening and myocardial cell hypertrophy in patients with hypertension, and can play a direct and indirect role in heart protection.
4. It can improve the quality of life of patients with hypertension and reduce the mortality rate.
See "in vivo process" in table 26- 1
Table 26- 1
Parameter captopril enalapril
Precursor? Yes
Active metabolite/enalapril
Bioavailability (%)
Plasma protein binding rate (%) 30 50
T 1/2 (high) 2 30
Maintenance time (h) 3 ~ 4 12 ~ 24
Elimination pathway kidney kidney
12.5-50mg
The dosage is 2 ~ 3 times/day 1 ~ 2 times/day.
"Clinical application" can reduce blood pressure 15% ~ 25% in the treatment of primary and renal hypertension, and the combination of moderate and severe hypertension and diuretics can strengthen the antihypertensive effect and reduce adverse reactions.
Although the incidence of adverse reactions is low, it is not absolutely safe. The main adverse reaction was hypotension (2%). When the initial dose is too large, a small dose should be tried. Hyperkalemia and angioneurotic edema. Patients with impaired renal function, especially renal vascular stenosis. Cough is an irritating dry cough, which may be related to the accumulation of kinin and prostaglandin in pulmonary vascular bed. Long-term use can reduce blood zinc and cause rash, taste, olfactory defect, hair loss and so on. Supplementing Zn2+ is expected to overcome it.
Drug interaction combined with diuretics can enhance the antihypertensive effect and reduce the excretion of Zn2+. Indomethacin can weaken the antihypertensive effect of captopril, which is related to the inhibition of prostaglandin synthesis by indomethacin. Combined with digoxin, the plasma concentration of digoxin can be increased.
V. Sympathetic nerve inhibitors
(1) antihypertensive drugs mainly acting on the central part.
clonidine
Clonidine is a derivative of imidazole.
Pharmacological effect: After intravenous injection of clonidine in anesthetized animals, blood pressure first increased briefly, and then decreased continuously, accompanied by slow heart rate and decreased cardiac output. The pressor effect is caused by clonidine activating peripheral vascular α receptor, and the subsequent hypotensive effect is related to central function. Oral administration can only reduce blood pressure but not increase blood pressure. After continuous administration, peripheral vascular resistance and renal vascular resistance gradually decreased, but did not significantly affect renal blood flow and glomerular filtration rate.
Clonidine has moderate to strong antihypertensive effect. It can also inhibit the secretion and movement of gastrointestinal tract, so it is suitable for patients with hypertension and ulcer.
Clonidine also has a sedative effect on the central nervous system, reducing spontaneous activity and significantly prolonging the hypnotic time of barbiturates.
The animal experiment of "mechanism of action" shows that a small amount of clonidine injected into vertebral artery or cerebellomedullary cistern can cause hypotension, but the same amount of intravenous injection will not, so it is speculated that the part that causes hypotension is in the center. It is suggested that clonidine acts on the medulla oblongata, reducing the function of peripheral sympathetic nerve, thus lowering blood pressure. Recently, it has been confirmed that the mechanism of clonidine-induced blood pressure drop is to stimulate I1-imidazoline receptor at the ventrolateral medulla, and reduce the blood pressure drop caused by peripheral sympathetic nerve tension. The α2 receptor in its excitation center is the cause of its side effects such as sedation.
In addition, an endogenous clonidine-like substance was extracted from animal brain, which acted on the ventrolateral medulla oblongata and played a clonidine-like role. Other studies have proved that the antihypertensive effect of clonidine involves the release of endogenous opioid peptides. Clonidine has analgesic effect and can be antagonized by opioid antagonist-naloxone. Clonidine also excites α2 receptor of peripheral sympathetic presynaptic membrane and its adjacent imidazoline receptor, causing negative feedback and reducing the release of norepinephrine. It can be seen that its antihypertensive mechanism is complex.
Clonidine is well absorbed orally and its bioavailability is about 75%. It takes effect half an hour after oral administration, peaks in 2-4 hours and lasts for 6-8 hours. It is evenly distributed in the body and easily penetrates the blood-brain barrier. T 1/2 is 7.4 ~ 13 hours. About 50% is metabolized in the liver, which leads to the breakage of imidazole ring and hydroxylation of benzene ring in the structure. The rest is excreted with urine in its original form.
"Clinical application" clonidine can treat moderate hypertension, which is often used when other drugs are ineffective. In addition, it can also be used as a morphine analgesic drug for addicts.
The common adverse reaction of "adverse reaction" is dry mouth, which is caused by its action on α2 receptor on cholinergic nerve endings, reducing the release of Ach and excessive saliva secretion. Water and sodium retention after long-term use is the result of decreased glomerular filtration rate after blood pressure reduction. Combined diuretics can be overcome. In addition, there are sedation, lethargy, headache, constipation, parotid pain, impotence and so on. It can disappear automatically after stopping the drug, and a few patients may have short-term sympathetic hyperfunction after stopping the drug suddenly. Such as palpitation, sweating, sudden increase in blood pressure, etc. It may be due to the decreased sensitivity of α2 receptor in presynaptic membrane, weakened negative feedback and excessive release of norepinephrine after long-term use. α receptor blocker clonidine or phentolamine can cancel it.
α methyldopa
The antihypertensive effect of methyldopa is similar to that of clonidine, and it is moderately strong. Hypotension is accompanied by a decrease in heart rate, cardiac output and peripheral vascular resistance. Treating moderate hypertension, suitable for hypertensive patients with renal insufficiency.
(2) Anti-noradrenergic nerve endings
Reserpine is an alkaloid contained in Rauvolfia in India, and the preparation of total alkaloids contained in Rauvolfia in China is called hypotensive tablet. The drug has weak antihypertensive effect and many adverse reactions, so it is rarely used now. Guanethidine, which has a strong effect, is rarely used because there are many adverse reactions.
(3) Adrenaline receptor blockers
Alpha receptor blocker
Prazosin
Prazosin is a synthetic quinazoline derivative.
"Pharmacological Action" prazosin can selectively block the α 1 receptor of postsynaptic membrane, and can competitively antagonize the vasoconstrictive and hypertensive effects of the agonist phenylephrine. It can relax veins and arterioles and exert moderate and strong antihypertensive effect. Different from phentolamine, it does not increase heart rate, contractility and plasma renin activity, but also increases the concentration of high density lipoprotein (HDL) in blood and reduces coronary artery disease.
The drug is easy to be absorbed by oral administration, and the blood concentration reaches the peak within 2 hours, the bioavailability is 60%, and the t 1/2 is 2.5 ~ 4 hours. However, the antihypertensive effect of oral administration can last 10 hour, and the binding rate with plasma protein is 97%, which is widely metabolized in the liver and obviously eliminated after the first pass.
"Clinical application and adverse reactions" are applicable to all types of hypertension. Single use can treat mild to moderate hypertension, and combined use of beta blockers and diuretics can enhance the antihypertensive effect in the treatment of severe hypertension.
Adverse reactions include dizziness, fatigue and weakness. The first dose can cause severe postural hypotension, syncope and palpitation. This is called the "first dose phenomenon" and it is more likely to occur in upright posture, hunger and low salt. Reduce the first dose to 0.5mg, and take it before going to bed to avoid it.
Ketoselin, another α 1 receptor blocker, not only has anti-serotonin S 1 receptor effect, but also can effectively treat hypertension.
α, β receptor blocker
Labelle
Labetalol has competitive antagonistic effects on both α and β receptors, among which blocking β 1 and β2 receptors is similar, but its effect on α 1 receptor is weak, but it is ineffective on α2 receptor, so negative feedback regulation still exists, and it does not cause heart rate to increase after medication.
The drug has mild antihypertensive effect, is suitable for treating all kinds of hypertension, has no serious adverse reactions, and is beneficial to reducing myocardial wall tension in the early stage of infarction. Intravenous injection can treat hypertensive crisis.
6. Antihypertensive drugs acting on vascular smooth muscle
Hydralazine is a hypotensive drug that directly acts on vascular smooth muscle, which can directly relax vascular smooth muscle, reduce peripheral resistance and correct hemodynamic abnormalities caused by high blood pressure. Unlike other antihypertensive drugs, these drugs do not inhibit sympathetic nerve activity and do not cause orthostatic hypotension and impotence. After long-term use, neuroendocrine and autonomic reflex can counteract the antihypertensive effect of drugs (Figure 26-3). As can be seen from the figure, the most important reflex changes are as follows: ① Sympathetic nerve activation can offset the hypotensive effect by increasing cardiac output and heart rate, and can increase myocardial oxygen consumption, which is easy to induce angina pectoris for those with severe coronary insufficiency or poor cardiac reserve. ② Enhance plasma renin activity. Reninemia can enhance sympathetic nerve activity, leading to the increase of circulating angiotensin and blood pressure. The above shortcomings must be corrected by combining diuretics and beta blockers.
Vasodilators acting directly on vascular smooth muscle may act on different parts of the excitation-contraction coupling process of vascular smooth muscle cells, so that the influx of Ca2+ and the release of Ca2+ stored in cells are exhausted, and the interaction between intracellular free Ca2+ and smooth muscle contraction protein is reduced. It is known that some vasodilators can increase the cGMP concentration of vascular smooth muscle, while others can hyperpolarize the cell membrane by opening potassium channels.
hydrazine
Hydralazine is an effective oral antihypertensive drug to dilate arterioles, and its dilating effect on kidneys, coronary arteries and visceral vessels is greater than that on skeletal muscle vessels. Suitable for moderate hypertension, often combined with other antihypertensive drugs.
Oral absorption is good, about 65% ~ 90%, and the effect reaches the peak after 1 hour, which lasts for about 6 hours. Its adverse reactions include headache, nasal congestion, palpitation and diarrhea. In severe cases, it is manifested as myocardial ischemia and heart failure. Large dose can cause systemic lupus erythematosus-like syndrome, the dose is 400mg/ day, or above, and its incidence rate can reach 10% ~ 20%, which is obviously dose-related. When the dose is reduced to 200mg/ day, the above reaction is rare. This book is rarely used alone.
minoxidil
Minoxidil is a powerful vasodilator, which is completely absorbed by oral administration and can be stored in arteriole smooth muscle for a long time. Its adverse reactions include water and sodium retention, palpitation and hirsutism, and the promotion of hair growth may be related to the increase of blood flow in skin and hair follicles. Recently, it has been confirmed that this drug activates a special gene that regulates hair dry protein and promotes the growth and maturity of hair dry, so it can be used as a drug to treat hair loss.
Diazoxazine
Diazoxazine (chlorobenzothiazine) directly relaxes vascular smooth muscle and lowers blood pressure. Like minoxidil, its hypotensive mechanism is partly through activating IK (ATP)-mediated potassium channels in smooth muscle cells, promoting potassium outflow, hyperpolarizing cell membranes, inactivating Ca2+ channels and reducing Ca2+ influx.
It is mainly used for intravenous injection of hypertensive crisis and hypertensive encephalopathy in clinic. No long-term medication. So there are few adverse reactions. If it is used continuously for several days, the blood sugar level should be tested. The drug can cause hyperglycemia, which is caused by activating IK(ATP) of islet β cell membrane and reducing insulin release.
Potassium channel openers pinacidil and Macarin are a new class of antihypertensive drugs, which activate IK(ATP) in vascular smooth muscle cell membrane and play a role in lowering blood pressure.
Sodium nitroprusside
Sodium nitroprusside, also known as sodium nitroprusside (Na2Fe (CN) 6NO 2H2O), is a nitrovasodilator, which is not absorbed by oral administration and needs intravenous administration. It takes about 1 minute to take effect quickly, and the blood pressure rises within 5 minutes after stopping the drug. Its mechanism of action is similar to nitrate, which can increase cGMP level in vascular smooth muscle cells and dilate blood vessels.
It is used for hypertensive crisis, especially for severe hypertensive patients with acute myocardial infarction or left heart failure. The treatment of hypertensive crisis is generally 3μg/kg/ min, and the blood pressure is maintained at the required level by adjusting the dripping speed.
Because the medicine can dilate arteries and veins, reduce the load before and after and improve heart function, it is used for refractory heart failure.
Drugs are easily destroyed when exposed to light, so the drops should be freshly prepared and protected from light.
Adverse reactions include vomiting, sweating, headache and palpitation, all of which are caused by excessive hypotension. This medicine is more toxic than you. CN- produced in the body is converted into SCN- in the liver, which is basically non-toxic and excreted by the kidney. However, after several days of use, SCN- accumulates in the body, and when its concentration exceeds 20mg/ 100ml, it can cause poisoning, so it is appropriate to monitor the concentration of SCN-.