Drugs used to treat arterial hypertension

If systolic BP remains above 140 mmHg or diastolic BP above 90 mmHg 6 months after lifestyle changes, treatment of hypertension involves the use of antihypertensive drugs. The use of drugs in parallel with lifestyle changes is indicated for all patients with prehypertension or with a combination of arterial hypertension with diabetes, kidney disease, target organ damage or cardiovascular risk factors, as well as for those patients whose BP figures are > 160/100 mmHg. Signs of a hypertensive crisis require immediate reduction in BP using parenteral diuretics.

Most patients with arterial hypertension are prescribed one drug (usually a thiazide diuretic) at the beginning of treatment. Depending on the patient's characteristics and the presence of concomitant pathology, drugs from other groups can be prescribed at the beginning of treatment or added to the diuretic. Low doses of acetylsalicylic acid (81 mg once a day) have been proven to reduce the risk of developing cardiac pathology in patients with arterial hypertension and are recommended if well tolerated and there are no contraindications ¹.

Some blood pressure pills are contraindicated in certain conditions (e.g., alpha-blockers for asthma) or are prescribed for a specific condition (e.g., beta-blockers or calcium channel blockers for angina, ACE inhibitors for diabetes or proteinuria). When using a single drug, black men respond better to calcium channel blockers (e.g., diltiazem). Thiazide diuretics have a better effect in people over 60 and in African Americans.

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Selection of groups of antihypertensive drugs

Medicine	Indications
Diuretics*	Old age. Negroid race. Heart failure. Obesity
Long-acting calcium channel blockers	Old age. Negroid race. Angina pectoris. Arrhythmias (eg, atrial fibrillation, paroxysmal supraventricular tachycardia). Isolated systolic hypertension in the elderly (dihydropyridines)*. High risk of PVA (non-dihydropyridines)*
ACE inhibitors	Young age. Caucasian race. Left ventricular failure due to systolic dysfunction*. Type 1 diabetes mellitus with nephropathy*. Severe proteinuria due to chronic kidney disease or diabetic glomerulosclerosis. Impotence when taking other drugs
Angiotensin II receptor blockers	Young age. Caucasian race. Conditions in which ACE inhibitors are indicated but patients cannot tolerate them due to cough. Type 2 diabetes mellitus with nephropathy
B-blockers*	Young age. Caucasian race. Angina pectoris. Atrial fibrillation (to control ventricular rate). Essential tremor. Hyperkinetic type of blood circulation. Migraine. Paroxysmal supraventricular tachycardia. Patients after MI (cardioprotective effect)*

¹ This view of the treatment of arterial hypertension is at odds with modern concepts. For example, taking thiazide diuretics increases the risk of diabetes mellitus in patients with hypertension.

*Reduce morbidity and mortality, according to randomized trials. Contraindicated in pregnancy. ⁺ b-Adrenergic blockers without intrinsic sympathomimetic activity.

If the initial drug is ineffective or poorly tolerated due to side effects, another drug may be prescribed. If the initial drug is partially effective and well tolerated, the dose may be increased or a second drug with a different mechanism of action may be added.

If the initial BP is > 160 mmHg, a second drug is most often prescribed. The most effective combinations are a diuretic with a beta-blocker, ACE inhibitor, or angiotensin II receptor blocker, and a combination of a calcium channel blocker with an ACE inhibitor. The necessary combinations and doses have been determined; many of them are available in a single tablet, which improves pharmacodynamics. In severe refractory hypertension, three or four drugs may be required.

Antihypertensive agents for high-risk patients

Concomitant disease	Class of drugs
Heart failure	ACE inhibitors. Angiotensin II receptor blockers. Beta-blockers. Potassium-sparing diuretics. Other diuretics
Post-MI	Beta-blockers. ACE inhibitors. Potassium-sparing diuretics
Risk factors for cardiovascular disease	Beta-blockers. ACE inhibitors. Calcium channel blockers
Diabetes mellitus	Beta-blockers. ACE inhibitors. Angiotensin II receptor blockers. Calcium channel blockers.
Chronic kidney disease	ACE inhibitors. Angiotensin II receptor blockers
Risk of recurrent stroke	ACE inhibitors. Diuretics

Achieving adequate control often requires increasing or changing drug therapy. Drugs must be titrated or added until the desired BP is achieved. Success in achieving patient adherence, especially since lifelong medication is required, directly impacts BP control. Education, empathy, and support are important in achieving success.

Combinations of drugs used to treat arterial hypertension

Class	Medicine	Acceptable doses, mg
Diuretic/diuretic	Triamterene/hydrochlorothiazide	37.5/25, 50/25, 75/50
	Spironolactone/hydrochlorothiazide	25/25, 50/50
	Amiloride/hydrochlorothiazide	5/50
Beta blocker	Propranolol/hydrochlorothiazide	40/25, 80/25
	Metoprolol/hydrochlorothiazide	50/25,100/25
	Atenolol/chlorthalidone	50/25,100/25
	Nadolol/bendroflumethiazide	40/5, 80/5
	Timolol/hydrochlorothiazide	10/25
	Extended-release propranolol/hydrochlorothiazide	80/50,120/50,160/50
	Bisoprolol/hydrochlorothiazide	2.5/6.25,5/6.25,10/6.25
Beta blocker	Guanethidine/hydrochlorothiazide	10/25
	Methyldopa/hydrochlorothiazide	250/15, 250/25, 500/30, 500/50
	Methyldopa/chlorothiazide	250/150,250/250
	Reserpine/chlorothiazide	0.125/250,0.25/500
	Reserpine/chlorthalidone	0.125/25,0.25/50
	Reserpine/hydrochlorothiazide	0.125/25,0.125/50
	Clonidine/chlorthalidone	0.1/15,0.2/15,0.3/15
ACE inhibitor	Captopril/hydrochlorothiazide	25/15,25/25,50/15,50/25
	Enalapril/hydrochlorothiazide	5/12,5,10/25
	Lisinopril/hydrochlorothiazide	10/12.5,20/12.5,20/25
	Fosinopril/hydrochlorothiazide	10/12.5,20/12.5
	Quinapril/hydrochlorothiazide	10/12.5,20/12.5,20/25
	Benazepril/hydrochlorothiazide	5/6,25,10/12,5,20/12,5,20/25
	Moexipril/hydrochlorothiazide	7.5/12.5,15/25
Angiotensin II receptor blocker	Losartan/hydrochlorothiazide	50/12,5,100/25
	Valsartan/hydrochlorothiazide	80/12.5,160/12.5
	And besartan/hydrochlorothiazide	75/12.5,150/12.5,300/12.5
	Candesartan/hydrochlorothiazide	16/12.5,32/12.5
	Telmisartan/hydrochlorothiazide	40/12.5,80/12.5
Calcium channel blocker/ACE inhibitor	Amlodipine/benazepril	2.5/10.5/10.5/20.10/20
	Verapamil (long acting)/trandolapril	180/2,240/1,240/2,240/4
	Felodipine (long acting)/enalapril	5/5
Vasodilator	Hydralazine/hydrochlorothiazide	25/25,50/25,100/25
	Prazosin/polythiazide	1/0.5, 2/0.5, 5/0.5
Triple combination	Reserpine/hydralazine/hydrochlorothiazide	0.10/25/15

Diuretics

Oral diuretics used in the treatment of arterial hypertension

Thiazide diuretics	Average dose*, mg	Side effects
Bendroflumethiazide	2.5-5.1 times a day (maximum 20 mg)	Hypokalemia (increasing cardiac glycoside toxicity), hyperuricemia, impaired glucose tolerance, hypercholesterolemia, hypertriglyceridemia, hypercalcemia, male sexual dysfunction, weakness, rash; serum lithium may increase
Chlorothiazide	62.5-500.2 times a day (maximum 1000)
Chlorthalidone	12.5-50.1 times a day
Hydrochlorothiazide	12.5-50.1 times a day
Hydroflumethiazide	12.5-50.1 times a day
Indapamide	1.25-5.1 times a day
Methyclothiazide	2.5-5.1 times a day
Metolazone (rapid release)	0.5-1.1 times a day
Metolazone (slow release)	2.5-5.1 times a day

Potassium-sparing diuretics

Amiloride	5-20.1 times a day	Hyperkalemia (especially in patients with renal failure and those treated with ACE inhibitors, angiotensin II receptor blockers or NSAIDs), nausea, gastrointestinal disorders, gynecomastia, menstrual dysfunction (spironolactone), possible increase in serum lithium levels
Eplerenone**	25-100,1 times a day
Spironolactone**	25-100,1 times a day
Triamterene	25-100,1 times a day

"Higher doses may be required in patients with renal insufficiency."*Aldosterone receptor blockers.

Thiazides are the most commonly used. In addition to other hypotensive effects, they produce vasodilation as long as the blood volume is normal. In equivalent doses, all thiazide diuretics are equally effective.

All diuretics, except for potassium-sparing loop diuretics, cause significant potassium loss, so its serum level should be monitored monthly until stabilization. Until the potassium concentration has normalized, the potassium channels in the arterial wall are closed; this leads to vasoconstriction, which complicates the achievement of an effect in the treatment of arterial hypertension. Patients with potassium levels < 3.5 mmol/l require additional potassium supplements. They can be prescribed for a long time in small doses; potassium-sparing diuretics can also be added (e.g., spironolactone at a daily dose of 25-100 mg, triamterene at 50-150 mg, amiloride at 5-10 mg). Additional potassium supplementation or potassium-sparing diuretics is also recommended for patients receiving cardiac glycosides who have proven heart disease, electrocardiogram changes, rhythm disturbances, and for patients who have developed extrasystoles or arrhythmias after diuretic use. Although potassium-sparing diuretics do not cause hypokalemia, hyperuricemia, or hyperglycemia, they are less effective than thiazides in controlling hypertension and are not used for initial therapy. Potassium-sparing diuretics and potassium supplementation are not needed when ACE inhibitors or angiotensin II receptor blockers are prescribed, since these drugs increase serum potassium levels.

In most patients with diabetes, thiazide diuretics do not interfere with control of the underlying disease. Rarely, diuretics provoke worsening of type 2 diabetes in patients with metabolic syndrome.

Thiazide diuretics may slightly increase serum cholesterol (primarily low-density lipoprotein) and triglyceride levels, but this effect is not present for more than 1 year. Subsequently, the numbers may increase only in some patients. An increase in these indicators appears 4 weeks after the start of treatment, and they may normalize with a low-fat diet. The likelihood of a slight increase in lipids is not considered a contraindication to prescribing diuretics to patients with dyslipidemia.

Hereditary predisposition probably explains some cases of gout development in diuretic-induced hyperuricemia. Diuretic-induced hyperuricemia without gout development is not considered an indication for discontinuing treatment or stopping the diuretic.

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Beta-blockers

These drugs slow the heart rate and reduce myocardial contractility, thus lowering blood pressure. All b-blockers are similar in their hypotensive effect. In patients with diabetes, chronic peripheral vascular disease or COPD, cardioselective b-blockers (acebutolol, atenolol, betaxolol, bisoprolol, metoprolol) can be preferred, although cardioselectivity is relative and decreases with increasing drug doses. Even cardioselective b-blockers are contraindicated in bronchial asthma or COPD with a pronounced bronchospastic component.

B-blockers prescribed for arterial hypertension

Preparation	Daily dose, mg	Possible side effects	Comments
Acebutolol*	200-800, 1 time per day	Bronchospasm, weakness, insomnia, sexual dysfunction, increased heart failure, masking the manifestations of hypoglycemia, triglyceridemia, increased total cholesterol and decreased high-density lipoproteins (except pindolol, acebutolol, penbutolol, carteolol and labetalol)	Contraindicated in patients with bronchial asthma, atrioventricular block above grade I or sick sinus syndrome. Prescribed with caution to patients with heart failure or insulin-dependent diabetes mellitus. Cannot be discontinued abruptly in patients with coronary artery disease, carvedilol is indicated for heart failure
Atenolol*	25-100, 1 time per day
Betaxolol*	5-20, 1 time per day
Bisoprolol*	2.5-20, 1 time per day
Carteolol	2.5-10, 1 time per day
Carvedilol**	6.25-25, 2 times a day
Labetalol**	100-900, 2 times a day
Metoprolol*	25-150, 2 times a day
Metoprolol slow release	50-400, 1 time per day
Nadolol	40-320, 1 time per day
Penbutolol	10-20, 1 time per day
Pindolol	5-30, 2 times a day
Propranolol	20-160, 2 times a day
Propranolol long acting	60-320, 1 time per day
Timolol	10-30, 2 times a day

*Cardioselective. **alpha-beta blocker. Labetalol can be administered intravenously in hypertensive crises. Intravenous administration begins with a dose of 20 mg and, if necessary, increases to a maximum dose of 300 mg. With internal sympathomimetic activity.

B-Adrenergic blockers are especially justified when prescribed to patients with concomitant angina, who have had a myocardial infarction or have heart failure. These drugs are currently recommended for use in the elderly.

B-blockers with intrinsic sympathomimetic activity (such as pindolol) do not have side effects on blood lipids and are less likely to develop severe bradycardia.

B-blockers are characterized by the appearance of CNS disorders as side effects (sleep disorders, weakness, lethargy) and the development of depression. Nadolol has the least effect on the CNS and is the best drug in terms of preventing such side effects. B-blockers are contraindicated in II and III degrees of atrioventricular block, bronchial asthma and sick sinus syndrome.

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Calcium channel blockers

Dihydropyridine drugs are potent peripheral vasodilators and reduce blood pressure by decreasing total peripheral vascular resistance; they sometimes cause reflex tachycardia. Non-dihydropyridine drugs (verapamil and diltiazem) decrease heart rate, inhibit atrioventricular conduction, and reduce contractility; these drugs should not be administered to patients with grades II and III atrioventricular block or left ventricular failure.

Calcium channel blockers used to treat hypertension

Benzothiazepine derivatives

Diltiazem short acting	60-180.2 times a day	Headache, sweating, asthenia, facial flushing, edema, negative inotropic effect; possible liver dysfunction	Contraindicated in heart failure due to systolic dysfunction, sick sinus syndrome, atrioventricular block of 11 degrees or more
Diltiazem slow release	120-360.1 times a day

Diphenylalkylamine derivatives

Verapamil	40-120, 3 times a day	Same as for benzothiazepine derivatives, plus constipation	Same as for benzothiazepine derivatives
Verapamil extended release	120-480.1 times a day

Dihydropyridines

Amlodipine	2.5-10.1 times a day	Sweating, facial flushing, headache, weakness, nausea, palpitations, swelling of the feet, tachycardia	Contraindicated in heart failure, with the possible exception of amlodipine. Short-acting nifedipine use may be associated with a higher incidence of MI
Felodipine	2.5-20.1 times a day
Isradipine	2.5-10.2 times a day
Nicardipine	20-40.3 times a day
Nicardipine slow release	30-60.2 times a day
Extended-release nifedipine	30-90.1 times a day
Nisoldipine	10-60.1 times a day

Extended-release nifedipine, verapamil, and diltiazem are used in the treatment of hypertension, but short-acting nifedipine and diltiazem are associated with an increased risk of MI and are not recommended.

Calcium channel blockers are preferable to beta-blockers for patients with angina and broncho-obstructive syndrome, coronary spasm and Raynaud's disease.

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Angiotensin converting enzyme inhibitors

Drugs in this group reduce blood pressure by influencing the conversion of angiotensin I to angiotensin II and inhibiting the release of bradykinin, thereby reducing peripheral vascular resistance without the development of reflex tachycardia. These drugs reduce blood pressure in many patients with arterial hypertension by reducing plasma renin activity. Since these drugs have a nephroprotective effect, they are becoming the drugs of choice for diabetes mellitus and are preferable for people of the Negroid race.

The most common side effect is a dry, irritating cough, but the most serious is angioedema. If it develops in the oropharynx, it can be life-threatening. Angioedema is more common in smokers and people of the Negroid race. ACE inhibitors can increase serum creatinine and potassium levels, especially in patients with chronic renal failure and those receiving potassium-sparing diuretics, potassium supplements, and NSAIDs. ACE inhibitors cause erectile dysfunction less often than other antihypertensive drugs. Drugs in this group are contraindicated in pregnancy. In patients with kidney disease, serum potassium and creatinine levels should be monitored at least once every 3 months. Patients with renal impairment (serum creatinine >123.6 μmol/L) receiving ACE inhibitors typically tolerate a 30-35% increase in serum creatinine from baseline. ACE inhibitors may cause acute renal failure in patients who are hypovolemic or have severe heart failure, severe bilateral renal artery stenosis, or severe stenosis of the renal artery to a solitary kidney.

ACE inhibitors

Benazepril	5-40.1 times a day
Captopril	12.5-150.2 times a day
Enalapril	2.5-40.1 times a day
Fosinopril	10-80.1 times a day
Lisinopril	5-40.1 times a day
Moexipril	7.5-60.1 times a day
Hinapril	5-80.1 times a day
Ramipril	1.25-20.1 times a day
Trandolapril	1-4.1 times a day

Side effects of ACE inhibitors

Rash, cough, angioedema, hyperkalemia (especially in patients with renal insufficiency or taking NSAIDs, potassium-sparing diuretics or potassium preparations), taste perversion, reversible acute renal failure if unilateral or bilateral renal artery stenosis leads to renal dysfunction; proteinuria (sometimes when drugs are prescribed in recommended doses), neutropenia (rarely), arterial hypotension at the beginning of treatment (mainly in patients with high plasma renin activity or hypovolemia due to the use of diuretics or other causes).

*All ACE inhibitors and angiotensin II receptor blockers are contraindicated in pregnancy (level of evidence C in the first trimester; level of evidence D in the second and third trimesters).

Thiazide diuretics enhance the hypotensive effect of ACE inhibitors more than other classes of antihypertensive drugs.

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Angiotensin II receptor blockers

Drugs in this group block angiotensin II receptors and thus interact with the renin-angiotensin system.

Angiotensin II receptor blockers

Candesartan	8-32.1 times a day
Eprosartan	400-1200, 1 time per day
Ibesartan	75-300,1 times a day
Losartan	25-100,1 times a day
Olmesartan medoxomil	20-40,1 times a day
Telmisartan	20-80.1 times a day
Valsartan	80-320.1 times a day

Side effects of angiotensin II receptor blockers

Increased sweating, angioedema (very rare), some influence of ACE inhibitors on renal function (except proteinuria and neutropenia), serum potassium levels and blood pressure is theoretically possible

Angiotensin II receptor blockers and ACE inhibitors are equally effective antihypertensive agents. Angiotensin II receptor blockers may have additional effects by blocking tissue ACE. Both classes have similar beneficial effects in patients with left ventricular failure or nephropathy due to type 1 diabetes. Angiotensin II receptor blockers used with ACE inhibitors or beta-blockers reduce the number of hospitalizations in patients with HF. Angiotensin II receptor blockers can be safely used in patients younger than 60 years with serum creatinine < 264.9 μmol/L.

The risk of side effects is low; development of angioedema is possible much less frequently than with the use of ACE inhibitors. Precautions when prescribing angiotensin II receptor blockers to patients with renovascular hypertension, hypovolemia and severe heart failure are the same as for ACE inhibitors. Angiotensin II receptor blockers are contraindicated in pregnancy.

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Drugs that affect adrenergic receptors

This class of drugs includes centrally acting a-agonists, postsynaptic a-blockers, and peripherally acting adrenergic receptor blockers.

A-agonists (such as methyldopa, clonidine, guanabenz, guanfacine) stimulate the a-adrenergic receptors of the brainstem and reduce sympathetic nervous activity, lowering blood pressure. Because they act centrally, they may cause drowsiness, lethargy, and depression to a greater extent than other classes of drugs; they are not widely used today. Clonidine can be given as a patch (transdermally) once a week. This may be useful in patients who are difficult to contact (e.g., patients with dementia).

Post-synaptic alpha-blockers (eg, prazosin, terazosin, doxazosin) are no longer used for the basic treatment of hypertension because experience shows no beneficial effect on mortality. In addition, doxazosin, given alone or with antihypertensive agents other than diuretics, increases the risk of heart failure.

Peripheral adrenergic receptor blockers (eg, reserpine, guanethidine, guanadrel) clear tissue norepinephrine receptors. Reserpine also clears norepinephrine and serotonin from the brain. Guanethidine and guanadrel block sympathetic transmission at the nerve synapse. Guanethidine is generally effective, but its doses are very difficult to titrate, so it is rarely used. Guanadrel is a shorter-acting drug and has some side effects. All drugs in this group are usually not recommended for initial therapy; they are used as a third or fourth drug when needed.

A-Blockers

Doxazosin	1-16.1 times a day	First-dose syncope, orthostatic hypotension, weakness, palpitations, headache	Should be used with caution in the elderly due to orthostatic hypotension. Reduces symptoms of benign prostatic hyperplasia
Prazosin	1-10.2 times a day
Terazosin	1-20.1 times a day

Peripheral adrenergic blockers

Guanadrell sulfate	5-50.2 times a day	Diarrhea, sexual dysfunction, orthostatic hypotension (for guanadrell sulfate and guanethidine), lethargy, nasal congestion, depression, exacerbation of peptic ulcer when taking rauwolfia alkaloids or reserpine	Reserpine is contraindicated in patients with a history of depression. It is prescribed with caution to patients with a history of gastrointestinal ulceration. Guanadrell sulfate and guanethidine are used with caution due to the risk of orthostatic hypotension.
Guanethidine	10-50.1 times a day
Rauwolfia alkaloids	50-100,1 times a day
Reserpine	0.05-0.25.1 times

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Direct vasodilators

These drugs (including minoxidil and hydralazine) act directly on the vessels, independent of the autonomic nervous system. Minoxidil is more effective than hydralazine, but has more side effects, including sodium and water retention, and hypertrichosis, which is especially bothersome to women. Minoxidil should be a reserve drug for severe, treatment-refractory hypertension. Hydralazine is prescribed during pregnancy (including preeclampsia) and as an additional antihypertensive agent. Long-term use of high doses of hydralazine (> 300 mg/day) is associated with the development of drug-induced lupus syndrome, which disappears after discontinuation of the drug.

Direct vasodilators prescribed for arterial hypertension

Preparation	Dose, mg	Possible side effects	Comments
Hydralazine	10-50.4 times a day	Positive antinuclear antibody test, drug-induced lupus (rare at recommended doses) Sodium and water retention, hypertrichosis, the appearance of new or an increase in existing exudates in the pleural cavity and pericardial cavity	Enhancement of the vasodilating effects of other vasodilators Reserve drug for severe refractory arterial hypertension
Minoxidil	1.25-40.2 times a day

"Both drugs can cause headache, tachycardia, fluid retention and provoke angina in patients with coronary artery disease.

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