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Abstract The incidence and prevalence of systemic hypertension are reaching global epidemic proportions. There are a variety of factors contributing to this including patient nonadherence due to complex drug regimens and medication side effects, undertreatment, and treatment resistance. There, thus, remains a need to develop novel agents and approaches to antihypertensive therapy that facilitate attainment of optimal blood pressure levels. This monograph will review a number of new pharmacologic targets and interventions as well as a novel method of drug delivery to patients.
Full text links Read article at publisher's site DOI : References Articles referenced by this article 88 Title not supplied American Heart disease and stroke statistics The burden of adult hypertension in the United States to a rising tide.
Trends in hypertension prevalence, awareness, treatment, and control in older U. Association of hypertension treatment and control with all-cause and cardiovascular disease mortality among US adults with hypertension.
Triple fixed-dose combination therapy: back to the past. Nebivolol: the somewhat-different beta-adrenergic receptor blocker. Realities of newer beta-blockers for the management of hypertension. Evolving mechanisms of action of beta blockers: focus on nebivolol. Show 10 more references 10 of Smart citations by scite. The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
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Joining Europe PMC. Tools Tools overview. ORCID article claiming. Wu , Gary Gerstenblith. The incidence and prevalence of systemic hypertension are reaching global epidemic proportions. There are a variety of factors contributing to this including patient nonadherence due to complex drug regimens and medication side effects, undertreatment, and treatment resistance.
There, thus, remains a need to develop novel agents and approaches to antihypertensive therapy that facilitate attainment of optimal blood pressure levels. This monograph will review a number of new pharmacologic targets and interventions as well as a novel method of drug delivery to patients. Update on newer antihypertensive medicines and interventions. N2 - The incidence and prevalence of systemic hypertension are reaching global epidemic proportions.
AB - The incidence and prevalence of systemic hypertension are reaching global epidemic proportions. When a patient fails a monotherapy for HTN, a combination should merit consideration.
A combination of two antihypertensive medications should be a therapeutic option for patients with stage 2 hypertension. Clinicians should use combinations containing beta-blockers when beta-blockers are indicated in patients with heart failure, tachycardia, or post-MI patients. Combination of thiazide with a potassium-sparing diuretic is as effective as CCB monotherapy in HTN management and showed less incidence of hypokalemia when compared to hydrochlorothiazide monotherapy [19].
The combination of benazepril-amlodipine is superior to benazepril-hydrochlorothiazide combination in decreasing the incidence of cardiovascular events in patients with high risk, and it decreases the progression of nephropathy.
The ACE inhibitor-ARB combination is not recommended; it showed a higher incidence of side effects with no added benefits. When the combination of 2 medications does not achieve the treatment goal, a third agent should be added, which is usually done by adding a third agent of the first line group of medications thiazide-like diuretics, CCB, ACE inhibitors, and ARBs. When the patient fails the three-drug regimen, the clinician should consider treatment for resistant HTN, adding a fourth antihypertensive agent from any of the other classes.
They have been approved to treat peripheral edema associated with congestive heart failure and other noncardiac causes of edema, as in liver and kidney diseases.
Potassium Sparing Diuretics: "Mineralocorticoid receptor antagonists" are not usually used as first-line treatment. Spironolactone and eplerenone are considered good in hypertension treatment when added to other antihypertensive medications in resistant HTN; this group of medication is effective when added to triple hypertension medications regimen but should be used cautiously when added to ACE inhibitors or ARBs due to higher incidence of hyperkalemia.
Spironolactone is superior to doxazosin and bisoprolol in lowering blood pressure when added to first-line antihypertensive agents in treating resistant hypertension. Hydralazine can be added for the treatment of resistant hypertension, either alone or in combination with nitrates, in case of heart failure. Hydralazine is associated with increased sympathetic tone and increases sodium avidity; adding a beta-blocker and loop diuretics helps to decrease these effects.
Clonidine : is a central alpha-2 agonist; it is not first-line therapy but can be used as an additional agent when the patient fails combination therapy. The transdermal form is preferred. Minoxidil is usually an option when the patient fails treatment with hydralazine.
It usually provides good blood pressure control, but it is associated with fluid retention, for which adding a loop diuretic is helpful. It increases the sympathetic tone that may require adding a beta-blocker.
Alpha-blockers should not be used to treat hypertension as a first-line agent because they are not as effective in the prevention of cardiovascular disease compared with other first-line agents. Thiazide and Thiazide like diuretics: mechanism of action for thiazide-type diuretics is not fully understood. Thiazides cause initial volume depletion associated with decreased cardiac output, which recovers within 6 to 8 weeks of starting the treatment in a reverse autoregulation mechanism while the blood pressure remains controlled; thiazide diuretics can acutely activate the renin-angiotensin system and cause systemic vascular resistance, which prevents a good response to the diuretic treatment, this increase in renin-angiotensin activity may resolve with chronic thiazide treatment, the addition of an ACE inhibitor or ARB can enhance the blood pressure control.
Also, the thiazide-type diuretics have a modest vasodilation effect, although the mechanism is still unclear. This effect can cause peripheral vasodilation, which is seen mainly in dihydropyridines, or negative inotropic effect on the heart muscle in non-dihydropyridines, inhibiting the sinoatrial and atrioventricular nodes leading to slow cardiac contractility and conduction.
ACE inhibitors decrease the blood pressure by inhibiting the angiotensin-converting enzyme; this causes a decline in the production of angiotensin II and increases the bradykinin level by inhibiting its degeneration, which leads to vasodilation.
Beta-blockers work by inhibiting the catecholamines from binding to the Beta 1,2, and 3 receptors. Beta-1 receptors are found primarily in the heart muscle, beta-2 receptors are located in the bronchial and peripheral vascular smooth muscles, and beta-3 receptors appear in adipose tissue of the heart. Cardio-selective beta-blockers e.
By inhibiting the catecholamines binding to the beta receptors, the beta-blockers have a negative inotropic effect, which results in vasodilation of coronary and peripheral arteries and decreases the heart rate, which helps to reduce the oxygen consumption. Loop diuretics work by increasing the sodium exertion at the level of the medullary and cortical aspects of the thick ascending limb.
This action causes a decrease in volume, which leads to decreased blood pressure. Potassium Sparing Diuretics: Act on the principal cells in the late distal tubule and the collecting duct; they inhibit the sodium reabsorption at this level in association with decreased excretion of potassium and hydrogen ions.
Spironolactone and eplerenone are considered mineralocorticoid receptor antagonists, and they inhibit the mineralocorticoid receptor. Clonidine : stimulates alpha-2 receptors located in the rostral ventrolateral medulla, which reduces the sympathetic outflow from the central nervous system and decreases plasma norepinephrine levels leading to decreased cardiac output. Minoxidil is an arteriolar vasodilator; it opens the adenosine triphosphate-sensitive potassium channels located in the smooth muscles of the vessels.
Alpha-blockers act by inhibiting alpha-1 receptors, which decrease vascular smooth muscle contractions, leading to vasodilation. Thiazide type diuretics are given only as oral forms, Hydrochlorothiazide is available in Chlorthalidone is available in 25 and 50 mg tablets, but the daily dose can be up to mg daily. Dihydropyridine calcium channel blockers are administered orally. Amlodipine's maximum dose is 10 mg daily.
The IV form is used for tachyarrhythmias, especially atrial fibrillation. Oral verapamil dose can be up to a maximum of mg daily. Beta-blockers are available in oral and IV forms. Hydralazine administration can be oral or intravenous. The maximum hydralazine oral dose is mg daily. Clonidine transdermal form is the preferred method of administration as the oral forms can increase the risk of rebound hypertension. Minoxidil is given orally for hypertension treatment. Alpha-blockers are available only orally for hypertension treatment.
Thiazide and thiazide-like diuretics are associated with multiple side effects. Most of these side effects are directly related to the diuretic dose; hypokalemia and hyponatremia are the most common metabolic effects, followed by hyperuricemia, hypomagnesemia, hyperlipidemia, and increased glucose levels.
Chlorthalidone was found in a study to have an increased risk of hospitalization due to severe hypokalemia in the elderly. Other non-dose-related side effects are sexual dysfunction and sleep disturbance.
The treatment with dihydropyridine CCBs is often associated with peripheral edema. Long-acting nifedipine is associated with a higher incidence of edema when compared to amlodipine; the edema is related to the dose of the CCB.
It is not related to sodium or fluid retention nor to developing heart failure. Dihydropyridines can cause lightheadedness, flushing, headaches, and gingival hyperplasia. CCBs inhibit platelet aggregation and are associated with an increased risk of gastrointestinal bleed; caution is necessary when prescribing these agents to older patients and patients with a high risk of GI bleed.
The most common side effects related to ACE inhibitors are cough, hypotension, fatigue, and azotemia; reversible renal impairment is a common side effect, especially if the patient develops volume depletion due to diarrhea or vomiting. It takes up to 14 to 28 days after discontinuation for the cough to resolve. The incidence of cough is less common with ARB treatment; comparing losartan with hydrochlorothiazide showed a similar incidence of cough in both medications.
ARBs are safe to use in asthma patients; candesartan did not correlate with an increase in the incidence of cough in patients with asthma compared to CCBs. Ramipril demonstrated a higher rate of cough incidence comparing to telmisartan.
ACE inhibitor treatment is commonly associated with mild hyperkalemia. Even in patients with normal renal function, the risk of hyperkalemia increases in patients with renal failure, diabetes, or CHF. Angioedema is a rare side effect of ACE inhibitors; it appears in 0. In Black patients, ARBs correlated with less incidence of both cough and angioedema. Beta-blockers: Common side effects of beta-blockers are bradycardia, constipation, depression, fatigue, and sexual dysfunction.
Additionally, they are associated with bronchospasm and worsening symptoms of peripheral vascular disease. They can cause a flare-up of Raynaud syndrome. Loop diuretics: are associated with electrolyte imbalance, mainly hypokalemia, hyponatremia, hypomagnesemia, and hypochloremia.
Ototoxicity and deafness may occur with loop diuretics treatment. Side effects of the Mineralocorticoid receptor antagonists: Hyperkalemia is the major side effect of this group of medications. They can cause metabolic acidosis as a result of decreased exertion of hydrogen ions. Erectile dysfunction and gynecomastia in men and irregular menstrual periods in women can occur as well. Hydralazine: can cause headaches, flushing, palpitations, dizziness, hypotension symptoms, and dizziness due to the sympathetic system stimulation.
Clonidine common side effects are drowsiness, headache, dizziness, irritability, nausea and vomiting, constipation, upper abdominal pain, and bradycardia, but other serious side effects can occur as angioedema, atrioventricular block, and severe hypotension. Minoxidil is associated with hirsutism.
Alpha-blockers are associated with tachycardia and orthostatic hypotension as a result of venous dilation. Thiazide type diuretics are contraindicated if the patient is anuric, and in patients with sulfonamide allergies. CCBs are contraindicated in patients with hypersensitivity to the drug. ACE inhibitors are contraindicated in patients with a history of previous hypersensitivity to ACE inhibitors, history of ACE inhibitor-related angioedema, other types of angioedema, pregnancy, or the use of aliskiren.
Other relative contraindications for ARB treatment include patients with volume depletion, patients on other medications that cause hyperkalemia, or patients with abnormal renal function. Beta-blockers are contraindicated in asthma patients, especially nonselective beta-blockers.
Relative contraindications are hypotension and bradycardia. They should be avoided in patients with cocaine-induced coronary artery spasm. Loop diuretics are contraindicated in patients with hypersensitivity to sulfonamides, anuric patients, and patients with hepatic coma. Potassium-sparing diuretics are contraindicated in patients with chronic kidney disease, hyperkalemia, and caution is necessary when combining them with ACE inhibitors, ARBs, and aliskiren.
Clonidine is contraindicated in patients with hypersensitivity to alpha-2 agonists and should be avoided in patients with depression and recent myocardial infarctions. Hydralazine is contraindicated if the patient has a history of hydralazine allergy. In patients with coronary artery disease, hydralazine can stimulate the sympathetic system.
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