Hypertensive Agents

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Introduction   

Hypertension, or high blood pressure, is a common medical condition diagnosed and treated by healthcare professionals. According to the Centers for Disease Control and Prevention, around 34 million Americans are prescribed antihypertensive medications. Additionally, hypertension was a primary or contributing cause of more than 690,000 deaths in the United States in 2021 [6].  

Healthcare providers must be knowledgeable of and follow current hypertension clinical practice guidelines. Understanding the different pharmacokinetics of antihypertensive medications is essential. This course outlines antihypertensive pharmacology and addresses pharmacokinetics, including mechanism of action, side effects, usage, and contraindications. 

Definitions 

Hypertension - high blood pressure above normal. Normal is considered anything less than 120/80 mmHg [7]. 

Antihypertensives - medications used to control hypertension and lower blood pressure [7]. 

Hypertensive crisis - severely elevated blood pressure of either: 

1. Systolic greater than 180 mmHg 

1. Diastolic greater than 120 mmHg [19]. 

Hypertensive emergency - acutely elevated blood pressure with signs of target organ damage [2]. 

Medications Overview 

Antihypertensive medications are used for the treatment of hypertension and are used in both inpatient, outpatient, and emergency settings.  

Some of the major antihypertensive medication classes include: 

• Diuretics 
• Beta-blockers 
• Angiotensin-converting enzyme inhibitors 
• Angiotensin II receptor blockers 
• Calcium channel blockers 
• Selective alpha-1 blockers 
• Alpha-2 Receptor Agonists 
• Vasodilators [3]. 

Different medical organizations have varying recommendations and hypertension treatment guidelines. Hypertension treatment clinical practice guidelines are available from organizations like the American Heart Association, the American College of Cardiology, and the European Society of Cardiology to name a few [21]. Healthcare providers should be aware of their healthcare institution’s recommendations for clinical practice guidelines and organizations.  

All organizational guidelines share the same recommended treatment of starting antihypertensives immediately when: 

1. Blood pressure is greater than 140/90 mmHg for patients with a history of ischemic heart disease, heart failure, or cerebrovascular disease. 
2. Blood pressure is greater than 160/100 mmHg regardless of underlying medical conditions [21]. 

Again, healthcare providers should follow current and evidence-based clinical guidelines for initiating or titrating antihypertensive medications. 

While most antihypertensives are prescribed in an outpatient setting, certain antihypertensives are indicated during hypertensive or medical emergencies. For example, intravenous (IV) vasodilators, like nitroprusside and nitroglycerin, and calcium channel blockers, like nicardipine, are used during hypertensive emergencies and crises. 

Pharmacokinetics 

Diuretics 

Diuretics are a class of drugs that help control blood pressure by removing excess sodium and water from the body through the kidneys. There are several varying types of diuretics, some including thiazide, potassium-sparing, and loop, and all work to lower blood pressure differently [3]. 

Thiazide Diuretics 

Thiazide diuretics remove excess sodium and water from the body by blocking the sodium-chloride (Na-Cl) channels in the kidneys’ distal convoluted tubule. As the Na-Cl channel becomes blocked, this inhibits the reabsorption of sodium and water into the kidneys. Concurrently, this causes a loss of potassium and calcium ions through the sodium-calcium channels and sodium-potassium pump [1]. 

Thiazide diuretics are approved by the Food and Drug Administration (FDA) for controlling primary hypertension and are available via oral route. Some common thiazide diuretics are hydrochlorothiazide, chlorthalidone, and metolazone [3].  

When initiating this medication, the healthcare provider should start with the lowest dose, which is usually 25mg daily, and then increase accordingly to aid with blood pressure control or if the patient has excess fluid retention, usually as evidenced by leg swelling or edema [1].  

Common side effects of thiazide diuretics include: 

• Increased urination 
• Diarrhea 
• Headache 
• Stomach and muscle aches [16]. 

As thiazide diuretics interfere with Na-Cl, Na-Ca, and Na-K channels, there is an increased potential for adverse effects, including: 

• Hypotension 
• Hypokalemia 
• Hyponatremia 
• Hypercalcemia 
• Hyperglycemia 
• Hyperlipidemia 
• Hyperuricemia 
• Acute pancreatitis 

When prescribing thiazide diuretics, healthcare providers should avoid prescribing thiazide diuretics to patients with a sulfonamide allergy, since thiazides are sulfa-containing medications. Also, they should avoid prescribing these to patients with a history of gout [1].  

Additionally, patients can experience a thiazide overdose if they take more than the amount prescribed. Patients with a suspected overdose may experience confusion, dizziness, hypotension, and other symptoms. These patients must seek emergency care and poison control must be alerted [16]. 

Potassium-Sparing Diuretics 

Potassium-sparing diuretics remove excess sodium and water from the body without causing loss of potassium. Depending on the type, they interrupt sodium reabsorption by either binding to epithelial sodium channels or inhibiting aldosterone receptors. When catatonic sodium is reabsorbed, this creates a negative gradient causing the reabsorption of potassium ions through the mineralocorticoid receptor [5]. 

Potassium-sparing diuretics are approved for controlling hypertension and are usually combined with other diuretics, like thiazide or loop diuretics since they have a weak antihypertensive effect.  

Common names of potassium-sparing diuretics are amiloride, triamterene, and spironolactone. These medications are available by either intravenous or oral routes. Spironolactone is commonly used for treating primary aldosteronism and heart failure [5]. Patients should be started on the lowest dose when first prescribing this class of medications.  

Common side effects can include: 

• Increased urination 
• Hyperkalemia 
• Metabolic acidosis 
• Nausea  

[4] 

Healthcare providers should avoid prescribing this class of medications to patients with hyperkalemia or chronic kidney disease. They should also be avoided during pregnancy or in patients who are taking digoxin. Since potassium-sparing medications can cause hyperkalemia, periodic monitoring for electrolyte imbalances and potassium levels is necessary [4]. 

Loop Diuretics 

Loop diuretics inhibit sodium and chloride reabsorption by competing with chloride binding in the Na-K-2Cl (NKCC2) cotransporter. Potassium is not reabsorbed by the kidney, which causes additional calcium and magnesium ion loss.  

Loop diuretics are FDA-approved for the treatment of hypertension but are not considered first-line treatment. They can also be used for treating fluid overload in conditions like heart failure or nephrotic syndrome [12]. 

Loop diuretics are available via oral or IV routes and furosemide, torsemide, and bumetanide are common forms [3].  

Bioavailability and dosage differ for each type and route of loop diuretics. The bioavailability of furosemide is 50%, with a half-life of around 2 hours for patients with normal kidney function, and dosages start at 8mg for oral medication. Torsemide has a bioavailability of about 80%, a half-life of about 3 to 4 hours, and oral dosages start at 5mg [12].  

Common side effects can include: 

• Dizziness 
• Increased urination 
• Headache 
• Stomach upset 
• Hyponatremia 
• Hypokalemia [13]. 

Loop diuretics can lead to several adverse effects, including toxicity, electrolyte imbalances, hyperglycemia, and ototoxicity. They have a black box warning stating that high dosages can cause severe diuresis. Therefore, electrolytes, BUN, and creatinine values should be monitored closely by a healthcare provider.  

People with a sulfonamide allergy may also be allergic to loop diuretics, so this should be avoided if the patient is allergic. Loop diuretics also interfere with digoxin and therefore should be avoided. Other contraindications include anuria, hepatic impairments, and use during severe electrolyte disturbances [12]. 

Beta-Blockers 

Beta-blockers work by reducing the body’s heart rate and thus, lowering cardiac output resulting in lowered blood pressure [3]. The mechanism of action for beta-blockers varies, depending on the receptor type it blocks, and are classified as either non-selective or beta-1 (B1) selective.  

Non-selective beta-blockers bind to the B1 and B2 receptors, blocking epinephrine and norepinephrine, causing a slowed heart rate. Propranolol, labetalol, and carvedilol are common non-selective beta-blockers.  

Alternatively, beta-1 selective blockers only bind to the B1 receptors of the heart, so they are considered cardio-selective. Some examples include atenolol, metoprolol, and bisoprolol. Sotalol is a type of beta-blocker that also blocks potassium channels and is, therefore, a class III antiarrhythmic [8]. 

Beta-blockers are not primarily used for the initial treatment of hypertension but can be prescribed for conditions like tachycardia, myocardial infarction, congestive heart failure, and cardiac arrhythmias. It’s also approved for use in conditions such as essential tremors, hyperthyroidism, glaucoma, and prevention of migraines.  

Beta-blockers are available in many forms, including oral, IV, intramuscular injection, and ophthalmic drops. Starting dosage and route are determined by the health condition being treated [8]. 

Common side effects of beta-blockers include: 

• Bradycardia 
• Hypotension 
• Dizziness 
• Feeling tired 
• Nausea 
• Dry mouth 
• Sexual Dysfunction  

[17] 

This class of medications can also lead to more severe adverse effects such as orthostatic hypotension, bronchospasm, shortness of breath, hyperglycemia, and increased risk of QT prolongation, torsades de pointes, and heart block [8]. Healthcare providers should avoid prescribing non-selective beta-blockers to patients with asthma. Instead, they can prescribe cardio-selective beta-blockers for patients with asthma.  

Additionally, the use of beta-blockers is contraindicated in patients with a history of bradycardia, hypotension, Raynaud disease, QT prolongation, or torsades de pointes. Healthcare providers must encourage patients to monitor their heart rate and blood pressure and follow administration parameters before taking beta-blockers daily since it decreases their heart rate.  

Overdose of beta-blockers is life-threatening and healthcare providers must discuss the symptoms of an overdose and the need for emergency care [8]. 

Angiotensin-converting Enzyme Inhibitors 

Angiotensin-converting enzyme (ACE) inhibitors prevent the body from producing angiotensin, a hormone that causes vasoconstriction. As angiotensin production is reduced, this allows the blood vessels to dilate and therefore lowers blood pressure [3].  

Moreover, ACE inhibitors act specifically on the renin-angiotensin-aldosterone system (RAAS) by preventing the conversion of angiotensin I to angiotensin II. It also works to decrease aldosterone, which in turn, decreases sodium and water reabsorption [9]. 

ACE inhibitors usually end in the suffix -pril and some common examples include lisinopril, benazepril, enalapril, and captopril, and they usually end in the suffix [3].  

While ACE inhibitors are approved for treating hypertension, they are also FDA-approved for other uses or combination therapies for medical conditions such as: 

• Systolic heart failure 
• Chronic kidney disease 
• ST-elevated myocardial infarction 

One non-approved FDA use is treatment of diabetic nephropathy [9]. This class of medication is available in oral, and IV forms, and dosages are dependent on clinical guidelines, underlying medical conditions, and route.  

ACE inhibitors have common side effects, with some including: 

• Dry cough 
• Dizziness 
• Hypotension [9]. 

This medication can also lead to adverse effects, such as syncope, angioedema, and hyperkalemia [9]. As angioedema is an adverse effect, healthcare providers should understand this class of medications is contraindicated in patients with a history of hypersensitivity to ACE inhibitors.  

Additionally, ACE inhibitors are contraindicated in patients with aortic valve stenosis, hypovolemia, and during pregnancy. Individuals with abnormal kidney function should have renal function and electrolyte values monitored. If a patient develops a chronic dry cough, then the healthcare provider should consider another antihypertensive medication class by following current guidelines [9]. 

Angiotensin II Receptor Blockers 

Similar to ACE inhibitors, Angiotensin II Receptor Blockers (ARBs) act on the RAAS by binding to angiotensin II receptors and thus block and reduce the action of angiotensin II. Again, this reduces blood pressure by causing blood vessel dilation and decreasing sodium and water reabsorption [11]. ARBs typically end in the suffix -artan and common names are losartan, valsartan, and Olmesartan [3]. Oral and IV routes of the medication are available and again, dosages are dependent on the medication specifically and form [11]. 

All ARBs are FDA-approved for the treatment of hypertension, but a select few are approved for treating other medical conditions, such as: 

• Candesartan for heart failure 
• Irbesartan for diabetic nephropathy 
• Losartan for proteinuria and diabetic nephropathy 
• Telmisartan for stroke and myocardial infarction prevention 
• Valsartan for heart failure and reduction of mortality in patients with left ventricular dysfunction [11]. 

Although not as common as ACE inhibitors, two side effects of ARBs are dry cough and angioedema.  

Other common side effects include: 

• Dizziness 
• Hypotension 
• Hyperkalemia  

[11] 

Contraindications for use are if the patient is pregnant or has renal impairment or failure. If a patient is on an ARB, the healthcare provider should closely monitor lab values for electrolyte imbalances and kidney function.  

Additionally, if a patient is taking lithium, ARBs can increase lithium concentration and therefore, lithium blood concentration should be frequently checked [11]. 

Calcium Channel Blockers 

Calcium channel blockers (CCBs), also known as calcium channel antagonists, act by preventing calcium from entering the smooth vascular and heart muscles. In turn, this reduces heart rate and causes vasodilation [3].  

They are further divided into two major categories, non-dihydropyridines and dihydropyridines, where there are differences in the mechanism of action. Non-dihydropyridines inhibit calcium from entering the heart’s sinoatrial and atrioventricular nodes and thus cause a cardiac conduction delay and reduce cardiac contractility.  

Alternatively, dihydropyridines do not directly affect the heart but do act as a peripheral vasodilator leading to lowered blood pressure. Both categories are metabolized by the CYP3A4 pathway [15]. 

Names of non-dihydropyridine CCBs are verapamil and diltiazem. Dihydropyridine CCBs typically end in the suffix  -pine and common names are amlodipine and nicardipine. Both categories are available via oral and IV routes for administration. Oral dosages of non-dihydropyridine CCBs start at 30mg daily and dihydropyridine CCBs start at 30mg daily for immediate release [15].  

Calcium channel blockers can be used to treat other medical conditions in addition to hypertension and include: 

• Coronary spasm 
• Angina pectoris 
• Supraventricular dysrhythmias 
• Pulmonary hypertension 
• Hypertrophic cardiomyopathy 

Non-dihydropyridine CCBs can cause side effects like bradycardia, and constipation, while dihydropyridine CCBs can cause: 

• Headaches 
• Feeling lightheaded 
• Leg swelling [15]. 

Both categories pose the risk of potential hypotension and bradycardia, so healthcare providers should closely monitor the patient’s blood pressure and heart rate when initiating or titrating the dosage.  

Also, an overdose of this medication can lead to cardiac conduction delays, complete heart block, and cardiovascular collapse. Patients with possible symptoms of overdose should be sent to the emergency room immediately.  

Additionally, healthcare providers should avoid prescribing CCBs to people with heart failure and sick sinus syndrome [15]. 

Selective Alpha-1 Blockers 

Selective alpha-1 blockers act on the body’s sympathetic nervous system to lower blood pressure. They prevent norepinephrine from binding to the alpha-1 receptors of the sympathetic nervous system, causing smooth muscle relaxation and vasodilation which leads to lowered blood pressure [18]. 

Selective alpha-1 blockers are available via the oral route, end in the suffix -osin and examples are doxazosin, terazosin, and prazosin [3]. They are FDA-approved for the treatment of hypertension but are not considered first-line therapy. Additionally, this class of medications may be used to treat benign prostatic hyperplasia. Dosages can start as low as 1mg daily depending on the drug selected. 

Common side effects include: 

• Hypotension 
• Tachycardia 
• Dizziness 
• Headache 
• Weakness [18]. 

As selective alpha-1 blockers can lead to orthostatic hypotension, the healthcare provider should instruct the patient to take this medication at night. They should also avoid prescribing to the elderly population when able because of hypotension and increased fall risk [18]. 

Alpha-2 Receptor Agonists 

Alpha-2 receptor agonists work by decreasing the activity of the sympathetic nervous system to lower blood pressure. It inhibits adenylyl cyclase and decreases the formation of cyclic adenosine monophosphate (cAMP). Alpha-2 agonists also cause vasodilation by reducing the amount of available cytoplasmic calcium [20].  

This class of medications is typically administered via oral route but is also available in intravenous and transdermal forms. Two FDA-approved alpha-2 agonists for hypertension treatment are methyldopa and clonidine and dosages are dependent on the name and route.  

Methyldopa is commonly prescribed to patients with hypertension and who are pregnant since it’s safe [20]. 

Common side effects of alpha-2 receptor agonists are: 

• Dry mouth 
• Drowsiness 
• Fatigue 
• Headache 
• Sexual dysfunction [3]. 

Contraindications for use are orthostatic hypotension and autonomic disorders. Healthcare providers must avoid prescribing alpha-2 receptor agonists to individuals taking phosphodiesterase inhibitors [20]. 

Vasodilators 

Vasodilators lower blood pressure by dilating the body’s blood vessels. It binds to the receptors of the blood vessel’s endothelial cells, releasing calcium. Calcium stimulates nitric oxide synthase (NO synthase), eventually converting to L-arginine to nitric oxide. As nitric oxide is available, this allows for GTP to convert to cGMP, and causes dephosphorylation of the myosin and actin filaments. As this occurs, the blood vessels’ smooth muscles relax, leading to vasodilation and lowered blood pressure.  

Common vasodilators that act via this pathway are nitrates and minoxidil. Hydralazine is another vasodilator, but the mechanism of action is unknown [10]. 

Available forms of vasodilators are sublingual, oral, and intravenous. Similar to other classes of antihypertensives, vasodilator dosages depend on the form and treatment setting [10].  

Nitrovasodilators like nitroprusside and nitroglycerin are used during hypertensive emergencies. Hydralazine is used for severe hypertension for the prevention of eclampsia or intracranial hemorrhage and minoxidil for resistant hypertension [10] [3]. 

Side effects for each will vary, but nitrates commonly cause: 

• Reflex tachycardia 
• Headache 
• Orthostatic hypotension  

[10] 

Common side effects of hydralazine are headaches, heart palpitations, and myalgias. Minoxidil causes excessive hair growth, weight gain, and fluid retention [3]. Additionally, nitroprusside can potentially cause cyanide toxicity.  

Vasodilators have varying degrees of contraindications, such as nitrates are avoided in patients with an inferior myocardial infarction. Hydralazine should not be given to patients with coronary artery disease, angina, or rheumatic heart disease. Healthcare providers should be aware of contraindications and monitor patients’ blood pressure and potential side effects [10]. 

Combination Antihypertensives 

Many antihypertensive medications come in combined forms, such as ACE inhibitors and thiazide diuretics, beta-blockers and diuretics, or calcium channel blockers and ACE inhibitors. The mechanism of action for combination antihypertensives depends on the blend of medications [3]. 

Considerations for Prescribers 

This section reviews potential considerations when prescribing antihypertensives. 

When prescribing antihypertensive medications, there are several factors that healthcare providers must consider. The route is typically determined by the healthcare setting and dosage by the underlying treatment goals. Again, healthcare providers should follow current guidelines when initiating or titrating antihypertensive medications.  

Healthcare providers must complete a thorough health history, and review lab values, and contraindications as mentioned above. Monitoring kidney function and electrolyte values is imperative while any patient is taking antihypertensive medications.  

While a single antihypertensive medication is recommended for initial treatment, there are some scenarios where combination therapy or combination antihypertensives are recommended [14]. 

Healthcare providers should also discuss the potential side effects of antihypertensives with patients and what to do if they are experiencing symptoms. For instance, if a patient reports syncope, they should be advised to go to the emergency room or be seen immediately for further evaluation. Also, healthcare providers must encourage patients to monitor their heart rate and blood pressure at home and abide by administration parameters.  

For example, instruct patients who are taking beta-blockers to measure their blood pressure and heart rate before taking their medication. If their heart rate is below 60 beats per minute, then they should not take the medication [14].  

If a patient is experiencing side effects from an antihypertensive medication, then another alternative should be selected. 

Upcoming Research 

This section reviews upcoming research and medications for hypertension treatment. 

Research on antihypertensive medications has slowed throughout the years. Some clinical trials were performed on the potential of endothelin receptor antagonists to reduce hypertension. However, some studies found several unwanted side effects, and thus clinical use was stopped for safety reasons.  

An endothelin-A and endothelin-B receptor blocker, called aprocinentan, has shown promise for the treatment of resistant hypertension by lowering blood pressure and decreasing vascular resistance.  

Research on sodium-glucose transport protein (SGLT2) inhibitors, which are typically used for the treatment of type II diabetes mellitus, is also ongoing. SGLT2 inhibitors may promote blood pressure reduction through diuresis and reduce sympathetic tone [21]. 

Conclusion

If hypertension is left untreated, it can lead to serious health complications, including death. When selecting antihypertensive treatment, healthcare providers should understand the pharmacokinetics of each drug class along with potential side effects and contraindications. They should also follow current clinical guidelines for an evidence-based approach. 

Final Reflection Questions 

• Which antihypertensive medication is often prescribed during pregnancy? 
• Which lab values are important when monitoring patients on each antihypertensive medication? 
• Which antihypertensive medications cause hypokalemia? 
• Which antihypertensive medications cause hyperkalemia? 

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