Hypertension

Normal levels of BP depend on an important balance between peripheral vascular resistance and cardiac output. Usually, peripheral vascular resistance is increased in patients with HTN, while cardiac output may be within normal limits. The small arterioles that contain smooth muscle cells aid in determining the level of peripheral resistance. The longer smooth muscles are contracted, the greater the likelihood of wall thickening and an irreversible rise in peripheral resistance (Beevers et al., 2001).

It is thought that the renin-angiotensin system may be the most significant contributor to HTN. Renin, secreted from the kidney's juxtaglomerular apparatus, is released in response to decreased salt consumption (glomerular underperfusion) or sympathetic nervous system stimulation. Renin is essential as it converts angiotensin to angiotensin I. Angiotensin I is eventually converted to angiotensin II by a converting enzyme and is known to be a significant vasoconstrictor, contributing to a rise in BP (Beevers et al., 2001).

The autonomic and central nervous systems both play a pivotal role in HTN. Because the sympathetic nervous system causes constriction and dilation of the arterioles, the autonomic nervous system acts to maintain BP within normal range. The autonomic nervous system also aids in correcting acute and short-term rises in BP, such as with stress (Beevers et al., 2001).

Research has shown that genetics may play a role in the development of HTN. It is twice as likely for someone with parents who have HTN to have the condition themselves. There are specific genetic mutations that can cause HTN. Genetic mutations and conditions that could contribute to this condition include congenital adrenal hyperplasia due to 17α-hydroxylase deficiency, the angiotensinogen gene, and glucocorticoid-remediable aldosteronism (Beevers et al., 2001).

Another pathophysiologic cause includes endothelial dysfunction involving peptide endothelin (vasoconstrictor) and nitric oxide (vasodilator). Vasoactive mechanisms and systems involving vascular tone and sodium transport also play a role in the development of HTN. Abnormalities of the vessel wall and blood, such as abnormal platelet activation, are often seen in patients with HTN (Beevers et al., 2001).

Primary HTN, also known as essential HTN, accounts for almost 90% of all cases. Primary HTN is characterized by SBP values of 130 mmHg or more and/or DBP of over 80 mmHg. Primary HTN can be idiopathic or without an identifiable cause (Carretero & Oparil, 2000). It is considered a heterozygous disorder where patients have casual factors causing their high BP. Previous research has identified that patients may be salt sensitive, leading to the development of HTN (Iqbal & Jamal, 2022).

Specific factors known to increase BP in primary HTN include:

• Increased consumption of alcohol
• Increased consumption of salt
• Aging
• Overweight/obesity
• Stress
• Low calcium and potassium intake (Carretero & Oparil, 2000)

Primary HTN may be asymptomatic; therefore, diagnoses may be based on BP screenings. If the HTN has been chronic, patients may present with symptoms of end-organ damage, such as encephalopathy or acute pulmonary edema.

If patients are symptomatic, they may experience:

• Headaches
• Nose bleeds
• Chest pain
• Dizziness
• Hematuria
• Fatigue (Cleveland Clinic, 2021)

Though the physical exam may appear unremarkable, healthcare providers should examine for aortic valve disease, polycystic kidney disease, coarctation of the aorta, thyroid disorders, and renovascular diseases. 

With examination, the patient should be seated for at least five minutes before taking BP. To diagnose primary HTN, the American College of Cardiology recommends that the BP be high on two office visits on separate dates. The European Society of Cardiology and European Society of Hypertension recommends recording the BP three times, at one to two minutes apart. Additional measurements may be warranted if the first two readings differ by > 10 mmHg. If not, BP is then recorded as an average of the readings. An ambulatory BP measurement, or a consistent measurement over 24 hours, has been noted to be the best method to diagnose HTN (Iqbal & Jamal, 2022).

The diagnosis and evaluation for primary HTN involve the following:

• Labs- blood count, electrolytes, cholesterol levels, erythrocyte sedimentation rate (ESR), serum uric acid, creatinine, estimated glomerular filtration rate (eGFR), thyroid levels, hemoglobin A1C (HbA1C), and urine albumin-to-creatinine ratio.
• 12-lead ECG- this will look at the rhythm and rate of the heart and if there is evidence of left ventricular hypertrophy.
• Fundoscopy- this will review maculopathy or retinopathy of the eye.
• Ankle-brachial pressure index (ABI)- to look for evidence of peripheral arterial disease.

Treatment for primary HTN consists of pharmacological and non-pharmacological interventions.

The Joint National Commission (JNC) has set treatment recommendations that include:

• Patients with diabetes mellitus and chronic kidney disease (CKD) whose BP is ≥ 140/90 mmHg should be given pharmacologic therapy and have a target BP less than 140/90 mmHg.
• Patients over the age of 60 with a BP of ≥ 150/90 mmHg should be given pharmacologic therapy and have a target BP of less than 150/90 mmHg.
• Patients between the ages of 18-59 with an SBP ≥ 140 mmHg should be given pharmacologic therapy and have a target BP less than 140 mmHg.
• Patients with diabetes who are African American should be treated with a thiazide diuretic and/or calcium channel blocker (CCB).
• Patients who have CKD should be treated with an angiotensin receptor blocker (ARB) unless contraindicated (Iqbal & Jamal, 2022).

Specific pharmacological agents depend on the level of BP and the patient's condition. Stage 1 HTN can be treated with one medication, also called monotherapy. Angiotensin-converting enzyme (ACE) inhibitors, ARBs, CCBs, and thiazide diuretics are generally the first choices. When using two medications, they should be from different drug classes. Most commonly, an ACE inhibitor or ARB and a CCB are the top choice. These guidelines change with patients who have significant comorbid conditions (Mann & Flack, 2023).

Secondary HTN is elevated BP with an identifiable cause; it occurs in nearly 10% of adults. It is pertinent that healthcare providers identify the etiology of secondary HTN as it may guide therapy or eliminate the need for treatment altogether.

Patients exhibiting any of the following may have secondary HTN:

• An acute rise in BP with no history of elevated pressures
• Resistant HTN despite proper interventions and treatment
• HTN associated with electrolyte disorders such as low potassium or metabolic alkalosis
• HTN in patients before age 30 without any risk factors (family history, obesity, diet, etc.)
• HTN before puberty
• Patients with severe HTN and end-organ damage
• Reverse dipping patterns while on a 24-hour ambulatory monitoring
• Snoring and daytime sleepiness
• Weight gain, fatigue, moon face
• History of renal insufficiency
• Palpitations, heat intolerance, tachycardia, tremors
• Recurrent urinary tract infections/kidney stones
• Decreased/delayed femoral pulses
• Atherosclerotic cardiovascular disease ((Hegde et al., 2013)

Secondary HTN can be caused by the following:

• Endocrine disorders- this can be an increase in hormone release. Specific hormone disorders include Cushing's disease, aldosteronism, pheochromocytoma, and thyroid disorders.
• Vascular disorders- this may include coarctation of the aorta.
• Renovascular disorders- this is a rare cause but includes stenosis of the renal arteries.
• Renal parenchymal disease- this is the most common cause of secondary HTN. This group includes diabetic nephropathy, polycystic kidney disease, and glomerulonephritis.
• Miscellaneous- obstructive sleep apnea, preeclampsia, and the intake of certain drugs (Hegde et al., 2013; Puar et al., 2016). 

A thorough history and physical should be taken to ensure the right underlying cause is found. The symptoms of secondary HTN may depend on what is causing the increase in BP. Symptomatic HTN may present with chest pain, dizziness, nose bleeds, fatigue, etc.

Treatment for secondary HTN is dependent on the underlying cause.

Resistant HTN is a form of high BP that does not readily respond to treatment and often requires many medications to achieve a BP within an acceptable range. Resistant HTN can present without an identifiable cause or may result from secondary HTN. Providers should recognize this disease as it can cause end-organ damage if not caught, and it may require non-traditional methods to control BP.

BP is said to be resistant when it remains above 140/90 mmHg despite using three antihypertensive medications, including a diuretic. Generally, resistant HTN is thought to be caused by a multitude of factors. These factors include genetics, altered salt and water handling due to a dysfunction in the renin-angiotensin-aldosterone system, and altered sympathetic nervous system activation (Yaxley & Thambar, 2015).

It should be noted that there is a difference between poor adherence and resistant HTN. When medication is not taken as prescribed, poor adherence can cause extremely high BP. Resistant HTN is when BP remains high, despite adhering to the prescribed medication regimen. 

There are a few specific causes or factors that may play a part in the development of resistant HTN and include the following:

1. Genetics- Studies have shown that some patients diagnosed with resistant HTN have mutations of the β and γ subunits of the epithelial sodium channel.
2. Obesity- obesity can cause elevated BP. Obesity-induced HTN is complex and involves multiple body systems.
3. Salt intake- salt intake affects BP in different ways; it can increase and blunt the effect of BP, decreasing the effect of many antihypertensive medications. This is more commonly seen in African Americans, older adults, and those with CKD.
4. Alcohol intake- not only does heavy consumptions cause an increase in BP, but it can also lead to treatment-resistant HTN.
5. Drug-related causes- Some pharmacological agents may increase BP and make it more difficult to control.

Medications include:

• Oral contraceptives
• Sympathomimetic agents such as decongestants or diet pills
• Stimulants, such as modafinil, amphetamine, or methylphenidate
• Natural licorice
• Cyclosporine
• Erythropoietin
• Ephedra

When the diagnosis of resistant HTN is made in older adults, usually, there is a secondary cause. More common causes include the following:

• Renal artery stenosis
• Obstructive sleep apnea
• Primary aldosteronism
• Renal parenchymal disease

Uncommon causes include the following:

• Aortic coaction
• Pheochromocytoma
• Cushing's disease
• Intracranial tumor (Calhoun et al., 2008)

A thorough history and physical should be completed. Beyond the typical examination, serum creatinine, a urine dipstick, and the eGFR should be checked (Yaxley & Thambar, 2015).

Pharmacological treatment for resistant HTN is often standardized and includes an ACE inhibitor or ARB, a CCB (usually amlodipine), and a thiazide-like diuretic (usually indapamide or chlorthalidone). Often, spironolactone is added as a fourth agent. Coupled with pharmacological treatments, additional non-pharmacological therapies are necessary to control this condition (Acelajado et al., 2019).

Hypertensive urgency occurs when BP is severely elevated, but end-organ damage has not occurred (Naranjo et al., 2022). Cutoffs for hypertensive urgency have been proposed but sometimes overlap with hypertensive emergencies and malignant HTN. However, standards generally say a hypertensive urgency is defined by an SBP > 180 mmHg and a DBP > 110 mmHg. Because of a lack of precise cutoffs for this condition, healthcare providers denote the patient as having a hypertensive urgency if the patient has severely elevated BP and has risk factors for end-organ damage, such as kidney failure.

Acute elevations of BP resulting in a hypertensive urgency can be caused by thyroid dysfunction, medication noncompliance, or the use of sympathomimetics. Extreme pain and heightened anxiety may also cause a significant rise in BP. The treatment is dependent on the cause of the very elevated BP (Alley & Copelin, 2022).

The history and physical examination for this condition should focus on pinpointing if there is any end-organ damage. Symptoms to watch for include dizziness, chest pain, vision changes, shortness of breath, vomiting, and a headache. BP should be taken while sitting, lying, and in both upper extremities to assess if aortic dissection is present. Specific physical signs and symptoms indicative of a more significant problem include rales, jugular venous distention, and a gallop. Fundoscopy and cerebellar testing should be performed to check for extensive organ damage.

Specific diagnostic exams may include the following:

• Tomography (of the brain)
• Chest X-ray
• ECG
• Metabolic panels
• Urinalysis- to identify hematuria or proteinuria and review the urine microscopy
• Pregnancy screen
• Toxicology screen (Alley & Copelin, 2022)

Sodium nitroprusside is commonly used to treat this condition because it is short-acting and can be titrated rapidly, depending on the patient's condition. Labetalol has also been used as it can be administered as a bolus dose or an IV infusion. Two other treatment options include fenoldopam or clevidipine (Alley & Copelin, 2022).

Malignant HTN is used to describe patients who have elevated BP, multiple complications, such as organ damage/failure, and who have a poor outlook or prognosis. Severe elevations of BP can be seen and are often called a hypertensive crises. SBP is usually ≥ 180 mmHg, and DBP is usually ≥ 120 mmHg.

Some of the more common causes of malignant HTN include:

• Poor medication adherence
• Amphetamines
• Renal parenchymal disease
• Renal artery stenosis
• Endocrine dysfunction
• Central nervous system disorders
• Head injury
• Coaction of the aorta
• Medication withdrawal

With malignant HTN, there is an increase in systemic vascular resistance and increased vasoconstriction. End-organ damage results from ischemia and hypoperfusion. Commonly, anemia is seen because of the red blood cell destruction in the obstructed vessels (Naranjo et al., 2022).

Patients with malignant HTN may present with headaches, back pain, chest pain, nausea, difficulty breathing, and visual disturbances. Healthcare providers should discuss antihypertensive medication regimens, the time of the last dose, if any has been missed, and if the patient is taking nonprescription medications. A funduscopic exam is performed to look for papilledema and may also reveal exudates and hemorrhages. Other signs and symptoms that may be present include seizures, agitation, delirium, bruits, pulmonary edema, and heart murmurs.

Besides the history and physical, the examination may include the following:

• Urinalysis
• Chest X-ray
• ECG
• Blood work- creatinine and electrolytes
• Toxicology screen
• CT/MRI of the brain and chest

Standard treatment options include the following:

• Nicardipine at 5 mg per hour, increasing by 2.5 mg per hour every 5 minutes to a maximum of 15 mg hourly.
• Sodium nitroprusside, 0.3-0.5 mcg/kg/minute, increased by 0.5 mcg/kg per minute as needed to a maximum dose of 10 mcg/kg per minute.
• Labetalol 10-20 mg followed by 20-80 mg bolus doses at 10-minute intervals. The maximum is a 300-mg cumulative dose.
• Esmolol with an initial loading dose of 500 mcg/kg/minute over 1 minute, then 50 to 100 mcg/kg/minute. The maximum dose is 300 mcg/kg per minute (Naranjo et al., 2022).

Isolated systolic HTN is characterized by a SBP > 140 mmHg while the DBP remains < 90 mmHg. Isolated systolic HTN is often seen in older adults; in fact, 15% of adults over 60 years of age have a BP that falls into this diagnostic category. Non-Hispanic African Americans are at the greatest risk.

Reduced elasticity of the arterial system is often the causative factor behind isolated systolic HTN. Reduced compliance, increased thickening of the vascular system, and decreased lumen-to-wall ratio lead to stiffened arteries, increasing the SBP and decreasing the DBP. The chronic diseases discussed in other types of HTN are also contributing factors to this diagnosis (Tan & Thakur, 2023).

History and physical exam with isolated systolic HTN include the following:

• Family history, including renal disease, HTN, and cardiovascular disease
• Diet, including usual salt consumption, alcohol intake, and processed foods
• Any risk factors, such as obesity, diabetes, and smoking
• Symptoms of end-organ damage, such as headache, chest pain, claudication
• Symptoms of secondary causes of isolated systolic HTN, such as tachycardia, depression, and loud snoring
• Prescription drugs, such as steroids or estrogen

The healthcare provider should do a complete examination, including the following:

• BP should be documented on two to three separate occasions. A home log detailing BP is acceptable evidence
• General appearance, including flushing, sweating, and body mass index
• The neck to look for carotid bruits and if the thyroid is enlarged
• The lungs for rhonchi or rales
• The heart for a heave, gallop, or distension
• The abdomen for an enlarged kidney or any bruits
• A neurologic exam for confusion or weakness
• Extremities for edema and the presence of pulses
• A fundoscopy for cotton wool spots, arteriolar narrowing, and arteriovenous nicking

Further evaluation should consist of diagnostic tests such as:

• ECG
• Urine analysis
• Electrolytes
• Creatinine
• Renal ultrasound
• ABI
• HgbA1c (Tan & Thakur, 2023)

First-line agents for treating isolated systolic HTN include CCBs and thiazide diuretics (Angeli et al., 2020).

White coat effect refers to the phenomenon of an elevated BP seen with a health care provider in the clinic versus outside the clinic, such as at home. The difference is considered clinically significant if it exceeds 20/10 mmHg. White coat syndrome is the sustained effect of high BP when seeing a health care provider, but a quick resolution when at home or ambulatory outside the clinic. White coat syndrome is essential to understand as it is a risk factor for target organ damage, MI, stroke, and sustained HTN; it can also lead to atherosclerosis. A BP reading of ≥ 140/90 mmHg in-office with a mean BP reading of 130/80 mmHg outside the healthcare office suggests white coat syndrome. 

The cause of white coat syndrome is not clear. Risk factors such as anxiety and public speaking are linked to this syndrome. The pathophysiologic mechanisms behind white coat syndrome involve the endocrine and sympathetic nervous system. Unfortunately, white coat syndrome is an under-researched topic that deserves more attention to understand the pathophysiology and treatment interventions (Nuredini et al., 2020).

Hypertensive disorders affect around 10% of pregnancies and are commonly called gestational HTN or preeclampsia. New onset of HTN after 20 weeks of gestation, with a BP of ≥ 140 mmHg systolic or ≥ 90 mmHg diastolic fits under the diagnosis of preeclampsia. Blood pressure measurements should be repeated to confirm the diagnosis; they should be taken at least four hours apart on two separate occasions. HTN during pregnancy has severe consequences on the mother and baby, including long-term HTN and significant cardiovascular events, such as MI or stroke. The fetus may experience preterm birth, distress, growth restriction, early placental abruption, or even death.

Risk factors for preeclampsia include the following:

• ≥ 40 years old
• BMI ≥ 35 kg/m
• Multi-fetus pregnancy
• Family history of preeclampsia
• Polycystic ovarian syndrome
• Sleep-disordered breathing
• Helicobacter pylori
• History of recurrent urinary tract infections
• Raised mean arterial BP before 15 weeks gestation 

Besides an increase in BP, the mother must experience one of the following to be diagnosed:

• Proteinuria- usually confirmed by a urine dipstick and then a 24-hour urine.
• Uteroplacental disruption- this may include oxidative stress and systemic inflammation.
• Organ (renal, liver, neurological) dysfunction- laboratory tests include hemoglobin, creatinine, liver enzymes, and uric acid (Fox et al., 2019).

Eclampsia is a significant condition that requires prompt attention. It can lead to liver failure, renal dysfunction, pulmonary edema, central nervous system abnormalities, and death. Tonic-clonic seizures mark the progression of preeclampsia to eclampsia. Other signs and symptoms may include agitation and unconsciousness. Before experiencing these symptoms, many women will experience headaches, swelling, vision changes, and gastrointestinal upset.

Specific signs of eclampsia include:

• New onset headache that does not respond to medications
• BP ≥ 160/110 mmHg
• Serum creatinine > 1.1 mg/dl

Rapid clinical interventions are necessary to prevent eclampsia from progressing to the deadly hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome (Akre et al., 2022).

First-line therapy includes labetalol, nifedipine, or methyldopa (Odigboegwu et al., 2018).

Diuretics have been used as a first-line agent to treat HTN. Diuretics promote diuresis, increasing the excretion of salt and water. The diuretic class is further broken down into three categories.

1. Thiazide diuretics- these diuretics block the sodium-chloride channel in the distal convoluted tubule. With these medications, a limited amount of sodium crosses the membrane, decreasing sodium and water passage. Chlorthalidone, hydrochlorothiazide, and indapamide are the most commonly used thiazide diuretics. Common adverse effects of thiazide diuretics include hypokalemia, hyponatremia, hyperglycemia, and hypercalcemia (Akbari et al., 2023).
2. Loop diuretics- these medications increase urine production resulting in the excretion of more fluid. They compete with chloride to bind to the sodium potassium chloride cotransporter, inhibiting sodium and chloride's reabsorption. The most common loop diuretics include furosemide, butanamide, and torsemide. Adverse effects usually occur from electrolyte abnormalities (Huxel et al., 2022).
3. Potassium-sparing diuretics- this type of diuretic has similar actions to the others, except it does not cause potassium loss with urination. It should be noted that this type of diuretic does not decrease BP as well as others. Common potassium-sparing diuretics include amiloride, triamterene, and spironolactone (Ellis, 2023).

Beta-blockers are a common medication for treating HTN and its associated side effects, such as tachycardia. Beta-blockers bind to the B1 and B2 receptors, which inhibit their effects. However, some beta-blockers also bind to alpha receptors. The inhibition of inotropic and chronotropic receptors results in a decreased heart rate. A reduction in cardiac output and a decrease in renin drops BP. Common adverse effects include hypotension and bradycardia. Other side effects include fatigue, nausea, and dizziness.

Commonly used beta blockers for treating HTN include propranolol, labetalol, carvedilol, atenolol, and metoprolol. Dosages depend on the specific medication and the level of HTN. However, they are often dosed twice daily (Farzam, 2022).

ACE inhibitors lower the mean arterial BP, the SBP, and the DBP. They interfere with the renin-angiotensin-aldosterone system and block the conversion of angiotensin I to angiotensin II. A decrease in angiotensin II lowers the BP. Common ACE inhibitors include enalapril, lisinopril, benazepril, captopril, and fosinopril. All ACE inhibitors, except enalapril, are given orally. The most common adverse effect noted with these medications is a bothersome dry cough for which there is no treatment (Herman et al., 2023).

These are also called ARBs, and they inhibit and reduce the action of angiotensin II type 1 receptor (which increases BP). They are often used in patients who cannot tolerate ACE inhibitors. Side effects of ARBs are minimal, and the medications are usually well tolerated. However, they are contraindicated in patients with renal artery stenosis and some cases of heart failure. Common ARBs include irbesartan, valsartan, losartan and candesartan (Hill et al., 2022).

CCBs block calcium's movement by binding to the voltage-gated calcium channels. Their effects on the atrioventricular and sinoatrial nodes in the heart slow contractility and conduction, decreasing BP. CCBs may cause worsening cardiac output, bradycardia, headaches, and flushing. Common CCBs include amlodipine, verapamil, diltiazem, and nifedipine (McKeever & Hamilton, 2022).

Alpha-blockers, which alter the sympathetic nervous system, fall into three categories:

1. Nonselective alpha-blockers- cause vasodilation when they block both alpha-1 and alpha-2 receptors.
2. Selective alpha-1 blockers- cause vasodilation as they prevent norepinephrine from activating the alpha-1 receptor.
3. Selective alpha-2 blockers- stimulate the sympathetic nervous system by inhibiting negative feedback of norepinephrine.

Adverse effects include hypotension, tachycardia, weakness, and tremors. Common alpha-blockers include prazosin, terazosin, and doxazosin (Nachawati & Patel, 2022).

Another class of medications for HTN includes alpha-2 adrenergic receptor agonists, though they are less commonly used. Alpha-2 adrenergic receptor agonists cause neuromodulation resulting in a reduction in BP, vasodilation, and a decreased heart rate (Nguyen et al., 2017). Some of the more common medications under this class include clonidine, dexmedetomidine, and tizanidine. Common side effects include drowsiness, fatigue, headache, and irritability (Nguyen et al., 2017).

Direct vasodilators are also used for HTN. They allow the blood to flow easier due to the widening of the blood vessels. Minoxidil and hydralazine are examples of direct vasodilators. Common side effects include tachycardia, headache, vomiting, and fluid retention (Hariri & Patel, 2022).