Hypertension

Hypertension

I. Problem/Condition.

Hypertension is defined as a systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg, based on the average of two properly measured readings following initial screening. It is one of the most common medical conditions treated in the United States, with a prevalence of more than 50 million adults who are 18 years of age and older. Based on JNC VII, a 55 year-old adult has a 90% chance of developing hypertension during their lifetime. The consequences of this silent killer can be devastating and include heart disease, stroke, peripheral arterial disease and end stage renal disease.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Hypertension can be further categorized based on underlying pathophysiology and the setting in which it occurs.

The pathogenesis of essential, also referred to as idiopathic or primary hypertension, is not well understood, although it accounts for up to 90% of hypertensive diagnoses. Potential contributors include sympathetic nervous system activation, blood pressure reactivity (i.e. an individual’s blood pressure response to external stimuli), increased angiotensin II activity, mineralocorticoid excess, genetics and reduced nephron mass. Risk factors associated with the development of essential hypertension include family history, black ethnicity, obesity, insulin resistance, physical inactivity, excessive alcohol consumption, salt sensitivity and possibly dyslipidemia, and certain personality traits.

Secondary hypertension, as the name implies, is hypertension associated with various underlying conditions including renal disease, renovascular disease, primary aldosteronism, Cushing’s syndrome, pheochromocytoma, coarctation of the aorta, preeclampsia, medication or drug-induced and sleep apnea. All patients diagnosed with hypertension do not require screening for secondary causes unless history, physical exam or initial laboratory testing indicates a specific possible etiology.

“White coat” hypertension refers to elevated blood pressure readings (≥140/90 mmHg) occurring within the confines of a doctor’s office, with normal out-of office blood measure measurements (<135/85 mmHg) when confirmed by home measurements or ambulatory blood pressure monitoring. White coat hypertension is associated with increased likelihood of progression to overt hypertension.

Masked hypertension refers to elevated blood pressure readings (>135/85 mmHg) confirmed with 24 hour ambulatory monitoring outside of the doctor’s office, with normal readings recorded at office visits.

Pseudohypertension is the finding of elevated systolic and diastolic pressures estimated by the sphygmomanometer that are 10 mmHg or greater than directly measured intraarterial or oscillometric pressure. This phenomenon is commonly seen in the elderly population due to stiff vessels caused by arterial calcification.

Hypertensive emergency refers to the presence of elevated blood pressure (typically systolic blood pressure >180 mmHg and/or diastolic pressure >120 mmHg) with end-organ damage. End-organ damage may include: retinal hemorrhage, papilledema, encephalopathy, intracranial bleed, lacunar infarcts, myocardial ischemia, left ventricular dysfunction, aortic dissection or malignant nephrosclerosis.

In hypertensive urgency, blood pressure is elevated to a similar degree as hypertensive emergency, however, there is no evidence of end-organ damage.

Refractory or resistant hypertension refers to blood pressure that remains above the treatment goal despite the concurrent use of three antihypertensive agents of different classes, one of which is a diuretic.

B. Describe a diagnostic approach/method to the patient with this problem.

The diagnosis of hypertension is made by two separate blood pressure measurements greater than 140/90 mmHg on two different office visits over one week apart, following an initial screening.

Emphasis should be made on correctly measuring blood pressure and should include the following components:

• Utilize the correct blood pressure cuff size (bladder cuff width should encircle at least 40% of arm circumference, cuff length should encircle at least 80% of arm circumference).
• Proper placement of the cuff (bladder center directly over palpated artery with lower edge of cuff 2.5cm above antecubital fossa).
• Measurement should NOT be taken over clothing.
• Preferentially using a mercury sphygmomanometer.
• Regular calibration (at least every 6 months) of aneroid manometer. Measure blood pressure with patient seated position and arm fully supported at heart level.
• Patient should sit quietly in a straight-backed chair with feet on the floor for five minutes before blood pressure is measured.
• Initial estimation of systolic pressure by use of the palpation technique to determine level of inflation necessary for an accurate reading.

1. Historical information important in the diagnosis of this problem.

When evaluating someone with suspected hypertension, the following should be addressed:

• Family history of hypertension, heart disease, kidney disease, stroke.
• Thorough medication history including over the counter medications, herbal supplements and oral contraceptives.
• Personal history of renal disease, heart disease, vascular disease, sleep apnea or endocrinologic disorder.
• Current or history of heavy alcohol use, recreational drugs, or nicotine use
• Exercise tolerance and level of routine physical activity.
• Cooking and dietary habits with attention to the intake of fruits and vegetables, sodium, potassium and caffeine
• Occupation, hobbies and perceived life stressors.
• Review of systems to include signs/symptoms of end target organ damage such as visual changes, severe headache, chest pain, palpitations, shortness of breath, peripheral edema, new neurologic deficits or change in urinary pattern or appearance (foamy urine).

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Blood pressure should ideally be measured manually with a mercury sphygmomanometer in both arms after the patient has been sitting quietly in the upright position with back supported for 5 minutes. Attention should be paid to utilizing the correct cuff size, correct placement of cuff on the arm (cuff bladder midline over brachial artery pulsation with lower edge of cuff two to three centimeters above the antecubital fossa) and supporting the arm at heart level (see above).

Initial assessment of the systolic blood pressure should be done with the palpation technique (inflating cuff to 30 mmHg greater than systolic pressure estimated by palpating for disappearance of the brachial pulse). This avoids problems associated with the auscultatory gap (the transient disappearance of Korotkoff sounds as the cuff is deflated), which is associated with increased arterial stiffness.

There are certain scenarios where utilizing the arm for blood pressure measurement is not possible such as in patients with suspected coarctation of the aorta, patients with breast cancer who have undergone axillary lymph node dissection and patients who are morbidly obese. In these situations, measuring the thigh or wrist blood pressure is an alternative method. Non-traditional blood pressure measure locations should be noted in the chart. Also, when using this value to diagnose or monitor blood pressure, it is important to note systolic blood pressure is typically higher in more distal arteries.

Physical examination should focus on identifying end target organ damage, or the presence of a secondary cause of hypertension and may include the following:

• Body habitus and weight, with consideration of waist circumference measurement.
• Fundoscopic examination to evaluate for arteriovenous nicking, copper wire changes, cotton wool spots, flame hemorrhages or papilledema.
• Neck examination for carotid artery auscultation and palpation of thyroid.
• Cardiovascular examination to assess for increased heart size, heaves, murmurs, gallops, arrhythmia, widened pulse pressure, or significant systolic pressure difference between upper and lower extremities.
• Pulmonary examination to auscultate for rales or evidence of pleural effusion.
• Abdominal examination to auscultate for renal artery bruits and palpate for renal masses or pulsatile aortic masses.
• Neurologic examination to assess for alertness, cognitive impairment, visual disturbances, dysarthria and sensory or motor deficits.
• Extremity exam to assess pulses and for presence of edema.
• Skin exam to evaluate for such as pigmented abdominal striae.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

On initial diagnosis of hypertension, the following labs/tests should be ordered, with labs routinely monitored:

• Assess renal function (creatinine)
• Fasting plasma glucose
• Fasting lipid panel
• Serum electrolytes, specifically potassium and calcium
• Electrocardiogram to assess for left ventricular hypertrophy, myocardial ischemia

Depending on the clinical scenario, one may also want to consider checking for microalbuminuria to screen for nephropathy, especially in diabetic patients and those with risk factors for coronary artery disease.

Obtaining an echocardiogram (EKG) or transthoracic echocardiogram to assess for left ventricular hypertrophy may be useful in helping to decide whether or not to initiate treatment for those with borderline blood pressure values.

Appropriate studies to investigate for secondary causes of hypertension should be obtained when dictated by the clinical presentation.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

The classification of blood pressure, as defined below by the Joint National Committee (JNC 7) guidelines in 2003, is based on the average of two or more properly measured blood pressure readings at each of two or more visits after an initial screen. NB: JNC 8 did not address the idea of “prehypertension”.

• Normal blood pressure: Systolic less than 120 mmHg and diastolic less than 80 mmHg
• Prehypertension: Systolic 120-139 mmHg and diastolic 80-89 mmHg
• Stage 1 Hypertension: Systolic 140-159 mmHg and diastolic 90-99 mmHg
• Stage 2 Hypertension: Systolic greater than 160 mmHg and diastolic greater than 100 mmHg
• Isolated systolic hypertension: Systolic greater than 140 with diastolic less than 90 mmHg
• Isolated diastolic hypertension: Diastolic greater than 90 with systolic less than 140 mmHg

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

Although renal artery stenosis is the most common cause of secondary hypertension that can be successfully corrected, screening for this disorder should be reserved for patients who have historical clues or physical examination findings suggestive of the disease, and in whom a corrective procedure such as renal artery angioplasty with stenting or surgical revascularization will be recommended.

III. Management while the Diagnostic Process is Proceeding.

A. Management of hypertension.

For hypertensive emergencies, it is imperative to reduce the blood pressure (BP) in a timely fashion to eliminate or reduce risk of target end organ damage. The initial treatment is not the immediate achievement of normotension, but rather lowering of BP to a safe, noncritical level which should be no more than 25% of the initial BP. Care should be taken to avoid rapid drops in blood pressure so as to prevent adverse outcomes associated with hypoperfusion of vital organs.

The treatment of hypertensive emergency requires hospitalization and the initiation of parenteral antihypertensive therapy. Once BP has been lowered to a safe range and the patient is able to tolerate oral medications, transition to oral medications is appropriate. Adjunct measures such as ICU or telemetry monitoring and treatment of complications related to target organ damage (i.e. unstable angina, myocardial infarction, pulmonary edema, acute kidney injury or cerebrovascular accident) should be implemented as dictated by the clinical situation.

For hypertensive urgency, rapid lowering of blood pressure in the acute setting has not been shown to be beneficial. The approach to management should include the administration of one or more oral antihypertensive agents with the goal being to lower blood pressure to an acceptable range (i.e. <160/100 mm Hg) within 24 to 48 hours. Based on the clinical presentation, a brief period of observation in the emergency department may be warranted to reduce BP over several hours. All patients should have timely follow-up with a healthcare professional in the outpatient setting to ensure optimal BP control.

For all patients diagnosed with hypertension in the absence of target organ damage, nonpharmacologic methods for controlling BP are first line therapy. In those with end-organ damage, lifestyle modifications should be combined with pharmacologic therapy. Recommended lifestyle modifications include:

• Weight loss
• A diet rich in fruits, vegetables and low fat dairy products with a reduced content of saturated and total fat (DASH – Dietary Approaches to Stop Hypertension – diet)
• Limiting sodium intake
• Adequate potassium intake (if not otherwise contraindicated)
• Consuming alcohol in moderation (no more than 2 drinks per day for men and no more than 1 drink per day for women)
• Engaging in regular brisk aerobic physical activity (at least 30 minutes daily most days of the week)
• Cessation of tobacco and illicit drugs

Once the decision has been made to initiate pharmacologic therapy, several factors must be considered including the degree of BP elevation, the presence of end-organ damage and the presence of a compelling indication or comorbid disease state that would warrant the use of a specific class of medications (i.e. angiotensin converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, alpha blockers).

Based on the Joint National Commission (JNC) 8 guidelines, goal blood pressure for patients <60 years old is <140/90 mmHg. This goal includes patients with diabetes and chronic kidney disease. In the general population ≥60 years old, goal blood pressure is <150/90 mmHg.

The choice of initial pharmacologic drug should be made based on individual factors. JNC 8 recommends one of four drug classes for initial therapy: thiazide diuretics, calcium channel blockers (CCBs), ACE-inhibitors and angiotension receptor blocking agents (ARBs). For patients with a BP >160/100 mmHg, initial pharmacologic therapy should include TWO drugs—a thiazide diuretic and a second medication of a different class.

For information on appropriate choice of antihypertensive agent, see below. Initial hypertension therapy, per JNC 8 recommendations should include:

• In the general nonblack population, including those with diabetes — a thiazide-type diuretic, calcium channel blocker, angiotensin converting enzyme inhibitor or angiotensin receptor blocker.
• In the general, black population, including those with diabetes — a thiazide-type diuretic or calcium channel blocker.
• In patients with CKD, initial (or add-on) hypertension therapy should include an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, regardless of race or diabetes status.

Pharmacologic Therapy

Thiazide diuretics:

Thiazide-type diuretics (chlorothiazide, chlorthalidone, hydrochlorothiazide, polythiazide, indapamide, metolazone) have proven to reduce morbidity and mortality associated with high blood pressure and should be used as initial therapy for most patients, either alone or in combination with another agent.

The thiazide diuretics inhibit sodium and chloride reabsorption at the distal renal tubules causing an increase in sodium and water excretion. Thiazides lower blood pressure by reducing plasma volume and decreasing vascular resistance.

In the United States, hydrochlorothiazide (HCTZ) is the most widely used agent in this class. However, clinicians should consider initiating hypertension treatment with chlorthalidone more often as it has been proven to be more potent than HCTZ and has a longer duration of action. In addition, there is more clinical evidence of improved cardiovascular outcomes with chlorthalidone verus HCTZ. Maximum recommended doses are chlorthalidone 25 mg daily and HCTZ 50 mg daily.

Side effects: Side effects are usually uncommon with low doses of thiazide diuretics. However, fatigue, lightheadedness, orthostasis and muscle cramping may occur along with electrolyte disturbances (hypokalemia, hypercalcemia and hypomagnesemia). Other symptoms may include transitory impotence and gout attacks (due to hyperuricemia).

Calcium channel blockers:

Calcium channel blockers (CCBs) reduce blood pressure in one of two ways: non-dihydropyridine (diltiazem, verapamil) CCBs act on the calcium channels of the heart causing slowed AV node conduction and increased cardiac relaxation; dihydropyridine CCBs (amlodipine, felodipine and nifedipine) act on vasculature calcium channels thereby causing vasodilatation. CCBs are a common first line anti-hypertensive therapy for all patients. Note that the FDA has issued a safety alert regarding the use of verapamil and diltiazem with simvastatin ≥10 mg and lovastatin ≥20 mg and amlodipine with simvastatin ≥ 20 mg due to increased risk of myopathy.

Clevidipine is an L-type dihydropyridine calcium channel blocker indicated for the treatment of hypertension when oral therapy is not feasible or desirable.

Side effects:

Diltiazem and verapamil have negative inotropic and chronotropic effects on the heart and should be used with caution in patients with cardiac conduction abnormalities and heart failure.

Verapamil use has also been associated with significant constipation and a stool softener may be necessary to reduce straining. Other common side effects of both verapamil and diltiazem include nausea, headache, rash and orthostatic hypotension.

Dihydropyridine calcium channel blocker use may be associated with peripheral edema, headache, dizziness, flushing, nausea or gingival hyperplasia.

ACE inhibitors:

The angiotensin converting enzymes (ACE) inhibitors (benazepril, captopril, enalapril, enalaprilat, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril) inhibit the conversion of angiotensin I to angiotensin II (a potent vasoconstrictor), thereby producing arterial and venous dilation as well as natriuresis. These agents should be considered as first-line therapy for the general non-black population as well as any patient with chronic kidney disease.

Side effects:

Side effects associated with the ACE inhibitors include hyperkalemia, taste disturbances, nausea, vertigo, hypotension, rash and a persistent dry cough (due to increased bradykinin).

Angioedema can occur as a side effect of ACE inhibitor use at any time during treatment, including after years of tolerating the drug. Patients who have experienced angioedema while on an ACE inhibitor can be trialed on an angiotensin receptor blocker (ARB). Creatinine may increase up to 30% on starting an ACE inhibitor.

Angiotensin II receptor blockers:

The angiotensin II receptor blockers (ARBs) interfere with angiotensin II binding to its AT₁receptors. Because these agents inhibit the actions of angiotensin II without inhibiting ACE, these agents offer a viable alternative for patients who do not tolerate ACE inhibitors. Currently, eight agents (azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan) are available in this class with azilsartan being the latest to be approved. According to recent clinical studies, azilsartan may be superior to both olmesartan and valsartan at reducing BP. Similar to ACE inhibitors, ARBs are considered first line anti-hypertensive therapy in the general non-black population as well as patients with chronic kidney disease.

Side effects:

Side effects are similar to ACE inhibitors, including hyperkalemia. Dry cough does NOT typically occur with ARBs and angioedema occurs at a much lower rate compared to ACE inhibitors. Like ACE inhibitors, ARBs are contraindicated in pregnancy.

Second line and additive anti-hypertensive drugs:

Beta-blockers:

Beta blockers (β-blockers) competitively inhibit the effects of catecholamines at beta-adrenergic receptors, decreasing blood pressure by causing a reduction in heart rate and cardiac output. Additional blood pressuring lowering affect is due to beta blockers’ decrease in angiotensin II production through the inhibition of renin. These agents may be used in hypertensive patients with heart failure, atrial fibrillation, paroxysmal supraventricular tachycardia, angina, post-myocardial infarction and diabetes (without nephropathy).

Cardioselective β-blockers include acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, nebivolol; nonselective (β1 and β2) β-blockers include nadolol, propranolol, timolol, carvedilol, sotalol and labetalol. Cardioselective β-blockers have a greater affinity for beta 1 (β1)-receptors (located in the heart) than beta 2 (β2)-adrenergic receptors (located in the lungs and blood vessels); because of this, cardioselective agents are less likely to cause a bronchospasm than the nonselective (β1 and β2) β- making them more appropriate for use in patients with respiratory illnesses (i.e. asthma, chronic obstructive pulmonary disease).

Nebivolol is the most recently approved β-blocker for the treatment of hypertension. It is a cardioselective β1 blocker that also causes vasodilation (via nitric oxide release) and may be more effective in African Americans compared to other β-blockers.

β-blockers with intrinsic sympathomimetic activity (acebutolol, penbutolol, pindolol) are less likely to cause a significant decrease in heart rate and may be preferred for patients who develop symptomatic bradycardia or postural hypotension with use of other β-blockers.

Carvedilol and labetalol are non-selective β-blockers that also possess alpha-adrenergic blocking properties and cause vasodilation. They exert a stronger blood pressure lower effect and may be useful in treating resistant hypertension and hypertensive crisis. Labetalol is also an effective treatment for hypertension during pregnancy, including during childbirth.

Side effects:

Both selective and non-selective β-blockers can cause fatigue, bradycardia, dizziness, insomnia/nightmares, decreased exercise tolerance and hypotension.

Non-selective β-blockers are more likely to worsen symptoms of asthma or other lung diseases and may also cause peripheral vasoconstriction, worsening Raynaud’s phenomenon or peripheral vascular disease.

Loop diuretics:

The loop diuretics (furosemide, bumetanide, ethacrynic acid, torsemide) cause diuresis by blocking sodium reabsorption in the thick ascending loop of Henle. Due to their short duration of action, they are not routinely used as first-line therapy in the treatment of hypertension unless a patient has clinically significant fluid retention. In stage IV chronic kidney disease (CrCl <30 ml/min), thiazide diuretics become less effective, and loop diuretics may be required.

Side effects:

Common side effects of loop diuretics include electrolyte abnormalities (hypocalcemia, hypokalemia and hypomagnesemia), orthostatic hypotension, muscle cramps, weakness and abdominal cramping.

Potassium sparing diuretics:

Spironolactone, eplerenone, amiloride and triamterene decrease sodium and water reabsorption in the distal convoluted tubules, thereby increasing potassium retention. They are useful in patients where potassium loss is significant or to be expected, however, they are weak diuretics and should be used in combination with other agents when treating hypertension.

Spironolactone is an aldosterone antagonist and maybe useful in the treatment of hyperaldosteronism, heart failure and edema associated with ascites and the nephrotic syndrome.

Eplerenone, also an aldosterone antagonist, exhibits greater selectivity for aldosterone receptors compared to spironolactone and is therefore associated with a lower incidence of endocrine-related adverse effects (i.e. gynecomastia and sexual dysfunction).

Side effects:

Hyperkalemia is a significant side effect of potassium-sparing diuretics and should generally be avoided in the setting of acute renal failure. Use with caution in patients with impaired renal function.

Triamterene should be avoided in patients with a history of kidney stones and hepatic disease.

Direct renin antagonists:

Aliskiren reduces peripheral resistance by directly inhibiting renin and preventing the conversion of angiotensinogen to angiotensin I. Currently, it is the only agent in its class and may be useful in patients who are intolerant of the ACE inhibitors. Its blood pressure lowering effect is comparable to that noted with the of ARBs.

Side effects:

The most frequently reported adverse effects associated with aliskiren include diarrhea, headache, nasopharyngitis, dizziness, fatigue, upper respiratory tract infection, back pain and cough. Angioedema has very rarely been reported.

Peripheral alpha-adrenergic blockers:

Prazosin, terazosin, and doxazosin are the only α1-adrenergic blockers currently approved for the treatment of hypertension in the United States. These agents cause both arterial and venous dilation by blocking the peripheral post synaptic α1-adrenergic receptor. Due to their side effect profile and ability to induce, or worsen, heart failure, these agents are infrequently used as first-line therapy in the treatment of hypertension; they are typically reserved for patients who do not respond to other anti-hypertensive therapy or for men who suffer from benign prostatic hypertrophy (BPH).

The alpha blocker, phentolamine, is indicated for the prevention or control of hypertensive episodes associated with pheochromocytoma due to stress or manipulation during pre-operative preparation and surgical excision.

Side effects:

A “first-dose phenomenon that includes syncope, postural hypotension and dizziness can occur shortly after taking the first dose of these drugs. To minimize this effect, patients should begin therapy with a starting dose of 1mg at bedtime, with upward titration as tolerated. Other side effects include nausea, headache, palpitations, sweating and priapism.

Phentolamine may cause acute and prolonged hypotensive episodes, tachycardia and cardiac arrhythmias. In addition, weakness, dizziness, flushing, orthostatic hypotension, nasal stuffiness, nausea, vomiting and diarrhea may occur.

Central alpha-adrenergic agonists:

Methyldopa and clonidine, the most frequently used central alpha-adrenergic agonists, stimulate α₂ -receptors primarily within the CNS and decrease sympathetic outflow to the cardiovascular system. They are often used to treat moderate to severe hypertension. Methyldopa is the one of two drugs of choice for treating chronic hypertension in pregnant patients due to its lack of adverse effects on the fetus.

Due to the availability of newer agents, guanfacine and guanabenz are not routinely used in the treatment of hypertension but may be employed as adjunct therapy for patients not responding to other antihypertensives.

Dosing

For the usual dosing range of the medications used to treat hypertension, see Figure 1.

Figure 1.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

Warnings/precautions listed by drug class below:

Thiazide diuretics

• Hypokalemia can occur and may require potassium supplementation or the use of a potassium sparing diuretic. Potassium level should be monitored after initiating a thiazide diuretic.
• Hyperuricemia may occur or acute gout may be precipitated in certain patients.
• Hyperglycemia may occur with thiazide diuretics. Dosage adjustments of insulin or oral hypoglycemic agents may be required.
• Thiazides have been shown to increase the urinary excretion of magnesium.
• Calcium levels may increase from thiazide use as a result of decreased urinary calcium excretion.
• Hyperlipidemia including hypercholesterolemia and hypertriglyceridemia may occur with thiazide diuretic therapy.
• Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate salt replacement is the therapy of choice.

Calcium-channel blockers (CCBs)

• Atrial fibrillation/flutter associated with accessory bypass tract (i.e. Woff-Parkinson-White, Lown-Ganong-Levine): Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil.
• Left ventricular dysfunction: Verapamil should be avoided in patients with severe left ventricular dysfunction (i.e. ejection fraction less than 30%) or moderate to severe symptoms of cardiac failure and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker.
• Second- or third-degree atrioventricular block (without functioning artificial pacemaker): The effect of verapamil on AV conduction and the SA node may lead to asymptomatic first degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms.
• Acute hepatic injury: Elevated liver enzymes, particularly serum transaminase levels, have been reported with diltiazem and verapamil use.
• Hypotension: Calcium channel blocker therapy may occasionally result in symptomatic hypotension.
• Angina: Some patients with severe obstructive coronary artery disease have developed increased frequency, duration and/or severity of angina or acute myocardial infarction when starting dihydropyridine CCBs.
• Peripheral edema: Mild to moderate peripheral edema may occur with the dihydropyridine CCBs.
• Gastrointestinal obstruction: There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of nifedipine extended release tablets.

ACE inhibitors

• Anaphylaxis: Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors may be subject to a variety of adverse reactions, some of them serious.
• Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in patients treated with ACE inhibitors. This may occur at any time during the treatment course.
• Intestinal angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.
• Hypotension: ACE inhibitors can cause symptomatic hypotension.
• Agranulocytosis: Captopril has been reported to cause agranulocytosis and bone marrow suppression, particularly in patients with renal impairment, especially if they also have a collagen vascular disease.
• Hepatic impairment: Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and possible death.
• Aortic stenosis: As with all vasodilators, the ACE inhibitors should be given with caution to patients with obstruction in the outflow tract of the left ventricle.
• Renal impairment: Changes in renal function may occur in susceptible individuals (i.e. patients with severe congestive heart failure and renal artery stenosis). Treatment with the ACE inhibitors may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
• Hyperkalemia: Hyperkalemia (serum potassium greater than 10% above the upper limit of normal) has occurred in patients receiving ACE inhibitors.
• Cough: Possibly due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy.
• Hemodialysis: Hypersensitivity-like (anaphylactoid) reactions during hemodialysis with high-flux dialysis membranes (i.e. AN69) has occurred in patients receiving ACE inhibitors.

Angiotensin II receptor blockers

• Hypotension: The angiotensin II receptor blockers may cause symptomatic hypotension, particularly in patients with heart failure or post-myocardial infarction.
• Renal impairment: Changes in renal function may occur in susceptible individuals (i.e. patients with severe congestive heart failure and renal artery stenosis).
• Heart failure: Some patients with heart failure have developed increases in BUN, serum creatinine and potassium.

Beta-blockers

• Beta-blockers are contraindicated in sinus bradycardia, heart block greater than first degree, cardiogenic shock and overt cardiac failure.
• Coronary artery disease: Following abrupt cessation of therapy with certain beta-blocking agents, exacerbations of angina pectoris and, in some cases, myocardial infarction have occurred.
• Thyrotoxicosis: Beta-adrenergic blockade may mask certain clinical signs (i.e. tachycardia) of hyperthyroidism. Abrupt withdrawal, in thyrotoxicosis may precipitate a thyroid storm.
• Bronchospastic disease: Patients with bronchospastic lung diseases should, in general, not receive beta-blockers. However, beta-blockers with beta₁ selectivity may be used with extreme caution in patients with bronchospastic disease.
• Diabetes mellitus: Beta-blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected.
• Heart failure: Worsening cardiac failure may occur during dosage increases; increase diuretic dose and restore clinical stability before further dosage increases; dose reduction or discontinuation may be needed.
• Major surgery and anesthesia: It is not advisable to withdraw beta-adrenoreceptor blocking drugs prior to surgery in most patients. However, care should be taken when using anesthetic agents such as those which may depress the myocardium.
• Peripheral vascular disease: Beta blockers may cause or aggravate symptoms of arterial circulatory disorders.
• Pheochromocytoma: Administration of beta-blockers alone in the setting of pheochromocytoma have been associated with a paradoxical increase in blood pressure due to the attenuation of beta-mediated vasodilatation in skeletal muscle; initiate an alpha-blocker prior to using any beta-blocking agent.
• Bradycardia: Beta-blockers may produce a decrease in sinus heart rate in the majority of patients; this decrease is greatest among patients with high initial heart rates and least among patients with low initial heart rates.

Loop diuretics

• Dehydration: May result in dehydration and volume depletion with circulatory collapse and the possibility of vascular thrombosis and embolism, particularly in the elderly.
• Hepatic cirrhosis and ascites: May precipitate hepatic encephalopathy and coma with sudden fluid or electrolyte alterations.
• Ototoxicity: Tinnitus, reversible and irreversible hearing impairment, deafness and vertigo has been reported. Typically associated with rapid injection (infusion rate not to exceed 4 mg/min in adults), severe renal impairment, higher than recommended doses, hypoproteinemia or concomitant ototoxic drugs.
• Electrolyte imbalance (i.e. hyponatremia, hypochloremic metabolic alkalosis, hypokalemia, hypomagnesemia, hypocalcemia) may occur, especially in patients with restricted salt intake who receive higher drug doses. Serum electrolytes should be monitored periodically.
• Radiocontrast nephropathy: Increased incidence of deterioration in renal function after receiving radiocontrast.
• Hypokalemia has been reported; especially prevalent with rapid diuresis, inadequate electrolyte intake, cirrhosis or concomitant use with corticosteroids, ACTH, large amounts of licorice or prolonged use of laxatives.
• Hypomagnesemia: Loop diruetics increase the urinary excretion of magnesium.
• Hypocalcemia: May lower serum levels of calcium (rarely cases of tetany have been reported).
• Hyperuricemia: Asymptomatic hyperuricemia can occur and gout may rarely be precipitated.
• Hyperglycemia: Blood glucose increases, alterations in glucose tolerance tests or precipitation of diabetes has been observed.
• Hyperlipidemia: Increases in Total-C, low density lipoprotein (LDL) and triglycerides may occur as well as minor decreases in high-density lipoprotein (HDL).
• Photosensitivity may occur; patients should be encouraged to wear protective clothing and sunscreen.

Potassium sparing diuretics

• Hyperkalemia may occur especially in patients with renal impairment or diabetes and the elderly or severely ill.
• Hyponatremia: Dilutional hyponatremia may occur or be aggravated, especially when used in combination with other diuretics.
• Metabolic acidosis: Spironolactone has been reported to cause hyperchloremic metabolic acidosis usually in association with hyperkalemia, in some patients with decompensated hepatic cirrhosis, even in the presence of normal renal function.
• Renal impairment: May cause a transient elevation of blood urea nitrogen (BUN), especially in patients with pre-existing renal impairment.
• Hepatic impairment: Hepatic encephalopathy may occur in patients with pre-existing liver impairment.
• Gynecomastia: Spironolactone use may cause gynecomastia which is usually reversible with discontinuation of the drug. In rare cases, breast enlargement may persist after spironolactone is discontinued.
• Kidney stones: Triamterene has been found in renal stones with other calculus components and therefore, should be used cautiously in patients with history of kidney stone formation.

Direct renin antagonists

• Angioedema: Angioedema of the face, extremities, lip, tongue, glottis and/or larynx has been reported in patients treated with aliskiren and has necessitated hospitalization and intubation.
• Volume- or salt depleted patients: In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (i.e. those receiving high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with aliskiren.
• Hyperkalemia: May occur when used in combination with an ACE inhibitor in a diabetic population.

Peripheral alpha-adrenergic blockers

• Cataract surgery: Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on, or previously treated with, alpha₁ blockers.
• Syncope: Alpha₁ antagonists can cause marked hypotension, especially in the upright position, with syncope and other postural symptoms such as dizziness.
• Priapism: Rarely, alpha₁ antagonists have been associated with priapism.
• Myocardial infarction, cerebrovascular spasm and cerebrovascular occlusion have been reported to occur following the administration of phentolamine, usually in association with marked hypotensive episodes.
• Tachycardia and cardiac arrhythmias may occur with the use of phentolamine or other alpha₁ adrenergic blocking agents.

Central alpha-adrenergic agonists

• Abrupt discontinuation: Abrupt cessation of therapy with orally active central alpha adrenergic agonists may result in nervousness, agitation, headache and tremor accompanied or followed by a rapid rise in blood pressure and elevated catecholamine concentrations in the plasma. Rare instances of hypertensive encephalopathy, cerebrovascular accidents and death have been reported after clonidine withdrawal.
• Central alpha-adrenergic agonists should be used with caution in patients with severe coronary insufficiency, conduction disturbances, recent myocardial infarction, cerebrovascular disease or chronic renal failure.
• Sedation: Orally active central α2 adrenergic agonists may cause sedation or drowsiness, especially when beginning therapy.
• Defibrillation or cardioversion: Transdermal clonidine systems should be removed before attempting defibrillation or cardioversion because of the potential for altered electrical conductivity which may increase the risk of arcing.
• Magnetic resonance imaging (MRI): Remove transdermal clonidine before undergoing MRI as the aluminium in the patch can cause skin burns at application site.
• Dialysis patients: Hypertension has recurred occasionally after dialysis in patients given methyldopa because the drug is removed by this procedure.
• Edema: Some patients taking methyldopa experience clinical edema or weight gain which may be controlled by the use of a diuretic. Methyldopa should not be continued if edema progresses or signs of heart failure appear.
• Hemolytic anemia: A positive Coombs test, hemolytic anemia and liver disorders have been reported with methyldopa therapy.

Arterial vasodilators

• Angina pectoris: Can increase heart rate and precipitate or worsen angina during first time usage. Concomitant administration of a beta-adrenergic blocking drug or other sympathetic nervous system suppressant is usually required to prevent this occurrence.
• Malignant hypertension: To prevent a rapid decrease in BP, any patient with malignant hypertension should have initial treatment with minoxidil carried out in a hospital setting.
• Fluid retention: Minoxidil should be administered concomitantly with a loop diuretic to prevent fluid retention and possible congestive heart failure.
• Myocardial infarction (recent): The use of minoxidl has not been established in patients who have had a myocardial infarction within the preceding month.
• Pericarditis and pericardial effusion: Pericarditis and pericardial effusion, occasionally with tamponade, has been reported with minoxidil use.
• Cerebrovascular disease: The “hyperdynamic” circulation caused by hydralazine may accentuate specific cardiovascular inadequacies (i.e. cerebrovascular disease).
• Coronary artery disease: Hydralazine may cause angina and ECG changes of myocardial ischemia.
• Peripheral neuritis: Peripheral neuritis, evidenced by paresthesias, numbness and tingling, has been observed with hydralazine.
• Blood dyscrasias: Blood dyscrasias, consisting of reduction in hemoglobin and red cell count, leukopenia, agranulocytosis and purpura have been reported with hydralazine use.
• Systemic lupus erythematosis: Hydralazine may cause drug-induced lupus including glomerulonephritis.

Postganglionic adrenergic neuron blocker

• Asthma: Postganglionic adrenergic neuron blockers could aggravate asthma and special care should be exercised when treating patients with a history of bronchial asthma.
• Depression: Reserpine may cause mental depression.
• Gastrointestinal disorders: Reserpine increases gastrointestinal motility and secretion and should be used cautiously in patients with a history of peptic ulcer, ulcerative colitis or gallstones (biliary colic may be precipitated).
• Orthostatic hypotension: Postural and exercise hypotension may occur with guanethidine and guanadrel use.
• Guanethidine and guanadrel should be avoided in patients with congestive heart failure, coronary insufficiency or recent myocardial infarction and cerebrovascular disease.
• Anesthesia: Guanethidine therapy should be withdrawn 2 weeks prior to surgery to reduce the possibility of vascular collapse and cardiac arrest during anesthesia.
• Peptic ulcer disease: Guanethidine should be used cautiously in patients with a history of peptic ulcer disease or other chronic disorders that may be aggravated by a relative increase in parasympathetic tone.
• Renal impairment: Guanethidine should be used very cautiously in hypertensive patients with renal disease and nitrogen retention or rising BUN levels.

Intravenous vasodilators

• Anesthesia: When vasodilators are used for controlled hypotension during anesthesia, the patient’s capacity to compensate for anemia and hypovolemia may be diminished.
• Cyanide toxicity: Nitroprusside infusions at rates above 2mcg/kg/min may cause cyanide toxicity.
• Intracranial pressure: Nitroprusside can cause increases in intracranial pressure.
• Excessive hypotension: Small transient excesses in the infusion rate of nitroprusside can result in excessive hypotension.
• Congestive heart failure: The antidiuretic property of diazoxide may lead to significant fluid retention and may precipitate congestive heart failure.
• Hyperglycemia: Diazoxide can decrease insulin secretion and cause hyperglycemia.
• Ketoacidosis and nonketotic hyperosmolar coma: Ketoacidosis and nonketotic hyperosmolar coma have been reported in patients treated with diazoxide.
• Polyvinyl chloride (PVC) tubing: Nitroglycerin may be absorbed by PVC tubing and should be used with the least absorptive infusion tubing (i.e. non-PVC tubing) available.
• Nitroglycerin is contraindicated in patients with pericardial tamponade, restrictive cardiomyopathy or constrictive pericarditis.
• Hypotension and shock: Severe hypotension and shock may occur with even small doses of nitroglycerin.
• Angina: Nitroglycerin therapy may aggravate angina caused by hypertrophic cardiomyopathy.

Dopamine-1 receptor agonist

• Glaucoma/intraocular hypertension: Fenoldopam may cause a dose-dependent increase in intraocular pressure (IOP) and should be used with caution in patients with glaucoma or intraocular hypertension.
• Hypokalemia: Occasionally hypokalemia (potassium levels <3 mEq/L) were observed after less than 6 hours of fenoldopam infusion.
• Hypotension: Fenoldopam may occasionally produce symptomatic hypotension; close blood pressure monitoring during administration is essential.
• Tachycardia: Fenoldopam causes a dose-related tachycardia, particularly with infusion rates above 0.1 mcg/kg/min.

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