Introduction
The formal classification and blood pressure (BP) threshold to define an individual as having hypertension continues to vary based on available evidence. The appraisal of such evidence by professional associations and societies has led to different BP thresholds adopted in guidelines worldwide. Given that the thresholds by which we define hypertension can and will continue to evolve, it is less helpful to think of hypertension in a binary sense, but more helpful to view increasing BP as a risk factor with a continuous linear-log relationship with coronary artery disease, stroke, heart failure (HF), and cardiovascular (CV) mortality. Ultimately, most clinicians would be operationally well served to consider defining hypertension as a BP level above which investigation and treatment does more good than harm.
While lifestyle intervention is the cornerstone of therapy by all guidelines, most people will also require antihypertensive medications. There are ten different medication classes available to lower BP. Each class addresses one or more of the multiple pathophysiological processes that are associated with development and maintenance of hypertension ( Fig. 2.1 ) and subsequent CV and renal complications ( Fig. 2.2 ). Although guidelines tend to favor certain drug classes in specific patient populations, it is critical to remember that the current available evidence suggests that more important than a specific class of medication used, is the magnitude of BP lowering achieved.
Individualizing the choice of medication based on the clinical presentation, keeping in mind the presence of other comorbid conditions and desire to limit adverse effects that may lead to medication nonadherence is critical. Additionally, it must be emphasized that more important than individualizing medication choice while treating hypertension, is appropriate patient education about lifestyle modifications.
An overview of the major drug classes and contemporary hypertension guidelines is initially discussed in the chapter. This is followed by a discussion of each pharmacologic class available for the treatment of hypertension, and the associated mechanism of action, data for use, side effects, and drug interactions for each drug class.
Drug Class Overview and Guidelines
Blood pressure–lowering medications can be grouped into ten major categories, with some subcategories within the group ( Table 2.1 ). These categories act by different mechanisms and at different sites in the body to address alterations in BP ( Fig. 2.3 ). Certain antihypertensive medications may lower BP by more than a single mechanism. For example, carvedilol has both β- and α-blocking properties, and spironolactone is a mineralocorticoid receptor antagonist, but also acts as a diuretic at higher doses. Care was taken to classify such drugs in the category that they are most commonly encountered. Table 2.2 provides a broad overview of the more commonly used drug categories for the outpatient managements of hypertension, including compelling indications and contraindications. Table 2.3 provides an overview of the medications used in the treatment of hypertensive emergency.
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| Class of drug | Favored indications | Possible indications | Compelling contraindications | Possible contraindications |
|---|---|---|---|---|
| Diuretics (thiazide-type) | Heart failure Older adults with hypertension Systolic hypertension Black patients | Obesity | Gout | Pregnancy Dyslipidemia Metabolic syndrome |
| Diuretics (loop) | Heart failure Renal failure | Hypokalemia | ||
| Mineralocorticoid receptor antagonists | Heart failure Post-MI Primary Aldosteronism | Resistant hypertension | Hyperkalemia Renal failure | Diabetic renal disease |
| Calcium channel blockers | Angina Older adults Systolic hypertension | Peripheral vascular disease Diabetes African origin | Heart block a Clinical heart failure (exception amlodipine) | Preexisting lower extremity edema |
| ACE inhibitors | Left ventricular systolic dysfunction or failure Proteinuria | CV protection Type 2 nephropathy | Pregnancy Hyperkalemia Bilateral renal artery stenosis | Severe cough |
| Angiotensin-II antagonists (ARBs) | ACE inhibitor cough LVH Heart failure | Post MI | Pregnancy Bilateral renal artery stenosis Hyperkalemia | Severe aortic stenosis |
| β-blockers | Angina Tachyarrhythmias Post-MI Heart failure | Pregnancy Diabetes | Asthma, severe COPD Heart block b | Obesity Metabolic syndrome Athletes and exercising patients Erectile dysfunction |
a Grade 2 or 3 atrioventricular block with verapamil or diltiazem.
| Agent | Dose | Onset/duration of action (after discontinuation) | Precautions/contraindications |
|---|---|---|---|
| Parenteral vasodilators | |||
| Nitroprusside | 0.25–10.0 μg/kg/min as IV infusion maximal dose for 10 min only | 1–2 min after infusion | Nausea, vomiting, muscle twitching; with prolonged use may cause thiocyanate intoxication, methemoglobinemia acidosis, cyanide poisoning |
| Fenoldopam | 0.1–0.3 μg/kg/min IV infusion, increase every 15 min until BP goal is reached | 5–15 min/30–60 min | Headache, tachycardia, flushing, local phlebitis |
| Nitroglycerin | 5–200 μg/min as IV infusion, 5 μg/min increase every 5 minutes | 1–5 min/3–5 min | Headache, reflex tachycardia, vomiting, flushing, methemoglobinemia |
| Nicardipine | 5–15 mg/h IV infusion | 1–5 min/30–40 min, but may exceed 12 h after prolonged infusion | Reflex tachycardia, nausea, vomiting, headache, increased intracranial pressure; hypotension may be protracted after prolonged infusions |
| Clevidipine | 2 mg/h IV infusion, increase every 2 min with 2 mg/h as IV bolus, repeated, or 15–30 mg/min by IV infusion | 2–3 min/5–15 min | Headache and reflex tachycardia |
| Hydralazine | 10–20 mg as IV bolus or 10–40 mg IM, repeat every 4–6 h | 10 min IV/>1 h IV; 20–30 min IM/4–6 h IM | Tachycardia, headache, vomiting |
| Enalaprilat | 0.625–1.250 mg every 6 h IV | 15–15 min/4–6 h | Renal failure in patients with bilateral renal artery stenosis, hypotension, history of angioedema |
| Parenteral adrenergic inhibitors | |||
| Labetalol | 0.25–0.5 mg/kg IV bolus; 2–4 mg/min as IV infusion until BP goal is reached, 5–20 mg/h subsequently | 5–10 min/3–6 h | History of 2nd- or 3rd-degree AV block, HFrEF, asthma, bradycardia |
| Metoprolol | 2.5–5 mg IV bolus over 2 min, repeat every 5 min to maximum of 15 mg | 1–2 min/5–8 h | History of 2nd- or 3rd-degree AV block, HFrEF, asthma, bradycardia |
| Esmolol | 0.5–1 mg/kg IV bolus or 50–300 μg/kg/min by infusion | 1–2/10–30 min | Greater than first-degree heart block, bradycardia, HFrEF, asthma |
| Phentolamine | 0.5–1 mg/kg as IV bolus OR 50–300 μg/kg/min by infusion | 1–2/10–30 min | Tachyarrhythmias, orthostatic hypotension |
| Clonidine | 150–300 μg IV bolus in 5–10 min | 30 min/4–6 h | Sedation and rebound hypertension |
The most contemporary guidelines for the treatment of elevated BP in the United States were published in 2017 and endorsed by the American College of Cardiology and the American Heart Association among other professional organizations. Additional American guidelines for the treatment of resistant hypertension were published in the fall of 2018. The European Society of Hypertension/European Society of Cardiology (ESH/ESC) BP guidelines were also published in the fall of 2018. A comparison of these guidelines demonstrates more similarities than differences. Highlighted in both is a stronger push toward use of combination therapy (i.e., multiple medications in a single tablet or pill). The ESH/ESC guidelines recommend this strategy as initial therapy in all hypertensive patients, while United States guidelines recommend such a strategy for patients that are greater than 20/10 mmHg above systolic and/or diastolic BP goals. Multiple studies demonstrate the value of combination therapy as more effective with fewer side effects.
Diuretics
Mechanism of Action
Diuretics alter physiologic renal mechanisms to increase the flow of urine with greater excretion of sodium or natriuresis. This results in a wide range of effects on BP. Moreover, thiazide type diuretics also result in mild vasodilation and, hence, provide an additional mechanism for BP lowering.
Thiazide-type diuretics inhibit the reabsorption of sodium and chloride in the more distal part of the nephron. This distal cotransporter is insensitive to loop diuretics. Increased sodium reaches the distal tubules to stimulate exchange with potassium, particularly in the presence of an activated renin-angiotensin-aldosterone system. Thiazides may also increase the active excretion of potassium in the distal renal tubule. Oral formulations are rapidly absorbed from the gastrointestinal tract to produce a diuresis within 1 to 2 hours, although the overall longevity of this effect varies significantly between the most commonly used thiazide-type diuretics in the United States, hydrochlorothiazide (HCTZ) and chlorthalidone.
Loop diuretics, including the most commonly used furosemide and torsemide, inhibit the Na + /K + /2Cl– cotransporter associated with the transport of chloride across the lining cells of the ascending limb of the loop of Henle. This site of action is reached intraluminally, after the drug has been excreted by the proximal tubule. The effect of the cotransport inhibition is that chloride, sodium, potassium, and hydrogen ions all remain intraluminally and are lost in the urine with the possible side effects of hyponatremia, hypochloremia, hypokalemia, and an alkalosis. In comparison with thiazide-type diuretics, there is a relatively greater urine volume and relatively less loss of sodium.
Thiazide-type diuretics as a class differ from the loop diuretics in that they have a longer duration and site of action. Additionally, thiazides are so-called low-ceiling diuretics, because the maximal response is reached at a relatively low dose and they demonstrate a decreased capacity to exert a predictable in the presence of renal failure. The fact that thiazides and loop diuretics act at different tubular sites explains their additive effects, termed sequential nephron block.
Potassium-sparing diuretics such as amiloride and triamterene are occasionally used in combination with thiazide-type diuretics to reduce hypokalemia and lessen the incidence of serious ventricular arrhythmias in hypertension. Amiloride acts on the renal epithelial sodium channel and triamterene inhibits the sodium-proton exchanger, so that both lessen sodium reabsorption in the distal tubules and collecting tubules. Unto themselves they are comparatively weak diuretics.
Differences Within Class
Among thiazide-type diuretics, HCTZ is the most widely used. It has a bioavailability ranging from 60% to 80%. Its absorption may be decreased in HF and/or chronic kidney disease (CKD.) Chlorthalidone and indapamide differ from HCTZ, and hence are called thiazide-like (leading to the terminology of thiazide-type encompassing both thiazide and thiazide-like diuretics.) Both chlorthalidone and indapamide are preferentially recommended for the treatment of resistant hypertension. Indapamide is widely used in Europe and is available in the United States, but much less commonly used. Head-to-head comparisons among thiazide-type diuretics do not demonstrate significant differences for BP reduction when equivalent doses are used. However, comparisons between thiazide and thiazide-type diuretics have clear differences regarding magnitude and duration of BP reduction. Moreover, chlorthalidone at a dose of 25 mg is comparatively effective to 50 mg of HCTZ, particularly with respect to the treatment of nocturnal hypertension.
Thiazide-like and thiazide diuretics can be very different pharmacokinetically. Chlorthalidone compared to HCTZ has both a considerably longer half-life, approximately 40–60 hours, and a larger volume of distribution. Metolazone is a powerful thiazide, diuretic with a quinazoline structure. An important advantage of metolazone is efficacy even despite decreased kidney function and is usually used in concert with loop diuretics for edema management. The duration of action is up to 24 hours. In combination with furosemide, metolazone may provoke a profound diuresis, with known risk of excessive volume and potassium depletion. Tables 2.4 and 2.5 highlight important pharmacokinetic differences between loop and thiazide diuretics.
| Drug | Dose | Pharmacokinetics |
|---|---|---|
| Furosemide | 10–40 mg oral, 2 × for BP Up to 250–2000 mg oral or IV | Diuresis within 10–20 min Peak diuresis at 1.5 h Total duration of action 4–5 h Renal excretion Variable absorption 10%–100% |
| Bumetanide | 0.5–2 mg oral 1–2 × daily (not licensed for BP treatment) | Peak diuresis 75–90 min Total duration of action 4–5 h Renal excretion Absorption 80%–100% |
| Torsemide | 5–20 mg oral 1 × daily for BP | Diuresis within 10 min of IV dose; peak at 60 min Oral peak effect 1–2 h Oral duration of diuresis 6–8 h Absorption 80%–100% |
| Dose | Duration of action (h) | |
|---|---|---|
| Hydrochlorothiazide | 12.5–25 mg, 12.5 mg preferred | 16–24 |
| Chlorthalidone | 12.5–50 mg, 12.5 to 15 preferred (BP) | ≈ 40–60 |
| Metolazone | 2.5–5 mg (BP); 5–20 mg (HF) | 24 |
| Chlorothiazide | 250 a –1000 mg | 6–12 |
| Indapamide | 1.25–2.5 mg, 1.25 mg preferred (BP); 2.5–5 mg (HF) | 24 |
a Lowest effective antihypertensive dose not known; may prefer to use other agents for blood pressure control.
Among loop diuretics, furosemide is the most widely used. However, its use can be complicated by erratic absorption, with wide bioavailability ranges and a half-life of < 6 hours. Also complicating the use of furosemide is that the coefficient of variation for absorption varies for different generic products. As such, substituting one furosemide formulation for another will not standardize patient absorption and thus response. Bumetanide and torsemide are more predictable for oral absorption.
The short duration of action of loop diuretics means that frequent doses are needed when sustained diuresis is required in patients with hypertension. Twice-daily doses of furosemide should be given in the early morning and midafternoon to avoid nocturia. Furosemide causes a greater and earlier (0 to 6 hours) absolute loss of sodium than HCTZ. However, because of its short duration of action, the total 24-hour sodium loss may be insufficient to maintain the slight volume contraction needed for sustained antihypertensive action. In oliguria (not induced by volume depletion), as the glomerular filtration rate (GFR) drops to less than 20 mL/min, very high dose of furosemide may be required because of decreasing luminal excretion. In hypertension , twice-daily low-dose furosemide can be effective even as monotherapy or combined with other agents and is increasingly needed as renal function deteriorates ; however, torsemide, because of its longer half-life, is preferred among those who require a loop diuretic for hypertension management.
With respect to bumetanide and torsemide, their clinical effects and side effects are very similar to furosemide. As in the case of furosemide, a combined diuretic effect is obtained by addition of a thiazide diuretic. In contrast to furosemide, oral absorption of both agents is predictable at 80% or more. In the United States, bumetanide use for hypertension is an off-label indication, but if used should be given three times a day because of its short half-life. It is much more effective for diuresis, intravenously, in low-albumin states. Torsemide demonstrates a longer duration of action than furosemide and bumetanide. The consistency of torsemide’s absorption and its longer duration of action are distinguishing pharmacologic features among loop diuretics.
Clinical Application
Thiazide diuretics remain among the medication classes recommended for first-line therapy for hypertension. Thiazide-type diuretics demonstrate wide-ranging CV benefits. Diuretics were key components of an additive regimen used by the Veterans Administration (VA) Cooperative Study Group started in the 1960s, a study that convincingly proved the benefits of BP control. Both the severe (diastolic, 115–129 mmHg) and mild to moderate (diastolic, 90–104 mmHg) subgroups demonstrated reduced CV morbidity and mortality with BP reduction. Only 2.7 patients needed to be treated to prevent a major CVD event in either BP group. There are outcome trials with doses of 100 and 200 mg of HCTZ, however, had very high adverse event profiles.
Chlorthalidone is effective in both BP reduction and improving CV outcomes. Chlorthalidone is preferred for hypertension the major reason being that HCTZ has no outcome studies in hypertension at the doses commonly used, i.e., 12.5 and 25 mg/day. Low-dose diuretics are often the initial agent of choice in low-renin groups such as older adults and in black patients. By contrast, in younger white patients (mean age 51 years) only one-third responded to escalating doses of HCTZ over 1 year. Thus the BP response rate in hypertension to thiazide-type monotherapy is variable and may be underwhelming, depending in part on the age and race of the patient, and also on the patient’s oral sodium intake.
Chlorthalidone was the sole agent used in three seminal BP trials: The Systolic Hypertension in the Elderly Program (SHEP), the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the Systolic Blood Pressure Intervention Trial (SPRINT).
SHEP examined the impact of first-line chlorthalidone based antihypertensive therapy compared with placebo on the incidence of stroke and other CV events in 4736 participants over the age of 60, with isolated systolic hypertension for an average of 4.5 years. The chlorthalidone-based regimen decreased the incidence of stroke by 36%, myocardial infarction (MI) by 27%, HF by 54%, and overall CV morbidity by 32%.
ALLHAT randomized 42,000 participants with hypertension and known CV disease or at least one other coronary artery disease risk factor to initial BP-lowering therapy with chlorthalidone, doxazosin, lisinopril, or amlodipine. There was no difference among these four agents for the primary outcome or mortality. However, secondary outcomes were similar except for a 38% higher rate of HF with amlodipine; a 10% higher rate of combined CVD, a 15% higher rate of stroke, and a 19% higher rate of HF with lisinopril; and a 20% higher rate of CVD, a 20% higher rate of stroke, and an 80% higher rate of HF with doxazosin, compared with chlorthalidone. For stroke, there was a statistically significant race-by-treatment interaction. Chlorthalidone was superior to lisinopril in preventing incident stroke only in blacks.
Most recently, the primary diuretic used in the SPRINT was chlorthalidone. Published in 2015, it was the major impetus for guideline recommendations for more aggressive BP lowering. The enrolled population was non-diabetics at elevated CV risk. The trial was stopped early due to a significant reduction of the primary composite endpoint of major adverse CV events in the lower BP target group. Interestingly the same BP targets were studied in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) BP trial published in 2010 and did not demonstrate a significant reduction in major adverse CV events. There are many theories about why a significant difference in adverse events was seen in SPRINT and not in ACCORD. Commonly cited reasons include the addition of acute decompensated HF as a component of the composite primary endpoint in SPRINT and was likely impacted by the use of chlorthalidone rather than HCTZ in ACCORD-BP. In a meta-analysis of 108 trials, chlorthalidone was better in lowering systolic BP, at the cost of more hypokalemia.
The major outcome trial for indapamide is the Hypertension in the Very Elderly Trial (HYVET) study. Patients 80 years of age or older with a systolic BP of 160 mmHg or higher received indapamide 1.5 mg with the angiotensin-converting enzyme (ACE) inhibitor perindopril (2 or 4 mg) added if necessary, to achieve the target BP of 150/80 mmHg. Benefits were a significant reduction of 21% in death from any cause, with 39% reduction in stroke deaths as well as a 64% reduction in HF.
One trial that suggests combination therapy with an ACE-inhibitor and HCTZ may not be preferable to an ACE-inhibitor and calcium channel antagonist combination is The Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension trial (ACCOMPLISH). It investigated the ideal initial combination therapy by comparing an ACE-inhibitor and diuretic or ACE-inhibitor and calcium channel blocker (CCB) combination. The trial randomized 11,506 patients to benazepril/amlodipine or benazepril/HCTZ. During a mean follow-up of 2.5 years, benazepril/amlodipine was associated with reduced CV events (9.6% versus 11.8%). The most significant criticism of the trial was the use of a short-acting HCTZ, rather than the long-acting chlorthalidone. However, a 2010 follow-up 24-hour ambulatory BP monitoring study from the ACCOMPLISH authors studied 573 patients on the HCTZ formulation and found no significant difference in BPs throughout a 24-hour period.
Loop diuretics should not be used as first-line therapy in hypertension, since there are no outcome data with them. They should be reserved for conditions of clinically significant fluid overload (i.e., HF and significant fluid retention with vasodilator drugs, such as minoxidil) or in the presence of advanced renal failure.
Side Effects
Many side effects of thiazides are like those of the loop diuretics and are dose dependent. These side effects include those with established mechanisms (electrolyte and metabolic derangements) and other side effects that are not as well understood mechanistically (such as erectile dysfunction.) Thiazide-related biochemical side effects are more common with longer-acting formulation at increasing doses. Lower doses of thiazide-type diuretics produce fewer biochemical alterations and provide full antihypertensive as shown in several large trials. In the SHEP study, chlorthalidone 12.5 mg was initially used and after 5 years 30% of the subjects were still on the lower dose.
Volume depletion
The possibility of excessive diuresis exists, thus resulting in reduced intravascular volume and ventricular filling so that the cardiac output drops and tissues become under-perfused. The renin-angiotensin system (RAS) and the sympathetic nervous system are further activated in a volume depleted state. Patients can manage their therapy well by tailoring a flexible diuretic schedule to their own needs. This can also include every other day dosing of chlorthalidone that has a very long duration of action.
Hypokalemia and Hypomagnesemia
Hypokalemia is likely an over-feared complication, especially when low doses of thiazides are used. Nevertheless, the frequent combination of thiazide-type diuretics with the potassium-retaining agents including the ACE inhibitors, angiotensin II receptor blockers (ARBs), or mineralocorticoid receptor antagonists is appropriate, with the alternative, but lesser, risk of hyperkalemia, particularly in the presence of renal impairment.
Dietary potassium increases are the simplest recommendation to provide patients that experience hypokalemia. High-potassium and low-sodium intake may be achieved by fresh foods and salt substitutes. If unable to achieve via one’s diet, a potassium-sparing agent, coadministration with an ACE-inhibitor, ARB, or a mineralocorticoid receptor antagonist is preferable to oral potassium supplementation, especially because the supplements do not correct hypomagnesemia.
Conventional doses of diuretics rarely cause magnesium deficiency, but hypomagnesemia, like hypokalemia, is blamed for arrhythmias of QT-prolongation during diuretic therapy.
Hyponatremia
Thiazides and thiazide-like diuretics can cause hyponatremia, especially in older patients (more so in women) in whom free water excretion is impaired. In SHEP, hyponatremia occurred in 4% of patients treated with chlorthalidone versus 1% in the placebo group. Occurring rapidly (within 2 weeks), mild thiazide-induced hyponatremia can cause a vague constellation of symptoms including fatigue and nausea. When severe hyponatremia occurs, it may result in confusion, seizures, coma, and death. Hyponatremia occurs more so with thiazide-type diuretics than loop diuretics because thiazide-type diuretics do not interfere with the ability of the kidney to maximally concentrate urine
Diabetes
Diuretic therapy for hypertension increases the risk of new diabetes by approximately one-third, versus placebo. The thiazides are more likely to provoke diabetes if combined with a β-blocker. This risk depends on the thiazide dose and possibly on the type of β-blocker, in that carvedilol or nebivolol are exceptions. Patients with a familial tendency to diabetes or those with the metabolic syndrome are probably more prone to the diabetogenic side effects. Although there are no large prospective studies on the effects of loop diuretics on insulin insensitivity or glucose tolerance in hypertensive patients, it is clearly prudent to avoid hypokalemia and to monitor both serum potassium and blood glucose values.
Hyperuricemia and Gout
Thiazide-induced hyperuricemia can occur as a result of volume contraction and competition of thiazides with uric acid for renal tubular secretion. Most diuretics decrease renal urate excretion with the risk of increasing blood uric acid, causing gout in a subset of patients. In 5789 persons with hypertension, 37% were treated with a diuretic. Use of any diuretic (HR 1.48; CI 1.11–1.98), a thiazide diuretic (HR 1.44; CI 1.00–2.10), or a loop diuretic (HR 2.31; CI 1.36–3.91) increased the risk of gout. Cotherapy with losartan lessens the rise in uric acid. Use of loop diuretics more than doubles the risk of gout.
Changes in blood lipids
Thiazides may increase the total blood cholesterol in a dose-related fashion. Low-density lipoproteins (LDL) cholesterol and triglycerides increase after 4 months with HCTZ (40-mg daily mean dose). In the TOMH study, low-dose chlorthalidone (15 mg daily) increased cholesterol levels at 1 year but not at 4 years. Atherogenic blood lipid changes, like those found with thiazides, may also be found with loop diuretics.
Hypercalcemia
Thiazide diuretics tend to retain calcium by increasing proximal tubular reabsorption (along with sodium). The benefit is a decreased risk of hip fractures in older adults. Conversely, especially in hyperparathyroidism, hypercalcemia may be precipitated.
Erectile Dysfunction
In the TOMH study, low-dose chlorthalidone (15 mg daily given over 4 years) was the only one of several antihypertensive agents that doubled impotence.
Sulfonamide Sensitivity
In addition to the metabolic side effects seen with previously used high doses, thiazide diuretics rarely cause sulfonamide-type immune side effects including intrahepatic jaundice, pancreatitis, blood dyscrasias, pneumonitis, interstitial nephritis, and photosensitive dermatitis. Ethacrynic acid is the only nonsulfonamide diuretic and is used generally only in patients allergic to other diuretics. It closely resembles furosemide in dose (25 and 50 mg tablet), duration of diuresis, and side effects. If ethacrynic acid is not available for a sulfonamide-sensitive patient, a gradual challenge with furosemide or, even better, torsemide may overcome sensitivity.
Drug Interactions
Adverse interactions include the blunting of thiazide effects by nonsteroidal antiinflammatory drugs (NSAIDs) and coadministration of corticosteroids, which may cause salt retention to disrupt the action of thiazide-type diuretics. Lithium levels should be monitored closely in lithium-treated patients because thiazide diuretics can reduce lithium excretion and precipitate lithium toxicity. Antiarrhythmic that prolong the QT-interval, such as Class IA or III agents including sotalol, may precipitate torsades de pointes in the presence of diuretic-induced hypokalemia. Cotherapy with certain aminoglycosides can precipitate ototoxicity. Nonsteroidal antiinflammatory drugs lessen the renal response to loop diuretics, presumably by interfering with formation of vasodilatory prostaglandins. High doses of furosemide may competitively inhibit the excretion of salicylates to predispose to salicylate poisoning with tinnitus. Steroid or adrenocorticotropic hormone (ACTH) therapy may predispose to hypokalemia.
Calcium Channel Blockers
Mechanism of Action
Calcium channel blockers (CCBs) impede the movement of extracellular calcium through ion-specific channels within the cell wall ( Fig. 2.4 ). This ultimately reduces calcium flux inward, which results in arterial dilation via smooth muscle relaxation and subsequent BP lowering. They may also cause a decrease in cardiac contractility and a slowing of AV conduction velocities. Calcium channel blockers act primarily to reduce peripheral vascular resistance and, within the renal vasculature, produce natriuresis by increasing renal blood flow, dilating afferent arterioles, and increasing glomerular filtration pressure. Nondihydropyridine CCBs also importantly reduce albuminuria by improving glomerular permselectivity and lowering the perfusion pressure of the kidney ( Fig. 2.5 ).
Differences Among Drugs in Class
A major differentiating point amongst CCBs is the classification of dihydropyridine and nondihydropyridine CCBs. Commonly used dihydropyridine CCBs include amlodipine and nifedipine. Commonly encountered nondihydropyridine CCBs include verapamil and diltiazem.
Dihydropyridines with short elimination half-lives typically cause reflex tachycardia and sympathetic activation. This effect has been mitigated with the advent of longer-acting and extended-release preparations.
Nondihydropyridine CCBs produce more negative chronotropic and inotropic effects than dihydropyridines, which is important for patients with cardiac arrythmias or who require concomitant administration of β-blockade.
Among nondihydropyridine CCBs, verapamil has more negative chronotropic effects than diltiazem, an effect that makes each useful for acute intravenous treatment and chronic prevention of atrial tachyarrhythmias.
Clinical Application
CCBs demonstrate significant BP reduction across all patient groups, irrespective of sex, race, ethnicity, age, and dietary sodium intake. Thus, they are among the medication classes noted to be first-line therapy for the treatment of primary hypertension.
There are several long-term CV outcome studies with CCBs in hypertension, and the overwhelming result is that CCBs are safe and effective, particularly for prevention of stroke.
CCBs compared with placebo reduced stroke, coronary heart disease, major CV events, and CV death with, however, a trend to increased HF. When compared to BP treatment with diuretics or β-blockers, CCBs had the same effect on CV death and total mortality, increased HF, with a trend toward decreased stroke. Additionally, there were fewer cases of new-onset diabetes with CCBs than with β-blockers or diuretics.
Amlodipine is often used in combination with an ACE inhibitor and provided greater antihypertensive efficacy and better protection against CV events, mortality, and the development of new diabetes than did atenolol-based therapy in the ASCOT trial.
ACCOMPLISH suggests that a combination of ACE inhibitor and CCB, rather than ACE inhibitor–thiazide diuretic, should be the preferred initial therapy in a high-risk hypertensive population. Significantly, initial antihypertensive treatment with benazepril plus amlodipine slowed progression of nephropathy to a greater extent than did benazepril plus HCTZ.
CCBs are particularly effective in older adult patients and do not have more prominent effects in one race or another. They are an ideal choice for the treatment of hypertension if there exist other compelling indications for a CCB such as angina pectoris, microvascular dysfunction, Raynaud phenomenon, or supraventricular tachycardia (use of nondihydropyridine).
The totality of data for the use of CCBs in the treatment of hypertension suggest that an initial strategy of CCB therapy can prevent all major types of CV disease, aside from HF. Initial dihydropyridine CCBs do not reduce the rate of progression of renal disease to the extent as inhibitors of the RAS; however, nondihydropyridine CCBs, such as diltiazem, can reduce albuminuria.
Side Effects
CCBs, unlike many other classes of antihypertensive therapy, do not lead to metabolic disturbances in potassium, glucose, uric acid, or lipid metabolism. However, they are not free from side effects. Higher doses of dihydropyridine CCBs often result in some degree of edema, and can additionally cause flushing, headache, and tachycardia. Lower extremity edema is the most commonly observed of these side effects and is particularly manifest in patients that display indiscretion in dietary sodium intake. Interestingly, a combination with an ACE-inhibitor or ARB is the best way to reduce dihydropyridine CCB–associated edema.
Nondihydropyridine CCBs are contraindicated in patients with bradycardia, sick sinus syndrome, or more advanced heart block (in the absence of a pacemaker.) Additionally, caution must be used in patients with atrial tachyarrhythmias and an accessory bypass tract. Nondihydropyridine CCBs are generally contraindicated in left ventricular systolic dysfunction, acute myocardial infarction, and individuals at high risk of HF with reduced ejection fraction. As an example, use of a diuretic initially in the treatment of hypertension was significantly more effective in preventing HF than any other drug class, including a CCB. Amlodipine’s effects in HFrEF was studied with two significant clinical trials, PRAISE 1 and PRAISE 2, given that is does not have negative inotropic effects. PRAISE 1 suggested a trend toward CV benefit of amlodipine in individuals with nonischemic cardiomyopathy, but PRAISE 2 demonstrated no significant effect on CV outcomes compared with placebo. Thus, use of amlodipine is not contraindicated in HFrEF, but it is often used in those individuals with HFrEF and hypertension.
In patients with CKD, it is uncommon to use CCBs as monotherapy while treating hypertension. Findings from the African American Study of Kidney Disease (AASK) demonstrated that amlodipine was inferior to an ACE-inhibitor in preventing a reduction renal function in nondiabetic patients. Amlodipine was also shown to be inferior to irbesartan in in patients with hypertension, nephropathy and type 2 diabetes.
Drug Interactions
CCBs have many important drug interactions. Chief among them are that diltiazem and verapamil interact with digoxin and cyclosporine, among others. They increase digoxin levels and increase plasma levels of cyclosporine, thus decreasing the dosing requirement for cyclosporine.
Verapamil and diltiazem are metabolized by CYP3A4 pathway; therefore, inducers and inhibitors are likely to result in decreased and increased plasma levels of these two CCBs, respectively. Because of their shared negative effects on heart rate and myocardial contractility, β-blockers and verapamil are not used simultaneously. Pharmacokinetic data show small increases in statin exposure with coadministration of amlodipine and lovastatin or simvastatin. There is no evidence of significant interaction when amlodipine is given with atorvastatin, pitavastatin, rosuvastatin, fluvastatin, and pravastatin.
Angiotensin-Converting Enzyme Inhibitors
Mechanism of Action
Frequent reference is made to the role of the RAS in CV pathologic conditions. The effect of excess angiotensin II and aldosterone contribute to adverse maladaptive vascular processes. Major effects of renin-angiotensin blockade are due to reduced circulating and local concentrations of angiotensin II, and subsequent effect on systemic arterioles, renovascular hemodynamics, the adrenal zona glomerulosa, and the sympathetic nervous system.
ACE inhibitors act on the ACE enzyme that generates angiotensin II from angiotensin I and inactivates the breakdown of bradykinin. Angiotensin I originates in the liver from angiotensinogen under the influence of the enzyme renin, a protease that is made in the juxtaglomerular cells of the kidney. Renin release is stimulated by impaired renal blood flow as seen in ischemia or hypotension, salt depletion or sodium diuresis, and β-adrenergic stimulation.
Understandably, ACE inhibition should work by lessening the complex and widespread effects of angiotensin II. Angiotensin II has essential structural as well as functional effects. A degree of the antihypertensive effect of ACE inhibition may be attributable to withdrawal of angiotensin II’s effect on vascular smooth muscle, which increases arteriolar wall thickness and maintains increased systemic vascular resistance. Additionally, angiotensin II affects matrix protein composition in the heart and blood vessels by promoting the synthesis and deposition of collagen and other structural proteins ( Table 2.6 ). Angiotensin II also stimulates that release of aldosterone from the adrenal cortex. Thus, ACE inhibition is also associated with aldosterone reduction and has potential indirect natriuretic and potassium-retaining effects. Aldosterone formation does not, however, stay fully blocked during prolonged ACE inhibitor therapy. ACE inhibitors also demonstrate indirect antiadrenergic effects because angiotensin II promotes the release of norepinephrine and enhances adrenergic tone. Furthermore, angiotensin II amplifies the vasoconstriction achieved by α 1 -receptor stimulation.
| Heart |
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| Coronary arteries |
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| Kidneys |
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| Adrenals |
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| Coagulation system |
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