Antihypertensive Pharmacology
Note: This is a pre-peer-reviewed version of a chapter in the AHA Comprehensive Guide on Hypertension.
Pharmacologic treatment is the mainstay of hypertension management and a wide variety of agents have proven effective in lowering blood pressure and reducing adverse sequelae of hypertension. Antihypertensive agents are typically grouped into classes according to their putative primary mechanism of antihypertensive action. Classes may be further grouped according to the pathophysiologic pathway or system being targeted, including volume reduction (various diuretics), renin-angiotensin-aldosterone system inhibition (angiotensin-converting enzyme [ACE] inhibitors, angiotensin-receptor blockers [ARBs], direct renin inhibitors), sympathetic nervous system inhibition (α-blockers, β-blockers, sympatholytics), or vasodilation (calcium channel blockers, direct arterial vasodilators).
General Principles of Antihypertensive Drug Action
Optimal use of antihypertensive pharmacotherapy requires a strong foundational knowledge of the general principles of antihypertensive drug actions. This section summarizes some of the important considerations related to pharmacology (pharmacokinetics, pharmacodynamics), dosing, and treatment response that are broadly applicable across antihypertensive classes and drugs.
Pharmacokinetics generally describes the processes that direct drug disposition within the body. From a clinical standpoint, there are four important pharmacokinetic parameters that govern drug disposition:
- Bioavailability: the extent to which the administered dose reaches the site of action or systemic circulation
- Volume of distribution (Vd): the space available in the body to contain the drug
- Clearance: the efficiency of the body in eliminating the drug from systemic circulation
- Elimination half-life (t1/2): the rate of removal of the drug from systemic circulation
For antihypertensives, oral bioavailability is usually high across most classes and Vd is of relatively little clinical significance. However, clearance is clinically relevant. Impaired clearance can occur in patients with significant renal impairment, and drugs relying on glomerular filtration or tubular secretion may require dosage adjustments or may be less effective (e.g., thiazide and thiazide-like diuretics). Likewise, hepatic impairment can reduce clearance of drugs that are cleared primarily by hepatic processes (e.g., some \(\beta\)-blockers and calcium channel blockers), or prevent the conversion of prodrugs (a medication or compound that, after administration, is metabolized into a pharmacologically active drug) into their active forms (e.g., many ACE inhibitors). Clearance is also closely related to elimination t1/2 because impaired clearance increases the elimination t1/2 for a drug (presuming Vd remains unchanged), which can increase risk for adverse effects.
Pharmacodynamics describe the biologic effects of the drug on the body, and pharmacodynamic properties can also vary significantly across antihypertensive agents. Several important concepts are relevant in therapeutic response to antihypertensive agents, as described below.
Dose-Response Relationship
Blood pressure lowering and adverse events are, in part, governed by dose-response relationships. For any given (approved) antihypertensive drug, the dose-response curve for efficacy is to the left of the dose-response curve for toxicity (Figure 1). The difference between these curves is the therapeutic window. Relatively modest dose increases (e.g., doubling of the dose) towards the lower end of the therapeutic window can increase blood pressure response (Figure 1, point A to A′), with little impact on toxicity response (Figure 1, point AT to AT′). At the higher end of the therapeutic window, doubling of the dose leads to almost no additional blood pressure response (Figure 1, point B to B′), whereas toxicity response increases more substantially (Figure 1, point BT to BT′) (Law et al. 2003).
However, an important caveat with antihypertensive agents is that additional gains in BP lowering by doubling the dose, even at the low end of the efficacy dose-response curve, are relatively modest, perhaps a few mmHg on average. As can be seen in Figure 2 (left panel), the relationship between dose (as a proportion of the standard dose) and additional BP reduction achieved is remarkably similar across the major antihypertensive classes. To double the BP response with any of these classes, a dose may need to be increased 4- to 8-fold. Conversely, the relationship between dose and adverse event rates differs more markedly across classes (Figure 2, right panel), reflecting differences in therapeutic windows (Law et al. 2003).
Patient-specific factors (e.g., pathophysiologic mechanisms causing hypertension, genetics, dietary factors, concomitant medications) can markedly affect the dose-response relationship, and these factors can differentially impact drugs or classes. For example, individuals whose hypertension is driven primarily by high RAS activity are likely to exhibit an enhanced dose-response curve to an ACE inhibitor or ARB, compared with an individual in a low-renin/high-volume state, who is likely to exhibit a flattened dose-response curve, or occasionally, no response or a pressor response, to the same drugs (Sinha and Agarwal 2019).
Combination Therapy
Because patient-specific factors have a significant influence on the dose-response relationship, dose-response curves to any given drug/class can exhibit remarkable population-level variation. Taking the example above, in a population, a significant portion of patients exhibit high-renin/low-volume hypertension, and who are more likely to have greater BP response to an ACE inhibitor or ARB, whereas those in the population with low-renin/high-volume hypertension are more notable to have a suppressed response. In the same population, the former group would have been more likely to have a suppressed BP response to diuretics, whereas the latter group would have an enhanced response. The net effect is wide variation in the dose-response relationship for both ACE inhibitors/ARBs and diuretics in the overall population (Figure 3). Combination therapy with these two classes in the same population shifts the dose-response relationship up (greater efficacy) and to the left (greater potency) and narrows the population-level variation. This occurs because each individual patient in the population is likely to have a significant response to at least one of these classes with complementary mechanisms of action. For this reason, combination therapy is often recommended over dose escalations to improve BP response at lower risk of toxicity (Sinha and Agarwal 2019).
Compensatory Responses
Dose-response relationships are also indirectly affected by compensatory mechanisms that occur following pharmacologic-mediated reductions in BP. Baroreceptor reflexes mediate activation of the sympathetic nervous system and renin angiotensin system which can promote increased cardiac output, increased peripheral vascular resistance (i.e., peripheral vasoconstriction), or sodium and water retention. These are common occurrences with some of the lesser-used antihypertensive classes (e.g., vasodilators), although more modest compensatory effects can occur with several of the first-line classes as well (Table 1). These effects can lead to pseudotolerance, where the drug remains effective at its site of action, but the net antihypertensive effect is gradually diminished due to compensatory mechanisms. Fortunately, many of these counterregulatory mechanisms can be mitigated by using rational combinations (e.g., diuretics + RAS inhibitors) or stepped therapy (e.g., diuretic, then RAS inhibitor).
| Class | BP Compensatory Mechanism |
|---|---|
| $\alpha$1-antagonists | Salt/water retention; tachycardia |
| $\alpha$2-agonists | Salt/water retention |
| Calcium channel blockers (esp. short-acting) | Tachycardia |
| Direct vasodilators (hydralazine, minoxidil) | Salt/water retention; tachycardia |
| Diuretics | Salt/water retention |
Key Takeaways
- Pharmacokinetic and pharmacodynamic properties differ widely across and within antihypertensive classes
- Dose-response relationships for most antihypertensive drugs indicate that relatively little additional BP reduction is achieved with dose titrations across the recommended dosing ranges, whereas adverse effect responses are more variable
- Combination therapy, with consideration for complementary mechanisms or possible compensatory effects, can achieve more stable, predictable dose-response relationships.
Thiazide and loop diuretics
Thiazide and loop diuretics inhibit renal sodium reabsorption and reduce extracellular fluid volume with consequent reduction in cardiac output and blood pressure; thiazides are also thought to reduce peripheral vascular resistance with chronic use.
Most diuretics used in the clinical treatment of hypertension are natriuretics, and their effects on increasing renal sodium excretion, and consequent reduction of extracellular fluid volume, are believed to be the primary mechanism by which these drugs influence blood pressure. However, there are key differences in sites of action, as well as in pharmacokinetic and pharmacodynamic attributes both across and within diuretic subclasses. Herein, the term thiazide is used to refer collectively to thiazide and thiazide-like diuretics, except where noted (Sica et al. 2011).
Thiazide Diuretics
Thiazide diuretics are secreted into the renal tubule. Their primary site of action is on the luminal side of the early distal convoluted tubule (DCT), where they inhibit the thiazide-sensitive sodium-chloride cotransporters to reduce sodium and chloride reabsorption. The enhanced urinary excretion of sodium, in turn, leads to extracellular fluid reduction and a consequent decrease in cardiac preload and output, and lowering of blood pressure. However, the duration of this effect is relatively short, lasting approximately 4 weeks. Thereafter, compensatory mechanisms, including activation of the renin angiotensin system, typically prompt a return of plasma volume to pre-treatment levels and induce transient increases in peripheral vascular resistance. Nevertheless, blood pressure typically remains suppressed with long-term use (Ernst and Fravel 2022).
The exact mechanism for long-term blood pressure effects with thiazides is unknown but is believed to be related to decreased peripheral vascular resistance, likely as a result of the negative sodium balance induced by all thiazides. Additional mechanisms may play a role for individual thiazides.7 For example, hydrochlorothiazide may hyperpolarize vascular smooth muscle and reduce vasoconstriction, leading to reduced peripheral vascular resistance over time. Conversely, chlorthalidone has comparatively more carbonic anhydrase activity than hydrochlorothiazide, although the extent to which this contributes to long-term blood pressure reductions is unknown (Ernst and Moser 2009).
Thiazide diuretics have noteworthy differences in pharmacokinetic properties (Table 2). Thiazides are extensively protein-bound and some (e.g., chlorthalidone, metolazone) also distribute into erythrocytes. A consequence of this high protein binding is that thiazides must be actively secreted by organic anion transporters in the proximal tubule to reach the luminal side and eventually be carried to their site of action; glomerular filtration of thiazides is generally inconsequential. Nevertheless, tubular transport capacity is an important determinant of adequate drug concentration at the site of action. Transport capacity is generally correlated with glomerular filtration rates (GFR); thus, low GFR generally indicates reduced transport capacity. Furthermore, the DCT is responsible for only a minority of sodium reabsorption. As GFR is reduced, filtered sodium is reduced, and absolute rates of sodium reabsorption in the DCT are diminished. In the absence of significant sodium reabsorption in the DCT, the natriuretic effect of thiazides is decreased. Accordingly, many clinicians consider thiazide efficacy to wane below a GFR of approximately 20-30 mL/min, although data supporting this cutoff are relatively sparse and thiazides maintain some efficacy even in severe renal impairment. The one exception is metolazone, which maintains its efficacy in more severe renal impairment, but its use is limited by slow, erratic absorption (Ellison 2019)
| Diuretic | Bioavailability | Distribution Volume (L/kg) | Protein Binding | Route | t1/2 (Normal) | t1/2 (CKD) |
|---|---|---|---|---|---|---|
| Thiazide | ||||||
| Hydrochlorothiazide | 60% - 70% | 2.5 | 40% | 95% renal | 9-10 hrs | Prolonged |
| Chlorothiazide | 15% - 30% | 1 | 70% | 100% renal | 1.5 hrs | Prolonged |
| Bendroflumethiazide | >90% | 1-1.5 | 94% | 30% renal | 9 hrs | Prolonged |
| Thiazide-like | ||||||
| Chlorthalidone | 65% | 3-13 | 99% | 65% renal | 50-60 hrs | Prolonged |
| Indapamide | 90% | 25-60 (total) | 75% | Hepatic | 14 hrs | Prolonged |
| Metolazone | 65% | 113 (total) | 95% | 80% renal | 8-14 hrs | Prolonged |
Onset of natriuretic action begins, on average, in 1-2 hours and dissipates by 6 hours for most thiazides. However antihypertensive duration of action persists beyond the natriuretic effects and is variable across agents. Most of the commonly-used thiazides have a duration of action of at least 12 hours, allowing for once-daily administration with most agents, though hydrochlorothiazide may require twice-daily dosing to achieve optimal blood pressure lowering and maintain such effects throughout the 24-hour dosing period. Chlorthalidone is somewhat unique among the thiazides owing to its binding to carbonic anhydrase and heavy partitioning into erythrocytes. This action effectively creates a depot, in which chlorthalidone is slowly leaked back into serum to maintain equilibrium between carbonic anhydrase-bound and free chlorthalidone. The net effect is a much longer duration of action (Carter and Ernst 2018).
Loop Diuretics
Loop diuretics, including furosemide, bumetanide, and torsemide, induce natriuresis by inhibiting the Na-K-2Cl cotransporter (NKCC2) in the luminal side of the thick ascending limb of the loop of Henle and in the macula densa. Similar to thiazides, these drugs are organic anions and gain access to the renal tubule via active secretion into the proximal tubule by organic anion transporters, whereas glomerular filtration is mostly prevented by their extensive protein binding (Ernst and Moser 2009).
A comparison of pharmacokinetic properties of loop diuretics is presented in Table 3. Substantial differences exist across this subgroup of diuretics. For example, oral bioavailability is high for torsemide and bumetanide, but only approximately 50% for furosemide. Furosemide also exhibits greater variation in oral bioavailability, both between patients and from day-to-day for a given patient, especially in those with edematous states such as heart failure.
| Diuretic | Bioavailability | Protein Binding | Route | t1/2 (Normal) | t1/2 (CKD) |
|---|---|---|---|---|---|
| Furosemide | 50% (10% - 100%) | ≥95% | 95% renal | 1.5-2 hrs | 2.8 hrs |
| Bumetanide | 80% - 100% | 97% | 100% renal | 1 hr | 1.6 hrs |
| Torsemide | 68% - 100% | ≥99% | 30% renal | 3-4 hrs | 4-5 hrs |
Onset of action of the loop diuretics is generally rapid (30 to 60 minutes), with peak effects achieved within about 1-2 hours for bumetanide and torsemide and 6-8 hours for furosemide. Although the elimination half-life of furosemide is short, gastrointestinal absorption is comparatively slow, resulting in ‘absorption-limited kinetics’ that extend furosemide’s duration of action to approximately 6-8 hours, similar to torsemide (Ernst and Moser 2009; Ellison 2019)
Blood pressure reduction with loop diuretics is contingent on the natriuretic and volume reduction effects of these drugs. However, their relatively short durations of action (on natriuresis) are followed closely by periods of significant antinatriuresis, where sodium and volume are conserved. As a consequence, these agents, especially furosemide, often require multiple doses per day to achieve BP-lowering throughout the 24-hour period. Accordingly, these agents are often reserved for select clinical scenarios in treating hypertension, for example, in patients with significant renal impairment or edematous states (as described above) or, rarely, in combination with thiazides in a strategy known as sequential nephron blockade (Ellison 2019)
Adverse Effects of Thiazide and Loop Diuretics
Relatively common adverse effects with both thiazide and loop diuretics include electrolyte derangements, most notably hypokalemia (thiazides ≈ loops), hyponatremia (thiazides > loops), and hypomagnesemia (thiazides ≈ loops). Serum potassium concentration reductions occur relatively soon (3-5 days) after therapy initiation, and typically average 0.4 mEq/L with hydrochlorothiazide 25 mg/day, or its equivalent. Coadministration with potassium supplements, potassium-sparing diuretics, or renin angiotensin system inhibitors can attenuate this effect. Reductions in magnesium are on the order of 5% to 10% for most patients, although some populations are more susceptible to clinically important hypomagnesemia, including the elderly and those routinely taking high doses of diuretics (e.g., concurrent heart failure). Hyponatremia, particularly with thiazides, can occur acutely or gradually. It is more common with thiazides than loop diuretics, and in older women, those able to restrict sodium intake, and in persons who are dehydrated or with diminished capacity to excrete free water (Carter and Ernst 2018).
Thiazides also are associated with changes in metabolic parameters, including hyperuricemia and hyperglycemia, the latter of which may be related to hypokalemia, although data are conflicting. The clinical significance of these effects is debated but given that gout and diabetes often co-occur with hypertension, monitoring of these parameters, particularly early in therapy, may be warranted in select patient groups (Carter and Ernst 2018).
Key Takeaways
- Thiazides are remarkably effective antihypertensive agents, but efficacy wanes in more severe kidney impairment; loop diuretics are more effective natriuretics, but rarely used in chronic hypertension treatment
- Among the thiazides, chlorthalidone has the most favorable pharmacokinetic and pharmacodynamic profile, including the longest duration of antihypertensive action
- Common adverse effects include electrolyte derangements (e.g., hypokalemia, hypomagnesemia), and thiazides can cause moderate adverse metabolic effects (i.e., hyperglycemia, hyperuricemia).
Potassium-sparing diuretics
Potassium-sparing diuretics consist of the aldosterone antagonists, otherwise known as mineralocorticoid receptor antagonists (spironolactone and eplerenone), and the epithelial sodium channel blockers (amiloride and triamterene).
In the context of hypertension treatment, potassium-sparing diuretics usually serve as add-on therapy in selected patients rather than monotherapy. Alone, they characteristically induce relatively little natriuresis; however, in combination with other diuretic therapies, typically thiazides, they can correct hypokalemia and hypomagnesemia, as well as have profound blood pressure lowering effects in some patients.
Aldosterone Antagonists
Aldosterone exerts effects on blood pressure via multiple mechanisms to promote vasoconstriction and retention of extracellular fluid volume. The latter effect is mediated through its interaction with the mineralocorticoid receptor (MR) in epithelial cells of the distal tubule and collecting duct, which promotes sodium reabsorption and potassium excretion. Spironolactone, and its analog, eplerenone, are synthetic steroids that exert their antihypertensive effects primarily through competitive blockade of this receptor in the kidney (Epstein and Calhoun 2011).
The main pharmacologic differences between these agents relate to their potency and affinity for the MR, their metabolism, and their duration of action. Spironolactone is modestly more potent than eplerenone in competitively inhibiting the MR and has a 10 to 20-fold greater affinity for the MR. However, spironolactone also has a several hundred-fold higher affinity for androgen and progesterone receptors, which accounts for its higher incidence of sex hormone-related side effects (e.g., gynecomastia, suppressed libido, menstrual abnormalities) (Epstein and Calhoun 2011).
Spironolactone is a prodrug that is metabolized in the liver to a number of active metabolites, most importantly canrenone and 7-\(\alpha\)-spironolactone. The parent compound has a relatively short terminal half-life of ~1.5 hours; however, onset and duration of the drug are mediated primarily by the active metabolites, with half-lives of approximately 12-20 hours (7-\(\alpha\)-spironolactone) and 14-16 hours (canrenone). Both metabolites are potent anti-mineralocorticoids. In contrast, eplerenone is metabolized to inactive compounds and has a relatively shorter half-life of approximately 4-6 hours. As a consequence, for hypertension treatment, eplerenone usually requires twice-daily dosing, compared with once-daily dosing for spironolactone. Eplerenone metabolism is mediated through the CYP3A4 isoenzyme, and strong inhibitors of this isoenzyme can have clinically relevant effects on blood concentrations of eplerenone (Ernst and Moser 2009; Ellison 2019).
Epithelial Sodium Channel Blockers
Amiloride and triamterene effectively counteract the effects of aldosterone in the collecting tubules, albeit through a different mechanism. Specifically, these drugs directly inhibit sodium influx in the distal convoluted tubule and collecting tubule and duct by interfering with epithelial sodium channels (ENaC) on the luminal membrane. Their potassium-sparing effect arises by virtue of the fact that potassium secretion and sodium entry are coupled in these segments of the nephron; thus, blocking sodium entry effectively impairs potassium secretion.
Of the two agents, amiloride has greater avidity for ENaC and is the more potent antihypertensive agent. Indeed, triamterene is used only in combination therapy (typically with hydrochlorothiazide in the U.S.) to mitigate diuretic-induced hypokalemia. Moreover, its use has substantially decreased over time concordant with lower thiazide dosing that leads to less hypokalemia (Carter and Ernst 2018; Epstein and Calhoun 2011).
Adverse Effects of Potassium-Sparing Diuretics
All of these agents cause dose-dependent increases in serum potassium, on average ~0.4–0.5 mEq/L for spironolactone 25 mg or its equivalent. Risk of hyperkalemia is substantially increased in the setting of CKD and heart failure, particularly with aldosterone antagonists, and in patients with hyporeninemic hypoaldosteronism. Amiloride can be used in patients with significant CKD, although lower doses are generally necessary to reduce the risk of hyperkalemia. Because these agents are typically used in more difficult-to-treat hypertension (e.g., resistant hypertension), and typically on top of background therapy with renin angiotensin inhibitors and other diuretics, careful monitoring of potassium is crucial, particularly early in therapy and following dose adjustments. All potassium-sparing diuretics also have the potential to cause hyperchloremic metabolic acidosis (Ernst and Moser 2009).
Spironolactone is associated with a number of sexual side effects, most notably gynecomastia, which may occur in up to 10% of patients using typical antihypertensive doses of spironolactone (e.g., 25-50 mg/day), and impotence. Importantly, onset of gynecomastia can be gradual and persist beyond discontinuation of therapy. Other side effects related to spironolactone inhibiting androgen and progesterone receptors include impotence, hirsutism, menstrual irregularities. Spironolactone should also be avoided during pregnancy, as it can adversely affecting sex differentiation of the male fetus during embryogenesis (Carter and Ernst 2018; Epstein and Calhoun 2011).
Key Takeaways
- Aldosterone antagonists (spironolactone and eplerenone) and amiloride, an ENaC inhibitor, are effective antihypertensive agents, particularly when combined with thiazide diuretics in patients with resistant hypertension who typically have volume overload
- Eplerenone is more selective for mineralocorticoid receptors than spironolactone and thus associated with fewer sexual side effects (e.g., gynecomastia, hirsutism)
- Triamterene, another ENaC inhibitor, is a weak diuretic, and is used only in combination with thiazides (e.g., hydrochlorothiazide) to prevent potassium wasting
Renin-angiotensin system inhibitors
First marketed in the 1980s and 90s, renin angiotensin system inhibitors have risen in prominence to some of the most commonly used antihypertensives due to their favorable efficacy: safety profile and major morbidity/mortality benefits.
The renin angiotensin system (RAS) is an important mediator of blood pressure. RAS inhibitors target one of several steps in the pathway, thus reducing the downstream effects of angiotensin II on sodium and water retention, aldosterone production, and activation of the sympathetic nervous system (Figure 4). RAS inhibitors are broadly categorized according to their primary mechanism of action as angiotensin-converting enzyme (ACE) inhibitors, angiotensin (AT1) receptor blockers (ARBs), and direct renin inhibitors (DRIs). Aldosterone antagonists are also considered inhibitors of the expanded renin angiotensin aldosterone system, but these agents are discussed in more detail in Section 3). All of these agents effectively lower blood pressure, although data regarding morbidity and mortality benefits are much more robust with ACE inhibitors and ARBs. ACE inhibitors and ARBs are also effectively interchangeable in most clinical scenarios with regard to cardiovascular and mortality benefits, although their side effect profiles differ meaningfully (Riet et al. 2015).
Angiotensin-Converting Enzyme Inhibitors
ACE inhibitors exert their antihypertensive effect via two pathways: 1) inhibition of ACE, preventing conversion of angiotensin I to angiotensin II and its downstream deleterious effects; and, 2) inhibition of bradykinin degradation. Following initiation of therapy, ACE is markedly suppressed, as is angiotensin II; during chronic therapy, ACE remains suppressed, but angiotensin II often returns to pre-treatment levels. This “ACE escape” or “Ang II escape” phenomenon is thought to be related to a compensatory rise in the production of angiotensin II via ACE-independent mechanisms, such as direct conversion of angiotensinogen or angiotensin I to angiotensin II via chymase, cathepsin G, and tonin. The return to pre-treatment angiotensin II levels does not appear to be correlated with blood pressure changes, as these agents maintain antihypertensive efficacy during long-term treatment despite the escape phenomenon (Fisher and Meagher 2011).
ACE is also largely responsible for bradykinin and other small vasoactive peptide degradation into inactive molecules. Inhibiting ACE increases circulating bradykinin, which in turn activates endothelial \(\beta\)1 and \(\beta\)2 receptors to release prostacyclin and nitric oxide, with resultant vasodilation. This vasodilation contributes to the blood pressure-lowering effects of ACE inhibitors, but the extent of this contribution is not well-characterized (Fisher and Meagher 2011).
Aside from their blood pressure-lowering effects, ACE inhibitors also reduce preload and afterload, increase cardiac output, and prevent the pathogenesis and worsening of left ventricular dysfunction. Angiotensin II causes various deleterious effects in the kidneys and ACE inhibition is known to have renoprotective effects via lowering of intraglomerular pressure and dilation of renal efferent arterioles. Reduced proteinuria, a slowing of progressive deterioration in renal function, especially in diabetic nephropathy, and reduction in the risk of developing end-stage renal disease have all been demonstrated with ACE inhibitors (Fisher and Meagher 2011).
All ACE inhibitors have approximately equal blood-pressure lowering effects when administered at equivalent doses. Most ACE inhibitors are prodrugs, requiring transformation to active metabolites that generally have more potent anti-ACE activity and longer durations of action than their parent compounds. The two exceptions are captopril and lisinopril, which do not undergo hepatic activation (Fisher and Meagher 2011).
ACE inhibitor pharmacokinetic and pharmacodynamic properties are displayed in Table 4 and Table 5, respectively. In general, the major pharmacokinetic differences between agents relate to the half-life, which partially (along with ACE binding) determines duration of action and dosing intervals. Most available ACE inhibitors can be dosed once daily, excepting captopril, which requires 2-3 doses/day; enalapril may also require twice daily dosing in some patients. Trough-to-peak ratios also differ across the class, though most agents have a ratio ≥0.5, an approximate indicator for once-daily dosing. The exceptions are captopril, enalapril, and moexipril. However, moexipril’s active metabolite (moexiprilat) is thought to slowly dissociate from ACE, explaining its longer duration of action (Fisher and Meagher 2011).
| RAS Inhibitor | Bioavailability | Protein Binding | Elimination Route | Elimination t1/2 |
|---|---|---|---|---|
| ACE inhibitors | ||||
| Benazepril | ≥37% | 97% | Hepatic (to benazeprilat) | 10-11 hrs (benazeprilat) |
| Captopril | 75% | 25%-30% | 50% Hepatic | 2 hrs |
| Enalapril | 60% | <50% | 60% hydrolysis (to enalaprilat) | 11-14 hrs (enalaprilat) |
| Fosinopril | 36% | 99% (fosinoprilat) | 50% renal | 12-14 hrs |
| Lisinopril | 25% | 0% | 100% renal | 12–13 hrs |
| Moexipril | 13% | 50% | 7% renal | 1 hr (moexipril);–9 hrs (moexiprilat) |
| Perindopril | 65%–75% | 60% (perindopril);%–20% (perindoprilat) | 5%–10% renal | 1 hr (perindopril);-120 hrs (perindoprilat) |
| Ramipril | 30%–60% | 73% | 60% renal | >50 hrs |
| Quinapril | 60% | 97% | 96% renal | 2–3 hrs |
| Trandolapril | 70% | 80% | 33% renal | 6–10 hrs |
| ARBs | ||||
| Azilsartan | 60% | >99% | 55% renal | 11 hrs |
| Candesartan | 15% | >99% | 60% renal | 9 hrs |
| Eprosartan | 15% | 98% | 30% renal | 5-9 hrs |
| Irbesartan | 70% | 90%–95% | 20% renal | 11-15 hrs |
| Losartan | 35% | 99% | 10% renal | 1-2 hrs (losartan);-9 hrs (E-3174) |
| Olmesartan | 29% | >99% | 40% renal | 14-16 hrs |
| Telmisartan | 40%–60% | >99% | 1% renal | 24 hrs |
| Valsartan | 25% | 95% | 30% renal | 6 hrs |
| DRIs | ||||
| Aliskiren | 2.5% | 50% | 25% renal | 20-45 hrs |
| RAS Inhibitor | Onset of BP-lowering | Peak BP-lowering | Duration of BP-lowering | Typical Dosing Frequency | Trough:Peak Ratio | Dose Reduce in Moderate Renal Insufficiency |
|---|---|---|---|---|---|---|
| ACE inhibitors | ||||||
| Benazepril | <1 hr | 1-2 hrs | 24 hrs | Once daily | 0.4–0.5 | Yes |
| Captopril | 1-1.5 hrs | 1-1.5 hrs | <24 hrs (dose-dependent) | Twice or thrice daily 0.25 | Yes | |
| Enalapril | 1 hr | 4-6 hrs | ≤24 hrs | Once or twice daily | 0.3–0.45 | No |
| Fosinopril | 1 hr | 2-6 hrs | 24 hrs | Once or twice daily | 0.6 | No |
| Lisinopril | 1 hr | 4-6 hrs | 24 hrs | Once | 0.5–0.6 | Yes |
| Moexipril | 1 hr | 3–6 hrs | ≤24 hrs | Once or twice daily | ≤0.1 | No |
| Perindopril | <1 hr | 6 hrs | 24 hrs | Once daily | 0.6–0.7 | Yes |
| Ramipril | 1–2 hrs | 3-6 hrs | 24 hrs | Once daily | 0.5–0.6 | Yes |
| Quinapril | <1 hr | 2–4 hrs | 24 hrs | Once daily | 0.5 | Yes |
| Trandolapril | 1 hr | 4–10 hrs | 24 hrs | Once daily | 0.5–0.9 | No |
| ARBs | ||||||
| Azilsartan | ~1-2 hrs | 1.5–3 hrs | 24 hrs | Once daily | 0.6–0.7 | No |
| Candesartan | 2-3 hrs | 3–4 hrs | ≤24 hrs | Once daily | 0.8–1.0 | Yes |
| Eprosartan | 1-2 hrs | ~2 hrs | ≤24 hrs | Once or twice daily | 0.3 | |
| Irbesartan | 1-2 hrs | 3–6 hrs | ≥24 hrs | Once daily | 0.4–0.7 | No |
| Losartan | ~1 hr | 1 hr (losartan);-6 hrs (E-3174) | 12-24 hrs | Once or twice daily | 0.3–0.7 | No |
| Olmesartan | 1-2 hrs | 1–2 hrs | ≥24 hrs | Once daily | 0.6–0.7 | No |
| Telmisartan | 0.5–1 hrs | 4–6 hrs | >24 hrs | Once daily | 0.9 | No |
| Valsartan | 2 hrs | 2–4 hrs | 24 hrs | Once daily | 0.6–0.7 | No |
| DRIs | ||||||
| Aliskiren | 1-2 hrs | 2-4 hrs | >24 hrs | Once daily | 0.6–0.9 | No |
Angiotensin Receptor Blockers
ARBs preferentially bind to, and block, angiotensin II (subtype I) receptors (AT1R) through two common mechanisms: 1) hydrophobic bonds between each drug’s phenyl group and the receptor; and, 2) ionic interactions between each drug’s acidic moiety and the receptor. Receptor blockade prevents angiotensin II from binding and mitigates the deleterious downstream consequences of sodium and volume retention, and aldosterone production, but also prevents the negative feedback loop between AT1R activation and renin production. As a consequence, plasma renin activity is increased during ARB therapy, similarly to ACE inhibitor therapy. Blocking of the angiotensin II–AT1R interaction also shunts angiotensin II to other angiotensin receptor subtypes, including AT2R, with beneficial downstream effects (reduced sodium and volume retention, aldosterone production) (Taylor, Siragy, and Nesbitt 2011).
ARBs have broadly similar blood pressure lowering efficacy at comparable doses. They are also believed to have broadly similar effects on cardiovascular and renal outcomes, i.e., these effects are “class effects,” rather than agent-specific effects. Moreover, they have broadly similar blood pressure lowering efficacy and cardiovascular/renal benefits as compared with ACE inhibitors and are generally considered interchangeable with ACE inhibitors in most clinical situations (Taylor, Siragy, and Nesbitt 2011).
Most ARBs are administered once daily, although some patients may need twice daily dosing with shorter-acting ARBs (losartan, eprosartan, candesartan). As with ACE inhibitors, duration of action is a function of both half-life and binding dissociation rates at the AT1R. For many of the ARBs (or their active metabolites), slow dissociation leads to longer durations of action (up to a week or more) than predicted based on half-life alone (Taylor, Siragy, and Nesbitt 2011).
Direct Renin Inhibitors
DRIs are a newer class of agents targeting the RAS system, and currently only aliskiren is approved in the U.S. These drugs directly bind to the active form of renin, preventing the cleavage of angiotensinogen to form angiotensin I. Following aliskiren administration, plasma renin activity, angiotensin I, and angiotensin II levels are suppressed, making it somewhat unique among the RAS inhibitors (Riet et al. 2015).
Aliskiren has very low bioavailability, but is not metabolized significantly, and thus not subject to CYP450-mediated drug-drug interactions. It also has a long half-life, approaching two days, and achieves steady state after ~1 week. Blood pressure-lowering is approximately similar to ACE inhibitors and ARBs during chronic therapy. However, whether aliskiren has the same cardiovascular and renal beneficial effects as the other RAS inhibitors is largely untested. It does not appear to have value as add-on therapy to ACE inhibitors or ARBs (Riet et al. 2015).
Adverse Effects of RAS inhibitors
All RAS inhibitors are contraindicated in pregnancy owing to concerns over fetal toxicity. These agents should also be avoided in severely volume-depleted patients and in those with renal hypoperfusion, including bilateral or unilateral renal artery stenosis, because these agents can precipitate renal failure in such patients (Izzo and Weir 2011).
All RAS inhibitors rarely cause angioedema, although the relative incidence appears greatest in ACE inhibitors, occurring in ~0.2% to 0.3% of patients treated with chronic ACE inhibitor therapy. Patients who have developed angioedema on one RAS inhibitor are at higher risk for angioedema with other RAS inhibitors and these agents are generally not recommended in patients with prior RAS inhibitor-induced angioedem (Izzo and Weir 2011).
Elevations in serum potassium are also common across all 3 RAS inhibitor classes, and potassium monitoring is warranted during therapy initiation and modification. These agents should also be used cautiously with other drugs that elevate serum potassium, including aldosterone antagonists. Similarly, potassium supplements should usually be discontinued when starting RAS inhibitors. Elevations in serum creatinine (and reductions in GFR) are also common, and usually a sign of effective modification of the RAS system because they reflect reduced resistance at the efferent arteriole and corresponding decreased intraglomerular pressure. Generally, minor elevations in serum creatinine (< ~30%) are appropriate and do not warrant therapy adjustment. And, these elevations frequently reverse to pre-treatment levels despite continued use of the RAS inhibitor. Conversely, elevations >50% from baseline should prompt evaluation and therapy discontinuation may be prudent (Izzo and Weir 2011).
ACE inhibitors also very commonly cause an irritating, dry cough, thought to be related to their effect on bradykinin levels. This cough is the most common cause of therapy discontinuation and non-adherence in ACE inhibitors. ARBs and DRIs do not affect bradykinin, or do so to a much lower extent, and are associated with much lower incidences of cough (Taylor, Siragy, and Nesbitt 2011).
Key Takeaways
- Renin angiotensin system inhibitors reduce blood pressure by interfering with critical steps in angiotensin I production via renin (aliskiren), angiotensin II production via ACE (ACE inhibitors) or angiotensin II interaction with the AT1 receptor (ARBs)
- Blood pressure reductions are comparable across drugs/classes, although side effects can differ (e.g., incidence of coughing: ACE inhibitors >> ARBs ≈ aliskiren); all RAS inhibitors cause angioedema and elevated potassium
- Most RAS inhibitors achieve effective 24-hour blood pressure reduction with once-daily dosing
Calcium channel blockers
Calcium channel blockers are among the most commonly prescribed antihypertensive drugs in the U.S. and worldwide; these agents are considered first-line therapies when used as monotherapy, or in combination with other first-line therapies (e.g., RAS inhibitors).
Ca2+ plays an important role in contraction and relaxation of cardiac and vascular smooth muscle cells. Under resting conditions, these cell membranes are highly impermeable to Ca2+ ions. Ingress and efflux of Ca2+ is mediated via specialized calcium channels, most notably voltage-gated calcium channels (VGCCs), as well as other mechanisms. VGCCs exist in several subtypes, with the most important for blood pressure being the L-type (‘Long-lasting’) channels which predominate in cardiac and vascular smooth muscle cells. Calcium channel blockers (CCBs) preferentially or exclusively bind the \(\alpha\)1 subunit of these L-type calcium channels (Elliott and Ram 2011; Godfraind 2017).
Two classes of CCBs are used clinically for hypertension: dihydropyridine CCBs (amlodipine and similar drugs) and non-dihydropyridines (verapamil, diltiazem). Dihydropyridines preferentially bind to L-type channels in the open or inactivated state (as opposed to resting or partially active states). These states are favored under more depolarized conditions, and in part because VGCCs in the vascular smooth muscle cells tend to be more depolarized than in cardiac myocytes, dihydropyridines preferentially exert their antihypertensive actions in the systemic vasculature. Numerous other mechanisms may also play a part in this selectivity. The non-dihydropyridines (especially verapamil) tend to block calcium channels in cardiac myocytes preferentially because they favor L-type VGCCs with frequent, repetitive openings, which are more prominent in cardiac tissue (Scholz 1997).
Thus, the primary antihypertensive mechanisms of CCBs can be summarized as follows:
DHPs and diltiazem: peripheral blockade of L-type VGCCs, reducing calcium entry into smooth muscle cells, and leading to vasodilation and reduced peripheral vascular resistance; DHPs have no significant negative chronotropic effects
Verapamil and diltiazem: blockade of L-type VGCCs and prevention of calcium entry into cardiac myocytes, resulting in reduced contractility, and slowed sinus pacemaker and atrioventricular conduction velocities; these effects are more pronounced with verapamil than diltiazem (Sica 2005)
Selected pharmacokinetic and pharmacodynamic properties of CCBs are summarized in Table 6.
| CCB | Bioavailability | Protein Binding | t1/2 | CYP3A4 Activity | Onset of Action | Duration of Action |
|---|---|---|---|---|---|---|
| Non-dihydropyridines | ||||||
| Verapamil | 20% - 35% | 90% | Inhibitor, Substrate | |||
| IR | 6–8 hrs | 1–2 hrs | 8–10 hrs | |||
| SR | 12–24 hrs | 1–2 hrs | 12 hrs | |||
| ER/HS/PM | 24 hrs | 4–5 hrs | 24 hrs | |||
| Diltiazem | 25% - 75% | 70% - 80% | Inhibitor, Substrate | |||
| IR | 3–4.5 hrs | 1 hr | 6–8 hrs | |||
| SR | 6–9 hrs | 2–3 hrs | 12 hrs | |||
| CD/LA/XR/XT | 24 hrs | ~2-3 hrs | 24 hrs | |||
| Dihydropyridines | ||||||
| Amlodipine | 64%–90% | 93%–98% | 30–50 hrs | Substrate | 4 hrs | ≥24 hrs |
| Bepridil | 100% | 99% | 24–64 hrs | Substrate | 2–3 hrs | ≥24 hrs |
| Felodipine | 15% | 99% | 11–16 hrs | Substrate | 2–5 hrs | 18–24 hrs |
| Isradipine | 15%–24% | 95% | 8 hrs | Substrate | 2–3 hrs | 12 hrs |
| Nicardipine | 35% ≥95% | 8–9 hrs | Substrate, Inhibitor | <1 hr | 6–8 hrs | |
| Nifedipine | 100% | 92% - 98% | Substrate | |||
| IR | 2 hrs | 0.5–1 hr | 4–6 hrs | |||
| XL/CC | 7 hrs | ~3–4 hrs | ~18 hrs | |||
| Nisoldipine | 5% | 99% | 7–12 hrs | Unknown | ~1 hr | 24 hrs |
The non-dihydropyridines, verapamil and diltiazem, come in a variety of formulations, including immediate-release formulations and several long-acting formulations. In most circumstances, these longer-acting formulations are preferred in the treatment of chronic hypertension, owing to smoother concentration curves throughout the 24-hour period (less 24-hour blood pressure variability) and less frequent dosing. The same is true for dihydropyridines, though most of these are inherently longer-acting drugs, or only marketed in longer-acting formulations for the purposes of hypertension management. Importantly, short-acting agents (e.g., immediate-release nifedipine) should generally be avoided in management of chronic hypertension, because of rapid onset, high peak, and rapid short duration of action. These agents also cause baroreceptor reflex-mediated tachycardia, and may increase risk of angina, myocardial infarction, and all-cause death. Extended-release versions of nifedipine have somewhat better concentration profiles for lowering 24-hour BP. However, these agents still require twice-daily dosing, and have substantially greater variability in concentration than the inherently longer-acting agents like felodipine, and especially, amlodipine. These longer-acting CCBs, with smoother concentration profiles, are among the most effective antihypertensives at reducing 24-hour blood pressure variability (Scholz 1997).
Because CCBs are substrates, and in some cases inhibitors, of common drug-metabolizing enzymes, especially CYP3A4, these drugs have the potential to cause numerous drug-drug interactions and some drug-food interactions. In some cases, these interactions can be useful in further reducing BP (e.g., combining the 3A4 inhibitor verapamil with a dihydropyridine 3A4 substrate) when employed carefully. Pharmacodynamic drug-drug interactions are also possible with these agents, e.g., with verapamil and β-blockers both of which have negative inotropic and chronotropic effects on the heart (Sica 2005).
Although CCBs are generally well-tolerated during long-term therapy, these drugs cause a number of well-known adverse effects. Adverse effects may be worsened in patients with active hepatic disease, who exhibit higher plasma concentrations of all CCBs. Conversely, renal disease does not preempt use of these drugs (Newton, Delgado, and Gomez 2002).
Dihydropyridines are frequently associated with dose-dependent peripheral edema. In clinical trials, approximately one-quarter to one-third of patients reported some degree of edema. Women tend to report this side effect more often, though it remains unclear whether there is a true sex-related difference in the incidence or degree of edema. Importantly, peripheral edema is almost assuredly a by-product of the fact that dihydropyridines preferentially target arteriole vasodilation and have little-to-no effect on veins. This increased pressure gradient between arteriole and venule capillaries leads to extravasation of intravascular fluid, which is not remediated by diuretic therapy. Combining dihydropyridines with RAS inhibitors, perhaps especially ACE inhibitors, may mitigate the incidence and degree of edema by reducing post-capillary resistance and thus reducing fluid extravasation. However, even with combination therapy, peripheral edema is still a common cause of CCB discontinuation (Godfraind 2017).
Dihydropyridines have little effect on metabolic parameters. For example, new-onset diabetes occurs at a similar rate with dihydropyridines and placebo, whereas RAS inhibitors (ARBs, ACE inhibitors) are associated with lower rates, and diuretics (and perhaps β-blockers) are associated with higher rates. They also do not appreciably alter electrolytes, in contrast to several other first-line antihypertensive classes (Scholz 1997).
Non-dihydropyridines are associated with an elevated incidence of gastrointestinal side effects. The most common is constipation, which occurs more often with verapamil treatment than diltiazem (Scholz 1997; Godfraind 2017).
Key Takeaways
- CCBs are comprised of two basic subgroups: non-dihydropyridines (verapamil and diltiazem) and dihydropyridines (e.g., amlodipine, felodipine, etc..)
- Dihydropyridines lower BP through blockade of calcium channels in the periphery, whereas non-dihydropyridines (especially verapamil) reduce BP primarily through negative chronotropic and inotropic effects
- The most common adverse events with dihydropyridines are peripheral edema (unresponsive to diuretic therapy), headache, and flushing; short-acting CCBs can prompt tachycardia, and verapamil also causes constipation
\(\beta\)-blockers
Although \(\beta\)-blockers have fallen out of favor as first-line treatment options, they are effective at lowering blood pressure and remain preferred agents in certain clinical scenarios.
The antihypertensive mechanism of action of \(\beta\)-blockers is not completely understood but is thought to be related to several effects. The primary mechanism of action is likely competitive antagonism of \(\beta\)1-adrenergic receptors in cardiac tissue and the vasculature. This antagonism in turn causes a reduction in cardiac output, lowering blood pressure. Peripheral vascular resistance is also reduced during long-term \(\beta\)-blocker therapy, through incompletely understood mechanisms. Within the kidneys, \(\beta\)-blockers inhibit release of renin from the juxtaglomerular apparatus via \(\beta\)1 receptor blockade, thus reducing angiotensin I and II production. Accordingly, these agents can also be thought of, secondarily, as RAS inhibitors, though the relative contribution of this effect to overall antihypertensive effects is not well-characterized. Several other mechanisms have been proposed, which may be agent-specific rather than class effects, including: reduction in norepinephrine release, suppression of catecholamine-induced pressor response during excitatory periods (e.g., exercise), improvements in vascular compliance, and reductions in venous return and fluid volume (Newton, Delgado, and Gomez 2002; Ripley and Saseen 2014).
| \(\beta\)-blocker | Oral Bioavailability | Receptor Activity & Selectivity | Intrinsic Sympathomimetic Activity | Membrane Stabilizing Activity | Lipid Solubility | Elimination Route | Elimination t1/2 |
|---|---|---|---|---|---|---|---|
| Acebutolol | 40% | $\beta$1 > $\beta$2 | + | – | Low | Hepatic | 3–4 hrs (acebutolol);–13 hrs (diacetolol) |
| Atenolol | 40% | $\beta$1 > $\beta$2 | – | – | Low | Renal | 6–7 hrs |
| Bisoprolol | 80% | $\beta$1 >> $\beta$2 | – | – | Moderate | Renal | 9–12 hrs |
| Carvedilol | 25%–35% | $\beta$1 ≈ $\beta$2 > $\alpha$1 | – | – | Moderate | Hepatic | 7–10 hrs |
| Esmolol | NA | $\beta$1 >> $\beta$2 | – | – | Low | Hepatic | 9 mins |
| Labetalol | 25% | $\beta$1 ≥ $\beta$2 > $\alpha$1 | + | – | High | Hepatic | 6 hrs |
| Metoprolol | 50% | $\beta$1 >> $\beta$2 | – | – | Moderate | Hepatic | 3–7 hrs |
| Nadolol | 30% | $\beta$1 ≈ $\beta$2 | – | – | Low | Renal | 20–24 hrs |
| Nebivolol | Unknown | $\beta$1 >>> $\beta$2 | – | – | Low | Hepatic | 12-19 hrs |
| Propranolol | 30% | $\beta$1 ≈ $\beta$2 | – | + | High | Hepatic | 3.5–6 hrs |
\(\beta\)-blockers vary substantially with regard to pharmacologic and pharmacokinetic properties (Table 7). These agents are often characterized by their selectivity for adrenergic receptors, specifically their $\beta$1 vs. $\beta$2 receptor selectivity, as well as their \(\beta\)- versus α-adrenergic receptor activity. Agents that exhibit little or no selectivity for $\beta$1 vs. $\beta$2 receptors are considered ‘non-selective’ \(\beta\)-blockers, whereas those that preferentially antagonize $\beta$1 receptors are considered ‘cardioselective’ \(\beta\)-blockers. Among the cardioselective \(\beta\)-blockers, there also exists relative differences in selectivity (Table 7). These differences are inconsequential with regard to their use as antihypertensive agents, as blood pressure-lowering effects are generally similar between nonselective and cardioselective agents. Nevertheless, receptor selectivity may be important in risk of adverse effects. For example, $\beta$2-blockade in the lungs can exacerbate reactive airway disease, such as asthma. An important caveat with regard to \(\beta\)-selectivity is that it is dose- (or concentration-) dependent, and all \(\beta\)-blockers lose selectivity at high enough concentrations (W. H. Frishman 2007).
Some agents (i.e., labetalol, carvedilol) also have significant \(\alpha\)-adrenergic blockade effects, which may contribute to antihypertensive effects through arteriole vasodilation and reduced vascular resistance. Nevertheless, there is little evidence to suggest that these agents are more efficacious as antihypertensives by virtue of this additional \(\alpha\)-blockade. Some agents (e.g., labetalol, acebutolol, pindolol) also exhibit intrinsic sympathomimetic activity (ISA), which means they have partial agonist activity at the \(\beta\)-receptor at the same time that they prevent access of catecholamines to the receptor. Among currently available agents, this agonist activity is generally weak at therapeutic doses. \(\beta\)-blockers with ISA slow the heart rate to a lower degree than those without, but also appear to reduce peripheral vascular resistance more than those without ISA. The net effect is generally similar blood pressure lowering between agents with and without ISA. There remains some controversy, though, with regard to whether \(\beta\)-blockers with ISA have differential side effect profiles (W. H. Frishman 2007).
\(\beta\)-blockers also differ somewhat with regard to elimination. Many are metabolized by CYP isoenzymes, including CYP2D6. Both metoprolol and nebivolol are extensively metabolized by CYP2D6 and individuals who are poor metabolizers exhibit prolonged \(\beta\)-blockade and greater reductions in heart rate and blood pressure. Likewise, potential exists for significant drug-drug interactions when these \(\beta\)-blockers are used concurrently with agents that influence CYP2D6 metabolism. For example, CYP2D6 inhibitors (e.g., buproprion, fluoxetine, paroxetine, quinidine, propafenone) markedly increase metoprolol steady-state concentrations (2- to 5-fold), prolong its half-life, and likely reduce its \(\beta\)1-selectivity.
Elimination half-lives and durations of action also differ substantially across agents. Esmolol is the shortest-acting \(\beta\)-blocker and is used intravenously only in acute treatment scenarios. Among the oral \(\beta\)-blockers, propranolol, labetalol, and immediate release forms of metoprolol and carvedilol all require multiple doses per day to maintain effective blood pressure lowering throughout the 24-hour period. Atenolol has historically been used as a once-daily agent, although some data suggest it too may offer better protection against hypertension sequelae when used twice-daily (W. H. Frishman and Saunders 2011).
Adverse effects of \(\beta\)-blockers are numerous, which may explain the comparatively low adherence with these agents relative to other commonly used antihypertensive classes. Nevertheless, most of the common adverse events are of relatively limited consequence. Major cardiac adverse effects include bradycardia, bradyarrhythmia (in patients with complete or partial atrioventricular conduction defect or taking other drugs that impair atrioventricular nodal conduction), exacerbation of heart failure (particularly in acute decompensated heart failure). Serious noncardiac effects include increased airway resistance, especially with nonselective \(\beta\)-blockers, but even \(\beta\)1-selective agents should be avoided in patients with severe or decompensated bronchospastic conditions (W. H. Frishman 2007).
Although less serious, metabolic derangements are also fairly common with \(\beta\)-blockers, including alterations in lipid parameters and effects on glucose. Regarding the latter, hyperglycemia and new-onset diabetes are more common with \(\beta\)-blockers than with some other antihypertensive classes (i.e., calcium channel blockers and RAS inhibitors), perhaps because these agents inhibit insulin release from the pancreas or because of unopposed \(\alpha\)1-blockade (by virtue of selective \(\beta\)-blockade) which can cause insulin resistance. \(\beta\)-blockers can also cause fatigue and impair exercise tolerance, which may reduce energy expenditure, and promote weight gain. It remains unclear whether these metabolic effects are class effects, as data from larger clinical trials have suggested differences across the class (W. H. Frishman 2007, 2013).
Central nervous system effects, including fatigue and depression, may also be class effects. However, lipid solubility of specific \(\beta\)-blockers may mediate the risk of these CNS effects. For example, agents with greater lipid solubility (e.g., propranolol) may be associated with a higher risk of CNS effects like depression and vivid dreams than agents with low lipid solubility. Sexual dysfunction is also reported more common with \(\beta\)-blockers than other commonly used antihypertensive classes (W. Frishman and Silverman 1979).
Key Takeaways
- \(\beta\)-blockers lower blood pressure by reducing cardiac output (via cardiac tissue \(\beta\)1-receptors blockade), peripheral vascular resistance, and renin release; for some drugs, other mechanisms may also contribute
- Pharmacokinetic and pharmacodynamic properties vary widely across the class, which can have important implications for choice of agent for a specific patient
- Cardioselective \(\beta\)-blockers (that exhibit preferential binding affinity for \(\beta\)1- vs. \(\beta\)2-receptors) are no more effective at reducing blood pressure, but may engender fewer side effects
\(\alpha\)1-blockers
\(\alpha\)1-adrenergic receptor blockers consist of non-selective agents (phentolamine, phenoxybenzamine) and the \(\alpha\)1-selective agents (doxazosin, prazosin, terazosin). These agents have largely fallen out of favor in the general management of hypertension; however, they can serve as effective antihypertensive therapies in selected patients.
\(\alpha\)-adrenergic receptors are widely distributed throughout the human body and activated by the catecholamines, epinephrine and norepinephrine. Two \(\alpha\)-adrenergic receptors are important in antihypertensive pharmacology:
\(\alpha\)1 receptors: activation of these post-synaptic receptors by endogenous catecholamines results in contraction of arterial, venous, and visceral smooth muscle.
\(\alpha\)2 receptors:
- In the periphery, activation of post-synaptic \(\alpha\)2 receptors (by endogenous catecholamines) in the periphery has similar effects to post-synaptic \(\alpha\)1 receptors (i.e., vasoconstriction), whereas activation of pre-synaptic \(\alpha\)2 receptors produces a negative feedback loop to inhibit catecholamine release
- \(\alpha\)2 receptors also play an important role in the brain by mediating sympathetic output and vagal tone (see Section 9 for a discussion of centrally-acting sympatholytics) (Grimm and Flack 2011; Reid 1986)
Pharmacologic blockade of these receptors inhibits catecholamine-induced vasoconstriction in both arteriolar resistance vessels and veins, leading to reduced peripheral vascular resistance and blood pressure lowering. In the peripheral vasculature, blockade of \(\alpha\)1 receptors is the primary driver of this effect. Furthermore, the net magnitude of blood pressure lowering is dependent on sympathetic nervous system (SNS) activity and the extent to which SNS activity is driving elevations in blood pressure. For example, supine blood pressure is affected less by \(\alpha\)-blockade than is standing blood pressure, and the difference may be amplified in hypovolemic states. At the same time, \(\alpha\) blockade-induced vasodilation is opposed by baroreceptor reflexes that increase heart rate and, by extension, cardiac output to maintain the ‘normal’ (untreated) state. These issues may help explain why \(\alpha\)-blockers are somewhat less effective at lowering blood pressure, on average, than other major antihypertensive classes (Grimm and Flack 2011).
The remainder of this section focuses on agents that antagonize \(\alpha\)-adrenergic receptors only. Information on mixed \(\alpha\)-/\(\beta\)-blockers are discussed in Section 6 and \(\alpha\)-adrenergic agonists are discussed in Section 9.
Non-selective \(\alpha\)-blockers
Phentolamine and phenoxybenzamine, sometimes referred to as “first-generation” \(\alpha\)-blockers, antagonize \(\alpha\)1 and \(\alpha\)2 receptors with approximately equal affinity. Binding of phentolamine to the \(\alpha\) receptors is competitive, whereas phenoxybenzamine binding is irreversible. Blockade of \(\alpha\)1 receptors and a resultant decrease in peripheral vascular resistance is likely the primary mechanism for their antihypertensive effects. Their blockade of \(\alpha\)2 receptors leads to vasodilation as well, but \(\alpha\)2 receptors are less numerous in many of the systemic blood vessels than \(\alpha\)1 receptors. Moreover, these agents block norepinephrine from pre-synaptic \(\alpha\)2 receptors, suppressing the negative feedback loop and allowing more norepinephrine release. And, unopposed \(\alpha\) blockade causes increased activation of post-synaptic \(\beta\) receptors (by endogenous catecholamines) in the heart and kidneys (Grimm and Flack 2011).
These agents cause significant postural hypotension and reflex tachycardia and may precipitate arrhythmias and myocardial infarction. They can also cause significant fluid volume retention. And, animal data suggest that phenoxybenzamine can cause certain types of cancers. Accordingly, they are not generally used for primary hypertension, but rather reserved for selected patients, most notably in the management of pheochromocytomas either preoperatively, or for longer-term treatment in inoperable patients (phenoxybenzamine only). These agents effectively manage severe elevations in blood pressure and minimize plasma volume contraction and myocardial injury in this setting (Grimm and Flack 2011; Reid 1986).
Selective \(\alpha\)1-blockers
Prazosin, and its derivatives, doxazosin and terazosin, are selective, competitive antagonists of post-synaptic \(\alpha\)1-adrenergic receptors. Developed after the non-selective α-blockers, they are sometimes referred to as “second-generation” \(\alpha\)-blockers. As noted above, \(\alpha\)1-blockade leads to arteriole and venous vasodilation, reduced peripheral vascular resistance, decreased cardiac preload, and a lowering of blood pressure. Absent appreciable \(\alpha\)2-blockade, these agents do not significantly affect heart rate or cardiac output, nor do they promote norepinephrine release from cardiac sympathetic nerve endings. Consequently, they lack many of the problematic adverse effects of the non-selective \(\alpha\)-blockers, including reflex tachycardia (Reid 1986).
These agents have similar blood pressure-lowering efficacy but differ somewhat in their pharmacokinetic profiles (Table 8). The most prominent difference relates to duration of action. Prazosin has a short duration of action and requires administration in two or three doses/day. Likewise, terazosin may require twice-daily dosing, whereas the long duration of action for doxazosin allows for once-daily dosing (Grimm and Flack 2011).
| $\alpha$1-blocker | Bioavailability | Tmax | Protein Binding | Elimination Duration of Action | Elimination t1/2 |
|---|---|---|---|---|---|
| Prazosin | 50%–70% | 1–3 hrs | 95% | Hepatic | 3 hrs |
| Doxazosin | 60%–70% | 2–3 hrs | 98% | Hepatic | 22 hrs |
| Terazosin | >90% | 1-2 hrs | 90%–94% | Hepatic | 12 hrs |
Selective \(\alpha\)1-blockers are associated with significant postural hypotension and syncope, particularly very early in therapy or with significant upward dose titrations. This effect is sometimes referred to as the “first-dose effect.” With prazosin, this effect may occur within the first two hours after the initial (or new) dose versus approximately 3-6 hours with doxazosin. Starting with low doses and slow titrations can prevent these effects. Orthostasis is also relatively common during long-term treatment with these agents (Grimm and Flack 2011; Reid 1986).
All \(\alpha\)-blockers cause renal sodium absorption and expansion of extracellular fluid volume and weight gain and swelling are commonly reported adverse effects. Thus, in the setting of chronic treatment (particularly with selective \(\alpha\)1-blockers), a common practice is to combine these agents with diuretic therapy to mitigate this effect (Grimm and Flack 2011; Reid 1986).
Key Takeaways
- \(\alpha\)-blockers lower blood pressure primarily through \(\alpha\)1-receptor antagonism, resulting in vasodilation, reduced vascular resistance, and decreased cardiac preload
- Selective \(\alpha\)1-antagonists (e.g., prazosin, doxazosin) promote similar blood pressure-lowering, but have fewer adverse effects, compared with non-selective \(\alpha\)-blockers (e.g., phentolamine, phenoxybenzamine)
- \(\alpha\)-blockers can cause significant postural hypotension and syncope; they also prompt salt/water retention, thus often need to be paired with a diuretic
Direct arterial vasodilators
Direct arterial vasodilators elicit antihypertensive effects through relaxation of smooth muscle in the peripheral vasculature. Owing to their side effect profile, they are typically reserved for add-on therapy in carefully selected patients.
The direct arterial vasodilators consist of hydralazine, minoxidil, and sodium nitroprusside. These agents elicit their effects through relaxation of smooth muscle in the large conduit arteries, small branch arteries, arterioles, and veins, to varying degrees. Hydralazine and minoxidil preferentially dilate resistance arteries, with little effect on capacitance veins, whereas nitroprusside has similar effects on arteries and veins (Cohn, McInnes, and Shepherd 2011).
Hydralazine and Minoxidil
The exact mechanism of action by which hydralazine relaxes smooth muscle is not well understood but is presumed to involve a reduction in intracellular Ca2+ concentrations. Hydralazine is also believed to have antioxidant effects via inhibition of reactive oxygen species in the vasculature, which may contribute to its vasodilatory effects. Minoxidil is largely inactive, but undergoes metabolism to its active form, minoxidil N-O sulfate, which activates ATP-modulated K+ channels and hyperpolarizes and relaxes smooth muscle in resistance arteries (Cohn, McInnes, and Shepherd 2011; Sica and Gehr 2001).
Both of these drugs prompt compensatory mechanisms that counteract the vasodilatory-mediated blood pressure lowering effects. Specifically, they cause baroreceptor reflex-mediated vasoconstriction and, in combination with other mechanisms, an increase in sympathetic activation and cardiac output. The latter can manifest as tachycardia, palpitation, flushing, and headache, particularly when first starting therapy. They also cause substantial excess sodium and fluid retention by reducing renal perfusion pressures and by sympathetic stimulation of renin release. Accordingly, these agents almost always require concurrent treatment with a \(\beta\)-blocker (or, central sympatholytic) and diuretic (often loop diuretic, especially with minoxidil) to prevent these deleterious effects. Additionally, absent these concurrent therapies, pseudotolerance often develops, whereby the drugs maintain their vasodilatory activity, but the aforementioned compensatory mechanisms (vasoconstriction, increased cardiac output, increased fluid retention) effectively cancel out the blood pressure reductions (Cohn, McInnes, and Shepherd 2011; Sica and Gehr 2001; McComb, Chao, and Ng 2016).
Pharmacokinetic properties of hydralazine and minoxidil are presented in Table 9. Hydralazine is metabolized in part by acetylation and rapid acetylators exhibit greater first-pass metabolism of hydralazine, lower plasma concentrations, and less antihypertensive benefit than slow acetylators. The duration of action of hydralazine is disproportionately long, given its half-life, presumably because hydralazine binds avidly in vascular tissue. In most patients, three daily doses are sufficient to maintain blood pressure throughout the 24-hour period. Minoxidil has a much longer duration of action and can be effectively dosed once daily. Minoxidil also does not require dose adjustments in the setting of renal impairment, whereas hydralazine dosing frequency may need to be reduced (i.e., to once or twice daily) in the setting of severe renal impairment (Cohn, McInnes, and Shepherd 2011; Sica and Gehr 2001).
| Drug | Bioavailability | Protein Binding | Elimination | Onset of Action | Duration of Action | Elimination Route |
|---|---|---|---|---|---|---|
| Hydralazine | 90% | 87% | 65%–90% | Renal | 1.5–3 hrs | 20-30 minutes |
| Minoxidil | 100% | Negligible | 90% | Hepatic | 2.5–4 hrs | 30 minutes |
Aside from the baroreceptor reflex and sympathetic-mediated issues previously mentioned, these agents can cause a number of other adverse effects:
Hydralazine and minoxidil: angina, ECG changes, and myocardial ischemia/infarction (particularly in patients with coexisting ischemic heart disease); propagation of aortic dissections due to increased stroke volume
Hydralazine only: lupus-like syndrome (highest risk in slow acetylators); gastrointestinal effects (vomiting, nausea, diarrhea); and less commonly, muscle cramps, tremors and paresthesias
Minoxidil only: hirsutism (up to 80% of patients with long-term therapy); and, rarely, rashes, Stevens-Johnson syndrome, glucose intolerance, serosanguineous bullae, formation of antinuclear antibodies, and thrombocytopenia (Sica and Gehr 2001)
Sodium Nitroprusside
Sodium nitroprusside is thought to cause vasodilation by nitric oxide donation. It also dilates resistance arterioles and lowers peripheral vascular resistance. In contrast to hydralazine and minoxidil, nitroprusside has little effect on heart rate and reduces myocardial oxygen demand, thus it is not associated with some of the adverse cardiac effects of these other agents. However, similar to hydralazine and minoxidil, nitroprusside can enhance propagation of aortic dissection and should be administered with concurrent \(\beta\)-blocker therapy (Cohn, McInnes, and Shepherd 2011).
Nitroprusside is generally reserved for treatment of hypertensive emergency, usually in the intensive care setting. It is administered via controlled infusion, with an onset of antihypertensive action <30 seconds, and peak effects within 1-2 minutes. Blood pressure returns to pre-treatment levels within approximately 3 minutes of discontinuing the nitroprusside infusion (Cohn, McInnes, and Shepherd 2011).
Side effects of nitroprusside are primarily related to its rapid hypotensive effects, i.e., excessive vasodilation. However, it can also be converted to cyanide and thiocyanate and cause severe lactic acidosis in patients receiving high doses or prolonged treatment (e.g., >24 hours) (Cohn, McInnes, and Shepherd 2011).
Key Takeaways:
- The direct-acting vasodilators, hydralazine and minoxidil, are effective antihypertensives but associated with significant adverse effects, relegating them to use primarily in resistant hypertension
- Hydralazine and minoxidil require concomitant \(\beta\)-blockade and diuretic therapy (usually loops) to prevent pseudotolerance and some adverse events
- Sodium nitroprusside is a rapid-acting vasodilator, typically reserved for hypertensive emergency in the intensive care setting
Central and Peripheral Sympatholytics
Sympatholytics lower blood pressure by reducing sympathetic output from the central nervous system (centrally acting sympatholytics), or through peripheral adrenergic inhibition (reserpine). These agents are typically considered add-on therapies, usually in treatment-resistant hypertension, except in select circumstances.
Centrally acting Sympatholytics
Centrally acting sympatholytics used in the treatment of hypertension include clonidine, methyldopa, guanfacine, and guanabenz, as well as imidazoline receptor agonists, moxonidine and rilmenidine. These agents lower blood pressure through stimulation of central post-synaptic \(\alpha\)2-adrenergic receptors, imidazoline 1 (I1) receptors, or both in the brainstem’s SNS control centers. However, differences in receptor selectivity exist among these agents: - Non-selective agents: Clonidine - \(\alpha\)2-selective agents: Methyldopa, guanfacine, and guanabenz - I1-selective agents (not marketed in the U.S.): Moxonidine and rilmenidine
Stimulation of these receptors, in turn, suppresses sympathetic outflow to the heart, blood vessels and kidneys. Other notable reactions to stimulation include: - Reduced norepinephrine release (and thus less \(\alpha\)1- and \(\beta\)1-receptor stimulation), leading to decreased peripheral vascular resistance - Diminished baroreceptor reflex compensation, and decreased heart rate and cardiac output - Decreased renin release, leading to suppressed angiotensin I, angiotensin II, and aldosterone production (McComb, Chao, and Ng 2016).
All of these mechanisms contribute to the blood pressure-lowering effects of these agents, particularly early in therapy, though the relative contributions are not well-characterized. Effects on heart rate and cardiac output are generally seen more at rest than with exercise. With chronic treatment, cardiac output tends to return to pretreatment levels, whereas the reduction in peripheral vascular resistance is sustained in most patients. However, some patients develop tolerance to the antihypertensive effects of these drugs during long-term therapy (Grassi 2016).
Pharmacokinetic and pharmacodynamic properties of the centrally acting sympatholytics are summarized in Table 10. Because all of these agents must cross the blood-brain barrier to impart their antihypertensive effect, there is a lag time between achieving plasma drug concentration and clinical antihypertensive effects, equal to the time required to achieve sufficient drug concentrations in the brainstem. Accordingly, some common general pharmacokinetic measures, such as Tmax, may be misleading with regard to determining differences in antihypertensive effect onset and duration within this class (McComb, Chao, and Ng 2016).
| Drug | Oral Bioavailability | Protein Binding | Elimination Route | Elimination t1/2 | Onset of Action | Duration of Action | |
|---|---|---|---|---|---|---|---|
| Clonidine (oral) | 100% | 20%–40% | 50% hepatic | ~12 hrs (41 hrs) | 0.5–1 hr | ~8 hrs | |
| Cloinidine (transdermal) | NA | 20%-40% | 50% hepatic | ~20 hrs | 2–3 days | 1 week | |
| Guanabenz | 75% | 90% | ≥95% hepatic | 4–6 hrs | 1 hr | ~12 hrs | |
| Guanfacine | 80% | 70% | 50% hepatic | 12–24 hrs | ~1 hr | ~24 hrs | |
| Methyldopa | 25% | <20% | 70% renal | 1.5–2 hrs (4-6 hrs) | ~1 hr | 6–8 hrs |
These agents have generally similar blood pressure lowering effects at equipotent doses, with an important caveat related to clonidine. Clonidine is typically administered either orally or transdermal. Oral administration has a much faster onset of action, but a relatively short duration of action, requiring 3 doses/day in most patients. Moreover, oral administration of clonidine results in significant peak and trough concentrations. These varied concentrations throughout the day can lead to substantial blood pressure variability. Moreover, trough periods can lead to substantial rebound hypertension (with severely elevated blood pressure) and other symptoms of sympathetic overactivity (headache, anxiety, palpitation, tremor), especially in patients who are not adherent. Conversely, transdermal application of clonidine (i.e., to the upper arm) results in much slower onset of action because the drug must be released from the adhesive layer (usually within ≤8 hours of application), then must fix to skin proteins before being released into the blood stream and, eventually, cross the blood-brain barrier to reach α2 receptors. Thereafter, clonidine is released from the patch reservoir at a constant rate, at least until the patch reservoir has been substantially depleted (≤ ~40% saturation), which does not occur until 9 days or more following application. When the patch is replaced weekly, this level of depletion is not reached. On patch removal, residual drug in the skin serves as a reservoir, leading to a more gradual downward slope in clonidine concentration. As a consequence, rebound hypertension is much less common and less severe than with transdermal versus oral clonidine. Similarly, rebound hypertension occurs less often with guanfacine, probably as a function of its relatively longer half-life (Vongpatanasin et al. 2011).
In contrast to α1 blockers, α\(\alpha\)2 agonists do not greatly affect postural reflexes and orthostasis is infrequent and generally mild when it does occur. However, all \(\alpha\)2 agonists are associated with significant dry mouth and CNS side effects, including sedation and fatigue. These adverse effects are major causes of treatment discontinuation and nonadherence, and are most pronounced with oral clonidine, guanfacine, and guanabenz, but considerably less so with transdermal clonidine. Methyldopa does cause sedation and fatigue, but these effects are usually transient and less severe than with the other \(\alpha\)2 agonists. Additionally, CNS effects are more pronounced when these drugs are used in combination with other CNS-depressing drugs, including benzodiazepines, ethanol, and sedative-hypnotics. Methyldopa also has other significant side effects, particularly with longer-term therapy, including a positive Coombs test (10% to 20% of long-term users), hemolytic anemia, and lupus-like syndrome (Vongpatanasin et al. 2011).
Contraindications differ somewhat between agents. Methyldopa has also been extensively used in pregnant women and does not affect maternal cardiac output, uterine blood flow, or renal blood flow and is not known to adversely affect the fetus, nor is it distributed significantly into breast milk. Accordingly, methyldopa is often considered a first-line therapy for treatment of pre-existing hypertension during pregnancy and immediately post-partum. Conversely, guanabenz should be avoided in pregnancy. Active hepatic disease should prompt avoidance of guanabenz and methyldopa. Significant renal impairment warrants dose adjustments or less frequent dosing for clonidine, methyldopa, and possibly guanfacine, but not for guanabenz (McComb, Chao, and Ng 2016; Vongpatanasin et al. 2011).
Peripheral Sympatholytics
The only currently available peripheral sympatholytic in the U.S. is reserpine. Reserpine depletes norepinephrine (and other neurotransmitters, including 5-HT) levels in the peripheral sympathetic nerves, brain, adrenal medulla, and other tissues. The mechanism of action is believed to be inhibition of the ATP/Mg2+ pump responsible for sequestering norepinephrine into storage granules in postganglionic sympathetic nerve endings. Because transport to these storage granules is prevented, the catecholamines, including norepinephrine, are metabolized by monoamine oxidase. This activity results in reduced peripheral vascular resistance, in a similar fashion to that seen with post-synaptic \(\alpha\)1- and \(\alpha\)2-blockade. Heart rate is also decreased with reserpine administration (McComb, Chao, and Ng 2016).
Because reserpine affects brain tissue sympathetic nerve endings as well, central nervous system side effects, e.g., sedation, fatigue, depression and nasal stuffiness, are common with this drug, particularly at higher doses (≥0.75 mg/day). Conversely, lower doses (0.05 to 0.5 mg/day) are usually effective and well-tolerated, particularly when combined with diuretics. Reserpine is extremely long-acting, with a terminal half-life of 8 to 9 days, and can be dosed once daily (McComb, Chao, and Ng 2016; Vongpatanasin et al. 2011).
Key Takeaways:
- \(\alpha\)2-agonists (clonidine, guanfacine, guanabenz, methyldopa), are centrally-acting sympatholytics; they are effective antihypertensives, but can cause dry mouth and significant CNS effects
- Reserpine reduces peripheral vascular resistance and heart rate; at low doses (0.05-0.25 mg once daily) it is very effective and well-tolerated