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198 THERAPEUTIC PRINCIPLES
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4. How has the recommendation for beta-blockers changed with time for hypertension?
Beta-blockers together with diuretics were the cornerstone of the pharmacological management of hypertension,
but this treatment strategy has been reappraised. Based both on US (the 2017 American Heart Association/American College of Cardiology [AHA/ACG]) and the European (2018 European Society of Hypertension/European Society
of Cardiology [ESH/ESC]) guidelines, beta-blockers are no longer recommended as first-line agents in pharmacotherapy of uncomplicated hypertension.
for the management of hypertension in patients with specific indications for their use, such as among patients
with concomitant heart failure (HF), angina, and atrial fibrillation or after an acute myocardial infarction.
In the following sections of this chapter, we provide a critical evaluation of the available randomized trials
that investigated the efficacy and safety of beta-blockers and reported outcomes in hypertensive patients with or
without chronic kidney disease (CKD). We discuss gaps in the existing evidence and conclude with clinical practice
recommendations and directions for future research in this important area.
5. What is the clinical trial evidence for beta-blockers use in hypertension?
The efficacy and safety of beta-blockers as first-line agents in pharmacotherapy of uncomplicated hypertension
was explored in an updated 2017 Cochrane metaanalysis of 13 randomized trials comparing beta-blockers either
with placebo or with active-treatment.10 Beta-blockers were not superior to placebo (relative risk [RR]: 0.99; 95%
confidence interval [CI]: 0.88–1.11) or active-treatment with diuretics (RR:1.04; 95% CI: 0.91–1.19) and reninangiotensin-system (RAS)-blockers (RR: 1.10; 95% CI: 0.98–1.24) in reducing all-cause mortality; in contrast,
all-cause mortality risk was higher when beta-blockers were compared with calcium-channel-blockers (CCBs)
(RR: 1.07; 95% CI: 1.0–1.14).10 Compared with placebo, beta-blockers provoked a 12% reduction in the risk of
cardiovascular events (RR: 0.88; 95% CI: 0.79–-0.97), a benefit that was driven mainly by a favorable effect of
beta-blockers on the incidence of stroke (RR: 0.80; 95% CI: 0.66–0.96). There was no difference between betablockers and diuretics (RR: 1.13; 95% CI: 0.99–1.28) or between beta-blockers and RAS-blockers (RR: 1.0; 95%
CI: 0.72–1.38) in the risk of cardiovascular events. However, the risk of cardiovascular events was higher when
beta-blockers were compared with CCBs (RR: 1.18; 95% CI: 1.08–1.29). Once again, this difference was driven
by the inferiority of beta-blockers to improve the incidence of stroke (RR: 1.24; 95% CI: 1.11–1.4).10 With respect
to safety outcomes, the likelihood of drug discontinuation due to adverse events was higher when beta-blockers
were compared with RAS-blockers (RR: 1.41; 95% CI: 1.29–1.54), but discontinuation rates did not differ when
beta-blockers were compared with placebo, diuretics, or CCBs.
This metaanalytic evidence suggests that initial treatment with beta-blockers confers modest improvement in the risk of cardiovascular morbidity and little to no benefit on all-cause mortality, providing support to
current international guidelines that do not recommend beta-blockade as first-line drug therapy of uncomplicated
hypertension.
8,9
It has to be noted, however, that these findings should be interpreted within the context of some
methodological limitations.11 First, all trials included in this metaanalysis provided add-on medications to the initial
antihypertensive regimen, implying that the reported outcomes might have been affected by between-arm differences in add-on treatment. Second, atenolol was the agent that was used as a comparator in the majority of the
trials included in this metaanalysis, limiting the generalizability of the results to the overall class of beta-blockers.
Third, there were no trials to evaluate the efficacy of third-generation vasodilating beta-blockers on “hard” cardiovascular outcomes. Therefore, the certainty of evidence for most of the outcomes tested in this metaanalysis was
qualified as low-to-moderate.11 Future trials are clearly warranted to elucidate the comparative effectiveness of
newer versus traditional beta-blockers in pharmacotherapy of uncomplicated hypertension.
8,9
Both guidelines recommend that beta-blockers should be considered
8,9
10
6. What is the evidence for beta-blockers use for preventing progression of kidney failure?
In the AASK (African-American Study of Kidney Disease and Hypertension) trial,12 1094 African-Americans with
hypertensive nephrosclerosis were randomized to a lower versus a standard mean BP target (<92 mm Hg versus
102–107 mm Hg) and to initiate antihypertensive therapy with metoprolol (50–200 mg/day), ramipril (2.5–10 mg/
day), or amlodipine (5–10 mg/day) in a 2 × 3 factorial design. Open-label, add-on therapy was administered to
achieve the assigned BP targets. The average on-treatment systolic BP was 135 ± 13 mm Hg in the metoprolol
group, 135 ± 14 mm Hg in the ramipril group and 133 ± 12 mm Hg in the amlodipine group.12 Thus, a beta-blocker-based regimen was equally effective with other antihypertensive regimens in controlling BP among AfricanAmericans with hypertensive kidney disease. It has to be noted, however, that compared with metoprolol, therapy
with ramipril lowered by 22% (P = .04) the composite kidney outcome of greater than 50% decline in glomerular
filtration rate (GFR), end stage kidney disease, or death.12 Compared with amlodipine, therapy with ramipril was
even more clinically efficacious as it lowered these end-points by 38% (P = .004).
7. What is the evidence for beta-blockers use for management of heart failure in CKD?
The cardioprotective action of beta-blockers among patients with CKD was investigated in a metaanalysis by
Badve et al.13 Despite the absence of stringent selection criteria, this metaanalysis included only 6 placebocontrolled trials (incorporating data from 5972 CKD participants). All these trials enrolled patients with HF and
reduced left ventricular (LV) ejection fraction. This systematic review identified two additional trials that were
BETA-BLOCKERS 199
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conducted in non-HF patients, but these studies were not eligible in quantitative data synthesis due to incomplete
outcome reporting. Among CKD patients with systolic HF, treatment with beta-blockers was superior to placebo in
lowering the risk of all-cause death RR 0.72; 95% CI: 0.64–0.80) and in reducing the risk of cardiovascular death
(RR: 0.66; 95% CI: 0.49–0.89).13 However, this benefit on survival was paralleled with a 4.92-fold elevation in the
incidence of bradycardia (RR: 4.92; 95% CI: 3.20–7.55) and a 5.08-fold higher risk of hypotension (RR: 5.08; 95%
CI: 3.48–7.41).13 These adverse events associated with beta-blockade use occur more commonly in HF patients
with than without CKD. An earlier metaanalysis exploring the safety and tolerability of these agents in the general
HF population showed that compared with placebo, beta-blockers were associated with a 3.62-fold relative
increase in the incidence of bradycardia (RR: 3.62; 95% CI: 2.48–5.28) and with only 41% higher risk of hypotension (RR: 1.42; 95% CI: 0.96–2.06).14 The metaanalysis of Badve et al.13 highlights the lack of direct evidence on
the efficacy of beta-blockers in the CKD population, as five out of six eligible studies were post-hoc analyses of
trials reporting mortality outcome data in subgroups of participants with CKD at baseline.
8. What is the evidence for beta-blockers use in management of hypertension in dialysis?
Evidence on the comparative effectiveness of different antihypertensive drug classes among patients on dialysis
was provided by the HDPAL (Hypertension in Hemodialysis treated with Atenolol or Lisinopril) trial.15 In this trial,
200 hypertensive dialysis patients with LV hypertrophy were randomized to open-label lisinopril or atenolol, each
administered on a thrice-weekly regimen immediately postdialysis. All participants were treated to the same
monthly monitored home BP target of less than 140/90 mm Hg following a prespecified algorithm that included
firstly, the dose titration of the study drugs and then, intensification of background antihypertensive therapy,
sodium restriction, and dry-weight reduction.15 Contrary to the original hypothesis that a lisinopril-based regimen would be superior to atenolol in causing regression of LV hypertrophy, both drugs were equally effective in
reducing LV mass index during the 12-month-long follow-up of the trial. In addition, atenolol appeared to be more
effective in improving BP control, as monthly monitored home BP was consistently lower in the atenolol group,
despite a greater need for intervention in the lisinopril group; in lisinopril-treated participants, antihypertensive
therapy and more aggressive dry-weight adjustment was required.15 Due to cardiovascular safety reasons, the
trial was terminated early. Serious adverse cardiovascular events occurred more commonly in the lisinopril than in
the atenolol group (incidence rate ratio [IRR]: 2.36; 95% CI: 1.36–4.23). The risk of hospitalization for HF was also
higher in lisinopril-treated than in atenolol-treated participants (IRR: 3.13; 95% CI: 1.08–10.99).15 A secondary
analysis of the HDPAL trial showed that compared with lisinopril, atenolol provoked a greater proportional reduction in aortic pulse wave velocity over the first 6 months of follow-up (between-drug difference: 14.8%; 95% CI:
1.5% to 28.5%).
16
Therefore, atenolol appears to be more effective than lisinopril in improving BP control, in causing regression of aortic stiffness and possibly, in reducing the occurrence of serious adverse cardiovascular events among
hypertensive dialysis patients.15 In contrast to the previously mentioned guidelines that do not recommend the
use of beta-blockers as first-line antihypertensive therapy,
8,9
the surprising results of the HDPAL trial support
the notion that beta-blockers, and particularly atenolol administered 3 times per week postdialysis, may be the
preferred choice in pharmacotherapy of hypertension in dialysis patients. Undoubtedly, the potential superiority
of beta-blockers over other antihypertensive drug classes in this particular population warrants confirmation in
future clinical trials.
9. What are the practical aspects in the use of beta-blockers for management of hypertension
in CKD?
Taken together, although beta-blockers are no longer recommended as first-line therapy of uncomplicated
hypertension,
8,9
these agents continue to be commonly prescribed in daily clinical practice, particularly in
patients with advanced CKD.
beta-blockers in this setting, we do not prescribe beta-blockers as first-line antihypertensive therapy to our
patients with CKD who are not on dialysis.1 However, based on the results of the HDPAL trial and in the absence
of other trials to provide head-to-head comparisons between agents from different antihypertensive classes, the
beta-blocker atenolol is our first-line choice in pharmacotherapy of hypertension for our dialysis patients without
specific indication for other treatment. Because atenolol is a hydrophilic beta-blocker with high dialyzability, we
prescribe this agent on a thrice-weekly regimen immediately postdialysis. This dosing regimen of atenolol is
effective in controlling 44-hour interdialytic ambulatory BP.19 The use of beta-blockers as second-line agents for
those with other specific cardiovascular indications (i.e., HF) appears reasonable and is often necessary due to
the need for multiple antihypertensive drugs to control hypertension in these patients. The signal of cardioprotection with beta-blockade from randomized trials among patients with eGFR less than 30 mL/min/1.73m2 or
those on dialysis is weak.20 However, pharmacoepidemiologic studies from Canada suggest that a mortality
benefit of beta-blocker use exists, even among patients with stage 4 CKD.
sitates the design of randomized trials to specifically investigate the efficacy and safety of beta-blockers in this
high-risk patient population, we continue to prescribe and use these drugs liberally among patients with CKD,
including those on dialysis.
17,18
In the absence of solid and robust clinical-trial evidence to guide the use of
20,21
Although scientific gap neces-
200 THERAPEUTIC PRINCIPLES
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KEY POINTS
1. Although the exact mechanisms through which beta-blockers lower systemic blood pressure remain unclear, it is
the blockade of the β1-adrenergic receptor that appears to be the predominant mechanism by which these drugs
reduce heart rate, cardiac output, and peripheral vascular resistance and thereby lower BP.
2. Beta-blockers differ substantially in their β1/ β2-adrenergic receptor selectivity, intrinsic sympathomimetic
activity, and vasodilatory properties.
3. Beta-blockers are no longer recommended as first-line agents in pharmacotherapy of uncomplicated
hypertension but should be considered for the management of hypertension in patients with specific indications
for their use, such as among patients with concomitant heart failure, angina, and atrial fibrillation, or after an
acute myocardial infarction.
4. Beta-blockers do appear to be more effective in improving BP control, and possibly in reducing the occurrence of
serious adverse cardiovascular events, among hypertensive dialysis patients.
Disclosures: R.A. has the following disclosures:
Member data safety monitoring committees: Astra Zeneca, Ironwood Pharmaceuticals;
Member steering committees of randomized trials: Akebia, Bayer, Janssen, Glaxo Smith Cline, Relypsa,
Sanofi and Genzyme US Companies;
Member adjudication committees: Bayer, Boehringer Ingelheim, Janssen;
Member scientific advisory board or consultant: Celgene, Daiichi Sankyo, Inc, Eli Lilly, Relypsa, Reata,
Takeda Pharmaceuticals, USA, ZS Pharma.
Financial support: R.A. is supported by NIH 5 R01 HL126903-04 and a grant from VA Merit Review
I01CX001753.
RefeRences
1. Sinha AD, Agarwal R. Clinical pharmacology of antihypertensive therapy for the treatment of hypertension in CKD. Clin J Am Soc
Nephrol. 2019;14(5):757–764.
2. Ripley TL, Saseen JJ. Beta-blockers: a review of their pharmacological and physiological diversity in hypertension. Ann
Pharmacother. 2014;48(6):723–733.
3. Sarafidis PA, Bakris GL. Metabolic effects of beta-blockers: importance of dissociating newer from conventional agents. J Hypertens.
2007;25(1):249–252.
4. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet.
2007;369(9557):201–207.
5. Ayers K, Byrne LM, DeMatteo A, Brown NJ. Differential effects of nebivolol and metoprolol on insulin sensitivity and plasminogen
activator inhibitor in the metabolic syndrome. Hypertension. 2012;59(4):893–898.
6. Bakris GL, Fonseca V, Katholi RE, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and
hypertension: a randomized controlled trial. JAMA. 2004;292(18):2227–2236.
7. Kampus P, Serg M, Kals J, et al. Differential effects of nebivolol and metoprolol on central aortic pressure and left ventricular wall
thickness. Hypertension. 2011;57(6):1122–1128.
8. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the
prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/
American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2018;71(19):e127–e248.
9. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: the task force for
the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension: the task
force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension.
J Hypertens. 2018;36(10):1953–2041.
10. Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH. Beta-blockers for hypertension. Cochrane Database Syst Rev.
2017;1:CD002003.
11. Wiysonge CS, Bradley HA, Volmink J, Mayosi BM. Heart. 2018;104(4):282–283.
12. Wright JT, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive
kidney disease: results from the AASK trial. JAMA. 2002;288(19):2421–2431.
13. Badve SV, Roberts MA, Hawley CM, et al. Effects of beta-adrenergic antagonists in patients with chronic kidney disease: a
systematic review and meta-analysis. J Am Coll Cardiol. 2011;58(11):1152–1161.
14. Ko DT, Hebert PR, Coffey CS, et al. Adverse effects of beta-blocker therapy for patients with heart failure: a quantitative overview of
randomized trials. Arch Intern Med. 2004;164(13):1389–1394.
15. Agarwal R, Sinha AD, Pappas MK, Abraham TN, Tegegne GG. Hypertension in hemodialysis patients treated with atenolol or lisinopril:
a randomized controlled trial. Nephrol Dial Transplant. 2014;29(3):672–681.
16. Georgianos PI, Agarwal R. Effect of lisinopril and atenolol on aortic stiffness in patients on hemodialysis. Clin J Am Soc Nephrol.
2015;10(4):639–645.
17. Frankenfield DL, Weinhandl ED, Powers CA, Howell BL, Herzog CA, St Peter WL. Utilization and costs of cardiovascular disease
medications in dialysis patients in Medicare Part D. Am J Kidney Dis. 2012;59(5):670–681.
18. Ku E, McCulloch CE, Vittinghoff E, Lin F, Johansen KL. Use of antihypertensive agents and association with risk of adverse outcomes
in chronic kidney disease: focus on angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. J Am Heart Assoc.
2018;7(19):e009992.
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19. Agarwal R. Supervised atenolol therapy in the management of hemodialysis hypertension. Kidney Int. 1999;55(4):1528–1535.
20. Agarwal R, Rossignol P. Beta-blockers in heart failure patients with severe chronic kidney disease-time for a randomized controlled
trial?. Nephrol Dial Transplant. 2020;35(5):728–731.
21. Molnar AO, Petrcich W, Weir MA, Garg AX, Walsh M, Sood MM. The association of beta-blocker use with mortality in elderly patients
with congestive heart failure and advanced chronic kidney disease. Nephrol Dial Transplant. 2020;35(5):782–789.
ALPHA-2 AGONISTS
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Christin Giordano McAuliffe, MD, and J. Matt Luther, MD MSCI
CHAPTER 38
QUESTIONS
1. How do alpha-2 agonists reduce blood pressure?
Norepinephrine activates the alpha-2 adrenergic receptor in the brain, which serves as a negative feedback
mechanism to suppress the sympathetic nervous system. Drugs with alpha-2 agonist activity mimic this effect
centrally, resulting in suppression of peripheral norepinephrine release and subsequently lowering blood pressure.
As a result, efficacy of these drugs is reflected by the suppression of circulating norepinephrine. This effect
is also used in the clonidine-suppression test to establish autonomous catecholamine secretion by pheochromocytomas, which do not suppress catecholamine secretion in response to clonidine.
2. Which medications act primarily as alpha-2 agonists?
Clonidine, guanfacine, and methyldopa are the most commonly used alpha-2 agonists for the management of
hypertension (Table 38.1). Guanfacine is also used in the treatment of attention deficit/hyperactivity disorder. In
addition, several medications used for other indications act primarily at the alpha-2 receptor including dexmedetomidine, which is commonly used for sedation in intensive care units (Table 38.2). Lofexidine is approved for
treatment of opioid withdrawal.
3. When prescribing an alpha-2 agonist, what are the usual doses?
Table 38.2 for usual doses of the most commonly used alpha-2 agonists.
Table 38.1 Dosing of Commonly Used Alpha-2 Agonists
MEDICATION
Clonidine 0.1–0.3 mg three
Guanfacine 1–4 mg once
Methyldopa 250–1000 mg
Moxonidine 0.2–0.6 mg once
TYPICAL
DOSE RANGE
times daily
daily
two to three
times daily
daily
1
Dosage Adjustment for Impaired:
KIDNEY
FUNCTION
Reduce dose
and/or
frequency
None Use with caution
Reduce dose
and/or
frequency
Reduce dose
and/or
frequency
LIVER
FUNCTION CONSIDERATIONS
None Half-life ∼12 hours
CYP3A4 substrate
None Rare autoimmune reactions
None Available outside the United
Prolonged half-life in renal
failure
Half-life ∼17 hours
(+ANA, hemolytic anemia)
and abnormal liver tests
Active metabolites are renally
cleared
States
Contraindicated in heart failure
Prolonged half-life in renal
failure
Tizanidine 4–32 mg every
4–6 hours
ANA, Antinuclear antibody.
202
Reduce dose
and/or
frequency
Contraindicated Markedly increased during
CYP1A2 inhibitors
ALPHA-2 AGONISTS 203
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Table 38.2 Medications with Alpha-2 Agonist Effects
MEDICATION NOTES
Apraclonidine eye drops
Clonidine Most commonly used for hypertension
Dexmedetomidine Used primarily for sedation
Guanfacine Approved for attention deficit/hyperactivity disorder; long half-life
Guanabenz
Lofexidine Approved for opioid withdrawal
Methyldopa Historically used in pregnancy
Moxonidine Available outside of the United States
Tizanidine Used as nonopioid pain relief
Xyalazine Veterinary tranquilizer; reported contaminant in street drugs (fentanyl)
4. What are the most common side effects of alpha-2 agonists?
The most commonly reported side effects are:
Catecholamine reduction during treatment characteristically reduces both blood pressure and heart rate.
worsen orthostatic hypotension. Patients with depression may not be a suitable candidate for treatment because
mental alterations such as sedation and depression are also relatively common.
Considerations specific to individual medications include the following:
anemia and antinuclear antibody positivity.
-
sion and exacerbation of side effects.
-
lones or fluvoxamine) and is contraindicated in these settings.
adhesive. It does not typically preclude the use of oral clonidine.
-
testinal tract and can rarely produce systemic side effects such as bradycardia and hypotension.
An imidazoline receptor antagonist
5. What issues can arise when discontinuing alpha-2 agonists?
Abrupt withdrawal of alpha-2 agonists in patients taking these medications long-term will produce rebound
hypertension, which can sometimes be severe (see Chapter 13). Therefore alternative medications are preferred in
patients who cannot reliably adhere to a regular medication schedule.
6. How does alpha-2 agonist rebound hypertension (drug withdrawal) present?
Rebound hypertension due to central alpha-2 agonist withdrawal is characterized by hypertension with
tachycardia due to excess sympathetic activation. In contrast, hypertension due to vasoconstrictor sympathetic
agents (e.g., phenylephrine) is usually accompanied by a reduction in heart rate due to baroreflex activation.
Hyperadrenergic symptoms and hypertension can appear abruptly within the first 1 to 2 days after stopping an
alpha-2 agonist, with maximal effect at 3 to 5 days if untreated, as a result of norepinephrine excess at peak
withdrawal. Hypertension may be worsened by concurrent use of a β1-selective beta-blocker, which can prevent
tachycardia and relieve symptoms during norepinephrine excess but does not block the vascular alpha-1 receptor–mediated vasoconstriction and hypertension. Chronic beta-blocker use also increases receptor sensitivity,
resulting in heightened response to norepinephrine if both agents are withdrawn simultaneously.
2
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Patients are frequently unaware of the risk of rebound hypertension. In particular, patients and physicians
using alpha-2 agonists for indications other than hypertension are often unaware of this risk. Patient education about withdrawal hypertension may improve medication adherence and reduce the risk of its occurrence.
Patients presenting with withdrawal have often discontinued the drug due to conditions out of their control, such
as hospital admission, incapacitation, or medication unavailability. A thorough comparison of home versus hospital
medications should be performed, and physicians should have a high index of suspicion when an abrupt change
in blood pressure occurs.
7. How can alpha-2 agonist rebound hypertension (drug withdrawal) be prevented or treated?
clonidine patch, transition to a lower dose patch requires a new prescription for the lower dose patch because
the patches should not be cut.
doses or abrupt cessation.
drug or replacing with an alternative alpha-2 agonist. Guanfacine is longer acting and can be used to taper
over a longer period.
8. What conditions, other than hypertension, are treated by use of alpha-2 agonists?
withdrawal
pheochromocytoma
increases blood pressure, particularly at a high dose, and this effect can rarely be used therapeutically in
patients with refractory autonomic failure
9. What commonly used muscle relaxer is primarily an alpha-2 agonist?
-
monly used as an alternative to opioids for treatment of chronic pain.
produce marked hypotension.
once daily.
in postoperative pain management. Pain practitioners may not be aware of the risk of hypotension or rebound
hypertension.
10. Should an alpha-2 agonist be the preferred agent in specific settings?
-
strated safety for the fetus. The primacy of methyldopa in pregnancy has recently been called into question
with a recent open-label, randomized controlled study that suggests that nifedipine more effectively achieves
blood pressure control in pregnancy, although it may have higher fetal risks of intensive care admission (see
Chapter 23).
3
take oral medications and thus may improve adherence.
11. Should these drugs be avoided in certain settings?
route.
an adverse or beneficial effect depending on the circumstance.
4
ALPHA-2 AGONISTS 205
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KEY POINTS
patch because the patches should not be cut.
2. Clonidine and other α2-agonists may produce an initial paradoxical vasoconstrictor response which increases
blood pressure, particularly at a high dose.
3. Clonidine causes initial vasoconstriction when given intravenously, and should not be administered via this route.
RefeRences
1. Sica DA. Centrally acting antihypertensive agents: An update. J Clin Hypertens. 2007;9:399–405.
Br J Clin
Pharmacol. 1979;7:55–62.
management of severe hypertension in pregnancy: an open-label, randomised controlled trial. Lancet. 2019;394:1011–1021.
patients with heart failure (moxcon). Eur J Heart Fail. 2003;5:659–667.
DRUG-DRUG AND PHARMACOGENETIC
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INTERACTIONS
CHAPTER 39
Jonathan D. Mosley, MD
QUESTIONS
1. What are the possible mechanisms by which medications or supplements affect antihypertensive medication effectiveness?
The mechanisms by which medications or supplements may impact antihypertensive effectiveness include
modulating the metabolism of the antihypertensive medication and activating molecular mechanisms which
counteract the targeted blood pressure–lowering mechanisms. Drug metabolism is mediated, in part, by the
cytochrome P450 proteins, which are monooxygenases which participate in activation, inactivation, and clearance
of drugs.1 Cytochrome P450 3A4 (CYP3A4), for instance, participates in the oxidation, inactivation, and removal
from the circulation for a number of drugs including dihydropyridine calcium channel blockers such as nifedipine.
Rifampin, an antibiotic often used in the treatment of tuberculosis, causes an induction of CYP3A4 which leads to
decreased systemic concentrations of nifedipine and worsening hypertension.
drugs (NSAIDs), by contrast, lead to increased blood pressure without altering drug metabolism. NSAIDS inhibit
the cyclo-oxygenase pathway of arachidonic acid metabolism and decrease the formation of prostaglandins which
modulate blood pressure though a number of mechanisms including altered tubular secretion of salt and water
and modulation of the renin-angiotensin-aldosterone system. The overlap between these mechanisms and those
modulated by thiazide diuretics
ers (ACEi/ARBs)9 results in attenuated activity of these classes of antihypertensives in the presence of NSAIDS.
Additional mechanisms are presented in Table 39.1. Antihypertensive medications affected by cytochrome P450
are listed in Table 39.2.
7,8
and angiotensin converting enzyme inhibitors/angiotensin receptor block-
2–6
Nonsteroidal antiinflammatory
Table 39.1 Notable Antihypertensive Medication Drug-Drug Interactions
DRUG INTERACTING
ACE inhibitor Angiotensin receptor
Alpha blockers PDE5 inhibitors
Beta blockers Verapamil
Calcium channel blockers
(dihydropyridine)
K-sparing diuretics
(Amiloride, Spironolactone, Eplerenone)
206
DRUGS
blocker
Neprilysin inhibitor Likely due to altered
DPP4 inhibitor Likely due to altered
Nitrates
Diltiazem
Clonidine
Alpha blockers
Hydralazine
Minoxidil
Trimethoprim
Pentamidine
ACEi/ARBs
MECHANISM EFFECT
RAS inhibition
↑
vasoactive peptide
degradation
vasoactive peptide
degradation
Shared side effect profile↑Risk of severe
Shared side effect profile Bradycardia, AV nodal
Shared side effect profile↑Risk of peripheral
Shared mechanism
Risk of renal
↑
dysfunction
Risk of angioedema
↑
Risk of angioedema
↑
Blood pressure at high
↑
dose ACEi
hypotension
block
edema
Risk of hyperkalemia
↑
DRUG-DRUG AND PHARMACOGENETIC INTERACTIONS 207
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Table 39.1 Notable Antihypertensive Medication Drug-Drug Interactions (Cont.)
DRUG INTERACTING
DRUGS
MECHANISM EFFECT
NSAIDs Thiazides/ACEi/ARB ↓Prostanoid biosynthesis ↓Antihypertensive
efficacy
Renin inhibitors ACE inhibitor or angioten-
sin receptor blocker
RAS inhibition
↑
Risk of stroke,
↑
Hyperkalemia, renal
failure in diabetics
Rifampin CCBs, others CYP3A4 induction ↓Drug, CCB
concentration
Thiazides Loop diuretics Augmented mechanism
Risk of hypokalemia
↑
and hyponatremia,
volume depletion
Selective serotonin
re-uptake inhibitors
Additive mechanisms,
ADH stimulation
Risk of hyponatremia
↑
(SSRIs)
Lithium
Renal reabsorption (↓
↑
Lithium toxicity
renal clearance)
Digoxin Hypokalemia augments
Digitalis toxicity
digoxin binding to
receptor
Diltiazem
Verapamil
CYP3A4-metabolized
drugs
CYP3A4 inhibition
Concentration of
↑
CYP3A4-metabolized
drugs
ACE, Angiotensin converting enzyme; ADH, antidiuretic hormone; ARB, angiotensin receptor blocker; AV, atrioventricular; CCB, calcium
channel blocker, DPP4, dipeptidyl-peptidase 4; NSAID, nonsteroidal antiinflammatory drug; PDE5, phosphodiesterase type 5; RAS,
renin angiotensin system.
Table 39.2 Antihypertensive Medication Cytochrome P450 Substrates and Inhibitors
P450 ISOFORM 1A2 2C8 2C9 2C19 2D6 3A4/5
Substrates Tizanidine
Triamterene
Verapamil
Torsemide Irbesartan
Losartan
Torsemide
Labetalol Carvedilol
Clonidine
Lofexidine
Metoprolol
Nebivolol
Propranolol
Tamsulosin
Timolol
Aliskiren
Amlodipine
Diltiazem
Eplerenone
Felodipine
Guanfacine
Lercanidipine
Nifedipine
Nisoldipine
Nitrendipine
Propranolol
Verapamil
Inhibitors Labetalol Diltiazem
Verapamil
No antihypertensive agents are known to commonly induce P450 activity.
Selected drugs are emphasized in bold (≥fivefold change in drug AUC exposure) or in italics (two- to fivefold change in drug AUC
exposure) due to their predicted effects by the FDA. This list is limited only to antihypertensive drugs. A more complete list can be
found at the Indiana University Clinical Pharmacology website, Cytochrome P450 Drug Interaction Table - Drug Interactions. https://
drug-interactions.medicine.iu.edu/MainTable.aspx.
2. What commonly used drugs are associated with drug interactions with antihypertensive
medications?
Some drug-drug interactions among antihypertensives are due to either overlapping mechanisms of action or
shared side effect profiles, which increase the risk of either exaggerated action or side effects. For instance,
simultaneous use of combinations of nondihydropyridine calcium channel blockers, beta-blockers and centralacting alpha-blockers, all of which lower heart rate, increases the risk of bradycardia and heart block. Hyperkalemia can be a side effect of inhibitors of the components of the renin-angiotensin-aldosterone system and
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