Merck

Antihypertensive Agents

Sami Barghshoon

Pharmaceutical Drugs and Drug Candidates

Angiotensin-Converting Enzyme (ACE) Inhibitors

Agents that inhibit angiontensin-converting enzymes (ACE) and angiotensin II formation are essential to cardiovascular medicine.1 These inhibitors are used not only to treat essential hypertension and complications associated with it, but also to prevent cardiovascular, cerebrovascular, and renal complications.2,3

The first oral ACE inhibitor therapeutic was developed in the 1970s, and was soon followed by other ACE inhibitors with more attractive pharmacodynamic effects.4

Millions of people use ACE inhibitors on a daily basis to manage hypertension. In the U.S., roughly 163 million prescriptions were filled in 2009, making this class of therapeutics the country’s fourth most widely prescribed medicine.5

The U.S. Food and Drug Administration (FDA) has approved 10 ACE inhibitors for the treatment of hypertension and there are 15 ACE inhibitors approved worldwide.

We offer all 15 approved ACE inhibitors at competitive prices. We strive to provide you with the highest quality of approved therapeutics available. Look no further thanus for precision and control over your research experiments.

Angiotensin II Receptor Blockers (ARBs)

Hypertension can result from excessive activity of the renin-angiotensin-aldosterone system (RAAS) and this overactivity can injure critical organs such as the heart and blood vessels.6

In the 1990s, angiotensin II receptor blockers (ARBs) became commercially available to block the activity of RAAS.7

Unlike ACE inhibitors which prevent angiotensin I conversion to II, ARBs bind to the angiotensin II AT1 receptor, blocking the cellular actions triggered by angiotension II.8

Over the past two decades, studies in the pressure in animals and humans.9

The pharmacological differences among ARBs are how they exert their effects. Some ARBs compete with angiotensin II in a concentration-dependent manner for AT1 receptor binding while others irreversibly bind to the receptor.10

We strive to provide you with a comprehensive selection of approved therapeutics so you don’t have to spend a lot of time and effort to find them. We currently offer six therapeutics in this class.

α1-Adrenoreceptor Blockers

α1-Antagonists (α-blockers) selectively block post-synaptic α1-adrenoreceptors and prevent catecholamine-induced constriction of arteries and venous vascular beds, thereby lowering blood pressure.11

However, α-blockers administered over time increase an individual's extracellular fluid and plasma volumes.12 This expansion typically manifests as weight gain and an attenuation of blood pressure. Therefore, these therapeutics are contraindicated in persons with heart failure because of their ability to expand extracellular and plasma volumes.13

One therapeutic strategy to counter the induced expansion is the administration of α1-adrenoreceptor antagonists with diuretics such as chlorthalidone or hydrochlorothiazide.14 The diurectics mitigate the expansion of the extracellular and plasma volumes, providing significant incremental reductions in blood pressure. Diuretics available in our catalog are discussed in a subsequent section.

We are your definitive source for all approved α-blockers that are available at competitive prices. This includes the first generation of nonselective α-receptor antagonists, phentolamine and phenoxybenzamine, as well as the quinazoline-selective α1-adrenoreceptor blockers.

β-Adrenergic Blockers

The first β-adrenergic blockers (β-blockers) were identified as antihypertensive agents in the early 1960s.15,16 The first approved drug, propranolol, was used as an adjunct therapy to phentolamine in the treatment of pheochromocytoma.17,18

In the U.S. and Europe, β-blockers are recommended as a first-line treatment for hypertension. This recommendation is based on reduced mortality and morbidity in large clinical trials. Most of the benefit from β-blockers stems from secondary vascular protection in established disease instead of primary prevention.19

There is no consensus regarding how β-blockers lower blood pressure and it is probable that several mechanisms are at work. Mechanisms to account for the antihypertensive actions of β-blockers include reduction in peripheral vascular resistance and inhibition of renin release.17

β-blockers are not uniform in their various pharmacologic effects. Some of the differences between β-blockers include sympathomimetic and membrane-stabilizing activities, β1 selectivity, α1-adrenergic-blocking, duration of action.20 This variation contrasts with other classes of antihypertensive drugs and may be important in the selection of a drug for clinical or research use.

β-blockers are taken by tens of millions of Americans everyday. In 2009, these therapeutics were the fifth most widely prescribed class of medicines in the United States with 128 million prescriptions filled.21

To date, the Food and Drug Administration (FDA) has approved 15 β-blockers for oral use in patients with systemic hypertension. We are the only commercial source for all 15 approved β-blockers.

Calcium Channel Blockers (CCBs)

Calcium channel blockers (CCBs) inhibit the movement of extracellular calcium across the cell membrane through ion-specific channels. Although several types of channels exist, CCBs target the L-type channels in humans. Inhibition of the inward calcium flux causes smooth vascular muscle cell relaxation, resulting in vasodilation and lowering of blood pressure.1

There are two groups of approved therapeutics that target L-type calcium channels, dihydropyridine and nondihydropyridine compounds. The two types bind to different sites on the channel.2 However, nondihydropyridine calcium channel blockers differ from the dihydropyridine subclass in that they are more negatively chronotropic and inotropic. This difference is important for patients who also require β-blockers to manage their hypertension.

One aspect of CCBs that differentiate them from other antihypertensive agents is their ability to reduce blood pressure across all patient groups, regardless of sex, race/ethnicity, age, and dietary sodium intake.3

Currently, there are eight dihydropyridine and two nondihydropyridine approved therapeutics. These therapeutics are for individual use or in combination with other antihypertensive drugs, including statins.3

In 2009, CCBs were the ninth most widely prescribed class of medicines in the United States with 92 million prescriptions. CCBs not only help people manage their high blood pressure, angina, and certain heart rhythm abnormalities, they can also be used to treat migraines, poor circulation to the hands and feet, and certain psychiatric disorders.4

We currently offer all the dihydropyridine approved therapeutics except for clevidipine, which is not available for research purposes. The two nondihydropyridine approved therapeutics, diltiazem (Product No. D2521) and verapamil (Product No. V4629), can also be obtained from our catalog.

There are other approved CCBs that are useful tools in hypertension research. These research therapeutics are listed below and include the two drug candidates azelnidipine (Product No. A7106) and cilnidipine (Product No. C1493).

Diuretics

First-line agents in the treatment of hypertension are the thiazide-type diuretics. These therapeutics are proven to reduce cardiovascular mortality and morbidity. This reduction occurs in both systolic and diastolic forms of hypertension.26

Hydrochlorothiazide (HCTZ) is the thiazidetype diuretic used most often. Another proven thiazide-type therapeutic is chlorthalidone, which resembles HCTZ structurally but differs in its pharmacology.27 These compounds are well tolerated antihypertensive agents with respect to symptomatic and adverse side effects.28

Loop diurectics such as fuorsemide, bumetanide, and torsemide are less effective than the thiazide-type drugs in reducing blood pressure. However, loop diuretics are important in hypertensive patients with significant fluid overload or advanced renal failure.29

Diuretics can be successfully combined with β-blockers, ACE inhibitors, ARBs, and CCBs. The combination of a diuretic with any one of these antihypertensive agents provides the best effect in lowering blood pressure when compared to combinations without a diuretic.30

You can obtain HCTZ and many of the loop diurectics from our catalog at competitive prices. We strive to provide you with the largest selection of products so you can focus more on your research.

References

1.
Gradman AH, Basile JN, Carter BL, Bakris GL. 2010. Combination therapy in hypertension. Journal of the American Society of Hypertension. 4(1):42-50. http://dx.doi.org/10.1016/j.jash.2010.02.005
2.
Ferguson R, Brunner H, Turini G, Gavras H, Mckinstry D. 1977. A SPECIFIC ORALLY ACTIVE INHIBITOR OF ANGIOTENSIN-CONVERTING ENZYME IN MAN. The Lancet. 309(8015):775-778. http://dx.doi.org/10.1016/s0140-6736(77)92958-0
3.
Re RN. 2001. The clinical implication of tissue renin angiotensin systems. Current Opinion in Cardiology. 16(6):317-327. http://dx.doi.org/10.1097/00001573-200111000-00002
4.
Ondetti M, Rubin B, Cushman D. 1977. Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents. Science. 196(4288):441-444. http://dx.doi.org/10.1126/science.191908
5.
2011. Consumer Reports: Using ACE Inhibitors to treat high blood pressure and heart disease. . [Internet]. Available from: http://consumerreportshealth.org
6.
Savoia C, Schiffrin E. 2007. Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. 112(7):375-384. http://dx.doi.org/10.1042/cs20060247
7.
Ferrario CM. 2006. Role of Angiotensin II in Cardiovascular Disease ? Therapeutic Implications of More Than a Century of Research. J Renin Angiotensin Aldosterone Syst. 7(1):3-14. http://dx.doi.org/10.3317/jraas.2006.003
8.
OPARIL S. 2000. Newly emerging pharmacologic differences in angiotensin II receptor blockers. American Journal of Hypertension. 13(1):S18-S24. http://dx.doi.org/10.1016/s0895-7061(99)00250-2
9.
Taylor AA, Siragy H, Nesbitt S. 2011. Angiotensin Receptor Blockers: Pharmacology, Efficacy, and Safety. 13(9):677-686. http://dx.doi.org/10.1111/j.1751-7176.2011.00518.x
10.
Munger M. 2011. Use of angiotensin receptor blockers in cardiovascular protection: current evidence and future directions. . Pharmacy & Therapeutics. 3622-40.
11.
Neaton JD. 1993. Treatment of Mild Hypertension Study. JAMA. 270(6):713. http://dx.doi.org/10.1001/jama.1993.03510060059034
12.
Wright JT. 2008. Clinical Outcomes by Race in Hypertensive Patients With and Without the Metabolic SyndromeAntihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 168(2):207. http://dx.doi.org/10.1001/archinternmed.2007.66
13.
Davis BR, Kostis JB, Simpson LM, Black HR, Cushman WC, Einhorn PT, Farber MA, Ford CE, Levy D, Massie BM, et al. 2008. Heart Failure With Preserved and Reduced Left Ventricular Ejection Fraction in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 118(22):2259-2267. http://dx.doi.org/10.1161/circulationaha.107.762229
14.
Barzilay JI, Davis BR, Bettencourt J, Margolis KL, Goff DC, Black H, Habib G, Ellsworth A, Force RW, Wiegmann T, et al. 2004. Cardiovascular Outcomes Using Doxazosin vs. Chlorthalidone for the Treatment of Hypertension in Older Adults With and Without Glucose Disorders: A Report From the ALLHAT Study. J Clin Hypertension. 6(3):116-125. http://dx.doi.org/10.1111/j.1524-6175.2004.03216.x
15.
Prichard BNC. 1964. Hypotensive Action of Pronethalol. BMJ. 1(5392):1227-1228. http://dx.doi.org/10.1136/bmj.1.5392.1227
16.
Prichard BNC, Gillam PMC. 1964. Use of Propranolol (Inderal) in Treatment of Hypertension. BMJ. 2(5411):725-727. http://dx.doi.org/10.1136/bmj.2.5411.725
17.
Frishman W. 2011. Cardiovascular Pharmacotherapeutics. 3. Minneapolis, MN: Cardiotext Inc.
18.
Frishman W, Sica D. 2008. In Hypertension Primer: The Essentials of High Blood Pressure. 4. Philadelphia, PA: Wolters Kluwer Lippincott Williams & Wilkins .
19.
Chobanian AV. 2003. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood PressureThe JNC 7 Report. JAMA. 289(19):2560. http://dx.doi.org/10.1001/jama.289.19.2560
20.
Frishman W. 2008. Adrenergic blockers: a 50-year historical perspective. 15565–76.
21.
2011. Consumer Reports: Using &bdeta;-blockers to treat high blood pressure and heart disease.. [Internet]. Available from: http://consumerreportshealth.org
22.
Abernethy DR, Schwartz JB. 1999. Calcium-Antagonist Drugs. N Engl J Med. 341(19):1447-1457. http://dx.doi.org/10.1056/nejm199911043411907
23.
MATERSON B. 1995. Calcium channel blockersIs it time to split the lump?. American Journal of Hypertension. 8(3):325-329. http://dx.doi.org/10.1016/0895-7061(94)00247-9
24.
Elliott WJ, Ram CVS. 2011. Calcium Channel Blockers. 13(9):687-689. http://dx.doi.org/10.1111/j.1751-7176.2011.00513.x
25.
2011. Consumer Reports: Using calcium channel blockers to treat high blood pressure and heart disease. [Internet]. Available from: http://consumerreportshealth.org
26.
Ernst ME, Carter BL, Zheng S, Grimm RH. 2010. Meta-Analysis of Dose-Response Characteristics of Hydrochlorothiazide and Chlorthalidone: Effects on Systolic Blood Pressure and Potassium. American Journal of Hypertension. 23(4):440-446. http://dx.doi.org/10.1038/ajh.2010.1
27.
Carter BL, Ernst ME, Cohen JD. 2004. Hydrochlorothiazide Versus Chlorthalidone. Hypertension. 43(1):4-9. http://dx.doi.org/10.1161/01.hyp.0000103632.19915.0e
28.
Psaty BM. 1997. Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis. 277(9):739-745. http://dx.doi.org/10.1001/jama.277.9.739
29.
Vargo DL, Kramer WG, Black PK, Smith WB, Serpas T, Brater DC. 1995. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure*. Clin Pharmacol Ther. 57(6):601-609. http://dx.doi.org/10.1016/0009-9236(95)90222-8
30.
Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, Hamburger RJ, Fye C, Lakshman R, Gottdiener J, et al. 1993. Single-Drug Therapy for Hypertension in Men -- A Comparison of Six Antihypertensive Agents with Placebo. N Engl J Med. 328(13):914-921. http://dx.doi.org/10.1056/nejm199304013281303