Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes
Curator: Aviva Lev-Ari, PhD, RN
Excellent review of Hypertension Medications is provided in the following two short videos:
VIEW VIDEOS
Hypertension Explained Clearly! 1 of 2
Hypertension Explained Clearly! 2 of 2
Hypertension Treatment in the Last Decade
The need for combination drug therapy was recognized in 2000, In Combination Antihypertensive Drugs: Recommendations for Use
NEIL S. SKOLNIK, M.D., JONATHAN D. BECK, M.D., MATHEW CLARK, M.D., Abington Memorial Hospital, Jenkintown, Pennsylvania
Am Fam Physician. 2000 May 15;61(10):3049-3056
Combination Medication: Impact on Compliance
Increased Compliance with fewer pills a favorable outcome of combination medication for Hypertension.
More medications, fewer pills: Combination medications for the treatment of hypertension Richard Lewanczuk, MD PhD1 and Sheldon W Tobe, MD2
Can J Cardiol. 2007 May 15; 23(7): 573–576.
Classification of Blood Pressure
Category SBP mmHg DBP mmHg
Normal <120 and <80
Prehypertension 120–139 or 80–89
Hypertension, Stage 1 140–159 or 90–99
Hypertension, Stage 2 ≥160 or ≥100
Principles of Hypertension Treatment
• Treat to BP <140/90 mmHg or BP <130/80 mmHg in patients
with diabetes or chronic kidney disease.
• Majority of patients will require two medications to reach goal.
Without Compelling Indications
Stage 1
Hypertension
(SBP 140–159 or DBP
90–99 mmHg)
Thiazide-type diuretics
for most. May consider
ACEI, ARB, BB, CCB,
or combination.
Stage 2
Hypertension
(SBP ≥160 or DBP
≥100 mmHg)
2-drug combination for
most (usually thiazidetype
diuretic and ACEI,
or ARB, or BB, or CCB).
Causes of Resistant Hypertension
• Improper BP measurement
• Excess sodium intake
• Inadequate diuretic therapy
• Medication
– Inadequate doses
– Drug actions and interactions (e.g., nonsteroidal anti-inflammatory drugs
(NSAIDs), illicit drugs, sympathomimetics, oral contraceptives)
– Over-the-counter (OTC) drugs and herbal supplements
• Excess alcohol intake
• Identifiable causes of hypertension (see reverse side)
Compelling Indications for Individual Drug Classes
Compelling Indication and Initial Therapy Options
• Heart failure THIAZ, BB, ACEI, ARB, ALDO ANT
• Post myocardial infarction BB, ACEI, ALDO ANT
• High CVD risk THIAZ, BB, ACEI, CCB
• Diabetes THIAZ, BB, ACEI, ARB, CCB
• Chronic kidney disease ACEI, ARB
• Recurrent stroke prevention THIAZ, ACEI
Key: THIAZ = thiazide diuretic, ACEI= angiotensin converting enzyme inhibitor, ARB = angiotensin receptor
blocker, BB = beta blocker, CCB = calcium channel blocker, ALDO ANT = aldosterone antagonist
http://www.nhlbi.nih.gov/guidelines/hypertension/phycard.pdf
JNC-7 on Treatment for Hypertension
According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure, or JNC-7, most people require more than one medication to achieve treatment goals. Some medications are being manufactured in combinations, which reduces the number of pills a patient must take and may reduce costs.
http://www.livestrong.com/article/217562-combination-drugs-for-hypertension/#ixzz1wD1wneZg
All combination drugs for Hypertension are presented in
http://www.livestrong.com/article/217562-combination-drugs-for-hypertension/#ixzz1wD3dqnrl
JNC-7 lists the following Combinations of Drugs for Hypertension:
ACE Inhibitors and Calcium Channel Blockers
The angiotensin converting enzyme inhibitors, or ACEIs, are a group of drugs that work in the kidneys to block a reaction that leads to tightening of the blood vessels and retention of sodium and water. They lower blood pressure by counteracting these effects. Calcium channel blockers, or CCBs, work by relaxing smooth muscle in the heart and blood vessels. One common side effect of this group of drugs is leg swelling. This can be lessened when they are used in combination with the ACEIs. Amlodipine-benazepril, enalapril-felodipine and trandolapril-verapamil are examples of these medicines that have been combined into a single pill. Multiple dosing variations are available.
ACE Inhibitors and Diuretics
Diuretics are commonly known as “water pills” because they work by increasing urine output and lowering blood volume, and therefore blood pressure. Diuretics are generally inexpensive, work well to enhance the effects of other medicines and have a proven track record in preventing cardiovascular complications of hypertension, as discussed in JNC-7. Many ACE inhibitors are available packaged with hydrochlorothiazide, or HCTZ. Benazepril, enalapril, lisinopril and others are commonly seen in this combination.
ARBs and Diuretics
The angiotensin receptor blockers, or ARBs, are related to the ACEIs, in that they work on the same renal pathway. However, the ARBs work farther down the process and often have fewer side effects. The beneficial effects on blood pressure are similar between the two groups. Candesartan, losartan, telmesartan, valsartan and others are available as combination drugs with HCTZ.
Beta-blockers and Diuretics
Beta-blocking medications work in the peripheral nervous system to slow the heart rate and decrease adrenalin-type effects on the blood vessels. JNC-7 notes that the beta-blockers are especially useful in those with hypertension and heart disease or angina. Atenolol is available with the diuretic chlorthalidone, which is similar to HCTZ. Bisoprolol, metroprolol, propranolol LA and timolol come in combination with HCTZ.
Centrally Acting Drugs and Diuretics
Methyldopa and reserpine affect the central nervous system to produce a lowering of blood pressure. They are not used often, but can be effective in the appropriate situation. Each come in a combination drug with HCTZ, while reserpine is also produced with chlorthalidone and chlorothiazide.
Diuretic Combinations
Various diuretics work in different locations of the kidneys to affect their anti-hypertensive properties. HCTZ tends to lower blood potassium, so is available in combination with spironolactone or triamterene, which are known to elevate potassium. The combination tends to be potassium neutral.
ARB and Calcium Channel Blocker and Diuretic
In July 2010, a triple combination drug for hypertension was approved by the US Food and Drug Administration. Tribenzor contains olmesartan medoxomil, amlodipine and hydrochlorothiazide, according to Monthly Prescribing Reference.
Three Combination Drug Therapy for Antihypertension from Daiichi Sankyo’s Portfolio of Products
Daiichi Sankyo has a comprehensive portfolio of drugs offering a wide range of treatments for patients in a number of disease categories including hypertension, heart disease and hyperlipidemia/atherosclerosis.
The discovery of epinephrine (also known as adrenaline) in 1889, to the development of the statin class of lipid-lowering agents and the development of the first glitazone, which revolutionized long-term control of type 2 diabetes.
New ideas and pairing of existing information with novel concepts, led to the creation of medicines as well as new methods of drug discovery and delivery.
Daiichi Sankyo products for hypertension, heart disease and hyperlipidemia/atherosclerosis which are currently marketed in the U.S. include several drug combinations for Cardiovascular disease.
http://dsi.com/c/document_library/get_file?uuid=5b356194-9d74-47ba-94a6-a82a7ea694cb&groupId=12065
TRIBENZOR is a Daiichi Sankyo’s product- ARB and Calcium Channel Blocker and Diuretic
How TRIBENZOR work
Tribenzor contains olmesartan medoxomil, amlodipine and hydrochlorothiazide. High blood pressure makes the heart work harder to pump blood through the body and causes damage to blood vessels. TRIBENZOR can help your blood vessels relax and reduce the amount of fluid in your blood. This can make your blood pressure lower. Medicines that lower blood pressure may lower your chance of having a stroke or a heart attack.
Some people may need more than 1—or even more than 2—medicines to help control their blood pressure. TRIBENZOR combines 3 effective medicines in 1 convenient pill. Read the following chart to learn how each medicine works in its own way to help lower blood pressure.
TRIBENZOR: 3 effective medicines in 1 pill
| The medicine in TRIBENZOR | How it works | What it does |
| Angiotensin II receptor blocker | Blocks a natural chemical in your body that causes blood vessels to narrow. |
Lowers Yours blood pressure |
| Calcium channel blocker | Blocks the narrowing effect of calcium on your blood vessels. This helps your blood vessels relax. | |
| Diuretic (water pill) | Helps your kidneys flush extra fluid and salt from your body. This lowers the amount of fluid in your blood. |
http://www.tribenzor.com/how_works.html
Effectively lower blood pressure. People taking the 3 medicines in TRIBENZOR had greater reductions in blood pressure than did people taking any 2 of the medicines combined
Start to work quickly. People taking TRIBENZOR saw results in as little as 2 weeks
AZOR is a Daiichi Sankyo’s product- ARB and Calcium Channel Blocker
How AZOR work
AZOR relaxes and widens blood vessels to help lower blood pressure.
You may have already tried another blood pressure medicine that works a certain way to lower blood pressure. But 1 blood pressure medicine may not be enough for you. You may find the help you need with the 2 effective medicines in AZOR.
AZOR combines 2 effective medicines in 1 convenient pill.
Learn how each medicine in AZOR works in its own way to help lower blood pressure.
| The medicine in AZOR | How it works | What it does |
| Angiotensin II receptor blocker (ARB) | Blocks a natural chemical in your body that causes blood vessels to narrow. This helps your blood vessels relax and widen. |
Lowers Your Blood pressure |
| Calcium channel blocker | Blocks the narrowing effect of calcium on your blood vessels. This helps your blood vessels relax. |
http://www.AZOR.com/how_works.html
Benicar and Benicar HCT are Daiichi Sankyo’s products an ARBs and Diuretics
How Benicar and Benicar HCT work
Benicar and Benicar HCT are prescription medicines used to lower high blood pressure (hypertension). They may be used alone or with other medicines used to treat high blood pressure. Benicar HCT is not for use as the first medicine to treat your high blood pressure.
Lowering blood pressure with Benicar or Benicar HCT
There are many different choices to treat high blood pressure. You may have started with some lifestyle changes or different medicines to find what works for you. You and your doctor can talk about whether Benicar or Benicar HCT is a good choice for you.
| The medicine in Benicar | How it works |
What it does |
| Angiotensin II receptor blocker (ARB) | Blocks a natural chemical in the body that causes blood vessels to narrow. This helps the blood vessels relax and widen. |
Lowers your blood pressure |
Some people may need more than 1 medicine to help manage high blood pressure. So doctors may choose to prescribe Benicar HCT. The 2 medicines in Benicar HCT help to lower blood pressure more than taking either medicine alone. You and your doctor can talk about what’s right for you.
| The medicines in Benicar HCT | How it works |
What it does |
| Angiotensin II receptor blocker (ARB) | Blocks a natural chemical in the body that causes blood vessels to narrow. This helps the blood vessels relax and widen. |
Lowers your blood pressure |
| Diuretic(a water pill) | Helps your kidneys flush extra fluid and salt from your body. This lowers the amount of fluid in your blood. |
Benicar and Benicar HCT are medicines that both
Block calcium
Block a chemical called angiotensin II
Block water and salt
There are no generic forms of Benicar or Benicar HCT
http://www.benicar.com/how_work.html
Risk of Antihypertensive drugs
Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study
Compatible with their urate lowering properties, calcium channel blockers and losartan are associated with a lower risk of incident gout among people with hypertension. By contrast, diuretics, β blockers, angiotensin converting enzyme inhibitors, and non-losartan angiotensin II receptor blockers are associated with an increased risk of gout.
http://www.bmj.com/content/344/bmj.d8190
Affordability of the Combination Medication for Hypertension from the Daiichi Sankyo’s product portfolio is supported by a Manufacturer Program to 2016.
There are no generic drugs for the Combination Medication for Hypertension from the Daiichi Sankyo’s product portfolio. Daiichi Sankyo, Inc., will cover up to $140 of the co-pay for BENICAR, BENICAR HCT, AZOR, and TRIBENZOR after the patient pays the first $25. Offer applies to patients with commercial insurance; $25 initial savings available for patients without insurance; offer expires 2016. If a retail or mail-order pharmacy does not accept the Savings That Last card, patients may obtain a Direct Member Reimbursement form by calling the number on the back of the card to receive instructions on how to obtain the savings benefit. Offer not valid for patients enrolled in a state or federal healthcare program including but not limited to Medicaid, Medicare, Veterans Administration, or TRICARE/CHAMPUS. Offer valid in the United States and Puerto Rico. Void where taxed, restricted, or prohibited by law. Void in Massachusetts, except for patients without insurance. Daiichi Sankyo, Inc., reserves the right to rescind, revoke, or amend this program, at any time, without notice.
TRIBENZOR is preferred on some of the largest Medicare Part D plans.
http://www.tribenzorhcp.com/savings_that_last.html
Cost Savings Associated with Filling a 3-Month Supply of Prescription Medicines
http://ideas.repec.org/a/wkh/aheahp/v7y2009i4p255-264.html
Out-of-pocket and Total Costs of Fixed-dose Combination Antihypertensives and Their Components
Atonu Rabbani1 and G. Caleb Alexander1,2,3,4
American Journal of Hypertension (2008); 21, 5, 509–513. doi:10.1038/ajh.2008.31
Given patient burden and non-adherence from out-of-pocket prescription costs, the clinical benefits of brand-named fixed-dose combination antihypertensive therapy should be balanced with their greater out-of-pocket costs.
http://www.nature.com/ajh/journal/v21/n5/abs/ajh200831a.html
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Great post! It has a very comprehensive review of hypertension, it’s available treatments, the problems associated with it, and the current research in this area for treatment. And the best part is it is very easy to follow even for a person with no background in this area.
This post provides a nice review of treating hypertension. While a triple combination drug products may be useful in selective patients, it does not provide the best treatment for most patients. Following EBM algorithms should generally be used in treating patients. Individual products or combinations should be tried and doses appropriately titrated prior to settling on a any double or triple combination product. Some other considerations include cost of therapy, compliance and adherence, and pharmacogenomic considerations.
Additional modalities of therapies are also available for consideration. On May 16, 2012, Covidien introduced a new treatment for drug-resistent hypertension new OneShot(TM) renal denervation system at the EuroPCR congress in Paris, France, on May 16, 2012. Adding to the Company’s broad and growing vascular therapies portfolio, the OneShot system is designed to treat patients with hypertension who are not responsive to traditional medical therapy.
http://www.marketwatch.com/story/covidien-introduces-new-treatment-for-drug-resistant-hypertension-2012-05-08
.
Updated guidelines for treating hypertension should be available soon. The NHLBI indicates that new Adult Cardiovascular Treatment Guidelines, including draft JNC-8 are expected to be available for public review and comment in 2012. The five reports (hypertension, cholesterol, obesity, risk assessment, lifestyle) will be released one at a time throughout the year, as they are completed. Public comment will last one month for each report.
[…] http://pharmaceuticalintelligence.com/2012/05/29/445/ […]
Informative!
Please review my post on
Lev-Ari, A. (2012c). Treatment of Refractory Hypertension via Percutaneous Renal Denervation 6/13/2012
http://pharmaceuticalintelligence.com/2012/06/13/treatment-of-refractory-hypertension-via-percutaneous-renal-denervation/
[…] http://pharmaceuticalintelligence.com/2012/05/29/445/ […]
[…] http://pharmaceuticalintelligence.com/2012/05/29/445/ […]
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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