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Combating Cardiovascular Disease With Compounded Medications: Part 2: Clinical and Compounding Issues for Antihypertensive Drugs

Posted on: Tuesday, 3 May 2005, 03:00 CDT

The advantages of customizing drug therapy for patients with cardiac disease by compounding multiple antihypertensive or other cardiac drugs into a single capsule was discussed in part 1 of this article. In this part, details on the clinical and compounding issues involved in combination therapy for cardiac conditions are discussed.

Clinical Issues

Selection of the "best" antihypertensive therapy was an issue of great debate among clinicians in the past. Recent studies that promote diuretic use, including the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT),1 have added to this controversy, which just detracts from the real need to keep blood pressure within goals in people with diabetes, kidney disease, or cardiovascular disease. High blood pressure is responsible for 62% of strokes and 49% of cases of ischemic heart disease and is the number one attributable risk factor for death, according to the World Health Organization.2 As the meta-analysis of Law et al has shown, all antihypertensive drugs lower blood pressure by about the same amount; the main differences are in their side effects, cost, and frequency of administration.' The side effect profiles, along with the patient's comorbid conditions, should determine the combination of drugs to use.

Side Effects

For the most part, side effects from antihypertensive drugs are predictable since they are dose-related. The frequencies of side effects by drug class at both standard and half doses is presented in Table 1.3 Thiazides at full dose have the highest frequency of side effects (10%); however, side effects can be minimized by using low doses. The metabolic effects of thiazides are dose dependent. The meta-analysis showed increases in total serum cholesterol of 1% at half standard dose and 3% at standard dose.3 Thiazides do not affect low-density lipoprmcm or high-density lipoprotein levels appreciably. Thiazides at half standard dose decrease serum potassium level by 6%, raise blood glucose level by 1%, and increase serum uric acid level by 9%.3 In combination therapy, the potassium- lowering effect of a thiazide could be offset by the use of a beta- blocker, angiotensin-converting enzyme (ACE) inhibitor, or angiotensin II receptor blocker (ARB), which increase potassium level slightly. It would be advisable to avoid the use of thiazides in patients with active gout because of the effect on uric acid level.

Hypertension and Comorbid Conditions

Hypertension often coexists with other cardiac conditions, especially in older individuals. It is useful to select drugs that can treat both hypertension and other conditions at the same time. Physicians should be encouraged to aggressively pursue treatment goals in hypertension. Compounded combinations let physicians tailor prescriptions to the patient; individualizing the mix of drugs and doses allows more aggressive treatment while controlling side effects and cost of therapy. And while there is an order to drug selection, physicians should be encouraged to prescribe at least two (even three) antihypertensive drugs concurrently. As illustrated by Table 2, a hypertensive patient with coexisting stable angina should be on low doses of a beta-blocker; a long-acting, dihydropyridine- type calcium channel blocker; aspirin; and a statin. If blood pressure or angina symptoms were not controlled by this combination, then an ACE inhibitor or a long-acting nitrate could be added.

Table 1. Side Effects of Antihypertensive Medicines at Standard and Half Standard Doses.3

Half Standard Dosing

Meta-analysis has shown that combination antihypertensive drug therapy allows the physician to reduce doses and side effects while maintaining effectiveness in blood pressure control. The low doses analyzed were on average one half of the standard dose. Table 3 provides half standard doses for the most popular antihypertensive drugs in the United States.4 Of course, when treating a patient with a coexisting cardiac condition, doses would be adjusted upward to an extent that depends upon the condition.

Table 2. Ordering Guide for Selecting Appropriate Antihypertensive Therapies.1,5,6

Cost Issues

Relative cost issues are most apparent when comparing brand name drugs to those available generically. Fortunately, most cardiac medicines are now available in generic formulations. Only the ARB class has no generic equivalents. There are some exceptions in the other classes: the preferred beta-blockers for heart failure are branded (Toprol XL, Ziac, Coreg), and all of the dihydropyridine calcium channel blockers are branded except for nicardipine and nifedipine.

If generic drugs are used exclusively for compounding, the cost is low enough to allow the use of three drugs in a compound for the price of two separately dispensed drugs. For example, a compounded combination of low-dose enalapril 2.5 mg, hydrochlorothiazide 12.5 mg, and atenolol 25 mg, priced with a usual margin, would cost about $26 per 90 capsules. The cost of a two-drug combination of enalapril 2.5 mg and hydrochlorothiazide 25 mg from www.drugstore.com is about $27.50 (includes shipping). The cost for the same two drugs from a chain drugstore would be substantially higher at $54, and the commercially available fixed combination of the two drugs would cost even more at $65. Patients with insurance may save some of this cost, depending on their copayment. There are situations in which a switch to a compounded combination might cost the patient or health plan more than separately purchased commercial drugs. One example is when a patient taking a single drug is switched to a compounded combination. Another is when a branded drug must be used in a compound.

Table 3. Half Standard Doses of Popular Antihypertensive Agents.

Compounding Issues

The preferred dosage form for most patients is the capsule. Capsules offer very good chemical and physical stability for cardiac drug formulations. Essentially, the goal is to protect the preparations from air, water, and light which tends to enhance degradation. Table 4 provides information on the stability of the most popular cardiac drugs. The compounding pharmacist will have to experiment with the capsule size to accommodate the quantity of active ingredients. The smallest capsule possible is best because it is easiest to swallow. The more popular combinations can be formulated as color-coded capsules, which should assist with quality control. Only four drugs require special handling. Aspirin, folic acid, and verapamil are hazardous skin irritants and pose inhalant hazards in powder form. All should be handled in a hood with gloves, safety glasses, and a respirator if necessary. Propranolol is an inhalation hazard and should be handled in a hood with safety glasses and a respirator if necessary.

The choice of diluent is left up to the compounder. For many older patients and women, calcium supplementation via the diluent might be good. For patients using a thiazide diuretic, supplementation with magnesium carbonate would be useful since thiazides tend to waste magnesium over time. The only caution is that captopril should not be mixed with metals, which includes magnesium and multivitamins. Also, spironolactone degrades more quickly in the presence of phosphate and citric acid buffers.

A New Option for Patients and Physicians

Better access to compounding pharmacy brings new options for cardiac patients and their physicians. A real ability to adapt doses and drugs to the patient (instead of the reverse) and to reduce the pill burden and cost for a patient is a step forward. The challenge for compounding pharmacists is to educate physicians and consumers about this new (old) age of pharmacy.

Table 4. Physical Stability,a Packaging, and Storage Considerations of Cardiac Drugs.

References

1. [No author listed.] ALLHAT Officers and Coordinators for the ALLHAT Collaborative Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high- risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blockervs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 29812997.

2. [No author listed.] World Health Report-2002: Reducing risks, promoting healthy life. [World Health Organization Website.] Available at: www.who.int/whr/2002/en. Accessed January 25, 2005.

3. Law MR, WaId NJ, Morris JK et al. Value of low dose combination treatment with blood pressure lowering drugs: Analysis of 354 randomised trials. BMJ 2003; 326(7404): 1427.

4. Chobanian AV, Bakris GL, Black HR et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension2003; 42(6): 1206-1252.

5. Snow V, Aronson MD, Hornbake ER et al. Lipid control in management of type 2 diabetes mellitus: A clinical practice guideline from the American College of Physicians. Ann Intern Med2004:140(8): 645-649.

6. Trissel LA. Trissel's Stability of Comp\ounded Formulations. 2nd ed. Washington, DC: American Pharmaceutical Association; 2000.

Catherine A. Harrington, PharmD, PhD

Jacintha Cauffield, PharmD, BCPS

Nova Southeastern University

College of Pharmacy

Palm Beach Gardens, Florida

Address correspondence to Catherine A. Harrington, PharmD, PhD, Palm Beach Compounding Pharmacy, 155 Toney Penna Drive, Suite 1B, Jupiter, FL 33458. E-mail: cathy.harrington@palmbeachcompounding.com

Copyright International Journal of Pharmaceutical Compounding May/ Jun 2005

Source: International Journal of Pharmaceutical Compounding

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