Kelly Dowhower Karpa, PhD, RPh

Nearly one in three American adults has high blood pressure, the "silent killer" that contributes substantially to heart failure, aneurysms, kidney failure, heart attacks, and strokes. Lifestyle modifications such as smoking cessation, reducing alcohol intake, losing weight, and dietary changes may reduce blood pressure slightly, but treatment with drugs is the only way to achieve major blood pressure reductions. Even with the numerous antihypertensives available, 70% of patients do not reach their blood pressure goals. 

Although acting on the same pathway as ACE inhibitors, angiotensin receptor blockers (ARBs), and aldosterone receptor antagonists, aliskiren acts on the initial step of the renin-angiotensin-aldosterone system (RAAS). Aliskiren is a direct inhibitor of renin. 

With cessation of therapy, blood pressure gradually returned to baseline over a period of several weeks, with no evidence of rebound hypertension. Despite aliskiren's antihypertensive efficacy, Wright pointed out, "The major goal of antihypertensive therapy is to prevent complications. We don't yet know the efficacy of Tekturna for end points such as heart failure and kidney protection." 

More than 6,460 patients have been evaluated in studies to assess the safety of aliskiren. The most common side effect associated with the drug during clinical studies was diarrhea-an effect that appears to be more common in women and the elderly, especially at higher dosages of the drug. "Even though diarrhea was reported at an incidence of 2%, the drug was still very tolerable," remarked Wright. 

Similar to other drugs acting on the RAAS, aliskiren was associated with a slight increase in cough, but it was substantially less than that resulting from use of an ACE inhibitor. The incidence of elevated uric acid, gout, and renal stones was also increased with aliskiren compared with placebo. 

One-fourth of aliskiren is eliminated unchanged in the urine, but CYP 3A4 appears to be involved with the drug's metabolism, too. As a result, increased levels of aliskiren could be possible when used concomitantly with potent CYP P450 inhibitors such as ketoconazole. Additionally, blood levels of furosemide were significantly reduced when aliskiren was administered. This means that patients could find the therapeutic efficacy of furosemide diminished after beginning therapy with aliskiren. 

According to Decision Resources, a leading research and advisory firm for pharmaceutical and healthcare issues, aliskiren is predicted to achieve blockbuster status, earning $2.1 billion over the next seven years. However, Wright, who runs a medication therapeutic management clinic at the VA medical center in Wilkes-Barre, Pa., believes in a wait-and-see approach. "I don't think aliskiren should be used early on in hypertension," he said. "We have many safe, proven, once-daily, less expensive alternatives already available. We don't know aliskiren's efficacy as far as reductions in end points and we don't know the long-term side effects."  

Articles

Aliskiren (Tekturna, Novartis) is a new molecular entity approved for treating hypertension either as monotherapy or in conjunction with other antihypertensive agents.

New drug approved for treating hypertension

Hypertension affects nearly one in three American adults. Untreated elevations in blood pressure (BP) predispose patients to heart failure, aneurysms, atherosclerosis, strokes, kidney failure, and blindness. Since hypertension usually has no symptoms, patients may not realize they have it until one or more of these complications develops.  

Amlodipine, the most frequently prescribed dihydropyridine-type CCB, prevents calcium from entering the cells that line the vasculature, thus preventing blood vessel constriction. Because the vessels relax with CCB therapy, the most common dose-limiting side effects are edema, dizziness, and flushing.  

Valsartan is the most commonly prescribed ARB. Similar to amlodipine, valsartan also relaxes blood vessels but does so by blocking the actions of a hormone called angiotensin II, a potent vasoconstrictor. As the vasculature relaxes with amlodipine and valsartan, blood flows more easily as total peripheral resistance falls, and blood pressure is lowered.  

In clinical studies, Exforge safely and effectively lowered blood pressure. In an abstract presented at the American Society of Hypertension meeting in May 2006, data from 79 patients who received Exforge revealed an average drop in BP of 35.8 mmHg for systolic pressure and 28.6 mmHg for diastolic after six weeks of treatment. Additionally, in a subset of patients with baseline systolic pressure ≥180 mmHg, an average systolic reduction of 43 mmHg was observed. These results were clinically comparable to those seen in a group of 77 patients receiving a lisinopril/hydrochlorothiazide combination.  

Side effects of Exforge in clinical studies-peripheral edema, nasopharyngitis, upper respiratory tract infections, and dizziness-were mild and short-lived. Women who are pregnant or may become pregnant should avoid taking valsartan because of the risk of injury or death to the developing fetus. Serum potassium should be monitored, especially in patients with renal dysfunction. Cautioned Sarah Spinler, Pharm.D., and professor of clinical pharmacy at University of the Sciences in Philadelphia and adjunct faculty with the cardiovascular division of the department of medicine, University of Pennsylvania, "Pharmacists should watch for duplication of ARB/ACE inhibitors, especially in patients taking combination products." 

Exforge tablets will be available in the following amlodipine/valsartan combinations: 5/160 mg, 10/160 mg, 5/320 mg, and 10/320 mg. 

THE AUTHOR is a medical writer based in Pennsylvania. 

Two commonly prescribed antihypertensive medications have now been combined into one tablet. With an anticipated availability this September, valsartan (Diovan, Novartis) and amlodipine (Norvasc, Pfizer) will be sold as a combination product under the trade name Exforge (Novartis). The Food & Drug Administration approval is tentative, pending expiration of market exclusivity and patent protection for amlodipine in September.

Combo antihypertensive gets FDA nod

Since the primary use of methadone for many years was to help patients beat heroin addiction, until rather recently there was confusion even among primary care physicians about who could prescribe methadone for pain management. "Within the past 15 years, methadone has become more accepted clinically for treating chronic pain," said Christine O'Neil, Pharm.D., associate professor and pain management instructor at Duquesne University Mylan School of Pharmacy. 

Frederick J. Goldstein, Ph.D., professor of clinical pharmacology at Philadelphia College of Osteopathic Medicine, said he thinks that the increased use of opioids for nonmalignant pain management is a good thing. "It means patients are being treated better. Increased use of methadone is not surprising given the drug is long-acting and inexpensive. Those are good features." 

Millions of patients have been successfully and safely treated with methadone since its approval nearly 60 years ago. However, "Methadone is not like your average opioid," cautioned O'Neil. "Methadone is not an easy drug to convert. There is a great deal of confusion about how to calculate equi-analgesic doses." She explained that historically, morphine and methadone doses were converted 1:1, but now the recommendation for conversion is 3:1 and even then, the patient's level of tolerance needs to be considered because the methadone dose may need to be reduced lower still.  

As with other opioids, the primary toxic effect of methadone involves respiratory depression. Most methadone-associated deaths occur during the drug's induction phase or after a dosage adjustment, when healthcare providers overestimate a patient's tolerance to opioids.   

Because of a delay in methadone's onset of analgesia, patients may take more methadone than prescribed. A recent survey revealed that half of Americans do not know that misusing prescription opioid painkillers is harmful to the body and can be as addictive as heroin abuse. When a patient self-medicates with methadone, the outcome can be deadly. "The respiratory depression effect is longer than the analgesic effect," warned Goldstein. The drug has a long half-life, so methadone can accumulate, leading to respiratory depression that may not become apparent until days after the patient self-medicated. 

Goldstein warned of the importance of "sticking to the prescribed dose. If episodic pain occurs, a different, short-acting drug should be added." He also emphasized that "methadone should be used only in patients who really understand this." 

Patients may also get into trouble when methadone is combined with other psychotropic drugs such as benzodiazepines, alcohol, opioids, and illicit drugs of abuse. In nearly 20% of opioid fatalities, heroin or cocaine is listed on the death certificate, too. 

In addition to respiratory depression, it is also now recognized that methadone can prolong the cardiac QT interval. This can lead to development of torsade de pointes, a serious, often deadly, ventricular arrhythmia. The possibility that methadone could trigger cardiac arrhythmias should be considered carefully in patients with cardiovascular disease, electrolyte imbalances, and those taking other medications known to perturb cardiac repolarization. Some clinicians even suggest electrocardiographic monitoring in patients receiving daily oral methadone doses that exceed 200 mg. 

Drug interactions can cause significant changes in methadone metabolism. More than 100 drugs are known to interact with methadone. The drug is metabolized by hepatic CYP3A4 and CYP2D6 enzymes, so any drugs, herbal products, or foods that inhibit these enzymes may increase methadone levels, creating toxic effects. 

Recent news reports linking methadone with a number of casualties, including that of the actress Anna Nicole Smith's son, have fostered the idea that the substance is a "killer" or dangerous drug of abuse. This is a bit paradoxical since methadone has been successfully used in heroin detoxification programs for decades.

Experts urge caution over use of methadone

According to the Pharmaceutical Research & Manufacturers of America, 34 medications are currently in clinical trials for brain tumors. More than one-third of those agents are being investigated for treatment of glioblastoma multiforme (GBM), a high-grade, aggressive form of brain cancer.  

Bevacizumab is a monoclonal antibody that inhibits activity of vascular endothelial growth factor (VEGF), an angiogenic peptide that promotes growth of new blood vessels in tumors. Via its angiostatic actions, bevacizumab disrupts a tumor's blood supply. This agent has already been shown to reduce microvascular growth and slow disease progression and is indicated for treatment of colon cancer. Also approved for colon cancer is irinotecan, an inhibitor of DNA topoisomerase. This enzyme normally repairs damaged DNA, but use of irinotecan prevents religation of broken DNA strands, thus leading to tumor cell death.  

Lead investigator for the study, James Vredenburgh, M.D., at Duke University Medical Center, believes that the reason for the combination's efficacy is that bevacizumab suppresses abnormal tumor blood vessel growth, thus decreasing the interstitial pressure around the tumor, which allows more irinotecan to reach cancer cells. Bevacizumab will likely be tested in combination with both radiation therapy and temozolomide in patients with newly diagnosed GBM.  

In the past, pharmacists played a somewhat limited role in the care and treatment of brain cancer. But all that is changing.