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The Family Practice Newsletter
The Ohio University College of Osteopathic Medicine
The Ohio Northern University Raabe College of Pharmacy
Doctors Hospital Family Practice
Volume 6, Issue 9
April 2007
A New Mechanism of Action for the Treatment of Hypertension
Bridget Factor, OSU Doctor of Pharmacy Candidate
Nearly 1 in 3 American adults are affected by hypertension (HTN). 1 It is often referred to as the silent killer because
the disease itself is asymptomatic; but, if left untreated, can lead to many life threatening problems. It is clear that optimal
blood pressure control is important to prevent the patient from experiencing a myocardial infarction, stroke, renal and eye
problems. Many medications are available for the management of hypertension, and should be used as an adjunct to
appropriate diet and exercise changes to optimize blood pressure control.
A new medication, alisikiren (Tekturna) was recently approved by the FDA. It is the first in a new class of
medications referred to as a direct renin inhibitor (DRI). The DRI works on the initial step in the Renin-AngiotensionAldosterone (RAA) cascade, to inhibit the production the renin. The physiologic action of renin is to convert
angiotensinogen to angiotensin I (ATI). ATI then gets converted to ATII, by Angiotension Converting Enzyme (ACE). ATII
is a potent vasoconstrictor which is responsible for the increase in blood pressure due to many mechanisms, some of which
include the release of aldosterone and systemic vasoconstriction. Two classes of medications currently available affect the
RAA system, but at different points in the cascade. ACE inhibitors and angiotensin receptor blockers (ARBs) inhibit the
cascade, but do not directly affect the first step involving renin. Interruption of the system earlier in the cascade may provide
a better mechanism to manage hypertension and decrease circulating renin, which could benefit other disease states.
Aliskiren is currently indicated for the treatment of HTN as monotherapy or in combination with other agents.2
Efficacy trials showed blood pressure lowering in six placebo-controlled eight-week clinical trials, which studied more than
2,000 patients across all demographic subgroups. The effect was maintained for up to one year. Safety was evaluated in more
than 6,460 patients finding side effects to be generally mild and brief. The most common side effect was dose-related
diarrhea, highest at doses greater than 300mg per day. Allergic reactions were rare. 3
Aliskiren was studied in combination mostly with diuretics and the ARB valsartan. It was also studied with ramipril
and amlodipine. It has not been studied with beta-blockers or max doses of ACE inhibitors.2
There are a few common issues that arise when using drugs that affect the RAAS. The incidence of cough for
aliskiren was approximately one-half to one-third the rate seen with ACE inhibitors. The incidence was less when used in
combination therapy compared to using either as monotherapy. Some side effects, such as increased potassium, increased
serum creatinine, or angioedema, were seen rarely with aliskiren. Based on the mechanism of action and previous findings
with other RAAS drugs, it was placed as a category C during the first trimester and a category D during the second and third
trimesters.2 When using drugs affecting the RAAS, African American patients tend to have smaller reductions in blood
pressure than Caucasians and Asians. This was found to be true for aliskiren as well. 3
The recommended starting dose for aliskiren is 150 mg once daily with no adjustment for mild to moderate renal
failure, hepatic failure, or in the elderly. There is limited data involving patients with severe renal impairment therefore the
manufacturer advises caution. If the patient is not adequately controlled after two weeks the dose may be increased to the
maximum dose of 300 mg once daily.2 An 85% to 90% antihypertensive effects is attained by 2 weeks of therapy initiation. 6
Aliskiren is manufactured by Novartis and is available in 150 mg or 300 mg tablets. Treatment costs about $2 to $3
a day. 2 There are trials in progress looking at possible compelling indications and more long-term data, including stable
congestive heart failure, proteinuria in diabetes, left ventricular hypertrophy, diabetic neuropathy, and prehypertension.2
Combination pills are being developed with an ACE inhibitor and calcium channel blocker. This may lead to a cost savings
for the patient.
There are many components to consider when deciding on drug therapy for the treatment of HTN. Patient specific data
such as other disease states, drug allergies, intolerances, compliance, side effects, and economic issues should be evaluated.
References:
1)
High Blood Pressure. http://www.nhlbi.nih.gov/health/dci/Diseases/Hbp/HBP_WhatIs.html accessed 4-9-07. National Heart, Lung, and Blood Institute 2007.
2)
O’Mara NB, et al. New Drug: Tekturna (Aliskiren). Pharmacist’s Letter/Prescriber’s Letter 2007; 23(4):230402.
3)
FDA Approves New Drug Treatment for High Blood Pressure. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01580.html accessed 4-9-07. FDA News 2007.
4)
Staessen J, Li Y, Richart T. Oral Renin Inhibitors. Lancet 2006; 368: 1449-1454.
5)
Ferro A, Pitt B. Renin Inhibitors: an important advance in hypertension treatment? Int J Clin Pract 2006; 60 (11): 1335-1342.
6) Prod Info TEKTURNA(R) oral tablets, 2007.
Gabapentin and Pregabalin, A Comparison
Jill Lee, OSU Doctor of Pharmacy Candidate
As the prevalence of neuropathic pain continues to increase, proper diagnosis and treatment becomes imperative.
Neuropathic pain is usually a result of disease or trauma affecting the nervous system, and usually presents as a constant
and/or intermittent spontaneous pain described as burning or shooting. Some common causes of neuropathic pain include
chemotherapy induced polyneuropathy, nerve compression, postherpetic neuralgia, diabetic peripheral neuropathy, poststroke pain, multiple sclerosis and Parkinson’s disease related pain.
Gabapentin (Neurontin®) and pregabalin (Lyrica®) are both antiepileptic drugs that are commonly used in the
treatment of neuropathic pain. Currently, the primary diagnosis for use of these medications is diabetic peripheral neuropathy
(DPN), which affects 20-33% of the diabetic population in the United States. To date, there are no head-to-head comparisons
of gabapentin and pregabalin and unfortunately since they are both manufactured by Pfizer, a randomized, controlled study is
unlike to be performed since the incentive is low. Gabapentin is FDA indicated for postherpetic neuralgia (PHN) while
pregabalin has an indication of both PHN and DPN. Both gabapentin and pregabalin act at the α-subunit voltage-gated
calcium channels slowing glutamate and norepinephrine transmission which decreases nerve transmission.
Dosage of gapapentin is a bit higher than pregabalin, but does not correlate to decreased efficacy when the agents
are compared. Gabapentin should be titrated up slowly to a maximum daily dosage of 3600 mg but efficacy has been shown
at doses of 600 mg three times daily with no added benefit at higher doses. 7 An adequate trial of gabapentin should include 38 weeks for titration plus 1-2 weeks at the maximum tolerated dosage.2 Gabapentin is renally cleared and should therefore be
dose adjusted in patients with creatinine clearance <60 to prevent accumulation and increased side effects in these patients.
Gabapentin may be taken with or without food with a high protein diet increasing drug absorption. Common adverse effects
include dizziness, sedation, somnolence, ataxia, mild peripheral edema, and rash. Concomitant administration with other
medication is generally safe as gabapentin is not metabolized by the cytochrome P450 system. Drug interactions with
gabapentin include mainly a reduction in efficacy when combined with aluminum and magnesium compounds.
In healthy individuals, pregabalin should be initiated at 75 mg twice daily or 50 mg three times daily with a titration
up to 300 mg daily as tolerated. Patients experiencing partial response in the absence of significant side effects may benefit
from doses as high as 200 mg three times daily. 7 Pregabalin is structurally similar to gabapentin but has a much greater oral
bioavailability at 90% versus 50-60%. Thus, the disadvantage of gabapentin is quick saturation of active transport sites
allowing only a small dose of medication to be systemically absorbed which results in the need to give lower doses more
frequently.5 Like its counterpart, pregabalin also requires a dose reduction in renal impairment. Pregabalin has a faster onset
to peak concentration than gabapentin and generally exhibits symptom improvement within the first week of therapy. The
most commonly reported adverse effects include dizziness, somnolence, dry mouth, peripheral edema, blurred vision, weight
gain, and difficulty concentrating. Drug interactions with pregabalin include additive CNS depression with sedatives, weight
gain and edema with thiazolidinediones, such as Actos ® and Avandia®.
The American Society of Pain Educators (ASPE) and The Diabetic peripheral neuropathic pain consensus guidelines
for treatment classify pregabalin as a first tier treatment and gabapentin as a second tier treatment1. This is based on the
number of randomized, controlled trials and clinical experience but suggest that therapy selection be based upon patient
comorbidities, adverse event profiles, and contraindications. Although both gabapentin and pregabalin have been well
studied and approved for the treatment of neuropathic pain, they are not necessarily better than older agents such as tricyclic
antidepressants (TCAs) in all patient populations. Pregabalin and gabapentin have relatively safe profiles compared to TCAs
but a study between amitriptyline and gabapentin reported no statistically significant difference between pain relief with the
two agents.6
As with drug selection in any disease state, consideration of patient response, adverse event profile, and benefit
versus risks should be weighed before therapy initiation. Gabapentin and pregabalin are both renally cleared drugs which
should be started at low doses and titrated up to achieve adequate pain control. Both drugs have similar adverse effects,
which are correlated to the rate of titration. The decision to prescribe one agent over another depends on patient and
prescriber preferences, tolerability, and efficacy.
References:
1.
2.
3.
4.
5.
6.
7.
8.
American Society of Pain Educators. Diabetic peripheral neuropathic pain Consensus Guidelines for Treatment. J Family Practice. June 2006. [Accessed 12 April 2007] Available at
www.jfponline.com
Dworkin, R.H., Backonja, M., Rowbotham, M.C., Allen, R.R., Argoff, C.R., Bennett, G.J. Advances in Neuropathic Pain Diagnosis, Mechanisms, and Treatment Recommendations. Arch
Neurol. Nov 2003; 60: 1524-1534.
Dworkin, R.H., Corbin, A.E., Young, J.P., et. Al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2003; 60: 1274-83.
Frampton, J.E., Scott, L.J. Pregabalin In the Treatment of Painful Diabetic Peripheral Neuropathy. Drugs. 2004; 64(24): 2813-2820.
Guay, D.R.P. Pregabalin in Neuropathic Pain: A More “Pharmaceutically Elegant” Gabapentin? The Amer J Geriat Pharm. Dec 2005;3(4):274-287.
Markman, J.D., Dworkin, R.H. Ion Channel Targets and Treatment Efficacy in Neuropathic Pain. J of Pain. Jan 2006; 7(15): S38-47.
Micromedex. DrugDex. System. Thomson MICROMEDEX, Greenwood Village, Colorado.
Rosenstock, J., Tuchman, M., LaMoreaux, L, Sharma, U. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-bline, placebo-controlled trial. Pain. 2004; 110: 628638.