Archive for 14 de maio de 2009

Serotonin-norepinephrine Reuptake Inhibitors


Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) used in the treatment of depression and anxiety disorders. The likely mechanism of venlafaxine-induced hypertension is the increase in levels of norepinephrine and the subsequent potentiation of noradrenergic neurotransmission.[38] The extended-release formulation of venlafaxine increases blood pressure in approximately 3% of patients when normal doses (75-150mg) are used.[38] The majority of these blood pressure elevations, however, were considered minor. Doses ≥300 mg of extended-release venlafaxine demonstrated clinically significant elevations in 13% of patients, with the majority of blood pressure increases between 10 and 15 mmHg.[39] However, it is important to note that dosing 300 mg or more is not common, and therisk of venlafaxine-induced hypertension will usually not warrant the discontinuation of this drug.[40]


The clinical significance of sibutramineinduced hypertension is not well defined. Sibutramine is an SNRI and is chemically similar to amphetamine. Sibutramine’s likely mechanism of blood pressure elevation in both normotensive and hypertensive patients is the elevated amount of norepinephrine present in the body.[41] A clinical trial evaluating the adverse reactions induced by sibutramine demonstrated a mean elevation of systolic and diastolic blood pressures of 2 mmHg in previously normotensive patients receiving 10 to 15 mg sibutramine daily. Interestingly, an elevation of 7 mmHg was demonstrated in hypertensive patients receiving similar doses.[42] Other trials have demonstrated similar findings.[43,44] Patients with established hypertension receiving sibutramine experienced significantly higher elevations in blood pressure than patients who had normal blood pressure before medication initiation. Sibutramine treatment should probably be limited to patients who do not have cardiovascular disease, including hypertension, functional abnormalities, and coronary artery disease.

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All corticosteroid drugs, including prednisone, can cause sodium retention, resulting in dose-related fluid retention.[19] Corticosteroids with strong mineralocorticoid effects, such as fludrocortisone and hydrocortisone, produce the greatest amount of fluid retention. However, some corticosteroids that lack significant mineralocorticoid activity (e.g., dexamethasone, triamcinolone, betamethasone) may produce minor fluid retention.[20] Corticosteroid-induced fluid retention can be severe enough to cause hypertension, and patients with preexisting hypertension may develop a worsening of blood pressure control when these drugs are initiated. The principal mechanism of corticosteroid- induced hypertension is the overstimula- tion of the mineralocorticoid receptor, resulting in sodium retention in the kidney. This results in volume expansion and a subsequent increase in blood pressure. Corticosteroid-induced hypertension may respond to diuretic therapy.[21] The smallest effective dose and shortest duration of steroid therapy should be used in order to decrease the development of this adverse effect.

Fludrocortisone causes significant blood pressure increases and, thus, is useful in treating patients with postural hypotension. In a study of 64 elderly patients receiving an average dose of 75 mcg of fludrocortisone for approximately five months, four patients had to withdraw because of druginduced hypertension.[22] The study investigators concluded that fludrocortisone therapy was poorly tolerated in elderly patients, even at low doses.

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NSAIDs and COX-2 Inhibitors

Nonsteroidal anti-inflammatory drugs (NSAIDs) have potentially adverse effects on blood pressure.[10,11] NSAIDs block both cyclooxygenase-1 (COX-1) and COX-2 enzymes, which leads to a reduction in prostaglandin formation. These drugs can have widespread beneficial and harmful effects, depending on the patient context. Drug-induced hypertension associated with NSAIDs is due to the renal effects of these drugs. Specifically, NSAIDs cause dose-related increases in sodium and water retention. This effect is also seen with COX-2 selective agents, such as celecoxib.[11]

The COX-1 and COX-2 isoforms are both expressed within the normal adult kidney, with COX-1 in the glomerulus and afferent arteriole and COX-2 in the afferent arteriole, the podocytes, and macula densa.[12] The specific location of each of these isoenzymes in the kidney translates into notably different effects on renal function. The prostaglandins produced by COX-1 primarily affect renal homeostasis by promoting vasodilation in the renal vascular bed, reducing renal vascular resistance, and consequently increasing renal perfusion. Prostaglandins produced by the COX- 2 isoenzyme have diuretic and natriuretic effects.[12,13] In patients who are hemodynamically compromised, the effects of the two isoenzymes are essential for the maintenance of renal perfusion because of their vasodilatory effects. Because NSAIDs block the production of the COX-1 and COX-2 prostaglandins, renal side effects are not uncommon, occurring in approximately 1% to 5% of NSAID users.[13]

By inhibiting COX-2’s natriuretic effect, thereby increasing sodium retention, all NSAIDs carry with them the consequent risk of increased fluid retention.[14] Additionally, the inhibition of vasodilating prostaglandins and the production of vasoconstricting factors, namely endothelin-1, can contribute to the induction of hypertension in a normotensive and/or controlled hypertensive patient.[14]

In a comparison of celecoxib with diclofenac conducted in 287 patients with arthritis, cardiovascular and renal side effects were seen in 79 patients (27.8%), with hypertension being the most common (16.6%).[14] There was no statistical difference in the incidence of hypertension between the traditional NSAID and COX-2 groups. This initiation of hypertension by NSAIDs is especially important in the discussion of COX-2 safety in light of the fact that hypertensive status is a key risk factor in the progression of virtually all cardiovascular diseases including stroke, myocardial infarction, and congestive heart failure.[15]

A recent meta-analysis of COX-2 inhibitors and their effects on blood pressure was published.[16] Data were collected in 45,451 patients from 19 clinical trials. Interestingly, there appeared to be a somewhat greater blood pressure elevation with COX- 2 inhibitors compared with placebo and nonselective NSAIDs (e.g., ibuprofen and diclofenac). Rofecoxib appeared to confer a greater risk of developing clinically important elevations in both systolic and diastolic pressures in comparison to celecoxib. However, rofecoxib was voluntarily pulled from the market in 2004 due to concerns about increased risk of heart attack and stroke.[17]

Because of the widespread availability of NSAIDs without a prescription, many patients with hypertension may be at risk for aggravated blood pressure effects caused by these drugs. Pharmacists should take a careful medication history and specifically inquire about OTC use of NSAIDs. Patients with hypertension should be more closely monitored for blood pressure elevations when using NSAIDs. Patients should be counseled that this adverse effect tends to be dose related, but it is not always predictable. The adverse effect of all NSAIDs and COX-2 inhibitors on blood pressure may have the most clinical significance in the elderly, in whom the prevalence of arthritis, hypertension, and NSAID use is high.[18]

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Darrell Hulisz, RPh, PharmD; Melissa Lagzdins, RPh, PharmD


Pharmacists often receive inquiries about the effects of medications on blood pressure. For example, concerns about OTC cough and cold products still arise even though some ingredients, such as phenylpropanolamine, have been removed from the U.S. market. While only a few classes of drugs cause clinically significant increases in arterial pressure, pharmacists should be aware of drugs that may interfere with effective blood pressure control. A review of drug-drug interactions with antihypertensive agents is beyond the scope of this article. However, some of the more common examples of druginduced hypertension will be discussed ( Table 1 ). Drug-induced blood pressure elevations represent an important and modifiable cause of secondary hypertension; therefore, it is imperative that pharmacists recognize this causal relationship.

Sympathomimetic Agents

It is well established that sympathomimetic amines cause dose-related increases in blood pressure.[1-4] While sympathomimetic-induced hypertension may not be clinically significant in healthy patients, it can become hazardous in others.[1-4] Sympathomimetic amines include amphetamines and similar compounds, such as pseudoephedrine, phenylpropanolamine, and ephedrine. Historically, these compounds were contained in some OTC cough and cold preparations. Because phenylpropanolamine use was correlated with hypertension and stroke, the FDA banned it from the market in November 2000.[3,4]


Pseudoephedrine is a bronchodilator and nasal vasoconstrictor that is generally innocuous when used in recommended doses. However, due to its potential for misuse, many retailers restrict its sale to behind the counter. Pseudoephedrine is commonly used to treat symptoms of rhinitis and rhinorrhea, but its effects on blood pressure and heart rate remain uncertain. Because of its pharmacologic similarity to ephedrine and phenylpropanolamine, use of pseudoephedrine has likewise been avoided in hypertensive patients.

Salerno et al assessed whether pseudoephedrine causes clinically meaningful elevations in blood pressure and heart rate.[5] In this meta-analysis, the primary data extracted included systolic and diastolic blood pressure and heart rate. Twenty-four clinical trials had extractable vital sign information and included a total of 1,285 patients. This analysis demonstrated that pseudoephedrine causes a small mean increase in systolic blood pressure (approximately 1 mmHg), with no significant effect on diastolic blood pressure, and a slight increase in heart rate (about 3 beats per minute). Immediate-release formulations had a greater effect than sustained-release formulations, which would be expected based on pharmacokinetics. Among immediate-release formulations, there was a dose-related increase in all three cardiovascular variables. More substantial increases in both systolic and diastolic blood pressure were noted with increasing doses of pseudoephedrine. Women seemed to be slightly less susceptible to the cardiovascular effects than men. In patients whose hypertension was stable and controlled, pseudoephedrine therapy increased systolic blood pressure but had no effect on diastolic pressure. There was no effect on heart rate in treated hypertensive patients, though this may have been because many patients were receiving beta-blockers. There was no documentation of any clinically significant adverse outcomes, such as hypertensive emergencies, stroke, or arrhythmia. Other investigators have similarly concluded that when it is used at standard doses, pseudoephedrine does not have a clinically significant effect on systolic or diastolic blood pressure in patients with controlled hypertension.[6]

Pharmacists should counsel patients that pseudoephedrine may modestly increase blood pressure and heart rate. These effects are greatest with immediaterelease formulations, higher doses, and short-term medication administration. Patients with stable, controlled hypertension do not seem to be at higher risk for blood pressure elevation compared to those without hypertension. However, one cannot predict how any individual patient will react. The risk-benefit ratio should be evaluated carefully before using any sympathomimetic agent in persons with hypertension. Pharmacists should instruct patients with cardiovascular disease to monitor their blood pressures carefully after starting pseudoephedrine- containing medications. Sustained-release products would generally be preferred to avoid increases in blood pressure. Alternatively, intranasal decongestants such as oxymetazoline could be used, since they have not been shown to induce hypertension when used at recommended doses.[7]

Amphetamine Derivates

A variety of drugs used for narcolepsy and attention-deficit/hyperactivity disorder are chemically related to amphetamine. These central nervous system (CNS) stimulants include dextroamphetamine, methamphetamine, and methylphenidate. The FDA recently issued a warning for dextroamphetamine, stating that using CNS-stimulant treatment at usual doses in children and adolescents with serious heart problems and structural cardiac abnormalities has been associated with sudden death.[8] However, adverse cardiovascular events induced by stimulants are not limited to children. Adults with known cardiac disease have also shown increased risk of sudden death with stimulant use at normal doses. As a general rule, amphetamine-related compounds (i.e., CNS stimulants) should be avoided in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that increase the risk of sudden death. Increases in both heart rate and blood pressure have been observed in children receiving drugs in this class.[9] Thus, this potential cardiovascular risk should be balanced against the beneficial behavioral effects of these medications.

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