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Archive for the ‘Drugs’ Category

Aspirin and nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs) are among the most commonly used medications. Prescription use of NSAIDs in the United States appears to be stabilizing, but nonprescription (over-the-counter, OTC) use is growing. Sales of ibuprofen – Advil, Motrin IB, Nuprin – have more than tripled since the analgesic was approved for OTC sales nearly a decade ago. Overall sales of OTC NSAIDs will get another boost now that naproxen (Aleve) has received OTC marketing approval.

The increase in over-the-counter (OTC) sales comes as no surprise. Buying an analgesic off the shelf is considerably easier and more convenient – and far less expensive – than seeing a doctor and going through the process of getting a prescribed drug. OTC medications are widely promoted and readily available. Unfortunately, the average American does not realize that a drug purchased OTC may be associated with the same adverse effects as the same drug purchased by prescription. In the case of OTC NSAIDs, adverse reactions may include kidney damage, hypertension, and gastrointestinal (GI) symptoms ranging from mild dyspepsia to serious or even fatal GI bleeding.

NSAID-induced GI Disease

GI disease associated with NSAIDs has been reported as the most common serious adverse drug effect in the United States. Nonsteroidal antiinflammatory drugs (NSAIDs) can exacerbate underlying disease or cause new lesions. From 38% to 50% of patients taking NSAIDs report dyspepsia, and gastric ulcers may develop in up to 28% of patients taking NSAIDs regularly. Studies have shown that a person exposed to NSAIDs has three to four times the risk of non-users for upper GI bleeding, perforation, or both. Increased risk of a serious adverse reaction has been associated with age, female sex, and rheumatoid arthritis, while independent risk factors associated with upper GI bleeding include male sex, history of peptic ulcer (with or without complications), and the use of alcohol, cigarettes, anticoagulants, and corticosteroids.

Lands et al. found that 80% of patients with either upper or lower GI bleeding, and 78% of patients with upper GI bleeding only, had recently consumed NSAIDs (verified by measuring platelet cyclooxygenase activity and serum salicylate levels, as well as taking patient history). Klein et al. also found a higher frequency of GI bleeding in NSAID users. They examined discharge data from hospitalized patients who had suffered GI hemorrhage (both NSAID users and nonusers). Patients using nonsteroidal antiinflammatory drugs (NSAIDs) spent more time in intensive care than nonusers (median 1 day versus 0 days), and daily users had a higher transfusion requirement than nonusers (4 units versus 1 unit), both of which suggest that NSAID use has a substantial impact on health-care resource allocation.

OTC NSAIDs and GI Hemorrhage

A two-year study of hospitalized patients admitted with upper GI bleeding has demonstrated that the self-administration of OTC NSAIDs can substantially increase the risk of bleeding. Wilcox et al. evaluated consecutive patients admitted with upper GI hemorrhage to a large inner-city hospital in Atlanta, Georgia. The use of any OTC or prescription nonsteroidal antiinflammatory drug (NSAID) during the week before admission was assessed prospectively (from patient and family interview and pharmacy records). Inclusion criteria included age more than 18 years; presence of hematemesis and a subnormal hematocrit (or a decrease in hematocrit of more than 5 points from baseline); and documented lesion (disclosed by endoscopy, barium upper GI series, or at autopsy). Patients were excluded if the GI bleeding first occurred during hospitalization.

During the 2-year period, 421 patients were evaluated. Mean age was 50 (range 18-89); 352 patients were black, 63 white, 4 Hispanic, and 2 Asian; 276 patients were male, and 145 were female. Peptic ulcer was the most common cause of bleeding, identified in more than half the patients. Acute gastric mucosal lesions – including nonspecific gastritis, portal hypertension, and gastropathy (alcohol- or aspirin- induced) – were relatively infrequent. More women than men and more subjects over age 60 than under 60 were taking prescription NSAIDs; those younger than 60 were more likely to use OTCs, and those over 60 were more likely to use prescription NSAIDs. Drug use was not related to race.

Aspirin was taken during the week before admission by 41% of patients (and OTC aspirin by a total of 35%). OTC nonaspirin-NSAIDs were taken by 9% of patients and prescription NSAIDs by 14%. The investigators described the use of OTC aspirin and nonaspirin NSAIDs as “striking” in patients with upper GI bleeding (all causes). These products were used most frequently by patients with ulcer-related bleeding (66%), esophagitis (62%), and Mallory-Weiss tears (laceration of the gastric cardia) (56%) but were also used commonly by patients with bleeding unrelated to ulcers. The investigators concluded, “We believe, as do others, that short-term NSAID use (less than 1 week) may be one of the most important precipitating factors for ulcer related hemorrhage.”

Epidemiology of NSAID-GI Bleeding

A large retrospective study of NSAID use and upper GI (gastrointestinal) bleeding has illuminated the use and misuse of nonsteroidal antiinflammatory drugs (NSAIDs). Rodriguez et al. used a database of 4 million patients (the UK General Practitioners’ Computerized Records) to identify 1467 patients with upper GI bleeding over a 3-year period, and 10,000 matched controls. The site of bleeding was gastric in 483 patients and duodenal in 787; 40 patients had multiple sites of bleeding, 147 had peptic ulcer only, and 261 had perforation; 64 patients died. One major indication for NSAID therapy was ill-defined back pain (13% for cases and 10% for controls). Although patients used any of 17 different NSAIDs, sufficient data for individual analyses were obtained for ibu- profen, naproxen, diclofenac, ketoprofen, indomethacin, piroxicam and azapropanone (the latter not available in the United States). Aspirin use was not specifically addressed, because use was seen as too widespread and underreported.

The investigators found that the mean relative risk for upper GI bleeding associated with current NSAID use was 4.7 (7.0 with high doses and 2.6 with low doses). Current users were patients who most likely used nonsteroidal antiinflammatory drugs (NSAIDs) within the previous month (last NSAID prescription ordered during the month before the index date, or duration of therapy including the index date). NSAIDs associated with highest risk of GI bleeding were azapropanone (relative risk 23.4) and piroxicam (relative risk 18). Ibuprofen at low doses had the smallest risk (2.1), although risk was substantially increased with higher doses (6.5 for 1500 mg/day or more). Both short- and long-duration exposure increased the risk of upper GI bleeding, long duration only slightly more than short duration. Patients who recently switched from one NSAID to another or used more than one NSAID simultaneously had more than twice the risk of patients exposed to only one NSAID. In cases where current aspirin use was recorded on the computer, adjustment did not greatly alter risks, which differs from the other studies.

The biggest risk factor for GI bleeding in NSAID users was a history of peptic ulceration (relative risk 17.2). Age also played a role: people under 60 exposed to NSAIDs had a relative risk of 2.8; people over 60 had a relative risk of 13.2. NSAID use was slightly greater in women than in men, yet male sex was associated with a greater risk. The investigators described the patient at greatest risk of presenting with an episode of upper GI (gastrointestinal) bleeding as “a male smoker of advanced age who has a history of peptic ulcer, and is a user of oral corticosteroids, anticoagulants, and NSAIDs.”

Managing NSAID-induced Dyspepsia

How should patients with NSAID-induced dyspepsia be managed? A prospective study by questionnaire (sent to 300 general practitioners, 261 of whom responded) found that management strategies include NSAID discontinuation (87%), switching to another NSAID (12%), and referral for endosco-py (14%) or barium meal (2%). The drugs preferred for management of dyspepsia included histamine2-receptor blockers (41%), antacids (about 25%), and misoprostol (25%).

The authors of the report offered the following guidelines for patients with persistent NSAID- related dyspepsia when simple analgesics are inadequate: Endoscopy is advisable when symptoms persist for more than 3 weeks in patients who need long-term NSAID therapy; when dyspeptic symptoms or signs suggest organic disease; and when the patient is receiving both steroids and NSAIDs. Misoprostol prophylaxis for NSAID-related dyspepsia is recommended at the onset of NSAID therapy for patients with a history of peptic ulcer disease and may also be justified if NSAID therapy is short term, or if endoscopy is intolerable, impractical, or unavailable.

NSAIDs and hypertension in the elderly.

Do NSAIDs alter blood pressure? In elderly patients, the answer to this question is a qualified “maybe.” Johnson et al. found NSAID use an independent risk factor for hypertension in nearly 3000 Australian subjects aged 60 years or more who answered a questionnaire and underwent blood pressure mea- surements. Frequency of NSAID usage was determined for all study participants – 1237 men and 1568 women stratified by age, sex, blood pressure group, and history of arthritis.

Nonsteroidal antiinflammatory drug (NSAID) usage was 26% overall (females 28% and males 23%). Usage increased with age and was higher in females than males in every group studied. Among patients with a history of “arthritis,” 45% were using NSAIDS; 12% were taking both NSAIDS and antihypertensive agents. NSAID usage significantly predicted the presence of hypertension, with an attributable risk of 29%. It is difficult to tell whether NSAIDs raise blood pressure or antagonize the effects of antihypertensive agents, said the investigators, however, “In this elderly population… 29% of the hypertension occurring amongst those taking NSAIDs could be attributed to the NSAID, underscoring the potential contribution of NSAID usage to the prevalence of hypertension in the elderly.”

Bromfenac (Duract, Wyeth-Ayerst Laboratories) was cleared for marketing by the FDA on July 15, 1997 and provides an alternative to opioids for the management of acute pain. It provides fast relief of acute pain without the bothersome side effects of opioid analgesics.

How It Works

Bromfenac is a peripherally acting analgesic that belongs to the nonsteroidal anti-inflammatory drug (NSAID) class. Although the exact mechanism of action of this class of drugs is not known, there are many theories. Duract (bromfenac) seems to have anti- inflammatory, antinociceptive, and antipyretic effects. These activities of the drug are thought to be the result of its inhibition of the arachidonic acid cascade at the cyclooxygenase level.

Following bromfenac administration, the onset of analgesia occurs within about 30 minutes. The peak effect is seen within 2 to 3 hours and lasts about 6 to 7 hours. Bromfenac is more than 99% protein bound and has an elimination half-life of about 1.3 hours. The half-life, however, does not correlate with the duration of action of this drug. Bromfenac is metabolized by the liver into a cyclic amide metabolite and four glucuronide conjugates of aglycone metabolites and is excreted via the urine.

Duract (Bromfenac): Clinical Tips

Currently, the recommended dose for bromfenac is 25 mg every 6 to 8 hours for short-term pain management. If bromfenac is to be taken with a high-fat meal, the dose should be increased to 50 mg every 6 to 8 hours. However, the total daily dose of bromfenac should not exceed 150 mg. If a physician wishes to prescribe this medication for longer than 4 weeks, it would be advisable to monitor the liver enzymes, which can become elevated. Other possible adverse events include abdominal pain, headache, nausea, and vomiting.

Although opioids have proved to be excellent agents in the management of moderate to severe pain, their adverse event profile leaves much to be desired. These agents are known to make people drowsy, tired, and “spaced out,” often leading to noncompliance with the drug regimen. The efficacy of Duract (bromfenac) in relieving pain has already been demonstrated, and, unlike opioids, it does not interfere with people’s lifestyles. As experience with this agent grows, people may elect to use it instead of the opioid analgesic because of its favorable adverse event profile.

Arthrotec is a new product that combines the NSAID diclofenac and the prostaglandin analog misoprostol. The diclofenac component of Arthrotec is responsible for the relief of the symptoms of arthritis. The misoprostol component is responsible for the mucoprotective properties. Arthrotec has the dual purpose of relieving the signs and symptoms of arthritis and protecting patients from the development of gastric and duodenal ulcers.

It is available in two strengths. One formulation (Arthrotec 50) contains 50 mg of diclofenac and 200 mcg of misoprostol while the other (Arthrotec 75) contains 75 mg of diclofenac and 200 mcg of misoprostol. The usual dose of Arthrotec in the management of osteoarthritis is 50 TID and for rheumatoid arthritis is 50 TID or QID; BID dosing can be used.

How it works:

Diclofenac sodium:

Diclofenac sodium is an NSAID that exhibits classical anti-inflammatory, antipyretic, as well as analgesic properties. As with other NSAIDs, its exact mechanism is not completely understood but it is believed that diclofenac, like other NSAIDs, works in part by inhibiting prostaglandin synthetase.

Misoprostol:

Misoprostol is a synthetic prostaglandin E1 analog. In animals, misoprostol inhibits gastric acid secretion and promotes mucosal protective properties. Misoprostol can increase bicarbonate and mucus production and decrease the secretion of gastric acid. The exact reason for protection against ulcers has not be determined.

Clinical Tips

Diclofenac:

Diclofenac is completely absorbed through the gastrointestinal tract following oral administration. The diclofenac portion of Arthrotec is stable in the acidic environment of the stomach. However, it is rapidly released from the formulation once it enters the more basic environment of the duodenum. Peak plasma levels of this portion are reached in about 2 hours. Because of the extensive first pass effect, only 50% of the dose is available for absorption. The diclofenac portion of Arthrotec is metabolized by the liver and cleared by the urine (65%) and the biliary route (35%).

Misoprostol:

Misoprostol is rapidly absorbed following oral administration, but must undergo metabolic activation into misoprostol acid before it can exerts it pharmacologic actions. The misoprostol acid that is present in Arthrotec reaches peak plasma levels in about 20 minutes and is rapidly eliminated with an approximate half-life of 30 minutes.

Arthrotec follows similar pharmacokinetic parameters as the individual components. The amount of absorption of the two components from the preparation of Arthrotec is comparable to the amount of absorption of the two individual components separately. Importantly, food tends to decrease the bioavailability of the two components of Arthrotec. The pharmacokinetic profile of the diclofenac component in Arthrotec is unchanged in elderly patients and in patients who are renally and hepatically challenged. The pharmacokinetics of misoprostol is influenced by age as well as renal and hepatic impairment; the levels of misoprostol in these individual may double. Hence, it is necessary to adjust the dose in elderly patients and in patients who have renal and hepatic problems.

Clinical studies have shown that diclofenac alone, or in combination with misoprostol, is effective in the treatment of the signs and symptoms of osteoarthritis and rheumatoid arthritis. When given alone, misoprostol has been shown to reduce the occurrence of gastric and duodenal ulcers in patients who were receiving a variety of NSAIDs for the management of arthritic conditions. When Arthrotec was compared to diclofenac alone in patients who had osteoarthritis, the incidence of drug-induced ulcers was lower in patients who were receiving Arthrotec than those who were receiving diclofenac. Even though the incidence of gastric and duodenal ulcers was lower with Arthrotec, only the incidence of gastric ulcers was significantly lower in patients who were receiving Arthrotec than those who were receiving diclofenac.

Abdominal pain, diarrhea, upset stomach, and nausea are among the most common side effects with Arthrotec. Diarrhea may be reduced if this medication is taken with meals. Most adverse effects that occur with misoprostol are mild to moderate and generally resolve following a few days of treatment.

Instructions for the Patient

Arthrotec should not be given to patients who are allergic to aspirin, who have pre-existing asthma, and who have severe renal failure. It should not be given to patients who are pregnant or who are planning to become pregnant because it is believed the misoprostol component can cause fetal death.

Patients should also be advised to swallow Arthrotec whole; they should not chew, crush or dissolve this medication. In addition, patients should be advised to report any signs and symptoms of liver failure (jaundice, itching, nausea) to their physician.

A new study concludes that the osteoarthritis drug Vioxx(R) (rofecoxib) is both safe and effective in relieving the pain associated with menstrual cramps.

• researchers at the Merck Research Laboratories compared the effects of rofecoxib to those of both the non-steroidal anti-inflammatory drug (NSAID) naproxen sodium and placebo in 127 women, aged 18 and older, who had histories of moderate to severe menstrual pain.
• found that menstrual pain at eight and 12 hours after medication was relieved similarly in both rofecoxib and naproxen sodium recipients.
• side-effects were similar among all three groups in the study.
• authors note that menstrual pain is thought to be caused, at least in part, by substances called prostaglandins, and that rofecoxib works to reduce the production of prostaglandins by inhibiting the COX-2 enzyme.

The physician should inform the guardian of the most frequent expected side-effects and the likelihood of the most untoward effects (Tables 2-4). The discussion of benefits and risks should be noted in the patient record.

Serious side-effects are usually related to dosage and duration of psychotropic medication. Intelligence and learning ability are affected when dosage exceeds optimum levels, usually associated with sedation or toxic effects. Behavioural changes, including irritability, temper tantrums, hyperactivity, or hypoactivity, however, may occur at lower dosages than those that produce even mild somatic complaints. These may be so irksome and so long-lasting that the particular drug must be discontinued.

The most dangerous effects of the major tranquilizer drugs (neuroleptics) are the central nervous system effects. Most effects will subside dramatically if the dose is reduced or if anticholinergic medication is added immediately (anticholinergic medication should not be given preventively, however, before symptoms occur). Neurological symptoms may include acute dystonic reactions, dykinesias, parkinsonian reactions, akathesia, and the “rabbit” syndrome (perioral chewing).

The most malignant of these conditions, tardive dyskinesia, involves involuntary movements of the face, eyelids, upper and lower extremities, fingers, toes, torso, and neck, and can occur as early as within three months of cumulative drug usage. The effect can occur during drug administration or after dose reduction or drug withdrawal. This condition is resistant to treatment with anticholinergic or other medication. It is difficult to differentiate tardive dyskinesia from withdrawal dyskinesia, in which the symptoms may abate within six months. It is worth noting that the poor responders to neuroleptics are the most likely to develop the dyskinesias. This emphasizes the importance of the physician’s evaluating the response to a psychotropic drug within the first month and preferably within a week of the first dose of some medications.

In general, prescription should begin at the lowest dosage. Give an adequate trial at each succeeding dosage level. Recognize that stimulants show an effect within hours, tranquilizers within days, and antidepressants sometimes not for weeks. Therapeutic blood levels for some psychotropic drugs may not be obtained routinely in clinical laboratories. Dosage for children and adolescents is more idiosyncratic than adults. Failure of one drug in a class of psychotropic drugs does not rule out using another drug in that same class. A general rule is not to use two or more drugs from the same class at once to guard against synergism. Usually dosage is increased until effective, which may sometimes be close to the level at which toxic signs appear.

Psychotropic drugs should not be discontinued quickly to minimize the occurrence of seizures or other withdrawal symptoms. “Drug holidays” should be discussed far in advance in order to assess the best opportunity for discontinuation.

Effectiveness should be judged on a weekly basis, with renewal of prescription on a monthly basis. Discontinuation of medication should be considered every three months. The responsibility of monitoring the risk-benefit ratio of long-term psychotropic drug use (for more than three months) must be shared with the guardians.

The physician should choose the one most appropriate medication.

Current indications for the use of psychotropic medications in children and adolescents can be summarized briefly (Table l). The listing in Table 1 is by no means an exhaustive review of this rapidly emerging field. In two situations, autism and obsessive-compulsive disorders, there is only recent evidence of the possible usefulness of psychotropic medication.

Certain psychotropic medications, such as lithium salts for manic-depressive disorders in children and adolescents, are best left in the hands of psychopharmacological specialists. The use of antihistamines, such as diphenhydramine, and benzodiazepines in treating anxiety disorders of children has not been clearly substantiated. These medications should be used in consultation with a child psychiatrist. They are, however, relatively safe in comparison to the major tranquilizers.

The physician should therefore become thoroughly familiar with a small number of psychotropic drugs in order to respond to parental questions. Three drugs, which are commonly used in pediatric psychiatry, are methylphenidate, imipramine, and thioridazine. The physician should have a certain range of knowledge about these drugs in order to provide appropriate care, although one may choose to use other drugs. One should know the indications, proper assessment procedures, optimum dosage, price, side-effects, drug interactions, contraintfications, common withdrawal effects, alternative therapy, and concurrent treatment recommended for the drug (Tables 2-4).