Drug Research

Drug Research

Drug Research Chronic Use of Long-Acting ACE Agents May Cause Renal, Cerebral Problems The angiotensin-converting enzymes (ACEs) are accepted therap...

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Drug Research

Chronic Use of Long-Acting ACE Agents May Cause Renal, Cerebral Problems The

angiotensin-converting enzymes (ACEs) are accepted therapy for severe heart failure. But there are scant data on whether short- or long-acting agents constitute the more intelligent choice for treatment. One long-acting drug, enalapril, has been purported to offer several advantages. It has a higher affinity for the converting enzyme than a short-acting drug like captopril, and lacks a sulfhydryl group, which may cause the rash and changes in taste sensation sometimes seen with captopril. But there has been some question about whether the amazing efficiency of enalapril is actually beneficial to patients with heart failure. New work by Milton Packer and colleagues from the Mount Sinai School of Medicine in New York suggests that there may indeed be a dark side to enalapril. Forty-two patients, aged 27 to 79 years with severe chronic heart failure, were assigned to captopril or enalapril for 1 to 3 months, and the hemodynamic effects of each drug evaluated. At first, both groups showed a similar response to drug treatment, as indicated by measures such as heart rate and mean arterial pressure. But by the second study period (about 72 days later), there was a marked difference between the two drugs, although both were effective in achieving similar decreases in mean arterial pressure. It was observed that captopril induced only brief decrements in mean arterial pressure each time the drug was administered; blood pressure quickly rose to pretreatment levels before the next scheduled dose. In contrast, with enalapril, the hypotensive response was prolonged and persisted at maximal values throughout the intervals between doses. This difference had real clinical consequences. Since the falls in arterial pressure can produce adverse symptoms like dizziness, the shorter duration of action of capto-

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pril meant briefer symptomatic periods. Any dizziness experienced by patients taking the drug wasn't drastic enough to interfere with their daily activities. But with enalapril, dizziness sometimes lasted for several hours. The difference in drug action also affected kidney function; enalapril caused a significant decrease in creatinine clearance. ACE drugs also result in impairment of potassium homeostasis, through suppression of aldosterone production. This interferes with the ability ofthe kidneys to secrete potassium, and leads to an increase in serum potassium levels. Even though the study patients took the precaution of not taking potassium supplements, those

given enalapril-but not those on captopril-had elevated levels of serum potassium. The authors conclude: ''Although converting-enzyme inhibition produces consistent benefits in patients with congestive heart failure, this therapeutic approach is associated with a significant risk of hypotension, whose magnitude and duration determine whether serious end-organ (cerebral and renal) will occur." Using the lowest possible doses of these drugs and avoiding simultaneous use of diuretics may help, but, in the end, how long the period of hypotension lasts is closely dependent on intrinsic pharmacokinetic properties ofthe drugs. Therefore, other things being equal, "agents with a prolonged duration of action may yield few therapeutic advantages and may significantly increase the risk of adverse effects."®

Minimal Benefit from Treating Hypertensives Older than 80

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esults from the European Working Party on High Blood Pressure in the Elderly (EWPHE) were recently reanalyzed for any differences according to subgroups such as those defined by age and sex (Lancet, 2, 589, 1986). While the benefits of treatment were unrelated to factors like entry blood pressure level and the presence or absence of cardiovascular complications at entry, the treatment effect seemed to wane as the patients' age advanced. "Little or no benefit from treatment could be demonstrated," the report notes, "in patients over the age of 80 years, the great majority of whom are women." Subjects entering the study had to meet several criteria: age of 60 years or more; sitting blood pressure on placebo, 160-239/90-119 mm Hg. Patients were randomized to active treatment (hydrochlorothiazide and triamterene) or placebo. If blood pressure failed to respond, methyldopa could be added to the active regimen. Two factors seemed to influence cardiovascular mortality-advanc-

ing age and higher systolic blood pressure at entry to the study. In contrast, level of diastolic pressure didn't seem to have any effect. Overall, cardiovascular mortality tended to decrease after treatment in all men (47% decrease) and, to a lesser extent in all women (18% decrease). The extent of decrease in mortality was the same for both those who had cardiovascular complications as those who did not--a 27% decline was observed. Nonsmokers had slightly more benefit (53% decrease in mortality) than smokers (53% decrease). Some studies of the benefits of antihypertensive treatment have implied that benefits are considerably less-and sometimes, even negative-in women. The EWPHE trial to some extent confirms this impression, since women of all ages realized only an 18% decrease in mortality from treatment, and patients over 80-most of whom were women-got little or no benefit from the regimen employed in the trial. ®

American Pharmacy, Vol. NS26, No. 12, December 1986/804

Drug Research

Analgesics Linked to Aplastic Anemia, Agranulocytosis Risk

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sing certain analgesics increases the odds of developing the rare blood disorders agranulocytosis and aplastic anemia, but the overall excess risks appear low, reports a study in JAMA (October 3, 1986). The International Agranulocytosis and Aplastic Anemia Study involved more than 300 hospitals in seven countries: Israel, Spain, Italy, Hungary, West Germany, Bulgaria, and Sweden. Data collection for the population-based, case-control study began in 1980 and continues in several countries. Agranulocytosis and aplastic anemia, two disorders of the blood cell-producing bone marrow, can be caused by many environmental factors, including drugs. The specific risk associated with particular drugs, however, was unknown. The new study looked at several analgesics, including dipyrone, salicylates, acetaminophen, butazones, indomethacin, and diclofenac, which are used for many ailments. Study subjects included those with agranulocytosis and aplastic anemia resulting in hospitalization or occurring during a hospital stay. For the study area, the overall annual incidence of agranulocytosis for all causes was figured at 6.2 cases per million population and 2.2 per million for aplastic anemia. Researchers then compared analgesic use by 221 agranulocytosis patients and 1,425 hospital controls in the week before the onset of illness, as well as analgesic use 29 to 180 days prior to hospital admission by 113 aplastic anemia patients and 1,724 controls. For both diseases, researchers found a significant association with exposure to indomethacin and butazones, with the indication that, for aplastic anemia, the risk increases with intensity and duration of use. For agranulocytosis, the study also found a significant association with dipyrone and one of borderline significance with salicylate use. A significant association

between aplastic anemia and diclofenac was reported as well. However, estimates of overall excess risk-the number of cases of disease actually due to the drugwere low: 0.2 to 1.1 cases ofagranulocytosis per million (for drug exposure in a 1-week period), and 6.6 to 10.1 million for aplastic anemia (for exposure in a 5-month period). The study did report some large relative increases in risk. For example, dipyrone users in some areas were about 24 times more likely to have agranulocytosis than nonusers, while users ofbutazones were nearly four times more likely to develop agranulocytosis and nearly nine times more likely to have aplastic anemia. Indomethacin users ran a nearly nine-fold greater risk of

American Pharmacy, Vol. NS26, No. 12, December 1986/805

agranulocytosis and about a 13-fold greater risk of aplastic anemia. "However, it is more important to note that the absolute risks associated with all of these drugs appear to be very low," the study says. It is these figures that should be used to gauge the incidence of blood disorders attributable to the drug, the researchers note. In an accompanying editorial, Gerald A. Faich, director of the Food and Drug Administration's Office of Epidemiology and Biostatistics, stresses that point. "Lest the study be misinterpreted," he writes, "it must again be emphasized that what counts is total drug risk ... gastrointestinal and other organs are far more frequently adversely affected by analgesics than the hematologic system .... Thus, choices of analgesics, once the need for them is clear, should not be solely on the basis of the hematologic toxicity described in this study. ®

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Drug Research

Nevv Somatostatin Analog for Hypotension or some people, occasional spells of hypotension are simply an irritation; for others, getting up from a bed (orthostatic hypotension) or a meal (postprandial hypotension) can have disasterous consequences. They will be unable to walk for many minutes, and may even black out. Previous work had shown that the hormone somatostatin, given IV, can prevent the onset of postprandial hypotension. But somatostatin itself has an extremely short half-life, so a long-acting analog has been developed by three researchers, Robert D. Hoeldtke, Thomas M. O'Dorisio, and Guenther Boden, which, given SC, proved capable of raising blood pressure significantly. The genesis of orthostatic hypotension is fairly well established. It results from a failure in postureinitiated sympathetic reflexes, pooling of blood in the legs, and a decrease in blood volume in the heart. However, the cause of postprandial hypotension is still a matter for conjecture. One likely hypothesis is that, in response to food, a gut hormone is secreted that dilates blood vessels. But nobody has yet been able to identify such a peptide. At any rate, when Hoeldtke and colleagues (Lancet, 2, 602, 1986) gave their somatostatin analog to eight patients with orthostatic and postprandial hypotension, low doses (0.2 to 0.4 mcglkg) elevated the blood pressure after breakfast in all six patients who had postprandial hypotension. With higher doses (as much as 1.6 mcglkg), upright pressures were raised during the postprandial period in five of seven patients. The pressure differences had significant clinical benefits. Before therapy, three patients couldn't stand after they had eaten. After treatment, given at the beginning of breakfast, they were able to walk for durations of35 to 100 minutes. Other drugs have been used to treat hypotension; for instance, indomethacin has been given to pa-

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tients whose hypotension is a consequence of autonomic neuropathy. However, there is considerable debate about its effectiveness, and some people can't tolerate longterm therapy. Caffeine can prevent postprandial hypotension for brief periods, but won't work for orthostatic hypotension. The new somatostatin analog produces more consistent favorable results, in both types of hypotension, but patients appear to have quite different responses to the drug, requiring a range of doses to achieve similar effects. The precursor compound, somatostatin, has a plethora of effects within the body; among these is hyperglycemia (it suppresses insulin excretion). The researchers say, though, that in most cases the doses required to correct hypotension are sufficiently low that this effect of their analog doesn't present a problem. But should high blood sugar levels result, insulin can be injected right along with the somatostatin analog, since the action of somatostatin on blood dynamics appears to be unrelated to the effect on insulin secretion. ®

NEW SEPTRA®GRAPE SUSPENSION

trimethoprim and sulfamethoxazole For kids, it means great taste. For you, even greater demand. SEPTRAe Suspension SEPTRAe Tablets SEPTRAe OS (Double Strentth) Tablets (Trimethoprimand Sulfamethoxazole)

INDICATIONS AND USAGE: For the treatment of acute otitis media in ch ildrendue to susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae when in the judgment of the physician Septra offers some advantage over the use of other antimicrobial agents. To date, there are limited data on the safety of repeated use of Septra in children under two years of age. Septra is not indicated for prophylactic or prolonged administration in otitis media at any age. CONTRAINDICATIONS: Hypersensitivity to trimethoprim or sulfonamides. Patients with documented megaloblastic anemia due to folate deficiency. Pregnancy at term and during the nursing period, because sulfonamides pass the placenta and are excreted in the milk and may cause kernicterus. Infants less than two months of age. WARNINGS: FATALITIES ASSOCIATED WITH THE ADMINISTRATION OF SULFONAMIOES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD OYSCRASIAS. SEPTRA SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR ANY SIGN OF ADVERSE REACTION. Clinical signs, such as rash, sore throat, fever, pallor, purpura or jaundice maybe early indications of serious reactions. In rare instances a skin rash may be followed by more severe reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatic necrosis or serious blood disorder. Complete blood counts ·should be done frequently in patients receivingsulfonamides. SEPTRA SHOULD NOT BE USED IN THE TREATMENT OF STREPTOCOCCAL PHARYNGITIS. Clinical studies have documented that patients with group A l3-hemolytic streptococcal tonsillopharyngitis have a greater incidence of bacteriologic failure when treated with Septra than do those patients treated with penicillin, as evidenced by failure to eradicate this organism from the tonsillopharyngeal area. PRECAUTIONS: General: Septra should be given with caution to patients with impaired renal or hepatic function, to those with possible folate deficiency and to those with severe allergy or bronchial asthma. In glucose-6-phosphate dehydrogenase-deficient individuals, hemolysis may occu r. This reaction is frequentlydose-related. Laboratory Tests: Complete blood counts should be done frequently in patients receiving Septra; if a significant reduction in the count of any formed blood element is noted, Septra should be discontinued. Urinalysis, with careful microscopic examination and renal function tests should be performed during therapy, particularly for those patients with impaired renal function. Drullnteractions: In elderly patients concurrently receiving certain diuretics, primarily thiazides, an increased incidence of thrombocytopenia with purpura has been reported. It has been reported that Septra may prolong the prothrombin time in patients who are receiving the anticoagulant warfarin . This interaction should be kept in mind when Septra is given to patients already on anticoagulant therapy, and the coagulation time should be reassessed. Septra may inhibit the hepatic metabolism of phenytoin. Septra, given at a common clinical dosage, increased the phenytoin half-life by 39% and decreased the phenytoin metabolic clearance rate by 27%. When administering these drugs concurrently, one should be alert for possible excessive phenytoin effect. Sulfonamides can also displace methotrexate from plasma protein binding sites, thus increasing free methotrexate concentrations. Carcinolenesis, Mutalenesis, Impairment of Fertility: Long-term studies in animals to evaluate carcinogenic potential and bacterial mutagenic studies have not been conducted with Septra. Prqnancy: TeratogeniC E"ects: Pregnancy Category C. In rats, oral doses of 533 mg/kg sulfamethoxazole or 200 mg/kg trimethoprim produced teratological effects manifested mainly as cleft palates. Because trimethoprim and sulfamethoxazole may interfere with folic acid metabolism, Septra should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ADVERSE REACTIONS: The most common adverse effects are gastrOintestinal disturbances (nausea, vomiting, anorexia) and allergic skin reactions (such as rash and urticaria). FATALITIES ASSOCIATED WITH THE ADMINISTRATION Of SULFONAMIDES, ALTHOUGH RARE, HAVE OCCURRED DUE TO SEVERE REACTIONS, INCLUDING STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLlSIS, FULMINANT HEPATIC NECROSIS, AGRANULOCYTOSIS, APLASTIC ANEMIA AND OTHER BLOOD DYSCRASIAS (SEE WARNINGS SECTION). Hematololic: Agranulocytosis, aplastic anemia, thrombocytopenia, leukopenia, neutropenia, hemolytic anemia, megaloblastic anemia, hypoprothrombinemia, methemoglobinemia, eosinophilia. Alleflic Reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylaxis, allergic myocarditis, erythema multiforme, exfoliative dermatitiS, angioedema, drug fever, chills, Henoch-Schoenlein purpura, serum sickness-like syndrome, generalized allergic reactions, generalized skin eruptions, photosensitivity, conjunctival and scleral injection, pruritus, urticaria and rash. In addition, periarteritis nodosa and systemic lupus erythematosus have been reported. Gastrointestinal: Hepatitis including cholestatic jaundice and hepatic necrosis, elevation of serum transaminase and bilirubin, pseudomembranous enterocolitis, pancreatitis, stomatitis, glossitis, nausea , emesis, abdominal pam, diarrhea, anorexia. Genitourinary: Renal failure, interstitial nephritis, BUN and serum creatinine elevation, toxic nephrosis with oliguria and anuria, and crystalluria. . Neurololic: Aseptic meningitis, convulsions, peripheral neuritis, ataXia, vertigo, tinnitus, headache. Psychiatric: Hallucinations, depression, apathy, nervousness. Endocrine: The sulfonamides bear certain chemical similarities to some goitrogens, diuretics (acetazolamide and the thiazides) and oral hypoglycemic agents. Cross-sensitivity may exist with these agents. Diuresis and hypoglycemia have occurred rarely in patients receiving sulfonamides. Musculoskeletal: Arthralgia and myalgia. Miscellaneous: Weakness, fatigue, insomnia. OVERDOSAGE: Chronic: Use of Septra at high doses and/or for extended periods of time may cause bone marrow depression manifested as thrombocytopenia, leukopenia, and/or megaloblastic anemia. If signs of bone marrow depreSSion occur, the patient should be given leucovorin 5 to 15 mg daily until normal hematopoiesis is restored. DOSAGE AND ADMINISTRATION: Not recommended for use in infants less than two months of lie. The recommended dose for children weighing less than 40 kg with acute otitis media is 8 mg/kg trimethoprim and 40 mg/kg sulfamethoxazole per 24 hours given in two divided doses every 12 hours for 10 days. A chll d weighing 40 kg or more should receive 4 teaspoonfuls (20 ml) or 2 tablets (or 1 OS tablet) every 12 hours for 10 days. For patients with renal impairment,. use recommended dosage regimen when creatinine clearance is above 30 mllmln. IfI creatinine clearance is between 15 and 30 mllmin, use one-half the usua regimen. SEPTRA is not recommended if creatinine clearance is below 15 mllmm.

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:rn. Wellcoma

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American Pharmacy, Vol. NS26, No. 12, December 1986/806

IBurrouahs WeUcome Co. Research Triangle Park North Carolina 27709

Copt C I985BurroughsWelicomeCo. Allrightsreserved .

85-SEP-9

Drug Research

Beta-Adrenergic and Anticholinergic Bronchodilators: Two Drugs Aren't Better than One

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or patients with chronic bronchitis and emphysema, treatment with oral theophylline and a beta-2-adrenergic bronchodilator has proved an effective regimen. But there's also another drug that appears to work just as well as the beta-adrenergic agent-the atropinelike anticholinergic agent ipratropium. Since the role of this drug in treating these diseases has never been well defined, clinicians are often tempted to simply add ipratropium. But careful investigation has come to question the rationality of this practice. Paul Easton and co-workers at the University of Manitoba examined the effects of albuterol and ipratropium in four protocol sequences: albuterol, then ipratropium; albuterol, then placebo; ipratropium,

then albuterol; and ipratropium, then placebo. Each drug was given as an aerosol, in the maximal dose. The patients studied were between the ages of 59 and 79 and had chronic bronchitis, emphysema, or

Differing Effects of Benzodiazepines Explained

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esearch into the possible therapeutic uses for two byproducts of common steroid hormones has suggested that these endogenous chemicals have the ability to work as "natural sedatives." At the same time, the action of these agents offers a partial explanation for the differential effects of benzodiazepines on different individuals. The byproducts are made in the body when two hormones, progesterone and deoxycorticosterone, are degraded. The fact that they are able to induce sedation was first discovered in the 1940s, but only in recent years have researchers· concocted theories as to why. It is now hypothesized that the two substances exert their effect by prolonging the action of the neurotransmitter GABA, which acts as a depressant in the central nervous system. 16

This magnitude of the action is tremendous-the two byproducts are 100 to 1,000 times more potent than pentobarbital. The two also act much more quickly than is common for steroids; their effect is exerted within seconds. The hypothesized mode of action of these agents has also suggested a rationale for the differing action of benzodiazepines within different individuals. When given these drugs, some people become quite sedated, while others show little response at all. Previous speculation held that this was a consequence of different drug levels within the brain. In fact, what may be happening is enhancement of the action of the benzodiazepine whenever concentrations of the steroid byproducts are sufficiently high, since all three chemicals bind to the same

both. All had smoked; the mean smoking history was 56 pack-years. Both agents produced dramatic improvement in parameters such as forced expiratory volume. But it was difficult to differentiate between the effects of the two drugs. The difference between the percent change with albuterol (41%) vs ipratropium (28%) was not significant. Further, there was little additional change when a second agent was added to the regimen-only 1.6% when ipratropium was added to albuterol, and 4% when albuterol was added to ipratropium. Rather than making any sweeping conclusions about their work, though, the authors hedge their bets a bit. They comment that, "Our results do not encourage the use of combination therapy, but they do not preclude the potential value of combinations of submaximal doses of both agents for some patients, especially those who have encountered adverse effects with large doses of a single agent." ®

nerve cell receptor site. Their combined depressant effect would be considerably higher than that of the benzodiazepine alone. In this regard, the two steroid byproducts may playa fascinating role in normal physiology: their sedating effect may work to keep nervous system stimulation within a limit tolerable by the body, in times of severe stress. In addition, the fact that women often report feelings of euphoria in pregnancy may be explained by the presence of high levels of progesterone during that time, which are being continually metabolized to the psychoactive byproduct. There's much more work to be done before we learn the whole story of how these byproducts act. One unknown is the specific site on the GABA receptor complex where the metabolites bind. Some evidence indicates that the site is that used by the barbiturate drugs. ®

American Pharmacy, Vol. NS26, No. 12, December 1986/808