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Drug-Drug Interactions at Receptors and Other Active Sites
Abstract
Pharmacodynamic interactions occur at receptor sites or result more broadly from the effect of the drugs on physiological processes. Both antagonism and synergism may be produced. The synergistic interactions, as far as they have the potential to be beneficial and clinically useful, are reviewed separately in this handbook (see Chap. 8.)
... Table 8 summarizes drug interaction information that has been given by Schorderet and Ferrero (1996) on these mechanisms in their review. ...
... *Source: references cited by Schorderet and Ferrero (1996). ...
Normal subjects and patients with adult-onset diabetes received 10 gm. of aspirin in four days. On the fourth day, the fasting serum glucose and the glucose response to oral glucose were decreased in both groups. These changes were associated with increased levels of serum insulin and pancreatic glucagon, although the glucagon responses to oral glucose were unchanged. In the diabetic patients, aspirin therapy was followed by a decreased glucose response to I.V. glucose and by the appearance of an early insulin peak, which could not be demonstrated before treatment. Aspirin did not affect the I.V. glucose tolerance in normal subjects, although it did enhance the early insulin peak. A decrease in the fasting levels of free fatty acids was noted in both groups, whereas the fasting level of triglycerides decreased only in the diabetic patients. Cholesterolemia did not change in either group. A few preliminary observations indicate that, in normal subjects, ibuprofen and ketoprofen, two other presumed prostaglandin inhibitors, did not affect fasting glycemia, glucose tolerance, or the insulin response to glucose. No changes were noted after the administration of placebo.
To compare the effectiveness and safety of spontaneous ascites filtration and reinfusion and total paracentesis plus intravenous albumin infusion in cirrhotic patients with tense ascites.
Randomised trial of the two treatments.
Teaching hospital and district general hospital in Milan.
45 consecutive cirrhotic patients with recurrent tense ascites and urinary sodium excretion rate less than 20 mmol/day. 35 fulfilled admission criteria and completed the study. 17 received spontaneous ascites filtration and 18 paracentesis plus albumin infusion.
Body weight; urinary volume; serum and urinary electrolyte, serum fibrinogen, and plasma aldosterone concentrations; and plasma renin activity before the procedure and 24 hours and eight days afterwards.
Both procedures were effective in all patients. Weight decreased in both groups and showed no substantial increase after eight days. In patients receiving ascites filtration, values decreased significantly (p less than 0.01) after 24 hours for platelet count (mean relative change 0.92; 99% confidence interval 0.86 to 0.98) and serum fibrinogen concentration (0.92; 0.88 to 0.98) but returned to pretreatment values after eight days; no laboratory and clinical signs of disseminated intravascular coagulation were noted. Three patients in this group had fever, which receded spontaneously. One patient in each group had dilutional hyponatraemia.
Spontaneous ascites filtration and reinfusion is an effective treatment for tense ascites. Reinfusion of the patient's concentrated proteins provides savings without compromising safety.
A cDNA encoding the dopamine transporter from bovine brain substantia nigra was identified on the basis of its structural homology to other, recently cloned, neurotransmitter transporters. The sequence of the 693-amino acid protein is quite similar to those of the rat gamma-aminobutyric acid, human norepinephrine, and rat serotonin transporters. Dopamine transporter mRNA was detected by in situ hybridization in the substantia nigra but not in the locus coeruleus, raphe, caudate, or other brain areas. [3H]Dopamine accumulation in tissue culture cells transfected with the cDNA was inhibited by amphetamine, cocaine, and specific inhibitors of dopamine transport, including GBR12909.
Sulfonylureas are powerful hypoglycemic drugs that have been used for decades to treat diabetic patients. This paper describes a 86Rb+ flux technique that permits one to study easily the properties of ATP-modulated K+ channels in RINm5F insulinoma cells. Sulfonylureas inhibit this type of K+ channel under conditions of intracellular ATP depletion. The most potent sulfonylureas (glibenclamide, glipizide, and gliquidone) are acting in the nanomolar range of concentration. Inhibition of the single ATP-modulated K+ channels by low concentrations of sulfonylureas was also observed using the patch-clamp technique. The sulfonylurea receptor has been biochemically identified with [3H]glibenclamide. For 10 different sulfonylureas (or sulfonylurea analogs) there was an excellent correlation between efficacy of blockade of ATP-modulated K+ channels and efficacy of binding to the sulfonylurea receptors using the 3H-ligand.
We conducted a double-blind crossover study to determine which patient characteristics best predict a beneficial response to combined insulin-glyburide therapy. Glyburide (15 mg/day) or placebo was added to the treatment regimen of 31 insulin-treated type II (non-insulin-dependent) diabetic subjects. During glyburide therapy, there was a significant improvement in glycemic control with a reduction in glycosylated hemoglobin from 9.9 +/- 1.3 to 9.1 +/- 1.3% (P less than .001). Patients who responded had higher fasting C-peptide levels (P less than .001) and shorter durations of insulin therapy (P less than .01) than those who did not respond. Glyburide withdrawal was associated with a greater than expected deterioration in glycemic control. Patients on insulin therapy for greater than 8 yr are unlikely to benefit significantly from the addition of glyburide to their treatment regimen.
The opiate analgesic propoxyphene produces cardiac toxicity when taken in overdose. We recently observed a patient with propoxyphene overdose in whom marked QRS widening was reversed by lidocaine. The reversal is apparently paradoxical as both agents block the inward sodium current (INa). We examined possible mechanisms of the reversal by measuring INa in rabbit atrial myocytes during exposure to propoxyphene and the combination of propoxyphene and lidocaine (60 and 80 microM, respectively). Propoxyphene caused use-dependent block of INa during pulse train stimulation. Block recovered slowly with time constants of 20.8 +/- 3.9 s. Block during lidocaine exposure recovered with time constants of 2-3 s. During exposure to the mixture, block recovered as a double exponential. The half time for recovery during exposure to the mixture was 1.6 +/- .9 s compared with a half-time of 14.3 +/- 2.9 s during exposure to propoxyphene alone. During pulse train stimulation, less steady-state block was observed during exposure to the mixture than during exposure to propoxyphene alone when the interval between pulses was greater than 0.95 s. Both drugs compete for a common receptor during the polarizing phase. The more rapid dissociation of lidocaine during the recovery period leads to less block during the mixture than during exposure to propoxyphene alone. The experiments suggest a mechanism for reversal of the cardiac toxicity of drugs which have slow unbinding kinetics.
Monoamine oxidase inhibitors can elicit increases in systolic blood pressure after tyramine ingestion (cheese effect). Moclobemide is a new, reversible, preferential monoamine oxidase A inhibitor with antidepressant properties. Its potentiation of the tyramine pressor effect during 200 mg t.i.d. chronic treatment was compared with tranylcypromine, 10 mg b.i.d., in a double-blind, parallel-group, placebo-controlled study (n = 16). Tyramine was mixed with food and ingested in increasing daily doses, during a normal meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (tyramine 30). When compared with the usual fasting oral tyramine tests performed in the same subjects, the mean tyramine 30 dose with a meal was 2.8 times higher. The mean tyramine 30 dose with a meal decreased from 1450 mg (range, 800 to 2000 mg) during placebo to 306 mg (range, 150 to 500 mg) during moclobemide (factor, 5.0) and from 1200 mg (range, 1000 to 1600 mg) during placebo to 35 mg (range, 20 to 50 mg) during tranylcypromine (factor, 38.2). The duration of the systolic blood pressure increase was longer with tranylcypromine (126 minutes) than with moclobemide (69 minutes) (p less than 0.01).
Synopsis:
Acarbose delays digestion of complex carbohydrates and disaccharides to absorbable monosaccharides, by reversibly inhibiting α-glucosidases within the intestinal brush border, thereby attenuating postprandial blood glucose peaks. Clinical trials have demonstrated that acarbose generally improves glycaemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM) managed with diet alone, or with other antidiabetic therapy, as evidenced by decreased postprandial plasma glucose and glycosylated haemoglobin levels. It does not appear to directly alter insulin resistance, but may lower postprandial plasma insulin levels. Fasting plasma glucose, triglyceride and/or cholesterol levels may also be decreased. Acarbose also improved metabolic control in patients with insulin-dependent diabetes mellitus (IDDM), frequently decreasing insulin requirements, although further studies are required in this indication. Improved metabolic control appears to delay or prevent long term vascular complications of diabetes, and indeed, acarbose appeared to inhibit development of such complications in preliminary animal studies, but this finding requires confirmation in clinical studies. While acarbose seldom causes systemic adverse effects, it is associated with a high incidence of gastrointestinal disturbances such as flatulence, abdominal distension, borborygmus and diarrhoea, caused by fermentation of unabsorbed carbohydrates. However, these symptoms tend to subside with continued treatment and adherence to an appropriate diet. Thus, acarbose appears to be a worthwhile adjunctive therapeutic option for patients with NIDDM inadequately managed by diet alone, or with pharmacological therapy, and possibly also for patients with IDDM. However, further long term efficacy and tolerability data are required, particularly in the latter indication.
Pharmacological properties:
Acarbose is an oligosaccharide which reversibly inhibits intestinal α-glucosidase enzymes responsible for digestion of complex carbohydrates and disaccharides to absorbable monosaccharides. Thus, acarbose delays postprandial absorption of glucose, resulting in attenuation of postprandial plasma glucose, insulin and triglyceride peaks in healthy volunteers. The beneficial effects of acarbose on postprandial glucose levels have been confirmed in patients with insulin-dependent or non-insulin-dependent diabetes mellitus (IDDM or NIDDM), whereas postprandial insulin and triglyceride levels were only occasionally lowered. Pooled data from several clinical trials indicate that acarbose lowers postprandial and fasting blood glucose levels in patients with NIDDM by approximately 20 and 10%, respectively, the latter presumably by an indirect mechanism. Acarbose does not appear to exert any direct effect on insulin resistance in humans. By decreasing the hyperglycaemic stimulus to insulin secretion, acarbose attenuates the blood glucose nadir and associated clinical symptoms which occur after carbohydrate ingestion in patients with reactive hypoglycaemia. Delayed carbohydrate digestion increases the amount of fermentable carbohydrate in the bowel, which does not appear to cause calorie loss, because of metabolism to other absorbable nutrients by colonic microflora, but can induce gastrointestinal adverse effects such as flatulence and borborygmi. Acarbose decreases the postprandial gastric inhibitory polypeptide response, while increasing the enteroglucagon response, and also decreases intestinal absorption of iron. It does not generally appear to lower bodyweight in humans, although this effect has consistently been demonstrated in animal models. Acarbose decreases serum triglycerides, cholesterol and free fatty acid levels in animal models of diabetes and/or hyperlipidaemia, but in human studies in diabetic and nondiabetic individuals, does not consistently lower fasting plasma triglycerides and produces only occasional decreases in fasting plasma cholesterol. The Diabetes Control and Complications Trial (DCCT) has demonstrated that optimal control of blood glucose levels can retard long term complications of diabetes. Indeed, acarbose decreases levels of glycosylated haemoglobin in patients with diabetes, and glycosylation of other body proteins in preliminary animal studies. Moreover, acarbose appeared to inhibit development of renal, cardiovascular, retinal, and neurological complications in various animal models of diabetes and/or hyperlipidaemia. The latter findings await confirmation in clinical studies. Consistent with its intestinal site of action, acarbose is minimally (<2%) absorbed in unchanged form following oral administration to healthy volunteers. However, it is rapidly and extensively metabolised by intestinal digestive enzymes, and absorption of metabolites formed in the gut yields a biphasic pattern of absorption in studies with radiolabelled acarbose, with separate peaks at 1 to 2 and 6 to 24 hours. Administration of acarbose 300mg 3 times daily for 90 days to healthy volunteers did not result in accumulation. Acarbose has a small volume of distribution (0.32 L/kg) and was minimally bound to animal plasma proteins at concentrations ≥ 1 μg/L, and 98% bound at 0.008 μg/L. Acarbose and/or its metabolites were secreted into breast milk and penetrated across the placental barrier in rats. Approximately 35% of an orally administered dose of acarbose is excreted in the urine, virtually all in metabolised form, and approximately 50% in the faeces. The total body clearance of acarbose was around 600 L/h and values of up to 39.5 hours have been reported for the terminal elimination half-life.
Therapeutic use:
In noncomparative and placebo-controlled studies of 2 to 12 months' duration, acarbose generally improved metabolic control in patients with NIDDM, whether used with diet alone, or with other antidiabetic agents, including sulphonylureas, biguanides or insulin. Postprandial plasma glucose levels were lowered by approximately 2 to 3 mmol/L and glycosylated haemoglobin levels were also decreased. Fasting plasma glucose and triglyceride levels, and insulin requirements, were also occasionally decreased. Acarbose was not effective in some patients, possibly reflecting low dosages used and/or severe carbohydrate restrictions in some instances, or lack of sensitivity of intestinal α-amylases to acarbose. Acarbose tended to be slightly less effective than sulphonylureas and biguanides, particularly with regard to effects on fasting plasma glucose, but was at least as effective as guar gum in 1 study. Acarbose has been less well studied in patients with IDDM, but improved glycaemic control, as evidenced by improved daily blood glucose profiles and decreased glycosylated haemoglobin levels, and frequently, decreased insulin requirements. It may also lower the risk of late hypoglycaemic episodes (those occurring several hours after a meal) in patients with IDDM. Data from preliminary studies indicated that acarbose might be useful in patients with reactive hypoglycaemia, dumping syndrome and types IIb or IV hyperlipidaemia, but to date no large-scale studies appear to have been performed in these indications.
Tolerability:
Gastrointestinal disturbances such as flatulence, abdominal distension, diarrhoea and borborygmus, caused by fermentation of unabsorbed carbohydrate in the bowel, are the most common adverse effects associated with acarbose therapy and may occur in up to two-thirds of patients. These symptoms generally improve with continued treatment, and may be minimised by initiating therapy at a low dosage and adherence to diet. The tolerability of acarbose in children aged 5 to 16 years is similar to that in adults. Systemic adverse effects are rare during acarbose therapy. However, analysis of data from phase III US studies indicated that anaemia and elevated transaminase levels were significantly more common in acarbose, than in placebo recipients, occurring in 3.8 and 1.1% of patients, respectively. Acarbose was reported to decrease both peak concentrations and area under the concentration-time curve of metformin by 35% when the 2 drugs were given concurrently to healthy volunteers.
Dosage and administration:
The recommended starting dose of acarbose for patients with NIDDM is 50mg 3 times daily, taken before meals, which may be increased to 100mg 3 times daily after 6 to 8 weeks if necessary, and subsequently to a maximum of 200mg 3 times daily if required. Dosages used in patients with IDDM in clinical trials were similar to those used in NIDDM. Patients receiving the maximum dose should be monitored closely for elevation of serum transaminase levels, preferably at monthly intervals, for the first 6 months of treatment. Contraindications to acarbose use include inflammatory bowel disease, partial intestinal obstruction or predisposition to intestinal obstruction, chronic intestinal disease associated with marked disorders of absorption or digestion, conditions which might be exacerbated by increased intestinal gas formation (such as hernias), and impaired hepatic function. Additionally, acarbose has not been studied in patients with severe renal impairment. As acarbose may potentiate the hypoglycaemic effects of insulin and sulphonylureas, dosages of these agents may require adjustment when acarbose is administered concurrently. If hypoglycaemia occurs, patients should take glucose rather than carbohydrate foods. The effects of acarbose may be reduced by concomitant administration of intestinal adsorbents such as charcoal, and digestive enzyme preparations such as amylase or pancreatin, and enhanced by concomitant administration of neomycin or cholestyramine.
Synopsis
Moclobemide is a reversible and selective inhibitor of the enzyme monoamine oxidase (MAO) subtype A with a broad spectrum of antidepressant activity. Controlled clinical studies suggest that the short term clinical efficacy of moclobemide is significantly superior to that of placebo, and comparable to that of the tricyclic antidepressants clomipramine, amitriptyline, imipramine and desipramine, the irreversible MAO inhibitor tranylcypromine and the second-generation antidepressants maprotiline, mianserin and fluvoxamine in the treatment of major depressive illness. Moclobemide appears to be equally effective in endogenous and nonendogenous depression, producing marked amelioration of clinical features of psychomotor retardation and depressed mood.
Moclobemide is well tolerated, being largely devoid of the anticholinergic adverse effects, symptomatic postural hypotension and weight gain variously associated with the tricyclic antidepressants and irreversible MAO inhibitors, and appears considerably safer on overdosage than the tricyclic and second generation antidepressants. Moreover, moclobemide offers the advantage over the older, irreversible MAO inhibitors of causing only minimal potentiation of the pressor response to dietary tyramine (the so-called ‘cheese effect’). Consequently, the risk of potentially fatal hypertensive crisis, a major deterrent to the wider acceptance of these earlier compounds, is substantially reduced with moclobemide, and the need for dietary precautions is minimised.
With its efficacy against endogenous and nonendogenous depression, relatively rapid onset of antidepressant activity, and absence of carry-over effects on treatment withdrawal, moclobemide is likely to make an important contribution to the treatment of major depressive illness. Its favourable tolerability profile, safety on overdosage and beneficial effect on age-related cognitive impairment may be of particular value in the elderly and those with concurrent physical illness.
Pharmacodynamic Properties
Moclobemide is a selective, potent and reversible inhibitor of MAO-A, devoid of significant affinity for central neurotransmitter binding sites or inhibitory effects on central monamine biosynthesis, reuptake or release. The moclobemide-induced changes in brain monoamine levels are consistent with its short-lasting inhibitory action on MAO-A. In humans, moclobemide increases plasma prolactin levels (an effect presumably mediated via central serotonergic mechanisms) but has no apparent effect on sympathoadrenal function or plasma melatonin levels. At therapeutic doses of 300 to 600 mg/day, moclobemide produces minimal (≈ 2- to 4-fold) potentiation of the pressor response to intravenous tyramine, and, in comparison with the irreversible MAO inhibitors, only slight (4- to 7-fold) potentiation of that to oral tyramine under fasting conditions. On coadministration with food, at least 150mg tyramine was required to produce a clinically relevant increase in systolic blood pressure (30mm Hg) in healthy volunteers receiving moclobemide 600 mg/day. Moclobemide has a less marked suppressant effect on rapid eye movement sleep than the irreversible MAO inhibitors, and its antidepressant action is characterised by an improvement in the quality and pattern of sleep. Therapeutic doses of moclobemide did not influence vigilance or short/long term memory in volunteers but attenuated the scopolamine-induced impairment of cognitive function.
Pharmacokinetic Properties
Following virtually complete (> 95%) absorption from the gastrointestinal tract, moclobemide undergoes extensive (but apparently saturable) first-pass hepatic metabolism, resulting in an oral bioavailability ranging from ≈ 45 to 60% on single-dose administration and ≈ 85% on multiple dosing. In patients with depression, steady-state plasma moclobemide concentrations on multiple oral dosing were significantly correlated with dose. Moclobemide displays a large volume of distribution (≈ 75 to 95L) on oral administration, suggesting extensive tissue distribution. Clearance of moclobemide is almost exclusively due to hepatic metabolism; the identified metabolites display at best only modest MAO-A inhibitory activity, although comparison of ex vivo and in vitro findings suggests the presence of active, but as yet unidentified, metabolites. Moclobemide obeys first-order elimination kinetics; the parent compound has a short elimination half-life (1 to 2 hours) and a relatively high systemic clearance (0.5 to 1.0 L/min). Multiple oral dosing results in a reduction in the drug’s hepatic clearance, suggesting auto-inhibition or metabolite-mediated inhibition of moclobemide metabolism. While the absorption and elimination kinetics of moclobemide are not significantly modified by advanced age or renal impairment, hepatic dysfunction or coadministration with cimetidine result in decreased systemic clearance of moclobemide.
Therapeutic Use
Moclobemide 150 to 600 mg/day displayed significantly superior efficacy to placebo on short term (4- to 6-week) administration to patients with major depression, as reflected by achievement of clinical response criteria [⩾ 50% reduction in total Hamilton Depression Rating Scale (HDRS) scores] in 60 to 70% of moclobemide recipients vs 30% of placebo recipients. The drug proved equally effective in endogenous and nonendogenous depression, showing the most pronounced ameliorative effects on features of psychomotor retardation and depressed mood. Dose-finding studies suggested a tentative dose-response relationship over the therapeutic range of 100 to 600 mg/day.
In randomised, double-blind, but predominantly non-placebo-controlled studies, moclobemide 150 to 600 mg/day demonstrated a similar antidepressant profile and overall therapeutic equivalence to the tricyclic antidepressants amitriptyline 125 to 250 mg/day, desipramine 50 to 175 mg/day, clomipramine 75 to 200 mg/day and imipramine 75 to 200 mg/day in major depression and dysthymic disorder, with approximately 60 to 70% of patients satisfying response criteria (⩾ 50% reduction in total HDRS score) over a 4- to 12-week treatment period. The onset of the antidepressant action of moclobemide 300 to 600 mg/day (day 10) occurred significantly earlier than that of clomipramine 100 to 200 mg/day (day 13). While moclobemide 150 to 600 mg/day appeared to be of comparable overall efficacy to the second-generation antidepressants maprotiline 75 to 225 mg/day, mianserin 75 to 150 mg/day and fluvoxamine 100 to 200 mg/day in major depression, its action was primarily activating, whereas that of the second-generation antidepressants tended to be more anxiolytic (fluvoxamine) or soporific (maprotiline). Preliminary indications suggest that moclobemide 100 to 350 mg/day is of at least comparable efficacy to the irreversible MAO inhibitor tranylcypromine 10 to 30 mg/day in endogenous depression, and that moclobemide 450 mg/day has a more marked and rapid antidepressant action than the reversible but relatively nonselective MAO-A inhibitor toloxatone 1000 mg/day, showing a significant advantage over the latter in normalising disrupted sleep patterns.
Meta-analysis of pooled controlled comparative data indicates that moclobemide is equally effective in the various subtypes of unipolar and bipolar depression, agitated and retarded depression, endogenous and nonendogenous depression, as well as in melancholic and non-melancholic depression.
Tolerability and Safety
On short term (⩾ 12 weeks) administration at doses of up to 600 mg/day moclobemide has proved to be almost as well tolerated as placebo in patients with depression, with only nausea occurring significantly more frequently on active treatment (10 vs 5%). Moclobemide had no consistent, clinically relevant effect on heart rate or systemic blood pressure; hypertensive episodes were infrequent (0.7%) and in the majority of eases were related to pre-existing labile hypertension rather than to dietary factors, while postural hypotension was no more common with moclobemide (1%) than with placebo. The drug appeared to be equally well tolerated in elderly and younger patients.
Moclobemide displayed superior overall tolerability to the tricyclic antidepressants, primarily on the basis of its relative lack of anticholinergic effects (dry mouth, blurred vision, constipation), less pronounced postural changes in blood pressure, and minimal weight gain. Additionally, moclobemide appeared to be devoid of the central excitatory effects (agitation, restlessness, irritability and insomnia) associated with the irreversible MAO inhibitors. Moclobemide displays considerably less toxicity on overdosage than the tricyclic and second-generation antidepressants. Moclobemide overdoses of up to 20g were associated with severe drowsiness and disorientation, but no life-threatening respiratory or cardiovascular depression or neurological sequelae, and there were no residual complications on recovery.
Dosage and Administration
Moclobemide is administered orally at a full therapeutic dose of 300 to 450 mg/day, in 2 or 3 divided doses, from the outset of treatment; subsequent upward dose titration to a maximum of 600 mg/day may be performed from the second week of therapy onwards. Moclobemide dosage reduction is warranted in the presence of hepatic dysfunction, or if the drug is coadministered with cimetidine. Moclobemide should be taken at the end of a meal to minimise any possible risk of hypertensive responses to dietary tyramine. Although dietary restriction is unnecessary, patients should be advised to avoid consumption of large amounts of tyramine-rich foods (e.g. mature cheese) at any one meal. The combined use of moclobemide with pethidine or dextromethorphan is contraindicated.
Exogenous pyridoxine is known to antagonize the neuropharmacologic action of levodopa in Parkinson disease. The metabolic interactions of levodopa, pyridoxine, and carbidopa, a peripheral decarboxylase inhibitor, were studied in 15 long-term, levodopa-treated patients. Pyridoxine reduced plasma dopa levels 67% but enhanced homovanillic acid synthesis 49% Carbidopa potentiated plasma dopa, inhibited homovanillic acid synthesis, and minimized the effects of pyridoxine.
The decarboxylase activity index following pyridoxine administration increased 483% and 136% for plasma and urine respectively. Carbidopa effected a 77% and 94% reduction.
It is suggested that pyridoxine accelerates systemic metabolism of levodopa, thereby decreasing availability of the amino acid to brain parenchyma. The combination of levodopa and carbidopa prevents the loss of levodopa effect produced by exogenous pyridoxine.
Study Objective: To evaluate the effects of three chemically distinct nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function in patients with asymptomatic, mild but stable chronic renal failure.
Design: Prospectively randomized, triple-crossover study with at least 1-month washout between each of three treatment periods.
Setting: Inpatient and outpatient clinical research center of a university teaching hospital.
Patients: Convenience sample of 12 women with serum creatinine levels between 130 and 270 µmol/L (1.5 and 3.0 mg/dL). Mean glomerular filtration rate ± standard error was 0.36 ± 0.03 mL/s · m² (37 ± 3 mL/min · 1.73 m²); mean effective renal plasma flow was 1.6 ± 0.18 mL/s · m² (166 ± 19 mL/min · 1.73 m²).
Interventions: Patients received ibuprofen, 800 mg three times daily; piroxicam, 20 mg daily; and sulindac, 200 mg twice daily for 11 days. Treatment was discontinued if serum creatinine rose by 130 µmol/L (1.5 mg/dL) or serum potassium exceeded 6 mmol/L (6 mEq/L).
Measurements and Main Results: Three patients met our criteria for stopping ibuprofen by day 8; however, all patients completed piroxicam and sulindac therapy. When the three patients in whom ibuprofen was withdrawn were rechallenged with ibuprofen, 400 mg three times daily, two again developed evidence of acute renal deterioration. All three regimens suppressed renal prostaglandin production.
Conclusions: These findings indicate that a brief course of ibuprofen, a compound widely used on a nonprescription basis, may result in acute renal failure in patients with asymptomatic, mild chronic renal failure. Additional studies are needed to assess the risk of piroxicam and sulindac in patients with more pronounced renal impairment and in patients receiving longer courses of therapy, which, according to our data, may result in drug accumulation.
Purpose:
A meta-analysis of randomized trials studying the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on blood pressure.
Data sources and study selection:
Eight databases were searched, yielding 38 randomized, placebo-controlled trials and 12 randomized but not placebo-controlled trials (comparing two or more NSAIDs).
Data extraction:
Pooled mean treatment effects were computed in each trial for blood pressure, weight, creatinine clearance, plasma renin activity, and daily urinary excretion of sodium and prostaglandins. Meta-analyses of these variables were done for all randomized, controlled trials; for all randomized, uncontrolled trials; and for several subgroups.
Data synthesis:
When pooled, NSAIDs elevated supine mean blood pressure by 5.0 mm Hg (95% CI, 1.2 to 8.7 mm Hg) but had no effect on variables other than blood pressure. Nonsteroidal anti-inflammatory drugs antagonized the antihypertensive effect of beta-blockers (blood pressure elevation, 6.2 mm Hg; CI, 1.1 to 11.4 mm Hg) more than did vasodilators and diuretics. Among NSAIDs, piroxicam produced the most marked elevation in blood pressure (6.2 mm Hg; CI, 0.8 to 11.5 mm Hg), whereas sulindac and aspirin had the least hypertensive effect.
Conclusions:
Nonsteroidal anti-inflammatory drugs may elevate blood pressure and antagonize the blood pressure-lowering effect of antihypertensive medication to an extent that may potentially increase hypertension-related morbidity. Although certain NSAIDs and antihypertensive agents could be more likely to produce these effects, the underlying mechanisms require further study.
A large number of drug interactions involving antidepressants have been described. Some of these are common to specific classes of antidepressant drugs, while others are related to peculiar properties of individual compounds and vary greatly from one compound to another within the same drug class.
In general, the broader the range of receptors and enzymes affected by a given drug, the greater the potential for pharmacodynamic interactions. Older generation monoamine oxidase inhibitors (MAOIs) are particularly likely to cause interactions. These can occur with a wide range of compounds including tyra-mine-containing foods, alcohol (ethanol), opioids, sympathomimetic agents and other antidepressant drugs [e.g. tricyclic antidepressants (TCAs) and selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs)]. The more recently developed reversible and selective inhibitors of monoamine oxidase-A, such as moclobemide, appear to carry a much lower risk of causing serious drug interactions.
TCAs affect several neurotransmitter systems, but to differing degrees. This may result in many clinically significant pharmacodynamic interactions, including the reversal of the hypotensive action of some centrally active antihypertensive agents and the potentiation of the effects of anticholinergic agents and CNS depressants. Important pharmacokinetic interactions with TCAs include induction of their metabolism by anticonvulsants and impairment of their elimination by metabolic inhibitors such as fluoxetine, fluvoxamine, antipsychotics and quinidine. Appropriate dosage adjustments may be required to minimise the potentially adverse effects resulting from these interactions.
Some second generation antidepressants do not differ greatly from TCAs in pharmacological profile and so may be involved in similar interactions. However, others have a more selective mechanism of action and a lower potential for drug interactions. This is especially true for the SSRIs, which cause fewer pharmacodynamic interactions than MAOIs and TCAs. Nevertheless, SSRIs may interact adversely with drugs that also affect serotonergic transmission (including lithium) and may inhibit selectively the hepatic enzymes involved in the metabolism of concurrently prescribed drugs such as TCAs, antipsychotics, carbamazepine, oral anticoagulants and β-adrenoceptor blocking agents. Fluoxetine and paroxetine, in particular, appear to be powerful inhibitors of CYP2D6, whereas fluvoxamine is a more potent inhibitor of CYP1A2.
Avoidance of unnecessary polytherapy, knowledge of the interaction potential of individual agents and careful individualisation of dosage based on close evaluation of clinical response are essential to minimise potentially adverse drug interactions among patients receiving antidepressant therapy.
Each of the selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) is alleged to have advantages and disadvantages in relation to its competitors. These were evaluated in a meta-analysis of 21 trials involving about 3000 patients and a review of data on safety monitoring, overdoses, interactions, and costs 1. How should the results influence choice? Each of the antidepressants was compared with the others as a group and with the other individual drugs when the numbers of patients included in trials were sufficient. The results showed no significant differences in efficacy, which is not surprising given the pharmacology of the compounds. However, fluoxetine had a slower onset of action than the other drugs at weeks 2 and 3 of treatment. This is plausibsy due to its lower potency at inhibiting serotonin reuptake and slower attainment of steady state therapeutic concentration due to the long elimination half-life of fluoxetine and its active metabolite, norfluoxetine 2.
Mefloquine is a quinoline-methanol compound structurally related to quinine.1 It is active against all the human malaria parasites, particularly multidrug resistant Plasmodium falciparum. Introduced a decade ago to treat falciparum malaria in Thailand, where multidrug resistance is a particular problem, it was formulated initially in a fixed combination with pyrimethamine-sulfadoxine to delay the onset of resistance. Unfortunately, that did not work, probably because of pharmacokinetic differences between the compounds and because P falciparum was already highly resistant to sulfadoxine and pyrimethamine when the combination was introduced.By 1990, after five years of well controlled use, significant resistance to mefloquine was evident on the eastern and western borders of Thailand.2 This has increased steadily in these regions, and, although cure rates have improved since the treatment dose of mefloquine was raised from 15 mg base/kg to 25 mg/kg,3high grade resistance (that is, failure to clear parasitaemia) now occurs in about 15% of patients, and low grade resistance (recrudescence of the infection) in almost 50%. Fortunately, the situation is considerably better everywhere else in the tropics, although some strains of P falciparum from west and possibly east Africa are intrinsically resistant to mefloquine.For treating uncomplicated …
Drug-drug interactions can be adverse or beneficial and can be classified as pharmacokinetic or pharmacodynamic. Several adverse pharmacokinetic drug interactions have been described for mexiletine. Because it is a weak base, mexiletine undergoes several pH-dependent drug interactions in the gastrointestinal tract and kidney. Since mexiletine is metabolized by hepatic mixed-function oxidases, its metabolic rate can be altered by drugs that induce or inhibit this drug metabolizing system. Phenytoin and rifampin have been shown to increase mexiletine clearance and decrease its plasma concentration. Striking examples of beneficial pharmacodynamic interactions occur with mexiletine. Combining mexiletine with either beta-adrenergic blocking drugs or with quinidine markedly increases antiarrhythmic efficacy and substantially decreases the incidence of adverse effects. These beneficial interactions will have a major impact on the clinical use of mexiletine.
The cardiovascular and renal effects of dopamine are mediated through peripheral catecholamine receptors. Knowledge of the receptor type responsible for each of the actions of dopamine leads to its rational use clinically and to understanding the hemodynamic actions of the newer dopamine receptor agonists recently introduced into clinical trials. Several of the newer agonists have profiles of receptor activities that differ from dopamine, and early clinical studies indicate that they will have different therapeutic indications and applications.
Hyporeninemic hypoaldosteronism was diagnosed in a young woman with glomerulonephritis who was receiving indomethacin therapy. Despite only mildly abnormal renal function, serum K+ was elevated to 6.2 meq/L, and plasma renin activity (0.12 ng/mL h) and aldosterone (4.4 ng/dL) failed to respond to the combined stimuli of furosemide and posture. Urinary prostaglandin E2 (PGE2) was suppressed (70 ng/24 h). When indomethacin was withdrawn, significant kaliuresis occurred, accompanied by normalization of serum K+ and PGE2 and a supranormal rebound in renin and aldosterone levels. Challenge with indomethacin resulted in antikaliuresis and resuppression of PGE2, renin, and aldosterone. This case study documents for the first time that indomethacin can cause the syndrome of hyporeninemic hypoaldosteronism, probably by inhibiting prostaglandin biosynthesis.
Twelve patients with congestive heart failure receiving maintenance therapy with digoxin and potent diuretics were followed closely during development of hypokalemia and potassium loss. Cardiac arrhythmias compatible with digoxtin toxicity developed in 6 patients in the presence of stable, normal serum digoxin concentrations. The mechanisms involved in the development of the rhythm disturbances are discussed with regard to hypokalaemia, intracellular potassium loss, intra-/extracellular potassium gradients and digoxin, and the significance of maintaining a normal potassium balance in this setting is stressed.
GABAA receptors are ligand-gated Cl- ion channels and the site of action of a variety of pharmacologically and clinically important drugs. In this review evidence is summarized indicating that these drugs, by interacting with several distinct binding sites at these receptors, allosterically modulate GABA-induced Cl- ion flux. Other results indicate that the affinity, as well as the modulatory efficacy of drugs, changes with receptor composition. A though investigation of the pharmacological properties of the individual binding sites on different GABAA receptor subtypes could open new avenues for selective modulation of GABAA receptors in different brain regions.
The availability of radiolabelled ligands selective for various putative neurotransmitter receptor sites and the development of quantitative autoradiography has led to a greater understanding of the neuronal pathway and receptor subtypes involved in the vomiting reflex induced by various mechanisms both within the central nervous system and the periphery. Receptors for acetylcholine, dopamine, histamine and serotonin have been detected in a number of brain regions associated with the vomiting reflex, and provide a rational basis for the antiemetic action of drugs that inhibit receptor subtypes for these neurotransmitters. The basis of the antiemetic action of other drugs such as dexamethasone and the cannabinoids is still obscure.
Some drugs act on more than 1 receptor subtype. Metoclopramide may inhibit both dopamine D2- and 5-HT3 receptors in producing its antiemetic effect. Both metoclopramide and domperidone appear to have additional peripheral actions that contribute to their effectiveness. The cannabinoids are effective in cytotoxic-induced vomiting, perhaps acting via endorphin receptors or by inhibiting prostaglandin synthesis. The effectiveness of 5-HT3 receptor antagonists may depend on the block of both central and peripheral neuronal 5-HT3 receptors.
Vomiting constitutes a major disadvantage to the use of many drugs; vomiting induced by aminoglycoside antibiotics appears to be due to ototoxicity and is relieved by histamine H1-receptor antagonists. The protracted vomiting associated with the use of some cytotoxics in cancer chemotherapy may involve psychic components, the chemoreceptor trigger zone and peripheral sensory neurons. Both 5-HT3 and dopamine D2-receptor antagonists exert some control, the former being more effective with cytotoxics of high emetogenic potential, such as cisplatin. Serotonin 5-HT3 receptor antagonists or high doses of metoclopramide in combination with anxiolytics and steroids as well as greater attention to pharmacokinetic profiles of the drugs involved would appear to offer improved control.
The use of dopamine receptor antagonists in controlling emesis induced by dopamine agonists used in Parkinson’s disease poses theoretical problems which can be overcome by using drugs with selectivity for the chemoreceptor trigger zone, such as domperidone or metoclopramide. However, higher doses of these drugs may produce some impairment of therapeutic responses to the agonists.
Muscarinic and nicotinic agonists currently under investigation in Alzheimer’s disease pose another therapeutic dilemma as emesis is due to a central action of these compounds. Several sites may be involved including the chemoreceptor trigger zone and frontal lobes. Opiates may act through dopamine receptors or µ-receptors on dopaminergic nerves, but serotonergic mechanisms may also be involved in the action of some opiates.
Part II of this article discusses treatment of migraine, morning sickness, motion sickness, postoperative vomiting, radiation-induced emesis and nausea from labyrinthine disorders.
Moclobemide is a reversible and selective inhibitor of the enzyme monoamine oxidase (MAO) subtype A with a broad spectrum of amidepressant activity. Controlled clinical studies suggest that the short term clinical efficacy of moclobemide is significantly superior to that of placebo, and comparable to that of the tricyclic antidepressants clomipramine, amitriptyline, imipramine and desipramine, the irreversible MAO inhibitor tranylcypromine and the second-generation antidepressants maprotiline, mianserin and fluvoxamine in the treatment of major depressive illness. Moclobemide appears to be equally effective in endogenous and nonendogenous depression, producing marked amelioration of clinical features of psychomotor retardation and depressed mood. Moclobemide is well tolerated, being largely devoid of the anticholinergic adverse effects, symptomatic postural hypotension and weight gain variously associated with the tricyclic antidepressants and irreversible MAO inhibitors, and appears considerably safer on overdosage than the tricyclic and second generation antidepressants. Moreover, moclobemide offers the advantage over the older, irreversible MAO inhibitors of causing only minimal polentiation of the pressor response to dietary tyramine (the so-called 'cheese effect'). Consequently, the risk of potentially fatal hypertensive crisis, a major deterrent to the wider acceptance of these earlier compounds, is substantially reduced with moclobemide, and the need for dietary precautions is minimised. With its efficacy against endogenous and nonendogenous depression, relatively rapid onset of antidepressant activity, and absence of carry-over effects on treatment withdrawal, moclobemide is likely to make an important contribution to the treatment of major depressive illness. Its favourable tolerability profile, safety on overdosage and beneficial effect on age-related cognitive impairment may be of particular value in the elderly and those with concurrent physical illness.
In animals, the occurrence of a behavioural syndrome consisting of hyperactivity, stereotyped movements and increased body temperature can be induced by monoamine oxidase inhibitors (MAOIs), the serotonin (5-hydroxytryptamine; 5-HT) precursor, tryptophan, and serotonin reuptake inhibitors, alone or in combination. Most of these manifestations can be specifically blocked by pretreatment with an inhibitor of serotonin synthesis.
The associated symptoms of myoclonus, diarrhoea, confusion, hypomania, agitation, hyperreflexia, shivering, incoordination, fever and diaphoresis can occur in patients treated with serotonergic agents. This constitutes the ‘serotonin syndrome’. Cases of the serotonin syndrome were reported after treatments with tryptophan, MAOIs, serotonin reuptake inhibitors and tricyclic antidepressants, alone or in combination. In some cases, the serotonin syndrome corresponds to a toxic reaction induced by a combination of serotonergic agents at high dosages. In other cases, a toxic and potentially fatal interaction can occur between MAOIs, tricyclic agents and selective serotonin reuptake inhibitors (SSRIs) given at therapeutic dosages.
The serotonin syndrome also provides a heuristic model of the putative mode of action of antidepressants. Serotonin-related symptoms are the physical and objective expression of an antidepressant-induced increase in serotonin neurotransmission.
Monoamine oxidase inhibitors (MAOIs) are widely accepted as effective antidepressants. Unfortunately their use has been limited by their capacity to potentiate dietary tyramine (the so called "cheese effect") and their interaction with other drugs. The latter poses a particular problem for patients undergoing anaesthesia. Traditional advice has been to stop MAOI therapy 2 weeks prior to anaesthesia. With the advent of reversible, specific inhibitors of MAO-A (RIMAs) there is less potential for dietary and drug interaction. While experience with these newer drugs is limited so far, this review suggests that combination of modern anaesthetic techniques and newer, specific reversible MAOIs should allow safe anaesthesia with maintenance of antidepressant therapy.
Interactions may occur on pharmacological or pharmacokinetic grounds. Both types of interactions are discussed in relationship with the pharmacological and pharmacokinetic data of moclobemide, a reversible MAO-inhibitor. A variety of interaction studies either designed more specifically as kinetic or as dynamic studies have been performed with moclobemide. The results of these studies are presented. In view of these results as well as in view of data stemming from clinical trials it can be concluded that apart from interactions with cimetidine and pethidine, moclobemide has been shown to be devoid of relevant interactions.
We report the cloning of a rat cDNA encoding a functional dopamine transporter. This cDNA, derived from an intron-containing gene, encodes a protein of 620 amino acids. Hydropathicity analysis of the protein sequence suggests the presence of 12 putative transmembrane domains. The protein displays considerable identity with transporters for noradrenaline and GABA (64 and 30%, respectively). Transient expression of the cDNA in COS7 cells directs the expression of dopamine uptake activity with appropriate pharmacology and in a sodium-dependent fashion. In situ hybridization reveals that the mRNA for this transporter is expressed in the substantia nigra and ventral tegmental area, regions that contain dopaminergic cell bodies.
Selective antagonism of serotonin (5-hydroxytryptamine, 5HT) and noradrenaline transport by antidepressants is a key element in the 'amine' hypothesis of affective disorders. Uptake and/or transport sites of 5HT have been reported to be reduced in platelets of patients suffering from depression and in post-mortem brain samples of depressed patients and suicide victims. To date there has been little molecular information available on the structure and regulation of 5HT transporters. Using the polymerase chain reaction with degenerate oligonucleotides derived from two highly conserved regions of the transporters for noradrenaline and gamma-aminobutyric acid (GABA), we have identified a large family of related gene products expressed in rodent brain. One of these products hybridizes to a single 3.7-kilobase RNA restricted to rat midbrain and brainstem, where it is highly enriched within the serotonergic raphe complex. Transfection with a single 2.3-kilobase brainstem complementary DNA clone is sufficient to confer expression of a Na(+)-dependent 5HT transporter upon nonneural cells, with transport selectively and potently antagonized by 5HT uptake-specific antidepressants, including paroxetine, citalopram and fluoxetine.
The action of dopamine and other monoamine neurotransmitters at synapses is terminated predominantly by high-affinity reuptake
into presynaptic terminals by specific sodium-dependent neurotransmitter transport proteins. A complementary DNA encoding
a rat dopamine transporter has been isolated that exhibits high sequence similarity with the previously cloned norepinephrine
and gamma-aminobutyric acid transporters. Transient expression of the complementary DNA in HeLa cells confirms the cocaine
sensitivity of this transporter.
A rat dopamine (DA) transporter complementary DNA has been isolated with combined complementary DNA homology and expression
approaches. The DA transporter is a 619-amino acid protein with 12 hydrophobic putative membrane-spanning domains and homology
to the norepinephrine and gamma-aminobutyric acid transporters. The expressed complementary DNA confers transport of [3H]DA
in Xenopus oocytes and in COS cells. Binding of the cocaine analog [3H]CFT ([3H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane)
to transfected COS cell membranes yields a pharmacological profile similar to that in striatal membranes.
To determine whether beta-adrenergic blockade augments cocaine-induced coronary artery vasoconstriction.
Randomized, double-blind, placebo-controlled trial.
A cardiac catheterization laboratory in an urban teaching hospital.
Thirty clinically stable patient volunteers referred for catheterization for evaluation of chest pain.
Heart rate, arterial pressure, coronary sinus blood flow (by thermodilution), and epicardial left coronary arterial dimensions were measured before and 15 minutes after intranasal saline or cocaine administration (2 mg/kg body weight) and again after intracoronary propranolol administration (2 mg in 5 minutes).
No variables changed after saline administration. After cocaine administration, arterial pressure and rate-pressure product increased; coronary sinus blood flow fell (139 +/- 28 [mean +/- SE] to 120 +/- 20 mL/min); coronary vascular resistance (mean arterial pressure divided by coronary sinus blood flow) rose (0.87 +/- 0.10 to 1.05 +/- 0.10 mm Hg/mL.min); and coronary arterial diameters decreased by between 6% and 9% (P less than 0.05 for all variables). Subsequently, intracoronary propranolol administration caused no change in arterial pressure or rate-pressure product but further decreased coronary sinus blood flow (to 100 +/- 14 mL/min) and increased coronary vascular resistance (to 1.20 +/- 0.12 mm Hg/mL.min) (P less than 0.05 for both).
Cocaine-induced coronary vasoconstriction is potentiated by beta-adrenergic blockade. Beta-adrenergic blocking agents probably should be avoided in patients with cocaine-associated myocardial ischemia or infarction.
At most synapses, chemical signalling is terminated by a rapid reaccumulation of neurotransmitter into presynaptic terminals. Uptake systems for the biogenic amines are the initial site of action for therapeutic antidepressants and drugs such as cocaine and the amphetamines. We have isolated a complementary DNA clone encoding a human noradrenaline transporter. The cDNA sequence predicts a protein of 617 amino acids, with 12-13 highly hydrophobic regions compatible with membrane-spanning domains. Expression of the cDNA clone in transfected HeLa cells indicates that noradrenaline transport activity is sodium-dependent and sensitive to selective noradrenaline transport inhibitors. Transporter RNA is localized to the brainstem and the adrenal gland. The predicted protein sequence demonstrates significant amino-acid identity with the Na+/gamma-aminobutyric acid transporter, thus identifying a new gene family for neurotransmitter transporter proteins. Analysis of its structure and function may lead to structure-based drug design for the treatment of human depression and could help determine whether transporter abnormalities underlie affective disorders.
Angiotensin-converting enzyme inhibitor-induced renal failure is now a well-recognized phenomenon that appears to occur almost exclusively in patients with a preexisting reduction in renal perfusion pressure, especially those with renovascular disease. In the latter group of patients, renal failure probably results from some combination of reduced poststenotic renal perfusion pressure and a unique disturbance in the autoregulation of glomerular filtration rate. Although traditionally regarded as functional and reversible, recent animal studies suggest that angiotensin-converting enzyme inhibitor-induced reductions of glomerular filtration rate may lead to progressive renal atrophy, an observation that raises concerns about the long-term safety of these agents in patients with renovascular disease. On the other hand, the deleterious consequences of angiotensin-converting enzyme inhibition in renovascular disease have been exploited as aids in the diagnosis of this disorder. Whether the adjunctive use of angiotensin-converting enzyme inhibitors will prove to be useful in screening large populations of hypertensive patients for renovascular hypertension remains to be determined. However, such adjunctive tests appear to be useful in judging the functional significance of angiographically documented renal artery stenosis.
Low dose quinidine-mexiletine combination therapy was compared with quinidine monotherapy in 15 patients with frequent ventricular premature complexes and nonsustained ventricular tachycardia in a dose escalation cross-over study. Oral combination therapy was initiated with quinidine gluconate (165 mg) plus mexiletine (150 mg) every 8 h. If ventricular premature complexes were not suppressed greater than or equal to 80% and nonsustained ventricular tachycardia greater than or equal to 90%, the dose was increased to a maximum of 330 mg of quinidine plus 200 mg of mexiletine. Quinidine monotherapy was initiated with 330 mg and escalated to a maximum of 660 mg every 8 h if criteria for effectiveness were not met. Combination quinidine-mexiletine therapy suppressed 80% of ventricular premature complexes in 13 of 14 patients and suppressed 100% of episodes of ventricular tachycardia in 6 of 8 patients (mean quinidine dose 200 +/- 70 mg; mean mexiletine dose 146 +/- 24 mg every 8 h). The mean effective trough quinidine and mexiletine concentration was 1.0 +/- 0.7 and 0.9 +/- 0.4 microgram/ml, respectively. Monotherapy was less effective; that is, greater than or equal to 80% suppression of ventricular premature complexes was observed in 5 of 15 patients and 100% suppression of ventricular tachycardia in 2 of 9 patients. The mean quinidine monotherapy dose was 462 +/- 155 mg every 8 h; the mean quinidine concentration was 1.8 +/- 0.8 microgram/ml. Adverse systemic effects occurred in 3 patients on quinidine-mexiletine therapy and in 11 on quinidine monotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)
To evaluate the effects of three chemically distinct nonsteroidal anti-inflammatory drugs (NSAIDs) on renal function in patients with asymptomatic, mild but stable chronic renal failure.
Prospectively randomized, triple-crossover study with at least 1-month washout between each of three treatment periods.
Inpatient and outpatient clinical research center of a university teaching hospital.
Convenience sample of 12 women with serum creatinine levels between 130 and 270 mumols/L (1.5 and 3.0 mg/dL). Mean glomerular filtration rate +/- standard error was 0.36 +/- 0.03 mL/s.m2 (37 +/- 3 mL/min.1.73 m2); mean effective renal plasma flow was 1.6 +/- 0.18 mL/s.m2 (166 +/- 19 mL/min.1.73 m2).
Patients received ibuprofen, 800 mg three times daily; piroxicam, 20 mg daily; and sulindac, 200 mg twice daily for 11 days. Treatment was discontinued if serum creatinine rose by 130 mumols/L (1.5 mg/dL) or serum potassium exceeded 6 mmol/L (6 mEq/L).
Three patients met our criteria for stopping ibuprofen by day 8; however, all patients completed piroxicam and sulindac therapy. When the three patients in whom ibuprofen was withdrawn were rechallenged with ibuprofen, 400 mg three times daily, two again developed evidence of acute renal deterioration. All three regimens suppressed renal prostaglandin production.
These findings indicate that a brief course of ibuprofen, a compound widely used on a nonprescription basis, may result in acute renal failure in patients with asymptomatic, mild chronic renal failure. Additional studies are needed to assess the risk of piroxicam and sulindac in patients with more pronounced renal impairment and in patients receiving longer courses of therapy, which, according to our data, may result in drug accumulation.
The authors describe two series of patients: 12 treated simultaneously with fluoxetine and a monoamine oxidase inhibitor and 6 patients started on treatment with an MAOI 10 days or more after stopping fluoxetine treatment. All patients had extremely refractory depression and were treated in open fashion before general knowledge was obtained of the side effects that may accompany the fluoxetine-MAOI combination. During the fluoxetine-MAOI trial, most patients continued to receive other psychotropic combinations that had been partially helpful. The use of fluoxetine and an MAOI, either together or in close succession, was accompanied by a very high incidence of adverse effects, especially the "serotonergic syndrome." This syndrome was characterized by mental status changes, such as hypomania and confusion, and physical symptoms, such as myoclonus, hypertension, tremor, and diarrhea. Because of the high incidence of side effects and the lack of definite efficacy, the concurrent use of fluoxetine and MAOIs should generally be avoided. The long half-lives of fluoxetine and norfluoxetine, as well as the prolonged metabolic effects of MAOIs, may also dispose patients to an interaction if one of the drugs is started soon after stopping the other.
The present review catalogues 1418 reported cases of drug-induced hypoglycemia. The main findings are that sulfonylureas (especially chlorpropamide and glyburide), either alone or with a second hypoglycemic or potentiating agent, still account for 63% of all cases; that alcohol, propranolol, and salicylate, either singly or with another hypoglycemic drug, are the next most frequent offenders (19% of the total); and that one older drug (quinine) and three new ones (pentamidine, ritodrine, and disopyramide) have caused an additional 7% of all episodes of severe hypoglycemia. The clinical factors that set the stage for drug-induced hypoglycemia are still restricted food intake, age, hepatic disease, and renal disease, both individually and even more so in combination. Drug-induced hypoglycemia continues to be so common that virtually every unconscious patient should be considered hypoglycemic until immediate estimation of the blood sugar level rules it in or out. If ruled in, the clinician should promptly start 10% intravenous glucose and plan to maintain it uninterruptedly for 1 or more days, with added glucagon, hydrocortisone, and diazoxide administration if necessary, until sustained hyperglycemia guarantees that all drug effects have worn off.
ORAL hypoglycemic agents are commonly prescribed drugs. In the United States they account for about 1 percent of all prescriptions.1 This review discusses the pharmacology, mechanisms of action, efficacy, safety, and recommended use of currently approved agents, as well as other agents that may become available in the near future. Background Diabetes mellitus affects nearly 15 million people in the United States. About 15 percent have insulin-dependent diabetes (IDDM), which is believed to be caused by the autoimmune destruction of pancreatic islet beta cells.2 In such patients, insulin therapy is essential for life. About 80 percent of patients have non-insulin-dependent . . .
There has been a recent renewal of interest in the use of monoamine oxidase inhibitors, but the concurrent administration of narcotic analgesics is often a cause for concern. This review clarifies the different types of MAOI/narcotic interactions and offers guidelines for the use of narcotic analgesics in the presence of MAOIs. The MAOI/pethidine interaction has two distinct forms: an excitatory and a depressive form. Pethidine must never be used in the presence of MAOIs because of the risk of a fatal excitatory interaction. Morphine does not cause this excitatory interaction, and is the drug of choice provided an allowance is made for possible potentiation of the depressive narcotic effect. It is inevitable that strong analgesia will occasionally be required as an emergency measure in patients on MAOIs, and insufficient attention is paid in psychiatric textbooks to the two different types of interactions and their therapeutic implications.
1. Epinephrine is widely distributed in brains of various species throughout phylogeny but maintains its localization to hypothalamus and brainstem/medulla in all species studied. 2. A general decrease in brain epinephrine content is observed phylogenetically beyond fishes with wide variation within species. 3. The cellular localization of epinephrine forming enzyme is dissociated from epinephrine stores in hypothalamus where epinephrine appears to be primarily a hormone. 4. Three proposed functional pools of epinephrine are described. Synthesis of a hormonal pool and a second, perhaps nonfunctional, pool co-stored in noradrenergic terminals in the forebrain occurs extraneuronally and is probably inhibited acutely in the presence of high corticosteroids due to inhibition of uptake 2. Synthesis of epinephrine in the neuronal pool found primarily in the medulla may be enhanced due to increased PNMT activity in the presence of elevated corticosteroids. 5. Phylogenetic and pharmacological data suggest that epinephrine may play an important role in tonic regulation of the level of arousal, reward and sensitivity to environmental stimuli in mammals.