dangerous and common drug interactions in patients with diabetes mellitus

ACUTE COMPLICATIONS OF DIABETES 0889-8529/00 $15.00 + .OO

DANGEROUS AND COMMON DRUG INTERACTIONS IN

PATIENTS WITH DIABETES MELLITUS

John R. White, Jr, PA-C, PharmD, and R. Keith Campbell, RPh, MBA, CDE

The choice of medications for the patient with diabetes presents special problems not encountered in the nondiabetic patient. The number of medications used in the management of hyperglycemia has dramatically increased in the past few years. The risk for possible drug interactions that may cause hyperglycemia, h poglycemia, or other

tions in a patient’s regimen increases. In addition to the risk for adverse interactions caused by prescription medications, the potential exists for interactions with over-the-counter medications. One other concern specifically encountered in the patient with diabetes is the potential for drug effects or interactions that may adversely affect diabetic complications, accelerating the progression of nephropathy, retinopathy, gastro- paresis, and sexual dysfunction, among others. In the patient with diabetes, the practitioner must consider the possibility of drug interactions that could alter glycemic control, interactions that could potenti- ate complications, and the usual types of interactions encountered in nondiabetic patients (e.g., cytochrome P450 interactions). This article provides a brief discussion concerning the importance of and pharma-

deleterious effects increases exponentially as t z e number of medica-

From the Drug Studies Unit, College of Pharmacy, Washington State University, Spokane P W ) ; and Department of Pharmacy, College of Pharmacy, Washington State Univer- sity, Pullman (RKC), Washington

ENDOCRINOLOGY A N D METABOLISM CLINICS OF NORTH AMERICA

VOLUME 29 NUMBER 4 * DECEMBER 2000 789

790 WHITELCAMPBELL

cologic basis of drug interactions and reviews some of the more common and potentially dangerous interactions encountered in the management of patients with diabetes.

BACKGROUND

Drug-induced morbidity and mortality are responsible for an esti- mated cost of more than $136 billion per year in the United States.*" 29

This cost is greater than the total expenditures for either diabetes care or cardiovascular disease. The lion's share of this cost is expended on adverse drug events and accounts for 140,000 deaths annually and an average of 360 deaths per day. The National Adverse Drug Event Study was undertaken in an attempt to evaluate the frequency of adverse drug events, delineate the causes, and initiate the development of preventative strategies?, 35 In that study, almost one third of the 6.5 events per hospi- talization were determined to be preventable.

Adverse drug events can be subdivided into two categories: adverse drug reactions and drug interactions. Adverse drug reactions are defined as a deleterious nontherapeutic effect of a drug that has been appropriately prescribed.3O Adverse drug reactions are difficult to avoid because they are difficult to predict and can occur at normal pharmacologic doses; however, their occurrence can be anticipated. Promethazine (Phe- nergankinduced torticollis in a patient treated for nausea is an example of an adverse drug reaction. Drug interactions cause an undesirable modification of the effects of one or more concurrently administered medications. Drug interactions may result in treatment failure, an enhanced pharmacologic effect, or toxic effects, and can be fatal. Because drug interactions occur with specific combinations of drugs, most of which are usually known, drug interactions are somewhat more predict- able and preventable than adverse drug reactions. Drug interactions account for one third of all adverse drug reactions but are responsible for approximately 50% of the cost of adverse drug events?

Many health care providers rely heavily on the safety net of pharmacists to identify and warn the prescriber about potentially problematic combinations. Although pharmacists can and often do identrfy potentially deleterious combinations, they cannot be solely relied upon. Often, patients will procure medications from various pharmacies, circumventing the safety net provided when a patient procures all medications from one pharmacy. Pharmacists sometimes do not recognize all potentially problematic combinations. In 1996 an investigative evaluation reported that 30% to 50% of pharmacies included in the study dis ensed potentially life-threatening combinations without warnings to eiger the patient or the prescriber.?5 The prescriber and the dispenser need to work together and remain independently vigdant in their constant survey for drug interactions.

DANGEROUS AND COMMON DRUG INTERACTIONS 791

PHARMACOKINETIC AND PHARMACYDYNAMIC INTERACTIONS

Pharmacokinetic or pharmacodynamic interactions can occur in patients managed with more than one medication. Pharmacokinetics is the mathematical study of drug disposition in the body. Pharmacokinetic interactions occur when an interacting drug alters the absorption, protein binding, hepatic elimination, or renal excretion of another drug.% For example, pharmacokinetic interactions may occur with oral sulfonylureas by three mechanisms:

1. Protein-binding changes-Sulfonylureas that are highly protein bound are subject to displacement from binding sites by other medications such as warfarin, salicylates, and phenylbuta~one.’~ Second-generation agents, such as glimepiride, bind nonionically, are effective at much lower serum concentrations, and are less likely to be affected by this type of interaction than are first- generation agents, which bind ionically and are titrated to much higher concentration^.^^

2. Altered renal excretion-Interacting medications may alter the renal excretion of a sulfonylurea or an active metabolite.

3. Altered hepatic function-This type of interaction affects cytochrome P450 function. Hepatic inducers or inhibitors, such as rifampin and cimetidine, may alter sulfonylurea clearance and may potentially cause hyperglycemia or hypoglycemia, respec- tively.=, 47 A myriad of interactions involving the cytochrome P450 enzyme system have been delineated, and many of these interactions are clinically ~ignificant.~” Cytochrome P450 refers to the group of heme-containing isoenzymes in smooth endoplasmic reticulum found primarily in the liver and in the intestinal tract. The number “450 alludes to the spectral absorbance in nanome- ters exhibited by these enzymes in the reduced state when bound to carbon monoxide, Cytochrome P450 changes may cause interactions with sulfonylureas, thiazolidinediones, and cisapride, medications commonly used to treat diabetes.

The pharmacokinetics of exogenously administered insulin could potentially be altered by drugs that affect the subcutaneous absorption, hepatic or renal metabolism, or renal excretion. The pharmacokinetics of insulin products are difficult to evaluate owing to many confounding factors, such as the injection site, insulin source, and ambient tempera- ture, which affect exogenous insulin. Further confounding occurs owing to factors that affect endogenous insulin secretion (of significance only in type 2 patients). For example, cigarette smoking has been shown to have a negative effect on insulin absorption and may induce the hepatic metabolism of insulin as well. This interaction, however, has not been well studied.”

Pharmacodynamic interactions occur with drugs that intrinsically affect glucose metabolism through alterations in insulin secretion or

792 WHITE&CAMPBELL

changes in hepatic or peripheral glucose disposition. Pharmacodynamic interactions occur when two medications independently have an effect on glucose metabolism but do not alter the disposition of each other. Examples of medications that affect glucose metabolism by pharmacodynamic means include corticosteroids and sympathomimetics.54 These medications do not alter the concentration of each other but increase glucose through different mechanisms.

INTERACTIONS CAUSING HYPERGLYCEMIA

Corticosteroids

Corticosteroids administered by any route carry the potential for causing elevations in blood glucose levels in patients with diabetes.54 The intensity of hyperglycemia will depend on several factors, such as the dose, route, patient-specific characteristics, and duration of therapy. Glucocorticoids administered to a patient with diabetes without appropriate concomitant blood glucose monitoring and pharmacotherapeutic adjustments can precipitate diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic coma and may even be fatal. In one case, an elderly female patient was given oral prednisone for treatment of a mild allergic reaction to beef insulin. She was being managed with human insulin but was inadvertently given beef insulin. The drug reaction was mild and was limited to a rash. The practitioner prescribed prednisone, 60 mg for several days, with a taper but without blood glucose monitoring. The patient experienced severe hyperglycemia, was hospitalized for hyperosmolar hyperglycemic nonketotic coma, and died (Henry B. Hine, RPh, MBA, JD, personal communication, 1991). In a study of more than 11,000 patients, corticosteroid use increased the relative risk for the development of hyperglycemia (2.21) re uiring treatment with a hypo-

to months to resolve even after discontinuance of the medication. The mechanisms of action are an increase in gluconeogenesis, a decrease in peripheral glucose use, and effects on receptor and postreceptor activity of in~ulin.4~ Alternate-day dosing of corticosteroids is often used as a means of circumventing many of the side effects of these drugs and may result in less blood glucose elevation; however, this practice has not been studied adequately relative to the effects on glycemic control." Patients with diabetes who are treated with corticosteroids should be closely evaluated with blood glucose monitoring.

glycemic agent.= Corticosteroid-induced a yperglycemia may take weeks

Sympathomimetics

Sympathomimetics, such as ephedrine, pseudoephedrine, phenylephrine, and phenylpropanolamine, can cause mild increases in blood glucose and blood pressure. Few studies have evaluated these effects in


patients with diabetes. Hyperglycemia and acetonuria have been reported with oral phenylephrine in a small number of children with diabetes.31 Epinephrine, albuterol, terbutaline, and ritodrine have been reported to cause hyperglycemia and ketoacid~sis.~~, 44 The hyperglycemia secondary to adrenergic agonists presumably occurs because of stimulation of glycogenolysis and gluconeogenesis. This reaction is not universal and depends on patient characteristics, the sympathomimetic agent, the dose, duration, and other confounding factors such as underlying illness. A recent study evaluated the effects of cough syrups containing the decongestant phenylephrine in 20 patients with type 2

There was no difference in fasting or postprandial blood glucose levels in patients treated with cough syrup versus baseline. Nevertheless, diabetic patients who require these agents should have therapy initiated with a low-dose regimen and be asked to monitor blood glucose. In addition to a host of prescription medications, many over-the-counter preparations contain adrenergic agonists.

Diuretics

The worsening of glucose intolerance by diuretic therapy has been recognized since the introduction of these agents more than 25 years ago.l0 The change in glucose tolerance, although extremely variable and probably dose related, occurs within 2 to 4 weeks after the initiation of diuretic therapy in patients with diabetesIM within weeks to months in patients predisposed to diabetes, and within months to years in patients without diabetes.31 Generally, the effect on blood glucose is most pronounced with thiazide diuretics, less pronounced with loop diuretics, and not associated with potassium-sparing diuretics (except when combination thiazide / potassium-sparing formulations are The reported incidence of worsening glucose tolerance ranges from 10% to 30% depending on several factors, including the duration of the given study, the dose of diuretic, and population demographics.54 Although the magnitude of diuretic-induced hyperglycemia is usually small in the patient without diabetes, severe hyperglycemia including hyperglycemic hyperosmolar nonketotic coma has been associated with diuretic use in patients with diabetes.15, 49 The deleterious glycemic effects of diuretics on glucose tolerance seem to be dose related. The likelihood of hyperglycemia increases at doses of greater than 25 mg per day of hydrochlorothi- azide (or its equivalent).

The clinical significance of this phenomenon continues to be a subject of much debate. In addition to negative effects on glucose disposition, diuretics have also been associated with increases in cholesterol." One study reported a 3.8-fold increase in cardiac mortality in patients with diabetes treated with d i~ re t i c s .~~ It was suggested that there was an urgent need to reconsider the use of diuretics in this population. This conclusion has been challenged by others who suggest that the results of the previous study are erroneous because of confounding by

794 W H I T E & W B E L L

Patients in the diuretic arm of the trial may have been treated with these agents for heart disease and not primary hypertension, thus confounding the results. In addition, the investigators noted that several other studies of diuretics in patients with diabetes have demonstrated a clear beneficial effect on morbidity and mortality. Regarding the use of antihypertensive medications in patients with diabetes, the sixth report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-VI) suggested that the preferred agents are angiotensin-converting enzyme (ACE) inhibitors, calcium channel antagonists, a antagonists, and low-dose diuretics."

The mechanism of action of the effect of diuretics on glucose disposition is not completely understood; however, it may be mediated through diuretic-induced hypokalemia.26 Conversely, other studies have failed to demonstrate a correlation between hypokalemia and hyperglycemia.z37 In a review of this subject, several trials demonstrated that potassium repletion reversed thiazide-induced hyperglycemia.'O

Beta-Adrenergic Antagonists

In addition to altering the signs and symptoms of and prolonging hypoglycemia, p-adrenergic antagonists frequently impair or worsen glucose tolerance in patients with and without diabetes.'" 44 Although this effect is usually mild, severe hyperglycemia has been reported." Glucose tolerance may be affected in a given patient by any of the p- adrenergic antagonists; however, noncardioselective agents (p-1 and p-2 adrenergic antagonists) have a greater effect on glucose intolerance than do cardioseledive agents (p-1 adrenergic antagonists).'O, 27 p-adrenergic antagonists with intrinsic sympathomimetic activity may have an even lesser This side effect is dose and duration related and is additive and possibly even synergistic with diuretic-induced hyperglycemia.'O, The mechanism of action may be related to the inhibitory effect of p blockade on pancreatic insulin secretion, but other mechanisms such as impairment of insulin sensitivity have also been suggested." Although reversible, the glucose intolerance induced by p-adrenergic antagonism may re uire months for resolution after discontinuance of the medica- tion3l l%e recent publication of the hypertension arm of the UK Prospec- tive Diabetes Study5'. 52 (UKPDS) has led many to suggest that P-adrenergic antagonists may be beneficial in patients with diabetes. This study reported that the ACE inhibitor captopril and the P-adrenergic antagonist atenolol were equally effective in reducing blood pressure and diabetic complications. Despite these encouraging results, f.3-adrenergic anta onists as a group may not always be reasonable first-line choices for 8 e management of primary hypertension in patients with diabetes. The cardioselective P-adrenergic antagonist atenolol may not be an un- reasonable choice.


Nicotinic Acid (Niacin)

Nicotinic acid, a water-soluble B vitamin, is recommended by the National Cholesterol Educational Program as a first-line treatment for hyperlipidemia.28 When given in therapeutic doses, niacin lowers low- density lipoprotein (LDL) by 10% to 25%, decreases triglycerides by 20% to 50%, and increases high-density lipoprotein (HDL) by 15% to 35%.12 Because patients with type 2 diabetes mellitus frequently present with hypertriglyceridemia and lower than average HDL cholesterol levels, nicotinic acid would seem to be an ideal choice for the correction of diabetic dyslipidemia; however, niacin is of limited use in these patients because of its adverse effects on glucose metabolism.'0, % Clinically significant metabolic side effects in patients with diabetes include hyperglycemia,'O, 54 hyperuricemia,18 and insulin resi~tance.'~ In addition to its adverse effects on glucose metabolism, niacin can cause flushing, pruri- tus, dry skin, headaches, nausea, and epigastric pain, each of which can drastically reduce patient adherence.2s Because of these problems, the use of niacin as first-line therapy in patients with diabetes is usually not recommended. The American Diabetes Association suggests that niacin should be reserved for patients with refractory dyslipidemias and used only after careful consideration with extensive follow-up and metabolic

Estrogen-Containing Compounds

In the 1960s, several studies reported alteration of carbohydrate metabolism with subsequent hyperglycemia in patients treated with estrogen-progestogen combination oral contraceptive^.^^ Conversely, other studies failed to demonstrate a deleterious glycemic effe~t.5~ If combination oral contraceptives do cause significant hyperglycemia, the likelihood of this effect would seem to be greatest with the use of products that contain greater than 70 p,g of estrogen in combination with estrane pr~gestogen~~; however, hyperglycemia has been described in patients taking a low-dose preparation (30 pg of ethinyl estradiol with 150 p,g of lev~norgestrel)?~ Oral contraceptives are not recommended for women with a history of gestational diabetes who are not overtly diabetic.31 Low-dose or triphasic birth control pills may be appropriate for patients with active diabetes who are monitored.%

Two trials have reported a reduced risk of type 2 diabetes, a risk factor for coronary heart disease, in females treated with estrogen replacement therapy.24, 39 A more recent trial of over 800 females who were observed for 10 to 15 years and that adjusted for major covariates reported a nonsignificant linear trend toward reduction in the development of type 2 diabetes.16

796 wHITE&CAMPBELL

HYPOGLYCEMIA

Ethanol

Ethanol overdose is the leading cause of hypoglycemic coma and death in all age groups in the United States.” Patients with diabetes who are treated with hypoglycemic medications, such as insulin, sulfonylureas, or repaglinide, are at risk for hypoglycemia with the ingestion of even moderate amounts of alcohol, particularly in the absence of food. In a report describing severe hypoglycemia in five insulin-treated patients ingesting a large quantity of alcohol, three of the patients sustained irreversible neurologic damage and two of the patients died? The hypoglycemia elicited by alcohol probably occurs as a result of alcohol’s ability to suppress gluconeogenesis or by a resultant increase in endogenous insulin secretion.4o Patients who are in a fasting state (particularly children) are especially prone to alcohol-induced hypoglycemic episodes.” Confounding the identification of this problem, patients may not be able to discern between mild intoxication and the signs and symptoms of hypoglycemia. Moderate intake of ethanol along with food is likely to be tolerated by most patients. One trial evaluating the glycemic effects of two glasses of red wine administered with a meal in patients with type 1 and type 2 diabetes reported no adverse glycemic events.2I It was concluded that it was unnecessary to proscribe the use of moderate amounts of red wine with meals in patients with diabetes.

The following guidelines may help to circumvent the development of ethanol-induced hypoglycemia in patients with diabetes.”

1. Never consume alcohol without concomitant food and never in a fasting state.

2. If alcohol is to be consumed, it should be taken in moderation (one to two glasses of wine, one to two beers, one to two mixed drinks at one sitting, no more than once or twice per week).

3. Drink slowly (the above mentioned quantities over 1.5 to 2 hours).

4. Avoid drinks containing high amounts of sugar. 5. Always have a blood glucose monitor available. Several other problems may occur in patients with diabetes who

choose to consume alcohol. Ethanol may cause induction of the metabolism of tolbutamide with a resultant reduction in the effectiveness of the medication.” Approximately 30% of patients who take chlorpropamide and consume alcohol experience a disulfiram (Antabuse)-like rea~ti0n.l~ Heavy consumption of alcohol is a risk factor for metabolic acidosis. The use of metformin in a patient who binge drinks may place the patient at a high risk for acidosis; hence, metformin should be used with caution in patients who consume excessive amounts of ethanol.=

Beta-Adrenergic Antagonists

Beta-adrenergic antagonists may increase the incidence of hypoglycemic episodes and cause severe hypoglycemia in some individuals.” A


single dose of labetolol administered 20 minutes before a cesarian deliv- ery for pregnancy-induced hypertension was associated with bradycar- dia, hypotension, and hypoglycemia in the preterm twins.32 The use of ophthalmic timolol for the management of glaucoma was reported to cause hypoglycemia in a patient with type 1 diabetes? Hypoglycemia may be severe particularly in patients with type 1 diabetes without normal counterregulatory responses.14, 33 The mechanism of action of P-adrenergic-induced hypoglycemia is through inhibition of hepatic glucose production.10 Hepatic glucose production is promoted by sympa- thetic nervous system stimulation or epinephrine infusion and conversely is attenuated by the administration of p-adrenergic blockade.

Although hypoglycemia is a possible sequela of P-adrenergic antagonists, it is not common. More predictably P-adrenergic antagonists, particularly noncardioselective agents, intensify hypoglycemia once present and delay recovery.+' Beta-adrenergic antagonists blunt the counterregulatory effects of epinephrine with a resultant reduction in glycogenolysis. This effect may not only cause hypoglycemia but may prolong the duration of the episode. Another potential problem of P- adrenergic antagonists is their ability to reduce or even obviate the development of hypoglycemic signs and symptoms.54 Adrenergically mediated tachycardia and palpitations are suppressed in many patients. Other important signs and symptoms, such as hunger, tremor, irritability, and confusion, may also be suppressed. Perspiration is usually enhanced and may serve as the hallmark of hypoglycemia in these patients. Cardi- oselective agents tend to cause less alteration of hypoglycemic symptoms than do noncardioselective agents'" %; however, all diabetic patients who are treated with P-adrenergic antagonists should be appropriately cautioned. Another problem that may occur in patients with diabetes treated with P-adrenergic antagonists is hypertensive crisis. Profound hypertensive states have also been reported in hypoglycemic patients treated with P-adrenergic antagonists. The counterregulatory release of epinephrine in patients receiving p-blockers causes unopposed a stimu-

The UKPDS trial reported similar risk reduction in patients treated with captopril or aten~lol.~', 52 Furthermore, the trial reported no particular problems with either agent. The JNC-VI concluded, "Although P- blockers may have adverse effects on peripheral blood flow, prolong hypoglycemia, and mask hypoglycemic symptoms, patients with diabetes who are treated with P-blockers experience a similar or even greater reduction in cardiovascular events compared with persons without diabetes."

lation.4*,50

Pentamidine

Hypoglycemia occurs in approximately 6% to 40% of patients treated with pentamidine and is considered to be the most common metabolic abnormality associated with this drug? The reaction is usually observed 5 to 14 days after therapy is initiated and may require intrave-

798 WHITE&CAMPBELL

nous glucose or oral diazoxide. This adverse reaction is caused by a cytolytic response in the pancreas accompanied by a release of insulin with the subsequent development of hyp~glycemia.~ As pancreatic de- struction progresses, patients may eventually become insulin deficient and experience hyperglycemia. Diabetes mellitus may ensue within days following the initial hypoglycemia but more commonly develops weeks to months later. In the patient with preexisting diabetes who requires pentamidine therapy, the practitioner should anticipate needed changes in antjhyperglycemic or hypoglycemic therapy.

Salicylates

Salicylates are so effective in lowering blood glucose that they have actually been used as hypoglycemic agents; however, this use was short lived because of the associated toxicity of the high doses needed to lower blood glucose consistently? High doses of aspirin (4-6 g/d) have been shown to decrease blood glucose concentrations in patients with and without diabetes. Although the mechanism of this effect remains uncertain, salicylates may increase insulin secretion in type 2 patients, increase insulin sensitivity, displace sulfonylureas from protein-binding sites, and inhibit renal excretion." Although this effect is not normally encountered when usual analgesic doses of aspirin are used, the potential should be anticipated. Hypoglycemia has also been reported with other nonsteroidal anti-inflammatory drugs, including piroxicam and indomethacin." Acetaminophen is probably a better choice for simple analgesia. If arthritic doses of aspirin are to be used, the patient should be started on low doses titrated in an upward manner slowly and asked to monitor blood glucose frequently. In most cases, alternative pharmacologic therapy, such as other nonsteroidal anti-inflammatory agents, is preferred.

CYTOCHROME P450 ISOENZYME SYSTEM

The cytochrome P450 enzyme system encompasses a group of isoenzymes that are essential in the metabolism of endogenous steroids, other hormones, prostaglandins, lipids, and fatty acids.30 Cytochrome P450 is also important for the detoxification of exogenous compounds, including drugs.

Much has been learned about this enzyme system in the last 20 years. In fact, the current nomenclature used in the labeling of specific isoenzymes was not developed until 1987.43 There are at least 74 families of isoenzymes denoted by an Arabic numeral (e.g., CYP2).30 Subfamilies are denoted by an uppercase letter (e.g., CYP2A). Twenty discrete subfamilies have been identified. Individual isoenzymes are represented b an Arabic numeral at the end of the sequence (e.g., CYP2A4). Althoug memorizing specific isoenzymes and the drugs that may affect or be

[


affected by those isoenzymes is not practical for the clinician, it is useful to have a working knowledge of concepts underlying the system.

Drugs that cause enzyme inhibition resulting in the accumulation of a second drug are most often responsible for life-threatening interac- t i o n ~ . ~ ~ Although some drugs may inhibit multiple isoenzymes, most drugs cause inhibition of a specific isoenzyme. Interestingly, an inhibitor may or may not be metabolized by the enzyme that it inhibits. For example, erythromycin is metabolized by and also inhibits CYP3A4, whereas quinidine is metabolized by CYP3A4 but inhibits CYP2D6.30

Enzyme induction is a complex process whose time course is difficult to predict. Some medications are capable of inducing multiple isoenzymes. Although enzyme induction does not cause as many serious problems as enzyme inhibition, its consequences can be grave.

Cisapride

Cisapride may cause quinidine-like effects.30 Similar to the deleterious effects observed with the nonsedating antihistamine terfenadine (Seldane), which has been removed from the market, potentially fatal cardiac arrhythmias, including ventricular fibrillation, torsades de pointes, and QT prolongation, can occur when CYP3A4, the enzyme responsible for the metabolism of cisapride, is inhibited-with a resultant accumulation of cisapride.zO This observation has led to a recent change in the availability of cisapride. The compound is now available only through an investigational limited access program. Compounds that are known to inhibit CYP3A4 include ketoconazole, itraconazole, intravenous miconazole, fluconazole, erythromycin, clarithromycin, nef- azodone, fluvoxamine, fluoxetine, and sertraline.” Coadministration of cisapride with these medications is contraindicated.

There are two methods for dealing with this potential interaction. First, one can simply avoid using cisapride in patients treated with any of the inhibitors of CYP3A4. Substitution of metoclopramde for cisapride is a reasonable alternative. Second, and particularly useful in patients who cannot tolerate metoclopramide, alternatives to the CYP3A4 inhibitors can sometimes be used. For example, one could substitute azithro- mycin, which is not a CYP3A4 inhibitor, for erythromycin; however, in this particular instance, one could probably stop the cisapride and use erythromycin for its anti-infective and prokinetic properties. Terbinafine could be used in place of the previously mentioned triazole antifungals.

Cardiac abnormalities can occur when cisapride is used in high doses (120-160 mg/d) even in the absence of a CYP3A4 inhibitor.”

Thiazolidinediones

Cytochrome P450 enzymes are responsible for the metabolism of the thiazolidinediones.’, 5, 48 CYP3A4 and CYP2CS are partially responsi-

800 W H I T & CAMPBELL

ble for the metabolism of pioglitazone.' Pioglitazone did not inhibit cytochrome P450 activity in vitro when incubated with human enzymes. In vivo studies have not been done. In vitro, ketoconazole significantly inhibits the metabolism of pioglitazone, and patients receiving this combination should undergo close monitoring of glycemic control. In vivo human studies have suggested that troglitazone (recently removed from the market) may induce CYP3A4.48 This isoenzyme is responsible for the metabolism of several medications, including oral contraceptives, erythromycin, astemizole, calcium channel antagonists, cisapride, corticosteroids, cyclosporine, and HMG-CoA reductase inhibitors. Specific pharmacokinetic studies have not been carried out for many of these agents. Troglitazone has been shown to cause a 30% reduction in the serum concentrations of oral contraceptives containing ethinyl estradiol and norethindrone.48 This change could result in a loss of contraception. The possibility of altered safety and efficacy should always be considered when using the previously mentioned medications with pioglitazone or troglitazone. Rosiglitazone is predominantly metabolized by CYP2C8 but also to a lesser degree by CYP2C9.5 In vitro metabolic studies have suggested that rosiglitazone does not inhibit the major cytochrome P450 enzymes at clinically relevant concentrations.

SUMMARY

As more medications are made available to the prescriber, the likelihood of drug interactions will increase. The number of drug interactions encountered by the provider treating the patient with diabetes has increased over the past few years because the number of medications used in the management of hyperglycemia has dramatically increased during that time. These interactions are complex but can be predicted.

References

1. Actose package insert. Eli Lilly and Company, Indianapolis, IN, July 1999 2. Amery A, Berthaux P, Bulpitt C, et al: Glucose intolerance during diuretic therapy:

Results of trial by the European Working Party on Hypertension in the Elderly. Lancet L681-683, 1978

3. Angelo-Nielson K Tim0101 topically and diabetes mellitus. JAMA 2442263, 1980 4. Arky RA, Veverbrants E, Abramson EA Irreversible hypoglycemia: A complication of

5. Avandia package insert. SmithKline Beecham Pharmaceuticals, Philadelphia, PA, May

6. Baron SH Salicylates as hypoglycemic agents. Diabetes Care 564-71, 1982 7. Bates DW, Cullen DJ, Laird N, et al, for the ADE Prevention Study Group: Incidence

of adverse drug events and potential adverse drug events: Implications for prevention.

8. Bates DW, Spell N, Cullen DJ, et al, for the Adverse Drug Events Prevention Study Group: The costs of adverse drug events in hospitalized patients. JAMA 277:307-311, 1997

alcohol and insulin. JAMA 206575578, 1968

1999

JAMA 274:29-34, 1995


9. Bouchard F', Sai P, Reach G, et al: Diabetes mellitus following pentamidine-induced hypoglycemia in humans. Diabetes 31:4&45, 1982

10. Bressler P, DeFronzo RA: Drugs and diabetes. Diabetes Reviews 2:53-84, 1994 11. Chan JCN, Cockram CS, Critchley JAJH: Drug-induced disorders of glucose metabo-

lism. Drug Saf 15:135157,1996 12. Clark AB, Holt JM: Identifying and managing patients with hyperlipidemia. Am J

Manage Care 3:1211-1219, 1997 13. Classen DC, Pestotnik SL, Evans Rs, et al: Adverse drug events in hospitalized patients:

Excess length of stay, extra costs, and attributable mortality. JAMA 277301-306, 1997 14. Cryer PE, White NH, Santiago JV: The relevance of glucose counterregulatory systems

to patients with insulin-dependent diabetes mellitus. Endocr Rev 7131-139, 1986 15. Fonseca V, Phear DN: Hyperosmolar nonketotic diabetic syndrome precipitated by

treatment with diuretics. BMJ 284:36-37, 1982 16. Gabal LL, Goodman-Gruen D, Barrett-Connor E: The effect of postmenopausal estro-

gen therapy on the risk of non-insulin-dependent diabetes mellitus. Am J Public Health 8743445, 1997

17. Garg A: Management of dyslipidemia in IDDM patients. Diabetes Care 17224-234, 1994

18. Gates G: Dyslipidemias in diabetic patients: Is standard cholesterol treatment appropriate? Postgrad Med 95:69-84, 1994

19. Gerich JE: Oral hypoglycemic agents. N Engl J Med 321:1231-1245, 1989 [erratum, N Engl J Med 1990; 322711

20. GI stimulants: Cisapride. In Olin BR (ed): Drug Facts and Comparisons. St. Louis, Drug Facts and Comparisons, 1996,308b-e

21. Gin H, Morlat P, Ragnaud JM, et al: Short-term effect of red wine (consumed during meals) on insulin requirement and glucose tolerance in diabetic patients. Diabetes Care 15:54&548, 1992

22. Glucophage package insert. Bristol-Myers Squibb Company, Princeton, NJ, January 1998

23. Gurwitz JH, Bohn RL, Glynn RJ, et al: Glucocorticoids and the risk for initiation of hypoglycemic therapy. Arch Intern Med 154:97-101, 1994

24. Hammond CB, Jelovsek FR, Lee KL, et al:. Effects of long-term estrogen replacement therapy. Am J Obstet Gynecol 133:525-536, 1979

25. Headden S, Lenzy T, Lostyu P, et al: Danger at the drugstore. US News and World Report August 26, 1993

26. Helderman JH, Elahi D, Andersen DK, et al: Prevention of the glucose intolerance of thiazide diuretics by maintenance of body potassium. Diabetes 32:106-111, 1983

27. Houston M C Adverse effects of antihypertensive drug therapy on glucose intolerance. Cardiol Clin 4:117-135, 1986

28. Iltz J, White J: Clinical management of hyperlipidemia in diabetic patients. Diabetes Spectrum 2:88-93, 1998

29. Johnson JA, Bootman J L Drug-related morbidity and mortality: A cost-of-illness model. Arch Intern Med 155:1949-1956,1995

30. Johnson MD, Newkirk G, White J R Clinically significant drug interactions: What you need to know before writing prescriptions. Drug Interactions 105:193-222, 1999

31. Kimble MA: Diabetes mellitus. In Young LY, Koda-Kimble MA (eds): Applied Thera- peutics: The Clinical Use of Drugs, ed 4. Vancouver, WA, Applied Therapeutics, 1988, 663-742

32. Klarr JM, Bhatt MV, Donn SM: Neonatal adrenergic blockade following single dose maternal labetalol administration. Am J Perinatol 11:91-93, 1994

33. Lager I, Blohme G, Smith U: Effect of cardioselective and nonselective P-blockage on the hypoglycemic response in insulin-dependent diabetes. Lancet 1:458-462, 1979

34. Lahtela JT, Gachalyi 8, Eksyma S, et al: The effect of liver microsomal enzyme inducing and inhibiting drugs on insulin mediated glucose metabolism in man. Br J Clin Pharmacol21:19-26, 1986

35. Leape LL, Bates DW, Cullen DJ, et al, for the ADE Prevention Study Group: Systems analysis of adverse drug events. JAMA 27435-43, 1995

802 WMTE&CAMPBELL

36.

37.

38.

39.

40. 41.

42.

43.

44.

45.

46.

47.

48. 49.

LeMar HJ, Georgitis WJ: Effect of cold remedies on metabolic control of NIDDM. Diabetes Care 16426428, 1993 Lewis PJ, Kohner EM, Petrie A, et ak Deterioration of glucose tolerance in hypertensive patients on prolonged diuretic treatment. Lancet 1:564-566, 1976 American Diabetes Association: Management of dyslipidemia in adults with diabetes. Diabetes Care 21:179-182, 1998 Manson JE, Rimm EB, Colditz GA, et al: A prospective study of postmenopausal estrogen therapy and subsequent inadence of non-insulin-dependent diabetes mellitus. Ann Epidemiol2665-673, 1992 McDonald J: Alcohol and diabetes. Diabetes Care 3:629437, 1980 McMuny RJ: Propranolol, hypoglycemia, and hypertensive crisis [letter]. Ann Intern Med 80669-670, 1974 National High Blood Pressure Education Program: The sixth report of the Joint Na- tional Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 157241S2441, 1997 Nebert DW, Adesnik M, Coon MJ, et ak The P450 gene superfamily: Recommended nomenclature. DNA 61-11, 1987 OByrne S, Feely J: Effects of drugs on glucose tolerance in non-insulin-dependent diabetes I. Drugs 40:6-18, 1990 OByme S, Feely J: Effects of drugs on glucose tolerance in non-insulin-dependent diabetics 11. Drugs 40:203-219,1990 Parving H-H: Diabetic hypertensive patients: Is this a group in need of particular care and attention? Diabetes Care 22(suppl2):B76-879, 1999 Pfeiffer EF, Galloway J A Type II diabetes mellitus and oral hypoglycemic agents. In Galloway JA, Potvin JH, Shuman CR (eds): Diabetes Mellitus, ed 9. Indianapolis, Eli

Rezulin package insert. Parke-Davis, Moms Plains, NJ, 1999 Rowe PA, Mather HG Hyperosmolar nonketotic diabetes mellitus associated with metolazone. BMJ 291:25-26, 1985

L i l l ~ , 1988, pp 139-158

50. Shepherd AM, Lin MS, Keeton TK Hypoglycemia-induced hypertension in a diabetic patient on metoprolol. Ann Intern Med 94357458, 1981

51. UK Prospective Diabetes Study (UKPDS) Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317:703-713, 1998

52. UK Prospective Diabetes Study (UKPDS) Group: Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 317713-726, 1998

53. Warram JH, Laffel LMB, Valsania P, et al: Excess mortality associated with diuretic therapy in diabetes mellitus. Arch Intern Med 151:135&1356, 1991

54. White JR, Hartman J, Campbell RK: Drug interactions in diabetic patients: The risk of losing glycemic control. Drug Interactions 3:131-139, 1993

55. Wynn V: Effect of duration of low-dose oral contraceptive administration on carbohydrate metabolism. Am J Obstet Gynecol 142:739-746, 1982

56. Wynn V, Adams PW, Godsland I, et ak Comparison of effects of different combined oral-contraceptive formulations on carbohydrate and lipid metabolism. Lancet 1:1045- 1049, 1979

Address reprint requests to John R. White, Jr, PA-C, PharmD

Washington State University College of Pharmacy, Drug Studies Unit

44 West 6th Avenue Spokane, WA 99204

dangerous and common drug interactions in patients with diabetes mellitus

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