insulin and digoxin

Skip Nav Destination

Chemist's shop Update | October 01 2006

Drug Interactions of Medications Commonly Used in Diabetes

Diabetes Spectr 2006;xix(4):202–211

When patients are diagnosed with diabetes, a large number of medications become advisable therapy. These include medications for dyslipidemia, hypertension, antiplatelet therapy, and glycemic control. So many medications can exist overwhelming, and it is imperative that patients are thoroughly educated about their drug regimen.

Patients have many concerns when multiple medications are started, including prescribing errors, the cost of medications, and possible adverse effects. Significantly, 58% of patients worry that they will be given medications that have drug interactions that will adversely affect their wellness.¹ These worries are non unfounded given that several highly publicized drugs accept been withdrawn from the U.S. market in the past several years because of adverse effects from drug interactions. Terfenadine, mibefradil, and cisapride accept all been withdrawn from the market specifically because of drug-drug interactions. When terfenadine or cisapride were given with a strong inhibitor of their metabolism, torsades de pointes, a life-threatening drug-induced ventricular arrhythmia associated with QT prolongation, could occur.² Cisapride, for gastroparesis or gastrointestinal reflux affliction, and mibefradil, for hypertension, were prescribed for many patients with diabetes.

An adverse drug interaction is defined every bit an interaction betwixt one or more coadministered medications that results in the alteration of the effectiveness or toxicity of any of the coadministered medications. Drug interactions tin be caused by prescription and over-the-counter medications, herbal products or vitamins, foods, diseases, and genetics (family history). The true incidence of drug interactions is unknown because many are not reported, do not result in significant harm to patients, or do not require access to a hospital. When a hospitalization does occur, it is unremarkably not documented as a drug interaction, but rather as an adverse drug reaction because the drug interaction may just be one component of the reason for admission.^3,4 Although drug interactions for a select few drugs are well known, nosotros often ignore the substantial evidence that potential interactions exist in many of the medications prescribed today.

Minimizing the hazard for drug interactions should be a goal in drug therapy because interactions can result in pregnant morbidity and mortality. Health care providers should take responsibility for the condom prescribing of medications, just we ofttimes discuss potential adverse drug reactions—not drug interactions—with patients. Nosotros may overlook this responsibility because at that place are rarely quick, easily accessible, and comprehensive resources that cover drug interactions. Even when available, comprehensive resource often list all drug interactions and do not emphasize those that are most important.

In addition, many diabetes educators are confused by drug interaction terminology and rely heavily on pharmacists and prescribers to properly screen for drug interactions. Causes and terminology common to drug interactions, common interactions with medications used in people with diabetes, and tools that decorated diabetes educators can employ will exist provided in this article. Not all drug interactions will be covered, and drug-herbal^5,6 and drug-food^6,7 interaction information can exist found elsewhere, too every bit non–diabetes-related drug-drug interactions.⁷

DRUG-DRUG INTERACTIONS

Drug interactions are often categorized equally pharmacodynamic or pharmacokinetic in nature. A pharmacodynamic drug interaction is related to the drug'southward consequence on the body. An instance is the combination of booze with medications that crusade sedation. A pharmacokinetic drug interaction is related to the body's outcome on the drug. An example is an increase in the systemic concentration of a renally eliminated drug considering of renal insufficiency. A pharmacokinetic drug interaction can be caused past an alteration in absorption, distribution, metabolism, or elimination of a drug.^viii

Pharmacodynamic Interactions

Pharmacodynamic drug interactions can be either beneficial or detrimental to patients. A benign case is the condiment blood force per unit area–lowering effect when an ACE inhibitor is added to a calcium channel blocker (CCB). Likewise, synergistic blood pressure lowering may be seen if a diuretic is added to an ACE inhibitor. The pharmacodynamic drug interaction tin can also be detrimental. When alcohol and a medication that causes sedation are combined, additive unwanted sedation may occur. Combative effects may likewise exist encountered, equally with the combination of an acetyl-cholinesterase inhibitor for myasthenia gravis or Alzheimer'due south disease with amitriptyline for painful diabetic peripheral neuropathy. The acetyl-cholinesterase inhibitor increases acetylcholine levels, whereas amitriptyline has antagonistic anti-cholinergic effects.⁸

Pharmacokinetic Interactions

Absorption interactions. Drug absorption is the movement of the drug from its site of assistants into the bloodstream (Figure 1). Absorption interactions are changes in a drug's effects acquired by food, drink, or medications taken meantime. Classically, we recall of the oral administration of a medication and absorption from the gastrointestinal system, only it applies to all routes of assistants, including injection, inhalation, topical, buccal, sublingual, and others.

Drug-food interactions can affect the total amount of drug absorbed (bioavailability), but nearly frequently they only irksome assimilation. For example, the hypoglycemic upshot of glipizide may exist delayed slightly if taken with a meal versus thirty–hr before a repast, although hemoglobin A_1c (A1C) values are unaffected.^9,ten Alteration of gastrointestinal motility, equally is the case with exenatide (Tabular array one), or pH may as well affect absorption. In addition, components of food may interact. For example, vitamin K intake from green leafy vegetables interacts with warfarin. Similarly, several medications may complex or chelate with coad-ministered medications, significantly reducing their absorption.⁶ For example, levothyroxine assimilation is reduced when coadministered with ferrous sulfate or antacids and should be moved either ane hour earlier or at least 2 hours after assistants of these drugs.^vii,11 It is best not to administer other medications with antacids because they can reduce the absorption of many medications.

Table one.

Common Diabetes, Hypertension, and Lipid Drug Interactions

Distribution interactions. Distribution is the motion of the absorbed drug through the bloodstream and its transport throughout extracellular or intracellular compartments to the site of action (Figure 2). Many medications extensively bind to plasma proteins such as albumin in the blood-stream. When a drug is bound to these plasma proteins, it is not actively distributed to the site of action, and only the "free" drug is available to crusade an effect. One drug can readapt another from the binding sites on the plasma proteins if its binding is stronger. This increases the amount of "costless" drug available to cause an effect.

Figure ane.

Graphic depiction of a theoretical drug absorption interaction.

Effigy one.

Graphic depiction of a theoretical drug assimilation interaction.

Close modal

In the past, many protein-displacing interactions were documented in vitro, with in vivo consequences assumed. The majority of protein-displacing interactions have since been documented to exist test-tube phenomena and are non clinically important.¹² Nearly of the suspected distribution interactions have now been reclassified every bit metabolism interactions. Distribution interactions can be significant for drugs that have extremely rapid distribution, narrow rubber margins, and possibly nonlinear kinetics.¹² No meaning distribution interactions are pertinent for oral medications commonly used for diabetes.¹²

Metabolism interactions. Drug metabolism is the modification or degradation of drugs. Metabolism can make drugs more or less toxic, active or inactive, or more than easily eliminated from the body.^xiii The primary organ involved in metabolism is the liver, although metabolism has been documented in the kidneys, lungs, gastrointestinal system, blood, and other tissues.^half-dozen The about extensively studied family unit of isoenzymes found in the liver and gastrointestinal tract is the cytochrome P450 (CYP) system. The proper noun "cytochrome P450" comes from the experimental techniques used to place the isoenzymes and is not clinically relevant.¹⁴ CYP2D6, for example, includes "2," the genetic family; "D," the genetic subfamily; and "6," the specific gene fellow member. The nomenclature used to classify different subsets of the CYP organisation has no functional implications simply clinically allows us to classify metabolism interactions.

Drugs can inhibit (decrease) metabolism, induce (increment) metabolism, or accept no result on each CYP450 isoenzyme subset. Thus, inhibition of metabolism volition likely increase the affected drug'southward systemic concentrations, whereas consecration of metabolism often reduces systemic concentrations. Not all isoenzymes are inducible, and only CYP2C9 and CYP3A4 induction is clinically relevant to people with diabetes. A drug may also be a substrate for (metabolized past) 1 or more of these enzyme subsets, and clinically, if an inhibitor or inducer affects that isoenzyme, it could affect the efficacy of the drug.

Drugs can take a complex contour, being a substrate for or an inhibitor or inducer of multiple subsets. For example, quinidine is a potent inhibitor of CYP2D6, simply it is primarily metabolized by CYP3A4. More than l% of all drugs are metabolized at to the lowest degree in office by CYP3A4 or CYP2D6, and several important diabetes drugs are metabolized by these pathways.¹⁵ Phase 2 metabolism (glucuronidation, acylation, sulfation, and so forth) includes attachment of a water-soluble molecule to aid elimination and detoxification of a drug. Stage two metabolism need not simply ofttimes does occur after metabolism by the CYP450 system. Research in this surface area is expanding, and glucuronidation is the basis of one important drug-drug interaction involving gemfibrozil and several hydroxymethylglutaryl (HMG) CoA reductase inhibitors (statins).

Effigy 2.

Graphic depiction of a theoretical drug distribution interaction.

Figure 2.

Graphic depiction of a theoretical drug distribution interaction.

Close modal

High-risk groups for drug interactions include neonates, infants, the elderly, and those with significant organ illness (i.e., renal or hepatic affliction) warranting increased screening vigilance. Neonates, infants, and the elderly will often metabolize drugs slower than salubrious adults, and lifestyle choices such as smoking (induces metabolism) and booze use (may induce or inhibit metabolism) can change metabolism. Metabolism patterns can besides be altered past genetically adamant variations. For instance, ∼5–ten% of Caucasians, but merely 0–one% of Asians, have little CYP2D6 enzyme activity, making them "CYP2D6 poor metabolizers," the consequences of this are dependent on the drug and alternative pathways available for metabolism.^sixteen

Elimination interactions. Drug emptying is the removal of a drug from the body. The major organs involved in emptying are the kidneys and liver, although other bodily processes, including saliva, sweat, or exhaled air, may be pathways for elimination. Elimination through the liver is primarily through bile. There are not many true drug-drug interactions through bile elimination, just drug-disease interactions, as described below, tin can be of import when bile elimination is afflicted, as with severe biliary or liver affliction. Renal drug-drug interactions are dependent on the pH of the urine and the pH of the drug or on competition for the aforementioned pathway of elimination. If the pH of the urine and the drug are the same, renal reabsorption of the drug will exist increased. When two drugs compete for elimination through a unmarried route, i drug may competitively inhibit the elimination of the other.⁸ Metformin and cimetidine, both cationic (positively charged) drugs, can compete for elimination through kidneys by renal tubular secretion, resulting in higher metformin concentrations in the plasma.¹⁷

DRUG-Affliction INTERACTIONS

Many comorbid diseases can bear on metabolism in people with diabetes. Patients with diabetes accept higher rates of cardiovascular, renal, gastrointestinal, neurological, and thyroid diseases and ophthalmological complications compared with individuals without diabetes. All may increase the take a chance of having drug-disease interactions. Metformin and dumb renal part is a well-documented drug-disease interaction. Serum creatinine ≥ 1.4 mg/dl in women or ≥ 1.5 mg/dl in men warrants discontinuation of metformin because systemic concentrations can exist elevated, increasing the take a chance of lactic acidosis.^eighteen Drug-disease interactions for specific medications used in people with diabetes will be covered below.

Diabetes Drug Interactions

Sulfonylurea drugs. Several drug-drug interactions occur with sulfonylureas. Offset-generation sulfonylureas, especially chlorpropramide, may cause a facial flushing reaction when alcohol is ingested. This may be similar to that caused by disulfiram, which blocks aldehyde dehydrogenase, resulting in increased levels of acetaldehyde. Acetaldehyde tin upshot in flushing and maybe nausea or vomiting at higher levels.^seven,19 A switch to a 2nd-generation sulfonylurea would be advised (Tabular array 1).

Sulfonylureas are commonly listed every bit having protein-binding drug interactions, and the start-generation sulfonylureas (acetohexamide, chlorpropamide, tolazamide, and tolbutamide), which bond ionically to plasma proteins, are thought to take a higher risk of protein-binding drug interactions.²⁰ If they do occur, they should occur soon after the 2d medication is added to the sulfonylurea by displacing the sulfonylurea and increasing the active drug bachelor. This would result in a reduction of plasma glucose and possibly hypoglycemia, if the plasma glucose was most normal. As stated previously, most of these take now been restated as interactions resulting from the CYP450 isoenzyme organization.¹²

Sulfonylureas are a substrate of CYP2C9. Thus, inducers and inhibitors of CYP2C9 can touch on the metabolism of sulfonylureas. Mutual medications that may interact with sulfonylureas are listed in Tabular array 2. Sulfonylureas have two meaning drug-illness interactions. Most are metabolized in the liver to active or inactive metabolites. When meaning damage in liver function is present, sulfonylurea metabolism may be altered. Active or inactive metabolites of sulfonylureas are eliminated past the kidneys, and renal insufficiency may reduce emptying (Table 3).

Tabular array 2.

Common Inducers, Inhibitors, and Substrates of Select CYP450 Isozymes

Table 3.

Metabolism and Emptying of Sulfonylureas

Brusque-interim secretagogues. Nateglinide, which is metabolized by CYP2C9 (lxx%) and CYP3A4 (30%), could be affected past strong inhibitors/inducers of CYP2C9, but significant drug-drug interactions take non been reported. Repaglinide is metabolized by the CYP3A4 and CYP2C8 isozyme systems and and so extensively glucuronidated. A serious drug-drug interaction may occur with gemfibrozil, which is used for triglyceride lowering. This is probable caused by gemfibrozil's inhibition of CYP2C8 and glucuronidation. In vivo, gemfibrozil increases the full exposure of repaglinide eightfold.²¹ Several reports of severe, prolonged hypoglycemia have been documented with the combination.²² Strong inhibitors of CYP3A4, such as azole antifungal agents and erythromycin derivatives, may also enhance the hypoglycemic upshot of repaglinide. Drugs that are inducers of CYP2C8/3A4 may reduce the efficacy of repaglinide, and a higher dose of repaglinide may exist necessary²³ (Table 2).

The main drug-disease interaction of concern is impaired liver function, and the gamble of hypoglycemia in this population may be increased. No adjustment in dosing is needed in renal impairment until the patient has end-stage renal disease. When low-dose sulfonylureas cause hypoglycemia in renally impaired type ii diabetic patients, repaglinide or nateglinide may be a skillful therapeutic culling. Neither has significant drug-food interactions, but both should be taken preprandially to better lucifer pancreatic insulin release with a meal (Table 1).

Metformin. Although not because of a drug interaction, metformin should be taken with a meal to limit gastrointestinal side furnishings. Metformin may cause malabsorption of vitamin B12, which may result in B12 deficiency and subsequent anemia. The mechanism by which metformin causes malabsorption of B12 is not conspicuously defined, although oral or injected B12 (cyanocobalamin) or calcium supplementation may exist effective for correction^24,25 (Table one).

Metformin does not undergo metabolism and is eliminated renally by tubular secretion and glomerular filtration. Metformin is a cationic (positively charged) molecule and may compete with other cationic drugs for renal secretion through organic cation transporters in the kidneys.¹⁷ Procainamide, digoxin, quinidine, trimethoprim, and vancomycin are all cationic drugs that accept the potential to collaborate with metformin, but but cimetidine, which is bachelor over the counter for eye-burn, has been implicated in one case of metformin-associated lactic acidosis (MALA)^26,27 (Table 1).

Metformin has many drug-disease interactions that tin increase the risk of MALA. Metformin may increase lactic acrid production from the splanchnic tissues slightly, merely MALA occurs in the setting of comorbid diseases that increase systemic levels of lactic acrid or reduce elimination of metformin. Any disease that may increase lactic acid product or subtract lactic acid metabolism may predispose to lactic acidosis. Tissue hypoperfusion from congestive middle failure, hypoxic states, shock, or septicemia tin increase lactic acid production, and booze or astringent liver disease tin can reduce removal of lactic acid in the liver, increasing the risk of lactic acidosis.

Metformin use in renal insufficiency, defined as a serum creatinine ≥ one.iv mg/dl in women and ≥ 1.v mg/dl in men, is contraindicated because information technology is renally eliminated. Elderly patients, who often have reduced muscle mass, should accept their creatinine clearance charge per unit estimated before employ. If the creatinine clearance rate is < 70–80 ml/min, metformin should not be given. Considering of the risk of acute renal failure during intravenous dye procedures, metformin should be withheld starting the solar day of the process and resumed in 2–3 days, when normal renal office has been documented.

Clinical presentation of lactic acidosis is oft nonspecific flu-like symptoms and may include altered consciousness, heavy, deep (Kussmaul) breathing, and abdominal pain and thirst. Thus, the diagnosis is ordinarily made past laboratory confirmation.^18,28

Thiazolidinediones. Pioglitazone and rosiglitazone can both be taken without regard to meals. Rosiglitazone is a substrate for the CYP2C8 and to a lesser extent CYP2C9 pathways, and pioglitazone is a substrate for CYP2C8 (39%) and CYP3A4 (17%), too as several other CYP450 pathways.^29,30 Rosiglitazone and pioglitazone metabolism in vivo can be afflicted past inhibitors or inducers of CYP2C8, but no significant drug-drug interactions have been reported to date^30,31 (Table 2). Neither drug has meaning elimination drug-drug interactions.

However, both thiazolidinediones (TZDs) have significant drug-disease interactions. Both can cause fluid retention that may upshot in peripheral edema or, rarely, pulmonary edema and/or heart failure. Mechanistically, this may relate to increased renal reabsorption of sodium, a reduction of systemic vascular resistance, or other mechanisms.^32,33 Unlike troglitazone, no information link pioglitazone or rosiglitazone to drug-induced hepatotoxicity.^34,35 Nevertheless, it is recommended that drug therapy not be started if the alanine aminotransferase (ALT) is > 2.5 times the upper limit of normal and stopped if the ALT is > 3 times the upper limit of normal (Table 1). Prudent clinical judgment is needed for TZD drug-illness interactions, just a full word is beyond the telescopic of this review.^36,37

α-Glucosidase inhibitors. Because neither acarbose nor miglitol is extensively metabolized, neither has pregnant metabolism interactions. Several case reports have documented a reduction in absorption of digoxin and an increase in assimilation of warfarin.^38,39 Information technology is recommended that any drug with a very small dose and a narrow safety margin be administered autonomously from acarbose or miglitol. Drug-disease interactions are related to α-glucosidase inhibitor–induced gastrointestinal side furnishings (gas, diarrhea, and abdominal gas pain), which could harm patients with certain gastrointestinal diseases (e.thousand., short bowel syndrome, Crohn'south disease, or ulcerative colitis).

Hypertension- and Lipid-Reducing Medications

Antihypertensive drugs. Many different classes of antihypertensive medications may be used for blood pressure control in diabetes, just the four most common include ACE inhibitors, angiotensin-Ii type 1 receptor blockers (ARBs), thiazide diuretics, and CCBs. CCBs can be farther subdivided into dihydropyridine CCBs, so called for their chemical construction, and the nondihydropyridine CCBs, diltiazem and verapamil, which are pharmacodynamically linked considering of their effect on the heart. Drug interactions may be present for some just not all medications within an antihypertensive class.

ACE inhibitors and ARBs

Drug-nutrient interactions are important for two ACE inhibitors, moexipril and captopril, which should exist administered 1 hour before or at least two hours after a meal.⁷ A 40–50% decrease in systemic levels may be seen when valsartan, an ARB, is taken with food.^twoscore Because both classes may increase serum potassium levels, caution should exist taken when potassium supplements or a high-potassium diet are consumed with either class (Tabular array 1).

ACE inhibitors and ARBs take several interactions of importance. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may blunt the antihypertensive effect of an ACE inhibitor, presumably through inhibition of ACE inhibitor–induced prostaglandin synthesis. Clinically, the interaction does not announced to affect the ACE inhibitor'due south ability to prevent adverse cardiovascular or renal outcomes.⁴¹ ACE inhibitors may increase hypersensitivity reactions, such as flulike symptoms and peel rash, with allopurinol, although the exact mechanism is not known.⁷ ACE inhibitors and ARBs may increase lithium levels, and concurrent use warrants shut monitoring of lithium levels.⁷

Captopril, a CYP2D6 substrate, and enalapril, a CYP3A4 substrate, may be affected by strong inhibitors or inducers of these pathways⁷ (Table ii). Concentration changes resulting from these interactions should be monitored past following the ambulatory claret pressure level. Losartan is the only ARB with significant interactions with CYP3A4, although losartan and irbesartan are substrates of CYP2C9. Strong inhibitors or inducers of these pathways would probable increase or decrease the antihypertensive effectiveness of losartan (Table 2).

Despite potential interactions, very few clinically significant drug interactions have been documented with ARBs. Caution should be taken when either course is started in renal insufficiency because both tin can worsen renal function or even cause acute renal failure in patients with renal artery stenosis. Neither grade is recommended in pregnancy because severe birth defects to neonatal kidneys can occur.

Calcium channel blockers. Most CCBs are metabolized past CYP3A4 and will exist affected by strong inhibitors and inducers of CYP3A4 (Table two). Grapefruit juice in sufficient quantities can block intestinal CYP3A4, which can lead to an enhancement of the effects of CCBs. This could touch the blood pressure response for all CCBs and further lower the pulse charge per unit when diltiazem and verapamil are used. Studies that take explored the issue of grapefruit juice on diltiazem and verapamil accept not reported changes in claret pressure or centre charge per unit, despite increases in systemic drug concentrations.^42–44 Alcohol ingestion appears to accept variable furnishings on the antihypertensive effects of CCBs, and intake should be limited. In add-on, diltiazem and verapamil are weak inhibitors of CYP3A4, and drug interactions with HMG-CoA inhibitors, which will be discussed later, take been documented.

The risk of cardiac conduction abnormalities with diltiazem or verapamil is the main drug-disease interaction to monitor. Diltiazem or verapamil given in combination with a β-blocker can farther lower the pulse rate, increasing the adventure for heart block. Dihydropyridine CCBs practice not crusade heart conduction drug-disease interactions, merely they may cause peripheral edema, which may worsen preexisting edema present from center failure, venous insufficiency, or other causes.

Nicardipine is an inhibitor of CYP3D6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4, and alcohol ingestion may enhance its antihypertensive effects.⁴⁵ Nicardipine is non recommended because other medications within the course have fewer drug interactions (Tables i and 2).

Diuretics

Thiazide diuretics are the most normally used diuretics for blood pressure control in people with diabetes. No pregnant drug-food interactions exist for diuretics, but bile acid sequestrants, used rarely to reduce cholesterol, may cause a significant reduction in absorption, and thus dosing should exist separated by several hours.⁷ Loop and thiazide diuretics may deplete potassium and magnesium; adequate intake of these minerals is essential. Hypokalemia may greatly increase the toxicity of some concurrent medications (e.g., digoxin and antiarrythmics).^seven Potassium-sparing diuretics (tri-amterene, amiloride, and spironolactone) may cause hyperkalemia. Monitoring of serum potassium is recommended for all diuretics on initiation and periodically thereafter. Thiazide diuretics decrease lithium excretion, and monitoring of lithium levels in conjunction with a reduction in dose is recommended. NSAIDs and phenytoin may decrease the effectiveness of loop diuretics.⁷ Diuretics may too exacerbate several diseases, including hyperuricemia or gout and systemic lupus erythematosus, and cause photo-sensitivity reactions⁴⁶ (Tabular array 1).

Lipid-lowering medications

Fibric acid derivatives

Both gemfibrozil and fenofibrate should be taken with nutrient to reduce gastrointesinal upset. Bile acrid sequestrants may interfere with absorption of fibric acid derivatives and should be separated from each other by at least 2 hours.^vii Gemfibrozil can significantly block CYP2C8/ix/19, glucuronidation, and possibly human being organic anion transporting polypeptide-2 (OATP2).^47,48 Several medications commonly used in the treatment of patients with diabetes are metabolized past these pathways, including sulfonylureas, repaglinide, sertraline, fluoxetine, and carvedilol. These medications may need dose reductions or close monitoring when combined with gemfibrozil⁷ (Table 2).

The interaction of gemfibrozil with statins may exist caused by a glucuronidated metabolite of gemfibrozil competing for metabolism after the OATP2 allows it into hepatocytes. Details can be further explored in a recent review article.⁴⁸ Farther information on this of import interaction can exist establish in the statins section.

When gemfibrozil is added to ezetimibe (Zetia), it likely blocks glucuronidation of ezetimibe, increasing systemic levels, but the clinical relevance of this interaction has yet to be documented.⁴⁹ Fenofibrate, which appears to have less potential to collaborate with the aforementioned drugs, also has a questionable power to lower cardiovascular events in people with type two diabetes.^l

Statins

Drug interactions that inhibit metabolism of statins increase systemic exposure, which may predispose to a greater risk of myopathy. The exact pathophysiological mechanism leading to myopathy is unknown, but direct effects of statins on the myocyte have been hypothesized.⁵¹

Although most myopathy cases occur as a result of drug-drug interactions, statins in monotherapy have as well caused myopathy.⁵¹ Patients often nowadays with muscle aches with or without creatinine phosphokinase elevations, which are indicative of muscle destruction. If the myopathy is allowed to progress, it may lead to rhabdomyolysis, with proximal weakness in the arms or legs. Myoglobinuria, characterized by dark-brown or blackness urine, may also develop and is associated with acute renal failure. The hazard of rhabdomyolysis is depression, but the majority of cases occur in patients with potential drug-drug interactions.⁵² Proper educational activity to stop the medication and report symptoms to their health care provider is essential to minimize risk to patients.

Figure 3:

Medication documentation/drug-drug interaction tool for diabetes educators.

Effigy 3:

Medication documentation/drug-drug interaction tool for diabetes educators.

Close modal

Caution should be taken when strong inhibitors of CYP3A4 are given with lovastatin, simvastatin, or atorvastatin. Strong inhibitors of CYP2C9 may increase fluvastatin and rosuvastatin levels (Table 2). Common classes of drugs that are strong inhibitors of CYP3A4 include azole antifungals, macrolide antibiotics (except azithromycin), protease inhibitors used for HIV, amiodarone, diltiazem, and verapamil⁵² (Tabular array ii). Gemfibrozil and the immunosuppressant cyclosporine appear to increase the hazard of myopathy with all statins.

To minimize the take chances of myopathy and rhabdomyolysis, the maximum recommended dose of immediate-release lovastatin is xx mg/day with cyclosporine, niacin (> one g/day), and fibric acid derivatives and 40 mg with verapamil or amiodarone. If the lovastatin sustained-release dosage form is used, the maximum recommended dose is half of the above-stated lovastatin doses.⁵³ The maximum recommended dose of simvastatin is 10 mg with cyclosporine, niacin (> 1 one thousand/day), and fibric acid derivatives and 20 mg with verapamil or amiodarone.^53,54

Other potential inducer/inhibitor drug-drug interactions of significance tin can exist institute in Tabular array 2. Food may increase the absorption of immediate-release lovastatin but decrease the absorption of extended-release lovastatin.

DRUG INTERACTIONS AND DIABETES EDUCATORS

It is virtually impossible to memorize the plethora of possible interactions currently affecting drug therapy in diabetes. Because of this complexity, it is essential that drug-drug interaction tools exist used. This responsibility is usually shouldered by prescribers and pharmacists, simply only diabetes educators may have a complete and up-to-date list of medications, and they should not assume that someone else volition cover these topics. Strive to keep the chat succinct and patient specific (just cover possible problems with drugs they are currently taking) when discussing possible drug interactions. Oft, this involves non discussing the interaction itself, just rather the possible adverse consequences of the interaction.

Tools to list medications and evaluate potential drug interactions may help. Resources such every bit drug product inserts, websites for a specific drug, reference books, and printed master literature review articles are frequently diabetes educators' best resource for evaluating the potential for drug interactions. It is important to involve a patient's health care team, and a chemist can be especially helpful when it is unclear whether drugs may interact. Pharmacists receive specialized grooming in drug interactions, often accept software or reference books that specifically address drug interactions, and take additional background that can aid with an educated recommendation if no data are available.

Abbreviated forms to help decorated diabetes educators proceed a current medication list and ascertain whether patients with diabetes may be at gamble for possible drug interactions can be establish in Figure 3.

CONCLUSIONS

Detecting potential drug interactions demand non exist burdensome, merely it must not exist ignored. Drug interactions resulting from absorption, distribution, metabolism, or emptying, as well as pharmacodynamic factors, are nowadays for many common medications given to people with diabetes. The squad approach is all-time, and it should not be causeless that prescribers and pharmacists are the only team members responsible for detecting and resolving drug interactions. Diabetes educators can and should be agile team members in screening, educating, and following up on suspected drug interactions. This volition probable lead to a lower risk of adverse effects and an improved quality of life for people with diabetes.

Curtis Triplitt, PharmD, CDE, is a clinical assistant professor in the Department of Medicine, Segmentation of Diabetes, and Clinical Pharmacy Programs of the University of Texas Health Science Center and the Texas Diabetes Constitute in San Antonio.

Article Information

The author cheers Magda Ortiz, RN, who was involved in the development, formatting, and editing of Figure iii and several tables.

References

2.

Zhou Southward, Chan SU, Goh BC, Eli C, Wei D, Min H, McLeod HL: Machinery-based inhibition of cytochrome P450 3A4 by therapeutic drugs.

Clin Pharmacokinet

44

:

279

–304,

2005

three.

Yu DT, Peterson JF, Seger DL, Gerth WC, Bates DW: Frequency of potential azole drug-drug interactions and consequences of potential fluconazole drug interactions.

Pharmacoepidemiol Drug Saf

14

:

755

–767,

2005

iv.

Malone DC, Hutchins DS, Haupert H, Hansten P, Duncan B, Van Bergen RC, Solomon SL, Lipton RB: Cess of potential drug-drug interactions with a prescription claims database.

Am J Wellness Syst Pharm

62

:

1983

–1991,

2005

5.

Hu Z, Yang 10, Ho PCL, Chan SY Chan, Hen PWS, Chan East, Wei D, Koh HL, Zhow S: Herb-drug interactions: a literature review.

Drugs

65

:

1239

–1282,

2005

six.

Sorenson JM: Herb-drug, food-drug, nutrient-drug, and drug-drug interactions: mechanisms involved and their medical implications.

J Altern Complement Med

viii

:

293

–308,

2002

8.

Rowland Thousand, Tozer T:

Clinical Pharmacokinetics: Concepts and Applications.

3rd ed. Baltimore, Md., Williams & Wilkins,

1995

9.

Wahlin-Boll East, Melander A, Sartor G, Schersten B: Influence of food intake on the absorption and upshot of glipizide in diabetics and in good for you controls.

Eur J Clin Pharmacol

18

:

279

–283,

1980

10.

Berelowitz M, Fischette C, Cefalu W, Schade DS, Sutfin T, Kourides IA: Comparative efficacy of a once-daily controlled-release formulation of glipizide and immediate-release glipizide in patients with NIDDM.

Diabetes Intendance

17

:

1460

–1464,

1994

11.

Campbell NRC, Hasinoff BB, Stalts H, Rao B, Wong NCW: Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism.

Ann Intern Med

117

:

1010

–1013,

1992

12.

Benet L, Hoener B: Changes in plasma poly peptide binding take piddling clinical relevance.

Clin Pharmacol Ther

71

:

115

–121,

2002

13.

Sikka R, Magauran B, Ulrich A, Shannon Grand: Bench to bedside: pharmacogenomics, adverse drug interactions, and the cytochrome P450 system.

Acad Emerg Med

12

:

1227

–1235,

2005

14.

Estabrook RW: The remarkable P450s: a historical overview of these versatile hemeprotein catalysts.

FASEB J

ten

:

202

–204,

1996

15.

Guengerich FP, Hosea NA, Parikh A, Bong-Parikh LC, Johnson WW, Gillam EMJ, Shimada T: 20 years of biochemistry of human P450s: purification, expression, mechanism and relevance to drugs.

Drug Metab Dispos

26

:

1175

–1178,

1998

xvi.

Hasler JA, Estabrook R, Murray M, Pikuleva I, Waterman M, Capdevila J, Holla V, Helvig C, Falck JR, Farrell Thou, Kaminsky LS, Spivack SD, Boitier East, Beaune P: Homo cytochromes P450.

Mol Aspects Med

20

:

i

–137,

1999

17.

Somogyi A, Stockley C, Keal J, Rolan P, Bochner F: Reduction of metformin renal tubular secretion by cimetidine in man.

Br J Clin Pharmacol

23

:

545

–551,

1987

18.

Bristol Myers Squibb: Glucophage (metformin HCl): prescribing data [article online]. Available from http://www.glucophage.com

19.

Groop L, Eriksson CJ, Huupponen R, Ylikahri R, Pelkonen R: Roles of chlorpropamide, alcohol and acetaldehyde in determining the chlorpropamide-alcohol affluent.

Diabetologia

26

:

34

–38,

1984

20.

White JR, Campbell RK: Dangerous and common drug interaction in patients with diabetes mellitus.

Endocrinol Metab Clin North Am

29

:

789

–802,

2000

21.

Niemi Thousand, Backman JT, Neuvonen M, Neuvonen PJ: Furnishings of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide.

Diabetologia

46

:

347

–351,

2003

22.

Novo Nordisk: Prandin (repaglinide): prescribing information [article online]. Available from http://world wide web.prandin.com

23.

Hatorp V, Hansen KT, Thomsen MS: Influence of drugs interacting with CYP3A4 on the pharmacokinetics, pharmacodynamics, and safety of the prandial glucose regulator repaglinide.

J Clin Pharmacol

43

:

649

–660,

2003

24.

Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V: Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin.

Diabetes Intendance

23

:

1227

–1231,

2000

25.

Gilligan MA: Metformin and vitamin B12 deficiency.

Arch Int Med

162

:

484

–485,

2002

26.

Kimura N, Okuda M, Inui K: Metformin transport by renal basolateral organic cation transporter hOCT2.

Pharm Res

22

:

255

–259,

2005

27.

Dawson D, Conlon C: Case study: metformin-associated lactic acidosis: Could orlistat exist relevant?

Diabetes Care

26

:

2471

–2472,

2003

28.

Triplitt C, Reasner C, Isley Due west: Diabetes mellitus. In

Pharmacotherapy: A Pathophysiologic Approach.

6th ed. Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, Eds. New York, McGraw-Hill. p.

1333

-1367

29.

Baldwin SJ, Clark SE, Chenery RJ: Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone.

Br J Clin Pharmacol

55

:

53

–56,

1999

30.

Niemi M, Backman JT, Neuvonen PJ: Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone.

Clin Pharmacol Ther

76

:

239

–249,

2004

31.

Jaakkola T, Backman JT, Neuvonen M, Neuvonen PJ: Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone.

Clin Pharmacol Ther

77

:

404

–414,

2005

32.

Zanchi A, Chiolero A, Maillard K, Nussberger J, Brunner 60 minutes, Burnier M: Furnishings of the peroxisomal proliferator-activated receptor-gamma agonist pioglitazone on renal and hormonal responses to salt in healthy men.

J Clin Endocrinol Metab

89

:

1140

–1145,

2004

33.

Nesto RW, Bell D, Bonow RO, Fonseca Five, Grundy SM, Horton ES, Le Winter G, Porte D, Semenkovich CF, Smith Due south, Young LH, Kahn R: Thiazolidinedione use, fluid retention, and congestive middle failure: a consensus statement from the American Centre Association and the American Diabetes Association.

Diabetes Care

27

:

256

–263,

2004

34.

Lebovitz HE, Kreider M, Freed MI: Evaluation of liver function in blazon two diabetic patients during clinical trials: evidence that rosiglitazone does not cause hepatic dysfunction.

Diabetes Intendance

25

:

815

–821,

2002

35.

Isley WL: Hepatotoxicity of thiazolidinediones.

Skilful Opin Drug Saf

ii

:

581

–586,

2003

36.

Takeda Pharmaceuticals and Eli Lilly: Actos (pioglitazone): prescribing information [article online]. Bachelor from http://world wide web.actos.com

37.

GlaxoSmithKline: Avandia (rosiglitazone): prescribing information [article online]. Available from http://www.avandia.com

38.

Ben-Ami H, Krivoy N, Nagachandran P, Roguin A, Edoute Y: An interaction between digoxin and acarbose.

Diabetes Intendance

ii

:

860

–861,

1999

39.

Morreale AP, Janetzky K: Probable interaction of warfarin and acarbose.

Am J Health Syst Pharm

54

:

1551

–1552,

1997

40.

Unger T, Kaschina E: Drug interactions with angiotensin-receptor blockers: comparison with other antihypertensives.

Drug Saf

26

:

707

–720,

2003

41.

Teo KK, Usuf South, Pfeffer Thousand, Kober L, Hall A, Pogue J, Latini R, Collins R: Effects of long-term treatment with angiotensin-converting-enzyme inhibitors in the presence of absence of aspirin: a systematic review.

Lancet

360

:

1037

–1043,

2002

42.

Fuhr U, Muller-Peltzer H, Kern R, Lopez-Rojas P, Jünemann Grand, Harder S, Staib HA: Effects of grapefruit juice and smoking on verapamil concentrations in steady country.

Eur J Clin Pharmacol

58

:

45

–53,

2002

43.

Ho PC, Ghose Thou, Saville D, Wanwimolruk South: Effect of grapefruit juice on pharmacokinetics and pharmacodynamics of verapamil enantiomers in good for you volunteers.

Eur J Clin Pharmacol

56

:

693

–698,

2000

44.

Christensen H, Asberg A, Holmboe AB, Berg KJ: Coadministration of grapefruit juice increases systemic exposure of diltiazem in good for you volunteers.

Eur J Clin Pharmacol

58

:

515

–520,

2002

45.

Nakamura K, Ariyoshi N, Iwatsubo T, Fukunaga Y, Higuchi S, Itoh K, Shimada N, Nagashima K, Yokoi T, Yamamoto K, Horiuchi R, Kamataki T: Inhibitory effects of nicardipine to cytochrome P450 (CYP) in homo liver microsomes.

Biol Pharm Bull

28

:

882

–885,

2005

46.

Kaplan NM:

Kaplan'south Clinical Hypertension.

eighth ed. Baltimore, Md., Williams & Wilkins,

2002

47.

Ogilvie BW, Zhang D, Li W, Rodrigues Advertizing, Gipson AE, Holsapple J, Toren P, Parkinson A: Glucuronidation converts gemfibrozil to a stiff, metabolism-dependent inhibitor of CYP2C8: implications for drug-drug interactions.

Drug Metab Dispos

34

:

191

–197,

2006

48.

Shitara Y, Hirano M, Sato H, Sugiyama Y: Gemfibrozil and its glucoronide inhibit the organic anion transporting polypeptide ii-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: analysys of the mechanism of the clinically relelvant drug-drug collaborate betwixt cerivastatin and gemfibrozil.

J Pharmacol Exp Ther

311

:

228

–236,

2004

49.

Kosoglou T, Statkevich P, Johnson-Levonas AO, Paolini JF, Bergman AJ, Alton KB: Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions.

Clin Pharmacokinet

44

:

467

–494,

2005

50.

FIELD Report Investigators: Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with blazon 2 diabetes mellitus (the FIELD study): randomised controlled trial.

Lancet

366

:

1849

–1861,

2005

51.

Bellosta Due south, Paoletti R, Corsini A: Safety of statins: focus on clinical pharmacokinetics and drug interactions.

Circulation

109

:

III50

–III57,

2004

52.

Thompson PD, Clarkson P, Karas RH: Statin-associated myopathy.

JAMA

289

:

1681

–1690,

2003

54.

Merck: Zocor (simvastatin): prescribing data [article online]. Available from http://www.zocor.com

American Diabetes Association

2006

Source: https://diabetesjournals.org/spectrum/article/19/4/202/1926/Drug-Interactions-of-Medications-Commonly-Used-in

Share this post