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Guide to Drug interaction
Drug interaction Guide Published By NPA Medafacts provided by Bonecare International
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Patients with acute renal failure, chronic kidney disease (CKD) or those treated with dialysis or kidney transplantation are frequently prescribed numerous medications. Drugs of many therapeutic classes are used to treat the underlying diseases leading to CKD, such as diabetes mellitus and hypertension, while others are used to control or treat the common complications of CKD, such as anemia, renal bone disease and lipid disorders. Dialysis patients often are prescribed 10 to 12 medications. With such a large number of medications, there is an increased risk for drug interactions. The accompanying table has been prepared as a reference regarding the most clinically significant drug interactions that might occur, together with an indication of the possible consequence. This table should be used as a general guideline. Sometimes information is known about one specific drug within a certain drug class, while additional information is not known about other agents within the

same therapeutic category. Clinicians must be aware of this possibility and use their best judgment when prescribing or assessing drug therapy.

Types of Drug Interactions

Drug interactions are often classified as either pharmacodynamic or pharmacokinetic interactions. Pharmacodynamic interactions include those that result in additive or antagonistic pharmacological effects. Pharmacokinetic interactions involve induction or inhibition of metabolizing enzymes in the liver or elsewhere, displacement of drug from plasma protein binding sites, alterations in gastrointestinal absorption, or competition for active renal secretion. The frequency and prevalence of interactions is dependent upon the numberof concomitant medications and the complexity of the regimens. The prevalenceis also dependent upon other variables, such as patient adherence, hydration and nutritional status, degree of renal or hepatic impairment, smoking and alcohol use, genetics and drug dosing. Additionally, some patients may exhibit evidence of a particular drug interaction, while others with the same drug combination do not.

Pharmacodynamic interactions

This type of interaction will not be addressed in this reference, since these should be reasonably easy to predict, knowing the pharmacology of any given drug.

Pharmacokinetic interactions


Interactions Resulting from Alterations in Gastrointestinal Absorption

The rate and extent of drug absorption after oral administration may be grossly altered by other agents. Absorption of a drug is a function of the drug’s ability to diffuse from the lumen of the gastrointestinal tract into the systemic circulation. Changes in intestinal pH may profoundly affect drug diffusion as well as dissolution of the dosage form. For example, the absorption of ketoconazole is reduced by the co-administration of antacids or H2-blockers (e.g. ranitidine, famotidine) that reduce the extent to which the ketoconazole tablet is dissolved. Formation of insoluble complexes by a process known as chelation is another mechanism by which a drug interaction may lead to reduced oral absorption. For example, fluoroquinolones (e.g. ciprofloxacin) and divalent metal ions (such as calcium and iron) form an insoluble complex that results in reduced absorption of both the antibiotic and the metal ion. Interactions that decrease

the rate of drug absorption may be of little importance, since the overall extent of absorption may remain unaltered.


Interactions Resulting from Alterations in Metabolizing Enzymes

The liver is the major, though not exclusive, site for drug metabolism. Other sites include the kidney and the lining of the gastrointestinal tract. The two main types of hepatic drug metabolism are phase I and phase II reactions. Phase I oxidative reactions are the initial step in drug biotransformation, and are mediated by the cytochrome P-450 (CYP) system. This complex superfamily of enzymes has been subclassified into numerous enzymatic subfamilies. The most common CYP

subfamilies include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. These enzymes may be induced or inhibited by other agents, thereby leading to an increase or decrease in the metabolism of the primary drug. Phase II reactions occur following Phase I reactions. In this process, drug metabolites are converted into more water-soluble compounds that can be more easily eliminated by the kidneys.


Enzyme induction may result in increased CYP enzyme synthesis, faster drug metabolism, subtherapeutic drug concentrations and the risk for ineffective drugtherapy. The rapidity of the enzyme induction is dependent upon the half-life of the inducing drug as well as the rate of synthesis of new enzymes. Examples of drugs that cause enzyme induction are the barbiturates, some anticonvulsants and rifampin.


Enzyme inhibition may result from noncompetitive or competitive inhibition of CYP enzymes by a second drug, an effect that may occur rapidly. Examples of hepatic enzyme inhibitors include cimetidine, fluconazole and erythromycin. The result of noncompetitive enzyme inhibition by addition of a second agent is slower metabolism of the first drug, higher plasma drug concentrations, and a risk for toxicity. In the case of competitive inhibition, the metabolism of both drugs can be reduced, resulting in higher than expected concentrations of each drug. A few drugs are metabolized by enzymes found in cells lining the gastrointestinal tract. One of these drugs is cyclosporine. Some foods and other preparations such as grapefruit juice contain certain substances that may inhibit those specific enzymes, resulting in elevated serum cyclosporine concentrations.


Interactions Resulting from Alterations in Protein Binding

Drugs may exist in plasma either reversibly bound to plasma proteins or in the free (unbound) state. The primary drug-binding plasma proteins are albumin and á1-acid glycoprotein. It is free drug that exerts the pharmacological effect. Drugs may compete with each other for plasma protein binding sites, and when this occurs, one drug may displace another that was previously bound to the protein. Displacement of a drug from its binding sites will therefore increase that agent’s unbound concentrations, perhaps resulting in toxicity.Some drugs normally exist in a state of high protein binding, often exceeding 90%. Thus, even a small decrease in protein binding could significantly increase the free concentrations. Drugs which are normally highly protein bound, and which might participate in binding interactions, include anticonvulsants and warfarin.


Interactions Resulting from Changes in Renal Excretion

The majority of renally eliminated drugs are excreted via passive glomerular filtration. Some drugs are eliminated via active tubular secretion, such as penicillins, cephalosporins, and most diuretics. The active secretion may be inhibited by secondary agents, such as cimetidine, nonsteroidal anti-inflammatory agents and probenecid, with resulting elevations in the serum drug concentrations and reduced urinary drug concentrations. In some cases, the interaction is desirable, while others may lead to adverse therapeutic outcomes.

Risk Factors and Management of Drug Interactions

In general, the more complex a patient’s drug regimen, the higher the risk for interactions. CKD patients often take numerous medications. The average age of a dialysis patient is over 60 years and as a group, elderly patients are more prone to experience drug interactions because of reduced hepatic and renal function. Identification of the potential for interactions may enable the clinician to avoid its occurrence. Drugs that require careful dose titration to maintain efficacy and avoid toxicity must be monitored particularly carefully for drug

interactions. Most drug interactions can be avoided or managed by substitution of one or more agents or more intense monitoring for the potential result. Other management strategies include separation of doses of interacting agents (e.g. ciprofloxacin and calcium) or prospective adjustment of doses.

Clinical Significance of Interactions

This guide lists only those interactions that have been previously rated as having a moderate or high level of clinical significance by the Drug Interaction Facts (see References). This rating scale requires that a potential interaction has a moderate to major severity. The effects of a moderate interaction may cause deterioration in the patient's clinical status, resulting in additional treatment, hospitalization, and/or an extended hospital stay. The effects of a major interaction are potentially life-threatening or can lead to permanent damage. In addition to being clinically significant, the interaction must be reasonably documented in the literature (suspected, probable, or established). Therefore, the accompanying table is NOT an all-inclusive list of every possible drug interaction.


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