Understanding How Diabetes Affects Patient Response To Medications

Robert G. Smith DPM, MSc, RPh, CPed

   The degree of binding to plasma proteins is an important determinant of drug disposition and response. Non-enzymatic glycation of albumin produces conformational changes in the structure of albumin, which can increase the free fraction of acidic drugs like aspirin, penicillin and phenytoin in patients with type 1 and type 2 diabetes.9 Furthermore, glycation of blood and plasma proteins leads to a reduction in protein binding capacity. Thus, drugs with reduced protein binding that may result in adverse reactions include warfarin, tolbutamide, phenytoin and salicylic acid. Diabetes can also affect drug binding by increasing the amount and concentration of circulating free fatty acids. Increasing the blood concentration of these substrates possibly inhibits drug binding and conformational changes of plasma proteins.5,6

Current Insights On Drug Metabolism In Patients With Diabetes

Drug metabolism is enzyme-mediated structural modification to a drug that changes its biological activity and/or water solubility. These enzymatic reactions result in metabolites that may be active or rendered inactive. The gastrointestinal wall, lungs, liver and blood possess enzymes that metabolize drugs.10-12 Drug metabolism by the liver occurs through one or both biotransformation reactions classified as either Phase I or Phase II reactions.10

   Building on the assertion centered on the direct relationship between diabetes mellitus and obesity, the effect of obesity on cytochrome P450 appears to be isozyme-specific with the activity of cytochrome P450 3A4 decreasing.13 The clearance of cytochrome P450 (CYP) 3A4 substrates is lower in obese patients in comparison with non-obese patients. Conversely, researchers saw trends indicating higher clearance values via the following cytochrome P450 isoenzymes: CYP1A2, CYP2C9, CYP2C19 and CYP2D6.14

   Researchers have observed experimentally that there is a decrease in protein levels and enzymatic activity of CYP450 3A4 in the presence of diabetes mellitus.15 CYP3A4 is the most abundantly expressed drug metabolizing enzyme in humans and is responsible for the breakdown of over 120 different medications.

   Among the drugs metabolized are: sedatives such as midazolam (Versed, Roche), triazolam (Halcion, Pfizer) and diazepam (Valium, Roche); the antidepressives amitriptyline (Elavil, Merck) and imipramine; the antiarrhythmics amiodarone (Cordarone, Sanofi Aventis), quinidine (Watson Pharmaceuticals), propafenone (Rythmol, GlaxoSmithKline) and disopyramide (Norpace, Pfizer); the antihistamines terfenadine, astemizole and loratadine (Claritin, Schering Plough); calcium channel antagonists such as diltiazem and nifedipine; and various antimicrobials and protease inhibitors.

   The observation from Dostalek and colleagues on decreased CYP450 3A4 activity is notable when the podiatric physician prescribes medications to patients with diabetes.15

Pertinent Points On Drug Elimination And Excretion

Drugs are either eliminated directly or converted into metabolites that the body subsequently excretes. Removal of a drug from the body may occur by a number of routes, the most important being through the kidney into the urine. Drugs enter the kidney through renal arteries that divide to form a glomerular capillary plexus. Other routes of elimination or excretion for drugs from the body include sweat, tears, breast milk or expired air.

   Diabetes is the most common cause of kidney failure, accounting for nearly 44 percent of new cases. Even when diabetes is under control, the disease can lead to chronic kidney disease and kidney failure. Diabetes-related nephropathy is the leading cause of end-stage renal disease in industrialized countries.16 Initially, diabetes mellitus causes microvascular and macrovascular changes that lead to hyperfiltration and an increased glomerular filtration rate.17

   As kidney dysfunction progresses, the renal excretion of the parent drug and/or its metabolites will be impaired, leading to their excessive accumulation in the body.

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