Diabetes mellitus is associated with a progression of microvascular and macrovascular complications.1,2 It is understandable that with the progression of these diabetes-related complications, the consumption of medications to prevent and treat them would be greater in comparison to those age-matched individuals without diabetes mellitus.3,4 Often, the use of medication by patients with diabetes is frequent and in many cases involves highly potent drugs or pharmaceuticals with narrow therapeutic ranges.5
Although drugs develop to treat patients who have diseases, relatively little attention has focused on the fact that the diseases themselves exert important effects that influence patient response to drug therapy. Variability in drug action and, consequently, drug response may be of a pharmacokinetic or a pharmacodynamic origin. The effects of diabetes mellitus on the pharmacokinetics and pharmacodynamics of drugs have been well described in experimental animal models. However, only minimal data exists for humans and the current knowledge regarding the effects of diabetes on these properties remains unclear.5,6
Diabetes mellitus affects protein, lipid and carbohydrate metabolism as well as the biochemical pathways that are involved in drug biotransformation.6 The principles of pharmacokinetics that may be influenced by diabetes mellitus include: absorption, distribution, biotransformation and excretion.5,6 Diabetic changes in subcutaneous and muscle blood flow, and delayed gastric emptying may influence how a drug is absorbed.5,6 Non-enzymatic glycation of albumin secondary to diabetes mellitus may affect a medication’s distribution within the body.5,6
The biotransportation of a drug may change in the presence of diabetes mellitus due to regulation of enzymes involved in drug biotransformation and drug transporters.5,6 Finally, a medication’s elimination, mainly its excretion, may be influenced by diabetic nephropathy.5,6 Once a clinician appreciates diabetes mediated changes as a source of drug-patient variability, it should lead to an improvement of medical management and clinical outcomes in patients with diabetes mellitus.
Absorption is the rate and extent to which a drug leaves its site of administration. Drug absorption occurs at different sites along the gastrointestinal tract, including the stomach and the small and large intestines. After a drug is absorbed or injected into the bloodstream, it enters circulation and distributes throughout the body. Gastric emptying is frequently abnormal in patients with long-standing type 1 and type 2 diabetes mellitus.7 Symptoms commonly associated with delayed gastric emptying include nausea, vomiting, bloating and epigastric pain. These patients are also at risk of malnutrition, weight loss, impaired drug absorption, disordered glycemic control and having a poor quality of life.7 Despite the fact that many studies have reported diabetes-mediated changes in gastric emptying time, the magnitude of the delay is modest and at this time, some authors may not consider it clinically important.5,6
Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the extracellular fluid or the cells of the tissues. Drugs can be distributed into different compartments of the body (i.e., blood, plasma, fat or bone). Clinicians commonly use the term “volume of distribution” to describe the extent of drug distribution to tissues relative to the plasma volume. The volume of distribution of a drug correlates with the degree of obesity and obesity is a factor in the development of insulin resistance and diabetes.5,6,8 Various authors have observed that the volume of distribution of lipophilic drugs is affected by diabetes mellitus.5,6,8
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
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
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.
In addition, the plasma protein binding of drugs may be significantly reduced. This could subsequently influence the pharmacokinetic processes of distribution and elimination. Researchers have shown that the activity of several drug metabolizing enzymes and drug transporters is impaired in chronic renal failure. Diabetic renal dysfunction affects more than just the renal handling of drugs and/or active drug metabolites.18 Even when patients with diabetes and renal dysfunction carefully follow recommended dosage adjustments, adverse drug reactions remain common.
Data regarding the effects of diabetes on pharmacodynamics is very limited.5,6 As I noted earlier, there is evidence that the effects of diabetes are not limited to drug absorption and disposition, but can alter drug response as well.5,6 Previously published studies have reported the effects of diabetes on the pharmacodynamics of cardiovascular drugs such as lipid lowering agents and antihypertension drugs.5,6
Clinical observations suggest that drug response to other therapeutic classes of drugs may also be altered in patients with diabetes.5 Available data indicates that there is a significant variability in drug response in patients with diabetes. An understanding of diabetes-mediated changes in pharmacodynamics as well as the source of the variability in patient response to treatment should lead to better podiatric medical management of patients with diabetes.
The available data indicates that there is significant variability in drug response in patients with diabetes. Researchers have shown that the pharmacokinetics and pharmacodynamics of a number of drugs are significantly altered by diabetes mellitus.
In regard to therapeutic medication regimens established for non-diabetic patients, applying these regimens in patients with diabetes may result in an increased incidence of therapeutic failures or undesirable adverse effects.
Dr. Smith is in private practice in Ormond Beach, Fla.
1. Engelau MM, Geiss LS, Saaddine JB, et al. The evolving diabetes burden in the United States. Ann Intern Med. 2004;140(11):945-950.
2. Girach A, Manner D, Porta M. Diabetic microvascular complications: can patients at risk be identified? A review. Int J Clin Pract. 2006;60(11):1471-1483.
3. Rendell M, Lassek WD, Ross DA, et al. A pharmaceutical profile of diabetic patients. J Chronic Dis. 1983;36(2):193-202.
4. Isacson D, Stallhammer J. Prescription drug use among diabetics: a population study. J Chronic Dis. 1987;40(7):651-660.
5. Gwilt PR, Nahhas RR, Tracewell WG. The effects of diabetes mellitus on pharmacokinetics and pharmacodynamics in humans. Clin Pharmacokinet. 1991; 20(6):447-490.
6. Dostalek M, Akhlaghi F, Puzanovova M. Effect of diabetes mellitus on pharmacokinetic and pharmacodynamic properties of drugs. Clin Pharmacokinet. 2012;51(8):481-499.
7. Ma J, Rayner CK, Jones KL, et al. Diabetic gastroparesis: diagnosis and management. Drugs. 2009;69(8):971-986.
8. Bonadonna RC, Groop L, Kraemer, et al. Obesity and insulin resistance in humans: a dose-response study. Metabolism.1990;39(5);452-459.
9. Worner W, Pressner A, Riebrock N. Drug-protein binding kinetics in patients with type 1 diabetes. Eur J Clin Pharmacol. 1992;43(1):97-100.
10. Benet LZ, Kroetz DL, Sheiner LB. Pharmacokinetics: The dynamics of drug absorption, distribution, and elimination. In (Hardman JG, Limbird LE, eds.) Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw Hill, New York, 1996, pp. 3-27.
11. Hansten PD, Horn JR. Drug interaction mechanisms: enzyme induction. In: Hansten and Horn’s Drug Interactions Analysis and Management. Facts and Comparison, St. Louis, MO, 2003, pp. PM1-PM-15.
12. Bauer LA. Clinical Pharmacokinetics and pharmacodynamics. In (Dipro JT, ed.) Pharmacotherapy: A Pathophysiologic Approach, Appleton & Lange, Stamford, CT, 1999, pp. 21-30.
13. Kotlyar M, Carson SW. Effects of obesity on cytochrome P450 enzyme system. Int J Clin Pharmacol Ther. 1999;37(1):8-19.
14. Brill MJ, Diepstraten J, van Rongen A, et al. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmcokinet. 2012; 51 (5):277-304.
15. Dostalek M, Court MH, Yan B, et al. Significantly reduced cytochrome P 450 3A4 expression and activity in liver from humans with diabetes mellitus. Br J Pharmacol. 2011;163(5):937-947.
16. Raine AE. The rising tide of diabetic nephropathy: the warning before the flood? Nephrol Dial Transplant 1995; 10 (4):460-461.
17. Meeme A, Kasozi H. Effect of glycaemic control on glomerular filtration rate in diabetes mellitus patients. Afr Health Sci. 2009;9(Suppl. 1):S23-S26.
18. Verbeeck RK, Musuamba FT. Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur J Clin Pharmacol. 2009;65(8):757-73.