Diabetes and drug therapy.

Aside from the drugs used in the direct treatment of diabetes, there are several other pharmacologic considerations in the management of these elderly patients. Drug-disease and drug-drug interactions are of considerable concern.

Renal Complications

In addition to the physiological loss of creatinine clearance that occurs with aging, diabetes can markedly accelerate loss of kidney function. NSAIDs can worsen renal function and cause increased blood pressure, especially in the diabetic, and this is evidenced as water weight gain. Weighing the patient weekly after an NSAD is started for at least 1 to 3 months is important.

Angiotensin converting enzyme inhibitors (ACEIs) such as captopril (Capoten) and enalapril (Vasotec) may be used to prevent urinary protein losses that are associated with diabetes damage to the kidney. ACEIs should however be closely followed with at least monthly serum creatinine measurements, as paradoxical reversible worsening of renal function may occur if the patient already has renal artery stenosis. It is important that routine serum creatinines be done, and that drug dosages be adjusted in response to diminished calculated creatinine clearance and increased serum creatinine.

Since up to half of insulin is metabolized in the kidney, the patient with severe renal impairment may need less insulin. In end-stage renal disease, regular insulin action may be as prolonged in effect as the intermediate-acting insulins.

Cardiovascular Complications

High blood pressure (HBP) is more prevalent in diabetics. Diuretics and beta blockers are often initial drugs used to treat HBP, but unfortunately, both drug classes can worsen diabetic control, produce unfavorable lipid profiles and actually increase the frequency of diabetic complications, such as hypoglycemia and peripheral vascular disease.

For these reasons, the ACEIs and calcium channel blocking drugs are preferred drugs for high blood pressure and other cardiovascular complications in the diabetic.

Gastrointestinal Complications

Diabetic gastroparesis may be evident from persistent nausea, vomiting, heart-burn, persistent fullness and bloating following meals. Delayed gastric emptying may produce a mismatch of digestion with antidiabetic drugs, i.e. the nutrient may not be absorbed in time to be acted on by insulin. Metoclopramide (Reglan) may be helpful in smaller dosages than those used in the younger patient (one-half recommended dosage in CrCl <40ml/min).

However, since this drug is a phenothiazine, any concurrent neuroleptic usage should be carefully evaluated and dosage tapered or discontinued to prevent additive effects, such as sedation and extrapyramidal effects (eg, pseudoparkinsonism).

Diabetics may have chronic diarrhea, which may require anticholinergics such as glycopyrrolate (Robinul) to lessen stool frequency. If they have concurrent hypertension, usage of an antihypertensive with anticholinergic side effects, such as clonidine (Catapres), may be more helpful to control both the diarrhea and hypertension.

Painful Peripheral Neuropathy

Leg and foot pain, usually described as burning, aching and refractory to analgesics, including NSAIDs and narcotics, may be improved by continuous infusion of insulin, as well as some psychotropic drugs and anticonvulsants.

Specifically, tricyclic antidepressants and phenothiazines are used to manage chronic severe pain not adequately relieved by full-dose continuous analegesics. The tricyclics amitriptyline, nortriptyline and imipramine, in gradually increasing doses of 50 to 100mg per day, have been shown to break the chronic pain-depression-pain cycle in as little as 24-48 hours or within several weeks. Fluphenazine in doses up to 3mg/d has also been used with tricyclics for pain relief in diabetic peripheral neuropathy.

In patients unresponsive to psychotropic therapy for painful neuropathy, carbamazepine 100-200mg TID and phenytoin 100mg TID have been used with some success. Topical therapy with capsaicin 0.025% (Zostrix) or 0.075% (Axsain) ointment 3 to 4 times a day with finger cot or Q-tip to affected areas may be used, with the warning that pain may be initially worsened, and it may take several weeks for the anesthetic effect to be maximal.

Less expensive topical therapy may involve a carefully applied salicylate cream or ointment, or simply crushing a 325mg ASA tablet in two tablespoonfuls of Vaseline Intensive Care Lotion and applying to affected area several times a day, being careful to not cause enough keratolytic effect to produce a break in the skin. Americaine ointment is a 20% benzocaine product that may be needed for temporary local relief.

Peripheral Vascular Disease-Intermittent Claudication

Both an increased rate of atherosclerosis and leg pain on exertion are seen in diabetics. Pentoxyphylline (Trental), 400mg TID with meals, along with decaffeination of diet, may be beneficial, especially if combined with an enteric-coated ASA 325mg tablet twice a week and a graded walking program to improve exercise tolerance. Be careful if the patient is also taking a theophylline product, however, because in the diabetic patient this may lead to added excitation, as well as interfere with measurement of theophylline levels, raising them by as much as a third.

Beta blockers, even the selective types, and oral decongestants can cause worsening peripheral vasoconstriction, and should be avoided; in the diabetic, beta blockers should be replaced by calcium channel blockers for angina or high blood pressure.

Infection Complications

Infections may make a diabetic more "brittle" or susceptible to poor glycemic control; by the same token, most infections of the skin, urinary and respiratory tracts occur more frequently in the poorly controlled diabetic state. Oropharyngeal and esophageal candidiasis are more commonly seen in older diabetics, especially after broad-spectrum antimicrobial usage. In addition to the availability of nystatin oral solution for "swish and swallow" routines, an oral antifungal such as the ketoconazole (Nizoral) or fluconazole (Diflucan) may be needed to clear resistant candidiasis.

Tuberculosis is reactivated by diabetes almost as commonly as by chronic alcohol abuse. Up to 40% of patients with TB have an abnormal glucose tolerance. Treatment of TB should follow the current Center for Disease Control (CDC) guidelines.

Influenza may be more devastating in the older diabetic. Viral antibody titers do not appear to last as long in diabetics, so that some recommend twice-a-year immunizations in October and January for the older diabetic at-risk of catching the flu. For either Type A flu prophylaxis or treatment of suspected flu symptoms to lessen their severity and duration, amantadine (Symmetrel) 100 mg per day for 7-14 days or longer may be necessary. The once a day dosing produces fewer anticholinergic side effects than the BID dosing schedule in older adults.

Aggressive treatment of symptomatic urinary tract infections, which are common in the poorly controlled diabetic, should be encouraged.

Nutritional Complications

In addition to zinc, deficits of chromium, magnesium and calcium may be more common in the diabetic. Supplementation for chromium deficiency has been linked to improved blood glucose control. Hypomagnesemia may be more common in elderly diabetics treated with diuretics than in younger non-diabetics. However, magnesium replenishment should be undertaken only in the presence of documented lower serum magnesium levels and normal renal function (i.e. serum creatinine <1.5mg/dl). Osteoporosis may be more common in older diabetics than older non-diabetics. Food sources of calcium are preferable to drug sources, especially skim milk 8 oz., a cup of cottage cheese or yogurt, each of which supply approximately 300mg of calcium. The post-menopausal woman needs 1000-1500mg calcium per day.

James W. Cooper, Pharm, Ph.D. F.A.S.C.P. is a professor and head of the Department of Pharmacy Practice at the University of Georgia.