Drug interactions with oral hypoglycaemic drugs

Gillian M. Shenfield, Professor in Clinical Pharmacology, Department of Clinical Pharmacology, Royal North Shore Hospital, Sydney

Summary

Oral hypoglycaemic drugs may interact with other drugs. Pharmacodynamic interactions occur with medications that alter blood glucose and may require the dose of the oral hypoglycaemic drug to be altered. Pharmacokinetic interactions vary with the drug group. Sulfonylureas and repaglinide are metabolised in the liver. Their plasma concentrations and activity can be reduced by drugs which induce hepatic enzymes and increased by hepatic enzyme inhibitors. Metformin is renally excreted and may have increased toxicity with drugs that impair renal function. Acarbose is only slightly absorbed across the gut and has few significant interactions. Significant interactions with the thiazolidinediones have not yet been reported, but pioglitazone is known to induce cytochrome P450 3A4.

Key words: diabetes, pharmacokinetics, lactic acidosis.

Aust Prescr 2001;24:83-5

SYNOPSIS

Oral hypoglycaemic drugs may interact with other drugs. Pharmacodynamic interactions occur with medications that alter blood glucose and may require the dose of the oral hypoglycaemic drug to be altered. Pharmacokinetic interactions vary with the drug group. Sulfonylureas and repaglinide are metabolised in the liver. Their plasma concentrations and activity can be reduced by drugs which induce hepatic enzymes and increased by hepatic enzyme inhibitors. Metformin is renally excreted and may have increased toxicity with drugs that impair renal function. Acarbose is only slightly absorbed across the gut and has few significant interactions. Significant interactions with the thiazolidinediones have not yet been reported, but pioglitazone is known to induce cytochrome P450 3A4.

Index words: diabetes, pharmacokinetics, lactic acidosis.

(Aust Prescr 2001;24:83-5)

Introduction

The sulfonylureas and metformin (a biguanide) have been the mainstay of drug treatment for type 2 diabetes. Recently three new types of drugs have become available; acarbose (an alphaglucosidase inhibitor), repaglinide (a meglitinide) and the `glitazones' (thiazolidinediones) (Table 1). Drugs from one or more groups are frequently used in combination and have additive effects in lowering blood glucose. The exception to this rule is that repaglinide should not be used with the sulfonylureas since they act through the same final common pathway.

Table 1

Oral hypoglycaemic drugs in Australia

Class Drug
Sulfonylureas

Chlorpropamide
Glibenclamide
Gliclazide
Glimepiride
Glipizide
Tolbutamide

Biguanides Metformin
a Glucosidase inhibitors Acarbose
Meglitinides Repaglinide
Thiazolidinediones

Pioglitazone*
Rosiglitazone

* Approved but not marketed

All of the oral hypoglycaemic drugs have the potential to interact with other medications and if the result is hypoglycaemia or hyperglycaemia the consequences can be serious. The interactions may be pharmacodynamic (another drug independently raises or lowers blood glucose) or pharmacokinetic (another drug alters the absorption, metabolism or excretion of the hypoglycaemic drug). Both mechanisms may have the effect of changing the apparent efficacy of the hypoglycaemic drugs. Pharmacokinetic interactions may also exacerbate other adverse effects of oral hypoglycaemic drugs.

Pharmacodynamic interactions

Interactions of this type apply to all classes of hypoglycaemic drugs.

Medications which may raise blood glucose

Any drug that has the potential to raise blood glucose may produce apparent inefficacy of an oral hypoglycaemic drug. Medications which are commonly reported to increase glucose concentrations are listed in Table 2 with their probable causative mechanisms. In some cases, for example high dose corticosteroids, the patient may need insulin to control their blood glucose until the steroids are ceased.

Table 2

Some medications that can raise blood glucose

Drug Probable mechanism
Clonidine Adrenergic action
Clozapine ? Impairs insulin secretion
Corticosteroids Oppose insulin action
Diuretics (especially thiazides) Oppose insulin action
Nicotinic acid ? Opposes insulin action
Nifedipine (but not other calcium antagonists) Delays insulin action
Oral contraceptive hormones Oppose insulin action
Phenytoin Blocks insulin secretion
Phenothiazines Not known
Sugar-containing syrups (e.g. antibiotics/cough mixtures) Increased glucose intake
Note: Clinical relevance of some effects is uncertain

Stopping a drug which causes hyperglycaemia may produce a significant fall in blood glucose. This may require a parallel reduction in the dose of a hypoglycaemic drug.

Medications which may lower blood glucose

Some drugs can lower blood glucose, but the mechanisms of action are not well understood (Table 3). Taking one of these drugs with a hypoglycaemic drug might cause clinically significant hypoglycaemia. The patient may need a lower dose or even have to cease the oral hypoglycaemic drug. Conversely stopping a drug with the potential to lower blood glucose might produce relative inefficacy of a hypoglycaemic drug and create a need for an increased dose.

Table 3

Some medications that may lower blood glucose

Drug Suggested mechanism
ACE inhibitors Increase insulin action
Alcohol Inhibits hepatic glucose production and release
Fibrates Not known
Monoamine oxidase inhibitors Not known
Quinine (? quinidine) Increases insulin secretion
Salicylates (large dose) Not known
Note: Clinical relevance of some effects is uncertain

Beta blockers can mask the warning signs of hypoglycaemia, and the non-selective drugs may impair the normal recovery reaction to hypoglycaemia. There is little evidence that they actually induce hypoglycaemia.

Pharmacokinetic interactions

These need to be considered separately for each drug class as the body handles the drugs in very different ways and the potential sites for interactions are different.

Sulfonylureas

All drugs in this class are partially or totally metabolised by the liver. Chlorpropamide is the only member of the class with substantial renal excretion, but is now rarely used. It is excreted much more rapidly in alkaline urine so its half-life and duration of action are reduced with excessive ingestion of alkalis. Antacids may increase the absorption of all the sulfonylureas and hence produce higher peak concentrations of the drugs and a risk of temporary hypoglycaemia.

Chlorpropamide has an additional interaction with alcohol which can produce significant facial flushing. This has been reported with very high doses of tolbutamide, but not with the other drugs in this group.

Sulfonylureas are highly protein bound drugs and may be displaced from blood protein binding sites by drugs such as the non-steroidal anti-inflammatory drugs. This can cause a short-term increase in free (unbound) sulfonylurea and hence temporary hypoglycaemia.

The majority of significant interactions with sulfonylureas are due to the induction or inhibition of cytochrome P450 enzymes in the liver. Table 4 lists the common interacting drugs and the resultant clinical outcomes. Although dicoumerol interacts with tolbutamide it is not used in Australia and there are no significant interactions reported for warfarin or phenindione.

Repaglinide

This is the only drug of its class currently available in Australia. It has been in use for too short a time for the full spectrum of its potential interactions to have emerged. Like the sulfonylureas it is metabolised by a liver enzyme (cytochrome P450 3A4) and is potentially subject to many of the interactions listed in Table 4.

Table 4

Potential interactions between sulfonylureas or repaglinide and drugs which alter hepatic enzymes

Inducers of metabolism (reduce concentration of hypoglycaemic drug) Inhibitors of metabolism (increase concentration of hypoglycaemic drug)
Phenytoin Allopurinol*
Phenobarbitone Chloramphenicol
Rifabutin Cimetidine*
Rifampicin Erythromycin
'Azole' antifungals
* Repaglinide concentrations not increased

Metformin

Metformin is the only biguanide available in Australia. It is not metabolised at all but is completely excreted in urine. Metformin may therefore accumulate and cause lactic acidosis if other medications have induced renal failure. Examples include contrast media, cyclosporin and aminoglycosides. Metformin should therefore be stopped before, and for 48 hours after, contrast radiography.

Metformin is excreted by the renal tubules and this process can be inhibited by cimetidine, but not the other H2 receptor antagonists. This interaction causes retention of metformin and increases the risk of lactic acidosis.

Acarbose

Acarbose inhibits alpha glucosidase in the gut wall. This reduces the release of glucose from carbohydrate and hence the amount of glucose available for absorption. The drug itself is only absorbed to a minor extent and any interactions relate to interference with its access to the gut lining. In general these interactions would be likely to reduce its efficacy and this has been reported with charcoal and digestive enzyme preparations. In addition neomycin may increase the unpleasant gastrointestinal adverse effects of acarbose.

Thiazolidinediones

So far three drugs in this group have been marketed but troglitazone has been withdrawn worldwide because of unacceptable hepatotoxicity. Troglitazone also induced cytochrome P450 3A4 and interacted with a number of drugs including cyclosporin and oral contraceptives. So far rosiglitazone and pioglitazone have not shown any significant interactions either in specific studies or in early clinical use. Pioglitazone is known to induce cytochrome P450 3A4 and it is possible that interactions with it and with rosiglitazone will become apparent over the next few years.

Conclusion

Interactions with oral hypoglycaemic agents are important because the outcomes, particularly hypoglycaemia, are serious. As with all interactions the times of high risk are when a second drug is started or stopped or has its dose changed. Regular co-prescription of the same dose of another drug is not likely to cause major problems.

E-mail: [email protected]

Self-test questions

The following statements are either true or false (click here for the answers)

1. Drug interactions with metformin are due to induction or inhibition of hepatic enzymes.

2. Patients with diabetes may need to increase the dose of their oral hypoglycaemic drug when they start a course of corticosteroids.



First published online: July 2001