chapter
Sulphonylureas
Pages 12

Due to these drugs causing hyperglycaemia, the mechanism being uncertain at present

≠ doses of metformin are often required for adequate glycaemic control

METFORMIN SOMATROPIN ↓ hypoglycaemic effect of metformin

Due to these drugs causing hyperglycaemia, the mechanism being uncertain at present

≠ doses of metformin are often required for adequate glycaemic control

METFORMIN SYMPATHOMIMETICS – EPINEPHRINE

May ≠ antidiabetic requirements Epinephrine causes the release of glucose from the liver and is an important defence/homeostatic mechanism. Hyperglycaemia due to an antagonistic effect

Larger doses of antidiabetic therapy may be needed during the period of epinephrine use, which is usually in the short term or in emergency situations

METFORMIN TESTOSTERONE ≠ hypoglycaemic effect and ≠ risk of hypoglycaemic episodes

Exact mechanism is uncertain. Low testosterone levels are associated with type II diabetes. Experimental work has suggested that testosterone may play a role in glucose efflux from cells

METFORMIN THYROID HORMONES ↓ hypoglycaemic effect of metformin

Due to these drugs causing hyperglycaemia, the mechanism being uncertain at present

≠ doses of metformin are often required for adequate glycaemic control

SULPHONYLUREAS

SULPHONYLUREAS ALCOHOL Tends to mask signs of hypoglycaemia and ≠ risk of hypoglycaemic episodes

Inhibits glucose production and release, from many sources including the liver and release

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Mechanism Precautions

which are highly protein bound. There have been reports of hyperglycaemia and hypoglycaemia (e.g. with diclofenac)

Attributed to displacement of sulphonylureas from protein binding sites, thus ≠ plasma concentration. Some NSAIDs may impair the renal elimination of sulphonylureas, particularly chlorpropamide

Be aware. There are conflicting reports. Suggestions that sulindac and diclofenac with misoprostol may interact minimally

SULPHONYLUREAS ANTIARRHYTHMICS – DISOPYRAMIDE

≠ risk of hypoglycaemic episodes – particularly in patients with impaired renal function. Hypoglycaemic attacks may occur even when plasma levels of disopyramide are within the normal range (attacks occurring with plasma disopyramide levels of 1-4 ng/mL)

Disopyramide and its metabolite mono-isopropyl disopyramide ≠ secretion of insulin (considered to be due to inhibition of potassium-ATP channels). Suggestion that disopyramide causes an impairment of the counterregulatory (homeostatic) mechanisms that follow hypoglycaemia

In patients receiving antidiabetic drugs, start with the lowest dose of disopyramide if there is no alternative. Measure creatinine clearance. If creatinine clearance is 40 mL/min or less, the dose of disopyramide should not exceed 100 mg and should be administered once daily if creatinine clearance is 15 ml/min. Watch for and warn patients about symptoms of hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

SULPHONYLUREAS ANTIBIOTICS

SULPHONYLUREAS CHLORAMPHENICOL Possibly ↓ hypoglycaemic effect of sulphonylureas

Mechanism uncertain. Chloramphenicol is an inhibitor of CYP3A4

Be aware

SULPHONYLUREAS ISONIAZID ↓ efficacy of antidiabetic drugs Isoniazid causes hyperglycaemia, the mechanism being uncertain at present

Monitor capillary blood glucose closely; ≠ doses of antidiabetic drugs may be needed

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Mechanism uncertain. Ciprofloxacin is a potent inhibitor of CYP1A2. Norfloxacin is a weak inhibitor of CYP1A2, but the quinolones may inhibit other CYP isoenzymes to varying degrees

SULPHONYLUREAS RIFAMPICIN ↓ hypoglycaemic efficacy Plasma levels of sulphonylureas are ↓ by induction of CYP-mediated metabolism

SULPHONYLUREAS ANTICANCER AND IMMUNOMODULATING DRUGS

CHLORPROPAMIDE BORTEZOMIB Likely to ≠ hypoglycaemic effect of chlorpropamide

Unknown Watch for and warn patients about symptoms of hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

GLIPIZIDE CYCLOPHOSPHAMIDE Blood sugar levels may be ≠ or ↓ Uncertain Need to monitor blood glucose in patients with concomitant treatment at the beginning of treatment and after 1-2 weeks

SULPHONAMIDES – GLIMEPIRIDE, GLIPIZIDE, TOLBUTAMIDE

IMATINIB ≠ plasma concentrations, with risk of toxic effects of these drugs

Imatinib is a potent inhibitor of CYP2C9 isoenzymes, which metabolize these drugs

Watch for the early toxic effects of these drugs. If necessary, consider using alternative drugs while the patient is being given imatinib

ANTIDIABETIC DRUGS SULPHONYLUREAS

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Mechanism Precautions Attributed to additive effects Avoid exposure of skin and eyes to

direct sunlight for 30 days after porfimer therapy

SULPHONYLUREAS PROCARBAZINE ≠ risk of hypoglycaemic episodes MAOIs have an intrinsic hypoglycaemic effect. MAOIs are considered to enhance the effect of hypoglycaemic drugs

SULPHONYLUREAS LANREOTIDE, OCTREOTIDE Likely to alter insulin requirements Octreotide and lanreotide suppress pancreatic insulin and counterregulatory hormones (glucagon, growth hormone) and delay or ↓ absorption of glucose from the intestine

Essential to monitor blood sugar at least twice a week after initiating concurrent treatment until blood sugar levels are stable. Advise self-monitoring

GLIPIZIDE CICLOSPORIN May ≠ plasma concentrations of ciclosporin

Glipizide inhibits CYP3A4mediated metabolism of ciclosporin

Monitor plasma ciclosporin levels to prevent toxicity

SULPHONYLUREAS CORTICOSTEROIDS Often ≠ requirements of hypoglycaemic agent, particularly with high glucocorticoid activity steroids

Corticosteroids, particularly the glucocorticoids (betamethasone, dexamethasone, deflazacort, prednisolone cortisone, hydrocortisone), have intrinsic hyperglycaemic activity in both diabetic and non-diabetic subjects

Monitor blood sugar during concomitant treatment, weekly if possible, or advise self-monitoring, until blood sugar levels are stable. Larger doses of glimepiride are often needed

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ANTIDIABETIC DRUGS SULPHONYLUREAS

Uncertain Monitor blood sugar closely. Watch for and warn patients about symptoms of hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

SULPHONYLUREAS ANTICOAGULANTS – ORAL Cases reported of hypoglycaemia when coumarins started in patients on tolbutamide. Conversely, there are several case reports of bleeding when tolbutamide was started in patients on oral anticoagulants

Oral anticoagulants inhibit hepatic metabolism of tolbutamide and ≠ its half-life threefold. Tolbutamide possibly alters the plasma protein binding of anticoagulants

Use an alternative sulphonylurea or another class of hypoglycaemic

SULPHONYLUREAS ANTIDEPRESSANTS

SULPHONYLUREAS MAOIs ≠ risk of hypoglycaemic episodes MAOIs have an intrinsic hypoglycaemic effect and are considered to enhance the effect of hypoglycaemic drugs

SULPHONYLUREAS SSRIs Fluctuations in blood sugar are very likely, with both hypoglycaemic and hyperglycaemic events being reported in diabetics receiving hypoglycaemic treatment. ≠ plasma concentrations of sulphonylureas (e.g. tolbutamide) may occur

Brain serotonin and corticotropinreleasing hormone systems participate in the control of blood sugar levels. ≠ (usually acute) in brain serotonergic activity induces a hyperglycaemic response. Fluvoxamine is a potent inhibitor and fluoxetine a less potent inhibitor of CYP2C9, which metabolizes sulphonylureas

Both hyper-and hypoglycaemic responses have been reported with SSRIs; there is a need to monitor blood glucose closely prior to, during and after discontinuing SSRI treatment ➣ For signs and symptoms of hypoglycaemia and hyperglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia, Hyperglycaemia

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Mechanism Precautions Plasma levels of sulphonylureas

are ↓ by induction of CYP-mediated metabolism

SULPHONYLUREAS TCAs Likely to impair control of diabetes TCAs may ≠ serum glucose levels by up to 150%, ≠ appetite (particularly carbohydrate craving) and ↓ metabolic rate

Be aware and monitor blood sugar weekly until stable. They are generally considered safe unless diabetes is poorly controlled or is associated with significant cardiac or renal disease. Amitriptyline, imipramine and citalopram are also used to treat painful diabetic neuropathy

SULPHONYLUREAS ANTIDIABETIC DRUGS ≠ risk of hypoglycaemic episodes Due to additive effects by similar or differing mechanisms to lower blood sugar

Combinations may be used therapeutically. Warn patients about hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

TOLBUTAMIDE ANTIEMETICS – APREPITANT

↓ tolbutamide levels Aprepitant ≠ CYP2C9-mediated metabolism of tolbutamide

Monitor blood glucose closely

SULPHONYLUREAS ANTIEPILEPTICS

SULPHONYLUREAS BARBITURATES ↓ hypoglycaemic efficacy Plasma levels of sulphonylureas are ↓ by induction of CYPmediated metabolism

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≠ metabolism of glipizide due to ≠ activity of the enzymes that metabolize glipizide by carbamazepine

A higher dose of glipizide may be needed for adequate control of high blood sugar

SULPHONYLUREAS HYDANTOINS ↓ hypoglycaemic efficacy Hydantoins are considered to ↓ release of insulin

Monitor capillary blood glucose closely; higher doses of antidiabetic drugs are needed

SULPHONYLUREAS ANTIFUNGALS – ITRACONAZOLE, FLUCONAZOLE, MICONAZOLE, VORICONAZOLE

≠ risk of hypoglycaemic episodes Inhibition of CYP2C9-mediated metabolism of sulphonylureas

SULPHONYLUREAS ANTIGOUT DRUGS

SULPHONYLUREAS PROBENECID ≠ risk of hypoglycaemic episodes due to ≠ plasma levels of glimepiride

Attributed to ↓ renal excretion of sulphonylureas by probenecid. Probenecid is also an inhibitor of CYP2C9 isoenzymes

SULPHONYLUREAS SULFINPYRAZONE ≠ hypoglycaemic effect of sulphonylureas

Uncertain Monitor blood glucose regularly

ANTIDIABETIC DRUGS SULPHONYLUREAS

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Mechanism Precautions

Mechanism uncertain. ACE inhibitors possibly ≠ insulin sensitivity and glucose utilization. Altered renal function may also be factor. ACE inhibitors may ≠ bradykinin levels, which ↓ production of glucose by the liver. Hypoglycaemia is reported as a (rare) side-effect of ACE inhibitors. Suggested that the occurrence of hypoglycaemia is greater with captopril than enalapril. Captopril and enalapril are used in the treatment of diabetic nephropathy

Concurrent treatment need not be avoided and is often beneficial in type II diabetes. Watch for and warn patients about symptoms of hypoglycaemia. Be aware that the risk of hypoglycaemia is greater in elderly people and in patients with poor glycaemic control ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

SULPHONYLUREAS ADRENERGIC NEURONE BLOCKERS

≠ hypoglycaemic effect Catecholamines are diabetogenic; guanethidine blocks the release of catecholamines from nerve endings

Monitor blood glucose closely

SULPHONYLUREAS – TOLBUTAMIDE

ANGIOTENSIN II RECEPTOR ANTAGONISTS – IRBESARTAN

Possible ≠ hypotensive effect of irbesartan

Tolbutamide competitively inhibits CYP2C9-mediated metabolism of irbesartan

Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (light-headedness, dizziness on standing, etc.)

SULPHONYLUREAS VASODILATOR ANTIHYPERTENSIVES – BOSENTAN

1. Risk of hepatotoxicity when bosentan is given with glibenclamide 2. ≠ risk of hypoglycaemic episodes when bosentan is given with glimepiride or tolbutamide

1. Additive effect: both drugs inhibit the bile sodium export pump 2. Bosentan may inhibit CYP2C9-mediated metabolism of sulphonylureas

1. Avoid co-administration 2. Monitor blood glucose levels closely. Warn patients about the signs and symptoms of hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

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ANTIDIABETIC DRUGS SULPHONYLUREAS

Diazoxide causes hyperglycaemia by inhibiting insulin release and probably by a catecholamineinduced extrahepatic effect. Sulphonylureas act by ≠ insulin release. Used in the treatment of hypoglycaemia due to insulinomas

Larger doses of sulphonylureas are often required; need to monitor blood sugar until adequate control of blood sugar is achieved

SULPHONYLUREAS ANTIOBESITY DRUGS – ORLISTAT, RIMONABANT, SIBUTRAMINE

Tendency for blood glucose levels to fluctuate. There may be a tendency to enhance the hypoglycaemic effect

These agents change dietary intake of carbohydrates and other foods, and the risk of fluctuations of blood glucose is greater if there is a concurrent dietary regimen. A side-effect of orlistat is hypoglycaemia

These agents are used often in type II diabetics on hypoglycaemic therapy. Need to monitor blood sugars twice weekly until stable. Advise selfmonitoring. Warn patients about hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

SULPHONYLUREAS ANTIPARKINSON’S DRUGS – RASAGILINE, SELEGILINE

≠ risk of hypoglycaemic episodes These drugs are MAO-B inhibitors. MAOIs have an intrinsic hypoglycaemic effect and are considered to enhance the effect of hypoglycaemic drugs

SULPHONYLUREAS ANTIPLATELET AGENTS – ASPIRIN

Risk of hypoglycaemia when high-dose aspirin (3.5-7.5 g/day) is given with antidiabetic drugs

Additive effect; aspirin has a hypoglycaemic effect

Avoid high-dose aspirin

SULPHONYLUREAS ANTIPROTOZOALS – PENTAMIDINE

May alter sulphonylurea requirements due to altered glycaemic control

Attributed to pancreatic beta cell toxicity

Need to monitor blood sugar until stable and following withdrawal of pentamidine

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loss of control of blood sugar

Clozapine can cause resistance to the action of insulin

Watch/monitor for diabetes mellitus in subjects on long-term clozapine treatment

SULPHONYLUREAS PHENOTHIAZINES May ≠ blood sugar-lowering effect and risk of hypoglycaemic episodes. Likely to occur with doses exceeding 100 mg/day per day

Phenothiazines such as chlorpromazine inhibit the release of epinephrine and ≠ risk of hypoglycaemia. May inhibit release of insulin, which is the mechanism by which sulphonylureas act

Chlorpromazine is nearly always used in the long term. Watch for and warn patients about symptoms of hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

SULPHONYLUREAS ANTIVIRALS – PROTEASE INHIBITORS

≠ adverse effects of tolbutamide with ritonavir (e.g. myelosuppression, peripheral neuropathy, mucositis)

Uncertain Monitor blood sugar closely

SULPHONYLUREAS APROTININ ≠ availability of insulin and risk of hypoglycaemic episodes

Aprotinin ≠ availability of insulin injected subcutaneously. The mechanism is uncertain. Sulphonylureas augment insulin release

SULPHONYLUREAS BETA-BLOCKERS Beta-blockers may mask the symptoms and signs of hypoglycaemia, such as tachycardia and tremor; there have even been cases of bradycardia and ≠ BP during hypoglycaemic episodes in patients on beta-blockers

Beta-blockers prevent or inhibit the normal physiological response to hypoglycaemia by interfering with catecholamine-induced mobilization – glycogenolysis and mobilization of glucose –thereby prolonging the time taken by the body to achieve normal (euglycaemic) blood sugar levels

Warn patients about the masking of signs of hypoglycaemia. Cardioselective betablockers are preferred, and all betablockers should be avoided in patients having frequent hypoglycaemic attacks; otherwise monitor glycaemic control, especially during initiation of therapy ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

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in the fetus, independent of maternal blood glucose levels. ≠ risk of ketoacidosis when administered intravenously

By inducing glycogenolysis, betaadrenergic agonists cause elevation of blood sugar in adults. In the fetus, these agents cause a depletion of fetal glycogen stores

Monitor blood sugar closely during concomitant administration until blood sugar levels are stable. Be cautious during use in pregnancy. Formoterol and salmeterol are long-acting beta-agonists

SULPHONYLUREAS CNS STIMULANTS – MODAFINIL

May cause ≠ plasma concentrations of sulphonylureas if CYP2C9 is the predominant metabolic pathway and the alternative pathways are either genetically deficient or affected

Modafinil is a moderate inhibitor of CYP2C9

Be aware

SULPHONYLUREAS DIURETICS

CHLORPROPAMIDE POTASSIUM-SPARING DIURETICS AND ALDOSTERONE ANTAGONISTS

Risk of hyponatraemia when chlorpropamide is given to a patient taking both potassiumsparing diuretics/aldosterone antagonists and thiazides

Additive effect; chlorpropamide enhances ADH secretion

Monitor serum sodium regularly

SULPHONYLUREAS THIAZIDES ↓ hypoglycaemic efficacy Hyperglycaemia due to antagonistic effect

Monitor blood glucose regularly until stable. A higher dose of oral antidiabetic is often needed

CHLORPROPAMIDE THIAZIDES Risk of hyponatraemia when chlorpropamide is given to a patient taking both potassiumsparing diuretics/aldosterone antagonists and thiazides

Additive effect; chlorpropamide enhances ADH secretion

Monitor serum sodium regularly

ANTIDIABETIC DRUGS SULPHONYLUREAS

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hypoglycaemic episodes

Cimetidine and ranitidine ↓ renal elimination of glimepiride and ≠ intestinal absorption of glimepiride. Cimetidine is also an inhibitor of CYP2D6 and CYP3A4

Consider alternative acid suppression, e.g. proton pump inhibitor (not omeprazole), and monitor more closely

SULPHONYLUREAS LIPID-LOWERING DRUGS

GLIPIZIDE ANION EXCHANGE RESINS Glipizide absorption may be ↓ by colestyramine

Colestyramine interrupts the enterohepatic circulation of glipizide

Avoid co-administration

TOLBUTAMIDE FIBRATES Fibrates may ≠ efficacy of sulphonylureas

Uncertain; postulated that fibrates displace sulphonylureas from plasma proteins and ↓ their hepatic metabolism. In addition, fenofibrate may inhibit CYP2C9-mediated metabolism of tolbutamide

SULPHONYLUREAS MUSCLE RELAXANTS – BACLOFEN

↓ hypoglycaemic effect of sulphonylureas

Due to these drugs causing hyperglycaemia, the mechanism being uncertain at present

≠ doses of sulphonylureas are often required for adequate glycaemic control

SULPHONYLUREAS NANDROLONE ≠ effect of antidiabetic drugs Uncertain Monitor blood sugar closely SULPHONYLUREAS NIACIN ↓ hypoglycaemic effect of

sulphonylureas Due to these drugs causing hyperglycaemia, the mechanism being uncertain at present

≠ doses of sulphonylureas are often required for adequate glycaemic control

SULPHONYLUREAS NICOTINE ↓ hypoglycaemic effect of sulphonylureas

Due to these drugs causing hyperglycaemia, the mechanism being uncertain at present

≠ doses of sulphonylureas are often required for adequate glycaemic control

SULPHONYLUREAS OESTROGENS Altered glycaemic control Uncertain at present Monitor blood glucose closely

SULPHONYLUREAS PROGESTOGENS Altered glycaemic control Uncertain at present Monitor blood glucose closely