chapter
Insulin
Pages 8

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

INSULIN 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

INSULIN ANTIBIOTICS

INSULIN 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 Precautions

Both hyperglycaemia and hypoglycaemia

Altered glycaemic control requires frequent monitoring

INSULIN OFLOXACIN ≠ risk of hypoglycaemic episodes Mechanism underlying hypoglycaemia is not known

INSULIN ANTICANCER AND IMMUNOMODULATING DRUGS

INSULIN CYTOTOXICS – PROCARBAZINE

≠ risk of hypoglycaemic episodes Procarbazine has mild MAO properties. MAOIs have an intrinsic hypoglycaemic effect and are considered to enhance the effect of hypoglycaemic drugs

INSULIN HORMONE ANTAGONISTS – OCTREOTIDE, LANREOTIDE

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. Warn patients re hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

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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 insulin are often needed

INSULIN ANTIDEPRESSANTS

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

INSULIN 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. An ≠ (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, and 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

ANTIDIABETIC DRUGS INSULIN

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Mechanism Precautions TCAs may ≠ serum glucose levels

by up to 150%, and ≠ 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

INSULIN 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

INSULIN ANTIHYPERTENSIVES AND HEART FAILURE DRUGS

INSULIN ACE INHIBITORS ≠ risk of hypoglycaemic episodes 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 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

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ANTIDIABETIC DRUGS INSULIN

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

Monitor blood glucose closely

INSULIN VASODILATOR ANTIHYPERTENSIVES – DIAZOXIDE

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

Larger doses of insulin are often required, and there is a need to monitor blood sugar until adequate control of blood sugar is achieved

INSULIN ANTIOBESITY DRUGS – ORLISTAT, RIMONABANT, SIBUTRAMINE

Tendency for blood glucose levels to fluctuate

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

These agents are used often in patients with type II diabetes who are on hypoglycaemic therapy. Need to monitor blood sugars twice weekly until stable. Advise self-monitoring and watch for and warn about symptoms of hypoglycaemia ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

INSULIN 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

INSULIN ANTIPLATELET AGENTS – ASPIRIN

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

Additive effect; aspirin has a hypoglycaemic effect

Avoid high-dose aspirin

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Mechanism Precautions

Attributed to pancreatic beta cell

toxicity Altered glycaemic control; need to monitor blood sugar until stable and following withdrawal of pentamidine

INSULIN ANTIPSYCHOTICS – CLOZAPINE

May cause ≠ blood sugar and loss of control of blood sugar

Clozapine can cause resistance to the action of insulin

Watch for diabetes mellitus in patients on long-term clozapine treatment

INSULIN ANTIVIRALS – PROTEASE INHIBITORS

↓ efficacy of insulin Several mechanisms considered include insulin resistance, impaired insulin-stimulated glucose uptake by skeletal muscle cells, ↓ insulin binding to receptors, and inhibition of intrinsic transport activity of glucose transporters in the body

Necessary to establish baseline values for blood sugar before initiating therapy with a protease inhibitor. Atazanavir, darunavir, fosamprenavir or tipranavir may be safer ➣ For signs and symptoms of hyperglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hyperglycaemia

INSULIN APROTININ ≠ availability of insulin and risk of hypoglycaemic episodes

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

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ANTIDIABETIC DRUGS INSULIN

hypoglycaemia. They also ↓ insulin sensitivity; however, beta-blockers that also have vasodilating properties (carvedilol, celiprolol, labetalol, nebivolol) seem to ≠ sensitivity to insulin

Beta-blockers ↓ glucose tolerance and interfere with the metabolic and autonomic responses to hypoglycaemia

Warn patients about the masking of signs of hypoglycaemia. Vasodilating beta-blockers are preferred in patients with diabetes, and all beta-blockers should be avoided in those having frequent hypoglycaemic attacks. Monitor capillary blood glucose closely, especially during initiation of therapy ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

INSULIN BETA-BLOCKERS – PINDOLOL, PROPRANOLOL, TIMOLOL EYE DROPS

Hypoglycaemia has occurred in patients on insulin also taking oral propanolol and pindolol, propanolol, and timolol eye drops

These beta-blockers inhibit the rebound in blood glucose that occurs as a response to a fall in blood glucose levels

Cardioselective beta-blockers are preferred, and all beta-blockers should be avoided in those having frequent hypoglycaemic attacks. Monitor capillary blood glucose closely, especially during initiation of therapy ➣ For signs and symptoms of hypoglycaemia, see Clinical Features of Some Adverse Drug Interactions, Hypoglycaemia

INSULIN BRONCHODILATORS – BETA-AGONISTS

≠ risk of hyperglycaemia. ≠ risk of hypoglycaemia in the fetus when administered during pregnancy even with normal maternal blood sugar levels. ≠ risk of ketoacidosis when administered intravenously

By inducing glycogenolysis, betaadrenergic agonists cause an 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 longacting beta-agonists

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Mechanism Precautions

NIFEDIPINE

≠ insulin requirements with diltiazem and nifedipine

Uncertain at present Evidence suggests that calcium channel blockers are safe in diabetics; monitor blood glucose levels when starting calcium channel blockers

INSULIN MUSCLE RELAXANTS – BACLOFEN

↓ hypoglycaemic effect of insulin Due to these drugs causing hyperglycaemia, the mechanism being uncertain at present

≠ doses of insulin are often required for adequate glycaemic control

INSULIN NANDROLONE ≠ effect of antidiabetic drugs Uncertain Monitor blood sugar closely INSULIN NIACIN ↓ hypoglycaemic effect of insulin Due to these drugs causing

hyperglycaemia, the mechanism being uncertain at present

≠ doses of insulin are often required for adequate glycaemic control

INSULIN NICOTINE ↓ hypoglycaemic effect of insulin Due to these drugs causing hyperglycaemia, the mechanism being uncertain at present

≠ doses of insulin are often required for adequate glycaemic control

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

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

INSULIN SOMATROPIN ↓ hypoglycaemic effect of insulin Due to these drugs causing hyperglycaemia, the mechanism being uncertain at present

≠ doses of insulin are often required for adequate glycaemic control

INSULIN SYMPATHOMIMETICS – EPINEPHRINE

May ≠ insulin requirement 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 insulin may be needed during the period of epinephrine use, which is usually in the short term or in emergency situations

INSULIN 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