Metformin should be withdrawn and insulin substituted before major elective surgery. Plasma creatinine and liver function tests should be monitored before and during its use. Mechanism of action This remains uncertain. Biguanides do not produce hypoglycaemia and are effective in pancreatectomized animals. Effects of metformin include: • reduced glucose absorption from the gut; • facilitation of glucose entry into muscle by a non-insulinresponsive mechanism; • inhibition of gluconeogenesis in the liver; • suppression of oxidative glucose metabolism and enhanced anaerobic glycolysis. Adverse effects Metformin causes nausea, a metallic taste, anorexia, vomiting and diarrhoea. The symptoms are worst when treatment is initiated and a few patients cannot tolerate even small doses. Lactic acidosis, which has a reported mortality in excess of 60%, is uncommon provided that the above contraindications are respected. Treatment is by reversal of hypoxia and circulatory collapse and peritoneal or haemodialysis to alleviate sodium overloading and removing the drug. Phenformin (withdrawn in the UK and USA) was more frequently associated with this problem than metformin. Absorption of vitamin B12 is reduced by metformin, but this is seldom clinically important. Pharmacokinetics Oral absorption of metformin is 50–60%; it is eliminated unchanged by renal excretion, clearance being greater than the glomerular filtration rate because of active secretion into the tubular fluid. Metformin accumulates in patients with renal impairment. The plasma t1/2 ranges from 1.5 to 4.5 hours, but its duration of action is considerably longer, permitting twice daily dosing. Drug interactions Other oral hypoglycaemic drugs are additive with metformin. Ethanol predisposes to metformin-related lactic acidosis. SULPHONYLUREAS AND RELATED DRUGS Use Sulphonylureas (e.g. tolbutamide, glibenclamide, gliclazide) are used for type 2 diabetics who have not responded adequately to diet alone or diet and metformin with which they are additive. They improve symptoms of polyuria and polydipsia, but (in contrast to metformin) stimulate appetite. Chlorpropamide, the longest-acting agent in this group, has a higher incidence of adverse effects (especially hypoglycaemia) than other drugs of this class and should be avoided. This is because of a protracted effect and reduced renal clearance in patients with renal dysfunction and the elderly; thus it is hardly ever used. Tolbutamide and gliclazide are shorter acting than glibenclamide, so there is less risk of hypoglycaemia, and for this reason they are preferred in the elderly. Related DRUGS USED TO TREAT DIABETES MELLITUS 289 drugs (e.g. repaglinide, nateglinide) are chemically distinct, but act at the same receptor. They are shorter acting even than tolbutamide, but more expensive. They are given before meals. Mechanism of action The hypoglycaemic effect of these drugs depends on the presence of functioning B cells. Sulphonylureas, like glucose, depolarize B cells and release insulin. They do this by binding to sulphonylurea receptors (SUR) and blocking ATP-dependent potassium channels (KATP); the resulting depolarization activates voltage-sensitive Ca2� channels, in turn causing entry of Ca2� ions and insulin secretion. Adverse effects Sulphonylureas can cause hypoglycaemia. Chlorpropamide, the longest-acting agent, was responsible for many cases. It also causes flushing in susceptible individuals when ethanol is consumed, and can cause dilutional hyponatraemia (by potentiating ADH, see Chapter 42). Allergic reactions to sulphonylureas include rashes, drug fever, gastrointestinal upsets, transient jaundice (usually cholestatic) and haematopoietic changes, including thrombocytopenia, neutropenia and pancytopenia. Serious effects other than hypoglycaemia are uncommon. Pharmacokinetics Sulphonylureas are well absorbed from the gastrointestinal tract and the major differences between them lie in their relative potencies and rates of elimination. Glibenclamide is almost completely metabolized by the liver to weakly active metabolites that are excreted in the bile and urine. The activity of these metabolites is only clinically important in patients with renal failure, in whom they accumulate and can cause hypoglycaemia. Tolbutamide is converted in the liver to inactive metabolites which are excreted in the urine. The t1/2 shows considerable inter-individual variability, but is usually four to eight hours. Gliclazide is extensively metabolized, although up to 20% is excreted unchanged in the urine. The plasma t1/2 ranges from 6 to 14 hours. Repaglinide and nateglinide exhibit rapid onset andoffset kinetics, rapid absorption (time to maximal plasma concentration approximately 55 minutes after an oral dose) and elimination (half-life approximately three hours). These features lead to short duration of action and a low risk of hypoglycaemia. They are administered shortly before a meal to reduce the postprandial glucose rise in type 2 diabetic patients. Drug interactions Monoamine oxidase inhibitors potentiate the activity of sulphonylureas by an unknown mechanism. Several drugs (e.g. glucocorticosteroids, growth hormone) antagonize the hypoglycaemic effects of sulphonylureas by virtue of their actions on insulin release or sensitivity. THIAZOLIDINEDIONES (GLITAZONES) Glitazones (e.g. piolitazone, rosiglitazone) were developed from the chance finding that a fibrate drug (Chapter 27) increased insulin sensitivity.
290 DIABETES MELLITUS Use Glitazones lower blood glucose and haemoglobin A1c (HbA1c) in type 2 diabetes mellitus patients who are inadequately controlled on diet alone or diet and other oral hypoglycaemic drugs. An effect on mortality or diabetic complications has yet to be established, but they have rapidly become very widely used. Mechanism of action Glitazones bind to the peroxisome-proliferating activator receptor γ (PPARγ), a nuclear receptor found mainly in adipocytes and also in hepatocytes and myocytes. It works slowly, increasing the sensitivity to insulin possibly via effects of circulating fatty acids on glucose metabolism. Adverse effects The first two glitazones caused severe hepatotoxicity and are not used. Hepatotoxicity has not proved problematic with rosiglitazone or pioglitazone, although they are contraindicated in patients with hepatic impairment and liver function should be monitored during their use. The most common adverse effects are weight gain (possibly partly directly related to their effect on adipocytes) and fluid retention due to an effect of PPARγ receptors on renal tubular sodium ion absorption. They can also exacerbate cardiac dysfunction and are therefore contraindicated in heart failure. Recently, an association with increased bone fractures and osteoporosis has been noted. They are contraindicated during pregnancy. A possible increase in myocardial infarction with rosiglitazone has been noted, but the data are controversial. Pharmacokinetics Both rosiglitazone and pioglitazone are well absorbed, highly protein bound and subject to hepatic metabolism. Drug interactions Glitazones are additive with other oral hypoglycaemic drugs. They potentiate insulin, but this combination is contraindicated in Europe because of concerns that it might increase the risk of heart failure, although the combination is widely used in the USA. Pioglitazone is an inducer of CYP3A and may cause treatment failure with concomitantly administered drugs which are CYP3A substrates (e.g. reproductive steroids). ACARBOSE Acarbose is used in type 2 diabetes mellitus in patients who are inadequately controlled on diet alone or diet and other oral hypoglycaemic agents. Acarbose is a reversible competitive inhibitor of intestinal α-glucoside hydrolases and delays the absorption of starch and sucrose, but does not affect the absorption of ingested glucose. The postprandial glycaemic rise after a meal containing complex carbohydrates is reduced and its peak is delayed. Fermentation of unabsorbed carbohydrate in the intestine leads to increased gas formation which results in flatulence, abdominal distension and occasionally diarrhoea. As with any change in a diabetic patient’s medication, diet or activities, the blood glucose must be monitored. Key points Type 2 diabetes mellitus and oral hypoglycaemic agents • Type 2 (non-insulin-dependent) diabetes mellitus is caused by relative deficiency of insulin in the face of impaired insulin sensitivity. Such patients are usually obese. • About one-third of such patients finally require insulin treatment. This is especially important when they are losing muscle mass. • The dietary goal is to achieve ideal body weight by consuming an energy-restricted healthy diet low in saturated fat (Chapter 27). • Oral hypoglycaemic drugs are useful in some patients as an adjunct to diet. • Metformin, a biguanide, lowers blood glucose levels and encourages weight loss by causing anorexia. Diarrhoea is a common adverse effect. It is contraindicated in patients with renal impairment, heart failure, obstructive pulmonary disease or congenital mitochondrial myopathies because of the risk of lactic acidosis, a rare but life-threatening complication. • Acarbose, an α-glucosidase inhibitor, delays the absorption of starch and sucrose. It flattens the rise in plasma glucose following a meal and may improve control when added to diet with or without other drugs. However, it can cause bloating, flatulence and diarrhoea associated with carbohydrate malabsorption. • Sulphonylureas (e.g. tolbutamide) and related drugs (e.g. nateglinide) release insulin from β-cells by closing ATP-sensitive K � channels, thereby depolarizing the cell membrane. They are well tolerated and improve blood glucose at least initially, but stimulate appetite, promoting weight gain. They differ from one another in their kinetics, the longer-acting drugs being particularly likely to cause hypoglycaemia which can be severe, especially in the elderly and should not be used in these patients. • Thiazolidinediones (e.g. pioglitazone, rosiglitazone) activate PPARγ receptors and increase insulin sensitivity. They lower blood sugar but cause weight gain and fluid retention. They are contraindicated in heart failure. Effects on longevity or complications are unknown. Case history A 56-year-old woman with a positive family history of diabetes presents with polyuria, polydipsia, blurred vision and recurrent attacks of vaginal thrush. She is overweight at 92 kg, her fasting blood sugar is 12 mmol/L and haemoglobin A1C is elevated at 10.6%. She is treated with glibenclamide once daily in addition to topical antifungal treatment for the thrush. Initially, her symptoms improve considerably and she feels generally much better, but after nine months the polyuria and polydipsia recur and her weight has increased to 102 kg. Comment Treatment with a sulphonylurea without attention to diet is doomed to failure. This patient needs to be motivated to take dietary advice, restricting her energy intake and reducing her risk of atherosclerosis. If hyperglycaemia is still not improved, metformin (which reduces appetite) would be appropriate.
Soliman s Auricular Therapy Textbook: New Localizations and Evidence Based Therapeutic Approaches was created ( M.D. Nader Soliman )
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Soliman s Auricular Therapy Textbook This textbook is considered the finest ever written in the field of auricular therapy. The auricular acupuncture microsystem is one of the most widely used special acupuncture techniques. This textbook is dedicated to teaching the sound foundations of this unique approach as introduced by its founder Dr. Paul Nogier of France. The scientific bases of the acupuncture microsystem with its three dime... Full description
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