Category Archive: Drugs
Subcategories: No categories
Current Oral Antidiabetic Therapy: Benzoic Acid Derivatives
Repaglinide
Brand Name Drug: Prandin in the U.S., GlucoNorm in Canada, NovoNorm elsewhere
Benzoic acid derivatives are the most recent addition to the list of treatment options for type 2 diabetes. In 1998, the FDA approved the first agent in this class, repaglinide. Benzoic acid derivatives are similar to sulfonylureas in that they are insulin secretagogues. However, they differ in that they bind to a different receptor on the beta cell membrane. Also, in contrast to sulfonylureas, benzoic acid derivatives do not cause direct exocytic insulin release in the absence of glucose stimulation.
The true benefit of these agents stems from the fact that they have a short duration of action. Repaglinide is administered just before the start of the meal and stimulates insulin secretion. However, the duration of action is much shorter than the sulfonylureas, and the main effect is to reduce postprandial hyperglycemia. Due to the short half-life, repaglinide is useful in patients who have erratic meal schedules.
The main advantage of repaglinide is the potential for decreased incidence of hypoglycemia, making it an effective agent in elderly patients and those with renal insufficiency or other predisposition to hypoglycemia. It is given only at the meal time in 1-mg and 2-mg tablets. Most patients are started on 0.5 mg prior to meals. It often is useful to initially monitor pre- and one-hour postprandial fingerstick glucoses to assess the effects of this agent.
Conclusion
Much of the benefit from tight control in patients with type 1 diabetes has now been extrapolated to the much larger group of patients with type 2 diabetes. Recent data have shown that tight control of type 2 diabetes is strongly associated with a decreased incidence and rate of progression of microvascular complications. Multiple new oral agents recendy have been developed for the treatment of this disorder. Effective use of these agents by physicians is imperative in controlling this disease and preventing or delaying acute and chronic complications in African Americans. It is important to remember that these new agents are relatively ineffective without proper dietary counseling and increased physical activity. In addition to glycemic control, treatment of hypertension and hyperlipidemia will also result in significant decreases in micro- and macrovascular disease in individuals with type 2 diabetes.
Comprehensive screening also is essential as it is estimated that 50% of Americans with the disease are unaware of their illness. The ADA now recommends testing of fasting glucose every three years for all adults >45 years. For higher risk groups, such as African Americans and those with a history of gestational diabetes, screening is recommended on a yearly basis. Those patients with a fasting glucose >126 mg/dL must receive proper dietary and exercise instruction as well as diabetic teaching about the importance of foot care and home glucose monitoring. These measures combined with the effective use of pharmacologic agents in those who fail conservative therapy will improve the control of the type 2 diabetes epidemic in the black community.
Effexor Improve Diabetic Nerve Pain
The drug Effexor (venlafaxine hydrochloride) was approved by the FDA in 1993 for the treatment of depression and anxiety. An extended-release once-daily version, Effexor XR, received marketing clearance in 1997. Now Effexor XR is showing promise for ameliorating the symptoms of another disorder: diabetic neuropathy. The results of the study were reported at the 60th annual meeting of the American Diabetes Association in June 2000.
Diabetic neuropathy causes numbness, tingling and pain in the arms and legs due to diabetes-associated nerve damage, and it afflicts some 60 percent of patients with diabetes. In doses ranging from 150-225 mg/day, Effexor XR was significantly more effective than placebo in relieving neuropathic pain. The drug is manufactured by Wyeth-Ayerst Laboratories, a division of American Home Products. Effexor inhibits the uptake of the neurotransmitters serotonin and norepinephrine in the brain. Both serotonin and norepinephrine are involved not only in mediation of mood, but also perception of pain.
The safety and effectiveness of Effexor XR as a treatment for painful diabetic neuropathy were assessed in a study of 244 patients age 18 or older with type 1 or type 2 diabetes who received either Effexor XR 75 mg, 150-225 mg or placebo for up to six weeks. Ratings of pain relief by patients and investigators were used to measure treatment effectiveness.
Effexor XR 150-225 mg produced significantly greater pain relief compared with placebo. By week six, 56 percent of patients treated with Effexor XR 150-225 mg experienced significantly lowered pain intensity compared with 39 percent treated with Effexor XR 75 mg and 34 percent given a placebo. Since patients with a major depressive disorder were excluded from the study, the improvement of symptoms was attributable to a pain-relieving, rather than an antidepressant, effect.
“As diabetic neuropathy progresses over time, the pain caused by nerve damage may become overwhelming, and medications such as aspirin, acetaminophen or ibuprofen do not work as well,” said Dr. Sherwyn Schwartz, director of the diabetes and glandular disease clinic in San Antonio, Texas. “Effexor XR is an effective medication that may represent a new treatment option for patients suffering from this condition.”
The most common adverse event associated with Effexor XR was nausea. Other side effects that may occur with use of Effexor XR include insomnia, nervousness, anorexia, weight loss and blood pressure increases.
Biguanide Antidiabetics
Antidiabeticos biguanfdicos
Adverse Effects
Gastrointestinal adverse effects including anorexia, nausea, vomiting, and diarrhoea may occur with bigua-nides patients may experience taste disturbance and there may be weight loss. Absorption of various substances including vitamin B12 may be impaired. Skin reactions have been reported rarely. Hypoglycaemia is rare with a biguanide given alone, although it may occur if other contributing factors or drugs are present.
Lactic acidosis, sometimes fatal, has occurred with biguanides, primarily with phenformin. When it has occurred with metformin most cases have been in patients whose condition contra-indicated the use of the drug, particularly those with renal impairment. Phenformin has been implicated in the controversial reports of excessive cardiovascular mortality associated with oral hypoglycaemic therapy (see under Sulfonylureas, Effects on the Cardiovascular System).
Effects on the blood. Megaloblastic anaemia has occurred with biguanide therapy (see Malabsorption, under Effects on the Gastrointestinal Tract, below). A few cases of metformin-induced haemolysis resulting in hyperbilirubinaemia and jaundice have also been described.
Effects on the gastrointestinal tract. DIARRHOEA. In a retrospective survey, 30 of 265 diabetic patients reported diarrhoea or alternating diarrhoea and constipation, comprising: 11 of 54 taking metformin 9 of 45 taking metformin with a sulfonylurea 3 of 53 taking a sulfonylurea only 5 of 78 on insulin therapy 2 of 35 on diet alone. Among 150 nondiabetic controls 12 reported diarrhoea. Chronic diarrhoea described as watery, often explosive, and frequently causing faecal incontinence, has been reported as an adverse effect of late onset in patients receiving metformin. Some patients had been on stable metformin therapy for several years before the onset of diarrhoea. Symptoms ceased upon withdrawal of metformin, and recurred in cases of rechallenge.
MALABSORPTION. Megaloblastic anaemia due to vitamin B12 malabsorption in a 58-year-old woman was associated with long-term treatment with metformin.
In a survey of diabetic patients receiving biguanide therapy,malabsorption of vitamin B12 was observed in 14 of 46 diabetics taking metformin or phenformin metformin was more commonly to blame. Withdrawal of the drug resulted in normal absorption in only 7 of the 14. In a series of 10 patients with vitamin B12 deficiency associated with metformin, vitamin B12 concentrations and blood count abnormalities were reported to have been corrected within 3 months of starting treatment with intramuscular or oral cyanocobalamin 2 patients were transferred to treatment with other antidiabetic agents.
Effects on the liver. Severe cholestatic hepatitis attributed to metformin has been reported.
Effects on the pancreas. Acute pancreatitis is more commonly associated with phenformin. However, there have also been a few cases of pancreatitis associated with metformin, in which renal failure may have precipitated metformin toxicity.
Hypersensitivity. Vasculitis and pneumonitis in a 59-year-old woman was associated with use of metformin. Symptoms improved on withdrawal of metformin, but reappeared on its re-introduction. Cutaneous vasculitis in a 33-year-old woman also resolved on withdrawal of metformin and recurred with its re-introduction.
Hypoglycaemia. UK licensed product information for metformin states that hypoglycaemia does not occur with metformin alone, even in overdosage, although it may occur if given with alcohol or other hypoglycaemics. Interim results from the UK Prospective Diabetes Study, however, indicate that metformin therapy was associated with fewer hypoglycaemic episodes than sulfonylurea or insulin treatment, but more than with diet alone. One or more hypoglycaemic episodes were reported in 6% of the patients receiving the biguanide in this study, although only 1 patient had a severe episode.
Lactic acidosis. There is a small but definite risk of lactic acidosis associated with use of biguanide antidiabetics. Most early reports involved phenformin, which was consequently removed from the market in many countries although cases of phenformin-associated lactic acidosis still occur. There has therefore been concern about the risks of lactic acidosis with metformin, which is still in wide use. However, lactic acidosis with metformin appears to be much less common: a review suggested that the incidence was of the order of 3 cases per 100 000 patient years, which was 20 times less frequent than with phenformin. This concurs with the findings of the FDA after the introduction of metformin to the US market: in the year after the marketing of metformin in the USA, the FDA had received reports of metformin-associated lactic acidosis in 66 patients, the diagnosis being confirmed in 47. This represented a rate of about 5 cases per 100 000. Most patients who do develop lactic acidosis with metformin have one or more precipitating risk factors such as renal impairment, congestive heart failure, or other conditions predisposing to hypoxaemia or acute renal failure, including septicaemia, acute hepatic decompensation, alcohol abuse, acute myocardial infarction, and shock. A systematic review, which considered results comprising nearly 48 000 patient years of treatment with metformin, concluded that provided metformin was prescribed taking into account the proper contra-indications, there was no evidence of an increased risk of lactic acidosis. Nonetheless, there have been a few reports of lactic acidosis developing in metformin-treated patients without apparent risk factors.
Treatment of Adverse Effects
Acute poisoning with biguanides may lead to the development of lactic acidosis (see Metabolic Acidosis) and calls for intensive supportive therapy. Glucose or glucagon may be required for hypoglycaemia, the general management of which is outlined in Insulin.
Precautions
Biguanides are inappropriate for patients with diabetic coma and ketoacidosis, or for those with severe infection, trauma, or other severe conditions where the biguanide is unlikely to control the hyperglycaemia insulin should be used in such situations. Biguanides should not be given to patients with even mild renal impairment, as it may predispose patients to lactic acidosis, and renal function should be monitored throughout therapy. Dehydration may contribute to renal impairment. Conditions associated with hypoxia, such as acute heart failure, recent myocardial infarction, or shock, may increase the risk of lactic acidosis. Other conditions that may also predispose to lactic acidosis in a patient taking a biguanide include excessive alcohol intake and hepatic impairment. Biguanides should be temporarily stopped for examinations using contrast media (see under Interactions, below).
Insulin is preferred for the treatment of diabetes in pregnancy.
Owing to the possibility of decreased vitamin B12 absorption, annual monitoring of vitamin B12 concentrations is advisable during long-term treatment.
Driving. In the UK, patients with diabetes mellitus treated with insulin or oral hypoglycaemics are required to notify their condition to the Driver and Vehicle Licensing Agency, who then assess their fitness to drive. Patients treated with oral hypoglycaemics are generally allowed to retain standard driving licences those treated with insulin receive restricted licences which must be renewed (with appropriate checks) every 1 to 3 years. Patients should be warned of the dangers of hypoglycaemic attacks while driving, and should be counselled in appropriate management of the situation (stopping driving as soon as it is safe to do so, taking carbohydrate immediately, and quitting the driving seat and removing the ignition key from the car) should such an event occur. Patients who have lost hypoglycaemic awareness, or have frequent hypoglycaemic episodes, should not drive. In addition, eyesight must be adequate (field of vision of at least 120°) for a licence to be valid. Patients treated with diet or oral hypoglycaemics are normally allowed to hold vocational driving licences for heavy goods vehicles or passenger carrying vehicles those treated with insulin may not drive such vehicles, and are restricted in driving some other vehicles such as small lorries and minibuses.
Interactions
Use of a biguanide with other drugs that lower blood-glucose concentrations increases the risk of hypoglycaemia, while drugs that increase blood glucose may reduce the effect of biguanide therapy.
In general fewer drug interactions have been reported with biguanides than with sulfonylureas. Alcohol may increase the risk of lactic acidosis as well as of hypoglycaemia. Care should be taken if biguanides are given with drugs that may impair renal function.
Anticoagulants. For the effect of metformin on phenprocoumon activity, see Antidiabetics.
Antivirals. Fatal lactic acidosis has been reported in a patient given metformin with didanosine, stavuc&ne, and tenofovir.
Cimetidine. Cimetidine increased plasma-metformin concentrations in 7 healthy subjects. The renal clearance of metformin was reduced competition for proximal tubular secretion was considered responsible. A reduction in metformin dosage may be required in patients taking metformin and cimetidine, in order to reduce the risk of lactic acidosis.
Contrast media. Biguanides should be temporarily stopped for examinations using iodinated contrast media and withheld after the examination until normal renal function is confirmed, because of the risk of contrast media-induced renal impairment leading to biguanide toxicity and associated lactic acidosis. Licensed product information for some contrast media preparations warns that biguanides should be temporarily stopped 48 hours before the examination, and withheld for at least 48 hours after and until normal renal function is confirmed.
A number of guidelines on the use of iodinated contrast media give advice for the management of patients taking metformin. Some suggest that, in general, metformin can be stopped at the time of the examination. Others are more detailed, suggesting that if serum-creatinine is normal metformin may be stopped at the time of the examination, but that if it is raised metformin should be stopped 48 hours before giving the contrast medium.’They all agree that metformin should be withheld for 48 hours after the examination and until normal renal function is confirmed, although one suggests that no special precaution is needed for patients with normal serum-creatinine who are to be given a low volume of iodinated contrast medium (up to 100 mL).
Ketotifen. Platelet counts in 10 diabetic patients receiving biguanides fell (markedly in 3 patients) when they were also given ketotifen. Counts returned to normal a few days after the end of ketotifen therapy. However, the investigators did not consider the effect clinically significant.
Sulfonylureas. For reference to an apparent increase in mortality with an intensive regimen of metformin plus a sulfonylurea.
Uses and Administration
The biguanide antidiabetics are a class of oral antidiabetic drugs used in the treatment of type 2 diabetes mellitus. They are given to supplement treatment by diet modification when such modification has not proved effective on its own. In addition, because biguanides are not associated with weight gain they are preferred in obese patients. Although sulfonylureas may be preferred in non-obese patients, a biguanide is often added or given instead to patients who are not responding to a sulfonylurea. The mode of action of biguanides is not clear. They do not stimulate insulin release but require that some insulin be present in order to exert their antidiabetic effect. Possible mechanisms of action include delay in the absorption of glucose from the gastrointestinal tract, an increase in insulin sensitivity and glucose uptake into cells, and inhibition of hepatic gluconeogenesis. Biguanides do not usually lower blood-glucose concentrations in non-diabetic subjects.
Hyperlipidaemias. The effect of biguanides on lipid metabolism is unclear, although some studies have shown a beneficial effect on serum-lipid profiles in both obese and lean patients with type 2 diabetes, hypertension, and/or hyperlipidaemia. Reductions in concentrations of total cholesterol, low-density and very low-density-lipoprotein cholesterol have been reported, as well as modest increases in high-density-lipoprotein cholesterol. Some studies have also reported a reduction in serum-triglyceride levels. Such effects may be beneficial in the long-term treatment of type 2 diabetes mellitus with concomitant lipid disorders.
Polycystic ovary syndrome. For discussion of the potential of metformin in polycystic ovary syndrome.
Gliquidone
(British Approved Name, rINN)
Drug Nomenclature
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Pharmacopoeias. In British and China
British Pharmacopoeia 2008 (Gliquidone). A white or almost white powder. Practically insoluble in water slightly soluble in alcohol and in methyl alcohol soluble in acetone freely soluble in dimethylforma-mide.
Adverse Effects, Treatment, and Precautions
As for sulfonylureas in general.
Interactions
As for sulfonylureas in general.
Pharmacokinetics
Gliquidone is readily absorbed from the gastrointestinal tract. It is extensively bound to plasma proteins and has a half-life of about 1.5 hours. It is extensively metabolised in the liver, the metabolites having no significant hypoglycaemic effect, and is eliminated chiefly in the faeces via the bile only about 5% of a dose is excreted in the urine.
Uses and Administration
Gliquidone is a sulfonylurea antidiabetic. It has been given orally in the treatment of type 2 diabetes mellitus in a usual initial dosage of 15 mg daily given as a single dose up to 30 minutes before breakfast. Dosage may be adjusted by increments of 15 mg to a usual dose of 45 to 60 mg daily in 2 or 3 unequally divided doses, the largest dose being taken in the morning with breakfast. Single doses above 60 mg and daily doses above 180 mg are not recommended.
Preparations
British Pharmacopoeia 2008: Gliquidone Tablets.
Proprietary Preparations
Austria: Glurenorm
Belgium: Glurenorm
Czech Republic: Glurenorm
Germany: Glurenorm
Greece: Devotan
Hungary: Glurenorm
Indonesia: Glurenorm
Italy: Glurenor
Poland: Glurenorm
Portugal: Glurenor †
Russia: Glurenorm
Spain: Glurenor
Thailand: Glurenor
Turkey: Glurenorm
UK: Glurenorm
Guar Gum
Pharmacopoeias. In Europe. Also in USNF.
European Pharmacopoeia, 6th ed. (Guar). Guar is obtained by grinding the endosperms of the seeds of Cyamopsis tetragonolobus. It consists mainly of guar galactomannan. Guar is a white or almost white powder, yielding a mucilage of variable viscosity when dissolved in water. Practically insoluble in alcohol.
European Pharmacopoeia, 6th ed. (Guar Galactomannan). A yellowish-white powder. It is soluble in cold and hot water practically insoluble in organic solvents. Its main components are polysaccharides composed of D-galactose and D-mannose at molecular ratios of 1:1.4 to 1:2. The molecules consist of a linear main chain of β-(1 —>4)-glycosidically linked mannopyranoses and single α-(1 —>6)-glycosidically linked galactopyranoses.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Guar Gum). A gum obtained from the ground endosperms of Cyamopsis tetragonolobus (Leguminosae). It consists chiefly of a high-molecular-weight hydrocolloidal polysaccharide, a galactomannan, composed of galactan and mannan units combined through glycosidic linkages. It is a white to yellowish-white, practically odourless, powder. Dispersible in hot or cold water forming a colloidal solution.
Adverse Effects and Precautions
Guar gum can cause gastrointestinal disturbance with flatulence, diarrhoea, or nausea, particularly at the start of treatment.
Because guar gum swells on contact with liquid it should always be washed down carefully with water and should not be taken immediately before going to bed. It should not be used in patients with dysphagia, oesophageal disease, or intestinal obstruction.
Interactions
Guar gum may retard the absorption of other drugs where this is likely to pose a problem the other drug should be taken at least an hour before guar gum.
Uses and Administration
Guar gum is used in diabetes mellitus as an adjunct to treatment with diet, insulin, or oral antidiabetics since it results in some reduction in both postprandial and fasting blood-glucose concentrations. It is given with or immediately before meals in doses of 5 g usually 3 times daily. Adverse gastrointestinal effects may be reduced by using a lower initial dose of 5 g once daily before breakfast for 1 week, then increasing to 5 g twice daily, then 3 times daily, as required. Each dose of guar gum granules should be taken stirred in about 200 mL of a cold drink. Alternatively it can be sprinkled over or mixed with food which must be taken with about 200 mL of fluid.
Guar gum is also used to slow gastric emptying in some patients with the dumping syndrome. It is also used as an adjunct in the treatment of hyperlipidaemias.
Guar gum is also used as a thickening and suspending agent, and as a tablet binder. It has been incorporated into processed foods.
Guar gum is an example of a soluble fibre. On contact with water it forms a highly viscous gel, the viscosity of which varies with such factors as its plant source or the form in which it is given.
Fibres such as guar gum reduce postprandial and fasting blood-glucose concentrations as well as plasma-insulin concentrations in healthy subjects and diabetic patients. Such reductions in blood-glucose concentrations and in glycosylated haemoglobin have been demonstrated in both type 1 and type 2 diabetes, but they have generally been small. Possible mechanisms for these effects of guar gum include a delay in gastric emptying, decreased small-bowel motility, decreased glucose absorption resulting from increased viscosity of the contents of the gastrointestinal tract, or inhibition of gastrointestinal hormones.
Guar gum also lowers serum total cholesterol and low-density -lipoprotein (LDL) cholesterol concentrations high-density-lipoprotein (HDL) cholesterol and triglyceride concentrations appear to be unaffected. The most likely mechanism is binding of bile acids, reducing their enterohepatic circulation in a similar way to bile-acid sequestrants. When used alone in patients with hype rcholesterolaemia guar gum has generally produced a modest reduction in plasma-cholesterol and LDL-cholesterol concentrations although some studies have been unable to demonstrate an effect. A few studies have suggested that the cholesterol-lowering effect is attenuated after 8 to 12 weeks of treatment but a long-term study observed a 17% decrease in total serum cholesterol that was maintained for 24 months. Some studies have shown further reductions in cholesterol and LDL-cholesterol concentrations on addition of guar gum to therapy with other li-pid regulating drugs. The usual treatment of hyper lip idaemias is discussed.
There have been suggestions that guar gum reduces appetite by promoting a feeling of fullness, but a meta-analysis has indicated that it is not effective for reducing body-weight. Products containing guar gum have, however, been promoted as slimming aids. Their use cannot be advocated because of the risk of tablets swelling before reaching the stomach and causing oesophageal obstruction.
Preparations
Proprietary Preparations
Argentina: Regudigl
Australia: Benefiber †
Brazil: Benefiber † Biofiber †
Finland: Guarem
Germany: Figur-Verlan Guar Verlan
Hong Kong: Guarem
Ireland: Guarem †
Italy: Novafibra
New Zealand: Guarcol
Spain: Fibraguar Plantaguar
Switzerland: Leiguar
UK: Resource Benefiber
USA: Benefiber
Multi-ingredient
France: Carres Parapsyllium Moxydar Mucipulgite Mulkine Seroxydar
Italy: Cruscasohn Resource Gelificata
Switzerland: Mucipulgite