Oral hypoglycaemic agents:
For the patient with NIDDM, if dietary measures and exercise do not produce adequate glycaemic control, oral
hypoglycaemic therapy will be required.
Oral hypoglycemic agents:
1. Sulphonylureas.
2. Biguanides.
3. α-Glucosidase inhibitors.
4. Insulin release stimulants.
1. Sulphonylureas:
(Figure: 11) Structure of Sulphonylurea
Pharmacokinetics:
The pharmacokinetic parameters of the oral hypoglycaemic agents are shown in (Table 2).
Chlorpropamide is the slowest and longest-acting agent. Although glibenclamide has been shown to have a short
elimination half-life, it has a prolonged biological effect, which may be explained by slower distribution and the existence
of a deep compartment, possibly the islet cells. All sulphonylureas are metabolized by the liver to some degree and some
may have active metabolites.
Choice of drug:
There are many factors that may influence the choice of sulphonylureas. These may relate to the drug itself, the patient or
the prescriber (Table 3).
There are few well-controlled long-term clinical comparisons between sulphonylureas. it would appear that when dosage is
individualized and governed by the effect on fasting blood glucose, there is little or no difference in clinical efficacy
between the different agents. In general, if a patient is not well controlled on the maximum dosage of one sulphonylurea,
it is not worthwhile changing to another one, except possibly for tolbutamide.
Adverse effects:
The frequency of adverse effects from sulphonylureas are slow. They are usually mild and reversible on withdrawal of the
drug (Table 4). The most common adverse effect is hypoglycaemia; this may be profound and long-lasting. Hypoglycaemia
due to sulphonylurea is often misdiagnosed, particularly in the elderly. The major risk factors for the development of
hypoglycaemia are:
• Use of long acting agent.
• Increased age.
• Inadequate carbohydrate intake and renal hepatic dysfunction.
Other adverse effects are rare; blood dysrasias occur in 0.1% of patients and rashes in up to 3%.
Chlorpropamide can produce troublesome flushing after ingestion of alcohol, and about 5% of patients develop
hyponatraemia due to its effect on increasing renal sensitivity to antidiuretic hormone (ADH). Most patients are
asymptomatic with this problem but occasionally severe hyponatraemia is observed. It is not widely appreciated that
patients treated with sulphonylureas often gain weight. This is unfortunate as it will exacerbate their resistance to insulin
and to the sulphonylureas themselves.
Sulphonylurea dosage:
The dosage should be individualized for each patient, and the lowest possible dose used to attain the desired levels of
blood glucose, without producing hypoglycaemia. Treatment should start with a low dose and be increased approximately
every 2 weeks. For many agents the maximum effect is seen if the dose is taken half an hour before a meal, rather than
with or after food. The number of daily doses required will depend on the agent used and the total daily dose. For several
drugs it becomes necessary to administer the drug two or three times daily when the dose is increased.
Drug interactions:
Several drugs can interfere with the efficacy of sulphonylureas, by influencing either their pharmacokinetics or
pharmacodynamics, or both. Tables 5 and 6 show some drugs that interact with sulphonylureas. Many reported cases
involve first-generation agents, which have a different protein-binding site to the second-generation agents. The first-
generation agents are readily displaced from albumin by other acidic drugs, whereas the second-generation agents bind in a
non-ionic fashion and are not readily displaced. Ingestion of alcohol can cause hypoglycaemia in itself and can also prolong
the hypoglycaemic effect of sulphonylureas.
Cautions:
Sulphonylureas can encourage weight gain and should be prescribed only if poor control and symptoms persist despite
adequate attempts at dieting; metformin is considered the drug of choice in obese patients. Caution is needed in the
elderly and in those with mild to moderate hepatic and renal impairment because of the hazard of hypoglycaemia. The
short-acting tolbutamide may be used in renal impairment, as may gliquidone and gliclazide which are principally
metabolized in the liver, but careful monitoring of blood-glucose concentration is essential; care is required to choose the
smallest possible dose that produces adequate control of blood glucose.
Contra-indications:
Sulphonylureas should be avoided where possible in severe hepatic and renal impairment and in porphyria. They should not
be used while breast-feeding and insulin therapy should be substituted during pregnancy.
Insulin therapy should also be instituted temporarily during intercurrent illness (such as myocardial infarction, coma,
infection, and trauma). Oral antidiabetic drugs should be omitted on the morning of surgery; insulin is often required
because of the ensuing hyperglycaemia in these circumstances. Sulphonylureas are contra-indicated in the presence of
ketoacidosis.
Side effects:
Side effects of sulphonylureas are generally mild and infrequent and include gastrointestinal disturbances such as nausea,
vomiting, diarrhoea and constipation.
Chlorpropamide has appreciably more side effects, mainly because of its very prolonged duration of action and the
consequent hazard of hypoglycaemia and it should generally no longer be used. It may also cause facial flushing after
drinking alcohol; this effect does not normally occur with other sulphonylureas. Chlorpropamide may also enhance
antidiuretic hormone secretion and very rarely cause hyponatraemia (hyponatraemia is also reported with glimepiride and
glipizide).
Sulphonylureas can occasionally cause a disturbance in liver function, which may rarely lead to cholestatic jaundice,
hepatitis and hepatic failure. Hypersensitivity reactions can occur, usually in the first 6-8 weeks of therapy, they consist
mainly of allergic skin reactions which progress rarely to erythema multiform and exfoilative dermatitis, fever and jaundice;
photosensitivity has rarely been reported with chlorpropamide and glipizide. Blood disorders are also rare but may include
leucopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic anaemia, and aplastic anaemia.
Generations of Sulphonylureas:
1. First generation:
• Chlorpropamide
• Tolbutamide
• Tolazamide
2. second generation:
• Glibenclamide
• Gliclazide
• Glimepiride
• Glipizide
• Gliquidone
1. First generation:
• Chlorpropamide
Indications:
Type II diabetes mellitus.
Rote of administration:
Initially 250 mg daily with breakfast ( Elderly 100-125 mg ), adjusted according to response; max. 500mg daily.
Trade names:
Chlorpropamide®.
Tolbutamide
Indications:
Type II diabetes mellitus.
Side effects:
Headache and tinnitus.
Rote of administration:
0.5-1.5 g (max. 2g) daily in divided doses; with or immediately after breakfast.
Trade names:
Tolbutamide®.
• Tolazamide
2. Second generation
• Glibenclamide
Indications:
Type II diabetes mellitus.
Rote of administrstion:
Initially 5mg daily with or immediately after breakfast (Elderly 2.5 mg), adjusted according to response; max. 15 mg daily.
Trade names:
Daonil®, Semi-Daonil®, Euglucon®.
• Gliclazide
Indications:
Type II diabetes mellitus.
Rote of administration:
Initially, 40-80 mg daily, adjusted according to response; up to 160 mg as a single dose, with breakfast; higher dose divided;
max. 320 mg daily.
Trade names:
Gliclazide®, Diamicron®, Diamicron®MR.
• Glimepiride
Indications:
Type II diabetes mellitus.
Rote of administration:
Initially 1 mg daily, adjusted according to response in 1 mg steps at 1-2 week intervals; usual max. 4 mg daily ( exceptionally,
up to 6 mg daily may be used); taken shortly before or with first main meal.
Trade names:
Amaryl®.
• Glipizide
Indications:
Type II diabetes mellitus.
Side effects:
Dizziness and drowsiness.
Rote of administration:
Initially 2.5-5 mg daily, adjusted according to response; max.20 mg daily; up to 15 mg may be given as a single dose before
breakfast; higher doses divided.
Trade names:
Glipizide®, Glibenese®, Minadiab®.
• Gliquidone
Indications:
Type II diabetes mellitus.
Rote of administration:
Initially 15 mg daily before breakfast, adjusted to 45-60 mg daily in 2 or 3 divided doses; max. single dose 60 mg , max. daily
dose 180 mg.
Trade names:
Glurenorm®.
2. Biguanides:
Metformin is the only biguanide available in the UK. The mechanism of action of biguanides is still poorly understood, but
many theories have been proposed. These include: reduced gastrointestinal absorption of carbohydrate; inhibition of
hepatic gluconeogenesis; stimulation of tissue uptake of glucose; and increased insulin receptor binding.
Of these, probably the most important is the effect on hepatic gluconeogenesis. The action of metformin does not involve
stimulation of pancreatic insulin secretion. The major advantages of metformin over sulphonylureas are that it does not
cause either hypoglyceamia or weight gain. Metformin has a short duration of action and is not bound to plasma proteins.
It is not metabolized and is totally renally eliminated.
Adverse effects:
The most common adverse effects of metformin result from gastrointestinal disturbance. These include anorexia, nausea,
abdominal discomfort and diarrhea. These effects are usually transient and can be minimized by starting with low dose,
increasing the dose slowly and administering the drug with or after food. One suggested regimen is to start with 500 mg
daily for 1 week, then 500mg twice daily for 1 week, and increasing the dosage at weekly intervals until the desired
glycaemic response is achieved. Despite these precautions a few patients are genuinely intolerant of the drug.
A rare but potentially life-threatening adverse effect is lactic acidosis. The patients at most risk are those with renal
insufficiency in whom the drug accumulates, those with coexisting conditions in whom lactate accumulates and those who
are unable to metabolize lactate. In practice, metformin should not be prescribed for patients who have renal impairment,
liver disease, alcoholism, uncontrolled cardiac failure or severe pulmonary insufficiency. It should also be withdrawn in a
patient who develops a severe intercurrent illness, e.g. acute myocardial infarction or septicaemia, or who is undergoing
major surgery.
Role of metformin:
Metformin is useful in the obese diabetic as it does not cause weight gain. If there are no contraindications it can be used
in conjunction with diet as second-line therapy in patients not adequately controlled on diet alone. As it has a different
mode of action to the sulphonylureas, it can be valuable when prescribed in conjunction with them.
Drugs of biguanides
• Metformin hydrochloride
Indications:
Diabetes mellitus.
Contra-indications:
Hepatic or renal impairment ( withdraw if renal impairment suspected), ketoacidosis, predisposition to lactic acidosis,
heart failure, severe infection or trauma, dehydration, alcohol dependence; pregnancy, breast feeding.
Side effects:
Anorexia, nausea, vomiting, diarrhoea (usually transient), abdominal pain, metallic taste; rarely lactic acidosis (withdraw
treatment), decreased vitamin-B12 absorption.
Rote of administration:
Initially 500 mg with breakfast for 1 week then 500 mg with breakfast and evening meal for 1 week then 500 mg with
breakfast, lunch and evening meal; max. 3g daily in divided doses but most physicians limit this to 2g daily.
Trade names:
Metformin®, Glucophage®.
3. α-Glucosidase inhibitors:
Acarbose is the only drug currently available in this class, others are in phase III clinical trials. These agents retard
carbohydrate digestion by interfering with gastrointestinal glucosidase activity. Although overall carbohydrate absorption is
not significantly altered, the postprandial hyperglycaemic peaks are markedly reduced. Acarbose is minimally absorbed in an
unchanged form from the gastrointestinal tract.
Adverse effects:
The most common adverse effect of acarbose is abdominal discomfort associated with flatulence and diarrhoea. These
symptoms usually improve with continued treatment, but can be minimized by starting with a low dose, for example 50 mg
daily for 1 to 2 weeks, increasing at weekly or fortnightly intervals.
Systemic adverse effects are rare, but high doses have been associated with idiosyncratic elevations of the levels of serum
hepatic transaminases. Patients titrated to the maximum dose of 200 mg three times daily should be closely monitored,
preferably at monthly intervals for the first 6 months. If elevated transaminase levels are observed, reduction in dose or
withdrawal of therapy should be considered.
Drugs
A. Acarbose
Acarbose, an inhibitor of intestinal alpha glucosidases, delays the digestion and absorption of starch and sucrose. It has a
small but significant effect in lowering blood glucose and is used eighter on its own or as an adjunct to metformin or to
sulphonylureas when they prove inadequate. Postprandial hyperglycaemia in type I (insulin-dependent) diabetes can be
reduced by acarbose, but it has been little used for this purpose. Flatulence deters some from using acarbose although this
side effect tends to decrease with time.
Role of acarbose:
Acarbose is a therapeutic option in NIDDM patients inadequately controlled on diet alone, or on diet and other oral
hypoglycaemic agents.
Indications:
Diabetes mellitus inadequately controlled by diet or by diet with oral hypoglycaemic agents.
Cautions:
Monitor hepatic transaminase levels (higher doses); may enhance hypoglycaemic effects of insulin and sulphonylureas
(hypoglycaemic episodes may be treated with oral glucose but not with sucrose).
Contra-indications:
Pregnancy and breast feeding; inflammatory bowel disease (e.g: ulcerative colitis, Crohn’s disease), partial intestinal
obstruction (or predisposition); hepatic impairment, severe renal impairment; hernia, history of abdominal surgery.
Side effects:
Flatulence, soft stools, diarrhoea (may need to reduce dose or withdraw), abdominal distention and pain; rarely abnormal
liver function tests and skin reactions; ileus, oedema, jaundice and hepatitis reported.
Rote of administration:
50 mg daily initially (to minimize side effects) increased to 50 mg 3 times daily, then increased if necessary after 6-8 weeks
to 100 mg 3 times daily; max. 200 mg 3 times daily; Child under 12 years not recommended.
Trade names:
Glucobay®.
B. Thiazolidinediones
Drugs
• Pioglitazone
• Rosiglitazone
• Ciglitazone
Caution:
Monitor liver function; cardiovascular disease (risk of heart failure).
Liver toxicity:
Rare reports of liver dysfunction; monitor liver function before treatment, then every 2 months for 12 months and
periodically thereafter; advise patients to seek immediate medical attention if symptoms such as nausea, vomiting,
abdominal pain, fatigue and dark urine develop; discontinue if jaundice occurs.
Contra-indications:
Hepatic impairment, history of heart failure, combination with insulin (risk of heart failure), pregnancy, breast feeding.
• Pioglitazone
Indications:
Type II diabetes mellitus
Side effects:
Gastro-intestinal disturbances, weight gain, oedema, anaemia, headache, visual disturbances, dizziness, arthralgia,
haematuria, impotence; less commonly hypoglycaemia, fatigue, sweating, altered blood lipids, proteinuria.
Rote of administration:
15-30 mg once daily.
Trade names:
Actos®.
• Rosiglitazone
Indications:
Type II diabetes mellitus.
Side effects:
Gastro-intestinal disturbances, headache, anaemia, fatigue, weight gain, oedema, hypoglycaemia; less commonly dizziness,
paraesthesia, rash, alopecia, dyspnoea, altered blood lipids, thrombocytopenia.
Rote of administration:
(In combination with metformin or a sulphonylurea) 4 mg daily; in combination with metformin may increase to 8 mg daily
(in 1 or 2 divided doses) after 8 weeks according to response.
Trade names:
Avandia®.
C. Guar gum
If taken in adequate quantities, results in some reduction of postprandial plasma-glucose concentrations in diabetes
mellitus, probably by retarding carbohydrate absorption. It is also used to relieve symptoms of the dumping syndrome.
Cautions:
Maintain adequate fluid intake.
Contra-indications:
Gastro-intestinal obstruction, oesophageal disease, dysphagia.
Side effects:
Flatulence, diarrhoea, abdominal distension, intestinal obstruction.
Rote of administration:
5 g 3 times daily with main meals ( either stirred into 200 ml fluid or sprinkled on food and eaten accompanied by 200 ml
fluid);Child under 12 years not recommended.
Trade names:
Guarem®.
4. Drugs that stimulate insulin release:
This group stimulates insulin release and have a rapid onset of action and short duration of activity, and should be
administered shortly before each main meal. Repaglinide is licensed for use in type II diabetes either as mono-therapy or in
combination with metformin; nateglinide is licensed only for use with metformin.
Cautions:
Substitute insulin during intercurrent illness (such as myocardial infarction, coma, infection, and trauma) and during
surgery; debilitated and malnourished patients; moderate hepatic impairment in nateglinide and renal impairment in
repaglinide.
Contra-indications:
Diabetic ketoacidosis; severe hepatic impairment; pregnancy and breast feeding.
• Nateglinide
Indications:
Type II diabetes mellitus in combination with metformin when metformin alone inadequate.
Side effects:
Hypoglycaemia; hypersensitivity reactions including pruritus, rashes and urticaria.
Rote of administration:
Initially 60 mg 3 times daily within 30 minutes before main meals, adjusted according to response up to max. 180 mg 3 times
daily; Child and Adolescent under 18 years not recommended.
Trade names:
Starlix®.
• Repaglinide
Indications:
Type II diabetes mellitus (as mono-therapy or in combination with metformin when metformin alone inadequate).
Side effects:
Abdominal pain, diarrhoea, constipation, nausea, vomiting; hypoglycaemia, hypersensitivity reactions including pruritus,
rashes and urticaria.
Rote of administration:
Initially 500 micrograms within 30 minutes before main meals (1 mg if transferring from another oral hypoglycaemic),
adjusted according to response at intervals of 1-2 weeks; up to 4 mg may be given as a single dose, max. 16 mg daily Child
and Adolescent under 18 years and Elderly over 75 years, not recommended.
Trade names:
NovoNorm®.
For the patient with NIDDM, if dietary measures and exercise do not produce adequate glycaemic control, oral
hypoglycaemic therapy will be required.
Oral hypoglycemic agents:
1. Sulphonylureas.
2. Biguanides.
3. α-Glucosidase inhibitors.
4. Insulin release stimulants.
1. Sulphonylureas:
(Figure: 11) Structure of Sulphonylurea
Pharmacokinetics:
The pharmacokinetic parameters of the oral hypoglycaemic agents are shown in (Table 2).
Chlorpropamide is the slowest and longest-acting agent. Although glibenclamide has been shown to have a short
elimination half-life, it has a prolonged biological effect, which may be explained by slower distribution and the existence
of a deep compartment, possibly the islet cells. All sulphonylureas are metabolized by the liver to some degree and some
may have active metabolites.
Choice of drug:
There are many factors that may influence the choice of sulphonylureas. These may relate to the drug itself, the patient or
the prescriber (Table 3).
There are few well-controlled long-term clinical comparisons between sulphonylureas. it would appear that when dosage is
individualized and governed by the effect on fasting blood glucose, there is little or no difference in clinical efficacy
between the different agents. In general, if a patient is not well controlled on the maximum dosage of one sulphonylurea,
it is not worthwhile changing to another one, except possibly for tolbutamide.
Adverse effects:
The frequency of adverse effects from sulphonylureas are slow. They are usually mild and reversible on withdrawal of the
drug (Table 4). The most common adverse effect is hypoglycaemia; this may be profound and long-lasting. Hypoglycaemia
due to sulphonylurea is often misdiagnosed, particularly in the elderly. The major risk factors for the development of
hypoglycaemia are:
• Use of long acting agent.
• Increased age.
• Inadequate carbohydrate intake and renal hepatic dysfunction.
Other adverse effects are rare; blood dysrasias occur in 0.1% of patients and rashes in up to 3%.
Chlorpropamide can produce troublesome flushing after ingestion of alcohol, and about 5% of patients develop
hyponatraemia due to its effect on increasing renal sensitivity to antidiuretic hormone (ADH). Most patients are
asymptomatic with this problem but occasionally severe hyponatraemia is observed. It is not widely appreciated that
patients treated with sulphonylureas often gain weight. This is unfortunate as it will exacerbate their resistance to insulin
and to the sulphonylureas themselves.
Sulphonylurea dosage:
The dosage should be individualized for each patient, and the lowest possible dose used to attain the desired levels of
blood glucose, without producing hypoglycaemia. Treatment should start with a low dose and be increased approximately
every 2 weeks. For many agents the maximum effect is seen if the dose is taken half an hour before a meal, rather than
with or after food. The number of daily doses required will depend on the agent used and the total daily dose. For several
drugs it becomes necessary to administer the drug two or three times daily when the dose is increased.
Drug interactions:
Several drugs can interfere with the efficacy of sulphonylureas, by influencing either their pharmacokinetics or
pharmacodynamics, or both. Tables 5 and 6 show some drugs that interact with sulphonylureas. Many reported cases
involve first-generation agents, which have a different protein-binding site to the second-generation agents. The first-
generation agents are readily displaced from albumin by other acidic drugs, whereas the second-generation agents bind in a
non-ionic fashion and are not readily displaced. Ingestion of alcohol can cause hypoglycaemia in itself and can also prolong
the hypoglycaemic effect of sulphonylureas.
Cautions:
Sulphonylureas can encourage weight gain and should be prescribed only if poor control and symptoms persist despite
adequate attempts at dieting; metformin is considered the drug of choice in obese patients. Caution is needed in the
elderly and in those with mild to moderate hepatic and renal impairment because of the hazard of hypoglycaemia. The
short-acting tolbutamide may be used in renal impairment, as may gliquidone and gliclazide which are principally
metabolized in the liver, but careful monitoring of blood-glucose concentration is essential; care is required to choose the
smallest possible dose that produces adequate control of blood glucose.
Contra-indications:
Sulphonylureas should be avoided where possible in severe hepatic and renal impairment and in porphyria. They should not
be used while breast-feeding and insulin therapy should be substituted during pregnancy.
Insulin therapy should also be instituted temporarily during intercurrent illness (such as myocardial infarction, coma,
infection, and trauma). Oral antidiabetic drugs should be omitted on the morning of surgery; insulin is often required
because of the ensuing hyperglycaemia in these circumstances. Sulphonylureas are contra-indicated in the presence of
ketoacidosis.
Side effects:
Side effects of sulphonylureas are generally mild and infrequent and include gastrointestinal disturbances such as nausea,
vomiting, diarrhoea and constipation.
Chlorpropamide has appreciably more side effects, mainly because of its very prolonged duration of action and the
consequent hazard of hypoglycaemia and it should generally no longer be used. It may also cause facial flushing after
drinking alcohol; this effect does not normally occur with other sulphonylureas. Chlorpropamide may also enhance
antidiuretic hormone secretion and very rarely cause hyponatraemia (hyponatraemia is also reported with glimepiride and
glipizide).
Sulphonylureas can occasionally cause a disturbance in liver function, which may rarely lead to cholestatic jaundice,
hepatitis and hepatic failure. Hypersensitivity reactions can occur, usually in the first 6-8 weeks of therapy, they consist
mainly of allergic skin reactions which progress rarely to erythema multiform and exfoilative dermatitis, fever and jaundice;
photosensitivity has rarely been reported with chlorpropamide and glipizide. Blood disorders are also rare but may include
leucopenia, thrombocytopenia, agranulocytosis, pancytopenia, haemolytic anaemia, and aplastic anaemia.
Generations of Sulphonylureas:
1. First generation:
• Chlorpropamide
• Tolbutamide
• Tolazamide
2. second generation:
• Glibenclamide
• Gliclazide
• Glimepiride
• Glipizide
• Gliquidone
1. First generation:
• Chlorpropamide
Indications:
Type II diabetes mellitus.
Rote of administration:
Initially 250 mg daily with breakfast ( Elderly 100-125 mg ), adjusted according to response; max. 500mg daily.
Trade names:
Chlorpropamide®.
Tolbutamide
Indications:
Type II diabetes mellitus.
Side effects:
Headache and tinnitus.
Rote of administration:
0.5-1.5 g (max. 2g) daily in divided doses; with or immediately after breakfast.
Trade names:
Tolbutamide®.
• Tolazamide
2. Second generation
• Glibenclamide
Indications:
Type II diabetes mellitus.
Rote of administrstion:
Initially 5mg daily with or immediately after breakfast (Elderly 2.5 mg), adjusted according to response; max. 15 mg daily.
Trade names:
Daonil®, Semi-Daonil®, Euglucon®.
• Gliclazide
Indications:
Type II diabetes mellitus.
Rote of administration:
Initially, 40-80 mg daily, adjusted according to response; up to 160 mg as a single dose, with breakfast; higher dose divided;
max. 320 mg daily.
Trade names:
Gliclazide®, Diamicron®, Diamicron®MR.
• Glimepiride
Indications:
Type II diabetes mellitus.
Rote of administration:
Initially 1 mg daily, adjusted according to response in 1 mg steps at 1-2 week intervals; usual max. 4 mg daily ( exceptionally,
up to 6 mg daily may be used); taken shortly before or with first main meal.
Trade names:
Amaryl®.
• Glipizide
Indications:
Type II diabetes mellitus.
Side effects:
Dizziness and drowsiness.
Rote of administration:
Initially 2.5-5 mg daily, adjusted according to response; max.20 mg daily; up to 15 mg may be given as a single dose before
breakfast; higher doses divided.
Trade names:
Glipizide®, Glibenese®, Minadiab®.
• Gliquidone
Indications:
Type II diabetes mellitus.
Rote of administration:
Initially 15 mg daily before breakfast, adjusted to 45-60 mg daily in 2 or 3 divided doses; max. single dose 60 mg , max. daily
dose 180 mg.
Trade names:
Glurenorm®.
2. Biguanides:
Metformin is the only biguanide available in the UK. The mechanism of action of biguanides is still poorly understood, but
many theories have been proposed. These include: reduced gastrointestinal absorption of carbohydrate; inhibition of
hepatic gluconeogenesis; stimulation of tissue uptake of glucose; and increased insulin receptor binding.
Of these, probably the most important is the effect on hepatic gluconeogenesis. The action of metformin does not involve
stimulation of pancreatic insulin secretion. The major advantages of metformin over sulphonylureas are that it does not
cause either hypoglyceamia or weight gain. Metformin has a short duration of action and is not bound to plasma proteins.
It is not metabolized and is totally renally eliminated.
Adverse effects:
The most common adverse effects of metformin result from gastrointestinal disturbance. These include anorexia, nausea,
abdominal discomfort and diarrhea. These effects are usually transient and can be minimized by starting with low dose,
increasing the dose slowly and administering the drug with or after food. One suggested regimen is to start with 500 mg
daily for 1 week, then 500mg twice daily for 1 week, and increasing the dosage at weekly intervals until the desired
glycaemic response is achieved. Despite these precautions a few patients are genuinely intolerant of the drug.
A rare but potentially life-threatening adverse effect is lactic acidosis. The patients at most risk are those with renal
insufficiency in whom the drug accumulates, those with coexisting conditions in whom lactate accumulates and those who
are unable to metabolize lactate. In practice, metformin should not be prescribed for patients who have renal impairment,
liver disease, alcoholism, uncontrolled cardiac failure or severe pulmonary insufficiency. It should also be withdrawn in a
patient who develops a severe intercurrent illness, e.g. acute myocardial infarction or septicaemia, or who is undergoing
major surgery.
Role of metformin:
Metformin is useful in the obese diabetic as it does not cause weight gain. If there are no contraindications it can be used
in conjunction with diet as second-line therapy in patients not adequately controlled on diet alone. As it has a different
mode of action to the sulphonylureas, it can be valuable when prescribed in conjunction with them.
Drugs of biguanides
• Metformin hydrochloride
Indications:
Diabetes mellitus.
Contra-indications:
Hepatic or renal impairment ( withdraw if renal impairment suspected), ketoacidosis, predisposition to lactic acidosis,
heart failure, severe infection or trauma, dehydration, alcohol dependence; pregnancy, breast feeding.
Side effects:
Anorexia, nausea, vomiting, diarrhoea (usually transient), abdominal pain, metallic taste; rarely lactic acidosis (withdraw
treatment), decreased vitamin-B12 absorption.
Rote of administration:
Initially 500 mg with breakfast for 1 week then 500 mg with breakfast and evening meal for 1 week then 500 mg with
breakfast, lunch and evening meal; max. 3g daily in divided doses but most physicians limit this to 2g daily.
Trade names:
Metformin®, Glucophage®.
3. α-Glucosidase inhibitors:
Acarbose is the only drug currently available in this class, others are in phase III clinical trials. These agents retard
carbohydrate digestion by interfering with gastrointestinal glucosidase activity. Although overall carbohydrate absorption is
not significantly altered, the postprandial hyperglycaemic peaks are markedly reduced. Acarbose is minimally absorbed in an
unchanged form from the gastrointestinal tract.
Adverse effects:
The most common adverse effect of acarbose is abdominal discomfort associated with flatulence and diarrhoea. These
symptoms usually improve with continued treatment, but can be minimized by starting with a low dose, for example 50 mg
daily for 1 to 2 weeks, increasing at weekly or fortnightly intervals.
Systemic adverse effects are rare, but high doses have been associated with idiosyncratic elevations of the levels of serum
hepatic transaminases. Patients titrated to the maximum dose of 200 mg three times daily should be closely monitored,
preferably at monthly intervals for the first 6 months. If elevated transaminase levels are observed, reduction in dose or
withdrawal of therapy should be considered.
Drugs
A. Acarbose
Acarbose, an inhibitor of intestinal alpha glucosidases, delays the digestion and absorption of starch and sucrose. It has a
small but significant effect in lowering blood glucose and is used eighter on its own or as an adjunct to metformin or to
sulphonylureas when they prove inadequate. Postprandial hyperglycaemia in type I (insulin-dependent) diabetes can be
reduced by acarbose, but it has been little used for this purpose. Flatulence deters some from using acarbose although this
side effect tends to decrease with time.
Role of acarbose:
Acarbose is a therapeutic option in NIDDM patients inadequately controlled on diet alone, or on diet and other oral
hypoglycaemic agents.
Indications:
Diabetes mellitus inadequately controlled by diet or by diet with oral hypoglycaemic agents.
Cautions:
Monitor hepatic transaminase levels (higher doses); may enhance hypoglycaemic effects of insulin and sulphonylureas
(hypoglycaemic episodes may be treated with oral glucose but not with sucrose).
Contra-indications:
Pregnancy and breast feeding; inflammatory bowel disease (e.g: ulcerative colitis, Crohn’s disease), partial intestinal
obstruction (or predisposition); hepatic impairment, severe renal impairment; hernia, history of abdominal surgery.
Side effects:
Flatulence, soft stools, diarrhoea (may need to reduce dose or withdraw), abdominal distention and pain; rarely abnormal
liver function tests and skin reactions; ileus, oedema, jaundice and hepatitis reported.
Rote of administration:
50 mg daily initially (to minimize side effects) increased to 50 mg 3 times daily, then increased if necessary after 6-8 weeks
to 100 mg 3 times daily; max. 200 mg 3 times daily; Child under 12 years not recommended.
Trade names:
Glucobay®.
B. Thiazolidinediones
Drugs
• Pioglitazone
• Rosiglitazone
• Ciglitazone
Caution:
Monitor liver function; cardiovascular disease (risk of heart failure).
Liver toxicity:
Rare reports of liver dysfunction; monitor liver function before treatment, then every 2 months for 12 months and
periodically thereafter; advise patients to seek immediate medical attention if symptoms such as nausea, vomiting,
abdominal pain, fatigue and dark urine develop; discontinue if jaundice occurs.
Contra-indications:
Hepatic impairment, history of heart failure, combination with insulin (risk of heart failure), pregnancy, breast feeding.
• Pioglitazone
Indications:
Type II diabetes mellitus
Side effects:
Gastro-intestinal disturbances, weight gain, oedema, anaemia, headache, visual disturbances, dizziness, arthralgia,
haematuria, impotence; less commonly hypoglycaemia, fatigue, sweating, altered blood lipids, proteinuria.
Rote of administration:
15-30 mg once daily.
Trade names:
Actos®.
• Rosiglitazone
Indications:
Type II diabetes mellitus.
Side effects:
Gastro-intestinal disturbances, headache, anaemia, fatigue, weight gain, oedema, hypoglycaemia; less commonly dizziness,
paraesthesia, rash, alopecia, dyspnoea, altered blood lipids, thrombocytopenia.
Rote of administration:
(In combination with metformin or a sulphonylurea) 4 mg daily; in combination with metformin may increase to 8 mg daily
(in 1 or 2 divided doses) after 8 weeks according to response.
Trade names:
Avandia®.
C. Guar gum
If taken in adequate quantities, results in some reduction of postprandial plasma-glucose concentrations in diabetes
mellitus, probably by retarding carbohydrate absorption. It is also used to relieve symptoms of the dumping syndrome.
Cautions:
Maintain adequate fluid intake.
Contra-indications:
Gastro-intestinal obstruction, oesophageal disease, dysphagia.
Side effects:
Flatulence, diarrhoea, abdominal distension, intestinal obstruction.
Rote of administration:
5 g 3 times daily with main meals ( either stirred into 200 ml fluid or sprinkled on food and eaten accompanied by 200 ml
fluid);Child under 12 years not recommended.
Trade names:
Guarem®.
4. Drugs that stimulate insulin release:
This group stimulates insulin release and have a rapid onset of action and short duration of activity, and should be
administered shortly before each main meal. Repaglinide is licensed for use in type II diabetes either as mono-therapy or in
combination with metformin; nateglinide is licensed only for use with metformin.
Cautions:
Substitute insulin during intercurrent illness (such as myocardial infarction, coma, infection, and trauma) and during
surgery; debilitated and malnourished patients; moderate hepatic impairment in nateglinide and renal impairment in
repaglinide.
Contra-indications:
Diabetic ketoacidosis; severe hepatic impairment; pregnancy and breast feeding.
• Nateglinide
Indications:
Type II diabetes mellitus in combination with metformin when metformin alone inadequate.
Side effects:
Hypoglycaemia; hypersensitivity reactions including pruritus, rashes and urticaria.
Rote of administration:
Initially 60 mg 3 times daily within 30 minutes before main meals, adjusted according to response up to max. 180 mg 3 times
daily; Child and Adolescent under 18 years not recommended.
Trade names:
Starlix®.
• Repaglinide
Indications:
Type II diabetes mellitus (as mono-therapy or in combination with metformin when metformin alone inadequate).
Side effects:
Abdominal pain, diarrhoea, constipation, nausea, vomiting; hypoglycaemia, hypersensitivity reactions including pruritus,
rashes and urticaria.
Rote of administration:
Initially 500 micrograms within 30 minutes before main meals (1 mg if transferring from another oral hypoglycaemic),
adjusted according to response at intervals of 1-2 weeks; up to 4 mg may be given as a single dose, max. 16 mg daily Child
and Adolescent under 18 years and Elderly over 75 years, not recommended.
Trade names:
NovoNorm®.
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Diabetes Mellitus
