BIGUANIDES
Presented by Group A (Roll-no. : 1 to 15)
What are BIGUANIDES?
They are a class of oral hypoglycemic drugs derived from
guanidine, where two guanidine molecules are linked by a
central carbon.
They were discovered in 1879 by Bernhard Rathke. Fig. Chemical structure
of Metformin
Metformin is the only member of the biguanide class of
oral hypoglycemic drugs available for use today.
Previously available biguanides, phenformin and buformin,
were removed from the market in the 1970s due to
unacceptable rates of associated lactic acidosis.
CLASSIFICATION
MECHANISM OF ACTION
Metformin acts on mitochondrial respiration reducing intracellular ATP and increasing AMP.
As a direct consequence of interference with mitochondrial respiratory chain by metformin, there is
increased peripheral glucose utilization through anaerobic glycolysis.
As an indirect consequence of interference with cellular respiration and lowering of intracellular ATP
and other energy sources by metformin, there is activation of AMPK, i.e. AMP (Adenosine
Monophosphate) dependent protein kinases, which leads to stimulation of hepatic fatty acid
oxidation, glucose uptake, and nonoxidative glucose metabolism; reduction of lipogenesis,
gluconeogenesis and glucose output from liver; and enhanced insulin mediated glucose uptake in
skeletal muscle and fat.
Metformin also inhibits the mitochondrial glycerol phosphate dehydrogenase, thereby changing the
redox state of the cell.
Metformin also retards intestinal absorption of glucose, other hexoses, amino acids and Vitamin
B12.
PHARMACOLOGICAL ACTIONS
Metformin is not effective in pancreatectomized animals and in type 1 diabetics, i.e. insulin is essential for their
action.
Suppression of hepatic gluconeogenesis and glucose output from liver is the major action responsible for
lowering of blood glucose levels in diabetes.
Enhanced insulin mediated glucose uptake and disposal in skeletal muscle and fat, (i.e. glycogen storage in
skeletal muscles, reduced lipogenesis in adipose tissue and enhanced fatty acid oxidation) leads to overcoming
of insulin resistance exhibited by type 2 diabetics, i.e. it improves insulin sensitivity
Metformin has little effect on blood glucose level in normoglycemic states but in persons with only mild
hyperglycemia, metformin lowers blood glucose level by reducing HGP(Hepatic glucose production) and
increasing glucose clearance.
It does not stimulate β cells but it does (reportedly) improve lipid profile in type 2 diabetics.
PHARMACOKINETICS
Route of administration: Oral (in solid dosage form)
Absorption: primarily absorbed in the small intestine
Bioavailability : ~70–80%
Plasma t = 4 to 5 hours with peak plasma concentration occurring at 2 hours after an oral dose
Metabolism : not metabolized by the liver
Excretion : Excreted unchanged in urine by the kidney
It does not bind to plasma protein; transport to hepatocytes is mediated by OCT1; renal uptake is mediated
by OCT 2
Recommended dose is 0.5 to 2.5g given once or twice daily. (maximum daily dose is 2550mg as given in
Goodman and Gilman’s Pharmacological Basis of Therapeutics; 2000mg as given in Harrison’s Principle of
Internal Medicine)
THERAPEUTIC USES OF METFORMIN
1. First drug of choice in treating type 2 diabetes mellitus except when not tolerated or contraindicated
2. In persons with Impaired Glucose Tolerance (IGT), treatment with Metformin delays progression to
diabetes
3. Metformin has been found to improve ovulation and fertility in some infertile women with Polycystic
Ovary Syndrome (PCOS) and this benefit is observed irrespective of the glycemic state of the woman
4. Off label uses of metformin include treatment of metabolic syndrome, non-alcoholic fatty liver disease,etc.
ADVANTAGES OF METFORMIN
1. It does not cause hypoglycemia (except in overdose)
2. weight loss promoting
3. has potential to prevent macrovascular as well as microvascular complications of diabetes
4. no acceleration of β cell exhaustion/ failure in type 2 DM.
5. antihyperglycemic efficacy (HbA1c reduction by 0.8–1.2%) equivalent to other oral drugs.
6. can be combined with any other oral or injectable antidiabetic, if one drug is not adequate.
The only limitation of Metformin is gastrointestinal intolerance especially at higher doses, i.e.
there is lack of serious toxicity.
ADVERSE EFFECTS OF METFORMIN
1. Abdominal pain, anorexia, bloating, nausea, metallic taste, mild diarrhoea and tiredness are
the common complaints, which usually subside with time
2. Long term usage of metformin may cause vitamin B12 deficiency as Metformin interrupts
with it’s absorption
3. Lactic acidosis is a rare(<1 per 10,000 ptients per year) and it can be precipitated by alcohol
ingestion
Contraindications of METFORMIN are:
1. Hypotensive states
2. Heart failure
3. Severe respiratory diseases or in hypoxic conditions
4. Severe hepatic diseases like liver cirrhosis
5. Severe renal diseases (with GFR < 30ml/min)
6. Alcoholics as it can precipitate lactic acidosis
Drug Interactions of METFORMIN
1. Drugs like CIMETIDINE and FUROSEMIDE compete with METFORMIN excretion and hence
enhance it’s toxicity
2. Interaction with alcohol may precipitate lactic acidosis
3. Interaction with RADIOGRAPHIC contrast agents may also increase risk of lactic acidosis
4. Combination with other oral antidiabetic agents gives additive effect on lowering the blood
sugar level
REFERENCES
1. Goodman and Gilman’s Pharmacological basis of Therapeutics
2. Essentials of Medical Pharmacology by KD Tripathi
3. Harrison’s Principle of Internal Medicine
4. [Link]