A REVIEW ON METFORMIN AND ITS LIFE THREATENING ADVERSE EFFECT

ABOUT AUTHOR:
Amitava Sinha Ray
Department of Pharmacy,
Bengal School of Technology
West Bengal University of Technology, West Bengal
a.amitava.s@gmail.com

INTRODUCTION:-
It was 1922 Metformin first published in the scientific literature by Emil Werner and James Bell, as a product in the synthesis of ''N'',''N''-dimethylguanidine. After doing an experiment on rabbit, Slotta and Tschesche concluded that Metformin has sugar-lowering action, in 1929.
Metformin was approved in Canada in 1972, but did not receive approval by the U.S. Food and Drug Administration (FDA) for type 2 diabetes until 1994.
Glucophage was the first branded formulation of Metformin to be marketed in the United States, beginning on March 3, 1995.
Metformin is a biguanide class of drug.Two biguanide antidiabetics, Phenformin and Metformin were introduced. Because of higher risk of lactic acidosis, Phenformin was withdrawn in many countries and has been banned in India since 2003.

REFERENCE ID: PHARMATUTOR-ART-1794

Mechanism of action:-
Biguanides do not cause insulin release. Presence of some insulin is essential for their action. This class of agents is capable of reducing sugar absorption from the gastrointestinal tract.
a)      The main therapeutic action is suppress of hepatic gluconeogenesis & glucose output from liver.
b)      Also it increase the insulin mediated glucose disposal in muscle & fats.
c)      Stop the intestinal absorption of glucose, other hexoses, amino acids & vitamin B_12.

Interactions:-
a) Alcohol:-Potentiates effect of metformin on lactate metabolism.

b) Cationic Drugs (eg, Amiloride, Digoxin, Quinidine):-May increase metformin serum concentration by competing for tubular secretion.

c) Cimetidine:-Increases metformin serum concentration.

d) Furosemide:-May increase metformin serum concentration; metformin may reduce furosemide serum concentration.

e) Iodinated Contrast Material:-May cause acute renal failure and has been associated with lactic acidosis in patients receiving metformin.

f) Nifedipine:-Increases metformin serum concentration.

Pharmacokinetic Data:-

Adverse Effect:-
Metformin has many adverse effects—
a)      Eye, Ear, Nose, Throat:- Unpleasant/metallic taste

b)      Gastrointestinal:- Diarrhea; nausea; vomiting; abdominal bloating; flatulence; anorexia.
Even these are not the most serious of side effects of Metformin it can still cause extreme discomfort. These are some of the symptoms of gastrointestinal discomfort: nausea, cramps, vomiting, diarrhea and it is often comes with flatulence. These side effects are most common when the drug is first prescribed or when the dosage is modified. For this reason the first dose should be low and will slowly be increased to the required levels.

c)      Metabolic:- Lactic acidosis

d)      Other:- Vitamin B₁₂ deficiency due to interference with its absorption can occur with high dose of Metformin.

Among these adverse effects two are very common & life-threatening
a) Lactic acidosis
b) Vitamin B₁₂ deficiency

Lactic acidosis:-
Lactic acidosis is a life-threatening condition caused by too much lactate in the blood and low blood pH. Low blood pH means that the blood contains too much acid, which can be harmful to the cells of your body. This is one of the most dangerous side effect of Metformin. Lactic acid is quickly converted to lactate in the blood. Though lactic acid and lactate are not the same. Lactate is formed when lactic acid loses a hydrogen atom. The hydrogen atom lost by lactic acid stays in the blood; this decreases the blood's pH and makes it more acidic. Women and people who are overweight are at increased risk of developing lactic acidosis. Fatal lactic acidosis has also occurred in pregnant women.

Normal Range of Lactate:-
Lactate levels are usually reported as mmol/dL  (millimoles of lactate per deciliter of blood). Lactate levels of 2 to 5 mmol/dL are elevated and should be considered with any symptoms you have. Levels greater than 5 mmol/dL are abnormal, and levels greater than 10 mmol/dL indicate a serious and possibly life-threatening situation.

Signs and symptoms of severe lactic acidosis are:

a)      Persistent nausea, vomiting, and abdominal pain

b)      Tiredness

c)      Shortness of breath

d)      Rapid breathing

e)      Enlarged or tender liver

f)       Cold or blue hands and feet

g)      Abnormal heart beat

h)      Weight loss

Vitamin B₁₂ deficiency:-
Vitamin B12 also called cobalamin, is a water-soluble vitamin with a key role in the normal functioning of the brain and nervous system, and for the formation of blood. It is one of the eight B vitamins. It is normally involved in the metabolism of every cell of the human body, especially affecting DNA synthesis and regulation, but also fatty acid synthesis and energy production.

Vitamin B₁₂ deficiency or hypocobalaminemia is a low blood level of vitamin B₁₂. It can cause permanent damage to nervous tissue if left untreated longer than 6 months. Vitamin B₁₂ itself was discovered through investigation of pernicious anemia, which is an autoimmune disease that destroys parietal cells in the stomach that secrete intrinsic factor. Pernicious anemia, if left untreated, is usually fatal within three years.

The patient's digestive system cannot absorb B12 properly. Signs and symptoms of pernicious anemia may include:
a)Fatigue
b)Shortness of breath
c)Palpitations

Anemia may also have the following signs and symptoms:
a)A sore mouth and/or tongue
b)Weight loss
c)Pale or yellowish skin
d)Diarrhea
e)Menstrual problems
f)Higher susceptibility to infections

If the deficiency continues untreated the patient may have the following neurological signs and symptoms:
a) General muscle weakness
b) Difficulty walking properly
c) Irritability
d) Confusion
e) Forgetfulness

Diagnosis of B12 deficiency:-
a) Patient has accelerated pulse and pale/yellowish skin.

Blood test- to determine whether the red blood cell count is low. The appearance of the red blood cells is also checked, because they may have an unusual shape. A blood test can also determine what the level of B12 is.

REFERRENCES:-
1.Essentials of Medical Pharmacology by KD TRIPATHI
2.Martindale-The Complete Drug Reference
3.A to Z Drug Facts, 4th edition by David S. Tatro
4.WILSON AND GISVOLD'S TEXTBOOK OF ORGANIC MEDICINAL AND PHARMACEUTICAL CHEMISTRY

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