1. insuline and anti diabetics

Prepared by: Mirza Anwar Baig

M.Pharm (Pharmacology)

Anjuman I Islam's Kalsekar Technical Campus,

School of Pharmacy.

New Panvel,Navi Mumbai

Synthesis, MOA & role of insulin. Diagnosis and symptoms of insulin related

disorders. Classification & MOA at receptor level, side

effects of antidiabetics. Pharmacotherapeutics of diabetic disorders.

COMPILED BY: PROF.ANWAR BAIG (AIKTC,SOP) 2

Outline:InsulinChemistry

SecretionDegradationReceptorsEffects on its targetsInsuline delivary systemComplication of insuline therapy

Diabetes & antidiabetics

TypesBenefits of tight blood glucose controlOral hypoglycemic drugsCombination therapy

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COMPILED BY: PROF.ANWAR BAIG (AIKTC,SOP)

It is hormone & protein. It contains 51 amino acids arranged in two chains (A and B).

Secreted by Beta cells of islets of Langerhans.Granules within the B cells store the insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin. The entire human pancreas contains up to 8 mg of insulin,Proinsulin, a long single/ chain protein molecule, is processed within the Golgi apparatus and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C/ peptide by removal of four amino acids.

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The liver and kidney are the two main organs that remove insulin from the circulation.

The half/ life of circulating insulin is 35 minutes.

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Portable Pen Injectors Continuous Subcutaneous Insulin Infusion

Devices (Csii, Insulin Pumps) Inhaled Insulin

COMPLICATIONS OF INSULIN THERAPY Hypoglycemia Insulin Allergy Immune Insulin Resistance Lipodystrophy at Injection Sites

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Diabetes mellitus (DM) is a group of diseases characterized by chronic hyperglycemia resulting from defects in insulin production, insulin action, or both.

It involves the disturbances of carbohydrate, fat and protein metabolism.

The effects of diabetes mellitus include longterm damage, dysfunction and failure of various organs.

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Diabetes mellitus affects approximately 5 to 8% of the population. A large number of individuals are asymptomatic and do not know they have the disease.

Prevalence of Diabetes in various Prevalence of Diabetes in various regions of world WHO regions of world WHO Report(Geneva)1997Report(Geneva)1997

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Random value : 200mg/dl or more DM

Fasting value: Below 100mg/dl Normal value100-125 mg/dl IFG126 mg/dl or more DM

Oral glucose tolerance test:less than 140 mg/dl Normal value140-199 mg/dl IGT200mg/dl or more DM


Type 1 Diabetes Mellitus Type 2 Diabetes MellitusGestational DiabetesOther types:


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Was previously called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes.

Type 1 diabetes develops when the bodys immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin that regulates blood glucose.

This form of diabetes usually strikes children and young adults, although disease onset can occur at any age.

Type 1 diabetes may account for 5% to 10% of all diagnosed cases of diabetes.

Risk factors for type 1 diabetes may include autoimmune, genetic, and environmental factors.


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Was previously called non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes.

Type 2 diabetes may account for about 90% to 95% of all diagnosed cases of diabetes.

It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As the need for insulin rises, the pancreas gradually loses its ability to produce insulin.

Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity.

Type 2 diabetes is increasingly being diagnosed in children and adolescents.


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Cells of pancreas Glands of pancreas



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A form of glucose intolerance that is diagnosed in some women during pregnancy.

It is also more common among obese women and women with a family history of diabetes.

During pregnancy, gestational diabetes requires treatment to normalize maternal blood glucose levels to avoid complications in the infant.

After pregnancy, 5% to 10% of women with gestational diabetes are found to have type 2 diabetes.

Women who have had gestational diabetes have a 20% to 50% chance of developing diabetes in the next 5- 10 years.


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Other specific types of diabetes result from specific genetic conditions, surgery, drugs, malnutrition, infections, and other illnesses.

Such types of diabetes may account for 1% to 5% of all diagnosed cases of diabetes.


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Research studies have found that lifestyle changes can prevent or delay the onset of type 2 diabetes among high/ risk adults.

These studies included people with IGT and other high/ risk characteristics for developing diabetes.

Lifestyle interventions included diet and moderate/ intensity physical activity (such as walking for 21/2 hours each week).

In the Diabetes Prevention Program, a large prevention study of people at high risk for diabetes, the development of diabetes was reduced 58% over 3 years.


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In the Diabetes Prevention Program, people treated with the drug metformin reduced their risk of developing diabetes by 31% over 3 years.

Treatment with metformin was most effective among younger, heavier people (those 25 to 40 years of age who were 50 to 80 pounds overweight) and less effective among older people and people who were not as overweight.

Similarly, treatment of people with IGT with the drug acarbose reduced the risk of developing diabetes by 25% over 3 years.

Other medication studies are ongoing. In addition to preventing progression from IGT to diabetes, both lifestyle changes and medication have also been shown to increase the probability of reverting from IGT to normal glucose tolerance.


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Management of Diabetes Mellitus


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The major components of the treatment of diabetes are:


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Dietary treatment should aim at:Ensuring weight controlProviding nutritional requirementsAllowing good glycaemic control with blood glucose levels as close to normal as possibleCorrecting any associated blood lipid

abnormalities


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Physical activity promotes weight reduction and improves insulin sensitivity, thus lowering blood glucose levels.

Together with dietary treatment, a programme of regular physical activity and exercise should be considered for each person.


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There are currently four classes of oral anti/ diabetic agents:

i. Biguanidesii. Insulin Secretagogues Sulphonylureasiii. Insulin Secretagogues Meglitinideiv. / glucosidase inhibitorsv. Thiazolidinediones (TZDs)


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1. Biguanides: Metformin, it increases glucose uptake and utilization by target

tissues. It requires the presence of insulin to be effective but does not promote insulin secretion. The risk of hypoglycemia is greatly reduced.

Mechanism: Metformin reduces plasma glucose levels by inhibiting hepatic gluconeogenesis. It also slows the intestinal absorption of sugars. It also reduces hyperlipidemia (LDL and VLDL cholesterol and HDL). Lipid lower requires 4-6 weeks of treatment. Metformin also decreases appetite. It is the only oral hypoglycemic shown to reduce cardiovascular mortality. It can be used in combination with other oral agents and insulin.

Adverse effects: Hypoglycemia occurs only when combined with other agents. Rarely severe lactic acidosis is associated with metformin use particularly in diabetics with CHF. Drug interactions with cimetidine, furosemide, nifedipine have been identified.

These agents promote the release of insulin from -cells;tolbutamide, glyburide, glipizide and glimepiride.

Mechanism:

These agents require functioning -cells, they stimulate release by blocking ATP-sensitive K+ channels resulting in depolarization with Ca2+ influx which promotes insulin secretion.

They also reduce glucagon secretion and increase the binding of insulin to target tissues.

They may also increase the number of insulin receptors

Pharmacokinetics: These agents bind to plasma proteins, are metabolized in the liver and excreted by the liver or kidney. Tolbutamide has the shortest duration of action (6-12 hrs) the other agents are effective for ~24 hrs.

Adverse Effects: These agents tend to cause weight gain, hyperinsulinemia and hypopglycemia. Hepatic or renal insufficiency causes accumulation of these agents promoting the risk of hypoglycemia.

Elderly patients appear particularly susceptible to the toxicities of these agents.

Tolbutamide is asociated with a 2.5X in cardiovascular mortality.

Onset and Duration Short acting: Tolbutamide (Orinase) Intermediate acting: Tolazamide

(Tolinase), Glipizide (Glucotrol), Glyburide (Diabeta)

Long acting: Chloropropamide, Glimerpiride

These agents (repaglinide (Prandin) and nateglinide (Starlix)) act assecretogogues.

MECHANISM: MOA is like sulfonylureas however their onset and duration of action are much shorter. They are particularly effective at mimicking the prandial and post-prandial release of insulin. When used in combination with other oral agents they produce better control than any monotherapy.

PHARMACOKINETICS: These agents reach effective plasma levels when taken 10-30 minutes before meals. These agents are metabolized to inactive products by CYP3A4 and excreted in bile.

ADVERSE EFFECTS: Less hypoglycemia than sulfonylureas; drugs that inhibit CYP3A4 (ketoconozole, fluconazole, erythromycin, etc.) prolong their duration of effect. Drugs that promote CYP3A4 (barbiturates, carbamazepine and rifampin) decrease their effectiveness. The combination of gemfibrozil and repaglinide has been reported to cause severe hypoglycemia.

This enzyme hydrolyses oligosaccharides to monosaccharides which are then absorbed.

Acarbose also inhibits pancreatic amylase.

Use with other agents may result in hypoglycemia. Sucrase is also inhibited by these drugs.

Eg: Acarbose and miglitol are two agents of this class used for type 2 diabetes.

Mechanism of action: These agents are oligosaccharide derivatives taken at the beginning of a meal delay carbohydrate digestion by competitively inhibiting -glucosidase, a membrane bound enzyme of the intestinal brush border.

Pharmacokinetics: Acarbose is poorly absorbed remaining in the intestinal lumen. Migitol is absorbed and excreted by the kidney. Both agents exert their effect in the intestinal lumen.

Adverse Effects: (flatulence, diarrhea, cramping). Metformin bioavailability is severely decreased when used concomitantly. These agents should not be used in diabetics with intestinal pathology.

Incretins are a group of metabolic hormones that stimulate a decrease in blood glucose levels.

Incretins do so by causing v an increase in the amount of insulin released from pancreatic

beta cells of the islets of Langerhans after eating, before blood glucose levels become elevated.

v Slow the rate of absorption of nutrients into the blood stream by reducing gastric emptying and may directly reduce food intake.

v Inhibit glucagon release from the alpha cells of the islets of Langerhans.

The two main candidate molecules that fulfill criteria for anincretin are the intestinal peptides glucagon/ like peptide 1(GLP1) and gastric inhibitory peptide. Both GLP/ 1 and GIP are rapidly inactivated by the enzymedipeptidyl peptidase4 (DPP4).

A new class of oral hypoglycemics called dipeptidyl peptidase/ 4 inhibitors work by inhibiting the action of this enzyme, thereby prolonging incretin effect in vivo.


As first line therapy:

Obese type 2 patients, consider use of metformin, acarbose or TZD.

Non/ obese type 2 patients, consider the use of metformin or insulin secretagogues.

Metformin is the drug of choice in overweight/obese patients. TZDs and acarbose are acceptable alternatives in those who are intolerant to metformin.

If monotherapy fails, a combination of TZDs, acarbose and metformin is recommended. If targets are still not achieved, insulin secretagogues may be added.


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Combination oral agents is indicated in:

Newly diagnosed symptomatic patients with HbA1c =10

Patients who are not reaching targets after 3 months on monotherapy


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If targets have not been reached after optimal dose of combination therapy for 3 months, consider adding intermediate/ acting/long/ acting insulin.

Combination of insulin+ oral anti/ diabetic agents has been shown to improve glycaemic control in those not achieving target despite maximal combination oral anti/ diabetic agents.

Combining insulin and the following oral anti/ diabetic agents has been shown to be effective in people with type 2 diabetes: Biguanide (metformin) Insulin secretagogues (sulphonylureas) Insulin sensitizers (TZDs) / glucosidase inhibitor (acarbose)

Insulin dose can be increased until target FPG is achieved.


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Diabetes Management Algorithm


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Short- term use: Surgery, stress Pregnancy Breast/ feeding Insulin may be used as initial therapy in type 2 diabetes In marked hyperglycaemia Severe metabolic decompensation

Long- term use: If targets have not been reached after optimal dose of

combination therapy , consider change to multi/ dose insulin therapy. When initiating this,insulin secretagogues should be stopped and insulin sensitisers e.g. Metformin or TZDs, can be continued.


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Patients should be educated to practice self/care. This allows the patient to assume responsibility and control of his / her own diabetes management. Self/ care should include:

Blood glucose monitoring Body weight monitoring Foot/ care Personal hygieneHealthy lifestyle/diet or physical activity Identify targets for control Stopping smoking


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Thank You


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1. insuline and anti diabetics

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