Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

These agents are useful in the treatment of type 2 DM who do not respond adequately to non-medical interventions (diet, exercise and weight loss).

Newly diagnosed Type 2s (less than 5 years) often respond well to oral agents, patients with long standing disease (often diagnosed late) often require a combination of agents with or without insulin.

The progressive decline in β-cell function often necessitates the addition of insulin at some time in Type II diabetes. Oral agents are never indicated for Type I DM.

Sulphonylureas–

First generation-Tolbutamide, Chlorpropamide

Second generation(24hrs)-Glybenclamide or glyburide, Gliclazide, Glipizide, Glimepiride

Biguanides----Metformin, Phenformin

Meglitinide Analogues— Repaglinide, Nateglinide

Thiazolidinediones- Rosiglitazone , Pioglitazone

-Glucosidase Inhibitors-- Acarbose , Miglitol, Voglibose

Incretin-mimetics -Exenatide

DPP-4 Inhibitors- Sitagliptin, Vildagliptin,

SaxagliptinAmylin-mimetic drugs- pramlintideSodium- glucose cotransporter-2(SGLT-2)-Dapaglifozin, Serglifozin, Remoglifozin

Tolbutamide, Glyburide, Glipizide and Glimepride.They bind to SURI(sulfonylurea receptors) and promote

the release of insulin from β-cells (secretogogues)Mechanism: These agents require functioning β-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. Orally active, low volume of distribution, 90% bound

to plasma proteinsOnset and Duration Short acting: Tolbutamide - 6-12 hrs Intermediate acting: Glipizide , Glyburide Long acting: Glimepiride, glyclazide Glybenclamide-150 times potent than tolbutamide

These agents tend to cause weight gain due to fluid retention and oedema

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 associated with high incidence of cardiovascular mortality.

Nausea, vomiting, abdominal pain, diarrhea

Hypoglycaemia

Dilutional hyponatraemia & water intoxication (Chlorpropamide)

Disulfiram-like reaction with alcohol (Chlorpropamide)

Weight gain

Hypersensitivity reactions

Two classes of oral hypoglycemics work by improving insulin target cell response; the biguanides and thiazolidinediones.

Indicated in most Type 2 DMMOA-Act by inhibiting liver gluconeogenesis & increasing insulin sensitivity in other tissues. Enhances insulin mediated glucose disposal in muscle and fatRetards intestinal absorption of glucose, Metformin is not metabolized, but excreted intact in 2-5hPerpetuates weight lossCan be combined with insulin to reduce insulin requirements

Enhances insulin mediated glucose disposal in muscle and fat. 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.Metformin:

Dosing from 500mg twice daily to 1 gram thrice a day

Nausea, Vomiting and diarhorrea(5%) Phenformin withdrawn for higher risk of lactic acidosislactic acidosis is associated with metformin use particularly in diabetics with CHFDrug interactions with cimetidine, furosemide, nifedipineand others have been identified.Contraindication

a) Malabsorption or GI disturbancesb) Low BMIc) Organ Failure: Creatinine: >1.4mg/dl

Liver failure, Active Vitamin B12 DeficiencyGI intolerance

These agents are insulin sensitizers, they do not promote insulin secretion from β-cells but insulin is necessary for them to be effective.

Metabolized with a long half life Partial mimics of insulin actions, may bind insulin

receptor or act through the peroxisomal proliferator activated receptor γ

Ligands for PPAR-γ regulate adipocyte production, secretion of fatty acids and glucose metabolism.

Agents binding to PPAR-γ result in increased insulin sensitivity is adipocytes, hepatocytes and skeletal muscle.

Hyperglycemia, hypertriglyceridemia and elevated HbA1c are all improved. HDL levels are also elevated. Accumulation of subcutaneous fat occurs with these agents.

Pharmacokinetics: Both are extensively bound to albumin. Both undergo extensive P450 metabolism; metabolites are excreted in the urine the primary compound is excrete unchanged in the bile. Adverse Effects:Fatal hepatotoxicity has occurred with these agents; hepatic function must be monitored. Drug interaction:Oral contraceptives levels are decreased with concomitant administration

These agents act as secretogogues.

Mechanism: These agents bind to ATP sensitive K+channels like sulfonylureas acting in a similar fashion to promote insulin secretion however their onset and duration of action are much shorter. 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. Hypoglycemia is a great risk if meal is delayed

Very rapid onset of action and short duration

(TMAX = 1 hour, metabolized by liver T1/2 = 70 minutes)

No hypoglycemic metabolites. Less hypoglycemia than sulfonylureas

Improves postprandial glycemia (nateglinide)

Less effective in decreasing fasting blood glucose levels and HbA1C

Demerits

Fails to provides a stable 24 hours blood glucose control

Complicated dosage style (3-8 tablets/daily)

Headache, dyspepsia, arthralgia and weight gainRepaglinide avoided in liver diseaseDrug interaction-Drugs that inhibit CYP3A4 (ketoconazole, 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.

Incretins are naturally occurring hormones that the gut releases throughout the day; the level of active incretins increases significantly when food is ingested.

Endogenous incretins GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropicpeptide) facilitate the response of the pancreas and liver to glucose fluctuations through their action on pancreatic β cells and α cells.

The combination of increased insulin production and decreased glucagon secretion reduces hepatic glucose production when plasma glucose is elevated.

The physiologic activity of incretins is limited by the enzyme dipeptidyl peptidase-4 (DPP-4), which rapidly degrades active incretins after their release.

The Incretin Effect Is Diminished in Type 2 Diabetes Levels of GLP-1 are decreased. The insulinotropic response to GIP is diminished

but not absent. Defective GLP-1 release and diminished response

to GIP may be important factors in glycemic dys-regulation in type 2 diabetes.

EXENATIDE- is a long acting analogue as it is resistant to DPP-IV degradation obtained from the salivary gland venom of gila monsterPotent agonist at GLP1 receptor(incretin mimetic)It is orally inactive and given sc5-10µg BD GLP1 receptor agonist -stimulates insulin secretion from β-cells of pancreas-decrease glucagon releaseSlows gastric emptying slows rate of nutrition absorptionDecrease appetite by acting at the level of hypothalamus(induces weight loss)It is used along with metformin or sulfonylureas in DM2

Incretin mimetics

Long acting synthetic GLP1 analog Long half life DM type 2 for once daily injectable therapy 0.6mg dose titratedADR- headache, dairrhoea, antibody formation

pancreatitis

This enzyme hydrolyses oligosaccharides to monosaccharides which are then absorbed.

Acarbose also inhibits pancreatic amylase. The normal post-prandial glucose rise is blunted, glucoselevels rise modestly and remain slightly elevated for a

prolonged period, less of an insulin response is required and hypoglycemia is avoided;

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

Acarbose, Voglibose and miglitolMechanism of action: These agents are taken at the beginning of a meal

delay carbohydrate digestion by competitively inhibiting α-glucosidase, a membrane bound enzyme of the intestinal brush border.

Lowers HbA1c levels, lowers body weightLowers Serum triglyceridesMeglitol can block isomaltase and β-glucosidases

Pharmacokinetics: Acarbose is poorly absorbed. Migitol is absorbed and excreted by the kidney. Both agents exert their effect in the intestinal lumen.Adverse Effects:Flatulence, diarrhea, crampingCan cause hypoglycemia when used with sulfonylureas Metformin bioavailability is severely decreased when

used concomitantly. These agents should not be used in diabetics with intestinal pathology.

Contraindication Inflammatory bowel disease and intestinal obstruction

Sitagliptin, VildagliptinOrally active selective inhibitors of DPP-4 enzyme that inactivates GLP-1Results in increase of GLP-1 activity and prolonged actionOnce daily dosage is effectiveMOA-Increased insulin secretion

Decrease glucagon releaseDelay gastric emptyingSuppress appetite

They can be used along with metformin and sulfonylureas

Adverse effects – nasopharyngitis( concentration of substance P can increaseGIT distress, diarrhoea, Sitagliptin therapy requires adequate levels of GLP-1, which may not be feasible in patients taking carbohydrate free diet

Amylin is a neuroendocrine hormone peptide hormone co-secreted with insulin from pancreatic B-cells.

It inhibits glucagon secretion Delays gastric emptying Suppress appetite Pramlintide is a modified amylin peptide which is

agonist at amylin receptor(GPCR) It is used 15-60µg sc before meals adjunct to insulin

in DM1 ADR- nausea, diarrhoea, headache

Dapoglifozin, Serglifozin, RemoglifozinInhibiting SGLT2 decrease the amount of glucose reabsorption from the proximal tubule and increases its excretion in urineSGLT2 is exclusively distributed on the proximal tubule of the kidneySGLT2 inhibitors can cause weight loss, no hypoglycemia as they are excreting only the excess glucose from the blood

Improve insulin resistanceBeneficial in patients having hypertension with diabetesDisadvantages Polyurea can cause polydipsiaIncreased risk of urinary infection in glycosuriaRisk of Na+ loss, as sodium-glucose co-transporter has been inhibited

Cholesevelam hydrochlorideBile acid sequestrant and cholesterol lowering drugTreatment of type 2 DMEnterohepatic circulation decrease in FXR(farsinoid X receptor nuclear receptor with multiple effects on cholesterol, glucose, and bile acid metabolismLowers HbA1c levelsS/E- GI complaints, constipation, flatulanceD/I- impairs glyburide, fat soluble vitamins

Body Mass Index ---- Metformin, GliptinsBMI> 22kg/m2

Presence of GI symptoms Sulpha, Gliptins, GlitazonesRenal Dysfunction Gliptins, Glitazones(+/-), Sulpha(variable) 4) Aging---- Meglitinides, Gliptins(?) 5) Hepatic Dysfunction Nateglinide, Saxagliptin(?) 6) Compliance Gliptins, Glitazones, 7) Cost Metformin, Sulphas, Glitazones

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Lifestyle modification

diet modification, weight control, exercise

Metformin

Sulphonylurea

DPP-4 Inhibitor

GlitazoneAcarboseInsulin