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Oral anti diabetic drugs

The document discusses diabetes mellitus, its types, and management through various oral anti-diabetic drugs, including sulphonylureas, biguanides like metformin, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, incretin-based therapies, and SGLT2 inhibitors. It highlights the mechanisms of action, benefits, side effects, and specific indications for each class of medication while noting the importance of appropriate patient selection and monitoring, especially in cases of pregnancy and coexisting conditions. It emphasizes the evolving landscape of diabetes management, including newer therapies with unique benefits and considerations.

Health & Medicine◦
Oral anti-diabetic drugs Supervision :Dr. Osama Othman By:Fatima Ehsan Abduluahab Hevi ahmed mohammed Alaa khilil Ibrahem Hajer abdulla Daroon kaua
Objectives: • 1.what is DM? • 2.types of oral anti diabetic drug • 3.take home messege
Introduction • Diabetes mellitus is a clinical syndrome characterized by an increase in plasma blood glucose (hyperglycemia). • Diabetes has many causes but is most commonly due to type 1 or type 2 diabetes.
• Type 1 diabetes is caused by autoimmune destruction of insulin-producing cells (β cells) in the pancreas, resulting in absolute insulin deficiency.
Pathogenesis of type 1 diabetes.
• Type 2 diabetes is characterized by resistance to the action of insulin and an inability to produce sufficient insulin to overcome this ‘insulin resistance’.
Natural history of type 2 diabetes.
• Hyperglycemia results in both acute and long-term problems. • Acutely, high glucose and lack of insulin can result in marked symptoms, metabolic decompensation and hospital-isation. • Chronic hyperglycemia is responsible for diabetes- specific ‘microvascular’ complications affecting the eyes (retinopathy), kidneys (nephropathy) and feet (neuropathy).
• Fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dL) • Glucose 2 hours after an oral glucose challenge ≥ 11.1 mmol/L (200 mg/dL) Diagnostic criteria for diabetes:-
Drugs to reduce hyperglycemia • For many years, there were only a few choices of drugs available for type 2 diabetes – the biguanide metformin, the sulphonylureas and insulin. Insulin is the only treatment for type 1 diabetes. • Since the late 1990s, however, several new classes of agents have been approved for use in type 2 diabetes, with more in development. • Newer drugs include thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium and glucose transporter 2 (SGLT2) inhibitors.
• The older drugs are cheaper and have established benefits for reducing microvascular disease. • Use of the newer drugs is not supported by evidence for reduction in microvascular-lar disease (because the trials have not yet beencompleted) and they are much more expensive, so are often reserved for later therapy after failure of metformin and sulphonylureas.
Sites of action of the most widely used oral antihyperglycemic agents.
Management of hyperglycemia in types 2 diabetes
Sulphonylureas • It is the first antidiabetic drug that been discoveered at 1942 • Sulphonylureas used in Patients with T2DM ,obese,not respond to dietary measures and exercise alone
Mechanism of action • Sulphonylureas are insulin secretagogeus that act through specific recepter which is linked to a k+ channel on the surface of pancreatic Beta cells k+ transport trigers insulin secretion .
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Sulphonylureas generations • First generation • Tolbutamide: mildest one has short duration of action usually adminstered 8 -12 hourly it useful in elderly • Chlorpropamide: half life about 36hr taken once daily rarely used
Second generation Gliclazide few side effects Glibenclamide avoid in elderly Glimepiride and modified release form of gliclazide taken once daily with no risk of hypoglycemia
pharmacokinetics • Sulphonylureas absorbed by intestine after oral use. • Hyperglycemia reduse sulphonylureas absorption as it impaire intestinal motility • For this reason sulphonylureas taken 30 min. before meals and dose increase every 2 wk if there is uncontrolled BS • But the first dose is low
Side Effects of Sulphonylureas • Signs of low blood sugar, such as sweating, dizziness, confusion, or nervousness • Hunger • Weight gain • Skin reactions • Upset stomach • Dark-colored urine
Sulphonylurea Precautions • Type1 DM • Diabetic ketoacidosis • Liver or kidney diseases • Pregnancy and breast feeding • Elderly
Drug interaction • Salicylates, phenylbutazone and antifungal potentiate hypoglycemic effect of sulphonylureas by displacing them from plasma protein binding sites.
BIGUANIDES
• Metformin is the only biguanide available, and it is now widely used as first-line therapy for type 2 diabetes, irrespective of body weight. Metformin is also used increasingly as an adjunct to insulin therapy in obese patients with type 1 diabetes. • However, it is less well tolerated than sulphonylureas because of a higher incidence of side-effects, particularly gastrointestinal symptoms.
Mechanism of action : • The mechanism of action of metformin has not been precisely defined. It has no hypoglycaemic effect in non-diabetic individuals, but in diabetes, insulin sensitivity and peripheral glucose uptake are increased, possibly through inhibition of mitochondrial respiration and activation of AMP-regulated kinase (AMPK) in muscle. There is some evidence that it also impairs glucose absorption by the gut and inhibits hepatic gluconeogenesis. • Although secretion of some endogenous insulin is mandatory for its glucose-lowering action, it does not increase insulin secretion and seldom causes hypoglycaemia.
Indications: • Administration of metformin is not associated with a rise in body weight and it may be beneficial for the overweight or obese patient. • In addition, as the glucose lowering effect of metformin is synergistic with that of sulphonylure as the two can be combined when either alone has proved inadequate. It can also be given in • combination with most other anti-diabetic medications. • can also be used in polcystic ovarian syndrome.
• Metformin is given with food, usually starting with 500 mg 12-hourly, gradually increased as required to a maximum of 1 g 8-hourly. • Excretion of the drug is through the kidneys
Contraindications : • Its use is contraindicated in patients with impaired renal or hepatic function and in those who drink alcohol in excess in whom the risk of lactic acidosis is significantly increased.
• It should be discontinued, at least temporarily, if any other serious medical condition develops, especially one causing severe shock or hypoxaemia. In such circumstances,treatment with insulin should be substituted.
• history of congestive heart failure • acute myocardial infarction • use of IV contrast media: This can affect kidneys function and put patient at risk for lactic acidosis • major surgical procedures • people with diabetic ketoacidosis
Metformin during pregnancy : • Metformin is safe and effective treatment option for women with type 2 diabetes in pregnancy with or without add-on insulin who require pharmacological treatment for glycemic control . • Metformin has advantages over insulin such as less maternal weight gain, no maternal hypoglycemia, being cheap, being oral therapy, and requiring no vigorous monitoring and frequent hospital admissions with good compliance and acceptability. • Metformin treatment when compared with insulin treatment showed less maternal hypertensive complications and less risk of neonatal hypoglycemia with few neonatal intensive care admissions.
• Metformin treatment is suitable for non obese type 2 diabetes patients in pregnancy without complications. • Metformin treatment in type 2 diabetes in pregnancy required lower dose of add-on insulin, at a later gestational age for maintaining glycemic control when compared with insulin treatment.
Side effects: GIT problems • Diarrhea (53%) • Nausea, vomiting (26%) • Gastric upset (6%) • Flatulance (12%) • heartburn • Metallic taste (1-5%)
Serious side effects • lactic acidosis. Symptoms include: • tiredness • weakness • unusual muscle pain • trouble breathing • unusual sleepiness • Abdominal pain , nausea, or vomiting • dizziness or lightheadedness • slow or irregular heart rate
• Metformin does not usually cause low blood sugar (hypoglycemia). Low blood sugar may occur if this drug is prescribed with other diabetes medications. low blood sugar. Symptoms include: • headache • weakness • confusion • shaking or feeling jittery • drowsiness • dizziness • irritability • sweating • hunger • fast heart rate
Meglitinides • These act, like the sulfonylureas, but they don’t have sulfonylurea moiety. • These include repaglinide and nateglinide • MOA : Same as sulfonylureas . • Short duration of action and a low risk of hypoglycaemia. • Given orally, rapidly metabolized by liver enzymes and excreated in the bile .
Thiazolidinediones Thiazolidinediones (TZDs) reduce insulin resistance, act as insulin sensitizers; thus, they require the presence of insulin to work. They must be taken for 12-16 weeks to achieve maximal effect. These agents are used as monotherapy or in combination with sulfonylurea, metformin, meglitinide, DPP-4 inhibitors, GLP-1 receptor agonists, or insulin. They are the only antidiabetic agents that have been shown to slow the progression of diabetes (particularly in early disease). most likely through activation of PPAR-γ, a nuclear receptor that regulates the transcription of several insulin-responsive genes that regulate carbohydrate and lipid metabolism.
The biologic effect of TZDs is principally mediated by stimulation of peripheral glucose metabolism. PPAR-γ activation also attenuates lipolysis and stimulates peripheral adipocyte differentiation, thereby redistributing fat stores from the liver and muscle to subcutaneous depots. This effect may be largely responsible for the “insulin-sensitizing” effects of the TZDs. There is a concomitant modulation in the circulating levels of adipocytokines, particularly in adiponectin, which is increased two- to three-fold after TZDherapy.
In 1997, troglitazone was the first TZD approved for use in the United States; although effective, the drug was withdrawn from the market 2 years later because of concerns about idiosyncratic hepatotoxicity. Rosiglitazone and pioglitazone were later approved; these agents have no significant hepatotoxicity.
pharmacokinetic: Both pioglitazone and rosiglitazone are absorbed very well after oral adminstration and are extensively bound to serum albumin both undergo extensive metabolism bt different cytochrome p450 isozymes
the therapeutic range for pioglitazone is 15–45 mg/d in a single daily dose, the majority of the active drug and metabolite are excreated in the bile and eliminated in the feces. and for rosiglitazone the total daily dose is 2–8 mg/d administered either once daily or twice daily in divided doses.the metabolite are excreated in the urine.
Adverse effects: A few cases of liver toxicity have been reported with these drugs, and periodic monitoring of liver function is recommended. Weight gain can occur because TZDs may increase subcutaneous fat and cause fluid retention. [Note: Fluid retention can worsen heart failure. These drugs should be avoided in patients with severe heart failure.] TZDs have been associated with osteopenia and increased fracture risk. Pioglitazone may also increase the risk of bladder cancer. Several meta-analyses identified a potential increased risk of myocardial infarction and death from cardiovascular causes with rosiglitazone. As a result, use of rosiglitazone was limited to patients enrolled in a special restricted access program. After a further review of safety data, the restrictions on rosiglitazone use were subsequently lifted.
ALPHA GLUCOSIDASE INHIBITORS
Mechanism of action : • Alpha-glucosidase inhibitors work on two different enzymes in the small intestine: – Intestinal enzymes (acarbose and miglitol) • Intestinal cells contain an enzyme called alpha-glucosidase that metabolizes carbohydrates so that they can be absorbed into the bloodstream • Alpha-glucosidase inhibitors block alpha-glucosidase thereby inhibiting the metabolism of carbohydrates and slowing their absorption into the bloodstream – Pancreatic enzymes (acarbose only) • When a person consumes food, the pancreas secretes enzymes that help digest the food so that it can be absorbed into the bloodstream • Alpha-amylase is a pancreatic enzyme that metabolizes carbohydrates • Acarbose blocks alpha-amylase thereby inhibiting the metabolism of carbohydrates and slowing their absorption into the bloodstream
• Acarbose and miglitol are available and are taken with each meal. • Both lower post-prandial blood glucose and modestly improve overall glycaemic control. They can be combined with a sulphonylurea. they must be taken at the start of main meals to have maximal effect. Their effects on blood sugar levels following meals will depend on the amount of complex carbohydrates in the meal.
• The main side-effects are flatulence, abdominal bloating and diarrhoea. • Patients with inflammatory bowel disease, colonic ulceration, or intestinal obstruction should not use these drugs. • The drug is not recommended in pregnancy and lactation.
Incretin-based therapies: Dipeptidyl peptidase-4 inhibitors and GLP-1 analogues DPP4 # inhibit the enzyme DPP-4, which is responsible for the degredation of incretin hormones such as GLP-1. The incretin effect is the augmentation of insulin secretion seen when a glucose stimulus is given orally rather than intravenously, and reflects the release of incretin peptides from the gut .
The incretin hormones are primarily glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP),which act to potentiate insulin secretion . These are rapidly broken down by the peptidase DPP-4 (dipeptidyl peptidase 4). The incretin effect is diminished in type 2 diabetes, and this has stimulated the development of two incretin-based therapeutic approaches.
The ‘gliptins’, or DPP-4 inhibitors, prevent breakdown and therefore enhance concentrations of endogenous GLP-1 and GIP. The first DPP-4 inhibitor to market was sitagliptin; others now available include vildagliptin, saxagliptin and linagliptin. These drugs are very well tolerated and are weight-neutral . The GLP-1 receptor agonists have a similar structure to GLP-1 but have been modified to resist breakdown by DPP-4. These agents are not orally active and have to be given by subcutaneous injection.
. Recently, GLP-1 receptor agonists and long-acting insulin analogue have been combined, enabling co- administration of insulin and GLP-1 receptor agonists with one injection. However, they have a key advantage over the DPP-4 inhibitors: because the GLP-1 activity achieved is supra-physiological, it delays gastric emptying and, at the level of the hypothalamus, decreases appetite. Thus, injectable GLP-1 analogues lower blood glucose and result in weight loss – an appealing therapy, as the majority of patients with type 2 diabetes are obese.
•Currently available GLP-1 receptor agonists include exenatide (twice daily), exenatide MR (once weekly) and liraglutide (once daily).
• All the incretin-acting drugs have been reported to be associated with an increased risk of pancreatitis, although this risk is small: between 1 and 10 cases per 1000 patients treated. • Unlike sulphonylureas, both incretin-based therapies only promote insulin secretion when there is a glucose ‘trigger’ for insulin secretion. Thus, when the blood glucose is normal, the insulin secretion is not augmented and so these agents do not cause hypoglycaemia.
sodium and glucose transporter 2 (SGLT2) inhibitors The sodium and glucose transporter 2 (SGLT2) inhibitor, dapagliflozin, was licensed for use in 2012. Glucose is filtered freely in the renal glomeruli and reabsorbed in the proximal tubules. SGLT2 is involved in reabsorption of glucose.
• Inhibition results in approximately 25% of the filtered glucose not being reabsorbed, with consequent glycosuria. Although this helps to lower blood glucose and results in calorie loss and subsequent weight loss, the glycosuria does result in increased urinary tract and genital fungal infections. • Euglycaemic diabetic ketoacidosis (i.e. DKA not associated with marked hyperglycaemia) has been recognised as a rare complication of this class of drugs.
Oral anti diabetic drugs