ORAL HYPOGLYCEMICS

ORAL HYPOGLYCEMICS AND INSULIN: 

ORAL HYPOGLYCEMICS AND INSULIN Presented By Anuradha RAVINDER NAIK

Diabetes : 

Diabetes Diabetes mellitus is a chronic metabolic disorder characterised by a high blood glucose concentration caused by insulin deficiency, often combined with insulin resistance.. fasting plasma glucose > 7.0 mmol /l, plasma glucose > 11.1 mmol /l 2 hours after a meal Symptoms : - hyperglycemia - polyuria - polydipsia - keto acidosis -weight gain and Glucosuria

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Reduced uptake of glucose Reduced Glycogen synthesis Increased glucose reabsorption Decreased Insulin secretion Uncontrolled hepatic glucose outcome hyperglycemia

Contd …: 

Contd … Complications with Diabetes : - Diseases of blood vessels - Dysfunction of vascular endothelium - Implication of ROS and non- enzymic products of glucose - Diabetic neuropathy - Diabetic nephropathy - Diabetic retinopathy

Types of Diabetes: 

Types of Diabetes Type 1: deficiency of insulin resulting from autoimmune destruction of B cells Without insulin treatment, such patients will ultimately die with diabetic ketoacidosis . Juvenile diabetes : Type 1 diabetic patients are usually young (children or adolescents) Causes : - Insulin deficiency - Genetic predisposition - Viral infection

Contd .… : 

Contd .… Type 2 : Is accompanied both by insulin resistance and by impaired insulin secretion Such patients are often obese and usually present in adult life Treatment is initially dietary, although oral hypoglycaemic drugs usually become necessary, and about one-third of patients ultimately require insulin

Insulin levels : 

Insulin levels

Oral hypoglycemics: 

Oral hypoglycemics Agents that are given orally to reduce the blood glucose levels in diabetic patients Five types of oral antidiabetic drugs are currently in use: • Biguanides : metformin • Sulfonylureas : glimepiride , glyburide,tolbutamide,glibenclamide,glipizide • Meglitinides : nateglinide , repaglinide • Thiazolidinediones : pioglitazone , rosiglitazone Alpha - glucosidase inhibitors: acarbose , miglitol

Contd …: 

Contd … The oral antidiabetic drugs are of value only in the treatment of patients with type 2 (NIDDM) diabetes mellitus whose condition cannot be controlled by diet alone. These drugs may also be used with insulin in the management of some patients with diabetes mellitus, Use of an oral antidiabetic drug with insulin may decrease the insulin dosage in some individuals.

Biguanides: 

Biguanides Metformin : is the only drug of this class presently available in market It does not cause hypoglycaemia MOA : They increase glucose uptake and utilisation in skeletal muscle (thereby reducing insulin resistance) and reduce hepatic glucose production ( gluconeogenesis ). Pharmacokinetic aspects : Metformin has a half-life of about 3 hours and is excreted unchanged in the urine.

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Unwanted effects : -dose-related gastrointestinal disturbances -Lactic acidosis is a rare but potentially fatal toxic effect -Long-term use may interfere with absorption of vitamin B 12 Contra indications - metformin should not be given to patients with Renal failure Hepatic disease Hypoxic pulmonary disease Heart failure or shock

sulfonylureas: 

sulfonylureas 1 st gen : Tolbutamide and Chlorpropamide 2 nd gen : glibenclamide , glipizide , glimperide MOA : Acts on B cells stimulating insulin secretion and thus reducing plasma glucose Tolbutamide : half-life : 6-12 hrs P’kinetics : Orally administered, Some converted in liver to weakly active hydroxytolbutamide ; some carboxylated to inactive compound. Renal excretion.

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ADR : Hypoglycaemia. May decrease iodide uptake by thyroid. Contraindicated in liver failure, renal failure patients. Glibenclamide : Half life : 18-24 hrs P’kinetics : Orally given, Some is oxidised in the liver to moderately active products and is excreted in urine; 50% is excreted unchanged in the faeces. ADR : May cause hypoglycaemia. The active metabolite accumulates in renal failure.

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Glipizide : half-life : 16-24 hrs P’kinetics : Peak plasma levels in 1 hour. Most is metabolised in the liver to inactive products, which are excreted in urine; 12% is excreted in faeces. ADR : Causes hypoglycaemia Has diuretic action Most sulfonylureas cross the placenta and enter breast milk; as a result, use of sulfonylureas is contraindicated in pregnancy and in breast feeding Drug interactions : NSAIDs, MAO inhibitors, anti bacterials , and anti fungals

Meglitinides : 

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

Glitazones : 

Glitazones currently marketed thiazolidinediones ( glitazones ) Rosiglitazone and Pioglitazone MOA : Thiazolidinediones bind to a nuclear receptor called the peroxisome proliferator -activated receptor- γ ( PPAR γ ), which is complexed with retinoid X receptor (RXR). PPARγ -RXR complex bind to DNA, promoting transcription of several genes with products that are important in insulin signalling. P’kinetics : A-Orally, highly plasma protein bound, peak plasma concentration-within 2 hrs M- liver enzymes. E- Rosiglitazone metabolites in urine, Pioglitazone metabolites in bile

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Unwanted effets : -W eight gain -fluid retention, headache, fatigue and gastrointestinal disturbances. Have also been reported. Thiazolidinediones are contraindicated in pregnant or breast-feeding women and in children.

α-Glucosidase inhibitors: 

α- Glucosidase inhibitors Acarbose : An inhibitor of intestinal α- glucosidase , is used in type 2 diabetes. MOA : It delays carbohydrate absorption, reducing the postprandial increase in blood glucose . Unwanted effects : flatulence, loose stools or diarrhoea, and abdominal pain and bloating. Like metformin , it may be particularly helpful in obese type 2 patients, and it can be coadministered with metformin .

Insulin : 

Insulin Insulin is a polypeptide hormone consisting of two peptide chains that are connected by disulfide bonds. It is synthesized as a precursor (pro-insulin) that undergoes proteolytic cleavage to form insulin and C peptide, both of which are secreted by the ß cells of the pancreas. Insulin and glucagon regulates blood glucose levels. Insulin Secretion is most commonly triggered by high blood glucose. ACTIONS : Insulin is the main hormone controlling intermediary metabolism, having actions on liver, muscle and fat. Its overall effect is to conserve fuel by facilitating the uptake and storage of glucose, amino acids and fats after a meal

Insulin structure: 

Insulin structure

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Sources of insulin : Human insulin is produced by recombinant DNA technology using special strains of Escherichia coli or yeast that have been genetically altered to contain the gene for human insulin. MOA : Acts on insulin receptors on liver cells ,fat cells and stimulates glucose transport across membrane by ATP dependent transporters like GLUT 4 &GLUT 1

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Insulin administration : Because insulin is a polypeptide, it is degraded in the gastrointestinal tract if taken orally. It therefore is generally administered by subcutaneous injection Types of insulin preparations : 1. Rapid-acting and short-acting insulin preparations : Regular insulin, insulin lispro , insulin aspart , and insulin glulisine -these insulin preparations reach peak plasma concentration in 30-90 mins . Insulin lispro is an insulin analogue in which a lysine and a proline residue are 'switched'

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2. Intermediate-acting insulin : Neutral protamine Hagedorn (NPH) insulin is a suspension of crystalline zinc insulin combined at neutral pH with a positively charged polypeptide, protamine . Delayed absorption of the insulin because of its conjugation with protamine , forming a less-soluble complex 3.Long-acting insulin preparations : a. Insulin glargine b. Insulin detemir

Pharmacokinetics of Insulin: 

Pharmacokinetics of Insulin Insulin is destroyed in the gastrointestinal tract, and must be given parenterally -usually subcutaneously, but intravenously or occasionally intramuscularly in emergencies Insulin should be administered 15-20 mins prior to meal Adverse reactions to insulin : - Hypoglycemia is the most serious and common adverse reaction to an overdose of insulin -Other adverse reactions include weight gain, lipodystrophy (less common with human insulin), allergic reactions, and local injection site reactions.

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Thank you…..