Endocrine Pharmacology Lecture Notes PDF

Endocrine pharmacology (Antidiabetic drugs) By Dr. Hamza Al Asbily For nd 2 year dental students Diabetes mellitus (DM) is a clinical syndrome characterized by hyperglycemia due to absolute or relative deficiency of insulin. Lack of insulin affects the metabolism of ca...

Endocrine pharmacology (Antidiabetic drugs) By Dr. Hamza Al Asbily For nd 2 year dental students Diabetes mellitus (DM) is a clinical syndrome characterized by hyperglycemia due to absolute or relative deficiency of insulin. Lack of insulin affects the metabolism of carbohydrate, protein and fat. Type 1 diabetes mellitus: It appears when more than 90% of cells of pancreas are destroyed by an autoimmune process. The onset is acute and the peak incidence is around 15 years. Insulin is essential for all patients with type-1 DM. Type 2 diabetes mellitus: It is the commonest form of diabetes where genetic influence , Overeating, obesity, underactivity and ageing are the main risk factors. Type-2 DM is associated with increased hepatic production of glucose and resistance of target tissues to the action of insulin. Insulin is a protein consisting of two amino acid chains, alpha (21 aa) and beta (30 aa) connected by two disulfide bridges. Insulin is synthesized as a precursor (pro-insulin) which is enzymatically cleaved in P cells into C peptide and mature insulin which are stored in granules. Insulin receptor & mechanism of action Insulin binds to specific receptors (receptor tyrosine kinase) present on the cell membrane. The receptor consists of 2 and 2 subunits.Binding of insulin to the receptor activates tyrosine kinase of the receptor. A complex series of events occur resulting in various actions of insulin. Regulation of insulin secretion 1. Chemical: Glucose, amino acids and fatty acids in the blood stimulate cell to release insulin. 2. Neural: Both parasympathetic and sympathetic fibers supply the islet cells. Parasympathetic stimulation causes increase in insulin secretion and lowers raised blood sugar level. 3. Hormonal: GLP-1 (glucagon-like peptide), GIP (GI inhibitory peptide), gastrin, secretin, cholecystokinin, etc. promote the secretion of insulin. Actions of insulin Insulin has profound effects on the metabolism of carbohydrate, fat and protein. Insulin facilitates the entry of glucose into all cells of the body. However, entry of glucose into red blood cells (RBCs), white blood cells (WBCs), liver and brain cells can occur independent of insulin. Muscular exercise also facilitates entry of glucose into muscle cells without the need for insulin. 1. Insulin inhibits hepatic glycogenolysis, gluconeogenesis and lipolysis in adipose tissue. 2. Insulin promotes protein synthesis in muscle, lipogenesis, hepatic and muscle glycogenesis. 3. Insulin also promotes peripheral utilization of glucose and K+ uptake into the cells. Pharmacokinetics Insulin is destroyed by proteolytic enzymes in the gut and, hence, is not effective orally. Insulin is administered usually by subcutaneous (s.c.) route; but in emergencies, regular (soluble) insulin is given by i.v. route. After i.v. injection, soluble insulin is rapidly metabolized by the liver and kidney with a half-life of about 6 min. Insulin sources and preparations 1. Animal insulin 2. Human insulin: They are produced by recombinant DNA technology 3. Insulin analogues: They are produced by DNA recombinant technology where they are obtained following alteration of amino acid sequence of human insulin. Insulin classification according to the onset and duration of action Site of administration Insulin is usually administered subcutaneously in the abdomen, buttock, anterior thigh or dorsal arm. In emergency regular insulin is administrated by intravenous rout. Indications of Insulin Therapy 1. Type 1 DM. 2. Type 2 DM. : insulin is added if diet regulation & exercise plus metformin or other oral antidiabetics fail to control hyperglycemia. 3. DM with pregnancy & lactation: To avoid risk of drug (S)-induced hypoglycemia in fetus & newborn. 4. DM with stress & emergency: regular insulin is used in diabetic ketoacidosis, surgery, infection, myocardial infarction or severe psychic stress (oral hypoglycemic fail to control hyperglycemia as in stress conditions (. 5. DM with severe liver or renal disease: To avoid risk of hypoglycemia by sulfonylurea. 6. Treatment of hyperkalemia: Insulin enhances k+ influx into cells. N.B.: Insulin use in pregnancy, lactation, stress, emergency or hyperkalemia is temporary. Adverse effects of insulin 1. Hypoglycemia is the most common and dangerous complication. Treatment: All these manifestations are relieved by administration of glucose. If the patient is conscious, oral glucose or if the hypoglycemia is severe (unconscious patient) 50 mL of 50% dextrose is injected intravenously. Glucagon 1 mg i.v. or adrenaline 0.2 mg s.c. may be given for severe hypoglycemia. 2. Allergic reactions ( rare). 3. Lipodystrophy (either atrophy or hypertrophy) may occur at the site of injection. It may be avoided by using purified insulin preparations and changing the injection site by rotation. 4. Insulin resistance: It is a state in which patient requires more than 200 U of insulin/day and is common among obese type-2 diabetics. 5. hypokalemia. Drug interactions 1. B.blockers : by masking the symptoms of hypoglycemia. 2. Salicylates : Salicylates exert hypoglycemic effect by increasing the sensitivity of pancreatic B-cells to glucose and potentiating insulin secretion. Other antidiabetic Drugs 1. Sulfonylurea Sulfonylureas are divided into two generations. All have the same mechanism of action, but differ in potency and duration of action. The second-generation drugs are more potent than first generation drugs. Mechanism of action They act primarily by stimulation of insulin secretion from pancreatic B-cells (main mechanism). In addition they may increase peripheral sensitivity and reduce glucagon release(minor mechanism). Note: For successful therapy with sulfonylureas, at least 30% functioning B- cells are necessary. Sulfonylureas are ineffective in type-1 DM because of absence of functioning B-cells in the islets of pancreas. Pharmacokinetics Sulfonylureas are well absorbed after oral administration, highly bound to plasma proteins and have low volume of distribution. They are metabolized in liver and excreted mainly in urine. Adverse effects 1. Hypoglycemia is common, particularly with long acting agents (glibenclamide and chlorpropamide) so glibenclamide is best avoided in elderly patients because of the high risk of hypoglycemia. 2. GIT disturbances. 3. Weight gain. 4. Allergic reactions. Use: Sulfonylureas are useful in patients with type 2 diabetes mellitus. Drug interactions 1. salicylates/sulphonamides: These drugs are highly bound to plasma proteins and displace sulfonylureas from the plasma protein-binding site resulting in an increase in free plasma concentration of sulfonylureas therefore potentiate the effects of sulfonylureas (severe hypoglycemia). 2. B.blockers :by masking the symptoms of sulfonylurea induced hypoglycemia. 3. Rifampicin, Phenobarbitone : Rifampicin and Phenobarbitone are enzyme inducers; hence, they accelerate the metabolism of sulfonylureas and reduce their effects. 2. Meglitinides (repaglinid and nateglinide) Repaglinid and nateglinide are structurally unrelated to sulfonylureas, but their mechanism of action is similar to sulfonylureas. They have rapid onset but short duration of action. They are less potent than sulfonylureas. They are used only in type-2 DM to control postprandial hyperglycemia. 3. Biguanides (metformin) Mechanism of action 1. inhibit hepatic gluconeogenesis. 2. inhibit alimentary absorption of glucose. 3. increase peripheral utilization of glucose and decrease lipogenesis in adipose tissue. Note: Metformin does not affect insulin release therefore It is not associated with weight gain or hypoglycemia even at high dose. Pharmacokinetics Metformin is taken orally, well absorbed through GI tract and is excreted mostly unchanged in urine. Adverse effects Adverse effects are metallic taste, anorexia, nausea, vomiting, diarrhea (GIT symptoms are the most common) and skin rashes. Lactic acidosis is the most serious complication , but is rare with metformin. Prolonged use can cause vitamin B12 deficiency due to malabsorption. Use 1. Type 2 diabetes. 2. Polycystic ovary syndrome. 4. Thiazolidinedione (Pioglitazone & rosiglitazone) Pharmacokinetics Pioglitazone is almost completely absorbed from GI tract, highly bound to plasma proteins (95%) and metabolized in the liver. Adverse effects Nausea, vomiting, anemia, weight gain, edema and precipitation of heart failure in patients with low cardiac reserve; rarely hepatotoxicity has been reported. In addition the use of these drugs is associated with increased risk of bladder cancer. Use: Pioglitazone is used alone or in combination with antidiabetic drugs in patients with type-2 diabetes. 5. alpha-glucosidase Inhibitors (Acarbose & Meglitol ) They reduce intestinal absorption of carbohydrates by inhibiting the enzyme alpha -glucosidase in the brush border of the small intestine and reduce postprandial hyperglycemia. They are mainly used in obese type-2 DM patients. Side effects are mainly on GI tract: flatulence, fullness and diarrhea. Newer Drugs 1. GLP-1 receptor agonists, e.g. exenatide Glucagon like peptide-1 (GLP-1) is released from the gut after meals. It stimulates insulin secretion, suppresses glucagon release and slows gastric emptying. It is degraded by dipeptidyl peptidase 4 (DPP-4); its plasma half- life is 1–2 minutes. GLP-1 receptor agonists, e.g. exenatide, are resistant to DPP-4. Their actions are similar to GLP-1. It is used in patients with type-2 diabetes mellitus. 2. DPP-4 (dipeptidyl peptidase–4) inhibitors, e.g. sitlagliptin, saxagliptin They inhibit the enzyme DPP-4 prevent inactivation of GLP-1 increase plasma concentration of GLP-1 increases insulin secretion, suppresses glucagon release, slows gastric emptying and improves control of postprandial hyperglycemia. They are administered orally in patients with type 2 diabetes mellitus. 3. sodium glucose cotransporter 2 inhibitors (SGLT2 inhibitors, Gliflozins) Glucose is freely filtered across glomerulus and is reabsorbed in proximal tubules by sodium glucose co-transporter-2 [SGLT-2]. Dapagliflozin and canagliflozin are taking orally and act by inhibiting this transporter and cause glycosuria in diabetics. These also result in weight loss. Use: Gliflozins are used for treatment of type 2 diabetes. Adverse effects genital and urinary tract infections are the most common adverse effects.