PHTH1011 012 Drugs for Endocrine Disorders.pdf

Drugs for Endocrine Disorders M R. R H A H E E M L A Y N E - YA R D E Objectives By the end of the session students should be able to: Explain endocrine disorders resulting in Diabetes Mellitus (DM). Classify drugs used to treat diabetes. Describe the mechanisms of action of anti-thyroid agents. Pan...

Drugs for Endocrine Disorders M R. R H A H E E M L A Y N E - YA R D E Objectives By the end of the session students should be able to: Explain endocrine disorders resulting in Diabetes Mellitus (DM). Classify drugs used to treat diabetes. Describe the mechanisms of action of anti-thyroid agents. Pancreatic Islet The Pancreas The pancreas is a glandular organ located in front of the spine and the behind the stomach Within the pancreas there are many clusters of cells known as the Islets of Langerhans which are composed of three major cell type: https://www.simplepharmanotes.com/2021/08/endocrine-pancreas.html https://www.olivelab.org/the-pancreas-overview.html The Pancreas Chronic syndrome of impaired carbohydrate, protein and fat metabolism secondary to insufficient insulin secretion or to decreased response of target tissue to insulin. Diabetes Mellitus (i) disturbance in glucose action   glucose utilization  hyperglycemia  glycosuria  polyuria  thirst & polydipsia (ii)  muscle proteolysis  weight loss (iii)  lipolysis   free fatty acids  ketonaemia (& ketonuria)  ketoacidosis { coma & death} The two types of Diabetes Treatment for Type 1 Insulin Management of Diabetes Treatment for Type 2 Lifestyle changes: Diet and Exercise Drugs: Insulin and Oral antidiabetic agents Mechanism of action of Insulin Insulin interacts with extracellular binding sites (alpha subunits) on membrane-bound tyrosine kinase linked receptors  autophosphorylation of beta subunits  signal transmission to inside of cell  activation of anabolic pathways or inhibition of catabolic pathways Effects of Insulin Carbohydrate Metabolism ▪  glucose transport ▪  glycogen synthesis ▪  gluconeogenesis ▪  glycogenolysis Effects of Insulin Protein Metabolism ▪  amino acid uptake into cells ▪  protein synthesis ▪  protein degradation Fat Metabolism ▪ ▪  triglyceride synthesis  lipolysis Pharmacokinetics of Insulin Rapidly inactivated by proteolytic enzymes, hence not effective orally. Usually administered subcutaneously. Rapid onset of action and short duration. Metabolized in liver and other tissues. Adverse effects of insulin Hypoglycemia (may be treated with glucose, other soluble sugar or glucagon) Weight gain Other anti-diabetic agents SULFONYLUREAS Glibenclamide BIGUANIDES Metformin Glibenclamide Mechanism of Action: Interact with receptors on pancreatic  cells  closing of ATP-sensitive K+ channels   K+ efflux  Ca2+ influx   secretion of insulin from  cells. Glibenclamide Clinical Use Type II diabetes (functional  cells required). ▪ ▪ Monotherapy or combination therapy Treatment may become less effective over time due to: (i) Progressive loss of  cells (ii) change in drug metabolism (iii) change in dietary compliance Pharmacokinetics of Glibenclamide Rapidly and completely absorbed from GIT. Bind extensively to plasma proteins Undergo metabolism in liver. Adverse effects of Glibenclamide Hypoglycemia GI disturbances (N,V, D and anorexia) Weight gain (insulin activity in adipose cells) Metformin Exact mechanism of action is not clear. ❖Insulin sensitizer Effects Suppress hepatic gluconeogenesis Stimulate glycolysis Inhibit glucose reabsorption from kidneys Increase uptake of glucose in skeletal muscles and adipose tissues Delay glucose absorption from GI tract Reduce plasma glucagon Metformin Clinical Uses ✓ Type II diabetes ✓ Diabetes + hyperlipidemia ✓ Diabetes + obesity Metformin Adverse Effects GI effects (metallic taste, nausea, diarrhea) May worsen heart failure Thyroid hormones Tetraiodothyronine (Thyroxine, T4) Triiodothyronine (T3) Regulation of Thyroid Hormone Secretion Secretion of thyroid hormones (TH) is stimulated mainly by thyroid stimulating hormone (TSH) released from the anterior pituitary in response to thyrotropin releasing hormone (TRH) stimulation. TH may bind to thyroxine binding globulin in plasma. Free (unbound) hormone is active. The regulation of the secretion of thyroid hormones is mainly by negative feedback. Physiological Effects of Thyroid Hormones Thermogenic action  mitochondria  BMR  protein synthesis  oxygen utilization  amino acid uptake  peripheral glucose utilization  gluconeogenesis & glycogenolysis  enzyme activity  sympathetic activity Dysfunctions of Thyroid Secretions I. Hypothyroidism (treat with thyroid hormones) II. Hyperthyroidism (treat with anti-thyroid agents) Clinical Manifestations of Hypothyroidism  BMR  cardiac output  appetite Fatigue Heart failure (low output) Hypercholesterolemia Constipation Mental deterioration Cold, dry skin Thin, dry hair Puffy, expressionless face Thyroid Hormone Preparations Levothyroxine (T4 ) Levothyroxine (t4) Mechanism of Action Interaction with T3 receptors in nucleus  interferes with gene transcription  alterations in conc. of selected mRNAs  interference with protein synthesis  biological effects Levothyroxine (t4) Pharmacokinetics Mostly administered orally. Absorption is enhanced with empty stomach. Bind extensively (> 99%) to plasma proteins (especially thyroxine binding globulin) Levothyroxine (t4) – Adverse Effects High doses of T4  symptoms of hyperthyroidism. Cardiac toxicity (may be most important. End