Principles of Drug Action II (PHA 4573) Hormonal Drugs

1. Principles of Drug Action II (PHA 4573) Hormonal Drugs John S. Cooperwood PhD

2. Contents

3. Total prevalence of diabetes Total: 25.8 million children and adults in the United States— 8.3% of the population. In 2007, death due to diabetes 71,382 contributing to an additional 160,022 death total of 231,404 deaths. American Diabetes Association (ADA)

4. Insulin • 86 amino acids consisting of two polypeptide chains • linked by two disulfide bonds (important). • Among two chains A chain is the most conservative • when comes to active • Plasma half-life of insulin is 4 minutes while proinsulin • is 30 minutes • Alpha adrenergic agonists inhibit insulin release. • Beta adrenergic agonists stimulate insulin release as well as • cholinergics • It effects metabolism of carbohydrates, lipids and protein. • The tissues effected are liver, adipose and muscle • the brain is nonresponsive to insulin. • It is used to treat Type I diabetes (juvenille-onset diabetes). • Diabetes associated with atherosclerosis (lipids), cataracts, • neurological dysfunction, gangrene.

5. Insulin Formation (Fig. 22-20).

6. Insulin Formation (Fig. 22-20 continue).

7. Amino Acid Sequence of Bovine Proinsulin (Fig. 23-1).

8. Schematic Representation of the Three-Dimensional Structure of Insulin (Fig.16-3).

9. Insulin Administration SubQ IM IV Inhalation (Exubera, human insulin origin rDNA) Injection of Insulin Stomach (fast rate of absorption)>Arm>thighs>buttocks U-100 or U-500 (100 or 500 units per ml or cc) Side effects Hypoglycemia Rash Cough, sore throat and dry mouth (Inhalation)

10. The Primary Structures of Glucagon and Somatostatin (Fig. 22-21).

11. Effect of Glucagon on Blood Glucose: Production and Release of Glucose by the Liver (Table 22-4 ).

12. Effect of Insulin on Blood Glucose: Uptake of Glucose by Cells and Storage as Triacylglycerols and Glycogen (Table 22-6 ).

13. Insulin Preparations(Table 20-10).

14. Name and abbreviations associated with insulin Prompt Insulin (lente) Insulin zinc (semilente) Extended Insulin zinc (ultralente) Isophane (NPH) Protamine zinc insulin (PZI) Major concerns associated with insulin use: Allergic reactions with NPH and PZI Lente insulins are not compatible with PZI or NPH (phosphate buffer)

15. Types of Insulin Products Short-actingDurationCompatible Humalog (Insulin Lispro) 6-8 h UltraLente and NPH Humulin R 8-12 h all insulin Novolin R 8-12 h all insulin Novolog 3-5 h None Intermediate-actingDurationCompatible Humulin L 24 h Regular, Semilente Humulin N 24 h Regular insulin Lente Iletin 24 h Regular, Semilente Novolin L 24 h Regular, Semilente Novolin N 24 h Regular insulin

16. Long-actingDurationCompatible Humulin U (Ultralente) >36 h Regular, Semilente Lantus 24 h None MixtureDurationCompatible Humalog 75/25 up to 24 h None onset 15 min Humulin 50/50 up to 24 h None Onset 30 min Humulin 70/30 up to 24 h None Onset 30 min Novolog Mix 70/30 up to 24 h None

17. ApidraSolostar (insulin glulisine) (recombinant DNA product) pen also Vials use for Type 1 and 2 diabetes LantusSolostar (insulin glargine) rDNA pen also vials A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain use for Type 1 and 2 diabetes

18. Currently Marketed Sulfonylureas(Table 26-1).

19. Pharmacokinetic Characteristics of Sulfonylureas(Table 26-2).

20. Sulfonylurea and Products

21. Metabolism of Glipizide and Glyburide(continue)

22. Sulfonylurea continue Amaryl (Glimepiride) Contain pyrrolidine ring Metabolism oxidation of alkyl groups on pyrrolidine ring Diamicron (Gliclazide) Similar to Orinase Heterocyclic ring makes it more lipophilic and increase duration

23. Nonsulfonylureas Prandin (Repaglinide) MOA bind to specific receptor on beta cells causing closure of the ATP-dependent K+ resulting calcium influx and release of insulin Fast onset (take with meals) and short duration incomparison with the sulfonylureas Starlix (Nateglinide)

24. Thiazolidindiones Actos (Pioglitazone) Agonist peroxisomeproliferator activated receptor Gama (PPAR –gama) increase sensitive to insulin Marketed as racemic mixture Avandia (Rosiglitazone) MOA same as Actos Marketed as racemicmixture Bone fracture and CHF

25. Bisguanidines Glucophage (Metformin) Antihyperglycemics Reduce sugar absorption in GI Increase glucose uptake in muscles and adipose tissue Decrease gluconeogenesis Alpha Glucosidase inhibitors Glyset (Miglitol) Competitive inhibitor alpha Glucosidase Prevent breaking down carbohydrates in small intestine

26. Precose (Acarbose) Natural Competitive inhibitor of alpha glucosidase

27. New Miscellaneous Drugs Symlin (Pramlintide) (Approved in 2005) Analog of amylin hormone (secreted by pancreatic beta cells) Amylin and insulin 1:20 (homeostasis) Used in combination with insulin (reduce insulin dose) Administered SubQ Byetta (Exenatide) Synthetic peptide (incretin-like) Enhances glucose dependent secretion of insulin Administered SubQ Reduce insulin dose in combination

28. Dipeptidyl Peptidase- 4 Inhibitors Onglyza (Saxagliptin) Caged ring (amantidine) Same mechanism and use As Januvia Januvia (Sitagliptin) Dipetidyl petidase -4 inhibitor Use: Type 2 Diabetes by slowing Incretin metabolism such as glucagon like peptide -1 (GLP-1) and glucose dependent insulinotropic polypetide (GIP)

29. Combination for Type 2 Diabetes Glucovance Oral (glyburide and Metformin) Avandaryl Oral (glimepiride and Rosiglitazone) AVANDAMET Oral (rosiglitazone and metformin) Prandimet Oral (repaglinide and metformin) Tradjenta (linagliptin) DPP-4 inhibitor Purine analog New combination with metformin marketed as Jentadeuto (Jan. 31, 2012)

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31. Definition of Hormone Hormones can be described as polypeptides, proteins or glycoproteins or small molecules, steroids that regulate organ functions. Endocrine system Release hormones into circulatory system to regulate a distant organ Exocrine system Release hormones into ducts

32. Two General Mechanisms of Hormone Action (Fig. 22-12).

33. The Major Endocrine Systems and their Target Tissues (Fig. 22-14).

34. The Class of Hormones and Hormonelike Compounds, with some Examples (Table 22-2).

35. Peptide Hormones (Table 27-4). Peptide Hormones(Table 27-4 )

36. Anterior Pituitary Adrenocorticotrophic hormone (ACTH) – stimulates adrenal gland to Secrete its hormones. Human growth hormone (HGH)- also somatotrophic hormone stimulate Long bones, muscles Thyroid Stimulating hormone (TSH)-stimulate the thyroid to secrete its Hormones Prolactin (PRL)- cause corpus luteum around the mature follicle to produce estrogen and progesterone and cause breast milk production Luteinizing Hormone (LH)- works in conjunction with Follicle stimulating Hormone (FSH) to ovulation and prepares the uterus implantation of the Fertilized egg; in male causes testes to produce testosterone. FSH-stimulates female egg production or male sperm production

37. ACTH Pharmaceutical Preparation • Acthar (Corticotropin) • 39 Amino Acids • Natural source (animals) • Uses: Adrenal insufficiency diagnoses • Antiinflammatory • Administered IM or IV • Acthar gel (Corticotropin) • Same uses • Administered IM, IV or SubQ • Slow releasing gelatin • Corticotropin-Zinc (Corticotropin) • Same uses • Zinc hydroxide suspension • Slow release • Administered IM

38. ACTH Pharmaceutical Preparation (continue) • Cortrosyn (Cosyntropin) • Synthetic analog of ACTH • 24 amino acids • Use diagnoses of adrenocortical insuffciency • Administered IM or IV • Acthrel (Corticorelin) • Corticotropin releasing factor (CRF) • Synthetic analog of ACTH release factor (41-peptide) • Use diagnoses of the pituitary gland function • ovine form has replaced human (longer half-life) HGH Pharmaceutical Preparation • Protropin (Somatrem) • Originally taken from cadavers (neurodegenerative diseases) • Biosynthetic form of human growth (extra methionine) • Administered IM or SubQ

39. HGH Pharmaceutical Preparation Continue • Humatrope (Somatropin) • Recombinant DNA 191 amino acids • Administered IM or SubQ • Uses Turner syndrome (missing one X chromosome) in females • GH deficiency associated with pituitary or hypothalamus • Weight loss of AIDs patients and patients w severe burns, • Short bowel snydrome TSH Pharmaceutical Preparation • Thyropar (Thyrotropin) • Glycoprotein consisting of two polypeptide chains • Cause iodide uptake and hormone synthesis in thyroid gland • Mechanism involve cAMP formation (adenylate cyclase) • Use diagnose hypothyroidism

40. FSH and LH Pharmaceutical Preparation FSH and LH are large glycoprotein with two subuints alpha and beta alpha subunits are identical while beta subunits are dissimilar FSH maturation of egg and secretion of estradiol in the female FSH maturation of the sperm in the male LH promotes ovulation (formation corpeus luteum) and progesterone secretion LH testosterone secretion • Pergonal (Menotropin) • Urine of postmenopausal women (1:1 ratio) • FSH and LH (glycoproteins) combination • Uses Male and Female infertility • Use incombination with human chorionic • gonadotropin HCG • Administered IV

41. FSH and LH Pharmaceutical Preparation continue Follitropin are drugs with FSH only used in combination HCG Bravelle (Urofollitropin) Uses: Female infertility, patient taking GnRH or superagonist, Polycystic ovary syndrome Ultrasound before administering HCG Gonal-F, Gonal-F RFF, Gonal-F RFF pen (Follitropin Alfa) Recombinant DNA Administer subQ Use for male and female infertility. Follistim AQ (Follitropin Beta) Differ by carbohydrates Luveris (Lutropin Alfa) Recombinant DNA Use female infertility in combination regimen with HCG

42. Posterior Pituitary Antiduretic hormone (ADH, vasopressin)-stimulates constriction of blood vessels,contract intestine and increase kidney permeability to water allowing body to reabsorb water. Oxytocin (OT) stimulate contraction of uterus during labor and stimulate milk ducts in the breast

43. Two Hormones of the Posterior Pituitary Gland (Fig. 22-16).

44. Posterior Pituitary Hormones: Pharmaceutical Products (Table 20-8)

45. Syntocinon (Oxytocin) • Natural (animals) • Nasal solution • Milk ejection • DDAVP, Stimate (Desomopressin) • Synthetic desamino arginine • Nasal solution and injection • Administered nasally, IM or IV • Long duration • Uses diabetes insipidus • Preferred in treatment of children • Diapid (Lypressin) • Synthetic as lysine analog • More stable • Nasal solution • Use the same

46. Middle Lobe Pituitary Gland • Melanocyte Stimulating Hormone (MSH) • Pigmentation during menses and pregnancy • Enkephalin (Met and Leu Enkephalins) • Polypeptide • Suppress pain • Endorphins • Polypeptide • Suppress pain more powerful than morphine

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48. Thyroid hormones • Synthroid (Levothyroxine sodium) • Natural and Synthetic • Use hypothyroidism, Enlarge • Thyroid Gland and cancer of the gland • Administer po and IV • Highly bound to plasma protein • Cytomel (Liothyronine sodium) • Natural and Synthetic • Uses and administration the same • Loosely bound to plasma protein • more active than thyroxine

49. Antithyroid Agents Tapazole (Methimazole) More potent PTU Same Uses and Side effects • Propacil (2-Thiouracil, PTU) • Synthetic • Delay response (stop • formation of T3 and T4) • Uses hyperthyroidism (Graves disease) • Side effect agranulocytosis

50. Antithyroid Drugs(Table 14-10).