Lecture 14 Chapter 46 Antidiabetic Drugs Antidiabetic Drugs

Lecture 14 Chapter 46 Antidiabetic Drugs

Antidiabetic Drugs • Drugs used to control diabetes mellitus - a chronic disease that affects carbohydrate metabolism • 2 groups of antidiabetic agents: Insulin & oral hypoglycemic agents - Oral hypoglycemic agents = synthetic preparations that stimulate insulin release or alter metabolic response to hyperglycemia - Insulin = a protein secreted from the beta cells of the pancreas - necessary for carbo metabolism & an important role in protein & fat metabolism

Antidiabetic Agents • Diabetes Mellitus - A chronic disease resulting from deficient glucose metabolism, caused by insufficient insulin secretion from the beta cells high blood sugar (hyperglycemia). 3 P’s 1. Polyuria - inc. urine output 2. Polydipsia - inc. thirst 3. Polyphagia - inc. hunger • 2 forms of diabetes 1. Insulin-dependent diabetes mellitus (IDDM) or type I was refereed to as juvenile-onset w/ no insulin secretion

Antidiabetic Agents 2. Non-insulin-dependent diabetes mellitus (NIDDM) or type II - was referred to as maturity-onset or adult-onset diabetes w/ some insulin secretion • Unknown how lack of insulin causes diabetes - poss. = infection, heredity • Insulin - Released from the beta cells of the islets of Langerhans in the pancreas in response to an increase in bld. glucose - Promotes the uptake of glucose, amino acids, & fatty acids & converts them to substances stored in body cells

Antidiabetic Agents - Glucose is converted to glycogen for future glucose needs in the liver & muscle = lowers bld. glucose level (range for bld. glucose is 70 - 110 mg/dl) * bld. glucose > 180 = sugar in urine = diuretic effects = polyuria - Insulin can be animal (pork or beef), or human (using DNA technology) - Concentration of insulin is 100 U/ml, & insulin packaged in a 10 ml vial. For accurate dosing, insulin can be given in insulin syringes ONLY.

Antidiabetic Agents - Before using insulin, need to ensure well mixed - always roll between hands - Do NOT Shake Vial = bubbles & inaccurate dose - insulin CANNOT be administered orally - GI tract secretions destroy insulin structure - Given subcutaneous at a 45 to 90 degree angle - Regular insulin ONLY can be given IV - Insulin sites need to be rotated to prevent lipodystrophy (tissue atrophy or hypertrophy) = interferes w/ insulin absorption

Antidiabetic Agents Insulin • Types of Insulin's - 3 standard types 1. Rapid-acting - Regular insulin - clear sol’n w/o added substances to prolong insulin action Onset = 1/2 to 1 h; Peak = 2 to 4 h; Duration = 6 to 8 h 2. Intermediate-acting - NPH, Lente - contain protamine (a protein that prolongs the action of the insulin) Onset = 1 to 2 h; Peak = 6 to 12 h; Duration = 18 to 24 h 3. Long-Acting - Ultralente - contain lg. crystals which dissolve slowly to prolong duration Onset = 4 to 8 h, Peak = 14 to 20 h; Duration = 24 to 36 h

Antidiabetic Agents Insulin • Lispro Insulin (Humalog) - a new rapid acting insulin approved in 1996 Action = 5 min. ; Duration = 2 to 4 h - can be administered 5 min. before meal time • Combination Insulin's - commercially premixed Humulin 70/30, Novolin 70/30, Humulin 50/50 (70/30 = 70% NPH and 30% Reg) • Reg can be mixed w/ NPH or Lente - Reg goes in first in the syringe *Clear to Cloudy*

Antidiabetic Agents Insulin • SE & adverse RXNS = -Hypoglycemic - when more insulin is administered than needed for glucose metabolism - S & S = nervous, trembling, uncoordinated, cold & clammy, incoherent (drunk) - Rx = giving sugar orally or IV - Ketoacidosis - An inadequate amt. of insulin = inability to metabolize sugar = fat catabolism = use of fatty acids (ketones) for energy - S & S = Extreme thirst, polyria, fruity breath odor - Rx = Insulin

Antidiabetic Agents Oral Agents • Used by persons w/ NIDDM - should NOT be used by persons w/ IDDM • NIDDM has some degree of insulin secretion by pancreas • Several classes of oral hypoglycemic agents • Sulfonylureas - First & Second generation - Chemically related to sulfonamides, but lack antibacterial activity - stimulate the beta cells to secrete more insulin - 1 st generation divided into short, intermediate & long acting antidiabetics

Antidiabetic Agents Oral Agents - tolbutamide (Orinase) - short; Tolazamide (Tolinase) intermediate; Chlorpropamide (Diabinese) - long - Action - Stimulate beta cells to secrete insulin - Use NIDDM - SE - similar to insulin - hypoglycemic rxn w/o adequate food intake - DI - ASA, anticoagulant, anticonvulsants, sulfonamides, & some NSAIDs can inc. action of sulfonylureas an insulin rxn

Antidiabetic Agents Oral Agents • Nonsulfonylurease: Newer drugs • Biguanides: Metformin (Glucophage) - Decreases hepatic production of glucose from stored glycogen = diminishes the inc. in serum glucose after a meal - Dec. the absorption of glucose from the small intestine - Evidence it inc. insulin receptor sensitivity - Does not produce hypo or hyperglycemia - SE - N &V, anorexia, abd cramping, gas - Can be combined w/ a sulfonylurea & insulin

Antidiabetic Agents Oral Agents • Alpha-Glucosidase Inhibitor: Acarbose (Precose) - Action - inhibits the digestive enzyme in sm. intestine responsible for release of glucose from the complex carbohydrates (CHO) in the diet - By inhibiting alpha glucosidase (enzyme) - the CHO cannot be absorbed & they pass into the lg. intestine - does not cause a hypoglycemic rxn - Use - for clients who do not achieve results on diet alone

Antidiabetic Agents Oral Agents • Thiazolidinediones: Troglitazone (Rezulin) - unrelated to other antidiabetic drugs - Action - Decrease insulin resistance, helps muscle cells respond to insulin & use glucose more effectively - May be used w/ sulfonylurea, metformin, or insulin - May cause serious hepatic toxicity - Not used in England • Rapaglinide (Prandin) - classification unknown - Newest - For use alone or w/ metfromin - short acting - Action - similar to sulfonylureas, but does not cause hypoglycemia

Antidiabetic Agents Oral Agents • Hyperglycemic Drugs - Glucagon - Action - A hyperglycemic hormone secreted by the alpha cells of the islets of Langerhans - Inc. bld sugar by stimulating glycogenolysis (breakdown of glycogen to glucose) in the liver - protects body cells - Use - Insulin-induced hypoglycemia when other methods not available or not working - Clients prone to hypoglycemia should keep in home & family members taught how to use - Begins to work in 5 to 20 min.

Antidiabetic Agents Oral Agents • Diazoxide (Proglycem) - chemically related to thiazide diuretics - Action - Inc. bld sugar by inhibiting insulin release from the beta cells & stimulating release of epi (adrenalin from the adrenal medulla - Use - Chronic hypoglycemia caused by hyperinsulinism d/t islet cell Ca or hyperplasia - Not used to Rx hypoglycemic rxns - Parenteral form (Hyperstat) used for malignant HTN - Oral diazoxide usually does not cause hypotension

Chapter 33 Anticancer Drugs

Anticancer Drugs • • In the US, cancer is the 2 nd cause of death (heart dx - 1 st) Results from the alterations in DNA w/in the cell Use of anticancer drugs include - cure, control, palliative Chemo may be used as sole Rx of Ca or in conjunction w/ radiation & surgery • Cell-Cycle Nonspecific & Specific - Anticancer drugs cause Ca cell death by interfering w/ Ca cell replication - Interferes w/ either all phases or a specific phase of the cell cycle (pg. 575, fig. VII-I)

Anticancer Drugs - Cell-cycle nonspecific (CCNS) = act on any phase during the cell cycle - kill the cell during the dividing & resting phase of cell cycle: alkylating drugs, antitumor antibiotics, hormones - Cell-cycle specific (CCS) = act on a specific phase of the cell cycle - effective against rapidly growing Ca cells: antimetabolites, vica alkaloids, antitumor antibiotics • Growth fraction & doubling time are two factors that play a major role in the Ca cell response to the anticancer drug

Anticancer Drugs - Anticancer drugs are more effective against the Ca cells having a high growth fraction - leukemias & some lymphomas - Ca of the breast & colon & melanomas = low growth fraction = poor response to antineoplastics - small & early forming Ca cells & fast-growing tumors respond well to anticancer drugs • Drug Rx for early dx = higher cure rate than late stages • Solid tumors = low growth fraction = less sensitive to drugs

Anticancer Drugs • Higher doses of drugs result in better tumoricidal (killing) effects • Ca growth usually faster in earlier stages. As tumor grows bld supply dec & growth rate dec. = drugs more effective against sm. tumors w/ sufficient bld supply • Cancer Chemotherapy - tumor cells are similar to normal cells in that it is difficult for anti. Ca drugs to be selective in killing tumor cells & not normal cells - Drug protocol = therapy too long & doses too high = toxic - Eliminating every Ca cell = difficult (1 mill. cells could remain w/o symptoms - ? ? ? on continuing Ca therapy

Anticancer Drugs • Drug Resistance - tumor resistance can develop against an anti. Ca drug d/t drug used infrequently or the tumor’s location limits the effectiveness - Brain tumors respond poorly (BBB) • Combination Chemotherapy - Single-agent drug therapy seldom used - Combo of drugs to enhance tumoricidal effects - CCS & CCNS are often combined to max. cell deaths - dec. drug resistance, shorten & intensify drug effect - inc. destruction of Ca cells, dec. drug toxicity - several drugs = lower doses = less injury to normal cells

Anticancer Drugs • Alkylating Drugs - one of the largest groups of Ca drugs - Kill cells by forming cross-links on DNA strands - Belong to the CCNS category & affect all phases of the cell cycle - effective against many types of cancers: acute & chronic leukemias, lymphomas, mult. myeloma, solid tumors (breast, ovaries, uterus, lungs) - Classified into 4 groups: Nitrogen mustards (Cyclophosphamide), nitrosoureas (Carmustine), alkyl sulfonates (Busulfan), alkylating-like drugs (Cisplatin)

Anticancer Drugs • Cyclophosphamide (Cytoxan) - Nitrogen mustard - Action - Inhibition of protein synthesis through interference w/ DNA replication by alkylation of DNA - Use - Hodgkin’s dx, solid tumors - SE - bone marrow suppression , alopecia, N & V, diarrhea, wt. loss, hematuria (maintain adequate hydration), impotence, sterility - An early anti. Ca drugs, can be administered PO

Anticancer Drugs • Antimetabolites - Oldest group - Resemble natural metabolites - disrupt the metabolic processes & some of the agents inhibit enzyme synthesis - CCS (5 -FU, floxuridine - also CCNS) - Subdivided into folic acid (folate) antagonists (Methotrexate) - also used as an immunosuppressant following organ transplant - substitutes for folic acid, needed for the synthesis of proteins & DNA; pyrimidine analogues (5 -fluorouracil); purine analogues (6 mercaptopurine)

Anticancer Drugs • Flurouracil (Adrucil, 5 -FU, Efudex) - IV - Action - CCS, blocks the enzyme action necessary for DNA & RNA synthesis - low therapeutic index - alone or w/ other drugs, can cross BBB - Use - Ca of breast, cervix, colon, ovary, stomach, pancreas - SE - N, V, diarrhea, alopecia, rash, bone marrow suppression, stomatitis (inflammation of oral mucosa)

Anticancer Drugs • Antitumor Antibiotics - (Bleomycin, dactinomycin, daunorubicin, doxorubicin) - inhibit protein & RNA synthesis & bind DNA causing fragmentation - Classified as CCNS (except for bleomycin) - Drugs differ from each other & are used for diff. Ca’s • Doxorubicin (Adriamycin) - IV - Action - Inhibits DNA & RNA synthesis - Use - W/ other agents for Ca of breast, ovaries, lung, bladder, leukemias, lymphomas - SE - Similar to general adverse rxns to antineoplastics

Anticancer Drugs - Capable of causing vesication - blistering of tissue if drug leaks out into surrounding interstitial tissue - rxn ranges from painful, reddened swelling to deep necrotic lesion needing debridement & skin grafts - Drug is a deep red color - urine will be red 1 - 2 days after administration - Can cause cardiotoxicity • Mitotic Inhibitors (Vinca Alkaloids) - block cell division at M phase of cell cycle (Vincristine, Vinblastine, Vinorelbine tartrate) - CCS

Anticancer Drugs - Single drugs or in combo therapy - SE - leukopenia, alopecia, stomatitis, N, V, neurotoxicity • Hormones & Hormone Antagonisits - Used in combo therapy for Rx of various Ca. - 2 major actions: 1) Agonists that inhibit tumor cell growth - estrogen, progestins, androgens, adrenocorticosteroids & 2) Antagonists that compete w/ endogenous hormone aminoglutethimide, tamoxifen • Corticosteroids (glucocorticoids) classified as antiinflammatory agents - suppressing the inflammatory process that occurs w/ tissue involvement

Anticancer Drugs - Hormones also suppress leukicytes & is effective in controlling leukemia & lymphoma - Used w/ other drugs as part of an antineoplastic regimen MOPP (oncovin, procarbazine & prednisone) - Hodgkin’s disease - Prednisone frequently prescribed - inexpensive cortisone derivative - Dexamethasone & hydrocortisone - IM or IV - can decrease cerebral edema caused by a brain tumor

Anticancer Drugs • Tamoxifen (Nolvadex) - Action - exact neoplastic action unknown, acts as an estrogen antagonist - Use - Breast cancer in women and men - SE - Adverse rxn’s usually minor & well tolerated • Miscellaneous Agents - antineoplastic drugs whose MOA does not place them in a category. Used in combo w/ other Ca drugs to Rx a variety of solid tumors & hematologic malignancies - pactitaxel (Taxol), docetaxel (Taxotere), pentostatin (Nipent), etoposide (VP-16)