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 AgentsInsulin

• 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 AgentsInsulin

• 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 AgentsInsulin

• 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 AgentsOral 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

- 1st generation divided into short, intermediate & long acting antidiabetics

Antidiabetic AgentsOral 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 AgentsOral 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 AgentsOral 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 AgentsOral 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 AgentsOral 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 AgentsOral 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 2nd cause of death (heart dx - 1st)• 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 antiCa 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

antiCa 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 antiCa 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)