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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
- 1st 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
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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 (6mercaptopurine)
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)