Chapter 28: Drugs for Diabetes • Type 1 - Insulin-dependent DM

• Type 2 - Non-insulin-dependent DM
Pancreatic Islet Cells & their Products • Type 3 – Alzheimer’s Disease
• Type 4 - Gestational DM
Approx. TYPE 1 DIABETES MELLITUS
Percent • Has selective B cell destruction and severe
Cell Types Secretory Products
of Islet or absolute insulin deficiency
Mass • Symptoms: Insulin deficiency (polydipsia,
polyphagia, polyuria, weight loss)
Alpha (A) • Tx: Insulin replacement therapy
20 Glucagon, Proglucagon
cells DIABETES KETOACIDOSIS
Beta (B) Insulin, C-peptide, • caused by insufficient or absence of insulin
75 and results from excess release of fatty
cells Proinsulin, Amylin
acids and subsequent formation of toxic
Delta (D) levels of ketoacids
3-5 Somatostatin
cells TYPE 2 DIABETES MELLITUS
• characterized by tissue resistance to the
G cells 1 Gastrin action of insulin combined with a relative
F cells (PP Pancreatic Polypeptide deficiency in insulin secretion
1 • impaired insulin action also affects fat
cells) (PP)
metabolism, resulting in increased free fatty
acid flux and triglyceride levels and
HORMONE PRODUCTS reciprocally low levels of HDL
● Insulin - the storage and anabolic hormone • Tx: Insulin or OHAs
of the body • Complications:
● Glucagon - the hyperglycemic factor that -Ketoacidosis: may occur as result of
mobilizes glycogen stores stress such as an infection or use of drugs
● Somatostatin - a universal inhibitor of (corticosteroid)
secretory cells - Dehydration leading to nonketotic
● Islet Amyloid Polypeptide (IAPP, Amylin) hyperosmolar coma
- modulates appetite, gastric emptying, Nonketotic Hyperosmolar Coma
glucagon & insulin secretion • blood glucose may rise to 6-20 times the
● Gastrin - stimulates gastric acid secretion normal range and an altered mental state
● Pancreatic Peptide - a small protein that develops or the person loses consciousness
facilitates digestive processes by a • urgent medical care and rehydration is
mechanism not yet clarified required
DIABETES MELLITUS
TYPE 1 TYPE 2
• defined as an elevated blood glucose
associated with absent or inadequate Age of onset Usually during Commonly over
pancreatic insulin secretion, with or without childhood or age 35
puberty
concurrent impairment of insulin action
Nutritional Commonly Obesity usually
status at time undernourished present
of onset

Prevalence 5% to 10% of 90-95%

diagnosed diagnosed
diabetics diabetics

Genetic Moderate Very strong

predisposition

Defect/ Β cells are Inability of B

deficiency destroyed, cells to produce
eliminating the appropriate
production of quantities of
insulin insulin; Insulin
resistance

TYPE 3 DIABETES MELLITUS

Four Categories of DM
 • refers to multiple other specific causes of an - Reversal of catabolic features of insulin
elevated blood glucose: pancreatectomy, deficiency
pancreatitis, nonpancreatic diseases and • Inhibits glycogenolysis
drug therapy; Alzheimer’s disease • Inhibits conversion of fatty acids and amino
TYPE 4 DIABETES MELLITUS acids to keto acids
• defined as any abnormality in glucose levels • Inhibits conversion of amino acids to
noted for the first time during pregnancy glucose
• the placenta and placental hormones create -Anabolic action
an insulin resistance that is most • promotes glucose storage as glycogen
pronounced in the last trimester • increase triglyceride synthesis and VLDL
INSULIN formation
• a small protein with a MW in humans of Effect on muscle:
5808 - Increased protein synthesis
• contains 51 amino acids arranged in 2 • Increases amino acid transport
chains linked by disulfide bridges • Increases ribosomal protein synthesis
• stored in the B cells in the form of crystals - Increased glycogen synthesis
consisting of 2 atoms of zinc and 8 • Increases glucose transport
molecules of insulin • Induces glycogen synthase & inhibits
PROINSULIN phosphorylase
• a long single-chain protein molecule, is Effect on adipose tissue:
processed within the Golgi apparatus of -Increased triglyceride storage
beta cells and packaged into granules, • Lipoprotein lipase is induced and activated
where it is hydrolyzed into insulin and a by insulin to hydrolyze triglycerides from
residual connecting segment called C- lipoproteins
peptide by removal of 4 amino acids • Glucose transport into cell provides glycerol
Insulin Secretion phosphate to permit esterification of fatty
• Insulin is released from pancreatic beta acids supplied by lipoprotein transport
cells at a low basal rate in a response to a • Intracellular lipase is inhibited by insulin
variety of stimuli:
– glucose Characteristics of Available Insulin
– other sugars (mannose) Preparations
– amino acids (leucine, arginine)
– hormones (GLP-1, GIP, glucagon, Principal Types & DOA of Insulin Preparations
cholecystokinin, vagal activity) • Rapid-Acting with rapid onset and short
Inhibitory Signals duration
• Somatostatin • Short-Acting
• Leptin • Intermediate-acting
• Chronically elevated glucose & fatty acid • Long-acting with slow onset of action
levels
Insulin Degradation • Injected rapid-acting & short-acting
• Liver & kidney insulins - dispensed as clear solutions at
Circulating Insulin neutral pH & contain small amount of zinc to
• Normal values: 5-15 μU/mL (30-90 pmol/L) improve their stability and shelf-life
• Peak (during meals): 60-90 μU/mL (360-540 • Injected intermediate-acting NPH insulins
pmol/L) - have been modified to provide prolonged
• Hormonal agents (eg. glucocorticoids) - action and are dispensed as turbid
lower affinity of insulin receptors for insulin suspension at neutral pH with protamine in
• Growth hormone (in excess) - increases phosphate buffer
insulin affinity • Insulin glargine & Insulin detemir - clear,
soluble long-acting solubles

Effects on liver:
 INSULIN PREPARATIONS • Insulin detemir (Levemir)
RAPID-ACTING INSULINS • Insulin glargine (Lantus)
• Insulin Lispro (Humalog)
• Insulin Aspart (Novolog) Insulin Glargine
• Insuline Glulisine (Apidra) • a soluble, "peakless" (having a broad
• permit more physiologic prandial insulin plasma concentration plateau), long-acting
replacement because their rapid onset and insulin analog
early peak action more closely mimic Insulin Detemir
normal endogenous prandial insulin • the most recently developed long-acting
secretion than does regular insulin insulin
• have additional of allowing insulin to be
taken immediately before the meal without INSULIN PRODUCTION
sacrificing glucose control • Mass production of human insulin and
insulin analogs by recmobinant DNA
INSULIN LISPRO techniques is carried out by inserting the
• produced by recombinant technology human or a modified human proinsulin gene
wherein there is a reversing of position of into E. coli or yeast and treating the
proline and lysine in the amino acid extracted proinsulin to form the insulin or
sequence insulin analog molecules.
INSULIN ASPART
• created by the substitution of the B28 INSULIN DELIVERY SYSTEMS
proline with a negatively charged aspartic • Portable Pen Injectors
acid • Continuous Subcutaneous Insulin Infusion
INSULIN GLULISINE Devices (CSII, Insulin pumps)
• formulated by substituting an asparagine for INSULIN REGIMENS
lysine at B3 and glutamic acid for lysine at • Intensive Insulin Therapy
B29 – Total daily insulin requirement in
units = Wt (lbs) divided by 4
SHORT-ACTING INSULINS – the meal or snack and high blood
• Regular Novolin R (Novo Nordisk) sugar correction boluses are
• Regular Humulin R prescribed formulas
• Conventional Insulin Therapy
REGULAR INSULIN – prescribed only for certain people
• a short-acting soluble crystalline zinc insulin with type 2 diabetes who are felt not
that is now made by recombinant DNA to benefit from intensive glucose
techniques control
• should be administered 30-45 mins before
meal Insulin Treatment of Special Circumstance
• only insulin preparation that can be DIABETES KETOACIDOSIS
administerd IV • a life-threatening medical emergency
caused by inadequate or absent insulin
INTERMEDIATE-ACTING INSULINS replacement, which occurs in people with
• NPH Humulin N type 1 diabetes and infrequently in those
• NPH Novolin N with type 2 DM
• S/Sx: N&V, abdominal pain, deep slow
PREMIXED INSULINS breathing, change in mental status, elevated
• Novolin 70 NPH/30 regular blood and urine ketones & glucose, arterial
• Humulin 70 NPH/30 regular blood pH higher than 7.3 & low bicarbonate
• 50/50 NPL (Lispro)
• 75/25 NPL, Lispro
• 70/30 NPA, Aspart

NPH Insulin
• Neutral Protamine Hagedorn or Isophane
• has delayed absorption and onset of action
Long-Acting Insulins Hyperosmolar Hyperglycemic Syndrome
 • diagnosed in persons with type 2 diabetes • α-Glucosidase Inhibitors - slow the
and is characterized by profound digestion and absorption of starch and
hyperglycemia and dehydration disaccharides
• associated with inadequate oral hydration,
especially in elderly patients, with other Insulin Secretagogues
illnesses, the use of medication that SULFONYLUREAS
elevates the blood sugar or causes • MOA: increase insulin release from the
dehydration (phenytoin, steroids, diuretics, pancreas; reduction of serum glucagon
B-blockers, hemodialysis) levels
First-Generation Sulfonylureas
Complications of Insulin Therapy • Tolbutamide - has short half-life and is the
Hypoglycemia safest sulfonylurea for elderly diabetics
• Sympathetic (tachycardia, palpitations, – S/E: prolonged hypoglycemia
sweating, tremulousness) • Chlorpropamide - average maintenance
• Parasympathetic (nausea, hunger) dose is 250 mg in the morning
• Convulsion – S/E: jaundice (500mg), renal
• Coma insufficiency, hyperemic flush after
alcohol ingestion in genetically
Immunopathology of Insulin Therapy predisposed patients, dilutional
• Insulin allergy - an immediate type hyponatremia, hematologic toxicity
hypersensitivity, a rare condition in which • Tolazamide - comparable to
local or systemic urticaria results from chlorpropamide in potency but has a shorter
histamine release from tissue mast cells DOA
sensitized by anti-insulin IgE antibodies Second-Generation Sulfonylureas
Immune insulin resistance • Glyburide - S/E: hypoglycemia; flushing
• a low titer of circulating IgG anti-insulin after alcohol ingestion
antibodies that neutralize the action of – CI: hepatic impairment & renal
insulin to a negligible extent develops in insufficiency
most insulin-treated patients • Glipizide - has the shortest half-lfe; should
Lipodystrophy at Injection Sites be given 30mins before breakfast
• atrophy of subcutaneous fatty tissue at the – CI: hepatic or renal impairment
site of injection • Glimepiride - given OD as monotherapy or
in combination with insulin
ORAL ANTIDIABETIC AGENTS
Categories MEGLITINIDE
• Insulin Secretagogues • MOA: modulate beta-cell insulin release by
– Sulfonylureas regulating potassium efflux
– Meglitinides • Repaglinide - the first member of the group
– D-phenylalanine derivatives – has rapid onset of action
• Biguanides – indicated for use in controlling
• Thiazolidinediones postprandial glucose excursions
• α-glucosidase Inhibitors (given before meal)
• Incretin-based Therapies – has no sulfur in its structure thus
• Amylin analogs (SQ) can be given to patients allergic to
• Insulin Secretagogues - increase insulin sulfonylureas
secretion from beta cells
• Biguanides - decrease hepatic glucose D-Phenylalanine Derivative
production • MOA: stimulates very rapid and transient
• Thiazolidinediones - reduce insulin release of insulin from beta-cells through
resistance closure of ATP-sensitive K+ channels
• Incretin-Based Therapies - control post- • Nateglinide - ingested just before meals
meal glucose excursions by decreasing – safest for patients with reduced
insulin resistance and decreasing glucagon renal functions
secretion – most efficacious when given alone
• Amylin analog - decreases post-meal or in combination with non-
glucose levels and reduce appetite secretagogues (ie. metformin)
 – used for isolated cases of glucose excursions by delaying the
postprandial hyperglycemia digestion and absorption of starch
• Miglitol - six times more potent in inhibiting
BIGUANIDES sucrase
METFORMIN • Acarbose
• MOA: reduce hepatic glucose production Adverse Effects
through activation of the enzyme AMP- • Flatulence
activated protein kinase (AMPK) • Diarrhea
• the patient may experience less fasting • Abdominal pain
hyperglycemia and lower postprandial • Hypoglycemia
hyperglycemia ("euglycemic agent")
Clinical Uses: Other Agents
• recommended as first-line therapy for type-2 PRAMLINTIDE
diabetes • a synthetic analog of amylin (injectable)
– an insulin-sparing agent and does • MOA: modulates postprandial glucose
not increase weight or provoke levels
hypoglycemia • CA: for preprandial use in persons with type
Toxicities: 1 and 2 diabetes
• GI distress (anorexia, N&V, abdominal • S/E: hypoglycemia, N&V, anorexia
discomfort, diarrhea) EXENATIDE
• Lactic acidosis (due to impairment of lactic • a synthetic analog of glucagon-like-
acid metabolism) polypeptide 1 (GLP-1)
Contraindications: • the first incretin therapy (injectable)
• Renal disease • MOA: increased insulin secretion
• Alcoholism • S/E: anorexia, weight loss, pancreatitis
• Hepatic disease SITAGLIPTIN
• Conditions predisposing to tissue anoxia • an inhibitor of dipeptidyl peptidase-4 (DPP-
(chronic cardiopulmonary dysfunction) 4), the enzyme that degrades incretin and
other GLP-1-like molecules
THIAZOLIDINEDIONES – decrease postprandial glucose
• MOA: act to decrease insulin resistance excursions
– are ligands of peroxisome • S/E: nasopharyngitis, URTI, headache,
proliferator- activated receptor- severe allergic reactions
gamma (PPAR-ɣ) DAPAGLIFLOZIN
– PPAR-ɣ receptors modulate the
exression of genes involved in lipid
and glucose metabolism Chapter 46: ANTICANCER DRUGS
• S/E: fluid retention, increase risk of heart CANCER
failure, increased bone fractures in women; • also called malignancies, is an abnormal
decreased triglyceride level and increased growth of cells (more than 100 types)
HDL and LDL; hepatotoxicity; weight gain METASTASIS
• Contraindicated in pregnancy • condition wherein cancer spreads from one
part of the body to another
PIOGLITAZONE BENIGN
• has PPAR-ɣ and PPAR-α activities • lump or tumor that is not cancer
• should not be given to patients taking MALIGNANT
estrogen-containing contraceptives • or cancerous tumors
BIOPSY
ROSIGLITAZONE • taking out a piece of tissue to see if cancer
• reported to increase cardiovascular cells are in it
diseases

ALPHA- GLUCOSIDASE INHIBITORS CAUSES OF CANCER

• MOA: competitive inhibitors of the intestinal • Carcinogens
α-glucosidases and reduce post-meal • Heredity
 • Viruses and other infections
• Smoking and tobacco
• Diet and physical activities
• Radiation
Viruses
• Hepatis B and C
• HIV (Hodgkin's & Non-Hodgkin's
Lymphoma)
• HPV (Cervical Cancer)
• Ebstein-Barr Virus (Nasopharyngeal
Cancer)
General S/Sx of Cancer CANCER CHEMOTHERAPY
• Unexplained weight loss • strives to cause a lethal cytotoxic event or
• Fever apoptosis in the cancer cells that can arrest
• Fatigue a tumor's progression
• Pain Goals of Treatment
• Skin changes • Ultimate goal: cure of cancer (long-term,
• Change in bowel habits and bladder disease-free survival)
functions • If cure is unattainable, then the goal
• Sores that do not heal becomes control of disease.
• White patches inside the mouth or white • In advance stages of cancer, the goal is
spots in tongue (smokers) palliation.
• Unusual bleeding or discharge Indications of Chemotherapy
• Thickening or lumps in the body • Used when neoplasms are disseminated
• Recent change in warts or moles and are not amenable to surgery
• Nagging cough or hoarseness • “Adjuvant Chemotherapy”
• “Neoadjuvant Chemotherapy”
CLASSIFICATIONS OF CANCER • “Maintenance Chemotherapy”
• Carcinoma Adjuvant Chemotherapy
• Melanoma • when chemotherapy is used as a
• Lymphoma supplemental treatment to attack
• Leukemia micrometastases following surgery and
• Sarcoma radiation treatment
Neoadjuvant Chemotherapy
CARCINOMAS • chemotherapy given prior to the surgical
• the most commonly diagnosed cancers -- procedure in an attempt to shrink the cancer
originate in the skin, lungs, breasts, Maintenance Chemotherapy
pancreas, and other organs and glands • chemotherapy given in lower doses to assist
• the abnormal cells start their growth in the in prolonging a remission
epithelial tissues
MELANOMA Tumor susceptibility and growth cycle
• are cancers that arise in the cells that make • Cell cycle specificity of drugs
the pigment in skin – Cell cycle specific drugs
LYMPHOMA – Cell cycle nonspecific drugs
• are cancers of lymphocytes • Tumor growth rate
• a tumor that develops in the lymphocytes of
the immune system, particularly and usually
in the lymph nodes
SARCOMA
• tumor grows in soft connective or supportive
tissues
• arise in bone, muscle, fat, or cartilage and
are relatively uncommon
LEUKEMIA
• is cancer of the blood. It does not usually
form solid tumors.
 Problems Associated with Chemotherapy
• Resistance (esp. melanoma)
– should be short-term, intensive,
intermittent therapy with
combinations of drugs
• Multidrug resistance
– caused by P-glycoprotein
• Toxicity
• Treatment-induced tumors (esp. with
alkylating agents)
Common Adverse Effects
• Severe vomiting
Cell-Cycle Specific Drugs • Stomatitis
-effective for high-growth-fraction malignancies, • Bone marrow suppression
such as hematologic cancers • Alopecia
• Bladder toxicity for cyclophosphamide
• Antimetabolites • Cardiotoxicity for doxorubicin
• Bleomycin • Pulmonary fibrosis for bleomycin
• Vinca Alkaloids
• Etoposide ANTIMETABOLITES
• structurally related to normal compounds
Cell-Cycle Non-Specific Drugs that exist within the cell
-effective for both low-growth-fraction malignancies, • generally interfere with the availability of
such as solid tumors, as well as high-growth- normal purine or pyrimidine nucleotide
fraction malignancies precursors, either by inhibiting their
synthesis or by competing with them in DNA
• Alkylating Agents or RNA synthesis
• Antibiotics • minimal cytotoxic effects: S-phase (cell
• Cisplatin cycle specific)
• Nitrosoureas
1. ANTIFOLATE AGENTS
Treatment Regimens & Scheduling METHOTREXATE
• Log kill phenomenon o MOA: structurally related to folic acid
– 5-log kill and acts as an antagonist of the
Treatment protocols vitamins by inhibiting mammalian
• Combinations of drugs dihydrofolate reductase (DHFR), the
– provide maximal cell killing within enzyme that converts folic acid to
the range of tolerated toxicity active, coenzyme form,
– effective against a broader range of tetrahydrofolic acid (FH4)
cell lines in the heterogenous tumor
population
– may delay or prevent the
development of resistant cell lines
• Treatment protocols
– R-CHOP (Rituximab,
Cyclophosphamide,
Hydroxydaunorubicin, Oncovin -
Vincristine, Prednisone)
• used in the treatment of non-
Hodgkin lymphoma
• scheduled intermittently
(usually 21 days apart)
 Adverse Effects
• Mucocutaneous reactions
• Alopecia
• Hypertrophic skin changes and
hyperpigmentation of the hands
• High incidence of fever & chills
• Pulmonary toxicity (bleomycin lung)

ALKYLATING AGENTS
• exert cytotoxic effects by covalently binding
to nucleophilic groups on various cell
• Therapeutic Uses: usually in combination constituents
with other drugs, effective against acute • alkylates the DNA
lymphocytic leukemia, Burkitt lymphoma in • all are mutagenic and carcinogenic
children, breast cancer, bladder cancer,
head and neck carcinomas 1. MUSTARD DERIVATIVES
• effective as a single agent against certain ● Cyclophosphamide
inflammatory dieases such as severe ● Ifosfamide
psoriasis, rheumatoid arthritis and Crohn
disease Mechanism of Action
• Adverse Effects: N/V/D, stomatitis, rash, • biotransformed first to hydroxylated
alopecia, myelosuppression, intermediates by CYP450 in the liver and
• high doses: renal damage then breaks down to active compounds
• IT: neurologic toxicities (phosphoramide mustard and acrolein)
• reaction of phosphoramide mustard with
• Leucovorin - or folinic acid, antidote for DNA is considered to be the cytotoxic step
methotrexate toxicities Adverse Effects
• Hemorrhagic cystitis leading to fibrosis of
PEMETREXED the bladder (acrolein)
MOA: similar to methotrexate; also inhibits – Antidote: Hydration and IV injection
thymidylate synthase and other enzymes of mesna (sodium 2-
involved in folate metabolism and DNA mercaptoethane sulfonate)
synthesis Resistance
• Therapeutic Use: non-small cell lung • Increased capability to repair DNA lesions
cancer • Decreased transport of the alkylating drug
• Adverse effects: hematologic and GI into the cell
toxicities (should be given with folic acid and • Increased production of glutathione and
vitamin B12 supplements) GSH-associated proteins needed to
• should also pretreat with conjugate the alkylating agents
corticosteroids to prevent cutaneous • Increased glutathione S-transferase activity
reactions
CYCLOPHOSPHAMIDE
PRALATREXATE ● most commonly used alkylating
MOA: similar to methotrexate agent
● Therapeutic Use: in relapsed or ● given IV or oral
refractory T-cell lymphoma IFOSFAMIDE
● Adverse Effect: mucositis (should be ● given IV only
given with folic acid and Vit B12 also) ● additional S/E: neurotoxicity
(chloroacetaldehyde)
2. FLUDARABINE
● the 5'-phosphate of 2-fluoroadenine
arabinoside, a purine nucleotide analog
● Therapeutic Uses: chronic lymphocytic
leukemia, hairy cell leukemia, non-
indolent non-Hodgkin lymphoma
2. NITROSOUREAS 1. VINCA ALKALOIDS
● Carmustine (IV) ● Vincristine
● Lomustine (PO) ● Vinblastine
● Vinorelbine
-can penetrate the CNS, thus primarily -obtained from Periwinkle (Vinca rosea)
employed in the treatment of brain tumors -generally administered in combination with other
Mechanism of Action drugs
• exert cytotoxic effects by an alkylation that Mechanism of Action
inhibits replication and, eventually, RNA and • cell cycle specific and phase specific -
protein synthesis blocks mitosis in metaphase (M-phase)
• binds to microtubular protein, tubulin, blocks
3. DACARBAZINE the ability of tubulin to polymerize to form
● MOA: must be converted to microtubules
methyltriazenoimidazole carboxamide Adverse Effects
(MTIC) that methylates DNA on the O6 • Phlebitis
position of guanine • Cellulitis
● CA: melanoma and Hodgkin lymphoma • N&V&D
• Alopecia
4. TEMOZOLOMIDE
● MOA: similar to Dacarbazine but can VINCRISTINE
cross the BBB • Oncovin®
● CA: glioblastomas, anaplastic • CA: used for acute lymphoblastic leukemia
astrocytomas, metastatic melanoma in children, Wilms tumor, Ewing soft tissue
sarcoma, Hodgkin and non-Hodgkin
5. OTHER ALKYLATING AGENTS lymphomas, and other rapidly proliferating
● Mechlorethamine - used for lymphatic neoplasms
cancers • S/E: Peripheral neuropathy (paresthesias,
● Melphalan - for multiple myeloma loss of reflexes, foot drop, ataxia),
● Chlorambucil - for chronic lymphocytic constipation
leukemia
- Melphalan & chlorambucil can VINBLASTINE
cause moderate hematologic • CA: administered with bleomycin and
toxicities and GI tract upset. cisplatin for metastatic testicular carcinoma;
• Busulfan - effective against chronic systemic Hodgkin and non-Hodgkin
granulocytic leukemia lymphoma
– S/E: pulmonary fibrosis (Busulfan • S/E: potent myelosuppressant
Lung)
VINORELBINE
MICROTUBULE INHIBITORS • a less neurotoxic agent
• Mitotic Spindle - part of a larger, • CA: advanced non-small cell lung cancer
intracellular skeleton (cytoskeleton) that is
essential for the movements of structures 2. TAXANES & RELATED DRUGS
occurring in the cytoplasm of all eukaryotic ● Paclitaxel
cells ● Docitaxel
– consists of chromatin plus a system
of microtubules composed of the Mechanism of Action
protein tubulin • active n the G2/M-phase of the cell cycle
– essential for the equal partitioning of • promotes polymerization and stabilization of
DNA into the two daughter cells that the polymer rather than disassembly,
are formed when eukaryotic cell leading to the accumulation of microtubules
divides Adverse Effects
• Neutropenia & leukopenia
• Alopecia
• Vomiting & diarrhea
PACLITAXEL PLATINUM ANALOGS
• the first member of the taxane family to be • Cisplatin
used in cancer chemotherapy • Carboplatin
• an alkaloid ester derived from pacific yew • Oxaliplatin
(Taxus brevifolia) & European yew (Taxus Mechanism of Action
baccata) • the same with alkylating agents
• CA: advanced ovarian cancer & metastatic • kill tumor cells in all stages of the cell cycle
breast cancer and bind DNA through the formation of
intrastrand and interstrand cross-links,
DOCETAXEL leading to inhibition of DNA synthesis and
• Semisynthetic taxane derived from function
European yew tree
• CA: second-line therapy in advanced breast Cisplatin
cancer, prostate, GI & non-small cell lung • cis-diamminedichloroplatinum
cancer • an inorganic metal complex that was initially
discovered through a serendipitous
IXABEPILONE observation that neutral platinum complexes
• not a taxane inhibited division and induced filamentous
• a novel microtubule inhibitor that was growth of E. coli
recently approved for metastatic breast
cancer in combination with oral Clinical Applications
fluoropyrimidine capecitabine or as • Non-small cell and small cell lung cancer
monotherapy • esophageal and gastric cancer
• head and neck cancer
EPIPODOPHYLLOTOXINS • genitourinary cancers (testicular, ovarian
ETOPOSIDE and bladder cancer)
• a semisynthetic derivative of
podophyllotoxin which is extracted from the Carboplatin
mayapple root (Podophyllum peltatum) • a second generation platinum analog
TENIPOSIDE • has broader spectrum of action than
• MOA: inhibition of topoisomerase II, which cisplatin
results in DNA damage through strand • S/E: myelosuppression
breakage induced by the formation of
ternary complex of drug, DNA, and enzyme Oxaliplatin
• a third-generation diaminocyclohexane
CAMPTOTHECINS platinum analog
• are natural products derived from • originally approved for use as second-line
Camptotheca acuminata tree originally therapy in combination with the fluoro-
found in China pyrimidine 5-fluorouracil and leucovorin
• MOA: inhibits the activity of topoisomerase (FOLFOX regimen) for metastatic colorectal
II, the key enzyme responsible for cutting cancer (now first-line)
and religating single DNA strands • S/E: Neurotoxicity (peripheral sensory
neuropathy)
TOPOTECAN & IRINOTECAN
• two camptothecin used in clinical practice in
USA
• Topotecan - for advanced ovarian cancer
as second-line therapy following platinum-
based chemotherapy
• Irinotecan - first-line therapy when used in
combination with 5-FU and leucovorin