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215 Cards in this Set
- Front
- Back
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Folate Antagonists
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Methotrexate, Pemetrexed, Lometrexol
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Folate Antagonists MOA
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Mimics folic acid
Inhibits DHFR |
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Where do eukaryotes obtain folate from?
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The Diet
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Methotrexate MOA
(Detailed) |
Enters cells through folate receptor or Reduced folate transporter
MTX binds and inhibits DHFR Polyglutamated--> more active than MTX & Binds/inhibits TS Inhibition of DNA & RNA synthesis |
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Type of Methotrexate administration used to treat ALL?
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Intrathecal-->prevents CNS metastases
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MTX common clinical uses?
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Breast CA (CMF)
Choriocarcinoma (can be cured by MTX) ALL Non CA uses: Rheumatoid arthritis, Psoriasis |
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MTX adverse effects?
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Bone marrow suppression (dose limiting)
GI toxicity Stomatitis Kidney damage (high dose) Hepatotoxicity- long term use (psoriasis, RA) *(Glutamated form accumulates in liver and kidney) |
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What is Leucovorin rescue? (folinic acid)
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Can prevent adverse effects but not reverse them.
Donates a carbon group w/o being reduced by DHFR (Allow low level of DNA synthesis) Rescue of normal not tumor cells |
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MTX resistance?
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Decreased drug entry (altered receptor/transporter)
Decreased polyglutamate formation Increased DHFR expression Decreased affinity for DHFR |
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Purine Antagonists
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Mercaptopurine (6-MP)
Thioguanine (6-TG) |
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Purine Antagonists MOA
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Mimic DNA precursors
Compete w/precursors to prevent DNA synthesis |
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Purine Antagonists MOA
(more detailed) |
6-MP and 6-TG converted to thio-dGTP
thio-dGTP incorporated into growing DNA chain & inhibition of DNA polymerase Chain termination & Inhibition of DNA synthesis |
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Metabolite of 6-Mp which also inhibits de novo purine biosynthesis?
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Me-TIMP (methyl thioinosine monophosphate)
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Absorption of 6-MP and 6-TG
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Oral
Reduced by food Does not cross BBB |
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Metabolism of 6-MP and 6-TG
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Xanthine Oxidase (inactivates 6-MP)
Thiopurine methyl transferase=TPMT (inactivates 6-MP & 6-TG) |
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Common clinical uses for 6-MP?
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ALL
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Common clinical uses for 6-TG?
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AML & CML
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Common clinical non-cancer uses for 6-MP & 6-TG?
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IBD & Immunosuppressant
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6-MP & 6-TG adverse effects?
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Myelosuppresion (dose limiting; TPMT levels)
Hepatotoxicity (hepatic TPMT levels) Immunosuppresion *Low TPMT levels increases drug accumulation & toxicity |
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Drug interactions w/ 6-MP
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Allopurinol
Inhibits xanthine oxidase and causes increased levels of 6-MP |
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Purine Antagonists methods of resistance?
(6-MP & 6-TG) |
Low levels of HPRT decreases drug activation.
High TPMT increase drug inactivation. |
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Pyrimidine Antagonist
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Flurouracil (5-FU)
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Flurouracil MOA
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Analog of uracil
Uracil is utilized more rapidly by tumor cells. |
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Flurouracil MOA
(more detailed) |
5-FdUMP bindsTS & inhibits dTTP synthesis (chain termination)
5-FdUTP incorporated into DNA--> repair attempts damage DNA 5-FUTP incorporated into RNA--> inhibition of RNA synthesis |
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Flurouracil Distribution & Metabolism
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Parenteral and Topical
Crosses BBB DPD inactivates 5-FU |
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5-FU common clinical uses of?
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Colorectal (+leucovorin +5-FU +Oxaliplatin)
Breast CA Actinic Keratosis & Basal Cell Carcinoma |
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5-FU Adverse Effects?
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Myelosuppresion (dose limiting)
Oral & GI ulceration Neurotoxicity Inflammation, irritation (topical) |
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MOA's of Leucovorin?
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Leucovorin + 5-FU
Increased binding affinity of 5-FU for TS (<inhibition of TS) Leucovorin + MTX Rescue (Provides carbon groups for normal cells & reduction in adverse effects) |
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5-FU Mechanisms of Resistance?
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Higher TS expression
-more drug than target -TS bound by FdUMP--> no feedback inhibition--> increased TS expression Increased levels of Dihydropyrimidine dehydrogenase (DPD)-->(inactivates 5-FU) |
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Ribonucleotide Reductase Inhibitor
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Gemcitabine
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Gemcitabine MOA
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Difluorodeoxycytidine (dFdC) inhibits ribonucleotide reductase
dFdCTP incorporates into DNA (chain termination) dFdCTP inhibits cytidine deaminase (regulates its own breakdown) |
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Gemcitabine administration and metabolism?
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Parenteral
Deaminated to inactive uracil metabolites |
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Gemcitabine common clinical use?
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Pancreatic CA
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Gemcitabine adverse effects?
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Myelosuppresion
Alopecia |
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Gemcitabine resistance?
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Cytidie daminase
-high levels-->drug inactivation Decreased Drug influx via CNT |
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DNA Alkylating Drugs
Nitrogen Mustards |
Cyclophosphamide
Ifosfomide |
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Cyclophosphamide MOA's
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Activated by P450 (CYP2B) to active, inactive, and cytotoxic molecules
Alkylates DNA at the N7 position of neighboring GUANINE residues |
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Cyclophosphamide MOA
(more detailed) |
Interstrand crosslinks correlate w/tumor cell toxicity
Intrastrand crosslinks introduce mutations which may lead to secondary cancer formation |
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Cyclophosphamide common clinical uses?
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CLL (CHOP-R)
Non-Hodkin's Lymphoma (CHOP-R) Breast CA (CMF) Lung CA (CAV & CAE) Non-CA uses: Immunosuppresion (autoimmune disease/ transplantation) |
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Cyclophosphamide adverse effects?
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Myelosuppresion (dose-limiting)
Pulmonary Toxicity GI Toxicity Secondary Malignancies (intrastrand crosslinking) High Risk Emetogenic Agent Severe Alopecia Hemorrhagic Cystitis |
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Explain Cyclophosphamide Hemorrhagic Cystitis and Treatment.
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Involves the urinary bladder.
Accumulation of acrolein Tx: Mesna (antioxidant) & Increase fluid intake |
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Cyclophosphamide method of resistance?
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Low CYP2B levels.
(CYP2B is needed for activation) |
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DNA Alkylating Drugs
Nitrosureas |
Carmustine (BCNU)
Lomustine (CCNU) Bendamustine |
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Carmustine MOA
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Activated intermediate formed spontaneously.
Cross-links DNA (interstrand) 1.Guanine-cytosine residues 2.Activates repair enzymes 3.DNA damage 4.Apoptosis |
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Carmustine Administration, Distribution, & Elimination?
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Parenteral & Wafer
Lipophillic & CNS Penetration Renal Excretion / Some expired as CO2 |
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Carmustine Clinical Uses?
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CNS tumors
Lymphomas |
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Carmustine Adverse Effects?
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Delayed Myelosuppresion
Delayed Pulmonary Toxicity -1m to 10yrs after treatment -Tx:corticosteroids- slow progression Seizures Secondary Cancer High risk emetogenic agent Tumor Lysis Syndrome -Can cause hyperurecemia & gout -Tx:prophylactic allopurinol |
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Carmustine mechanisms of resistance?
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2 Step Cross-link
-Guanine -Cytosine Increased AGT, Increased repair, Increased resistance Decreased AGT, Decreased repair, Increased efficacy *AGT removes crosslinking |
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DNA Alkylating Drugs
Platinum Compounds |
Cisplatin
Carboplatin Oxaliplatin |
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Cisplatin MOA
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DNA Crosslinks
-Primarily adjacent Guanines -Also adenine & cytosine Intrastrand |
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Cisplatine MOA
(more detailed) |
Bends DNA
-Proteins bind irreversibly -Inhibits DNA synthesis -Prevents DNA repair |
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Cisplatin Common Clinical Uses?
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Testicular CA (90% cure rate+bleomycin+etoposide)
Colon Cancer -(FolFOX) (folinic acid +5-FU+oxaliplatin) Ovarian CA (+taxane) Melanoma |
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Cisplatin Adverse Effects?
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Renal Toxicity (cisplatin>carboplatin)
-Tx:Mannitol, Sodium Thiosulfate & Hydration High risk emetogenic agent Peripheral neuropathy Ototoxicity |
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Cisplatin mechanisms of resistance?
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Increased Efflux
-ATP7B transporter Decreased Influx -CTR1 (CTR degradation & delocalization) Drug Inactivation/Increased Efflux -Glutathione inactivates Cisplatin -MRP2 removes drug from cell |
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Differences in Platinum Compounds?
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Carboplatin
-Same anticancer spectrum as Cisplatin -Less renal toxicity Oxaliplatin -Anticancer spectrum: Cisplatin + greater activity against Colon CA (FOLFOX) -Activity against Cisplatin resistant CA |
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Other DNA Alkylating Drugs
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Darcarbazine
Procarbazine Busulfan |
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Darcarbazine & Procarbazine MOA
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Alkylates DNA
-Metabolic activation by liver enzymes -Crosslinking, DNA damage -Inhibits RNA & protein synthesis |
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Darcarbazine Common Clinical Uses?
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Hodgkin's Disease
(ABVD--> adriamycin, bleomycin, vinblastine, darcarbazine) Melanoma |
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Procarbazine Common Clinical Uses?
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Brain Tumors [PC; Procarbazine, CCNU (lomustine)]
Hodgkin's Disease |
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Darcarbazine & Procarbazine adverse effects?
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High risk emetogenic agent (darcarbazine)
Alopecia Myelosuppresion Leukemogenic, teratogenic, mutagenic (procarbazine) |
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Busulfan MOA
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Alkylates DNA
DNA cross-linking, DNA damage Greater activity against myeloid cells than lymphoid cells |
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Busulfan Common Clinical Use?
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CML
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Busulfan adverse effects?
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Myelosuppresion (dose-limiting)
-Thrombocytopenia Pulmonary Fibrosis (Busulfan lung) -onset 3-10 yrs after tx begins -no successful tx Alopecia (permanent) |
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High Risk Emetogenic Agents?
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Cisplatin
Carmustine Darcarbazine |
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Natural Products Anthracyclines
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Doxorubicin
-Adriamycin (A) -Hydroxydaunorubicin (H) Daunorubicin Idarubicin Epirubicin |
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Doxorubicin & Daunorubicin MOA 1
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DNA Intercalation
-Planar molecule inserted b/w base pairs -Blockade of DNA & RNA synthesis -Alters structure and unwinds DNA --Activates DNA repair enzymes --DNA damage |
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Doxorubicin & Daunorubicin MOA 2
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Inhibits DNA Topo II (Poison)
-Religation is inhibited -DNA strand breakage |
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Doxorubicin & Daunorubicin MOA 3
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Generation of ROS
-Reduced to semiquinone (produces ROS) |
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Doxorubicin & Daunorubicin Metabolism and Elimination
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Metabolized in the liver.
Mostly biliary & some urinary excretion -Red Urine & Red Bodily Fluids |
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Doxorubicin Common Clinical Uses?
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-Breast CA (CA- Cyclophosphamide, Adriamycin)
-Non-Hodgkin's (CHOP-R) -Hodgkin's Lymphoma (ABVD) -Lung CA (CAV, CAE) *Epirubicin similar efficacy to Doxorubicin |
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Daunorubicin Common Clinical Uses?
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*Not effective against solid tumors
AML ALL *Idarubicin has similar activity to Daunorubicin |
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Doxorubicin & Daunorubicin Adverse Effects?
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Cardiotoxicity (due to ROS)
-Tx: Dexrazoxane (neutralizes ROS) -Idarubicin has less cardiotoxicity -Liposomal formulations have less cardiotoxicity (doxorubicin) |
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Doxorubicin & Daunorubicin Adverse Effects continued...
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Vessicant tissue damage (due to ROS)
-Tx:Dexrazoxane, DMSO (topical), Liposomal formulations |
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Doxorubicin & Daunorubicin Adverse Effects continued...
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Myelosuppresion (dose limiting)
-neutropenia Mucosal Ulcers (doxorubicin) Alopecia Hand-Foot Syndrome (Palmar-Plantar Erythrodysesthesia) -Most common w/pegylated form (helps drug accumulate in skin) |
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Doxorubicin & Daunorubicin mechanisms of resistance?
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Increased efflux
-MDR1, MRP Drug Inactivation -Glutathione Altered drug target -Topo II |
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Where is Bleomycin isolated from?
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Streptomyces Verticillus
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Bleomycin MOA 1
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Cell Entry
Free Radical Formation through association w/ Cu or Fe & O2 Nuclear Migration |
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Bleomycin MOA 2
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DNA intercalation--> SS DNA damage--> DS DNA damage
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Bleomycin Administration & Distribution?
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Parenteral
Concentrates in lung and skin |
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Bleomycin Common Clinical Use?
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Hodgkin's Lymphoma
(ABVD- Adriamycin, Bleomycin, Vinblastine, Darcarbazine) |
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Bleomycin Adverse Effects?
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Pulmonary Toxicity
-Inactivated by amino hydrolase (lungs and skin express low levels) Skin Toxicity Alopecia Little Myelosuppresion |
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Natural Products--> Topoisomerase I Inhibitors
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Camptothecins
-Camptothecin -Irinotecan (CPT-11) -Topotecan |
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Camptothecins MOA
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Topo I cleaves a single strand of DNA.
Topo II cleaves both strands of DNA. Camptothecins prevent religation of cleaved DNA. |
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Camptothecins MOA (more detailed)
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Topo I relaxes DNA by adding a nick in 1 strand. Camptothecins bind Topo I and the cleaved DNA forming the cleaved complex. DNA in the cleaved complex can't be religated.
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Topotecan Administration, Distibution, Metabolism, & Elmination?
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Parenteral
Crosses BBB Inactive Metabolites Renal Excretion |
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Irinotecan Administration, Metabolism, & Elimination?
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Parenteral
Rapidly metabolized to SN-38 (1000X greater activity than Irinotecan) Inactivated by UGT Billiary Excretion |
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Topotecan Common Clinical Use?
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Ovarian Cancer
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Irinotecan Common Clinical Use?
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Colorectal Cancer
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Irinotecan Adverse Effects?
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Neutropenia (dose limiting)
Severe Diarrhea (dose limiting) -Mostly late diarrhea bc active drug causes more diarrhea Alopecia |
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Topotecan Adverse Effects?
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Neutropenia (dose limiting)
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Topoisomerase I inhibitors mechanisms of resistance?
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Increased Efflux (ABC Transporters)
Drug Metabolism (Inactivation) -by CYP3A & UGT Decreased interaction w/ Topo I -mutations & decrease expression of Topo I |
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Natural Products
Topoisomerase II Inhibitors |
Epipodophyllotoxins
-Etoposide -Teniposide |
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Etoposide & Teniposide MOA
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Topo II unwinds DNA by cleaving both DNA strands.
Topo II blocks the religation of cleaved DNA. DNA strand breakage. |
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Etoposide & Teniposide Administration & Metabolism?
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Parenteral
Metabolized by P450's to active and inactive products. |
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Etoposide & Teniposide Common Clinical Uses?
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Lung CA
(CAE - Cyclophosphamide, Adriamycin, Etoposide) |
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Etoposide & Teniposide Adverse Effects?
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Myelosuppresion (dose-limiting)
Mild Alopecia |
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Etoposide & Teniposide Mechanisms of Resistance?
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Increased Efflux (MDR1)
Decreased Interaction w/drug -Topo II mutations -Decreased Topo II expression |
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Natural Products
Vinca Alkaloids |
Vincristine
Vinblastine |
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Vincristine & Vinblastine MOA
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Binds tubulin dimer
-Prevents addition of next tubulin molecule to the microtubule |
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Vincristine & Vinblastine MOA
(more detailed) |
Blocks assembly of microtubule
-Causing depolymerization -Prevents chromosome segregation -Causes M-phase arrest & apoptosis |
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Vincristine & Vinblastine Administration & Elimination?
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Parenteral
*Fatal if administered intrathecally* Billiary Excretion |
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Vincristine Common Clinical Uses?
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Non-Hodgkin's Lymphoma (CHOP-R)
Lung CA (CAV - Cyclophosphamide, Adriamycin, Vincristine) |
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Vinblastine Common Clinical Uses?
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Hodgkin's (ABVD - Adriamycin, Bleomycin, Vinblastine, Darcarbazine)
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Vincristine Adverse Effects?
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Neurotoxicity (dose limiting)
-Peripheral Neuropathy Vesicant -blistering and ulceration Hyperuicemia -Tx: Allopurinol + Hydration |
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Vinblastine Adverse Effects?
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Neurotoxicity (dose limiting)
-Peripheral Neuropathy Vesicant -blistering and ulceration Hyperuicemia **Myelosuppresion (dose limiting) |
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Vincristine & Vinblastine Mechanisms of Resistance?
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MDR1
Microtubule Mutations |
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Natural Products
Taxanes |
Paclitaxel
-Pacific yew tree bark Docetaxel -European yew tree needles |
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Paclitaxel & Docetaxel MOA
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Binds Beta-Tubulin subunit
Inhibits microtubule disassembly -Micotubule Polymerization -Apoptosis |
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Paclitaxel & Docetaxel Administration & Metabolism?
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Parenteral
Biliary Excretion |
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Paclitaxel & Docetaxel Common Clinical Uses?
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Breast CA
Kaposi's Sarcoma |
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Paclitaxel & Docetaxel Adverse Effects?
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Myelosuppresion (dose limiting)
-Neutropenia Peripheral Neuropathy Hypersensitivity Rxns -Pretreat w/antihistamine Alopecia < 80% |
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Paclitaxel & Docetaxel Resistance
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Increased Drug Efflux
-MDR1 Decreased Affinity for Drug Target -Tubulin Mutations |
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Monoclonal Antibodies
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Cetuximab
Panitumumab Trastuzumab Bevacizumab Rituximab Gemtuzumab Ozogamicin |
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Epidermal Growth Factor Receptor
Explanation |
EGF or EGFR overexpressed in numerous epithelial tumors.
Overexpression of EGF & EGFR promotes uncontrolled cell growth. |
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Cetuximab & Panitumumab MOA
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Binds extracellular domain of EGFR
Prevents ligand binding Blocks receptor dimerization Inhibits EGFR signaling -Inhibition of cell proliferation |
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Cetuximab & Panitumumab MOA
(more detailed) |
Elicits host immune response
Induces receptor internalization & degredation |
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Cetuximab & Panitumumab Clinical Uses?
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Colon Ca (+Irinotecan)
Squamous Cell CA (head & neck) |
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Cetuximab & Panitumumab Adverse Effects?
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Acneiform rash (90%)
Hypersensitivity Infusion Rxns Diarrhea |
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Cetuximab & Panitumumab Mechanism of Resistance?
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Constitutive activation of down stream kinases
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Trastuzumab MOA
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Human Epidermal Growth Factor-2 Receptor (HER-2) overexpressed in 30% of breast CA.
Antibody blocks HER-2 mediated tumor cell growth. |
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Trastuzumab Clinical Uses?
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Metastatic Breast CA (HER2+)
-+Doxyrubicin +Paclitaxel |
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Trastuzumab Adverse Effects?
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Hypersensitivity xns
Diarrhea Cardiotoxicity (+anthracyclines) -should be administered sequentially instead of at the same time. |
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Bevacizumab MOA
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Circulating Protein (ligand)
Binds VEGFA and prevents it from binding its receptor. Blocks growth of new blood vessels need to nourish the tumor. |
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Bevacizumab Clinical Uses?
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Metastatic Colon CA (+5FU +Irinotecan +Leucovorin)
Non-Small Cell Lung CA Metastatic Breast CA |
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Bevacizumab Adverse Effects?
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Fatigue
Diarrhea GI Bleeding |
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Bevacizumab Mechanisms of Reistance?
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Evasive Resistance
-Alternative pathways develop to sustain tumor growth Intrinsic Resistance -Pre-existing non-responsiveness |
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Rituximab Target
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CD20 antigen present on Non-Hodkin's Lymphoma Cells, B Cell precursors, & mature B Cells
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Rituximab MOA
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Complement-mediated cytotoxicty
Antibody-directed cellular cytotoxicity Antibody-induced apoptosis |
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Rituximab Clinical Uses?
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Non-Hodgkin's Lymphoma (CHOP-R)
CLL (CHOP-R) *Rheumatoid Arthritis (+Methotrexate) |
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Rituximab Adverse Effects?
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Hypersensitivity Infusion Rxn
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Gemtuzumab ozogamicin Target
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Antibody is conjugated w/ a cytotoxic antibiotic called calicheamicin.
CD33 expressed on the surface of 90% of AML cells |
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Gemtuzumab ozogamicin MOA
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Taken up into cells and sequestered into lysosomes where calicheamicin is released.
Calicheamicin binds DNA and causes double strand breaks-->cell death. |
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Gemtuzumab ozogamicin Clinical Uses?
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CD33 Positive AML cells
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Gemtuzumab ozogamicin Adverse Effects?
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Hypersensitivity Infusion Rxn
Myelosuppresion |
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Tyrosine Kinase Inhibitors
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Imatinib (Bcr-Abl)
Erlotinib (EGFR) Gefitinib (EGFR) Sorafenib (VEGFR) Sunitinib (VEGFR) |
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Imatinib Target/MOA
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Inhibits activity of kinase expressed in CML cells.
Bcr-abl kinase results from translocation of genes -Philadelphia Chromosome |
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Imatinib Clinical Uses?
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CML
GI tumors containing c-kit mutation |
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Imatinib Adverse Effects?
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N/V
Diarrhea |
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Imatinib Mechanism of Resistance?
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Bcr-abl amplification
Bcr-abl gene mutation |
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Erlotinib & Gefitinib Target/MOA
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EGFR tyrosine kinase.
Competes reversibly w/ATP for intracellular catalytic domain. Inhibits autophosphorylation. |
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Erlotinib & Gefitinib Clinical Uses?
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Non-Small Cell Lung CA
Pancreatic CA (+gemcitabine) |
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Erlotinib & Gefitinib Adverse Effects?
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Rash
N/V/D |
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Hormonal Modulators
Antiestrogens Slective Estrogen Receptor Modulators (SERMS) |
Tamoxifen
Raloxifene Toremifene Arzoxifene |
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Hormonal Modulators
Antiestrogens Aromatase Inhibitors |
Anastrozole
Letrozole |
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Tamoxifen MOA
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Estrogen promotes growth of breast ca cells.
Inhibits binding of estrogen to the estrogen receptor. |
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Tamoxifen MOA
(more detailed) |
ER partial agonist
-less expression of genes involved in proliferation |
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Tamoxifen Clinical Uses?
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ER+ early stage and metastatic breast cancer
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Tamoxifen Adverse Effects?
|
Hot Flushes
Increased risk of endometrial CA -less w/Raloxifene Increased risk of thromboembolitic events |
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Aromatase Inhibitors MOA
(Anastrozole & Letrozole) |
Inhibit estradiol synthesis
Inhibist testosterone conversion to estrogen-->inhibits proliferation of ca cells |
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Anastrozole Clinical Uses?
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Postmenopausal, ER+ Breast CA
Postmenopausal, ER+ Breast CA-Tamoxifen resistant |
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Anastrazole Adverse Effects?
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Hot Flushes
Fatigue Weight Gain May increase risk of osteoporosis Thrombolytic events (less than Tamoxifen) |
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Hormonal Modulators
Antiandrogens |
Flutamide
Bicalutamide |
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Flutamide & Bicalutamide MOA
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Non-Steroidal.
Binds androgen receptor & inhibits effects of androgen. Blocks synthesis of androgen-targeted genes. *(Inhibits expression of PSA) |
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Flutamide & Bicalutamide Clinical Uses?
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Prostate CA (+leuprolide)
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Flutamide & Bicalutamide Adverse Effects?
|
Hot Flushes
Gynecomastia Potential increase in breast CA incidence |
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Hormonal Modulators
Synthetic Analogues of Gonadotropin-Releasing Hormone (GnRH) |
Leuprolide
Goserelin |
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Leuprolide & Goserelin MOA
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Stimulates synthesis & release of FSH and LH from pituitary.
FSH & LH stimulates synthesis & release of testosterone & estradiol from testis & ovaries (respectively) |
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Leuprolide & Goserelin MOA
(Continued) |
Low Concentrations stimulate release of testosterone & estradiol
High Concentrations inhibit release of testosterone & estradiol |
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Leuprolide & Goserelin Common Clinical Uses?
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Prostate CA (+antiandrogen)
Uterine Fibroids Endometriosis |
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Leuprolide & Goserelin Adverse Effects?
|
Hot Flushes
Impotence Gynecomastia |
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Erlotinib Metabolism?
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CYP3A4
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Imatinib Metabolism?
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Inactivation-P450's
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Tamoxifen Metabolism?
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P450
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Immunosuppressants
Immunophilin Ligands |
Cyclosporine
Tacrolimus (FK 506) Sirolimus (rapamycin;;;;;;;;;;;;;;;;;;;;) |
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Cyclosporine MOA
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Binds Cyclophilin
Cyclosporine-Cyclophilin complex inhibits Calcineurin activity Prevents NF-ATc from entering the nucleus. Prevents IL-2 Synthesis Blocks T-Cell Proliferation |
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Cyclosporine Administration & Metabolism
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Parenteral, Oral, Topical
Hepatic P450 CYP3A4 |
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Cyclosporine Clinical Uses?
|
Organ Transplantation
Graft vs. Host Severe dry eyes syndrome Autoimmune diseases |
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Cyclosporine Adverse Effects?
|
Nephrotoxicity
Diabetogenic (+glucocorticoids) |
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Sirolimus MOA
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Binds FKBP12
-Inhibits mTOR Inhibition of cell cycle progression Inhibition of protein synthesis Inhibits B & T Cell proliferation |
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Sirolimus Administration & Metabolism?
|
Oral
P450 |
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Sirolimus Clinical Uses?
|
Transplantation
Graft vs. Host Disease |
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Sirolimus Adverse Effects?
|
Myelosuppresion
Hyperlipidemia (increase in VLDL & TAG's) |
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Immunosuppressant
DNA Synthesis Inhibitors |
Mycophenolate mofetil (MM) (prodrug)
Azathioprine (prodrug) |
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Mycophenolate mofetil MOA
|
Hydrolized to active drug in the liver
(Mycophenolic acid - MPA) Non-competitve inhibitor of IMPDH IMPDH is critical for de novo purine synthesis De novo pathway mostly used in T&B lymphocytes (other cells can use the salvage pathway) |
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Mycophenolate mofetil Administration & Absorption?
|
Oral & Parenteral
Decreased by antacids (Aluminum and magnesium containing food) |
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Mycophenolate mofetil Common Clincal Uses?
|
Transplantation
Graft vs. Host Disease |
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Mycophenolate mofetil Adverse Effects?
|
GI Irritation
D/V |
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Mycophenolate mofetil Drug Interactions?
|
Tacrolimus decreases elimination.
Blocks MPA conversion to MPAG -Fatal viral infections and increase GI toxicity (from over suppression of the immune system) |
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Azathioprine MOA
|
Converted to 6-MP
Inhibits DNA synthesis in T-Cells |
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Azathioprine Administration & Elimination?
|
Oral, Parenteral
Renal |
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Azathioprine Clinical Uses?
|
Organ Transplant
Rheumatoid Arthritis |
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Azathioprine Adverse Effects?
|
Bone Marrow Suppression
GI Disturbances |
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Immunosuppressants
Glucocorticoids |
Prednisone
|
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Prednisone MOA
|
General inhibitor of the immune system.
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Prednisone MOA
(more detailed) |
-Inhibits proliferation of lymphoid cells.
-Inhibits production of inflammatory mediators -Inhibits IL-1 production in monocytes |
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Prednisone Administration & Metabolism?
|
Oral
Activated by liver metabolism to Prednisolone |
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Prednisone Clinical Uses?
|
Non-Hodkin's Lymphoma (CHOP-R)
Organ Transplant Graft vs. Host Autoimmune disease |
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Prednisone Adverse Effects?
|
Long Term Use (many toxicities)
-Muscle Wasting -Cushing's Syndrome -Inhibits osteoblast protein production |
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Immunomodulators
Cytokines |
Aldesleukin
Interferon Alpha |
|
|
Cytokines
|
Produces primarily by WBC's that provide signals to regulate growth, inflammation and other immune responses.
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Aldesleukin MOA
|
Recombinant interleukin-2 (IL-2)
IL-2 is a T-Cell growth factor Activates and induces proliferation of T-Cells. -Activation & recruitment of T and B cells |
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Aldesleukin Administration & Elimination?
|
Parenteral
Renal |
|
|
Aldesleukin Clinical Uses?
|
Renal Cell Carcinoma
Metastic Melanoma |
|
|
Aldesleukin Adverse Effects?
|
High Dose (adverse effects)
Hematologic Deficiencies Fluid Retention Renal Dysfunction |
|
|
Interferon Alpha MOA
|
Increases activity of immune cells.
Immune cells inhibit growth of tumor cells. |
|
|
Interferon Alpha Administration & Elimination?
|
Parenteral
Renal |
|
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Interferon Alpha Clinical Uses?
|
Melanoma
Karposi's Sarcoma |
|
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Interferon Alpha Adverse Effects?
|
Leukopenia
Flulike Illness |
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|
Immunomodulators
Hematopoietic Growth Factors |
Erythropoietin (EPO)
Filgrastim (G-CSF) Sargramostim (GM-CSF) |
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|
Erythropoietin (EPO) MOA
|
Binds to erythropoietin receptors on red cell progenitors to stimulate proliferation and differentiation.
Induces release of erythrocytes from bone marrow. |
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|
Erythropoietin Administration?
|
Parenteral
|
|
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Erythropoietin Clinical Uses?
|
Anemia of chronic renal failure.
CA HIV |
|
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Erythropoietin Adverse Effects?
|
Hypertension
Thrombolytic Complications Allergic Rxns |
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|
Filgrastim (G-CSF) & Sargramostim (GM-CSF) MOA
|
Interacts w/ receptors on myeloid progenitor cells to stimulate proliferation and differentiation
|
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Filgrastim (G-CSF) MOA
|
Increases proliferation and differentiation of granulocytes.
-Shortens duration of neutropenia -Decreases infection rates -Decreases days of hospitalization |
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Filgrastim (G-CSF) Clinical Uses?
|
Bone marrow deficiency following chemotherapy and bone marrow transplantation.
|
|
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Filgrastim (G-CSF) Adverse Effects?
|
Mild to moderate bone pain.
*Better tolerated than GM-CSF |
|
|
Sargramostim (GM-CSF) MOA
|
Increases proliferation and differentiation of granulocytes, monocytes/macrophages
-Shortens duration of neutropenia -Decreases infection rates -Decreases days of hospitalization |
|
|
Sargramostim (GM-CSF) Clinical Uses?
|
Bone marrow deficiency following chemotherapy and bone marrow transplantation.
|
|
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Sargramostim (GM-CSF) Adverse Effects?
|
Fever
Myalgia Malaise Capillary Leak Syndrome |
|
|
Immunomodulators
Vaccine |
Gardasil
|
|
|
Gardasil MOA
|
L1 capsid protein
-HPV 6 & 11 (genital warts) -HPV 16 & 18 (cervical ca) |
|
|
Gardasil Clinical Use?
|
Prevention of cervical ca and genital warts caused by HPV 6, 11, 16, 18
|
|
|
Gardasil Administration?
|
3 IM shots
0,2,6 months |
|
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Gardasil Adverse Effects?
|
Fever
Pain at injection site Hypersensitivity Rxns |
