mech: heparin
cofactor for antithrombin activation
PT or PTT elevated with heparin?
Only PTT
heparin side effects
- thrombocytopenia (HIT)
2. osteoporosis
benefit of low molecular weight heparins?
act more on factor Xa, better bioavailability and a longer half life
–no lab monitoring needed
pathophys: hepariin induced thrombocytopenia
development of IgG antibodies against heparin bound to platelet factor 4
Lepirudin, bivalirudin: derived from?
derivative of hirudin, from leeches
mech: lepirudin, bivalirudin?
inhibit thrombin
when would you use lepirudin/bivalirudin?
If a pt cannot use heparin because of HIT
warfarin metabolized by
cytochrome P450
warfarin affects PT or PTT?
PT. affects extrinsic pathway.
clinical use of warfarin
chronic anticoagulation after STEMI, DVT, prevention of stroke in Afib
warfarin contraindicated in
pregnancy. Unlike heparin, which does NOT cross the placenta
Tox: warfarin
skin/tissue necrosis
drug/drug interactions
-teratogenic
which inhibits coagulation in vitro, heparin or warfarin?
heparin
alteplace, reteplace, tenecteplase
tPA, rPA, TNK-tPA
thrombolytics
tPA mechanism
aids conversion of plasminogen to plasmin, which cleaves thrombin and fibrin
tPA: PT or PTT change?
Increases both
reversal of tPA overdose with
aminocaproic acid
tPA contraindicated in
active bleed
history of intracranial bleed
bleeding diathesis
severe hypertension
aspirin effect on PT or PTT
none
aspirin decreases plasma levels of
TXA2 and prostaglandins
tox: ticlopidine
neutropenia
clopidogrel
ticlopidine
prasugrel
ticagrelor
ADP receptor inhibitors
ADP receptor inhibitor: usage
acute coronary syndrome
coronary stenting
decreased incidence of thrombotic stroke
cilostazol mechanism
phosphodiesterase III inhibitor. Increases cAMP in platelets, inhibiting aggregation
–also a vasodilator
indications: cilostazol
intermittent claudication, prevention of stroke
angina prophylaxis
dipyridamole class
phosphodiesterase II inhibitor like cilostazol.
tox: cilostazol
nausea, headache, facial flushing, hypotension
eptifibatide
GpIIb/IIIa inhibitor
tirofiban
GpIIb/IIIa inhibitor
toxicity of GpIIb/IIIa inhibitors
bleeding, thrombocytopenia
which cancer drugs work on the M phase
vinca alkaloids
taxols
which cancer drugs work on the G2 phase
bleomycin and etoposide
which cancer drugs work on the S phase
etoposide and antimetabolites
Methotrexate: mechanism
decreases dTMP
decreases dNA
methomtrexate for which cancers?
leukemia
lymphoma
choriocarcinoma
sarcoma
methotrexate use: nonneoplastic
abortion
ectopic pregnancy
RA
psoriasis
tox: methotrexate
myelosuppression
macrovesicular fatty change in liver
mucositosis
teratogen
tx of methotrexate myelosuppression
folinic acid
leucovorin
5-FU: indication
colon cancer
basal cell carcinoma, topical
tox: FU
myelosuppression.
photosensitivity
tx for FU myelosuppression?
thymidine.
Note: leucovorin does NOT help! Because even if sufficient amount of N5, N10 THF, the enzyme thymidylate synthase doesn’t work
mechanism: cytarabine
inhibition of DNA polymerase. A pyrimidine analog
Use: cytarabine
leukemia and lymphoma
tox: cytarabine
leukopenia
thrombocytopenia
megaloblastic anemia
azathioprine, 6mercaptopurine, and 6thioguanine mech
purine analog decrease purine synthesis
activation of azathioprine/6MP requires
HGPRT
tox of azathioprine
bone marrow, GI, liver
what drug should you NOT give with azathioprine and 6MP?
allopurinol. Because it’s metabolized by xanthine oxidase!
mechanism: dactinomycin
intercalates DNA
tox: dactinomycin
myelosuppression
clinical use of dactinomycin
wilms’ tumor
ewing’s sarcoma
rhabdomyosarcoma
CHILDHOOD tumors
doxo/daunorubicin mechanism
generates free radicals
–INTERCALATES into DNA, causing breaks
Clinical use of doxorubicin
solid tumors, leukemias, lymphomas
toxicity of doxo/dauno
dilated cardiomyopathy
myelosuppression
alopecia
prevention of doxo/dauno cardiotoxicity
dexrazoxane
Bleomycin mechanism
free radicals
-breaks DNA
use: bleomycin
testicular cancer
hodgkins
toxicity of bleomycin
pulmonary fibrosis
skin changes
which cancer agents are alkylating
cyclophosphamide, ifosfamide
busulfan
nitrosoureas
cyclophosphamide, ifosfamide mech
covalently X links DNA at guanine N7
cyclophosphamide requires activation by
liver
Side effects of cyclophosphamide
myelosuppression
hemorrhagic cystitis
how to prevent cyclophosphamide hemorrhagic cystitis
mesna, binds toxic metabolite
use: cyclophosphamide
solid tumors, brain cancers
leuk, lymph
carmustine, lomustine, semustine, stretpzocin
nitrosureas
carmustine and friends mechanism
bioactivation then crosses blood brain barrier
use: nitrosureas (carmustine)
brain tumors like GBM
tox of nitrosureas
CNS dizziness and ataxia
busulfan mechanism
alkylates DNA
use: busulfan
CML
–also bone marrow ablation
tox: busulfan
pulmonary fibrosis
hyperpigmentation
Mech: vincrinstine, vinblastine
Bind tubulin and block microtubule polymerization
vincristine tox
neurotox (areflexia, peripheral neuritis, ileus)
vinblastine tox
bone marrow suppression
paclitaxel mechanism
stabilizes polymerized microtubules in M phase. mitotic spindles can’t break down–>no anaphase
indications of paclitaxel
ovarian/breast
tox of paclitaxel
myelosuppression
hypersensitivity
cisplatin/carboplatin tox
nephrotoxicity and acoustic nerve damage
prevent cisplastin nephrotoxicity with
amifostine, a free radical scavenger and chloride diuresis
indications of cisplatin
testicular, bladder, ovary, lung cancer
etoposide, teniposide mechanism:
inhibit topoisomerase II=DNA degradation
tox of etoposide
myelosuppression
GI
alopecia
hydroxyurea affects which phase of cell cycle
S phase
–inhibits ribonucleotide reductase
prednisone cancer use?
CLL
non-hodgkins. triggers apoptosis
tamoxifen/raloxifene mechanism
blocks estrogen binding to receptor
SERM indication
breast cancer and osteoporosis
tamoxifen tox
increased endometrial cancer and hot flashes. partial endometrial agonist
raloxifen tox
NO increase in endometrial carcinoma. complete antagonist
trastuzumab mechanism
antibody against HER2, a tyrosine kinase
trastuzumab tox
cardiotoxicity
imatinib toxicity
fluid retention
rituximab indications
NHL, rheumatoid arthritis
vemurafenib mechanism
inhibits B-Raf kinase with V600E mutation
use: vemurafenib
metastatic melanoma
bevacizumab use:
Solid tumors
mechanism bevacizumab
monoclonal antibody against VEGF