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195 Cards in this Set

  • Front
  • Back
HIV infection
-is an RNA virus/retrovirus
-reproduced in our immune system in a certain type of WBC - CD4+ lymphocyte
-HIV integrates into CD4 cell & replicates causing the CD4 cell to die. no CD4 no immune system
5 FDA approved classes of HIV meds
>Entry Inhibitors (2)
>Nucleoside Reverse Transcriptase Inhibitors (8)
>Non-Nucleoside Reverse Transcriptase Inhibitors (5)
>Integrase Inhibitors (1)
>Protease inhibitors (10)
candida in general
-most common cause of invasive fungal infections
-4th most common cause of nosocomial blood stream infections (2ndary to broad spect. abx, IV caths, TPN, CRRT, neutropenia)
-majority are from native C albicans
-azole resistance & non-albicans
Azoles:
Mechanism of Action
-Target: Ergosterol biosynthesis
--inhibition of fungal cytochrome p450 dependent enzyme lanasterol 14 alpha demethylase
--the enzyme functions to convert lanasterol to ergosterol
--inhibits the P450 dependent enzymes in fungal respiration change
--by altering the cell membrane & function --leads to death or inhibition of growth
--generally considered FUNGISTATIC, possibly fungicidal for Aspergillus & filamentous fungi
Azoles:
Pharmacokinetics & Bioavailability
->Oral and IV duration, 1–2 d poor entry into central nervous system (CNS) Toxicity and interactions: Low toxicity
->Fluconazole has excellent CNS penetration, used in fungal meningitis
Azoles:
Drug Interactions
-tons:
-antiarrhythmics
-benzos
-CCBs, macrolides, rifampin/rifabutin, ritonavir & other HIV protease inhibitors
-statins, warfarin
Azoles:
More detail on Fluconazole
-is a CYP450 inhibitor
-does have renal dose adjustments
-interacts with rifampin (decr fluco)
-warfarin/PT/INR prolonged
-increases phenytoin
-also: put reason for putting patient on a super high dose so pharmacy knows what you're doing
echinocandins:
MOA & available agents
->noncompetitive inhibitors of the synthesis of 1,2beta-glucan essential cell wall polysaccharide
->essential constituent of fungal cell wall: so it disrupts structure & function of cell wall, osmotic instability
-->spectrum of activity limited to CANDIDA and ASPERGILLUS species. NOT active against Cryptococcus sp.
echinocandins:
PK/PD
IV only! Duration, 11–15 h
Toxicity: Minor gastrointestinal effects, flushing
Interactions: Increases cyclosporine levels (avoid combination)
Echinocandins:
Micafungin
-dosing ranges are wide
-no renal or hepatic adjustments needed
-hepatic metabolism withOUT CYP 450, no P-gp effects
-AE: rare histamine-like reactions. Can avoid if you infuse over an hour.
Echinocandins:
Anidulafungin
-practically insoluble in water: need to give with a big fluid load.
-infusion related reactions possibly mediated by histamine incl flushing/hypotension. admin slowly.
--no dose adjustments for renal/hepatic diz. not metab by CYP450.
-btw: cyclosporine incr. level
Cryptococcus neoformans
-HIV pts with CD4 <50 cells/mcL at greatest risk
-causes subacute meningitis/meningoencephalitis
-skin lesions: can mimic molluscum contagiousum
S&S: fever, malaise, stiff neck, HA MOST COMMON.
Dx: spinal tap. incr protein, lymphocytes, 75% HIV+pts are pos for C. neoformans
Cryptococcal Meningitis
Preferred Treatment
-Amphotericin B + flucytosine
OR
-Lipid amphotericin + flucytosine

Consolidation Tx: Fluconazole
2ndary Prophylaxis: Fluconazole. CD4 count drops <200 cells/mL must reinitiate 2ndary prophylaxis
Cryptococcal Meningitis
What NOT to treat with
->Echinocandins: have NO in vitro activity against Crypotococcus, no role in clinical mgmt of these pts.
>Intrathecal/Intraventricular Ampho B discouraged
>Azole exposed pts incr the dose fo azole for persistence or relapse unlikely to be successful/not recommended.
>NO mannitol, acetazolamide, or steroids
Polyenes:
Amphotericin

-overview
-Natural polyene macrolide antibiotic
-Elongated cyclic molecule: amphipathic
-broad spectrum of activity-
-(candida, crypto, asper, histo, blasto, etc)
Polyenes:
Amphotericin

MOA
(note: ergosterol is a primary sterol in the fungal cell membrane, is similar to cholesterol)
-binds to sterol component and leads to alterations in cell permeability and cell death
--formation channels w/ leakage of cell contents
--possible dual mechanism?
--oxidative reactions linked to drug's own oxidation w/ free radical formation
Polyenes:
Amphotericin
Indications & Usage
Abelcet--invasive fungal infections refractory/intolerant to conventional tx
AmBisone--empiric tx in febrile neutropenia
-cryptococcoal meningitis in AIDS pts
-for aspergillus/candida or crypto refractory or with renal impairment/tox excludes use of ampho B, and visceral leishmaniasis
-Amphotec-- invasive aspergillosis refractory or where renal impartment tox to amph B
Polyenes:
Amphotericin
:Toxicity
-mechanisms: membrane changes of renal tubular cells results in decr. K, Mg, acidosis
-constriction of afferent arterioles to reduce GFR
--tubular dysfunction w/in 7-14 days of tx
--nephrotox exacerbated by all other concom. agents look at other meds
--risk factors: abnormal baseline SCr, dehydration, diuretics, elderly, DM, CHF,
--keep pt well hydrated!!!
Polyenes:
Amphotericin
PK/PD
--Oral but not absorbed IV for systemic use intrathecal for fungal meningitis topical for ocular and bladder infections duration, days Toxicity: Infusion reactions renal impairment Interactions: Additive with other renal toxic drugs
HIstoplasma capsulatum
overview: and tx's for varying stages of diz
--seen in HIV+ pts with CD4 count <150 cells/mL
--fever, fatigue, wt loss, hepatosplenomeg, lymphaden
--Dx: antigen detection in blood/urine. CNS infx dificult to dx
Preferred tx: moderate/severe dz-->lipo AmphoB,
Maintenance: itraconazole
Less severe: Itraconazole
Histoplasmosis
Preferred Tx:
-Meningitis: --Lipo Ampho B.
-Maintenance: Itraconazole 1 year
-Alterntvs: Lipo amphoB, Ampho B deoxycholate,
-LT suppressive: Itraconazole
Histoplasmosis
other tx issues
-no evidence to rec. Echinocandins
-Fluconzaole has little activity against
-reististance may develop to fluconazole,
Itraconazole
overview:
-extensive liver metab
-tx drug monitoring available.
-ensure adequate absorption due to erratic oral bioavail. & drug intrx
-level of parent &metabolite obtained
-box warning: valvular disease, and/or HF with neg inotropic efcts
coccidiomycosis
overview
-HIV+ pts with CD4 count<250 cells/mcL but can occur in immunocompetent hosts
-pnuemonia, meningitis, & disem diz
Dx: IgM & IgG serology, tissue biopsy. CSF cultures often negative
relapse: tx should be lifelong for pts with diffuse pulmonary/dissem diz, as relapse can occur in 25-33% HIV neg
-relapse occurred in 80% of HIV+ w/ meningitis of azole tx
coccidiomycosis
:preferred tx:
-moderate/severe diz: ampho B
-meningitis tx: fluconazole
-less severe tx: fluconazole
-maintenance tx: itraconazole
aspergillus
overview:
-invasive aspergillosis, most common life threatening mold infx
-incidence 5-10% in hi risk
-definitive dx may take up to 4 weeks
-galactomannon EIA & beta-D glucan assays
-> 5-FC (drug we don't need to know about) and fluconazole.
Voriconazole
SE & PK
->visual distubrances
-(altered color discrimination, blurred vision, appearance of bright spots & wavy lines, photophobia)
-LFT abnormalities/cholestasis
->non-linear pharmacokinetics
-sat of metabolism high interpt variability, homozygous/hetero cyp2c19 metabolzrs
->parent compound important as metabolite, does not have appreciable antifungal
>only free or unbound portion of drug ~40-50% is microbiologically active & avail. for penetrn to infected tissues
Voriconazole
Therapeutic drug monitoring
-tr 1 hr prior next dose day 5
-Minimum IinhibConc for most fungal pathogens
-candida peak AUC over MIC best PD parameters
-steady state reached in 1 day w/ loading dose
-neuroltox observ trough >5.5 mcg/mL
-note: can't use rifampin and voriconazole no bueno
"breakthrough" zygomycetes
-fusarium species, scedosporium and zygomycetes are becoming incr more common infections as prophylaxis & tx for aspergillus has improved for immunocomp pts
-zygomycetes "achilles heel of voriconazole"
Posaconazole
-FDA approved indications: prophylaxis of invasive Aspergillus & candida infex in hi-risk pts
-tx: of oropharyngeal candidiasis incl. candidiasis resist to itra/flucoazoles
-Therapeutic Uses: invasive fungal disease caused by Aspergillus, candida, fusarium, & zygomycetes
-limited data on tx of fungal infx
-approved in europe for salvage tx of invasive aspergillosis
Conclusvie thoughts on antifungals:
Fluconazole
-when in doubt, amphotericin is a good guess (it covers most fungal infex. you can add flucytosine
-Fluconzaole is good for:
-HIV candida. tx of candida in hospitalized non-neutropenia pts until species identification & susceptibilities known
Conclusvie thoughts on antifungals:
Itraconazole
-tx: of chioce for histoplasmosis, follow levels
Conclusvie thoughts on antifungals:
voriconazole
-is tx of choice for Aspergilus
-very difficult to use with HIV meds due to DI, follow levels
Conclusvie thoughts on antifungals:
Posaconazole
-is appropriate for:
--fluconazole resistant to candida
--prophylax of transplant/onc pts against a wide variety of fungi
--not FDA approved for tx of IFI utilized in severe illnesses, liquid only can't load, needs food & acid, follow levels
Conclusvie thoughts on antifungals:
Echinocandins
-appropriate for IV tx for
-candidemia, esp with non-albicans specis
-pssible role in combo or alt to LAB for Aspergillus
DHHS adult HIV guidelines for meds
2 NRTIs (preferred Truvada or Epzicom/Combivir)
+
NNRTI (efavirenz w/ Truvada) [Atripla] [chicken]
or
Protease Inhibitor (prefer boost w/ ritonavir) [beef]
-Integrase inhibitor: only 1 fda approved, raltegravir [fish]
-if pregnant: combivir & kaletra both BID dosing
NRTI
nucleoside reverse transcriptase inhibitors
Zidovudine, Abacavir, Emtricitabine
MOA:
-structurally similar to DNA bases
-must be phosphorylated intracellularly to triphosphate, incorporates itself into viral DNA, and messes it up because it incorrect and incapable of infecting other cells
NRTIs
Zidovudine, Abacavir, Emtricitabine
place in therapy
-dual NRTIs recommended as the 'nucleoside backbone' of all HIV regimens
-NRTIs used from 'naive' to salvage
-resistance mutations often reduce viral fitness, so often continue NRTIs in salvage even when resistance testing indicates not actively fighting HVI
-can use combo products so do not incr daily pill burden
NRTIs
combo drugs:
-Combovir = zidovudine + lamiduvine

-Epzicom= abacavir + lamivudine

-Trizivir =zidovudine, lamivudine +abacavir

-Truvada= tenofovir + emtricitabaine
NRTIs
Zidovudine, Abacavir, Emtricitabine
-quick review of tox,pharm stuff
-water solubility, generally good bioavailability
-excellent distribution
-metab: no CYP few drug intrxns
-renal excretion
NTRIs
Zidovudine
-1st HIV med approved
-causes bone marrow suppression (anemia, neutropenia, caution in pts with sickle cell & thalassemia)
-watch overlapping toxicities w/ meds
-do not give with stavudine, antagonistic
NTRIs
moar on
Zidovudine
-weak inhibitor of DNA polymerase a and gamma
-potential for lactic acidosis with ALL NTRIs (black box warning on all b/c of this drug)
-anemia more common in women
-burns out mitochondria more
"D" Drugs:
NRTIs
-lactic acidosis with hepatomegaly & steatosis possible with all NRTIs
-peripheral neuropathy with stavudine
-lipoatrophy largely attributed to stavudine
-no longer recommended for naive pts.
More on Stavudine and Lipoatrophy
-'fat wasting'
-loss of subQ fat in extremities, face & buttocks
-prominent veins in arms&legs
-buccal fat pad loss, sunken cheeks, w/ prominent bones/facial folds
-male pts have hi rate of peripheral fat wasting
NRTIs
Tenofir
-parent compound too nephrotoxic for HIV, tx licensed for HBV
-reengineered as tenofir & active against HBV
-is renally eliminated; really hard on the kidney (Faconi syndrome)
-avoid use with other nephrotoxic drugs
NRTIs
Abacavir
-hypersensitivity rxns
-life threatening/stop immediately!
-NEVER rechallenge
-usually occurs w/in first 6 wks
-rash common but can occur w/out a rash
GI (N/V/D & fever)
Emitricitabine FTC
neat fact
-can cause darkening of palms of hands and soles of feet
SE: Headache, diarrhea, nausea, asthenia, skin hyperpigmentation
>Do not administer concurrent lamivudine. Avoid disulfram and metronidazole with oral solution
NNRTIs
basics/MOA
(Efavirenz)
-non-nucleoside reverse transcriptase inhibitors
-5 drugs
-MOA: binds directly to the reverse transcriptase enzyme blocking the RNA dependent and DNA dependent DNA polymerase from replicating the virus (close the window on the box office)
NNRTIs
pharmacokinetics
(Efavirenz)
-liver metab with extensive CYP450 syst effects translates into drug intrxns
-efavirenz most commonly used
-INDUCER of CYP3a4
-may require dose incr of other meds
-all: SE is SKIN RASH
NNRTI
Efavirenz
(featured)
PREGNANCY CAT. D.
->causes false + cannabinoid drug screen
->well absorbed fasting
>SE: drowsiness, imp concentration, abnorm/vivid dreams
>take on empty stomach/bedtime
->single point mutation renders drug ineffective
Integrase inhibitor
(Reltegravir)
overview
-no dosage for renal impairment
-really well tolerated/few SE
-low genetic barrier to resistance/resist testing not redily avail
-hardly any drug rxns EXCEPT rifampin.
Protease Inhibitors:
(Ritonavir, Atazanavir, Darunavir, Lopinavir/Ritonavir)
MOA:
-inhibits HIV-1 protease preventing cleavage of the gag-pol polyprotein resulting in the production of immature noninfectious virus
Protease Inhibitors:
(Ritonavir, Atazanavir, Darunavir, Lopinavir/Ritonavir)
SE's:
->insulin resistance & hyperglycemia that can lead to DM
->dyslipidemias including- hypercholesterolemia & hypertriglyceridemia
->fat redistribution: central obesity (protease paunch), buffalo hump, breast engorgement
->more common in adults than peds
Protease Inhibitors:
(Ritonavir2, Atazanavir2, Darunavir2, Lopinavir/Ritonavir2)
Big Facts
-poor oral absorp. take w/ food
-tons of drug interaxns/uses CYP450
-anyd drugs taht use these are CI with protease inhibitors
-elimination: renal excretion
Protease inhibitors2:
Ritonavir
-can use it to cause a 'therapeutic' drug interaction:
-can use it to shut down CYP3a4 which increases its levels. you have to take PI and ritonavir every day
-is used as a 'booster', not for HIV anymore
Protease Inhibitors2:
Atazanavir
-naive pts can use
-less effect on cholesterol than other PIs
-need gastric acid to absorb, **watch pts on PPIs/alternative for GERD pts**
-unconjugated hyperbilirubinemia common
-prolongs the PR interval (watch for intratns with CCBs)
Protease Inhibitors:
Darunavir
--used in experienced/naive pts
-rash is common (10% including SJS) pos. cros reactivity to sulfa
-however sulfa allergy is nOT a contraindication to use
-hepatotoxic; monitor LFTs
-**high genetic barrier to resistance. very potent HIV med*
>the bEST DRUG we have
Protease inhibitors:
Lopinavir/ritonavir
-used in pregnant women
-preg cat C in 3rd trimester
Protease inhibitors:
significant drug interactions
-statins interact with PIs.
-cause rhabdomyalsis
NRTI
Tenofovir
>Take with food.
>Nausea, diarrhea, vomiting, flatulence, headache, renal insufficiency
>Avoid concurrent atazanavir, probenecid, didanosine
NRTI
Lamivudine
>Nausea, headache, dizziness, fatigue
>Do not administer with zalcitabine
Fusion Inhibitor
Enfuvirtide
>blocks entry into the cell, has no activity against HIV2
given subQ, no CYP involvement of metab
>Store at room temperature as a powder; refrigerate once reconstituted
>Local injection site reactions, hypersensitivity reaction
Protease inhibitors 1&2
Lopinavir/Ritonavir
>Take with food. Separate dosing from ddI by 1 h. Store capsules and solution in refrigerator
>Diarrhea, abdominal pain, nausea, hypertriglyceridemia, headache, liver enzymes
>Avoid fosamprenavir. Avoid disulfiram and metronidazole with oral solution
NRTI
Emtricitabine
>Oral solution should be refrigerated
>Headache, diarrhea, nausea, asthenia, skin hyperpigmentation
>Do not administer concurrent lamivudine. Avoid disulfram and metronidazole with oral solution
Integrase inhibitor:
Raltegravir
>is a pyrimidinone analog that binds integrase, a viral enzyme essential to the replication of both HIV-1 and HIV-2--->it inhibits strand transfer, the third and final step of the provirus integration, thus interfering with the integration of reverse-transcribed HIV DNA into the chromosomes of host cells.
Use for : in tx-experienced adult pts infected with strains of HIV-1 resistant to multiple other agents.
>Separate dosing from antacids
>Diarrhea, nausea, fatigue, headache, dizziness, muscle aches, creatine kinase
>**Avoid rifampin**
tuberculosis:
overview
-most potent factor that increases the chance of being infected with TB is also being infected with HIV
HIV and TB
-macrophages and T-lymphocytes used to fight the mycobacterium activate and proliferate the HIVirus
-replication is accelerated in activated CD4 lymphocytes fighting TB
-HIV replication then depletes the CD4 cell count, allowing TB to reproduce and disseminate quickly
-treatment of TB alone withouth antiretrovirals is assoc with a decrease in HIV viral load
Immune Reconstitution Syndrome
(why HIV pts die)
-results from restored immune fucntion with response to TB tx alone or ART
-paradoxical reaction during TB treatement
-temporary exacerbation of TB S&S
-recurrence of fever, enlarged lymph nodes
-CXR finding increase or newly appear
-Tx with steroids
Latent TB disease
-infected with TB
-immune system sequesters organisms involving the lymph nodes, macrophages and lung granulomas
-in the US most of the TB cases are reactivations
Active TB disease
-HIV patients: are more likely to have TB and are less likely to have typical TB symptoms
-the lower their CD4 count the weirder the symtpoms
-may have extrapulmonary disease
-disseminated, miliary TB more common
-less likely to present with primary progressive.
-TB in an HIV+ pt is an AIDS defining illness
Diagnosis process of TB
-PPD
-QuantiFERON - TB gold
-T-spot TB
-Sputum: AFB stain, culture to identify organism
-CXR: identify cavitary lesions & mark changes over time
Treatment Goals for TB:
Latent TB
-prevent reactivation of TB & progression to active disease
Treatment Goals for TB:
-Active TB
-render the patient noninfectious
-cure the patient, reduce M&M
-reduce replication of HIV

it is vital to r/o active TB prior to initiation of tx for latent TB
Treatment principles for TB:
-treat with multiple agents,
-treat for enough time
-duration depends on # doses not days
-directly observed tx is superior to pt administered tx
-monitor pt at monthly intervals
-review all meds for drug intrxns thru-out tx
First line TB meds:
RIPD
-rifampin
-isoniazid
-pyrazinamide
-ethambutol
Second line TB meds:
-streptomycin
-capreomycin
-ethionamide
-amikacin/kanamycin
-cycloserine
-qinlolones
-p-aminosalicyclic acid
second line TB meds: thoughts on them
-the evidence is weaker on their use
-some meds are not FDA approved for TB
-more issues with long term use
-but... it's used in pts unable to take first line due to liver disease and used to tx multi-drug resistant TB.
--also: quinolones are frequently used due to resistance & drug intrxns with rifamycins
multidrug resistant TB
-the reason we use 4 drug tx
-regimen must contain at least 2 drugs the TB is susceptible to
-treat for 12 mo in HIV pts
Rifampin (RIF)
overview
-is bactericidal against rapidly dividing cells
-has STERILIZING activity against semidormant TB
-vital component of all short course regimens
-safe to give in CKD
Rifapmin
Side effects
-R- red discolors every bodily fluid orange
-GI: nausea, anorexia, abd pain
-hyerbilirubinemia
-skin: pruritis
-immune rxns: flu-like symptoms, ARF, thrombocytopenia, hemolytic anemia, TTP (rare)
TB (rifamycin) and HIV meds
-rifamycins induce/substrates for CYP450 enzyme
-rifabutin alt to rifampin due to less severe drug interactions
-better for HIV pts
other TB drug (rifampin) interactions
-anticonvulsants
-antipsychotics
-antirejection meds
-AZOLE antifungals
-benzos
-CCBs, levothyroxine, oral contraceptives, statins, warfarin
Isoniazid
overview
-bactericidal against rapidly dividing cells, acts against mycobacterial cell wall
-CSF penetration is excellent
-hepatic clearance, inhibits bunch of CYPs
Isoniazid
Side effects
-asymp incr in LFTs, but normalize later in tx
-clinical hepatitis in <2% pts
-peripheral neuropathy, prevent with vitamin B6
-~20% pts get ANA (lupus)
-CNS effects like seizures
Pyrazinamide
overview
-sterilizing activity against semidormant & dormant TB in macrophages & caseous foci
-CSF penetration excellent
-liver metab, kidney excrete
Pyrazinamide
side effects
-polyarthralgias 40% of pts: take NSAIDs to relieve pain
-hyeruricemia*, can flare up gout
-hepatotoxic
-GI: N/V/anorexia
-Photosensitivity/rash
Ethambutol
Overview
-rec in all adult pts as 4 drug empiric tx due to high proportion of TB resistant to INH/RIF
-acts against mycobacterial cell wall
-CSF penetration LOW, only penetrates meninges in presence of inflammation, but does not have demonstrated efficacy in TB meningitis
-renal dosing needed
Ethambutol
Side Effects
-retrobulbar neuritis: decr visual acuity in red-green color discrimination in one or both eyes
-generally not recommended in kids <5 y/o. STOP immediately if signs of visual toxicity
-peripheral neuritis is rare
-skin reactions
Hepatotoxicity in TB meds
-overlapping hepatotoxicity with several TB meds
-counsel patients on S&S of hepatitis:
--anorexia
--N&V
--abd pain
--jaundice.
-instruct pts to immediately d/c TB meds & seek MD tx
-frequently follow LFTs
Streptomycin
MOA & effects
MOA: Prevents bacterial protein synthesis by binding to the S12 ribosomal subunit
Effect: Bactericidal activity against susceptible mycobacteria
Streptomycin:
Clinical Application
PK/PD/Tox
IM, IV renal clearance (half-life 2.5 h) administered daily initially, then 2 x week
Toxicity: Nephrotoxicity, ototoxicity
2nd line TB meds:
Moxifloxacin
>In TB has bactericidal effects similar to that of standard doses of isoniazid
>When replacing ethambutol in the standard multi-drug regimen, 400 mg/day of moxifloxacin produces faster sputum conversion at 4 weeks than ethambutol.
>Moxifloxacin is being studied to replace either isoniazid or ethambutol.
AE: N/V/D
2nd line TB meds:
Moxifloxacin
administration
-antacids/other meds with divalent cations markedly decrease abs of FQs, resulting in abx failure
-critical to separate dose from these meds or foods (Ensure, supplements, zinc, calcium, Mg etc)
basic strategies of chemotherapy
-target rapidly dividing cells
-inhibit aberrant molecules (like kinases) which are responsible for abnormal signal transduction and uncontrolled growth
-starve the tumor (by inhibiting angiogenesis)
-target antibodies to markers on selective groups of cells
log cell kill model
theory behind why
-describes tumor growth & tumor regression in response to chemotherapy
-tumor growth is exponential
-double time is tumor-specific
--ex: colon CA doubles every 3 months, whereas some aggressive double BID (Burkitt's)
basic facts of tumor growth
-it takes approximately 10^9 cells to achieve a clinically observable tumor of 1-1.5 cm
-a tumor burden of 10^12 cells (1 kg) is often incompatible with life
log cell kill model: how it works
-cell destruction is FIRST order
-each dose of a chemotx drug kills a *constant fraction* of cells and the number of cells killed depends on the total number of cells remaining
i.e. - each dose of chemo will reduce the number of cancer cells by 99% or by 2 logs (so 10^10 drops to 10^8 etc)
log cell kill model:
a problem... resistance
-chemo drugs need to be intermittantly dosed to reduce toxic SE & allow recovery of normal cells
--however, it also allows for RECOVERY of cancer cells & allows for them to develop resistance
Genetic causes of drug resistance
-chromosomal changes that:
-->prevent uptake of drug (alter receptor binding protein/carrier)
-->promote efflux of drug (upregulate expression of proteins that pump drug out of cell)
-->alter drug target
-->desensitize the cell to apoptosis (mutations in p53 or Bcl-2 can result in failure to induce apoptosis)
non-genetic causes of drug resistance
poor patient compliance
-drugs that can't pass the blood brain barrier
types of drugs:
drugs that target DNA synthesis & mitosis, their basic classes
->antimetabolite drugs
--inhibitorsthymidylate synthase (5-FU)/purine metabolism 6-mp/inhibitors ribonucleotide redutase/purine&pyrimidine analogues
->agents that modify DNA structure - alkylating agents/platinum compounds
->inhibitors of topoisomerase
->inhibitors of microtubules
Antimetabolite drugs:
overview
-are compounds that either:
-->inhibit enzymes involved in nucleotide synthesis/metabolism
-->are incorporated as analogues into DNA & result in chain termination or strand breaks
-act during S-phase when cells are undergoing DNA replication
Thymidylate Synthase is...
(aside from a target for 5-FU)
-is an enzyme in nucleotide synthesis
-uracil is the base in dUMP and is the substrate for the thymidylate synthase enzyme
5-FU MOA
-replaces the substrate uracil (in DNA synthesis of the cancer) and irreversibly inhibits the enzyme (thymidylate synthase)
-which decreases cellular availability of dTMP, decreases DNA snythesis, leads to cell death
5 Fluorouracil
cancers used for:
-treatment of breast cancer, GI cancer, skin cancer (topically)
5 Fluorouracil
Toxicities
->mucositis, myelosupression, stenosis of lacrimal system, alopecia, photosensitivity, diarrhea, stomatitis
5 Fluorouracil
recap
>class: antimetabolite
>cell phase affected: S-phase
>adverse events: Nausea, mucositis, diarrhea, bone marrow depression, neurotoxicity
>check on peripheral neuropathy & CBC
Pemetrexed
thymidlyate synthase inhibitors
>Used to treat: NSCLC (non-small cell lung cancer)
>Toxicities: myelosupression, MI, CVA, liver toxicity, bullous skin rash
>monitor: LFTs, CBC, heart studies like MUGA/ECHO
>affects S-phase of cell cycle
purine & pyrimidine analogues
MOA:
-incorporate into DNA & RNA, resulting in inhibition of DNA polymerase, thereby causing cell death
>affects S-phase
purine & pyrimidine analogs:
>Gemcitabine
>Used for: pancreatic cancer, NSCLC, breast, ovarian, bladder, sarcoma, HD (hodgkin disease)
>Toxicities: severe myelosupression, pulmonary toxicity, hepatotoxicity
>Monitor: CBC, LFTs, lung function tests
>Affects: S-phase
alkylating agents MOA
(subset of agents that modify structure, which is a subset of drugs that target mitosis/DNA synth
->directly modify DNA structure by covalently attaching to (an) alkyl group(s) at nucleophilic sites on DNA (ie- N7 in guanine)
->results in base ring cleavage
->abnormal base pairing
->base excision
->cross-linking of DNA, RNA and/or proteins, ultimately cell death
alkylating agents:
Cyclophosphamide
>used for: autoimmune disease, *leukemias*, *lymphomas*, ovarian & breast cancer
>Toxicities: myelosupression, cardiomyopathy, SJS, hemorrhagic cystitis, 2ndary cancers
>targets S-phase
>monitor hydration status
Alkylating agents:
general safety precaution for all
->are highly reactive, will alkylate target molecules w/in seconds to minutes
->ARE POWERFUL VESICANTS can severely damage skin ->need central line to administer
->alkylating agents such as cyclophosphamide are *mutagenic* so they cause DNA damage to normal cells so they give RISE TO 2NDARY CA more than any other class (2ndary AMLs can develop 5-7 years later)
Alkylating agents:
Mechlorethamine
->used for: Hodgkin's and non-Hodgkin's lymphoma
->toxicities: Nausea and vomiting,
Moderate depression of peripheral blood count;
->monitor CBC diff
->S-phase
Alkylating agents:
Dacarbazine
->used for: Hodgkin's lymphoma, melanoma, soft tissue sarcoma
->toxicities:N&V Myelosuppression, CNS toxicity with neuropathy, ataxia, lethargy, and confusion
->monitor: peripheral neuropathy, S&S of neuropathies
Platinum Compounds:
Cisplatin (Platinol)
-crosslinks intra-strand guanine bases
-used for: genitourinary cancer,
Toxicities: nephrotox, myelosupression, peripheral neuropathy, ototox. (carboplatin has replaced cisplatin because of its lesser nephrotox effects)
>Monitor: serum creatinine, BUN
>S-phase
agents that modify DNA structure
Bleomycin
MOA
>binds and chelates Fe(i), binds to DNA and leads to strand breaks via generation of oxidative intermediates
agents that modify DNA structure
Bleomycin
in general
>used for: Hodgkin's and non-Hodgkin's lymphoma, germ cell cancer, head and neck cancer
>Toxicities: Skin toxicity, pulmonary fibrosis, mucositis, alopecia
>S-phase
Topoisomerases
in general (how they work in the cell)
->are enzymes that help unwind DNA during replication of S-phase of cell cycle
->thereby facilitating access to genetic code as dictated by the base pairing sequences ATGC stored in the double stranded helix
Inhibitors of Topoisomerase:
-several chemotherapeutic agents damage DNA by *intercalcating* into DNA & interfering in the nuclease/ligase function of topoisomerases
ex: anthracyclines, epipodophyllotoxins
topoisomerase inhibitors:
-anthracycline
DOXORUBICIN (Adriamycin)
Red Devil
>used for: leukemia, lymphoma, breast cancer, bladder, lung, GI...
>Toxicities: heart failure, myelosupression, alopecia, N&V
>monitor MUGA, ECHO, EKG, CBC
>acts in S-phase
Anthracyclines: secondary neoplasms
-> anthracyclines are often associated with history of treatment with topoisomerase II inhibitors
Inhibitors of Microtubules:
MOA
1->agents that bind tubulin subunits & prevent polymerization of microtubules
2->agents that bind polymerized tubulin & inhibit microtubule depolymerization
--in either event, these agents interfere with mitosis
microtubule inhibitors:
Vincristine
->used for: Hodgkins & NHL (ABVD and CHOP)
->toxicities: peripheral neuropathy, myelosupression
>monitor for signs of neuropathy & CBC
-S-phase
microtubule inhibitors:
Vinblastine:
>used for: Hodgkin's and non-Hodgkin's lymphoma, germ cell cancer, breast cancer, Kaposi's sarcoma
>toxicities: N&V, Myelosuppression, mucositis, alopecia, SIADH, vascular events
>monitor CBC, blood pressure, PT/INR, weight changes
microtubule inhibitor:
paclitaxel
>used for: Breast cancer, non-small cell and small cell lung cancer, ovarian cancer, gastroesophageal cancer, prostate cancer, bladder cancer, head and neck cancer
>toxicities: arrhythmias, hypersensitivity, Myelosuppression, peripheral sensory neuropathy
->S-phase
Summarizing traditional chemotherapy
->consisted of agents directed against DNA replication & cell division - offering some degree of selectivity against cancer cells (cancer cells grow faster)
-->however therapeutic window is narrow (limited by toxicity to normal good cells)
Traditional Chemotherapy Drugs for this Test
-5-flurouracil
-vincristine
-vinblastine,
-paclitaxel
-doxorubicin
-bleomycin
-dacarbazine
-mechlorethamine
-pemetrexed
-gemcitabine
-cyclophosphamide
More Modern Chemotherapy Drugs for this Test:
-Trastuzumab
-Erlotinab
-Imatinib
-Sorafinib
-Bortezomib
-Bevacizumab
-Lenalidomide
-Rituximab
New School Chemo Drugs:
Classes & Agents of Targeted Therapy:
overview of broad classes
->growth factor receptors & signal transduction antagonists:
--inhibitors of all of the following: EGFR,Her2/BCR-ABL/C-KIT, & PDGF/RAS/MAP/mTOR
->Proteasome inhibitors
->angiogenesis inhibitors
->Tumor-specific monocloncal antibodies/recombinant proteins
What are Growth Factors and GFRs?
-> stimulation of cell growth & proliferation is mediate by the interaction of growth factors with specific growth factor receptors
->GFRs Contain:
-extracellular binding domain, hydrophobic trans-membrane domain, cytoplasmic tail that has either intrinsic tyrosine kinase activity OR associated protein tyrosine kinase
Growth Factors & GFRs more...
-binding of a growth factor ligand to the GFR results in receptor oligormerization, conformational change,s in the cytoplasmic domain, and TYROSINE KINASE ACTIVATION
>intracellular targets are subsequently phosphorylated, propagating intracellular signaling pathways that culminate in progression through the cell cycle & cellular proliferation
RAS-MAP kinase pathway is one intracellular signalling pathway:
more on this..
->RAS protein (oncogene product) can be activated by a receptor tyrosine kinase... or by non-receptor kinases (ABL,SRC also other oncogene products)
->triggering a series of phosphorylation events thru RAF,MEK,&MAP kinases
->signal extends into the nucleus
->where target proteins MYC, JUN,&FOS promote transcription of genes involved in cell-cycle progression
Receptor Tyrosine Kinases:
(what are they? facts)
-are normally expressed on epithelial cells
>BUT are often activated or overexpressed in a variety of carcinomas
(they are NOT unique to cancer cells: cancer cells just happen to have more on their surface)
Oncogenic mutations & RAS
-oncogenic mutations of RAS is one of the most common events in malignancy
->it occurs in ~30% of human cancers including:
--K-ras in colon/pancreatic
-->H-ras in kidney bladder, thyroid
-->N-ras-mutations in melanoma and liver cancer/blood cancer
EGF Receptor Antagonists:
Erlotinib (Tarceva)

note: EGFR = epidermal growth factor receptor
-used for: targeting the cytoplasmic tyr-kin domain of EGFR
-statistically significant survival benefit over genfitinib
->FDA approved for 2nd/3rd line tx of NSCLC
->Also active in other epithelial cell cancers, where EGR is over-expressed (colon, pancreas, head/neck cancers)
->Tox: rash & diarrhea, interstitial lung disease
EGF Receptor Antagonists:
Trastuzumab (Herceptin)
->chimeric mouse/human monoclonal antibody
->monocloncal antibody binds to Her2 (ErbB2)
->down regulates Her2 receptor, disrupts cell prolif. signaling downstream
->25-30% of breast cancers overexpress Her2/neu
->Toxicities: **cardiac (follow MUGA)**
Signal Transduction Antagonists:
-ABL Kinase Inhibitors:
Imatinib (Gleevec)
->small molecule/oral form
->potent inhibitor of ABL kinases, including BCR-ABL fusion protein generated as a result of the t(9:22) (philadelphia chromosome) found in CML
->True example of a targeted therapeutic agent b/c BCR-ABL is uniquely expressed by leukemic cells & is essential for their survival
->excellent hematologic, cytogenetic & molecular responses (BCR-ABL transcripts by PCR)
Toxicity: *superficial edema, nausea, muscle cramps, skin rash & diarrhea*
Signal Transduction Antagonists:
-ABL Kinase Inhibitors:
Imatinib (Gleevec) Resistance!!
->results from point mutations at or around the ATP binding pocket of the ABL kinase domain
->2nd gen. ABL kinase inhibitors:
(dasatinib,nilotinib)
Signal Transduction Antagonists:
RAS/MAP Kinase pathway
Sorafinib (Nexavar)
->inhibits serine/threonine kinase RAF (downstream from RAS), blocks phosphorylation of MAP kinase... blocks activation of transcription factors
->significant activity in tx of melanoma (which often has RAF mutations & are over expressd)
->also inhibits tyrosine kinase activity of VEGFR & PDGFR (sig act in treatment of *RenalCellC*)
Toxicities: CVD, VenousThrombolicEvents, ART
Proteasome Inhibitors:
MOA
-are drugs that block proteasomes
-Cellular complex involved in breakdown of proteins such as p53 (tumor supressor gene products - involved in apoptosis)
->retrieve tumor suppressor activity & apoptotic activity
Proteasome Inhibitors:
Bortezomib (Velcade)
->used to treat: multiple myeloma & mantle cell lymphoma
->Toxicities: THROMBOCYTOPNIA, heart failure, peripheral neuropathy
Angiogenesis in cancer
->solid tumors require development of 'new blood vessels' in order to sustain growth & avoid hypoxia
-> tumor angiogenesis is a complex process involving a number of angiogenic factors
-->VEGFR family of proteins/receptors have emerged as key regulators in this process
-->new strategies are emerging to block VGEF & VEGFR in order to disrupt the NEOvascularization process
Angiogenesis Inhibitors:
Bevacizumab (Avastatin)
->a recombinant humanized mouse anti-VEGF antibody
->used to treat: metastatic colerectal, metastatic breast, NSCLC
Toxicities: impaired wound healing, thromboembolism, nephrotic syndrome, HTN
Angiogenesis Inhibitors:
Lenalidomide
-> a 2nd gen. analogue of thalidomide - inhibits angiogenesis AND induces apoptosis
->both (thalidomide & lenalidomide) are used to treat:
MULTIPLE MYELOMA
->toxicities: peripheral neuropathy, thrombosis, is teratogenic
Tumor Specific monoclonal antibodies in general
-most hematologic malignancies express specific cell-surface markers that are used to sub-classify the malignancies by:
-immunohistochemistry/flow cytometry
->the development of chimeric monoclonal antibodies against several of these antigens has provided a great target for antibody therapy
Tumor Specific Monoclonal Antibodies:
Rituximab
-is and anti-CD20 antibody
->Used For: B cell NHL
->Toxicities: immunosupression & opportunistic infections, anaphylactoid rxn related to chimeric antibody
Recent Advances in supportive therapy of cancer treatment
->have increased maximum tolerated doses for many antineoplastic agents & supported use of combination regimens
ex:
-antiemetics, growth factors, tumor lysis prophylaxis, prophylactic broad spectrum antimicrobials
Why use combination drug regimens?
->strategy is to use agents that act on different molecular targets, at different phases of the cell cycle & with different dose-limiting toxicities in order to:
--target asynchronously dividing tumor cells
--reduce the emergence of drug resistance --allow for each drug to be given at its highest tolerable dose --take advtg of synergistic effects
--Therapy: maximizing w/out excessive toxicity
Examples of some combination:
-Hodgkin's Disease: ABVD (adriamycin, bleomycin,vincristine, dacarbazine)
-NHL (CHOP) cytoxan, adriamycin, vincristine, prednisone
-Testicular Cancer (BEP) bleomycin, etoposide, cis-platin
-Colorectal Cancer: FOLFOX (folinic acid/leucovorin, 5FU, oxoplatin)
5HT3 Serotonin Receptor Antagonists:
-Ondansetron (Zofran)
-5HT3 receptors are found in CNS in the 'chemo-trigger' zone - making it a potent antiemetic
->multipe routes of amdin
->premedication, scheduled/prn
-very expensive
-reserved for highly/moderately emetogenic agents
SE: HA & constipation
Growth Factor Injections;
Filigastrin (G-CSF/Neupogen)
-given daily,
->reduces risk for neutropenic fever in setting of chemo induced myelosupression
->$$
->bone pain
Risk factors for clots:
Hereditary
-Factor 5 leiden mutation
-hyperhomocysteinemia
-dysfibrinogenemia
-protein C or S deficiency
-prothrombin gene mutation
Risk factors for clots:
Acquired
-surgery,
-trauma
-pregnancy, oral contraceptives
-caner/cancer treatments
-inflammatory bowel disease-
-long airplane travel
-BMI>30
Unfractionated Heparin:
MOA:
-binds to anti-thrombin creating a conformational change in antithrombin that enhances activation of thrombin (IIa) and factor Xa
Unfractionated Heparin:
Clinical Uses
Prevention & treatment of DVT, & pulmonary embolism
->management of unstable angina, acute myocardial infarction, angioplasty & stent placement
Unfractionated Heparin:
(PK/PK)
>Bioavailability 85-99%
-IV immediate onset (not routinely used)
-SQ-4-5 hours
-T 1/2 - 4 hours
-Elimination - renal
-Ratio of factor Xa:IIa = product specific
Unfractionated Heparin
Adverse Effects
-Heparin-induced thrombocytopenia (HIT)
-HIT1- non-immune, no incr risk of thrombosis
-HIT2- immune-mediated, incr risk of thrombosis
-Bone-loss and osteoporosis
Unfractionated Heparin:
-Monitoring &CI/precautions
-aPTT (1.5-2.5x the mean)
-control 20-30 sec
-Hgb, Hct, Platelets
-CI: pts with documented allergy to heparin or HIT
Unfractionated Heparin
Clinical Pearls
-drug of choice for hospitalized pts
-SQ route not optimal for outpt DVT tx
-safe to use with pregnant women
-dosing is wt based
-aPTT is critical for eval of efficacy!! (except SQ!)
-considered a high alert med according to ISMP
-OD is reversable by PROTAMINE SULFATE
LMW (low molecular weight)
Heparin (Lovenox)
MOA:
->binds to anti-thrombin creating a conformational change in antithrombin w/ greater activity for factor Xa than thrombin (IIa)
LMW heparin/lovenox
Clinical Uses
-prevention & treatment of DVT & PE
-treatment of acute coronary syndromes
LMW Heparin/Lovenox
PK/PD
-Bioavailability 85-90%
-IV immediate onset (not routine)
-SQ- 4-5 hours
-T1/2 = 4 hours
-elimination - renal
-ratio of factor Xa:IIa = product specific
LMW Heparin/Lovenox
Adverse Events/Monitoring
AE: bleeding, heparin induced thrombocytopenia, osteoporosis

Monitoring: Scr (CrCL), Hgb, Hct, platelets,
**anti-Xa levels if available, but not necessary to monitor for efficacy**
LMW Heparin/Lovenox
CI/Precautions
-HIT
-Caution in renal dysfunction
LMW Heparin (lovenox)
-Clinical Pearls
-easy outpt dosing for DVT tx & bridge with vit. K antagonist
-expensive
-SQ route
-predictable anticoagulant response
--*no routine lab monitoring required to assess efficacy--*
-do not use in pts with pORK allergies
-use extreme caution in pts with renal dysfunction.
-HIGH alert medication (for bleed)
Factor Xa inhibitors
Fondaparinux (Arixtra)
MOA
-binds to AT (antithrombin) to cause conformational change so that Factor Xa can be inhibited
Factor Xa inhibitors
Fondaparinux (Arixtra)
Clinical Uses
-Prophylaxis of DVT in pts undergoing surgery (such as....)
--hip surgery, knee replacement, hip fracture/extended prophylaxis following hip fracture surgery)
--abdom surg, (in pts at risk)
--tx of acute PE
--tx of acute DVT w/out PE
Factor Xa inhibitors
Fondaparinux (Arixtra)
PK/PD & AE
-bioavail = 100%
-T1/2= 17-21 hours
-elmination = renal
-protein binding - 94% to antithrombin II
AE: bleeding, spinal/epidural hematoma, thrombocytopenia
Factor Xa inhibitors
Fondaparinux: (Arixtra)
monitoring parameters
Hgb, Hct
-Platelets, Scr, CrCL
-hepatic function (when PO)
-anti-factor Xa when necessary
Factor Xa inhibitors
Fondaparinux: (Arixtra)
CI/precautions
-weight <50kg or >100 kg
(requires change in dose)
-CrCL <50 ml/min will require dose adjust
-different dosing recs for rivaroxban
-avoid in severe hepatic failure
Factor Xa inhibitors:
Fondaparinux
Drug interactions
-other anticoagulants
-aspirin products (antiplatelets)
-antithrombotics
-herbs with anticoagulant properties (Alfalfa, anise berry, St John's Wort)
Factor Xa inhibitors:
Fondaparinux
other facts
-fixed once a day due to good bioavailability
-SQ route
-pregnancy category B
-there is NO REVERSAL agent
-no monitoring for efficacy, will need to administer factor VII
Direct Thrombin Inhibitors:

MOA/Clinical uses
MOA: -directly inhibits thrombin without antithrombin

Clinical Uses: prophylax & tx of VE
-percutaneous coronary intervention
-unstable angina undergoing PTCA or PCI in non-HIT pts
-prevention of stroke & systemic embolism in pts with nonvalvular a-FIB (dabigatran)
Direct Thrombin Inhibitors:
Lepirudin (Refludan)
basics:PK/PD
-recominant analog of hirudin/ irreversibly binds to thrombin
-admin by continuous IV infusion (pt may develop antibodies to lepiruden as duration of tx incr)
-renal elimination, half-life-90min.
Direct Thrombin Inhibitors:
Argatroban (Acova)
overview
PK/PD
-synthetic molecule made from arginine that binds to thrombin at the catalytic site
->reversible inhibitor of thrombin
-PK/PD: metab in liver to inactive metabolite, half-life 30-50 min.
Direct Thrombin Inhibitors:
Argatroban (acova)
Drug Interactions
-other anticoagulants
-aspirin products/antiplatelets
-antithrombotics
-herbs with anticoagulant properties (alfalfa, anise berry)
Direct Thrombin Inhibitors:
Dabigatran (paradaxa)
MOA & overview
-1st PO DTI: is irreversible
-indicated for: non-valvular A-fib
-MOA: prodrug lacking anticoag activity
-specific, reversible, direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin
Direct Thrombin Inhibitors:
Dabigatran (paradaxa)
PK/PD
-metabolism: hepatic
-half-life elimination 12-17 hours
-elderly 14-17 hours, mild to moderate renal impairament 15-18 hours
-time to peak, plasma: 1 hour, delayed 2 hours by food (no effect on bioavail)
Direct Thrombin Inhibitors:
Dabigatran (paradaxa)
AE/ Monitoring
AE: bleeding, fever, N&V allergic reactions
Monitoring: ACT (activated clotting time), aPTT, PT/INR, Hgb, HCT, platelets, Scr*/CrCL*, LFTs* (organ check)
Direct Thrombin Inhibitors:
overall considerations precautions
&
Clinical Pearls
-liprudin renally eliminated
-dabigatrin hepatic metab
Clinical Pearls:
-only one avail PO is dabigatran
-lepirudin use cautiously in RF
-argatroban are metab by liver
-THERE IS NO ANTIDOTE FOR DTIs.
Direct Thrombin Inhibitors:
Drug Interactions
-other anticoagulants, aspirin products/antiplatelets
-antithrombotics, herbs with anticoagulant properties (Alfalfa, anise berry)
[-amiodarone, antacids, atorvastatin, quinidine] -> CYP450
warfarin (coumadin)
MOA:
Clinical Use:
MOA: inhibits vit K depedent clotting factors (SNOT) factors 'seven', nine, 10, and two
Clinical Use:
prevention & tx of VTE, prevention of thromboembolic events related to A-fib & heart valve replacement
warfarin (coumadin)
PK/PD
PK/PD: is a racemic mixture (R&S isomers). onset of 90 min. bioavail 90% p.o. highly protein bound.
-half-life 36-42 hours
warfarin (coumadin)
AE &CI & monitoring
AE: bleeding, purple toe syndrome, skin necrosis
CI: pregnancy category X
-Monitoring:
PT/INR (goal is 2-3 or 2.5-3.5)
warfarin (coumadin)
interactions
drug-food
vitamin K rich foods
-turnip greens, cabbage, broccoli, kale, spinach, brussel sprouts, salad, liver
warfarin (coumadin)
interactions
Drug Drug
Increase INR: amiodarone, fluconazole, metronidazole, rosuvastatin, SMX/TMP, fluoroquinolones, macrolides & alcohol binge

Decrease INR: phenytoin, rifampin, phenobarbital, vitamin K, nafcillin, carbamazepine
warfarin (coumadin)
interactions
Drug-herbal
Increase INR: ginko,ginseng, garlic

Decrease INR: co-q-10, St John's Wort, green tea
warfarin (coumadin)
interactions
Drug-disease state
Thyroid:
--Hypo: decrease INR
--Hyper: increase INR

-Cirrhosis/Liver fail: increase INR
-CHF: increase INR
warfarin( coumadin)
other interactions
things that increase INR not already mentioned
-increase INR:
-diarrhea, elevated temperature, vitamin K deficiency, cranberry juice
warfarin (coumadin)
other interactions
things that Decrease INR that aren't already mentioned
-decrease INR
-exercise
-hereditary coumarin resistance
-nephrotic syndrome
Warfarin (coumadin)
Clinical pearls
-only oral vitamin K antagonist
-category X drug
-5-7 days to reach steady state (due to SNOT)
-dose low & go slow DO NOT LOAD.
-monitor for drug drug, drug-disease state, drug-food interactions
-antidote is vitamin K
-pharmacogenomics - every pt is unique
-patient education is important!!
warfarin (coumadin)
patient education
-take dose at same time daily & in the evening
-avoid missing doses or taking extra doses
-eat a low & consistent amount of vitamin K rich foods weekly
-avoid interacting meds/OTC/herbals
-seek medical attention if bleeding episodes
-always keep follow up appointments with healthcare providers for PT/INR monitoring
even if stable.
Comparison:
Warfarin
Target: vitamin K epoxide reductase
Prodrug: no
Bioavailability: >95%
T(max): 72-96 hours
t1/2: 40 hours
Admin: daily
Metab/elim: CYP 2C9, 3A4,1A2
Drug inrxns: CYP 2C9, 1A2,3A4
Monitoring: PT/INR
Antidote: vitamin K
Comparison:
Dabigatran
Target: Thrombin
Prodrug: yes
Bioavailability: 3-7%
T(max) 2 hours
t1/2: 12-17 hours
Admin: twice daily
Metab/Elim: 80% renal, 20% fecal
Drug interactions: P-gp inhibitors/inducers
Monitoring: none
Antidote: none