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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 |
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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 |
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"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. |
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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:
|
->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 |