Pharm Final Flashcards
Adjuvant
tx when there is no measurable dz to suppress secondary tumor formation. Generally a treatment after surgical resection
Neoadjuvant
treatment to shrink or pre-treat tumor prior to sx
different goals for cancer tx
Cure, Remission, Palliation (reduce pain, improve fx),
Multi drug chemo protocols
standard for curative intent, or intense tx
Ideally drug combos have complimentary activity and don’t have overlapping toxicity
MTD (max tolerated dose)
dose that allows for the highest exposure (aka max pharm response/efficiacy) w/ acceptable toxicity
DLT (dose limiting toxicity)
MTD is determined by highest dose level at which no more than 1/6 patients develop a DLT
CR (complete remission) measurement response
complete disappearance of tumor and symptoms of dz
PR (partial remission) measurement response
decreased volume by > or = 50% or max diam > or = to 30%
SD (stable disease) measurement response
no increase of decrease (or increased <20% in diam)
PD (progressive dz) measurement response
increase volume >25%, increase diam >20% new lesions
Methods of resistance to chemo drugs
- decrease drug uptake
- decrease biotransformation/activation
- increase inactivation
- Multidrug resistance: ABCB-1 gene & p glycoprotein transporter
Glucocorticoids MOA
alter gene transcription
direct lytic effect on malignant cells in lymphoid malignancies, leukemia, myeloma
Antimetabolites MOA
block purine/pyrimidine biosynth (so no DNA made)
Methotrexate
folate analog
rarely used in vet med b/c enterohepatic recycling + GI accum = toxicity before therapeutic effect
5-Fluorouracil
treat epithelial tumors
Contraindicated in cats - deficient in DPD to metabolize this drug –> drug accum = toxicity
Cytosine Arabinoside, Ara-C, Cytarabine
Used for dz w/ CNS involvement because can cross BBB
Alkylating agents MOA
Interfere w/ replication
Cross link DNA by covalently binding macromolecs - no longer separatable for replication
or cause non-repairable DNA lesion
Common side effects from alkylating agents
BAG: bone marrow suppression, alopecia, GI
Cyclophosphamide
- must be metabolized in the liver to be active (drug alone won’t kill tumors) - PRO drug
- Causes SHC (sterile hemorrhagic cystitis), neutropenia, thrombocytopenia, GI side effects in cats
Chlorambucil
- use if Cyclophosphamide causes SHC or for certain chronic tumors
- delayed onset, may cause cerebellar toxicity
Chemo drugs able to cross BBB
Cytidine analogs
CCNU
Decrease occurrence of SHC
Caused by acrolein metabolite - damage bladder tissue
Mesna - neutralizes acrolein in bladder
Furosemide - diuretic dilutes & increases acrolein clearance
Also, switch to Chlorambucil
Anti-tubulin agents MOA
Interfere w/ spindle fiber formation, thus chrom separation during mitosis
stop replicating cells in M phase –> then they die
Vinca Alkaloids
inhibit microtubule assembly
- Vinchristine = peripheral neuropathy but minimal myelosuppression, for lymphoma
- Vinblastine - BAG, less neurotoxicity, for mast cell tumors
Anti-tumor antibiotics MOA
form complexes w/ DNA, inhibit DNA/RNA synth
BAG side effects
Single most broadly used chemotherapeutic active agent used in veterinary oncology
Doxorubicin. very efficaious!!
Doxorubicin MOA
inhibits RNA, DNA polymerase, topoisomaerase II
Doxorubicin toxicity
- GI, hematopoietic and cardiac toxicity
- Cardiac in dogs, renal in cats
- Cardiac related to total lifetime dose, but can also get acute toxicity, messes w/ heart through multiple mechs
- Vesicant - bad local tissue damage if leaves vessels
Mitoxantrone
synthetic doxorubicin
similar MOA but forms less ROS’s
used in dogs w/ cardiac issues or that have reached lifetime doxo limit
L-Asparaginase MOA
depletes asparaginase in blood –> inhibits protein synth in tumor cells
L-Asparaginase
- Exclusively used for lymphoproliferative disorders often in relapse settings (e.g. lymphoma)
- blocks methotrexate efficacy & toxicity
- long half life
- can get anaphylaxis, pancreatitis, DIC
Cisplatin
contraindicated in cats - fatal fulminant pulmonary edema
renal toxicity, BAGS, neurotox, ototox,
Carboplatin
BAGs, neurotox, rare nephrotoxicity
Dose based on renal fx (GFR) not weight
Molecular target agent vs. Cytotoxic agents
MTA’s block signaling pathways for tumor cell proliferation, survival
Mostly targeted toward kinase reactions (used in cell signaling ubiquitously)
Pro - only target tumors, not local tissue (vs. cytotoxic target any dividing cells)
Toceranib
TKI
Inhibits c-Kit - expressed by mast cell tumors to block formation in dogs
- resistance to drug happens quickly
- GI toxicity, neutropenia
Chemo agents that cross-link DNA
Platinum agents
alkylating agents
only 2 vet-approved chemo drugs
Palladia & Tanovea
Drugs to not give to cats
5-fluoricil
cisplat
4 ways antimicrobial drugs are classified
- class of microorganism they show activity against
- antibacterial spectrum of activity
- bacteriostatic or cidal
- time of conc dependent activity
broad spec means it potentially works against:
bacteria (G+,G-, aerobic, anaerobic), mycoplasma (no cell wall), rickettsia & chlamydia (intracellular), protozoa (euk)
What antibacterials are always static at all concentrations?
Tetracyclines
Sulfonamides
Concentration dependent drugs
higher the conc of a drug above MIC = faster rate of killing (steady state not important)
peak of Cmax (max serum conc achieved)
To optimize: give higher doses less frequently
aminoglycosides, metronidazole
Concentration and time dependent drugs
AUC (unbound drug at steady state)
fluoroquinolones
Time dependent drugs
the longer a drug maintains serums conc’s exceeding MIC, the more efficacious (higher doses don’t improve this)
T>MIC
To optimize: give lower doses more frequently
beta lactams, some macrolides, tetracyclines, TMS, chloramphenicol
MIC (minimum inhibitory conc)
lowest concentration of a drug required to inhibit visible growth of bacteria
Breakpoint MIC
value where plasma conc unlikely to be achieved, no clinical benefit against bacteria w/ MIC above that breakpoint
4 indications for use of antimicrobial combos
- antimicrobial synergism
- polymicrobial infections
- decrease chance of resistant isolates emerging
- decrease dose-related toxicity
Fluoroquinolone & Quinolone PK’s
- good oral bioavailability in monogastrics
- large vol of distribution, even to CNS, eye
- accum in macrophages, neuts, urine
- extended half-life, dose every 1-2 days
Enrofloxacin
can often metabolize into cirprofloxacin (lower MIC than enro)
Quinolone characteristics
- Extended spec (limited against strep, obligate anaerobes)
- Good against G-‘s, variable against G+
- anaerobes mostly resistant
- efficacy is concentration dependent
Quinolone MOA
Inhibit bacterial DNA gyrase and/or topoisomerase IV to inhibit DNA replication
Fluoroquinolone characteristics
- active against bacteria, mycoplasma, rickettsia, chlamydia
- antibacterial against G+/- aerobes
Bacteriostatic at MIC, bacteriacidal at higher doses - Concentration dependent activity
Fluoroquinolone contraindications
- Don’t give cats enrofloxacin at higher doses = retinal degeneration, photoreactivity
- Younger animals in rapid growth phases
- Enrofloxacin has some reported neurotoxic effects (hum, dog, cat)
- Antagonism if Cipro combined w/ chloramphenicol and rifampin
How are bacteria resistant to fluoroquinolones
- DNA gyrase mutation and/or topoisomerase IV mutation
(exception - Campy highly resistant w/ just gyrase mutation) - decreased permeability (porins altered)
- drug efflux
- target protection (plasmids)
Beta lactam MOA
Bacteriacidal for growing cells only
prevent cell wall formation, cause lysis
Time dependent
beta lactam “eagle” paradoxical effect
given in concentrations above optimal killing zone = reduced bactericidal effect
- bad b/c BL’s have large margin of safety, tend to be overdosed
beta lactam characteristics
Active against G+, variable G-‘s
Bacteriacidal, can be static if conc too high
Time dependent activity
Mech’s of resistance to BL’s
make beta lactamase enz’s that break beta lactam ring
G+ make them extracellularly
G- make them in periplasmic space so more resistant to penicillins vs cephalosporins
Penicllins
poorly absorbed orally, short half life, eliminated rapidly (renal)
Procaine has delayed absorption, exotics susceptible to toxicity
Antistaphylococcal resistant to lactamases from S. aureus
MRSA, MRSP resistant to all BL’s
Antipseudomonals against Pseudomonas
Extended spectrum aminopenicillins
Amp & amoxicillin
More activity against G-‘s, with slightly less G+
Amoxicillin more bioavailable than ampicllin
Combine w/ beta-lactamase inhibitors = increased efficiacy
Give oral to avoid GI issues
Do not use Ampicillin in small rodents or rabbits (clostridial enteritis)
What is Amoxicllin best choice to use for
best penicllin to treat UTI’s
drug of choice to treat Lepto
Cephalosporins
Reistant to beta-lactamases
parenteral, short half life = freq doses, excreted in urine
with generation # increasing, see more G- coverage, less G+
Gen 3 & 4 = can induce very resistant super beta lactamses, last resort for uncomplicated infections
Ceftiofur
resp dz in cattle, sheep, pig, horse
UTI in dogs
Carbapenems
widest spectrum of activity, resistant to BLases
last resort drugs - usually for resistant nosocomial infections
pair w/ aminoglycoside for pseudomonas (decrease resistance)
Clavulonic Acid
Beta lactamase inhibitor
used in combo with beta-lactames to inhibit beta-lactamase hydrolysis –> increases BL efficiacy
Protein Synthesis inhibitors MOA
Bind to a ribosomal subunit to inhibit polypeptide chain formation –> block protein synth
Tetracycline characteristics
- against G+, G-‘s, mycoplasma, some mycobacteria, anaplasma, rickettsia, protoza, filarial parasites
- bind to 16s RNA of 30s subunit
- antiinflammatory activity
- mostly bacteriostatic
- osteotropic
Resistance mechs against tetracyclines
efflux out drug
ribosomal protection proteins remove tetracycline from tRNA binding site
Contraindications of tetracyclines
- irritants - see vomiting, local tissue damage at injection site
- GI flora imbalance –> enterocolitis
- Doxy tablets = esophageal stricture in cats
- acute heart toxicity, renal toxicosis, yellow teeth
Uses for tetracyclines
bov/porcine resp dz complexes
plague, tulaermia, listeriosis
Top choice for rickettsia (SA), Chlamidophila felis in cats
Chloramphenicol characteristics
- broad spec against G+, G- aer and anerobes, mod against R. equi, G- eneterics develop resistance
- bind 50s, inhibit mitochondrial prot synth in mammal bone marrow cells
- bacteriostatic
- hepatic metabolism - glucuronidation, eliminated in urine or bile
Mech of resistance to chloramphenicol
enzymatic inactivation by acetylation of the drug (by CATs)
or efflux drug
Chloramphenicol toxicity
Inhibits cytochrome P450 enzymes
bone marrow suppression (dose dependent)
Banned from food animals
limit use to ~10 days
Chloramphenicol uses
SA anerobic infections, MRSP
extreme ocular infections, prostatitis, otitis, salmonellosis
Aminoglycoside characteristics
- G-aerobes, enteroccoci, some G+ (often MRSP)
- Combine w/ BL to increase efficacy against strep
- bind to 30 s subunit
- bactericidal, conc dependent
- drugs not effective against anerobic infections
(bact actively pump AG’s into cell by oxygen-dependent mech)
Resistance to aminoglycosides
plasmi-mediated enz prevent binding to ribosome
adaptive resistance lasting ~24 hrs if surive first exposure - reduced uptake (High, SId dose is WAY more effective than freq dose or CRI)
aminoglycoside toxicity
ototoxicity
nephrotoxicity - acute tubular nephrosis from drug accum
How to reduce aminoglycoside nephrotoxicity
Ca supplement
high prot/Ca diet
give drug SID and higher dose
aminoglycoside uses
more toxic - topical or oral use against enterobacteriaceae
less toxic drugs - parentally for G- aerobe sepsis, MRSP infec
Ondansetron/Zofram
5HT3 receptor antagonist (aka anti-emetic)
caution for patients w/ hepatic dysfunction
side effects: constipation, sedation, head shake, arrythmias
Maropitant/Cerenia
NK1 receptor antagonist (anti-emetic) - dog & cat by blocking substance P from binding
motion sickness in dogs
lower dose w/ hepatic dysfunc
stings
Apomorphine
D2 agonist used as a canine emetic
Cats don’t have D2 in chemoreceptor trigger zone, not useful
What is a more efficacious acid suppressant - Famotidine or Omprazole
Omeprazole (proton pump inhibitor) - more efficacious
Famotidine (H2 receptor antagonist)
Don’ts when stimulating a cat’s appetite
No oral diazepam (–> fulminant hepatic failure)
Cyproheptadine + Mirtazapine together (–> serotonin synd)
A Ghrelin agonist will ____ appetite
increase
Immodium
binds to mu opioid receptors –> decreased GI activity –> constipation
(–> megacolon in cats BAD)
Drug of choice to move a cats colon
Cisapride (5-HT4 serotonineric and ACh agonist)
metaclopramide only stims SI, not colon
Erythromycin
pro-motility drug, antibiotic
mimics motilin activity - increases upper gI activity like metaclop
Acts on ACh, 5-HT4 receptors
Options to treat IBD
novel protein, hydrolyzed diet
antibiotics: metronidazole, Tylosin, Budesonide (if intolerant of steroids), Prednisolone!!
Cyclosporine (inhibits cytokines, cell-mediated immunity by targeting T cells)
Probiotics, fecal microbiota transplantation
Endectocides are effective against
nematodes, arthropods
Benzimidazoles are effective against
nematodes, some cestodes, protozoans
Macrycylic Lactones
- broad spec
- safe in mammals (can’t cross BBB) except ivermectin
- paralytics
Avermectins
lipophilic (fatter animal = longer presence/protection
longer withdrawal in rum - not for milk producers
fasting - better efficacy
Fecal residue issue
fecal residues
arthropods, annelids don’t want to live there
more toxic to immature (feed directly on organic matter)
poop lasts longer on pasture
Benzimidazoles
some teratogenic - don’t give during 1st trimester
nematodes
alter metabolic processes - block mitochondrial fx, glu uptake
poorly absorbed, short withdrawal (no residue issues)
Tetrahydropyrimidines
nematodes
orally
paralytic
Pryantel tartate vs. pamoate & morantel
tartate: water sol, well absorbed orally, EQ
pamoate: water insol, poor absorbed to act in LI, dog/cat/EQ
morantel: withdrawal time, rum
What anthelminitics cause resistance
Macrocyclic lactones
Benzimidazoles
Tetrahydropyrimidines
d/t repeated anthelminitic use eliminated susceptible worms
Who specifically is resistant
Strongyles, Ancylostoma against Benzimidazoles via tubulin resistance & tetrahydropyrimidines
Strongyles, Ascarids, Dirofilaria, Ancylostoma against ML’s
Emodepside
new compound class new MOA - paralytic mech Cats - Ancylostoma trubaforme, Toxavara cati (topical + prazi)
Piperazone
very good against ascarids
paralytic
non-toxic to host, gone in 24 hrs
Arsenicals
alternative to monthly preventatives - not idea b/c arsenic
limited against Dirofilaria
Isoquinolones
very safe
cestodes, trematodes
MOA - some kind of paralytic
Prazi
Praziquantel
Taenia, Dupylidium in dogs, cats (but resistance likely)
echinococcus in dogs
anoplocephala in EQ
Benzene sulfonamide
Fasciola hepatica (trematod)
inhibits glycolytic pathway
best at 10-12 wks post infection (b/c flukes in bile duct)
liver damage - slaughter issue (also withdrawal)
Sulfonamides & Macrolides
bacteriostatic broad spec antimicrobials (systemic dz)
inhibit bacteria, protozoa
rarely used along - extensive resistance has developed
Sulfonamide MOA
outcompetes PAbA to inhibit DHP’s from forming pteroic acid –> no folic acid synth for purine biosynth
Who is resistant to Sulfonamides & Macrolides
Mycobacterium, mycoplasma, pseudomonas
via changes to PABA or DHP
Sulfonamides and urine
water insoluble –> form crystals in acidic environ –> lots of UT side effects
metabolized form less soluble but dogs deficieny in this pathway
Sulfonamide side effects
UT probs hematopoetic disorders derm reactions - toxic epidermal necrolysis KSC Idiosyncratic drug reactions
Potentiated sufonamides
sulfonamide +Trimethoprin (1:5 ratio)
bactericidal synergistic combo
Macrolide MOA
bind to 50s ribisome –> no protein synth
bacteriostatic, can be cidal at high conc
anti-biofilm
immunomodulatory effects (decrease inflamm rxn)
pro-GI kinetics (motilin receptor agonist)
mechs of resistance to Macrolides
rRNA methylation (can’t bind to ribosome)
drug efflux
enz inactivation
macrolide adverse effects
irritants w/ injection
dose related GI disturbances
Tilmicosin - cardiovascular toxicity (not bov, pig)
Drug of choice for campy diarrhea or abortion
erythromycin
alternate for penicllin sensitivity, treating lepto, rickettsia
Lincosamides
inhibit prot synth
contraindivated in EQ, rabbits, hamsters, GP’s –> necrotizing enterocoloitis from clostridum overgrowth
Salmonellosis in dogs
allyamines
block ergosterol formation
fungicidal
synergystic when combined w/ flu, itra, vori
Amphotericin B
given IV - systemic treatments fungicidal - binds and lyses ergosterol lipid form = less kidney issues synergistic w/ flucytosine most toxic antifungal
Antifungal azoles
bacteristatic - yeast, mycoses, dermatophytes
Flu and vori penetrate CNS
Flu excreted in urine as active drug (rest as bile)
Do not give any for systemic use during pregnancy
Ketokonazole
better for dogs
may see repro, hepatic, haircoat issues
hepatotoxicity in cats
Itraconazole
better for cays
dogs get hepatic toxicosis
contraindicated for heart failure
Griseofulvin
taken orally for dermatophytosis
b/c distributes to keratin precursor cells
successful antiviral drug moa’s
nucleoside analogues, protease inhibitors
target certain enz of structural target
antivirals
Idoxuridine - herpesvirus keratitis or skin infec
Acyclovir - herpesvirus family
Ribavirin - small window or toxic
neuramidase inhibitors
cleave sialic acid residues - viral particles can’t release
influenza A & B
Lysine
nutritional supp
reduces severity/freq of FHV-1 b/c interferes with arginine absorption
CB1 receptors
glutamatergic, ganaergic g prot receptors mostly in CNS activated = decreased NT mostly responsible for cannabis high relax eat sleep forget
CB2 receptors
g prot receptors in periphery
activated = decrease cAMP
therapeutic effects of CBD
pain, inflammation modulation
potential CBD uses
anti emetic diabetes mellitus cancer antimicrobial pain, inflammation, immunomodulatory epilepsy anxiolytic
cannabis toxicity in dogs
high dose, enters CNS b/c lipid soluble effect in 1 hr, lasts 1-3 days, gone in a week cB1 receptors dominate toxicity Ataxia, depression, mydriasis treat w/ supportive care
cannabis vet products
all unregulated
dose/bioavailaiblity is variable
no data on dosing
might have regulatory restrictions to comply w/
