Pharmacology Flashcards
MOA of Sanguinarine (blood root plant)
Sanguinarine interacts with DNA via intercalation, and its binding impairs DNA polymerase, inducing DNA strand breaks and cell death.
MOA of Imiquimod?
Imiquimod stimulates the innate immune system by activating toll-like receptor 7 (TLR7), commonly involved in pathogen recognition.[ Cells activated by imiquimod via TLR-7 secrete cytokines (primarily interferon-α (IFN-α), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)). There is evidence that imiquimod, when applied to skin, can lead to the activation of Langerhans cells, which subsequently migrate to local lymph nodes to activate the adaptive immune system. Other cell types activated by imiquimod include natural killer cells, macrophages and B-lymphocytes.
Imiquimod exerts its effect by increasing levels of the opioid growth factor receptor (OGFr).
Azathioprine is a synthetic modification of ______?
6-mercaptopurine
What is the MOA of azathioprine?
Antagonizes purine metabolism, thereby interfering with DNA and RNA synthesis. thiopurine analog converted to active 6-mercatopurine which inhibits DNA and RNA synthesis inhibits B and T cell proliferation
Which IL is markedly suppressed by azathioprine?
IL-2
What is chlorambucil? MOA?
AKA Leukeran
alkylating agent derived from nitrogen mustard
cytotoxic effect d/t crosslinking of DNA
Alopecia and delayed hair growth have been reported in dogs with Chlorambucil. Which breeds are at greater risk?
Poodles
Kerry blue terriers
What is colchicine?
Alkaloid; suppresses neutrophil chemotactic and phagocytic functions via disruption of microtubule assembly and elongation = tubulin disruption.
Increasing cAMP inhibiting lysosomal degranulaion
Also inhibits Ig secretion, IL-1 production, and Histamine secretion
Which phase of cell division is affected by colchicine?
Metaphase - by interfering with sol-gel formation and the mitotic spindle
What is cyclophosphamide? MOA?
AKA Cytoxan
Nitrogen mustard alklylating agent
Inhibits mitosis by interfering with DNA replication and RNA transcription and replication.
Lymphocytes especially affected
Cyclophosphamide is especially toxic to lymphocytes. Are T or B cells more affected?
B cells.
Suppresses antibody production
Which drug may decrease hemorrhagic cystitis that can be seen with cyclophosphamide?
Concurrent furosemide therapy
What are major toxic SE of cyclophosphamide?
Sterile hemorrhagic cystitis Bladder fibrosis teratogenesesis/infertility alopecia/poor hair growth, nausea, GI tract, BM, infection Cats may lose whisker
mycophenolate mofetil
immunosuppressant; general cell growth inhibitor used to decrease lymphocyte proliferation (prevents purine synthesis by inhibiting inosine monophosphate dehydrogenase) uses: autoimmune diseases; organ transplant adverse effects: myelosuppression, nausea, vomiting
List some known anti-inflammatory and immunomodulatory properties of tetracyclines:
Sup. of in vitro lymphocyte blastogenic transformation and Ab production
Inhib. of MMPs
downregulation of cytokines
Sup of in vivo leukocyte chemotactic responses
Inhib. of complement component 3
Inhib. lipases and collagenases
Inhib. prostaglandin synt.
What are some immunomodulatory properties of Niacinamide?
Block Ag IgE-induced histamine release
Prevent degranulation of mast cells
Photoprotectant from inducing immunologic damage
Cytoprotectant that blocks inflammatory cell activation and apoptosis
Inhib. phosphodiesterases
Decrease protease release
What is the proposed mechanisms of IVIG therapy?
Presumably via Fas (CD95) blockade
_______ is the use of gold as a therapeutic agent.
Chrysotherapy
________ is a methylxanthine derivative that produces a variety of physiologic changes at the cellular level.
Pentoxyfylline
Name 7 immunomodulatory and rheologic effects of pentoxifylline:
increased leukocyte deformability and chemotaxis
decreased platelet aggregation
decreased leukocyte responsiveness to IL-1 and TNF-a
Decreased production of TNF-a from macrophages
decreased production of IL-1, IL-4, and IL-12
Inhibition of T and B lymphocyte activation
Decreased NK cell activity
What drugs can cause urticara-angioedema in horses?
penicillin, tetracyclines, phenylbutazone, ciprofloxacin, streptomycin, sulfonamides, neomycin, aspirin, contacts, hormones, vaccines, antisera, guaifenisen, vit B complex and liver extract, flunixin, iron dextrans, acepromazine
Which class of drugs is most commonly associated with EM and exfoliative dermatitis?
Sulfonamides
Name 5 drugs associated with vasculitis in horses
Phenylbutazone Penicillin Acepromazine TMS Tiludronate
Proposed MOA of FAs?
Competition of essential fatty acids with arachidonic acid for cyclooxygenase and lipoxygenase enzymes, resulting in a modification of LT synthesis and reduction of highly proinflammatory products.
What is ophytrium?
It is a Ophiopogon japonicus (Japanese mondo grass) derived product. There is some evidence that it blocks inflammatory pathways, maintains epidermal morphology and barrier function, and reduces staphylococcal adherence and biofilm formation in human and canine epidermis models.
It has been incorporated in shampoos and foams for dogs (Douxo S3 ® ; Ceva Sante Animale, Libourne, France)
What is PEA?
Palmitoylethanolamide (PEA) is a naturally occurring lipid compound with antiallergic and anti-inflammatory effects.
It is a parent molecule of aliamides and a congener of the endocannabinoid anadmide, with which is shares, metabolic pathways and molecular targets.
The anti-inflammatory effects of PEA are known to be mediated through several receptors including the peroxisome proliferator-activated receptor (PPAR) and cannabinoid type 1 and type 2 receptors (CB1, CB2).
Which systemic treatment for dermatophytosis has the highest MIC compared other common treatments?
Fluconazole has poor antifungal efficacy against dermatophytes; it has the highest MIC comapared to itraconazole, terbinafine, ketoconazole and
griseofulvin for both Microsporum spp. and Trichophytonspp.
Which systemic treatment for dermatophytosis has the lowest MIC compared to other common treatments?
Compared to itraconazole, fluconazole, ketoconazole and griseofulvin, terbinafine has the lowest MIC for Microsporum sp. and Trichophyton spp.
MOA fluconazole
Triazole (synthetic), blocks ergosterol synthesis resulting in increased permability of fungal membrane and inhibits fungal growth. Less side effects than ketoconazole but can cause GI and hepatotoxicity
MOA terbinafine
Terbinafine is a synthetic allylamine which was developed by chemical modification of naftitine.
It reversibly inhibits the membrane-bound enzyme squalene epoxidase in a concentration-dependent manner which prevents conversion of lanosterol to cholesterol and/or ergosterol.
Its mode of action does not affect mammalian cytochrome P450.
MOA Ketoconazole
It works by inhibition of lanosterol 14a demethylase leading to ergosterol depletion and accumulation of aberrant and potentially toxic sterols in the cell membrane. Mammalian cells can use exogenous cholesterol from the diet and can compensate for the temporary effects of ketoconazole on cholesterol. The drug is highly lipophilic and this leads to high concentrations in fatty tissues. Its absorption may be enhanced by administration with a small amount of food. The drug is dissolved by gastric acidity and any other drugs that decrease gastric secretions will decrease bioavailabilty. Ketoconazole has been shown to interfere with endogenous steroid synthesis, which is reversible.
MOA Griseofulvin
Griseofulvin inhibits nucleic acid synthesis and cell mitosis by arresting division in metaphase. The drug also interferes with the function of spindle microtubules. It causes morphological changes in fungal cells and may antagonize chitin synthesis in the fungal cell wall.
MOA Lufenuron
Lufenuron is a benzoylphenylurea drug that disrupts chitin synthesis. Chitin is a critical component of the exoskeleton of arthropods, and is also an important component of the outer cell wall of fungi. Interest in lufenuron as a possible antifungal treatment was triggered by a retrospective computer review of medical records which found that animals receiving lufenuron as a flea preventativewere not treated for dermatophytosis
MOA itraconazole
Itraconazole is a first generation triazole. At low doses it is fungistatic and at high doses it is fungicidal. Itraconazole works by inhibiting fungal cytochrome P450 enzyme 14a demethylase to prevent the conversion of lanosterol to ergosterol. Ergosterol is best suited for maintaining cell wall integrity and activity. Itraconazole is insoluble and requires specific formulations to be absorbed in the gastrointestinal tract because it is highly lipophilic and a weak basic compound. The bioavailability is pH dependent with absorption being greater in an acidic environment.
Summary of treatments for dermatophytosis
- Itraconazole (noncompounded) and terbinafine are the most effective and safe treatments for dermatophytosis.
- Griseofulvin is effective but also has more potential adverse effects compared to itraconazole and
terbinafine. - Ketoconazole and fluconazole are less effective treatment options and ketoconazole has more potential for adverse effects.
- Lufenuron has no in vitro efficacy against dermatophytes, does not prevent or alter the course of dermatophyte infections, does not enhance the efficacy of systemic antifungal or topical antifungal treatments and has no place in the treatment of dermatophytosis.
- Antifungal vaccines do not protect against challenge exposure but may be a useful adjunct therapy.
What are five situations which may indicate the likelihood of AMD resistance?
i) less than 50% reduction in extent of lesions within 2 weeks of appropriate systemic antimicrobial therapy
(ii) emergence of new lesions (papules, pustules, collarettes) 2 weeks or more after the initiation of appropriate AMD therapy
(iii) presence of residual SBF lesions after 6 weeks of appropriate systemic antimicrobial therapy together with the presence of cocci on cytology (while a typical course of therapy may be 21–28 days,16 several studies indicate that therapy for up to 6 weeks may be necessary to resolve the infection in some cases)
(iv) intracellular rod-shaped bacteria are detected on cytology
(v) there is a prior history of multidrug-resistant infection in the dog or in a pet from the same household as the affected dog.
If erythromycin resistance is determined in the presence of clindamycin susceptibility, what should be performed (or molecular methods for detection of erm genes) to determine whether inducible clindamycin resistance is likely?
the D-test
Clinical microbiology laboratories must perform tests to differentiate coagulase-positive staphylococci from CoNS; S. aureus should be distinguished from other coagulase- positive staphylococci. This is important for what two reasons?
(i) the CLSI-determined breakpoints for oxacillin differ for S. aureus and the other veterinary coagulase-positive staphylococci (S. pseudintermedius, S. schleiferi subsp. coagulans, etc.); and
(ii) the potential public health risk from S. aureus is different from that of the other
It is not acceptable to limit the reporting of staphylococcal isolates as ‘coagulase-positive’ or ‘coagulase-negative’ Staphylococcus sp. or for a laboratory to assume that a coagulase-positive staphylococcus isolated from a dog is S. pseudintermedius. Specific biochemical tests or validated molecular tech- niques should be used for speciation.
According to Hillier et al Review - how long should antiseptic bathing/spraying be continued?
In the absence of studies, it is recommended that topical antimicrobial therapy be continued until 7 days beyond clinical resolution of all lesions associated with the infection, that contact time should be at least 10 min and that the hair coat be kept short to assist optimal contact of antimicrobial agents with the skin surface.
What are the potential concerns for prescribing a 3rd generation cephalosporins?
There is concern among some members of this panel about the potential selective effects of third generationcephalosporins (cefpodoxime and cefovecin) on the Gram-negative microbiota, due to their broader spectrum of activity compared with first generation cephalosporins. Both drugs are marketed as extended-spectrum cephalosporins; in addition to approval for use in infections caused by S. pseudintermedius, cefpodoxime is regarded as a broad-spectrum AMD and has been approved in the USA for use in the treatment of skin infections associated with Escherichia coli and Proteus mirabilis.
What three organisms is cefovecin effective against compared to 1st generation cephalexin?
Cefovecin is significantly more active against E. coli, Klebsiella pneumoniae and Proteus spp. compared with cefalexin and cefadroxil, and its in vitro activity against E. coli and Proteus spp. is comparable to that of cefpodoxime. Although cefovecin may be considered as a ‘narrower-spectrum’ drug due to the high-affinity protein binding (and subsequent low free plasma concentration), pharmacokinetic data provided by the manufacturer45 indicate that the free plasma concentra- tion exceeds the MIC90 of E. coli for 2 days following injection and exceeds the MIC50 of E. coli for 6 days.
What is a common concern for using cefovecin for treatment of superficial folliculitis compared to cefpodoxime?
There are concerns raised about possible selection of highly resistant extended-spectrum b-lactam- ase (ESBL)-producing E. coli by use of cefovecin. As for cefpodoxime, this extended-spectrum cephalosporin is administered as a prodrug, cefpodoxime proxetil, which is absorbed and de-esterified in the gastrointestinal tract to its active metabolite.46 Thus, it is questionable whether the active metabolite may reach sufficient concentrations in the large intestine to select for ESBL-producing bacteria. These concerns notwithstanding, at least one member of the panel was not convinced that there is sufficient published evidence indicating that cefovecin or cefpodoxime produce active concentrations in the intestinal lumen of dogs that are sufficient to affect the microbial population.
This has been modified further, such that there is now a Staphylococcus intermedius group (SIG) with members including what three species?
S. intermedius, S. pseudintermedius and S. delphini.
Why is important to differentiate S. epidermidis and S. schleiferi schleiferi)?
Coagulase negative S. schleiferi schleiferi is a pathogen that is potentially zoonotic. For this reason, it is important that laboratories identify coagulase negative staphylococci down to the species level (for example, to differentiate non-pathogenic S. epidermidis from pathogenic S. schleiferi schleiferi).
Is Staphylococcus schleiferi coagulase positive or negative?
S. schleiferi may be either coagulase positive (S. schleiferi coagulans) or coagulase negative (S. schleiferi schleiferi) . In the past, coagulase negative staphylococci were considered to be contaminants when found on a culture from a superficial lesion in a dog.
What is disc-diffusion susceptibility test (DDST)?
is semiquantitative in that the drug concentration achieved in the agar surrounding the disc can be roughly correlated with the concentration achieved in the dog’s serum. It will only report the organism’s susceptibility (susceptible, intermediate or resis- tant, SIR) based on an approximation of the effect of an antimi- crobial agent on bacterial growth on a solid medium.
What is tube dilution (MIC)?
is quantitative, not only reporting SIR, but also the amount of drug necessary to inhibit microbial growth. The MIC is reported as the lowest concentration of an antimicrobial agent (in lg/mL) necessary to inhibit visible growth of the tested bacteria. This allows a clinician to decide on, not only susceptibil- ity or resistance, but also the proper dosage and frequency of administration of the antimicrobial agent. The MIC method can imply the relative risk of emerging resistance and thus the need for a high treatment dose.
In order to avoid mislabeling MRSP as susceptible, what is used as the breakpoint for MRSP?
In order to avoid mislabeling MRSP as susceptible, a new lower breakpoint (reduced from 2.0 to 0.5 lg/ mL for oxacillin when testing S. pseudintermedius) should be used.
What are the two genes responsible for Clindamycin resistance for treatment of Staph?
Two genes (msrA and erm) are responsible for the resistance of S. aureus to macrolides (e.g. erythromycin). The msrA gene accounts for the resistance only to macrolides, while the erm gene encodes for macrolide and lincosamide (lincomycin and clindamycin) resistance. The erm gene can be expressed constitutively and the culture will report resistance to clindamycin; this gene can also be inducible, in which case the MRSA will be susceptible initially to clindamycin (and therefore reported as sensitive).
How is erythromycin used as a surrogate to indicate the presence of this inducible gene (erm gene) if D-test is not available?
Since commercial veterinary laboratories currently are not performing this additional culture, resistance to erythromycin may be used as a surrogate to indicate the presence of this inducible gene. This is because the msrA gene and the erm gene both encode staphylococcal resistance to eryth- romycin. Therefore, if the Staphylococcus sp. is resistant to erythromycin, there is a potential for the inducible erm gene to be present.
Side note: Rich et al. (2005) found that that 97.3% of erythromycin-resistant isolates of MRSA were truly resistant to clindamycin, even though only 25.5% demonstrated clindamycin resistance on routine laboratory testing. On the basis of this study, it would be pru- dent to avoid clindamycin for all S. aureus infections that report resistance to erythromycin
Resistance of Staphylococcus spp. to tetracycline is mediated by what two genes?
tet(K) and tet(M)
Resistance ONLY to tetracycline (not doxycycline or minocycline) is mediated by tet(K)
tet(M) will confer resistance to all three members of the tetracycline family.
If an MRSA isolate has the tet(K) gene, exposure to either tetracycline or doxycycline can induce doxycycline, but not minocycline, resistance.
Side note: This has led to the recommendation that MRSA infections that are resistant to tetracycline should be considered to be resistant to doxycy- cline regardless of the in vitro test result. In cases of tetracycline resistant MRSA infections, minocycline should be tested since, if the tet(M) gene is present, minocycline will be ineffective, but if the tet(K) gene is present, minocycline will be effective
Cefovecin (Convenia, Zoetis)
is a parenterally administered third generation cephalosporin. The concern about using this antibiotic is that, after the first injection, therapeutic drug concentrations (above MIC) are only maintained for 7–14 days, depending on the infectious agent, while tissue levels persist for up to 65 days.
