Pharmacology Flashcards
1
Q
MOA of Sanguinarine (blood root plant)
A
Sanguinarine interacts with DNA via intercalation, and its binding impairs DNA polymerase, inducing DNA strand breaks and cell death.
2
Q
MOA of Imiquimod?
A
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).
3
Q
Azathioprine is a synthetic modification of ______?
A
6-mercaptopurine
4
Q
What is the MOA of azathioprine?
A
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
5
Q
Which IL is markedly suppressed by azathioprine?
A
IL-2
6
Q
What is chlorambucil? MOA?
A
AKA Leukeran
alkylating agent derived from nitrogen mustard
cytotoxic effect d/t crosslinking of DNA
7
Q
Alopecia and delayed hair growth have been reported in dogs with Chlorambucil. Which breeds are at greater risk?
A
Poodles
Kerry blue terriers
8
Q
What is colchicine?
A
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
9
Q
Which phase of cell division is affected by colchicine?
A
Metaphase - by interfering with sol-gel formation and the mitotic spindle
10
Q
What is cyclophosphamide? MOA?
A
AKA Cytoxan
Nitrogen mustard alklylating agent
Inhibits mitosis by interfering with DNA replication and RNA transcription and replication.
Lymphocytes especially affected
11
Q
Cyclophosphamide is especially toxic to lymphocytes. Are T or B cells more affected?
A
B cells.
Suppresses antibody production
12
Q
Which drug may decrease hemorrhagic cystitis that can be seen with cyclophosphamide?
A
Concurrent furosemide therapy
13
Q
What are major toxic SE of cyclophosphamide?
A
Sterile hemorrhagic cystitis Bladder fibrosis teratogenesesis/infertility alopecia/poor hair growth, nausea, GI tract, BM, infection Cats may lose whisker
14
Q
mycophenolate mofetil
A
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
15
Q
List some known anti-inflammatory and immunomodulatory properties of tetracyclines:
A
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.
16
Q
What are some immunomodulatory properties of Niacinamide?
A
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
17
Q
What is the proposed mechanisms of IVIG therapy?
A
Presumably via Fas (CD95) blockade
18
Q
_______ is the use of gold as a therapeutic agent.
A
Chrysotherapy
19
Q
________ is a methylxanthine derivative that produces a variety of physiologic changes at the cellular level.
A
Pentoxyfylline
20
Q
Name 7 immunomodulatory and rheologic effects of pentoxifylline:
A
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
21
Q
What drugs can cause urticara-angioedema in horses?
A
penicillin, tetracyclines, phenylbutazone, ciprofloxacin, streptomycin, sulfonamides, neomycin, aspirin, contacts, hormones, vaccines, antisera, guaifenisen, vit B complex and liver extract, flunixin, iron dextrans, acepromazine
22
Q
Which class of drugs is most commonly associated with EM and exfoliative dermatitis?
A
Sulfonamides
23
Q
Name 5 drugs associated with vasculitis in horses
A
Phenylbutazone Penicillin Acepromazine TMS Tiludronate
24
Q
Proposed MOA of FAs?
A
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.
25
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)
26
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).
27
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.
28
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.
29
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
30
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.
31
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.
32
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.
33
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
34
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.
35
Summary of treatments for dermatophytosis
1. Itraconazole (noncompounded) and terbinafine are the most effective and safe treatments for dermatophytosis.
2. Griseofulvin is effective but also has more potential adverse effects compared to itraconazole and
terbinafine.
3. Ketoconazole and fluconazole are less effective treatment options and ketoconazole has more potential for adverse effects.
4. 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.
5. Antifungal vaccines do not protect against challenge exposure but may be a useful adjunct therapy.
36
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.
37
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
38
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.
39
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.
40
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.
41
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.
42
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.
43
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.
44
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).
45
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.
46
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.
47
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.
48
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.
49
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).
50
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
51
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
52
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.
53
What is the concern about both fluoroquinolones and third generation cephalosporins use and the development of what types of infections?
Both independent risk factors for development of ESBL-producing bacterial infectionsESBLs are a concern in human medicine be- cause they are frequently MDR, not only to b-lactam antibiotics, but also to other antimicrobial agents, such as aminoglycosides, fluoroquinolones, tetracyclines, chloramphenicol and sulfameth- oxazole–trimethoprim. This wide ranging resistance greatly limits effective treatment options. The genes encoding this resistance are mediated by plasmids and/or mobile elements, allowing horizontal transfer between the same and different species of bacteria. .
54
Meticillin-resistant S. pseudintermedius are characterized by the presence of what gene that confers resistance to methicillin and other antibiotics?
MecA gene, which has been shown in meticillin-resistant S. aureus (MRSA) to confer resistance to meticillin and all other b-lactam antibiotics, including the cephalosporins and carbapenems.
55
MecA gene encodes for what protein that leads to resistance?
The mecA gene encodes an altered, surplus cell wall penicillin-binding protein (PBP)2a, which has a low affinity to virtually the entire class of b-lactam antibiotics. The mecA gene is likely to have originated from members of the Staphylococcus sciuri group, which are coagulase- negative staphylococci that commonly colonize animals and sometimes humans, but it has since been identified from several staphylococcal species isolated from animal infection, including S. aureus, Staphylococcus schleiferi subsp. coagulans, S. schleiferi subsp. schleiferi and S. pseudintermedius.
56
Chloramphenicol MOA
Bacteriostatic antibiotic with good activity against Staphylococcus spp. Cats are more susceptible to adverse effects with this medication; therefore, the recommended dose is 12.5–20 mg ⁄ kg twice daily.
**chloramphenicol inhibits cytochrome P450 3A isoenzymes and can therefore inhibit metabolism of drugs that are substrates for these enzymes, resulting in increased concentration and potential drug toxicity.**
57
Rifampin MOA
Bactericidal antibiotic with excellent tissue penetration. It has a broad spectrum of activity against many Gram-negative and most Gram-positive micro-organisms and is the most active antibiotic known against staphylococci. The dosage currently recommended in dogs is 5–10 mg ⁄ kg once to twice daily.
SE: Rifampicin is potentially hepatotoxic, and this adverse effect appears to occur more commonly in dogs than in people. Mild increases in alkaline phosphatase activity occur frequently and appear to be benign; however, treat- ment should be discontinued if there are concurrent increases in other hepatic enzyme activities, because acute hepatic toxicity and death have been described.
rifampicin is a potent inducer of cytochromeP450 3A isoenzymes and, as such, results in decreased concentrations of drugs that are substrates for these enzymes, possibly resulting in subtherapeutic levels. ALSO - induces expression of transmembrane efflux pumps, such as p-glycoprotein, leading to decreased absorption of medications that are substrates
***A recent study showed rapid emergence of rifampicin resistance during rifampicin treatment, even when used in combination with another antibiotic.
58
Amikacin MOA
Aminoglycoside that is not typically used for treating dogs with skin infections because of its paren- teral administration; however it is being used more frequently now, with the emergence of MRSP. The recommended dose for dogs is 15–30 mg ⁄ kg subcutane- ously (s.c.) every 24 h and for cats 10–14 mg ⁄ kg s.c. every 24 h
59
Resistance to minocycline should indicate the presence of ___, while susceptibility to minocycline but resistance to tetracycline should indicate the presence of ___. The recommended dose for mino- cycline is 5–12 mg ⁄ kg twice daily.
tet(M)
| tet(K)
60
Palladia
Palladia is a targeted agent that was developed specifically for dogs with Mast Cell Tumors.
It is a tyrosine kinase inhibitor that targets receptors on the mast cell that have undergone mutation (c-kit receptors).
Side effects include kidney and liver damage, proteinuria, and hypertension.
61
Dapsone MOA
As an antibacterial, dapsone inhibits bacterial synthesis of dihydrofolic acid, via competition with para-aminobenzoate for the active site of dihydropteroate synthase, thereby inhibiting nucleic acid synthesis. Though structurally distinct from dapsone, the sulfonamide group of antibacterial drugs also work in this way.
62
CSA MOA
Cyclosporin A blocks the transcription of many proinflammatory genes in activated immune cells by forming a complex with cyclophilin, a cytosolic protein. The cyclosporin-cyclophilin complex in- hibits the phosphatase calcineurin, which blocks dephosphorylation of the nuclear factor of activated T cells. In activated T cells, the phosphorylated nu-clear factor cannot move into the nucleus to induce gene transcription.
The main action of cyclosporin is to decrease T-cell activation by inhibiting IL-2 production and release.
It also suppresses production of mRNA for IL-2, IL-4, and interferon-γ in stimulated canine peripheral blood mononuclear cells, inhibits mast cell and eosinophil degranulation, and depresses pro-inflammatory eicosanoid formation.
63
Oclacitinib MOA
Apoquel inhibits the activity of cytokines that are dysregulated in cases of atopic dermatitis by selectively inhibiting certain JAKs (those most inhibitory against JAK1, compared with activities against JAK2, JAK3, or TYK2 in cell-free enzyme studies) associ- ated with the intracellular portion of type I and type II cytokine receptors. Inhibition of JAKs blocks the cytokine signal, thereby preventing gene transcription and protein production. Cytokine receptors use distinct combinations of different JAKs. In in vitro canine and human cell cultures, oclacitinib preferen- tially inhibits cytokines whose signaling is mediated by JAK1 and JAK3 (both of which are involved in itch- ing and inflammation) over JAK2 (which is important in hematopoiesis and innate immunity).
64
Oclacitinib inhibits the activity of which cytokines (mainly)?
IL-2, IL-4, IL-6, IL-13, and IL-31
65
What does it mean for a biologic to be 'caninized??
A caninized (ie, murine antibody genetically modi- fied to contain sequences from canine IgG) anti-canine IL-31 mAbd has been developed to neutralize the ef- fects of canine IL-31
66
In-creased allergen penetration of the skin facilitates uptake, processing, and presentation of the allergen as major histocompatibility complex class II peptides by _______ cells, which further promotes the TH2-cell response, thereby leading to a vicious cycle of inflammation and sensitization to multiple allergens.
Langerhans
67
In an experimental model of atopic dermatitis in dogs, removal of the stratum corneum by tape stripping enhanced expression of what surface mol- ecules on Langerhans cells and promoted allergic sensitization?
major histocompatibility complex class II, CD86, CD40, CD54, and CD11c
68
Self-trauma and damage of the skin barrier trigger the release of ______, which polarizes skin dendritic cells to stimulate a TH2-cell response.
epidermal TSLP
69
What are the functions of moisturizers (emollients and humectants) in atopic dermatitis?
Moisturizers (emollients and/or humectants) have multiple functions. The most impor- tant action is increasing the amount of water in the skin by reducing the transepidermal water loss (TEWL) via blocking agents (ie, oils) or using hygroscopic molecules. These latter act as occlusive agents and attract water from the environment and/or from the dermis/subcutaneous tissues (eg, oatmeal).
70
Pentoxyfylline
* Methylxanthine and phosphodiesterase inhibitor pentoxifylline has been used in human medicine for years.
* It has effects on leukocyte deformability and decreases platelet activation; decreases endothelial leukocyte adhesion and neutrophil degranulation, production of cytokines such as TNF and T- and B-cell activation.
71
Tacrolimus
Tacrolimus acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription.
72
Misoprostol
Synthetic prostaglandin E analogue with antiallergic action
73
Capsaicin
It is an alkaloid, that active component of chili peppers, that binds to a receptor on neutron and leads to neuronal depletion of substance P, a neurotransmitter involved in pain and neurogenic inflammation.
74
Serotonin uptake inhibitors and tricyclic antidepressants
* Serotonin is one of the preformed inflammatory mediators released with mast cell degranulation.
* Cyproheptadine has been administered orally at a dose of 0.1-0.2 mg/kg daily to 16 dogs with allergic pruritus and no improvement was seen in any of the dogs.
75
Salicylic acid (0.1% to 2%)
SA is keratoplastic and exerts a favorable influence on the new formation of the keratinous layer.
o It is also mildly antipruritic and bacteriostatic. In stronger concentrations (3% to 6%), it solubilizes the intercellular "cement," thus acting as a keratolytic agent, causing shedding and softening of the stratum corneum.
o When salicylic acid is combined with sulfur, it is believed that a synergistic effect occurs.
o A common combination is a 2% to 6% concentration of each drug. In human dermatologic practice, a 40% salicylic acid plaster is used to treat calluses and warts.
76
Tar
Keratolytic, keratoplastic, and mildly degreasing.
Tar is believed to normalize epidermal proliferation by decreasing deoxyribonucleic acid (DNA) production with a resultant decrease in the mitotic index of the epidermal basal cells. As with sulfur shampoos, tar products usually contain other ingredients, usually sulfur and salicylic acid.
77
Benzoyl peroxide
BP is keratolytic, antibacterial, degreasing, antipruritic, and follicular flushing.
o It is metabolized in the skin to benzoic acid, which lyses intercellular substance in the horny layer to account for its keratolytic effect.
o It is not a stable ingredient and should not be repackaged, diluted, or mixed with other products.
o Benzoyl peroxide is drying, can induce a contact dermatitis (in less than 10% of patients), and bleaches hair, clothing, and furniture.
o Because of its potent degreasing action, benzoyl peroxide excessively dries out normal skin with prolonged use, and it is generally contraindicated in the presence of dry skin or significant irritation, or both.
78
Selenium sulfide
SS alters the epidermal turnover rate and interferes with the hydrogen bond formation in keratin.
The human product that contains 1% selenium sulfide (Selsun Blue, Abbot Laboratories) is effective in dogs and usually is not too irritating
79
Emollients versus moisturizers
Emollients are agents that soften or soothe the skin, whereas moisturizers increase the water content of the stratum corneum.
Both types of drugs are useful in hydrating and softening the skin. Many of the occlusive emollients are actually oils (safflower, sesame, and mineral oil) or contain lanolin.
These emollients decrease transepidermal water loss and cause moisturization. These agents work best if they are applied immediately after saturation of the stratum corneum with water.
80
What are hygroscopic (humectant) agents?
They are moisturizers that work by being incorporated into the stratum corneum and attracting water.
These agents draw water from the deep epidermis and dermis, and from the environment if the relative humidity is greater than 70%.
These agents, such as propylene glycol, glycerin, colloidal oatmeal, urea, sodium lactate, and lactic acid, may also be applied between baths.
81
Naturally occurring vitamin A
It is an alcohol, all-trans retinol.
o It is oxidized in the body to retinal and retinoic acid. Each of these compounds has variable metabolic and biological activities, although both are important in the induction and maintenance of normal growth and differentiation of keratinocytes.
o Only retinol has all of the known functions of vitamin A.
o The two most widely used retinoids in veterinary dermatology were isotretinoin (13-cis-retinoic acid; Accutane, Roche), synthesized as a natural metabolite of retinol, and etretinate (Tegison, Roche), a synthetic retinoid.
o Etretinate is no longer available because tissue residues in humans can persist for years after drug withdrawal and might result in fetal defects. It was replaced with acitretin (Soriatane, Roche), a free-acid metabolite of etretinate.
82
Vitamin D analogs
It inhibits keratinocyte proliferation, induce terminal differentiation of keratinocytes, and decrease immunologic reactivity by reduced production or transcription of various cytokines and reduced antigen-presenting function of Langerhans cells.
When calcitrol was given at 10 nglkg q24h to seborrheic Cocker spaniels, significant improvement was noted in approximately two thirds of the dogs.
83
Patients that have no or low Thiopurine methoyltrasnferase (TPMT) are more likely to experience myelosupression making them more susecptanble to toxicity. Which breeds are known to have low TPMT activity?
Schnauzers and Alaskan Malamutes
84
Azathioprine is a synthetic modification of _____ that can be given orally or by injection. The drug antagonizes ____ metabolism, thereby interfering with DNA and RNA synthesis.
6 - mercaptopurine
| purine
85
6 - mercaptopurine is then metabolized by what enzymes?
Xanthine oxidase
| thiopruine methyltransferase
86
What are side effects of azathioprine?
anemia, leukopenia, thrombocytopenia, vomiting, hypersensitivity reactions, elevated ALP, rashes and alopecia.
*The most common side effect is diarrhea
87
Dosing and monitoring of Azathioprine?
50 mg/m2 or 1.5-2.5 mg/kg every 24 hours.
Patients should be monitored every 2 weeks with a complete blood count. There is usually a lag phase with clinical improvement occurring 3-6 weeks.
88
Cats and Azathioprine
Cats are susceptible to azathioprine toxicity (including fatal leukopenia and thrombocytopenia), and this drug should be really be used.
89
Chlorambucil is an orally administered ____ agent derived from nitrogen mustard. It's cytotoxic effect is due to cross-linking ___. Compared with other alkylating agents, it is slow acting and less toxic.
alkylating agent
| DNA
90
Chorambucil monitoring
Hemograms every 2 to 4 weeks.
91
Chorambucil SE
Anorexia, vomiting, and diarrhea have been reported at daily dosages but often resolve with alternate day therapy.
92
What drug may be used to replace cyclophosphamide if hemorrhagic cystitis develops?
Chlorambucil
93
What drug is an alkaloid that surpasses neutrophil chemotactic and phagocytic functions via disruption of microtuble assembly and elongation, increasing cellular cyclic adenosine monophosphate levels and inhibiting lysosomal degranulation?
Colchicine
**it also inhibits immunoglobulin secretion, IL-1 production, histamine release, and human leukocyte antigens expression.
** It inhibits cell division during metaphase nu interfering with sol-gel formation and the mitotic spindle.
**plant derived drug to treat gout.
94
What drug is a nitrogen mustard alkylating agent that is metabolized to agents that inhibit mitosis by interning with DNA replication and RNA transcription and replication. Lymphocytes are especially sensitive to this drug?
Cyclophophamide
95
Cyclophosphamide is more effective against __ cells than ___ cells. Cyclophosphamide suppresses antibody production.
B, T
96
What are the toxic effects of cyclophosphamide?
sterile hemorrhagic cystitis (~30%, decreased with concurrent furosemide therapy), bladder fibrosis, teratogenesis, infertility, alopecia and poor hair growth, nauseam inflammation of the gastrointestinal tract, increased susceptibility to infections and depression of bone marrow and hemotopoetic systems.
Cats may lose their whiskers.
97
What drug inhibits de novo purine synthesis and suppresses both T and B lymphocytes?
mycophenolate
98
Mycophenolate is a prodrug of the anti proliferative agent _____. It specifically and irreversibly inhibits _____, thereby inhibiting synthesis of _____ nucleotides, blocking synthesis of purine, and presenting maturation of T and B lymphocytes.
mycophenolic acid
inosine monophosphate dehydrogenase
guanine
99
IVIG
```
Intravenous immunoglobulin (IVIG) contains the pooled immunoglobulin G (IgG) immunoglobulins from the plasma of approximately a thousand or more blood donors.
- via CD95 blockade
```
100
In alopecia areata, CD4 and CD8 cells are found around affected hair follicle bulbs, ___ cells are likely responsible for inducing the hair loss in humans and lab models.
CD8
101
What dies is characterized by focal or multifocal patches of asymptomatic noninflammatory alopecia, most commonly affecting the head or face?
Alopecia areata
***GSD, Beagles and Dachshunds may be predisposed?
102
Microscopic examination of hairs plucked from the main reveal what shape of hairs?
"exclamation point" hairs
hairs often grow back white**
103
Describe the histopathology of AA
Early histologic findings include a peribulbar to inferior follicle accumulation of lymphocytes, macrophages or dendritic cells nd usually some plasma cells. Peribulbar mucin deposition and pigmentary incontinence may also be seen.
104
Linear Immunoglobulin A Pustular Dermatoses
This is a rare, idiopathic , sterile, superficial pustular dermatoses of dachshunds.
Clinically, linear iGA pustular dermatosis is characterized by multifocal to generalized pustular dermatitis. Trunk is typically involved.
Direct immunofluresence is positive for IgA deposited at the BMZ.
105
Drug metabolites are generated by _______ (Phase I enzymes) but also by other oxidative metabolizing enzymes, some of which are present in the skin Reactive drug metabolites must be detoxified by phase 2 enzymes such as _____ or ______ to prevent toxicity.
Cytochrome p450 mixed function oxidases
| Epoxide hydrolase or glutathione S transferase
106
What drug typically causes alopecia that beings on the head and extends to the ventral neck, thorax and abdomen and induces an immunologist response.
Doxorubicin
107
Drug-induced depigmentation is frequently observed in humans undergoing tyrosine kinase inhibitor therapy. A presumed drug-induced skin depigmentation in a dog receiving what drug?
toceranib phosphate (Palladia)
**Tofacitinib (Xeljanz)** I get these two confused.
108
Sulfasalazine (Azulfidine)
kills bacteria by acting as a competitive antagonist for aminobenzoic acid. 5-aminosalicylic acid is an anti-inflammatory agent although the mode of action is unclear. It is thought to inhibit lipoxygenase, cycloxygenase, and some folate metabolizing enzymes.
109
What drug is a ribonucleotide reductase inhibitor that leads to decreased DNA synthesis. It I mainly lethal to cells in the S phage of the growth cycle.
Hydroxyurea
**Treats hypereosinophila syndrome when used in conjunction with steroids**
110
Cells activated by imiquimod via TLR-7 secrete which cytokines?
(primarily interferon-α (IFN-α), interleukin-6 (IL-6), IL-12 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.
111
Megulamine
Pentavalent antimonials bind to polypeptides, inhibit DNA topoisomerase glycolytic enzymes and fatty acid beta-oxidation. Electron microscopy studies show antimonial-induced changes in parasite cell membranes.
112
What are the major biological activities of DMSO?
Penetration enhancement Anti-inflammatory
Free radical scavenger Antioxidant Bacteriostatic
Antifungal
Antiviral
Vasodilatory
Fibrinolytic
Analgesic
Decreases fibroplasia
Stabilizes lysosomal membranes Decreases prostaglandin synthesis Solvent (calcinosis cutis) Histamine release
Cryoprotectant
113
How do most drugs travel through this layer of the skin?
Passive process
Most of the transport is through the intercellular route
(between cells, through the lipid matrix)
114
What is a liquid in which a medicinal agent (often a powder) is dissolved or suspended?
Lotion
115
Production of alkaline phosphatase can be induced by the administration of corticosteroids. Name other drugs that have been reported to induce production of this enzyme.
Phenobarbital
Primidone
Ketoconazole
Rifampin
116
What antimicrobial peptide is produced by Lactococcus lactic?
Nisin
117
Amikacin
Bactericidal – irreversibly binds to ribosomal 30s and inhibits protein synthesis.
118
Rifampin
Bactericidal – inhibits bacterial RNA polymerase.
119
Chloramphenicol
Bacteristatic – Reversibly binds to 50s ribosomal subunit inhibiting protein synthesis.
120
Cefpodoxime
Bactericidal - Inhibits cell wall synthesis by inhibiting the final transpeptidation step of peptidoglycan synthesis in cell walls. It is highly protein bound and has a longer half life which is why it maintains longer concentration compared to first generation cephalosporines.
121
Minocycline
Bacteriostatic – Inhibitor of bacterial protein synthesis by reversibly binding to the 30S ribosome. Also, inhibits activity of matrix metalloproteinases, suppresses neutrophil chemotaxis, lymphocyte activation and inhibits mast cell degranulation.
122
Vancomycin
bactericidal - binds to peptidoglycan monomer units thereby blocking the addition of murein units to polymer chain and inhibiting cell wall synthesis.
123
Marbofloxacin
Bactericidal - Inhibits DNA gyrase and topoisomerase IV which interferes with DNA supercoiling preventing DNA replication.
124
Mupirocin
Bacteriostatic at low concentrations and bactericidal at high concentrations - Reversibly binds to isoleucyl transfer RNA synthetase inhibiting protein synthesis and RNA synthesis.
125
Silver compounds
Bactericidal - Bind to cell wall and inhibit ion transport in and out of cell, block cell division by binding to DNA and blocks the bacterial respiratory system leading to cell death.
126
Sulfas
Bacteristatic – inhibits DHPS therefore interfering with folate synthesis.
127
With regards to fluoroquinolones, both topoisomerase II and IV are relevant. Which is activity is more important for Gram negative vs. Gram positive bacteria?
Topoisomerase II (DNA Gyrase) is the primary target site for gram-negative bacteria; Topoisomerase IV is the major target for gram-positive organisms.
128
What is the target of Dapsone?
Dapsone inhibits bacterial synthesis of dihydrofolic acid, via competition with para-aminobenzoate for the active site of dihydropteroate synthase, thereby inhibiting nucleic acid synthesis.
129
What is the target of cimetidine?
is a histamine H2 receptor antagonist that inhibits stomach acid production.
130
Clindamycin MOA
Clindamycin works primarily by binding to the 50s ribosomal subunit of bacteria. This agent disrupts protein synthesis by interfering with the transpeptidation reaction, which thereby inhibits early chain elongation.
