Pharmacology Flashcards
How does the potency of synthetic glucocorticoids compare to endogenous cortisol?
synthetic glucocorticoids are more potent immunosuppressive and immunoregulatory agents and have relatively minimal mineralocorticoid activity
How do glucocorticoids pass through the cell membrane?
Glucocorticoids are lipophilic and diffuse easily through the cell membranes
What happens to glucocorticoids once they pass through the cell membrane?
They bind to the chaperone-GC receptor complex –>
chaperone dissociates –>
now the glucocorticoid-GC receptor complex can pass through the nucleus –>
causes genomic effects
What are the three theorized ways that glucocorticoids can interact with DNA and cause genomic effects?
1) Direct binding to glucocorticoid response elements (positive and negative)
2) Tethering
3) Composite (both direct binding and tethering)
What happens if the ligand-bound glucocorticoid binds to the positive glucocorticoid response element (+GRE)?
induces transcription of anti-inflammatory and immunomodulatory genes:
annexin-A1 (ANAX1, also known as lipocortin 1)
GC-induced leucine zipper (GLIZ)
mitogen-activated protein kinase phosphatase 1 (MPK1)
*the effects that we are looking for
What happens if the ligand-bound glucocorticoid binds to the negative glucocorticoid response element (nGRE)?
inhibits the transcription of genes:
corticotropin-releasing hormone
melanocyte-stimulating hormone
β-endorphin
*some of the side effects
What happens in the tethering scheme of how glucocorticoids exert genomic effects?
physical interaction with another transcription factor without direct contact with DNA
interferes with activators of most inflammatory cytokines/adhesion molecules
- NF-κB
- activator protein-1 (AP-1)
also interferes with key proinflammatory transcription factors
- STAT
- nuclear factor of activated T cells (NFAT)
How do glucocorticoids affect B cells?
Uncertain exactly how, some through genomic effects
Chronic use of GC is associated with inhibition of B cell antibody production
The genomic mechanism of glucocorticoid activity may take hours to days to take effect. How can glucocorticoids act within minutes?
nongenomic mechanism
interaction of GCs with membrane-specific GR, cytosolic GR (resulting in the release of a variety of proteins without the need to translocate into the nucleus) and nonspecific interactions with cell membranes leads to alteration of transmembrane currents, signal transduction and intracellular calcium levels (all have anti-inflammatory effects)
How do the effects of glucocorticoids correlate to time of detection in plasma?
the effects of GCs do not necessarily correlate to the time detectable in plasma
Doses are therefore often derived from human use, or based on the pharmacodynamic (clinical) response in the individual animal
Why should you give cats prednisolone and not prednisone?
Thought to be lacking hepatic 11-β-hydroxysteroid dehydrogenase type 1
needed to convert prednisone to prednisolone
only approximately 20% of drug is converted to prednisolone
(might also be lower oral absorption of prednisone)
When should prednisolone be used instead of prednisone for dogs?
altered hepatic function
poor response to prednisone (so individuals may have less 11βHSD1 activity)
In an over-conditioned animal, how should glucocorticoids be dosed?
dosed on lean body mass
over-conditioned cats plasma concentrations of prednisolone was 2x normal cats
What is the bioavailability of transdermal dexamethasone in cats?
not good, plasma concentrations were low to undetectable
What happens to plasma neutrophil and lymphocyte counts in dogs after 1 mg/kg of prednisolone IV?
plasma neutrophil counts increased and lymphocyte counts decreased, and had returned to baseline within the suggested 24-hour dosing interval
Why are cats less responsive to the anti-inflammatory, immunosuppressive and adverse effects of GCs compared to dogs?
a reduced number of GR in the skin and liver of cats compared to dogs
those receptors present are also lower-affinity receptors in cats
Which glucocorticoid has been associated with the induction of congestive heart failure in cats and why is it thought to happen?
methylprednisolone acetate (Depo-Medrol)
consequence of a shift in fluids resulting in an increased plasma volume secondary to glucocorticoid-induced hyperglycemia
What happened to the hearts of healthy cats with allergic dermatitis given prednisolone at 1-2 mg/kg/day for 14 days?
no significant hemodynamic and echocardiographic changes
How should glucocorticoids be dosed in large breed dogs?
mg/m2
(40 mg/m2 is roughly equal to 2 mg/kg)
Why do steroids cause skin atrophy and fragility?
Inhibitory effect on keratinocyte proliferation in the epidermis
Inhibition of collagen 1 and 3 synthesis in the dermis
Inhibition of fibroblasts and hyaluronan synthase 3 enzyme resulting in the reduction of hyaluronic acid in the extracellular matrix leading to dermal atrophy
Topical steroids cause the synthesis of lipocortin. What pro-inflammatory enzyme does this inhibit?
Phospholipase A2
acts on the cell membrane to release arachidonic acid
Why do steroids cause delayed wound healing?
various reasons
Inhibition of keratinocytes may cause delayed re-epithelialization
Inhibition of fibroblasts-reduced collagen and ground substance
Inhibition of vascular connective tissue
Delayed granulation tissue formation may be caused by inhibition of angiogenesis
What does the NFkB family do in normal cells? Cells with inflammatory stimuli?
Normally the NfkB members (p50, p65, p52, REL, RELB) are bound by an inhibitor
With inflammatory stimuli the inhibitor is dephosphorylated –>
disassociates and now NfkB can enter the nucleus and do many actions:
1) induce proinflammatory cytokines and chemokines (TNFa, IL-1, IL-6, CXCL8)
2) induce anti-apoptosis enzymes (BCL-2)
3) enhance lymphocyte survival and activation
4) increase adhesion molecules (ICAM1, VCAM1)
How does nuclear factor of activated T cell (NFAT) work?
NFAT is normally phosphorylated and cannot enter the nucleus but…
MCH II presents an antigen to the TCR –>
increases intracellular calcium (via release from ER) –>
Ca2+ activates calmodulin which binds calcineurin –>
together dephosphorylates NFAT –>
NFAT can enter nucleus –>
increase transcription of IL-2, IL-4, TNF-a, IFN-y –>
activates lymphocytes
What is the mechanism of cyclosporine A?
binds to intracellular cyclophilin which creates a complex that has a high affinity for calcineurin –> calcineurin cannot bind to calmodulin and dephosphorylate NFAT
What is the drug absorption of human generic modified cyclosporine absorption like in dogs?
generic human formulations in dogs has been shown to result in a threefold variability in drug absorption between formulations
What is the bioavailability of Atopica per os in dogs?
35%
What is the bioavailability of Atopica per os in cats?
25%–29%
What does administration of cyclosporine with food do to its bioavailability in dogs?
reduces the mean bioavailability by 22% in dogs
but did not affect the clinical outcome in 15 dogs treated for AD
What is the absorption of transdermal cyclosporine like in cats?
poor
In which breeds of dogs should cyclosporine be used with caution?
dogs with the MDR1 (ABCB1-1Δ) mutation (also reported in cats)
because it is a substrate for p-glycoprotein efflux pumps
animals heterozygous for this mutation may develop excessive immunosuppression at lower-than-expected doses
Which family of metabolizing enzymes is primarily responsible for the metabolism of cyclosporine A?
cytochrome P450 3A (CPY3A) in the liver
What happens to the pharmacokinetics of cyclosporine A in diabetic dogs?
overall drug exposure (as measured by AUC) was decreased by 52%, clearance was significantly increased and, subsequently, half-life was significantly decreased (9.32 h vs. 22.56 h)
speculated to be caused by increased clearance secondary to hyperglycemia or alterations in the lipid profile of these dogs
What tests can you do to determine the effectiveness of cyclosporine in dogs?
therapeutic drug monitoring (TDM)
- poor correlation btw blood conc and clinical response in dogs with AD
- clinical response plus TDM is superior to TDM alone
quantitative reverse transcription polymerase chain reaction (qRT-PCR)
- measures cytokine (IL-2) gene expression
Why might some dogs with PF be able to be maintained in CR with CsA as monotherapy?
inhibition of B-cell activation (via inhibition of Th cell function)
reduction in metalloproteinase-9 expression
blocking of the JNK and p38 signaling pathways
When is CsA most likely be to effective as monotherapy?
cell-mediated autoimmune dermatoses such as chronic cutaneous lupus erythematosus and sebaceous adenitis
Which drug is frequently combined with glucocorticoids and CsA for control of canine PF?
azathioprine (AZA)
potentially because CsA and AZA target different pathways, the risk of myelosuppression from the combination can be expected to be no higher than that from AZA monotherapy
What is the mechanism of action of azathioprine?
it is a pro-drug of 6-mercaptopurine (6-MP) and interferes with nucleotide synthesis
What happens once azathioprine is ingested?
absorbed in the intestinal tract –>
in the the intestinal wall, liver and RBCs, AZA is converted to 6-MP –>
metabolic pathway involving HPRT converts 6-MP to 6-TGN –>
has cytotoxic effects
What happens when xanthine oxidase (XO) acts on 6-MP?
makes largely inactive 6-thiouric acid
What are the 3 enzymes that can convert 6-MP?
xanthine oxidase (XO)
thiopurine-S-methyltransferase (TPMT)
hypoxanthine-guanine phosphoribosyltransferase (HPRT)
What happens when thiopurine-S-methyltransferase (TPMT) acts on 6-MP?
makes largely inactive 6-merthymecaptopurine (6-MMP)
What happens when hypoxanthine-guanine phosphoribosyltransferase (HPRT) acts on 6-MP?
converts 6-MP to 6-thioguanine nucleotide
What does 6-thioguanine nucleotide (6-TGN) do?
can be considered a ‘false’ nucleotide (e.g. nonfunctioning purine)
generation of 6-TGNs ‘provides’ a pool of nonfunctioning purine
when incorporated into DNA, results in mutation –> cessation of the cell cycle
also reduces the formation of purine nucleotides by inhibiting amidotransferase enzymes and purine ribonucleotide interconversion
In which cells does azathioprine have the greatest effect?
cells that are actively dividing such as lymphocytes (B and T cells) and thrombocytes
In addition to inhibiting cell division, what does azathioprine do?
affect T cell migration and adhesion
reduce survival/prolif of T cells through inhibition of RAC1 and/or BCL-XL
- RAC1 is also important in formation of ICAM-1 and VCAM-1
Which drugs should azathioprine be used with caution in?
other alkylating agents that interfere with DNA synthesis (e.g. cyclophosphamide) as it may lead to profound myelosuppression
allopurinol because the antagonism of xanthine oxidase may interfere with the metabolism of AZA
What can concurrent use of glucocorticoids and azathioprine increase the risk of?
acute pancreatitis
Which breed of dog may have increased risk of myelosuppression with azathioprine?
Giant Schnauzers (lower TPMT activity)
Which breed of dog has high TMPT activity?
Alaskan Malamutes
Which are cats at higher risk of myelosuppression from azathioprine?
Compared to dogs, blood TPMT activity in cats is much lower
Why does hepatotoxicity occur with azathioprine?
not fully known, may be idiosyncratic or dose-dependent
In one study that included 34 dogs, the prevalence of hepatotoxicity was 15%, with the median time to onset of 14 days
*recommended that liver enzymes are monitored within 2–3 weeks of starting
Which group of anticancer drugs does chlorambucil belong to?
nitrogen mustard group
includes melphalan, cyclophosphamide and ifosphamide
Other than immune-mediated diseases, what is chlorambucil commonly used to treat?
humans: chronic lymphocytic leukemia and Hodgkin’s lymphoma
cats: treat low-grade T-cell lymphoma
Other than cutaneous diseases, which immune-mediated disease in cats is chlorambucil frequently used to treat?
inflammatory bowel disease
What is the mechanism of action of chlorambucil?
classified as an alkylating agent
converted into its active metabolite (phenylacetic) in the liver
alkylates a DNA molecule through covalent bonds
- Nucleophile: provides a pair of electron to form covalent bond
- Electrophile: accepts a pair of electron to form covalent bond
- Chlorambucil is a reactive electrophile
- Guanine is the most nucleophilic site (generous “donor”)
causes ‘unwanted’ cross-linking of DNA
- forming adducts at the guanine-N7 position
causes intrastrand cross-links or interstrand cross-links –> cell death
- interstrand cross-links are most cytotoxic = double-strand breaks
targets rapidly dividing cells (ex. lymphocytes most)
What is the onset of activity of chlorambucil?
slow-acting drug (it may take ≤2 weeks for its therapeutic effects)
What drugs should chlorambucil be used in caution with?
will potentiate other immunosuppressive/chemotherapeutic drugs (ex. vincristine, doxorubicin and cisplastin)
may lead to severe myelosuppression if used together
For which autoimmune dermatopathy is chlorambucil most commonly used in cats?
as an adjunct or steroid-sparing agent for the treatment of PF
What are some side effects of chlorambucil?
GI effects
cytotoxic myelosuppression 7–14 days after initiation of treatment
reversible myoclonus (in cats)
Fanconi syndrome (in cats)
Which alkylating agent can cause sterile hemorrhagic cystitis?
Cyclophosphamide
What is the mechanism of action of colchicine?
Not fully known but does the following:
1) inhibits activation of P2X2 and P2X7 receptors and further pro-inflammatory cascades without affecting cell death
2) inhibits (NALP3) inflammasome
3) inhibits the RhoA/ Rho effector kinase (ROCK) pathway via cytoskeleton rearrangement and thus the activation of caspase- 1 and downstream maturation and release of IL1β
4) inhibits release of various substances including ROS, NO and TNFα
5) irreversibly binds tubulin, thereby blocking microtubule polymerization and preventing leukocyte migration
*classified cytotoxic
What is the mechanism of action of mycophenolate mofetil?
pro-drug that is converted to mycophenolic acid (MPA)
inhibits the de novo formation of guanine nucleotides (a purine)
- MPA inhibits the function of IMPDH (necessary enzyme)
guanine can only be made through the salvage pathway
- lymphocytes only have the de novo pathway so are very affected
Other than decreasing proliferation of lymphocytes, what does mycophenolate mofetil do?
inhibit the proliferation of fibroblasts
inhibit expression of cytokines and co-stimulatory receptors
inhibit various adhesion molecules needed for leucocyte chemotaxis
What is the oral absorption of mycophenolate mofetil in dogs?
highly variable (max of 380 to 5040 ng/mL at 45 min after 10 mg/kg PO)
plasma concentration decreased by80% within eight hours of administration
- suggests relatively high clearance and short half-life
Why was mycophenolate mofetil considered potentially not safe in cats?
In humans (and dogs) elimination of MPA is mainly as the glucuronide conjugate
cats are deficient in the glucuronyl transferase enzymes responsible for this reaction
*but it is ok in cats, main metabolic route appears to be glucosidation
In humans, which drugs reduce the oral bioavailability of mycophenolate mofetil?
CsA, antacid drugs (e.g. omeprazole) and certain antibiotics (e.g. ciprofloxacin and amoxicillin/clavulanic acid)
For which variant of lupus erythematosus in dogs is mycophenolate most likely to be able to be used as monotherapy?
ECLE
marked improvement within three weeks
Why is there a variable response to oral MMF in dogs?
narrow therapeutic index and high inter- and intrapharmacokinetic variability
What is the mechanism of action of pentoxifylline?
Methylxanthine derivative
increases RBC flexibility by increasing ATP and cyclic nucleotide levels
- reduces blood viscosity
- enhance the ability of blood to flow
competitive phosphodiesterase inhibitor (PDE) so increases cAMP in peripheral vessels
inhibits thromboxane synthesis and increases prostacyclin synthesis
- results in reduced platelet aggregation and adhesion to vessel walls
exerts vasodilation in the skeletal muscle vascular bed
inhibits the leukocyte-derived free radicals
improves leukocyte deformability and chemotaxis
- depressed neutrophil degranulation
- decreased endothelial leukocyte adhesion
- lowered sensitivity of leukocytes to cytokines
stimulates fibroblasts
decreases production of TNF-α, IFN-γ, IL-1, IL-6, IL-8, and IL-10
Increase collagenase production and decreasing synthesis of collagen, fibronectin and glycosaminoglycans
What are the mechanisms by which pentoxifylline may be useful in some animals with allergic and immune-mediated dermatoses?
decreased leukocyte responsiveness to IL-1 and TNF-a
decreased production of TNFa from macrophage
decreased production of IL-1, IL-4, and IL-12
inhibition of T- and B-lymphocyte activation
decreased natural killer cell activity
inhibit T-cell adherence to keratinocytes
Which drugs should be used with caution in combination with pentoxifylline?
quinolone and macrolide antibiotics (increased blood levels of pentox)
cimetidine (increased levels of pentoxifylline)
theophylline (increases theophylline levels)
blood thinners
With which comorbidities should pentoxifylline be used with caution?
seizures
renal insufficiency
liver insufficiency
brain/retinal bleeding
What is the time to steady state for prednisone/prednisolone?
4-5 days
What is the time to steady state for cyclosporine?
~4 weeks
What is the time to steady state for mycophenolate?
1-3 weeks
What is the time to steady state for azathioprine?
2 weeks
evidence that lymphocyte response is decreased within 7 days of therapy
What is the time to steady state for chlorambucil?
2 weeks
What are the members of the JAK family?
JAK1, JAK2, JAK3 and TYK2
(can all form various pairings)
What have high doses of oclacitinib been shown to do in vitro?
reduced secretion of IL-2, IL-15, IL-18 and IFN-γ by lymphocytes
induce apoptosis of canine CD4+ and CD8+ T cells
prevented the generation of regulatory T cells and the production of IL-10
Why might JAK/STAT inhibitors be a good option for the treatment of canine cutaneous lupus erythematosus?
skin lesions transcriptome show strongly activated IFNαβ signaling via JAK–STAT with upregulation of CXCL10, ISG15 and S100
- CLE variants represent a form of interferonopathy
What is the mechanism of oclacitinib?
non-selective JAK inhibitor though highest affinity for JAK 1 and JAK 3
JAK can’t phosphorylate STAT so it can’t form a dimer and enter the nucleus
What is the mechanism of action of Bruton’s tyrosine kinase inhibitors?
BTK is an important signaling protein that serves as a link between the BCR and B-cell proliferation and survival
also is expressed in many other cells of hematopoietic origin but not T cells
inhibits many signaling cascades downstream of BCR binding, including the PI3K-ALT pathway, PLC, PKC and NFκB
What is human intravenous immunoglobulin?
purified product of pooled human plasma from multiple healthy donors
90% of hIVIg is purified IgG (trace other immunoglobulins)
used for its ability to regulate the immune system, inhibit phagocytosis, and
decrease tissue damage
What are the mechanisms of action of human intravenous immunoglobulin?
Fc receptor blockade
autoantibody elimination
cytokine modulation
complement inhibition
Fas–Fas ligand blockade
How does the mechanism of tacrolimus differ from that of cyclosporine?
tacrolimus binds to FK506 binding protein, which then suppresses the activation of the NFAT pathway and inhibits early activation of T cells
What is the mechanism of action of amoxicillin?
Bactericidal
Time dependent
Inhibits the biosynthesis and repair of the bacterial mucopeptide wall
What is the mechanism of action of Clavamox?
Bactericidal
Time dependent
Clavalanic acid is a b-lactamase inhibitor
Amoxicillin inhibits the biosynthesis and repair of the bacterial mucopeptide wall
What is the mechanism of action of cephalexin?
1st generation cephalosporin
Bactericidal
Time dependent
utilizes its beta-lactam ring to inhibit the synthesis of peptidoglycan
- binds to/inactivates penicillin-binding proteins (PBP)
- on the inner membrane of the bacterial cell wall
What is the binding site of b-lactams?
Unstable, 4 member beta-lactam ring
Have two adjacent rings with subclasses:
- Penicillin
- Cephalosporine
What is the basic cell wall of bacteria?
Peptidoglycans layers
- Repeating disaccharide units
Cross-bridging of pentapeptides
- Provides rigidity
- D-ala-D-alanine is normal substrate for cross-link
- Catalyzed by transpeptidase enzymes
–>“Penicillin Binding Proteins”
How to b-lactams work in general?
Target: transpeptidase enzyme (mimicked by b-lactam)
- 9 different penicillin binding proteins
- Terminal D-ala-D-alanine pentapeptide substrate
Causes:
- Instability (autolysins contribute to instability)
- Cell wall becomes permeable –> osmotic lysis and cell death
What category of antibiotics are b-lactams?
Time-dependent
Bactericidal
Which organisms have inherent resistance to b-lactams?
Cell wall-deficient microbes
- Mycoplasma, Chlamydia (most)
Those with b-lactamases
Those with mecA genes
Describe concentration (dose)-dependent antibiotics.
Irreversible effects
High concentrations to assure all targets impacted
Increase dose
- Cmax:MIC 10 to 12 X MIC
Generally once daily therapy
Generally excellent postantibiotic effect
- Gram negative > gram positive
- Aminoglycosides, Fluoroquinolones
Describe time-dependent antibiotics.
Reversible effects
- Minimal post antibiotic effect
Drug must be present
Goal: T>MIC
- Most of dosing interval
- T>MIC 50-100%
- Shorten dosing interval
- Cell wall drugs (b-lactams, vancomycin)
- “Static” drugs
- Potentiated Sulfonamides
What are the natural b-lactams?
Penicillin
Works best on:
- Gram +
- Anaerobes
- “Easy” G-
What are the semi-synthetic b-lactams?
Ampicillin
Amoxicillin
Work against:
- Gram-positive
- Gram-negative (E. coli, Klebsiella, Proteus)
- Anaerobes
- With or without clavulanic acid
What are the extended-spectrum penicillins?
Semi-synthetic penicillins
Ticarcillin
Carbenicillin
Piperacillin
Works against:
- same as other penicillins
- Addition of virulent Gram –
- Pseudomonas
- Serratia, Enterobacter
- With or without clavulanic acid
How does the bactericidal activity of cephalosporins compare to that of penicillins?
Cephalosporins are:
More resistant to penicillinase
Better against gram positive
- Staphylococcus
Less effective toward anaerobes
What are the 1st generation cephalosporins?
Cephalexin
Cefazolin
- Cefazolin > cephalexin for E. coli
What are the 3rd generation cephalosporins?
Ceftiofur
Cefovecin
Cefpodoxime
Ceftazidime
Cefotoxime
What are the mechanisms of b-lactam resistance?
Beta-lactamases
- Destruction of ring
- Drug inactivated
Failed delivery to PBP
- Decreased porins
- Efflux pumps
Altered PBPs due to mutations
- Failed drug binding
- PBP-2 (mec gene)
- others
How can genes related to b-lactamases be acquired by bacteria?
Mutational and plasmid-mediated
Where are b-lactamases expressed?
Periplasmic space and cell wall
What is New Dehli metallo-betalactamase (NDM-1)?
carbapenemase beta-lactamase
- hydrolyzes and inactivates these carbapenem antibiotics (and all others)
What is the elimination of b-lactams like?
Renal excretion
- Active tubular secretion
- 1 to 2 hr half-life
–> 90% of drug gone in 3-6 hr
- Exceptions
–> Ceftiofur (4-5 h)
–> Cefpodoxime (4-5 H0
–> Cefovecin (120 h)
Occasional hepatic metabolism
- Ceftiofur (produces active metabolites)
What are the side effects of b-lactams?
Rare except for hypersensitivity
- No cell wall = no target
Hypersensitivity (allergy)
- Haptens
- Type I hypersensitivity
–> Penicillins> cephalosporins
–> Risk in humans impacts withdrawal
Electrolyte (anionic) imbalance
- K+ (hyperkalemia)
- Na+ (cardiac disease)
What are some considerations of b-lactams in large aminals?
Withdrawal issues
- 10% of humans allergic to penicillins
–> Restrictions vary with drug and state
–> Preparation specific
–> Slow > regular release
- Dressing loss
- Milk residues
- ELDU of cephalosporins prohibited (very limited exception)
Absorption with intrauterine infusion
Potassium Penicillin G:
- Less expensive (large animal)
- Caution with K+ overload
How do antihistamines interact with the H1 receptor?
inverse agonists
bind to and stabilize the inactive form of H1R
act quickly
What are the pharmacologic effects of antihistamines other than preventing histamine activity?
prevent the release of mediators from mast cells and basophils
- inhibit the formation of Ca ion channels
inhibit eosinophil migration
What are the 4 aspects of the immune system that are affected by corticosteroids?
1) affect leukocyte production and circulation
2) influence the effector mechanisms of lymphocytes
- block NF-kB signaling
- upregulate FoxP3
3) modulate the activities of inflammatory mediators
4) modify protein, carbohydrate, and fat metabolism
What are the effects of glucocorticoids on lymphocytes?
block NF-kB signaling
-inhibit proinflammatory cytokines
upregulate IL-4, IL-10, and IL-13 by Th2
upregulate CD121b
- IL-1 decoy receptor
upregulate FoxP3
JAK-STAT signaling pathways to reduce ILC2
enhance the production of lipocortin
- inhibits phospholipase A2 and COX
need high doses to affect B cells
In which species do corticosteroids have no effect on phagocytosis by neutrophils?
horses and goats
What is misoprostol?
synthetic prostaglandin E1 analog
elevates intracellular
levels of cyclic AMP –>
reduces the production of the inflammatory cytokines
IL-1, TNF-a and leukotriene B4 as well as lymphocyte proliferation and granulocyte activation
What drugs should be used be avoided with colchicine?
drugs that inhibit P-glycoprotein and CYP3A4, such as erythromycin or clarithromycin
What is the mechanism of action of allopurinol?
Metabolized to active metabolite (oxypurinol/alloxanthine) in the liver which inhibits xanthine oxidase, the enzyme that converts hypoxanthine to xanthine and xanthine to uric acid
is metabolized by Leishmania into an inactive form of inosine that is incorporated into the parasite’s RNA (leading to faulty protein synthesis)
What is the mechanism of action of meglumine antimoniate?
selectively inhibits the Leishmania enzymes required for glycolytic
and fatty acid oxidation
What is the mechanism of action of miltefosine?
is thought it inhibits the penetration of the parasite into macrophages by interacting
with glycosomes and glycosylphosphatidylinositol-anchored proteins that are important for the survival of the parasites in the host cells
also inhibits phospholipase
What is the mechanism of dapsone?
is an antibiotic that has also been used for autoimmune disease
- inhibits bacterial synthesis of dihydrofolic acid thereby inhibiting nucleic acid synthesis
- inhibits myeloperoxidase in neutrophils
What are the potential side effects of dapsone?
hypersensitivity
hemolysis
methemoglobinemia
hepatitis
What are potential side effects of allopurinol?
hypersensitivity syndrome with eosinphilia and hepatitis
SJS/TEN in humans
bone marrow depression
Why should concomitant use of allopurinol and certain immunomodulatory medications be avoided?
azathioprine’s metabolite 6-mercaptopurine needs xanthine oxidase to be inactivate but that is the target of allopurinol
increases half-life of cyclosporine
What is the mechanism of action of azoles?
non-competitive, reversible, binding to lanosterol 14αdemethylase (CYP51)
- part of the CYP450 family
stops the conversion of lanosterol to ergosterol
- accumulation of toxic sterol intermediates and a depletion of ergosterol
- fungal cell membrane becomes more permeable and less functional
requires hydrogen bond
between oteseconazole and His-377
Which drugs are imidazoles?
clotrimazole, ketoconazole, thiabenazole
Which drugs are first generation triazoles?
fluconazole, itraconazole
* broader spectrum of activity and better pharmacokinetic properties compared to imidazoles
Which drugs are second generation triazoles?
voriconazole, posaconazole, and ravuconazole
*even broader antifungal spectra and improved pharmacokinetic profiles
What are the non-antifungal effects of ketoconazole?
Inhibits cytochrome P450 3A
Inhibits 5-LOX
Inhibits migration of neutrophils
Suppresses lymphocyte proliferation (blastogenesis)
Inhibits CYP11B1
- involved in cortisol biosynthesis
Activates the AhR-Nrf2 pathway
- reduces oxidative stress
- leads to the suppression of pro-inflammatory cytokine production
What is the mechanism of action of griseofulvin?
binds to the microtubules in the fungal cells, disrupting the mitotic spindle and inhibiting cell division
- arrests cell division in metaphase
may antagonize chitin synthesis
What is the mechanism of action of terbinafine?
belongs to the allylamine class of antifungal agents
inhibits the enzyme squalene epoxidase
- leads to the accumulation
of squalene which is toxic and disrupts cell membrane integrity
- cannot make ergosterol
What is the mechanism of lufenuron?
benzoylphenylurea drug that disrupts chitin synthesis
What is the mechanism of amphotericin B?
Bind with ergosterol in fungal cell membrane, alters cell permeability and creates channels
- K+ and Mg+ loss
- internal acidification
- loss of enzyme activity
What is the mechanism of nystatin?
Bind with ergosterol in fungal cell membrane, alters cell permeability = cell death
What is the mechanism of action of acetic acid?
Lowers pH of cell protoplasm
What is the mechanism of action o chlorhexidine?
Synthetic biguanide – disrupts microbial cell membrane and coagulate cytoplasmic proteins
What is the mechanism of action of clindamycin?
Inhibits protein synthesis
at the 50S ribosomal
subunit
How does resistance to clindamycin occur?
inducible resistance occurs by methylation of 23S rRNA
What is the mechanism of action of doxycycline?
Binding 30S ribosomal
subunit, affect bacterial
protein synthesis
is lipophilic
may have calcium chelation
What fluid should amphotericin B be reconstituted in to avoid precipitation?
5% dextrose
How is amphotericin B modified to make it less nephrotoxic?
liposomes which are phagocytized by macrophages at the site of infection –> more drug to target site
local therapy (topical or local infusion)
How does amphotericin B cause nephrotoxicosis?
1) intense arteriole vasoconstriction (4-5 hr long) –> renal tubular ischemia
- pretreat with sodium containing fluids
1) increase distal tubular permeability –> renal tubular acidosis
- consider mannitol
Other than nephrotoxicity, what are some side effects of amphotericin B?
Thrombophlebitis
Anaphylactoid reaction
How do the drug interactions of voriconazole differ from ketoconazole?
voriconazole appears to INDUCE rather than inhibit drug metabolizing enzymes
Why do azole cause so many drug interactions?
Inhibit CYP450 drug metabolizing enzymes
compete with other drugs for efflux transport by P-glycoprotein
- inhibition of both metabolism and transport of other drugs
What are the bactericidal inhibitors of bacterial ribosomes?
Aminoglycosides
- Gentamicin
- Amikacin
What are the bacteriostatic inhibitors of bacterial ribosomes?
Tetracyclines
Phenicols
Lincosamides
Macrolides
Tilmicosin
What is the mechanism of action of aminoglycosides?
Aminocyclitol sugar
- Water soluble
- Weak Base
Concentration dependent
Inhibits 30s subunit of ribosome
- Boothe notes say whole 70s
How does bacterial protein formation occur?
Happens on ribosomal subunits
Initiation: 30s and 50s become 70s
Elongation: RNA transfers amino acid to growing complexes on 50s subunit
Peptide transferred to next 30s subunit
What organisms are inherently resistant to aminoglycosides?
Obligate anaerobes
- also active transport at cell membrane has minimal activity in anaerobic environments
How does TrizEDTA help antibiotic efficacy?
Chelates ions in bacterial cell wall/membrane
What organisms are aminoglycosides effective against?
Gram - (ex. Pseudomonas)
Selected gram +
Nocardia and atypical mycobacteria
Why can aminoglycosides not be given orally?
They are trapped in acidic pHs
Why are aminoglycosides nephrotoxic?
Accumulate in kidneys due to active uptake
- tubular > glomerular
- lysosomal trapping and rupture –> cell death
Impaired cellular respiration and renal prostaglandins
What is the mechanism of action of linezolid?
binds to 50s and prevents the formation of a functional 70S ribosomal initiation complex
What is the spectrum of activity of linezolid?
Gram + only
What are some side effects of linezolid?
is a weak MAO inhibitor
GI toxicity
Allergic reactions (rare)
Peripheral neuropathies
Inhibitor of P-glycoprotein
Other than nephrotoxicity, what are some side effects of aminoglycosides?
Ototoxicity
- hair cells
Neurologic
- Interfere with calcium flux and acetylcholine release
Other than aminoglycosides, what are the antibiotic characteristics of ribosomal inhibitors?
Time dependent
Bacteriostatic
Lipid soluble (excellent distribution)
Hepatic/biliary elimination
- tetracyclines have some renal
What is the mechanism of action of tetracyclines?
Target the 30s ribosomal subunit
- impaired translocation
Best efficacy in immunocompetent patients
What is the spectrum of activity of tetracyclines?
“Broad”
fair to good gram +
fair to good gram -
fair to good anaerobic
works against intracellular parasites
What are the mechanisms of resistance against tetracyclines?
Efflux protein
- Plasmid mediated
Altered penetration
Why do tetracyclines stain growing teeth?
They bind to cations in forming bone and teeth as inactive drug
- doxycycline not as much
What are the anti-inflammatory effects of tetracyclines?
inhibit matrix metalloproteinases (MMP), hydrolases, and phospholipase A2
reduce the secretion of pro-inflammatory cytokines
modulation of lymphocyte activation and neutrophil chemotaxis
What is the mechanism of action of phenicols?
Bacteriostatic
Time-dependent
Target the 50s ribosomal subunit
- loss of amino acid addition
What is the mechanism of resistance to phenicols?
Acetylation
- minimized with the addition of F (ex. in florfenicol)
What is the spectrum of action of phenicols?
Similar to tetracyclines
Broad Spectrum
Gram negative, fair to good
Gram positive, fair to good
Anaerobic, good to excellent
Rickettsial, good
- Doxycycline better
Mycoplasma/chlamydia, good
- Doxycycline better
Why are cats more susceptible to side effects of acetaminophen, propofol, carprofen, phenicols, azathioprine, and acetylsalicylic acid (aspirin)?
Cats lack the major phenol UDP-glucuronosyltransferase (UGT) enzymes, including UGT1A6 and UGT1A9
Also deficient in N-acetyltransferase (NAT) 2 and thiopurine methyltransferase (TMPT)
What is the primary mechanism for interactions between phenicols and other drugs?
Phenicols are potent inhibitors of hepatic drug metabolizing enzymes
What is the mechanism of action of lincosamides?
*Clindamycin
Bind to 50s ribosomal subunit
Bacteriostatic
Time-dependent
Accumulate in WBCs
Lipid soluble with good distribution
What is the spectrum of activity of lincosamides?
Gram positive aerobes
- Staphylococcus sp
- Streptococcus sp
Anaerobic
- “Antirobe®”
Actinomycetes
Some protozoa
What is the mechanism of action of macrolides?
*erythromycin, azithromycin
Bind to 50s ribosomal subunit
Bacteriostatic
Time-dependent
Accumulate in WBCs
Lipid soluble with good distribution
What is the spectrum of activity of macrolides?
Excellent Gram positive
Selected Gram negative
Anaerobes (good)
Actinomycetes
Mycoplasma
Decreases biofilm
How do macrolides cause drug interactions?
Inhibition of metabolism and efflux (P-glycoproteins)
What is the mechanism of action of sulfonamides and diaminopyridines (ex. trimethoprim)?
Each competitively inhibit steps in bacterial folic acid synthesis so they synergistically have bactericidal effects and are combined
- time dependent
What is the spectrum of activity for potentiated sulfonamides?
Broad spectrum
Gram positive
Gram negative (non-virulent)
Anaerobic
- Limited by resistance
Nocardia/Actinomyces
* Are ineffective against cell-wall deficient microbes ex Mycoplasma or Chlamydia
Which sulfonamide is orally bioavailable and has the best tissue distribution?
Sulfadiazine
What are some side effects of sulfonamides
Hypersensitivity (drug allergy)
- Arylamine to nitrosamine (toxic metabolite)
- Dog predisposed esp Dobermans with SNP in canine cytochrome b5 reductase (CYB5R3)
- Any tissue but especially KCS
Bone marrow suppression?
Crystalluria (?)
Hypothyroidism (high doses)
- Reversible
- inhibit thyroid peroxidase
What characterizes 3rd and 4th generation fluroquinolones?
enhanced efficacy toward anaerobes and decreased resistance
- larger molecules that bind better
What is the mechanism of action of fluoroquinolones?
Target topoisomerases
II (DNA gyrase)
- unwinding during replication
- Gram - > Gram +
IV
- Repairs supercoils
- Gram + >Gram -
Irreversibly destroys bacterial DNA
accumulate in WBCs
What is the spectrum of activity of fluoroquinolones?
Aerobic
Gram negative
- Pseudomonas sp
Limited Gram positive
- Staphylococcus sp
- Corynebacterium
Anaerobes
- Pradofloxacin
Chlamydia, Mycoplasma, Ehrlichia (?)
Atypical mycobacteria
What are some side effects of fluoroquinolones?
Cartilage defects
- Growing large breeds and high concentrations
Ligament damage in athletes
Acute retinal degeneration esp cat
- Enro»_space; marbo, prado
Lowered seizure threshold
- Increased risk in epileptics and IV bolus
Gastrointestinal
Drug interactions
- Selective inhibition of drug metabolism
Prado and bone marrow suppression in US dogs
What is the mechanism of action of metronidazole?
DNA reduction in an anaerobic environment
What is the mechanism of action of rifampin?
inhibits RNA polymerase thus preventing DNA transcription
concentrates in RBCs
What is the spectrum of activity of rifampin?
Gram positive
- MRS
- Rhodococcus sp
- Tuberculosis
Rapid resistance: combination therapy
How does rifampin cause drug interactions?
is a marked inducer of drug metabolizing enzymes
What is the mechanism of action of fipronil?
2GABA-gated chloride channel antagonist
What is the mechanism of action of imidacloprid?
Neonicotinoid
Mimics ACh by competitive inhibition at the post-synaptic nicotinic acetylcholine
receptors leads to influx of Na
ions and little or no effect on
the muscarinic ACh receptors
Which animals should you avoid fipronil use in?
Rabbits and hedgehogs
What is the mechanism of action of dinotefuran?
Neonicotinoid
Nicotinic aCh receptors agonist
Mimics ACh by competitive inhibition at the post-synaptic nicotinic acetylcholine
receptors leads to influx of Na
ions and little or no effect on
the muscarinic ACh receptors
What is the mechanism of action of nitenpyram?
Neonicotinoid
Nicotinic aCh receptors agonist
Mimics ACh by competitive inhibition at the post-synaptic nicotinic acetylcholine
receptors leads to influx of Na
ions and little or no effect on
the muscarinic ACh receptors
What is the mechanism of action of spinosad?
Neonicotinoid
Nicotinic aCh receptors agonist
Activation of nicotinic acetylcholine receptors of the nerve cell membranes of insects
What is the spectrum of action of fipronil?
Fleas
Ticks
Lice
Extra-label activity against Cheyletiella and Chorioptes
What is the mechanism of action of isoxazolines?
potent inhibitors of γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and l-glutamate-gated chloride channels (GluCls)
What is the mechanism of action of macrocyclic lactones?
glutamate-gated chloride channels agonist
What is the mechanism of action of macrocyclic lactones?
glutamate-gated chloride channels agonist
What is the mechanism of action of indoxacarb?
Potent blocker of voltage-gated sodium ion channels in fleas
What is the mechanism of action of pyrethrins/pyrethroids?
Sodium channel disruptor
What species should you avoid use of pyrethrins/pyrethroids in?
Most are toxic to cats (except flumethrin)
What is the mechanism of action of lufenuron?
Chitin biosynthesis inhibitor
What is the mechanism of action of organophosphates/carbamates?
Irreversibly inhibit acetylcholinesterase (AChE) by phosphorylation, results in accumulation of acetylcholine (ACh) at cholinergic receptors
What are the side effects of organophosphates/carbamates?
Miosis, lacrimation, vomiting, diarrhea, urination, dyspnea,
bradycardia, hypertension,
tremors, twitching, paresis,
paralysis
What is the mechanism of action of amitraz?
Inhibits monamine oxidase (MAO) that normally metabolize neurotransmitter amines present in the CNS of ticks and mites
What are the side effects of amitraz?
Toxicity (CNS depression, bradycardia, polyuria, hyperglycemia, and sedation)
What animals should you avoid use of amitraz in?
Cats and horses
Why were dips with amitraz and metaflumizone discontinued?
Pemphigus reactions
What is the mechanism of action of pyriproxyfen?
Juvenile hormone mimetic
What is the mechanism of action of methoprene?
Juvenile hormone mimetic
What is the mechanism of action of leflunomide?
Isoxazole immunosuppressant
Converted to active metabolite (M1 or teriflunomide), inhibits synthesis of pyrimidine via inhibition of dihydro-orotate dehydrogenase
Which ectoparasiticide should you avoid in birds?
Imidacloprid
Which ectoparasiticide should you avoid in chelonians?
Ivermectin
What is the mechanism of action of topiramate?
Inhibits glutamate activity, blocks neuronal excitability, preventing seizures and migraines. Also blocks voltage dependent sodium channels, blocking seizure activity
What is the mechanism of action of mitotane?
Binds to reactive acyl chloride intermediates in adrenal cortex leads to cell death/destruction
- zona glomerulosa is relatively resistant
also interferes with steroid biosynthesis, primarily through inhibition of the 11-hydroxylase and cholesterol side-cleavage enzymes
What is the mechanism of action of trilostane?
competitive inhibitor of adrenal 3-B-hydroxysteroid
dehydrogenase (precursor for cortisol synthesis)
- effects are reversible and dose dependent
What is the mechanism of action of methimazole?
inhibition of thyroid peroxidase
What are some side effects of cortisol?
related to a rapid decrease in serum cortisol
- usually mild and resolve with administration of glucocorticoids
- Addison’s disease develops in ~2-5%
Rare delayed drug-induced central nervous system signs
- usually transiet and resolve with lower doses
What is the efficacy of mitotane?
effective treatment in 85-90 % of dogs with PDH
approximately 50% of dogs will relapse within the first year
How does ketoconazole work in treating Cushing’s disease?
inhibits 11 -hydroxylase and cholesterol side-chain cleavage enzymes (desmolase)
Other Imidazole antifungals do NOT do this, but etomidate anesthetic (is an Imidazole) does
What are the drugs indicated by letters?
(A) Mitotane
(B) Trilostane
(C) Ketoconazole
What is levodeprenyl (a.k.a., selegiline)?
FDA approved medication for the treatment of PDH in dogs, and is also used to treat canine cognitive dysfunction
irreversible inhibition of monoamine oxidase B
- results in increased central dopamine levels
decreased concentrations of dopamine in the brain may play a role in excessive release of ACTH so levodeprenyl may inhibit ACTH secretion
What is the mechanism of action of cyproheptadine?
serotonin antagonist
Inhibits CNS serotonin concentrations
seratonin stimulates pars intermedius ACTH production)
therefore decreases ACTH secretion from the pars intermedius
- poor efficacy for Cushing’s
What is the mechanism of action of bromocriptine?
Dopamine agonist
dopamine inhibits par intermedia ACTH production
very poor efficacy against Cushing’s in dogs but works well in horses
What is the mechanism of action of pergolide?
ergot derivative similar to bromocriptine which acts as a dopamine receptor agonist
has agonist activity on both D1 and D2 dopamine receptors and acts directly on the substantia nigra
used for PPID in horses
What is the mechanism of action of retinoic acid in Cushing’s disease?
been shown to inhibit proliferation, invasion, and tumor growth in vivo and induces differentiation and apoptosis in different cell types by binding of the transcription factors AP-1 and Nur77 to their cognate DNA sites
- factors also control POMC gene, which results in ACTH and α-MSH production
What is the mechanism of action of imiquimod?
activates the innate and adaptive immune responses via binding to Toll-like receptor 7
- activates NFkB
- releases IFN-a, IFN-y, TNF-a, IL-1, IL-6, and IL-8
Activation of Langerhans cells
- activate adaptive immune system
Activation of macrophages, NK cells, and B-cells
Immune-system independent anti-proliferative effects
induces apoptosis of skin cancer cells and has demonstrated anti-tumoral activity
What is the typical cause of hypothyroidism in horses?
hypothyroidism and dysmaturity in foals
- mares fed diets that contain abnormal amounts of iodine
Rare/anecdotal in adults
What effects does retinol have on the skin?
promotes their proliferation
enhances turn-over
strengthens the epidermal protective function
reduces TEWL
protects collagen against degradation and inhibits the activity of MMPs
reduce pigmentation
block differentiation and cellular divisions of sebocytes
improves skin elasticity (removes degenerated elastin fibers)
promotes angiogenesis
What do retinoids rely on for transportation in the blood?
prealbumin (transthyretin)
What is the active form of retinol?
retinoic acid
How does retinol become retinoic acid?
retinol enters a cell –>
retinol dehydrogenase or alcohol dehydrogenase catalyse the oxidation of retinol to retinal (retinaldehyde) –>
xidized to retinoid acid by retinaldehyde dehydrogenase or some enzymes of the CYP family
What is the mechanism of action of cisplatin?
binds to DNA, causing inter-strand and intra-strand cross-links
may be combined with sesame seed oil for injection
What is the mechanism of action of 5-fluorouracil?
a fluorinated pyrimidine that blocks the methylation reaction of deoxyuridylic acid to thymidylic acid, thus interfering with the synthesis of DNA
What are the alkylating agents?
include nitrogen mustard, cyclophosphamide, chlorambucil, melphalan, busulfan, and Ifosfamide
nitrosoureas (CCNU and BCNU)
the tetrazines (DTIC, or dacarbazine)
the aziridines (thiotepa and mitomycin C)
the non-classical alkylating agents such as procarbazine and hexamethylmelamine
What is the mechanism of action of nitrogen mustard derived alkylating agents?
cross-linking strands of DNA, particularly at the N-7 position of guanine
What is the mechanism of action of non-nitrogen mustard derived alkylating agents?
covalent cross-links in DNA, more typically at the 0-6 position of guanine
What are the folic acid antagonist antimetabolites?
methotrexate and 5-fluorouracil
What are the purine antagonists antimetabolites?
azathioprine, mercaptopurine, and 6-thioguanine
What are the pyrimidine antagonists antimetabolites?
cytosine arabinoside and gemcitabine
What is the mechanism of action of L-asparaginase?
antimetabolite
inhibits lymphoma cells with an absolute requirement for the pre-formed amino acid asparagine
- normal cells can make their own
What are the antitumor antibiotics or topoisomerase inhibitors?
doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, and bleomycin
What are the side effects of nitrogen mustard alkylating agents?
myelosuppression, gastrointestinal toxicity, and sterile hemorrhagic cystitis (cyclophosphamide and iphosphamide. Ifosfamide must be given with the bladder-sparing agent Mesna, to avoid severe urothelial injury)
What are the side effects of antimetabolite agents?
myelosuppression and gastrointestinal toxicity (especially methotrexate)
What is the mechanism of action of antitumor antibiotics (ex. doxorubicin)?
intercalation of DNA and interference with
topoisomerase enzyme function
A induced failure to replicate DNA, impaired protein production through interference with transcription of messenger RNA, and chromosomal strand breaks caused by interference with the unwinding of DNA via
topoisomerase
What are the side effects of antitumor antibiotics or topoisomerase inhibitors?
myelosuppression, GI signs, cardiac (doxorubicin), pulmonary (bleomycin) and renal (doxorubicin in cats), perivascular sloughing, anaphylaxis, and alopecia
What are the plant alkaloids?
derived from periwinkle, mayapple, and Pacific yew tree
mitotic spindle poisons active in G2 and M phases of cell division (vinca alkaloids ex vincristine and vinblastine, taxanes)
or are topoisomerase interactive agents (etoposide and teniposide)
What is a major problem with the taxane class (paclitaxel and docetaxel) of chemotherapeutics?
extremely anaphylactogenic
must be administered with extensive and thorough premedication with steroids and antihistamines
What are the side effects of the plant alkaloids?
mild with vincristine are mild
- perivascular reactions can happen Vinblastine is more myelosuppressive than is vincristine in general
anaphylaxis is the greatest problem associated with administration of taxanes, along with myelosuppression and GI toxicity
How do platinum chemotherapeutic agents work?
crosslinking DNA, generally at the guanine base
What are the platinum chemotherapeutic agents?
Cisplatin and carboplatin
What are the side effects of platinum chemotherapeutic agents?
Cisplatin is highly nephrotoxic and must be given with extensive fluid diuresis.
Carboplatin is not nephrotoxic but is renally cleared so care must be taken when giving carbo to patients with mild renal insufficiency. Cisplatin is not for use in cats, as it causes a fatal pulmonary edema in this species
What are some breed sensitivities associated with doxorubicin?
Shelties, Collies, Westies, Yorkies (GI toxicity)
Dobes, Rotts, Boxers (subclinical cardiomyopathy–always echo these)
How do conditioners work?
are cationic so neutralize charge
slightly acidic so hardens keratin and removes hard water residues
contain a fatty or oily component
What are occlusive emollients?
oils or contain lanolin
decrease transepidermal water loss and cause moisturization
What are hygroscopic agents (humectants)?
work by being incorporated into the stratum corneum and attracting water
propylene glycol, glycerin, colloidal oatmeal, urea, sodium lactate, carboxylic acid, and lactic acid
In which ways can topical anti-pruritics work?
- Decreasing the pruritic load by depleting,
removing, or inactivating pruritic mediators - Substituting some other sensation
- Protecting from external influences
- Anesthetizing the peripheral nerves
- Raising the pruritic threshold by cooling or moisturizing
- Using specific biochemical agents
What are the the mechanisms of action of propylene glycol?
antibacterial and antifungal agent
40-50% concentration is best
has humectant properties
higher concentrations denatures and solubilizes protein and is keratolytic
What are examples of common topcial oxidizing agents?
Hydrogen peroxide
Potassium permanganate
Benzoyl peroxide
Why is lime sulfur keratoplastic and keratolytic?
hydrogen sulfide [H2S] breaks down keratin
Why is lime sulfur thought to be antimicrobial?
presumably by conversion to pentathionic
acid and H2S (this conversion can be accomplished by cutaneous bacteria and by keratinocytes)
What are some properties of dDimethyl sulfoxide (DMSO)?
freely miscible with lipids, organic solvents, and water
cryoprotective, radioprotective, antiischemic, antiinflammatory (free radical scavenger, decreases prostaglandin synthesis, stabilizes lysosomal membranes), and analgesic (blocks C fibers)
What is hyperthermia chemotherapy?
enough heat in a local superficial area to cause tissue necrosis
Heat is controlled to affect only the tumor and 2-3 mm of surrounding normal tissue
What are the effects of glucocorticoids on eosinophils?
Decrease formation in bone marrow
Induce apoptosis and inhibit prolongation of eosinophil survival and function from IL-3 and IL-5
What are the effects of glucocorticoids on lymphocytes and monocytes?
Reduce number of lymphocytes and monocytes that bear low affinity IgE and IgG receptors
Decrease serum immunoglobulin levels
Decrease all lymphocyte subpopulations
Decrease lymphocyte production of IL-1, 2, 3, 4, 5, 6, and IFN-g
Inhibit release of IL-1 and TNF-a from monocytes
What are the effects of glucocorticoids’ inhibition of phospholipase A2?
Decrease production of arachidonic acid metabolites
Decrease production of platelet-activating factor
What are thought to be the useful immunologic effects are possible with cryosurgery?
When a cell mass is frozen and left to die in situ, membrane lipoprotein complexes, and hence antigen-antibody complexing and receptor sites, may cause antigenicity and produce a strong specific immunologic response that may kill escaped cells of the same tumor species
What is the mechanism of action of mupirocin?
inhibiting isoleucyl-transfer RNA, thereby obstructing bacterial protein and RNA synthesis, ultimately resulting in cell death
Which formulation of penicillin should be avoided in horses?
procaine penicillin G
What are the side effects of macrolides in horses?
not used in adults due to the occurrence of severe and sometimes fatal colitis
in foals, macrolides may produce distress syndromes
Which fluoroquinolone is contraindicated in horses?
Ciprofloxacin is contraindicated in horses due to poor PO absorption and possible severe colitis
Why might enrofloxacin concentrations be greater in black hairs than white hairs?
enrofloxacin is extensively bound to
melanin in vitro
Which classes of antibiotics are b-lactams synergistic with?
aminoglycosides and fluoroquinolones
What are some anti-inflammatory or immunomodulatory properties of macrolides?
inhibit leukocyte chemotaxis, IL-1, and lymphocyte blastogenesis
What are some anti-inflammatory or immunomodulatory properties of trimethoprim?
inhibits leukocyte chemotaxis
What are some anti-inflammatory or immunomodulatory properties of fluroquinolones?
inhibit IL-1, leukotriene, and TNF-a synthesis
inhibit granulomatous inflammation
What are some anti-inflammatory or immunomodulatory properties of tetracyclines?
inhibition of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6
inhibition of proinflammatory enzymes such as inducible nitric oxide synthetase and matrix metalloproteinases
downregulation of MHC class II expression
suppression of T cell proliferation and activation
induction of tolerogenic dendritic cells (DCs)
What are the side effects of excessive systemic iodides in horses?
scaling and alopecia, depression, anorexia, fever, cough, lacrimation, serous nasal discharge, salivation, nervousness, or cardiovascular abnormalities
What are the mechanisms of action of systemic iodides?
antifungal (unknown mechanism)
- not antifungal in vitro
enhance the halide-peroxidase killing system of phagocytic cells
antiinflammatory agents by virtue of their ability to quench toxic oxygen metabolites and inhibit neutrophil chemotaxis
What have systemic iodides been used to treat in horses?
sporotrichosis
basidiobolomycosis and conidiobolomycosis
nodular cutaneous candidiasis
eumycotic mycetoma
Why does ivermectin not affect trematodes and cestodes?
GABA is not involved in neurotransmission in those species
What does ivermectin do to ticks?
Ticks are not killed, but their egg production and molting are suppressed
