Pharmacology- random bits Flashcards
Immunomodulatory properties of doxycycline/niacinamide
Tetracycline:
1) suppresses antibody production
2) inhibits complement activation
3) inhibits prostaglandin synthesis
4) inhibits lipase and collagenase function
Niacinamide:
1) Blocks IgE-induced histamien release
2) Prevent mast cell degranulation
3) Decreased protease release
4) inhibit phosphodiesterases
Which comorbidity should you be cautious of when prescribing doxycycline to dogs
Hx seizures
(neurologic AEs reported in humans)
MOA of pentoxifylline
*Synthetic xanthine derivative
*Inhibits phosphodiesterase
ALLERGY: inhibits T and B cell activation, increase IL-10, PGE2, decrease leukocyte adhesion, decrease neutrophil superoxide, degranulation, IFNg, NK cell activity
*Rheological effects
*Improves wound healing (Increased fibroblast collagenases, decrease TNFa)
Borates + vacuuming can kill ____ in carpets and sofas for up to 6 months
House dust mites
Which inflammatory transcription factor do omega 3 fatty acids inhibit, thereby preventing TNFa production
NFkB
T or F: diphenhydramine is readily available in the horse
False. Poor bioavailability. Need injectables.
How do omega 3 fatty acids prevent prostaglandin synthesis
Inhibit prostaglandin H synthase
Which immunosuppressants target the T cells
*Glucocorticoids
*Azathioprine
*Cyclosporine
*Chlorambucil
*Mycophenolate
*Oclacitinib
Which immunosuppressants target antibodies (IgG)
IVIg
Plasmapharesis
Which immunosuppressants target tissue inflammation
*Glucocorticoids
*Doxycycline/Niacinamide
*Hydroxychloroquine
Primary cellular of glucocorticoid therapy
T cells
What do glucocorticoids bind? Where in the cell?
Glucocorticoid receptor
Bind in the cytoplasm
When GC is unbound to glucocorticoid receptor, what inhibits glucocorticoid receptor action
Chaperon molecule
What are the 4 possible actions of GCs once they bind GRs
1) Translocate to nucleus –> bind to GRE (glucocorticoid response element) on DNA
2) Translocate to nucleus –> bind to NEGATIVE GRE (nGRE)
3) GRs bind to a DIFFERENT transcription factor to repress inflammation (NKfB, STAT, AP-1)
4) NON-genomic effects. Direct action on cell membranes, adhesion molecules, membrane ion channels.
ie: increase expression of demosomal cadherins, for better keratinocyte adhesion
Why might dogs on high dose cyclosporine be more prone to fungal infections
Altered neutrophil function = increased susceptibility to opportunistic infections
T or F: NFAT is only present on T cells
False. NFAT present in almost every cell in body.
HIGH DOSE Cyclosporine can cause altered function in myeloid cells (macrophages, DCs, neut, MC, eos). Low dose cyclosporine is T cell only
Which transcription factor is blocked by cyclosporine
NFAT
Major cytokine made by NFAT
IL-2
(Cyclosporine blocks IL-2, blocks T cell proliferation)
Why does it take a few weeks for cyclosporine to work for lupus and AISBDs?
Limits antibody production via T-B cell interactions
It takes a few weeks after inhibiting T cells to then have an effect on antibody production
Binding to GRE induces transcription of these genes (3):
Antiinflammatory
1) Annexin-1
2) GC-induced leucine zipper, which inhibits NFkB, MAPK
3) Mitogen activated protein kinase phosphatase 1 (MAPKP1)
Binding to nGRE inhibits transcription of these genes (3):
1) CRH
2) b-endorphins
3) MSH
Name the 4 janus kinase family members
JAK1
JAK2
JAK3
TYK2
Apoquel: most-to-least potent effect on JAKS
JAK1>JAK3> JAK2, TYK2
Allegedly JAK1 specific
Which JAK is important for hematopoiesis
JAK2
Which JAK is important for Th1 immune response
TYK2
Effect of inhibition of JAK1
*Impaired T cell proliferation, differentiation
*Impaired signaling, esp Th2 cytokines
(infections, hypercholesterolemia, possible NK cell impairment)
Effect of inhibition of JAK2
*Impaired erythropoiesis and myelopoiesis
(infections, anemia, neutropenia)
Effect of inhibition of JAK3
Impaired T cell proliferation
(infections)
Effect of inhibition of TYK2
Impaired Th1 and Th17 response
(infections)
What is the active metabolite of azathioprine (pro-drug)
6-mercaptopurine
MOA of azathioprine
6-MP blocks purine metabolism, interferes with DNA synthesis
“antimetabolite”
Why are lymphocytes susceptible to azathioprine
They have de novo purine synthesis
Reduces B and T cell proliferation
Elevation in which enzyme makes some animals more susceptible to hepatotoxicity 2’ azathioprine
Thiopurine methyltransferase (TPMT)
Do cats and horses have a HIGH or LOW activity of their TPMT (azathioprine enzyme)
LOW activity
Makes cats at higher risk for myelosuppression
Why do horses have a LOWER risk of myelosuppression with azathioprine at standard doses
Low bioavailability of azathioprine in horses
Which metabolite of azathioprine is immunosuppressive
6 thioguanine nucleotides
“false purine” stops cell cycle –> apoptosis
Which medication should NOT be combined with azathioprine
Allopurinol
Allopurinol is a xanthine oxidase inhibitor, so more of the azathioprine is pushed to active metabolite form (XO would make inactive metabolite = safer)
Which medication should NOT be combined with azathioprine, as it inhibits TPMT
Sulfasalazine
Myelosuppression
Category of medication of chlorambucil
Nitrogen mustard alkylating agent
MOA chlorambucil
Cross-links DNA during all phases of the cell cycle. INTERstrand is most cytotoxic
Cell cycle arrest –> Apoptosis
Effects B and T cells
AE of chlorambucil
Myelosuppression
GI upset
Reversible myoclonic neurotoxicity
Fanconi syndrome (cats)
Main metabolite of mycophenolate mofetil
Mycophenolic acid
Function of Mycophenolic acid
Inhibits inosine-5’-monophosphate dehydrogenase
Depletes guanosine nucleotides in activated B and T cells –> inhibits proliferation and antibody formation
Higher doses of Mycophenolate mofetil increase the risk of _____ side effect
GI issues (diarrhea, hematochezia, vomiting)
T or F: it is crucial to monitor for myelosuppression with mycophenolate mofetil
False. GI side effects primarily
Why are IVIg beneficial for autoimmune diseases
IVIg increases catabolism of pathogenic IgG
IVIg preferentially binds to neonatal Fc receptors (FcRn). If bound to FcRn, Ig is protected from degredation. Because IVIg is taking all the FcRn spots, pathogenic IgG cannot bind–> so it is degraded.
What are the risks of IVIg
Hypercoagulation
Renal failure
Hypotension
Hypersensitivity
Anaphylaxis (xenoproteins!)
Which cytokines does doxycycline inhibit
IL-1
IL-6
IL-8
TNFa
4 anti-inflammatory mechanisms of doxycycline
1) Decrease cytokines (IL-1, IL-6, IL-8, TNFa)
2) Inhibit MMPs
3) Reduce leukocyte chemotaxis
4) Reduces NO synthase function
MOA of niacinamide
Endogenous inhibitor of PARP-1
1) Inhibits proinflammatory cytokines
2) Reduces ICAM-1 expression (decreased neutrophil chemotaxis)
3) Reduces B cell differentiation
Mechanisms of colchicine
1) Inhibits neutrophil chemotaxis, adhesion, and mobilization
2) Inhibits superoxide production
3) Inhibits NALP3 inflammasomes (IL-1b processing)
Prevents tubulin polymerization, so poor neutrophil motility!! Cannot migrate through tissues!!
Which immunomodulatory medication works primarily on neutrophils
Colchicine
(niacinamide works on neuts via ICAM, but also B cells)
Most common AE from colchicine
GI upset (nausea, vomiting, diarrhea, abdominal pain)
Which medication should be avoided with colchicine
Cyclosporine
Both are p-glycoprotein substrates!
Immunomodulatory effects of hydroxychloroquine
*Inhibits TLR7, TLR9 signaling on pDC
*Disrupts IFNs, TNFa, IL-6 production
*Inhibits prostaglandin production
*Changes antigen presentation
(For CLE in people)
Diseases in vet med that hydroxychloroquine has been used in
ECLE
GDLE
Drugs that ACCELERATE glucocorticoid metabolism by the liver
*Rifampin
*Phenobarbital
*Trimethoprim
*Azathioprine
*Clindamycin
INDUCE cytochrome p450 enzymes, so faster metabolic clearance
How do glucocorticoids cause neutrophilia
Decrease ICAM, ECAM expression on endothelial cells –> less neutrophil migration to tissues.
Less margination
More released from bone marrow
Less neutrophil apoptosis
Impact of glucocorticoids on lipcortin 1
Increased
Results in decreased PLA2 on cell membrane, so less arachidonic acid
Decreased PAF
Order of most to least impact on leukocytes by GC
Decrease in CD4 T cells»_space; CD8 T cells»_space;» least impact on B cells
GC impact on IL-1, TNFa, histamine
IL-1, TNFa by monocytes
Decreased histamine synthesis by mast cells
GC impact on antibody synthesis
ONLY decreases Ig synthesis at HIGH DOSES, long term
How do glucocorticoids cause PUPD in dogs
Interference with ADH –> polyuria
How do glucocorticoids cause PUPD in cats
Glucosuria and osmotic diuresis
Which steroid is the most diabetogenic in cats
Dexamethasone
How do aminoglycosides cause nephrotoxicity
Accumulate in proximal renal tubules
Apoptosis of renal tubular epithelium and glomerular damage
Which antibiotic should be avoided in patients with myesthenia gravis? Why?
Aminoglycosides
Can cause neuromuscular blockade
Mechanism of why fatty acids can decrease pruritus
Fatty acids compete with COX/LOX enzymes, so decreased arachidonic acid metabolism
Also induce less inflammatory byproducts during fatty acid metabolism
Immunomodulatory and rheologic effects of pentoxifylline (6)
1) Fluid cell membrane
2) T cells flow better through vessels
3) Decreased response to IL-1, IL-4, IL-12, TNFa
4) Decreased platelet aggregation
5) Inhibit B and T cell activation
6) Decreased NK cell activity
Which enzymes does melatonin inhibit
*21-hydroxylase (decreased cortisol levels)
*aromatase (decreased estradiol levels)
Which enyzme does phytoestrogens inhibit
3-B hydroxysteroid dehydrogenase
(sama as trilostane)
Which bacteria is inherently resistant to TMS
Enterococcus
Which bacteria are resistant to aminoglycosides
Anaerobes
Aminoglycosides require oxygen to be transported to cytoplasm
(Aminoglycosides are best for gram negative bacteria, with more LPS)
Which breeds are more likely to have hypersensitivity reactions to TMS
Doberman pinschers»_space;
Samoyeds, mini schnauzers
How does erythromycin cause GI upset
Stimulates motilin hormone –> smooth muscle contractions
Why should you be cautious when combining macrolides with other medications
Affect cytochrome p450. Can increase concentration of other drugs
What is an adverse effect of linezolid
Inhibits MAO –> interferes with SSRIs.
Bone marrow suppression
Which antibiotics affect cell wall synthesis
*Beta lactams (PBP, peptidoglycan linking)
*Glycoprotein (vancomycin, Ala-ala crosslinking)
Which antibiotics affect bacterial protein synthesis
*Lincosamides (50s)
*Macrolides (50s)
*Chpc (50s)
*Linezolid (50s)
*Aminoglycosides (30s)
*Tetracyclines (30s)
Which antibiotics affect nucleic acid synthesis
*Fluoroquinolones (DNA gyrase, topoisomerase IV)
*TMS (PABA analog, decreased dihydrophenoic acid, decreased folic acid)
*Rifampin: (b-subunit of RNA synthase)
*Metronidazole (electron acceptor ->nitroso -> ROS -> DNA damage)
Which tetracycline is ok to give with food, but should be avoided in CKD
Doxycycline
Why is doxycycline immunomodulatory
*Decreased nitric oxide synthase activity
*Decreased TNFa
TetM offers resistance to ____
ALL tetracyclines (including mino)
Amitraz MOA
1) Monoamine oxidase inhibitor (avoid SSRIs, TCAs)
2) Alpha-2 adrenergic agonist (like dexdomitor. Avoid sedatives. Tx for toxicity = atipamezole, yohimbine)
3) Inhibits prostaglandin synthesis
High dose, off-label Apoquel can affect which cytokines (4)
IL-2
IL-15
IL-18
IFNg
Which animals have LOW levels of TPMT, resulting in more bone marrow suppression with azathioprine use
Cats
Giant Schnauzers
Which species have HIGH levels of TPMT, resulting in LESS azathioprine toxicity (but also less efficacious)
Malamutes
Dapson affects which cell type
Dapson decreases neutrophil production
Which cytokines does cyclosporine inhibit (4)
IL-2
IL-4
IFNg
TNFa
Which cytokines does Imiquimod stimulate
IFNa
TNFa
IL-12
Via TLR7
Which immunomodulatory medication kills cats
5-FU
Pyrimadine analog
How is mycophenolate excreted
Kidney (+ bile)
