Pharmacology Flashcards
MDR1 - which non-chemotherapeutic drugs?
Sedatives - butorphanol, ACP
Macrocyclic lactones (ivermectin, selamectin, milbemycin, moxidectin)
Loperamide
Apomorphine
Drugs removed from brain by MDR1 gene but safely tolerated by dogs?
Cyclosporin
Digoxin
Doxycycline
Morphine
Buprenorphine
Fentanyl
Nitrofurantoin - MOA, indications, adverse effects?
MOA - bacteriostatic - inhibits DNA, RNA, protein synthesis, acetyl co-A, energy metabolism & cell wall synthesis. Bactericidal with higher concentration + depending on organism susceptibility. More efficacious in acidic environment. Targets G- & some G+. Little-no activity vs proteus, serratia, Actineobacter sp. NO activity vs Pseudomonas & Corynebacterium sp.
Indications - 2nd line abx for bacterial cystitis - when resistant to other drugs. NOT pyelo as drug only achieves therapeutic concentrations in the urine not kidneys.
SE: GI (most common), peripheral neuropathy (weakness), hepatopathy (monitor liver enzymes). Humans - jaundice, hepatitis, hepatic necrosis (rare), pulmonary toxicity (tx >6mths).
Contraindications: renal impairment (high risk of neurotox), hypersensitivity.
Cyclosporin MOA?
Inhibits enzyme calcineurin in lymphocytes –> impairs lymphocyte function by suppression of nuclear factor of activated T-cell-regulated cytokines (e.g. IL-2, IFN-γ).
Mycophenolate mofetil MOA?
Purine synthesis inhibitor - similar to azathioprine
Azathioprine MOA?
Purine synthesis inhibitor - similar to mycophenolate
Leflunomide MOA?
Pyrimidine synthesis inhibitor –> impairs nucleotide synthesis, suppresses multiple DNA- & RNA-dependent functions of B- & T-cells.
Definition of a breakpoint?
Chosen concentration (mg/L) of an abx which defines whether a bacterial spp. is susceptible or resistant to the abx.
Breakpoint is not reported to the clinician. Breakpoints are established on the basis of multiple factors, which include 1) a knowledge of MIC distributions and resistance mechanisms for each organism-drug combination, 2) clinical response rates in humans and animal models, 3) how the drug is distributed and metabolized in the body (pharmacokinetics), and 4) whether the drug is concentration-dependent or time-dependent as it relates to antibacterial effect (pharmacodynamics).
If MIC for the bacteria falls within the published breakpoint (concentration required) –> then it is considered susceptible.
E.g. breakpoint for amoxyclav in dogs in urine is HIGHER than serum, meaning more bacteria are likely to be susceptible as will include bacteria which are killed by clav at higher concentrations.
E.g. breakpoint for clav in urine <8ug/ml. MIC for E coli: 2ug/ml –> susceptible (vs plasma breakpoint 0.5ug/ml = resistant)
Meropenem
- Antibiotic class
- Effective against?
β-lactam antibiotic of the carbapenem class.
Wide spectrum of activity against many aerobic and anaerobic G+ (except MR-S & MR-Enterococcus spp) & G- bacteria. Relatively resistant against destruction via hydrolysis of many β-lactamases.
Carbapenems are more potent bactericidal and have longer post-antibiotic effect than other β-lactams because they bind to penicillin-binding proteins (PBP-1 & PBP-2). PK studies have been done in cats at 10mg/kg.
Fluoroquinolones
- MOA
- Bacteriostatic or -cidal?
Blocks DNA replication via blocking DNA topoisomerase IV or gyrase (3rd generation do both).
Bactericidal.
Tetracyclines
- MOA
- Bacteriostatic or -cidal?
Blocks tRNA access to 30s ribosomes. Bacteriostatic.
Which 2 cardiorespiratory drugs may be rare causes of coughing in dogs?
ACE-I, beta-blockers (not reported in cats)
What drugs could be indicated for a hypertensive emergency? MOA?
**Fenoldopam: **
* Dopamine-1 agonist. Causes renal arterial vasodilation, natriuresis & increased GFR in normal dogs.
**Hydralazine (0.5-2 mg/kg PO q12h) **
* Rapid onset of action. Can be used for rapid reduction of BP in cats & dogs. Direct acting s.m. relaxant. Inhibits Ca release within the muscle.
Nitroprusside
* Provides intracellular NO which activates guanylate cyclase > increased intracellular cGMP > inhibits s.m. contraction.
* Potent arterial + venous dilation.
* Mildly increases HR, mild decreased CO, significantly reduces SVR.
What is the median time of onset for hepatotoxicity with azathioprine use and the incidence? What breed is over represented?
Median 14 days, occurs in 15% of dogs. GSDs overrepresented.
Cytopenias occur later (median 53d, up to 196d).
Capromorelin - MOA? Was it effective in improving appetite in dogs? Adverse effects?
Zollers JVIM 2016
Other names = AT-002 and CP-424,391
Small molecule, GH secretagogue. Potent & selective ghrelin agonist (GHS compounds mimic ghrelin secreted from endocrine cells in the stomach). Stimulates appetite.
Drug improved appetite at day 3.
AE: GI signs (V+, D+)
Ratio of glucocorticoid: mineralocorticoid properties of the following drugs?
Hydrocortisone
Cortisone
Methylpred
Dexamethasone
Betamethasone
Fludrocortisone
Hydrocortisone - G 1, M 1
Cortisone - G 0.8, M 0.8 (similar to hydrocortisone)
Methylpred - G 5, M minimal
Dexamethasone - G 30, M minimal
Betamethasone - G 30, M negligible
Fludrocortisone - G 15, M 150
Impact of cyclosporine on glucose homeostasis in dogs?
Decreases insulin secretion –> increases glucose & fructosamine [ ] –> uncommonly leads to DM
(Also found to decrease glucose uptake via GLUT-4 receptors on adipocytes, independent of insulin in people)
What are the 2 phases of drug metabolism?
Phase I: oxidation (add O2), hydrolysis (add H2O), reduction (add H+), hydration
- Drugs undergo chemical changes to become more water soluble
- CYP 450 enzymes
Phase II: AA conjugation, glucuronidation, sulfation, acetylation»_space; inactivation
- Drug molecule becomes larger + less lipophilic, to become sufficiently water soluble for renal/hepatic excretion.
For phase II of drug metabolism, name 2 examples of spp differences (1 each for dog & cat) & implications for drug toxicity/adverse effects?
UGT (uridine diphosphate glucuronosyltransferase) enzymes catalyze glucuronide conjugation.
- **Cats lack UGT1A6 & 1A9 **» decreased/ alternate conjugation of acetaminophen»_space; large amt of acetaminophen undergoes phase I metabolism»_space; reactive metabolites»_space; toxicosis even at subtherapeutic doses.
- Also morphine, but not a clinical concern as no reactive metabolites are formed; and drug is rapidly eliminated by sulfation conjugation
N-acetyltransferase enzymes – lacking in dogs
- Sulfonamide metabolism involves acetylation + sulfation reactions, so in dogs, increased risk of sulfonamide HS reactions
- Procainamide has different anti-arrhythmic effects in dogs (Class I effects only/Na+ channel antagonist) vs other spp (Class I + III/K+ channel antagonist) – as lack NAPA metabolite formation of drug.
Name 2 drugs that are excreted intact (i.e. not metabolised)
Gentamicin in urine
Doxycycline in bile
What should be considered when a dog receiving phenobarbitone is also being fed a urinary alkalinizing diet?
Pheno = weak acid.
Alkalinizing the urine leads to pheno ionization –> traps it in renal tubules & prevents diffusion back into vasculature –> so significantly inreases elimination.
What is the mechanism & effects of enterohepatic recirculation?
List drugs that undergo this?
Phase II of drug metabolism - drugs that are excreted by bile. Some drug undergoes conjugation by intestinal bacteria –> liberates free drug that can undergo intestinal absorption so recycled.
Effects - prolongs elimination half-life, also increased GIT exposure to drug (higher risk of AE)?
Antibiotics
NSAIDs (e.g. acetaminophen)
Hormones
Opioids
Digoxin
Warfarin
Methylxanthine (theobromine tox) – also through bladder epithelium
Gabapentin MOA?
Structural analogue of GABA, but does not interact with GABA receptors or influence endogenous GABA activity.
Inhibit voltage-gated Ca2+ channels (bind to alpha-2-beta subunit on channels)
Bisphosphonates MOA?
