Pharmacology

Question 1

MDR1 - which non-chemotherapeutic drugs?

Answer 1

Sedatives - butorphanol, ACP
Macrocyclic lactones (ivermectin, selamectin, milbemycin, moxidectin)
Loperamide
Apomorphine

Question 2

Drugs removed from brain by MDR1 gene but safely tolerated by dogs?

Answer 2

Cyclosporin
Digoxin
Doxycycline
Morphine
Buprenorphine
Fentanyl

Question 3

Nitrofurantoin - MOA, indications, adverse effects?

Answer 3

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.

Question 4

Cyclosporin MOA?

Answer 4

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).

Question 5

Mycophenolate mofetil MOA?

Answer 5

Purine synthesis inhibitor - similar to azathioprine

Question 6

Azathioprine MOA?

Answer 6

Purine synthesis inhibitor - similar to mycophenolate

Question 7

Leflunomide MOA?

Answer 7

Pyrimidine synthesis inhibitor –> impairs nucleotide synthesis, suppresses multiple DNA- & RNA-dependent functions of B- & T-cells.

Question 8

Definition of a breakpoint?

Answer 8

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)

Question 9

Meropenem
- Antibiotic class
- Effective against?

Answer 9

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.

Question 10

Fluoroquinolones
- MOA
- Bacteriostatic or -cidal?

Answer 10

Blocks DNA replication via blocking DNA topoisomerase IV or gyrase (3rd generation do both).
Bactericidal.

Question 11

Tetracyclines
- MOA
- Bacteriostatic or -cidal?

Answer 11

Blocks tRNA access to 30s ribosomes. Bacteriostatic.

Question 12

Which 2 cardiorespiratory drugs may be rare causes of coughing in dogs?

Answer 12

ACE-I, beta-blockers (not reported in cats)

Question 13

What drugs could be indicated for a hypertensive emergency? MOA?

Answer 13

**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.

Question 14

What is the median time of onset for hepatotoxicity with azathioprine use and the incidence? What breed is over represented?

Answer 14

Median 14 days, occurs in 15% of dogs. GSDs overrepresented.
Cytopenias occur later (median 53d, up to 196d).

Question 15

Capromorelin - MOA? Was it effective in improving appetite in dogs? Adverse effects?

Answer 15

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+)

Question 16

Ratio of glucocorticoid: mineralocorticoid properties of the following drugs?
Hydrocortisone
Cortisone
Methylpred
Dexamethasone
Betamethasone
Fludrocortisone

Answer 16

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

Question 17

Impact of cyclosporine on glucose homeostasis in dogs?

Answer 17

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)

Question 18

What are the 2 phases of drug metabolism?

Answer 18

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&raquo_space; inactivation
- Drug molecule becomes larger + less lipophilic, to become sufficiently water soluble for renal/hepatic excretion.

Question 19

For phase II of drug metabolism, name 2 examples of spp differences (1 each for dog & cat) & implications for drug toxicity/adverse effects?

Answer 19

UGT (uridine diphosphate glucuronosyltransferase) enzymes catalyze glucuronide conjugation.
- **Cats lack UGT1A6 & 1A9 **» decreased/ alternate conjugation of acetaminophen&raquo_space; large amt of acetaminophen undergoes phase I metabolism&raquo_space; reactive metabolites&raquo_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.

Question 20

Name 2 drugs that are excreted intact (i.e. not metabolised)

Answer 20

Gentamicin in urine
Doxycycline in bile

Question 21

What should be considered when a dog receiving phenobarbitone is also being fed a urinary alkalinizing diet?

Answer 21

Pheno = weak acid.
Alkalinizing the urine leads to pheno ionization –> traps it in renal tubules & prevents diffusion back into vasculature –> so significantly inreases elimination.

Question 22

What is the mechanism & effects of enterohepatic recirculation?
List drugs that undergo this?

Answer 22

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

Question 23

Gabapentin MOA?

Answer 23

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)

Question 24

Bisphosphonates MOA?

Question 25

MOA of FQ-induced retinotoxicity in cats?

Answer 25

Changes in the ABCG2 transporter –> leads to accumulation of photoreactive fluoroquinolones in the retina.

Risk factors - large doses or plasma concentrations of drug, 2) rapid IV infusion, 3) prolonged tx courses, 4) age

Question 26

3 advantages of pradofloxacin vs other FQs (regarding MOA)?

Answer 26

• Higher efficacy vs G+ aerobes & anaerobes, some mycobacteria
• Higher efficacy vs other G- bacterial spp (Bartonella, B. bronchiseptica, extra-intestinal E. coli)
• Lacks retinotoxicity in cats

Question 27

What is main adverse effect of amphotericin B in dogs & cats & mechanisms involved?
What treatment strategies can be employed to reduce this AE?

Answer 27

Nephrotoxicity, dose dependent.
Transient with early detection, can have acute & chronic cumulative effects.
MOA:
- Amp B binds to cholesterol in membranes of the renal distal tubules –> changes cell permeability –> PUPD, [ ] defects, acidification abnormalities –> distal RTA + nephrogenic DI
- Also causes excessive Ca release into blood –> Ca precipitates in the acidic envt of the distal tubules –> nephrocalcinosis

Use of liposomal formulations less nephrotox. Also IVFT before/after tx to avoid GFR drop.
Avoid co-admin with nephrotox drugs (cyclosporine, digitalis, aminoglycosides)

Question 28

How does frusemide (loop diuretics) affect venous capacitance?

Answer 28

Mediates renal prostaglandin (PGI2) release by blocking PG synthetase inhibitors) –> increases renal blood flow + systemic venous capacitance

Question 29

Dopamine
- MOA

Answer 29

Central + peripheral receptors > effects through SNS
- Low doses: preferentially stimulates D1 and D2 receptors in the renal vasculature > vasodilation & promotes RBF to preserve glomerular filtration
- Intermediate doses: CVS effects > **stimulates β1 receptors (heart) **> increases HR & FOC  increases C.O. & BP (afterload)
- High doses: pressor effects > stimulates **α1 adrenergic receptors in vessels **> vasoconstriction, further increases BP (afterload)

Question 30

Fenoldopam
- MOA

Answer 30

• Selective dopaminergic (D1) agonist, may have a renoprotective effect in acute ischemic injury. Dilates the renal afferent arterioles/arteries, inhibits Na/K/ATPase activity, inhibits AT-II & ADH.
• Lacks D2, alpha or beta adrenergic activity so it does not cause vasoconstriction, tachycardia or arrhythmias that can sometimes be seen with dopamine

Question 31

Name 2 pharmacologic differences between liposomal formulations vs conventional formulations of amphotericin B?

Answer 31

Liposomal formulation:
- Achieves higher plasma [ ] (not taken up by reticuloendothelial system)
- Achieves higher tissue [ ] (remains tightly bound to phospholipid until it reaches areas of inflammation)
- Overall 8-10 x less nephrotoxic

Question 32

What are the effects of calcium channel blockers?
Apart from myocardial & nodal cells, where are L-type Ca channels located?

Answer 32

E.g. diltiazem, verapamil, amlodipine. Effects:
- CCBs prevent Ca influx in the nodal and myocardial cells > slow sinus rate in the SA node & reduced AV conduction.
- Prevent Ca influx into cardiomyocytes & vascular s.m. > reduced cytosolic Ca & Ca-induced Ca release from SR > decr inotropy & vascular tone.
- Inhibit platelet aggregation
- Decr insulin release > hyperglycemia (pancreatic receptors)
- Decr mitochondrial Ca > decr pyruvate dehydrogenase activity > lactate accumulation
- Natriuretic (direct effects on renal tubules) > monitor serum Na+ for few days

Locations:
Skeletal muscle.
Pancreatic beta cells
Lungs, brain etc.

Question 33

Describe treatment strategies for calcium channel blocker toxicity.

Answer 33

*Plasma CCB levels not useful (can get tox at therapeutic doses)

• Decontamination (induce emesis, gastric lavage, AC)
• Dialysis not useful (highly protein-bound)
• Atropine (persistent bradycardia)
• High-dose insulin euglycemic therapy (used in people; give to reduce hyperglycemia then dextrose supp PRN)
• Glucagon - incr BG +** inotrope + chronotrope **- acts on cardiac G protein–coupled receptors > increase myocardial Ca influx
• IVLE (drug sequestration + provide FFA for myocardium)
• Inamrinone (PDE-III inhibitor) > increases cAMP > incr myocardial Ca influx > improves contractility & impulses. Caution vasodilation.
• Temporary pacemaker placement
• 4-aminopyridine (Ampyra) - K+ channel blocker, incr Ca influx

Question 34

What properties of antibiotics allow good penetration into prostatic parenchyma? Name some examples of abx.

Answer 34

Lipophilic, low protein-binding
Weak bases, pKa >7.0 > acidic prostatic pH allows trapping of ionic drugs within prostatic fluid.
Amphoteric drugs.

E.g. FQs, TMPS, chloramphenicol.
NB FQ have good penetration at any pH.
NOT penicillins, cephalosporins, aminoglycosides.