Pharmacology

Question 1

MDR1 (ABCB1) - which are problem vs safe drugs?

Answer 1

MDR1 (ABCB1) problem drugs:
- Sedatives - butorphanol, ACP
- MLs (ivermectin, selamectin, milbemycin, moxidectin)
- Loperamide
- Apomorphine
- Chemo: vincristine, vinblastine, doxorubicin, paclitaxel

Drugs pumped out by MDR1, but safe:
- Cyclosporin
- Digoxin
- Doxycycline
- Morphine, buprenorphine, fentanyl

Drugs pumped out by human MDR1, but unknown in dogs:
- Mitoxantrone
- Ondansetron
- Etoposide
- Domperidone
- Rifampicin

Question 2

Nitrofurantoin - MOA, indications, adverse effects?

Answer 2

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 3

Cyclosporin MOA?

Answer 3

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 4

Mycophenolate mofetil MOA?

Answer 4

Purine synthesis inhibitor - similar to azathioprine

Question 5

Azathioprine MOA?

Answer 5

Purine synthesis inhibitor - similar to mycophenolate

Question 6

Leflunomide MOA?

Answer 6

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

Question 7

Definition of a breakpoint?

Answer 7

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 8

Meropenem
- Antibiotic class
- Effective against?

Answer 8

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 9

Fluoroquinolones
- MOA
- Bacteriostatic or -cidal?

Answer 9

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

Question 10

Tetracyclines
- MOA
- Bacteriostatic or -cidal?

Answer 10

Blocks tRNA access to 30s ribosomes. Bacteriostatic.

Question 11

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

Answer 11

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

Question 12

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

Answer 12

**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 13

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

Answer 13

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

Question 14

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

Answer 14

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 15

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

Answer 15

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 16

Impact of cyclosporine on glucose homeostasis in dogs?

Answer 16

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 17

What are the 2 phases of drug metabolism?

Answer 17

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 18

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

Answer 18

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 19

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

Answer 19

Gentamicin in urine
Doxycycline in bile

Question 20

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

Answer 20

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 21

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

Answer 21

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 22

Gabapentin MOA?

Answer 22

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 23

Bisphosphonates MOA?

Question 24

MOA of FQ-induced retinotoxicity in cats?

Answer 24

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 25

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

Answer 25

• 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 26

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

Answer 26

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 27

How does frusemide (loop diuretics) affect venous capacitance?

Answer 27

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

Question 28

Dopamine
- MOA

Answer 28

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 29

Fenoldopam
- MOA

Answer 29

• 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 30

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

Answer 30

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 31

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

Answer 31

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 32

Describe treatment strategies for calcium channel blocker toxicity.

Answer 32

*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 33

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

Answer 33

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.

Question 34

Cisapride
- MOA
- Indications
- AE

Answer 34

5-HT4-receptor agonist. Enhances ACh release without stimulating nicotinic or muscarinic receptors or inhibiting acetylcholinesterase activity –> s.m. (e.g. GI myenteric plexus, detrusor) contraction
–> Increase bladder contraction and reduce residual urine volume

Increase lower oesophageal peristalsis & LES pressure), increases gastric contractions, accelerates gastric emptying, promotes SI & LI motility.
- Blocks dopaminergic receptors to a lesser extent than metoclopramide and does not increase gastric acid secretion.

Megacolon, urine retention, GI functional stasis/ileus

SE: GI, abdo discomfort

Question 35

Bethanechol
- MOA
- Indications
- AE

Answer 35

Cholinergic agent (minimal nicotinic effects).
Increase bladder contractility, dysautonomia (prokinetic)
AE - SLUD signs, V+, miosis, cholinergic crisis if given IV/IM.
AVOID - GI/urinary tract obstructions, hyperT (NE sensitivity > exacerbate arrhythmias/AFib)

Question 36

ABCB1 mutation - types & how much to dose reduce?

Most common breeds affected by ABCB1 mutation?

Answer 36

3 types:
- NULL (mutant/mutant)
- INTERMEDIATE (mutant/normal)
- WILD (normal/normal)

With homozygous - reduce dose by 50%
With heterozygous - reduce dose by 25%

Aus Shepherd 50%, Collies 70%, McNab 30%, Silken Windhound 30%
(Border collie <5%, GSD 10%, Eng Shepherd 15%)