Comparative pharmacology

Question 1

Veterinary pharmacology

Answer 1

Challenges in working with many species

Question 2

What does ADME stand for?

Answer 2

Absorption, Distribution, Metabolism, Excretion

Question 3

What does PKPD mean?

Answer 3

Pharmacokinetic/ Pharmacodynamic = relates drug effects to a measure of drug concentration in a body compartment.

Question 4

Factors influencing interspecies PKPD differences

Answer 4

Anatomy - size, skin, muscles, internal organs- influences administration, absorption and distribution

Physiology - systems - GI, repro, liver, kidneys

Behaviour - directly and indirectly, effects how we administered

Genetics - Explains similarities and differences between and within species

Question 5

Drug administration (interspecies PK differences)

Answer 5

Influenced by: Anatomy, Physiology, Behaviour, Husbandry/ management - individual animal and herd approach

Question 6

Different routes and challenges across species

IV route

Answer 6

Intravenous route - challenges of size and venous access across species - behaviour as well due to domestication of species

Question 7

Intramuscular route

Answer 7

similar skeletal muscles system between species = similar bioavalibility between species

Need to be mindful of renal portal system in birds and reptiles - Blood from the caudal half of the body drains through renal system before getting back to the heart so it will have implications for drugs injected in caudal half of body

Tolerance

Question 8

Subcutaneous route

Answer 8

Variable tolerance

Vaccine induced sarcomas = Malignant transformation of fibroblastic cell associated w/ prolonged inflammatory reaction after injection

Fibromatous reaction s following SC injection in cats

Question 9

Oral administration

Answer 9

Importance of feeding behaviours
- neophobia vs neophobia
- cats vs dogs and variation between species
- Importance of taste (salt, sugars, flavours) - taste Varys between species and will need palatable tablets

Challenges of mass administration
- e.g. antibiotics in food- easy, less stress

Question 10

Neophobia vs Neophilia

Answer 10

Neophobia = unwilling to take in novel substances e.g. non-vomiting species

Neophillia = willing to take in novel substances e.g. carnivores

Question 11

Intramammary administration

Answer 11

Good for cattle due to their anatomy - e.g compared to a cat

Question 12

Transdermal administration

Answer 12

Pour on/ spot on treatments
depends on
- behaviour
- structure of skin
- Variation in bioavailability e.g ivermectins more bioavalible in cattle than dogs

Question 13

Drug absorption and distribution (interspecies PK differences)

Digestive system

Answer 13

Mono vs polygastric (ruminants)

monogastic system:
- Variation in oesophageal anatomy - cats having potential to retain tablets - Tendency to obstruction/ choke in horses
- Fast passage in stomach - important role in disintegration and dissolution of drug formulations
- Pylorus = sieve - regulates passage to duodenum where major absorption occurs

Polygastric system: continues on next card

Question 14

Polygastric system - ruminants

Answer 14

The reticule-rumen (RR) can influence PK (PD)
- has a large capacity and is slow emptying
- Has a keratinised wall - so poor absorption (except weak acids)
- Acidic (5.5-6.5) - trapping of weak bases - they get ionised so will be poorly absorbed
- Dilution and increased residence time of orally administered drugs
- Microflora of the rumen can inactivate drugs by metabolic or chemical reactions

e.g. salicylic acid - has sustained plasma concentrations after oral administration in ruminants despite short half life after iv administration

Question 15

Ruminants continued

Answer 15

The reticulo-omasal orifice - equivalent to the pylorus

Need the development of prolonged/ sustained delivery devices
- in order to stay in reticulo-rumen for days, weeks, months
- wings to prevent regurgitation
- dense to prevent floating
- release drugs close to ROO - Reticulo omasal orrfice

Question 16

Cellulose binding

Answer 16

Is specific to herbivores
Has an importance in horses
- Release of drug with cellulose breakdown
- will mean that feeding will have an influence on bioavalibility.
- will explain the GI side effects of NSAIDS in LI of horses - ulceration in not only stomach also in colon

Question 17

Metabolism ( Interspecies PK differences)

Answer 17

Phase 1 and Phase 2 metabolic pathways

• Inter-species quantitative differences in phase 1 and qualitative difference in phase 2 metabolism
• Cytochrome P450 -
• e.g poor capacity of cats to carry out some glucuronidatitons - paracetamol toxicity, PK of NSAIDS
• e.g. deficiency of dogs for acetylation reactions
• e.g. low level of sulphate conjugation in pigs

Question 18

What is phase 1 and phase 2 metabolism

Question 19

Excretion (interspecies PK differences)

Answer 19

Urinary pH is determined by diet - will differ in herbivores and carnivores - will effect excretion of drugs

Question 20

Factors affecting within species difference

Answer 20

• Age
• Sex
• Disease/ healthy
• Physical state
• Mobility
• Diet
• Genetics
• Circadian rhythms

Question 21

Pharmacogenetics definition=

Answer 21

The study of variability in drug response due to heredity - largely used in gene determining drug metabolism

Question 22

Pharmacogenomics definition =

Answer 22

A broader term that encompasses all genes in the genome that may determine drug response

Both terms can be used interchangeably- Arbitrary distinction

Question 23

Examples of polymorphism

Answer 23

CYP450 enzymes polymorphism
- Thiopental greyhounds - Slow recovery after thiopental anaesthesia due to metabolism of barbituets through CYP450

CYP2B11
- Propofol beagles - they have a greater proportion of hydroxylase activity

MDR1 mutation in dogs
- have a glycoprotein gPg in blood brain barrier
- leads to inefficient blockade of toxins
- Means dogs are very sensitive to ivermectine and loperamide

Question 24

Dose extrapolation

Answer 24

Linear extrapolation = Same dose for all species (mg/kg) - assumes differences in PK/PD are not clinically relevant e.g. larger animal larger dose

Metabolic scaling
- Non-validated and failures reported

Allometric scaling
- Most common - not perfect
- assumes species difference in PD are negligible and that PK has a log-log (allometric) relationship to weight - dose extrapolations to determine initial dose in veterinary species

Question 25

Summary

Answer 25

Interspecies differences
- Pharmacokinetic and pharmacogenetics
- genetic influences drug administration

Intraspecies difference
- Multiple factors including pharmacogenetics

Interspecies extrapolation
- Approximation at best
- Always check the dose sheet for dose differences in species