Comparative pharmacology Flashcards
Veterinary pharmacology
Challenges in working with many species
What does ADME stand for?
Absorption, Distribution, Metabolism, Excretion
What does PKPD mean?
Pharmacokinetic/ Pharmacodynamic = relates drug effects to a measure of drug concentration in a body compartment.
Factors influencing interspecies PKPD differences
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
Drug administration (interspecies PK differences)
Influenced by: Anatomy, Physiology, Behaviour, Husbandry/ management - individual animal and herd approach
Different routes and challenges across species
IV route
Intravenous route - challenges of size and venous access across species - behaviour as well due to domestication of species
Intramuscular route
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
Subcutaneous route
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
Oral administration
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
Neophobia vs Neophilia
Neophobia = unwilling to take in novel substances e.g. non-vomiting species
Neophillia = willing to take in novel substances e.g. carnivores
Intramammary administration
Good for cattle due to their anatomy - e.g compared to a cat
Transdermal administration
Pour on/ spot on treatments
depends on
- behaviour
- structure of skin
- Variation in bioavailability e.g ivermectins more bioavalible in cattle than dogs
Drug absorption and distribution (interspecies PK differences)
Digestive system
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
Polygastric system - ruminants
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
Ruminants continued
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
Cellulose binding
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
Metabolism ( Interspecies PK differences)
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
What is phase 1 and phase 2 metabolism
Excretion (interspecies PK differences)
Urinary pH is determined by diet - will differ in herbivores and carnivores - will effect excretion of drugs
Factors affecting within species difference
- Age
- Sex
- Disease/ healthy
- Physical state
- Mobility
- Diet
- Genetics
- Circadian rhythms
Pharmacogenetics definition=
The study of variability in drug response due to heredity - largely used in gene determining drug metabolism
Pharmacogenomics definition =
A broader term that encompasses all genes in the genome that may determine drug response
Both terms can be used interchangeably- Arbitrary distinction
Examples of polymorphism
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
Dose extrapolation
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
