Variation of Pharmacokinetics and Pharmacodynamics of Veterinary Medicines in Animals
PST 06107
Basic Veterinary Pharmacology
Session 2: Variation of Pharmacokinetics and Pharmacodynamics of Veterinary Medicines in Animals
Learning Tasks
By the end of this session students are expected to be able
to:
Outline
species of Interest in Veterinary
Medicine
Describe Drug Administration in Different Animal Species
Describe Drug Absorption in Different Animal Species
Describe Drug Metabolism of veterinary medicines in animals
Describe Dosage regimes of in Different Animal Species
Describe Pharmacodynamics of Drugs in Different Animal Species
Activity: Buzzing
What is the uniqueness of veterinary pharmacology compared to human pharmacology?
Species of Interest in Veterinary Medicine
Veterinary medicine is unique in that many types of animals, that is, livestock, companion animals, working animals, sports animals, laboratory animals, and some invertebrates such as honeybees
Most are domesticated species, but exotic animal species are also kept as pets (reptiles, amphibians, birds) and may therefore require treatment
In veterinary medicine, the critical step is to determine a rational dosing regimen (involving dose rate, inter-dosing interval, duration of treatment and mode of administration) for a selected drug
Species of Interest in Veterinary Medicine
Cont
…
The dosage regimen for a drug in a given species depends on its anatomy, biochemistry, physiology, and behaviour, as well as on the nature and causes of the condition requiring treatment. Hence, major biological differences impacting on dosage exist between animal
species
In
addition, within some species there may be considerable differences within and between breeds in pharmacokinetic (PK) and
pharmacodynamic
(PD)
profiles
Species of Interest in Veterinary Medicine
Cont
…
Also to be considered is veterinary pharmacogenetics, which is a new branch of veterinary science which identifies genetic variations (polymorphisms) as the origin of differences in the drug response of individuals within a given
species
These between
and
within species
differences in drug response are largely explained by variations in drug PK and PD, the magnitude of which varies from drug to drug.
Drug
Administration in Different Animal Species
Differences
in the modalities of drug administration across species result from anatomical, physiological, and/or behavioural
differences
Modality
of administration also depends on animal and management husbandry procedures, as in the case for food-producing animals, for which treatments are often collective
Drug
Administration in Different Animal
Species
Cont
…
Intramammary infusion
In
cattle, the udder has a single large teat canal for each quarter leading to a single large teat cistern and this enables the entire mammary quarter to be treated conveniently by
intramammary
infusion.
In dogs, the nipples have several fine openings (7–16) preventing local drug administration.
Drug
Administration in Different Animal
Species
Cont
…
Intramuscular administration
Intramuscular administration is a popular modality of drug administration in veterinary medicine and apparently no major differences exist across species in their skeletal muscular systems, so that no major differences are expected between species for the bioavailability of intramuscularly injected
drugs
In
poultry, however, the site of administration should be carefully selected (generally the pectoral muscle is chosen), because the bioavailability of a drug injected into the leg can be low or even null due to a first-pass effect in the
kidney
This
is because the kidney in birds is of a reptilian type with a renal portal system draining the lower regions of the body
Drug
Administration in Different Animal
Species
Cont
…
Subcutaneous route
For subcutaneous administration, it is reasonable to assume considerable similarity between species regarding the local tolerance of
formulations
However
, cats are specifically prone to the development of localised
fibro granulomatous
reactions to injectable vaccine products, producing vaccine-induced sarcomas as a result of malignant transformation of the fibroblastic cells associated with the prolonged inflammatory reaction
Drug Administration in Different Animal Species
Cont
…
The oral route
Oral administration is the most natural route of drug administration and there are many examples of interspecies differences in the modalities of oral administration that are linked to some aspects of feeding
behaviour
The
oral route is chosen because it enables large numbers of animals (sometime several thousands) to be treated conveniently and cheaply at the same time
Drug Administration in Different Animal Species
Cont
…
The oral
route……
For
antibiotic use in livestock, the objective is commonly to limit the progression of contagious disease in the overall population, rather than to treat a single subject as for companion
animals
Thus, the oral administration of drugs in drinking water (e.g. in poultry) or as medicated feed (e.g. for pigs) ensures that all animals are treated with minimum of
labour
The oral route is advantageous due to absence of stress that may occur with individual treatments that require first catching and then restraining and injecting animals individually
Drug Absorption in Different Animal Species
After
a drug administered by the oral route has been swallowed, it passes to the stomach from the esophagus
Esophageal transit normally takes a few seconds but the esophagus shows large interspecies histological differences with practical consequences for therapeutics
Esophageal muscle is striated in fish but smooth in birds, whilst mammals show considerable species variation in the presence of these two types of muscle
Drug
Absorption in Different Animal
Species
Cont
….
Both layers of muscle are striated throughout the length of the esophagus in dogs, sheep and cattle, whereas in cats the esophagus contains smooth muscle over approximately the terminal 8% of its length and 16% for its
circular muscle
This
is why cats are prone to retain foreign bodies in the distal part of the esophagus, including
tablets
This
may be problematic if highly acidic medications are retained that may cause severe irritation
Drug Absorption in Different Animal Species
Cont
….
In ruminants, the
reticulo
-rumen (RR) has a profound influence on the fate of all drugs due to its large capacity (225L in adult cattle), which leads to dilution and affects the residence time of orally administered
drugs
In
addition, the
microflora
of the rumen can inactivate drugs by metabolic or chemical reactions
Drug Absorption in Different Animal Species
Cont
….
The horse and rabbit are hindgut fermenters and the caecum and colon are major sites of microbial digestion of feed for these species
This makes horses and rabbits particularly prone to antimicrobial drug-induced
enterocolitis
, secondary to disruption of their normal microflora leading to an overgrowth of pathogenic microorganisms like Clostridium ssp.
In
the rabbit, C.
spiriforme
has been implicated as the primary causative agent producing iota toxin and causing enterotoxaemia and death
Drug Absorption in Different Animal Species
Cont
….
It should be stressed that the delay between the end of antibiotic administration and these catastrophic events may be up to 10 days, making it sometimes difficult to identify the origin of an enterotoxaemia
For this reason, antibiotics administered by the oral route and having a poor bioavailability and also extensively excreted in the bile (such as
oxytetracycline
) or by enterocyte efflux (doxycycline) after parenteral administration should not be used or should be used with caution in horses and rabbits
Drug Metabolism in Different Animals Species
Biotransformation
is a major factor accounting for species differences in the disposition of drug
The group of P
450
cytochromes (CYP
450
) represents a large superfamily of
oxygenases
involved in drug biotransformation
The CYP
450
enzymes are considered to be the most important metabolising enzymes for
xenobiotic
in veterinary medicine
Drug Metabolism in Different Animals Species
Cont
…
In veterinary medicine, inter-species quantitative differences in Phase I and qualitative differences in Phase II metabolism have been known for several decades
Examples are the poor capacity of the cat to carry out some
glucuronidations
, the deficiency of dogs for acetylation reactions and the low level of sulphate conjugation in pigs
A common assertion in veterinary pharmacology is that in general drugs have lower clearance in carnivores than in herbivores with omnivores having an intermediary position
Drug Metabolism in Different Animals Species
Cont
…
Herbivores are well-endowed with oxidative enzyme systems such as the cytochrome P
450
group, which provide rapid drug clearance by hepatic metabolism
Therefore differences in the rate of elimination for drugs that are metabolized by the liver usually accounts for most of the differences in the T
1/2
values between species.
Drug Metabolism in Different Animals Species
Cont
…
It is for phase II metabolism that the main qualitative interspecies differences have been reported and explained by genetic factors, namely deficiencies in
glucuronidation
in
felidae
and acetylation in
canidae
.
Glucuronidation
represents one of the major phase II reactions in the metabolism of drugs
Among food-producing animals, rabbits, pigs, and horses show the maximal
glucuronidating
capacity towards phenolic substrates, while broilers and cattle display a relatively low conjugation rate
Drug Metabolism in Different Animals Species
Cont
…
It is also important to be careful about comparing duration of action between different species of birds
There is significant variation between t
1/2
values of chickens, turkeys, and different wild birds which is again related to differences in metabolism
Although there are different types of cholinesterase in the tissues and blood, the overall levels in ruminants are lower than in horses and humans
Drug Metabolism in Different Animals Species
Cont
…
This means that sheep, goats, calves, and cattle, are more sensitive to
organophosphorous
compounds than horses and humans
Sheep have been suggested as possible “sentinel” animals for the detection of toxic anticholinesterase (organophosphate nerve gases) because of their sensitivity
Interspecies variability in acetylation has been known for many years. N-acetyltransferases are widely distributed among animal species and are active in metabolising
sulfonamides
Drug Metabolism in Different Animals Species
Cont
…
Two
families of N-acetyl-transferases (NAT) have been recognised and called
NAT-1
and NAT-2
Rabbits and pigs have high acetylating capacity, while chickens and horses are poor
acetylators
.
Dogs and other
canids
fail to express functional NAT-1 and NAT-2, which are essential for the excretion of
sulfonamides
while in cats, only NAT-1 is expressed
In man and rabbit, NAT activity is subjected to genetic polymorphism resulting in “low” and “high”
acetylator
phenotypes
Drug Metabolism in Different Animals Species
Cont
…
In clinical practise, fatal intoxication may occur in horses exposed to
monensin
, an
ionophoric
coccidiostat
used in poultry
One likely reason for their high susceptibility in horses is their relative inability to
demethylate
compounds that are not CYP2D substrates
Comparative investigations with
microsomes
from various animal species, including horses, pigs, broiler chickens, cattle and rats, showed that the horse had the lowest catalytic ability to
demethylate
(and hence detoxify)
monensin
Dosage
Regimens in Different Animals Species
For
each drug in each species an efficacious and safe dosage regimen (dose level, interval of administration, and dosing duration) should be determined
Dosage regimens may vary markedly between species, even when doses are expressed
by
Kilogram
(kg) of body weight
For
xylazine
, an alpha-2 agonist used as a sedative, the effective dose is tenfold lower in cattle than in horses, despite similar PK profiles
Dosage Regimens in Different Animals
Species
Cont
…
For
morphine, the effective dose is ten-fold lower in cats than in dogs
For aspirin, dosage is approximately 40 times higher in cattle than in cats,
For
suxamethonium
(succinylcholine), a depolarising neuromuscular blocker, the dose in cattle is some 40 times lower than in cats
From these examples, it seems that no generalisation can be established between interspecies variability and certain physiological traits, such as herbivorous Vs. carnivorous species or
monogastric
species vs. ruminants
Dosage Regimens in Different Animals Species
Cont
…
Coprophagia is another individual and social behaviour phenomenon specific to veterinary medicine
It comprises the consumption of faeces by animals.
Many domestic species such as horses, pigs, rabbits and dogs either regularly or occasionally practise
coprophagia
Coprophagy may lead to drug transfer between animals (
allocoprophagy
) or drug recycling when an animal re-ingests its own faeces (
autocoprophagy
) or its own
manure
Dosage Regimens in Different Animals Species
Cont
…
The faeces of treated foals may contain extremely high concentrations of antibiotics especially for drugs with poor oral bioavailability
If such contaminated faeces are ingested by an adult horse, ingested concentrations of antimicrobial drugs may suffice to disrupt the normal adult colonic microflora, which are exquisitely sensitive to some antibiotics
Pharmacodynamics of Drugs in Different Animal Species
Species
differences in drug action and effect, i.e. of PD, reflect differences in target functions (anatomy, physiology, pathology) and/or target receptors including those of parasites and bacteria
In contrast with interspecies differences in Pharmacokinetics,
Pharmacodynamics
interspecies differences are less numerous
Example of
mydriatic
drugs with the
parasympatholytic
agent atropine being
mydriatic
in mammals but not in birds
In birds, the iris and ciliary muscles are composed mainly of striated muscle fibres with an associated nicotinic cholinergic neuromuscular
Pharmacodynamics of Drugs in Different Animal
Species Cont..
These
striated muscle fibres facilitate a rapid pupillary and accommodation response and this is likely to be an adaptation to the visual requirement of flight. In birds, atropine, a muscarinic receptor antagonist has no
mydriatic
effect, whereas neuromuscular blockers such as d-
tubocurarine
dilate pupils
Pharmacodynamics of Drugs in Different Animal Species
Cont..
In mammals, the iris is composed of smooth muscle, and muscarinic agonists act on receptors of the M-3 subtype to cause pupil dilatation
Example of
Xylazine
This is an alpha2-adrenergic agonist, which is used widely in several species as a sedative, is also a reliable emetic, particularly in cats, in which it stimulates the chemoreceptor trigger zone (CTZ) in the medulla oblongata, while it does not induce emesis in species such as ruminants and horses lacking the vomiting reflex
Key
Points
Metabolism
of drugs is affected by various factors
Metabolism of drugs mainly takes pale in the liver through Phase I and Phase II reactions
In veterinary medicines, no generalisations are possible; rather, each drug must be specific to the species to guarantee the effective and safe use of veterinary drugs
Proper use of veterinary medicines will ensure the wellbeing of animals and safeguarding also the environment and human consumption of animal products
Evaluation
What
is the influence of species differences on disposition of veterinary medicines?
What is the influence of species differences on metabolism of veterinary drugs?
What is the influence of species differences on absorption of veterinary drugs?
References
Riviere
J. E.,
Papich
M. G. (2009).
Veterinary Pharmacology and Therapeutics
(9
th
Ed) Iowa, Wiley-
Blackwel
Publishers
Hsu W. H. (2008).
Handbook of Veterinary Pharmacology
(1
st
Ed) Iowa,
Wiley-
Blackwel
Publishers
Kuafmann
J, (1996).
Parasitic infections of domestic animals
, (2
nd
ed
).Berlin,
Birkhäuser
Verlag
Press
Hoare E. W. (2013).
A manual veterinary therapeutics & pharmacology
(2
nd
ed
),New
York, Forgotten Books
Press
Maddison. J. (
ed
) (2008).
Small Animal Clinical Pharmacology
, (2nd
ed
). Philadelphia, Saunders Elsevier Limited
Unataka kutumiwa notes hizi kupitia WhatsApp?Kwa notes zilizopangiliwa vizuri kwa kusoma offline au PDF, bonyeza kitufe hapa chini. Ujumbe wenye Level, Semester, Module na Topic utaandaliwa moja kwa moja.TUMIWA NOTES WHATSAPP
