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

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