1. qualitative: a reaction is deficient in a particular species e.g. dog dont
acetylate
2. quantitative: difference in the amount of enzyme present, result PK
difference, in clearance and elimination half-life
3. species difference in biotransformation:
a. drug being used safely providing the dosing interval is increased
b. drug used in one species is not safe to use in another
4. the important of enterohepatic recycling varies between species
breed differences
1. Half life → Beagles have shorter half lifes (faster metabolism) compared to
other dogs
2. Passage across the blood-brain barrier → Avermectins are more likely to
accumulate in the CNS of collie dogs result toxcity, caused by a defect in
the ACB1 efflux transporter located in the BBB
3. Evidence of breed difference in metabolism of the COX-2 inhibitor celecoxib
→ Two sub-populations of beagles have different elimiation for celecoxib
4. Breed difference in CYP isoenzyme activity → Lower activity of CYP2B11;
greyhounds recover more slowly from general anaesthetic propofol,
explained by reduced rate of hydroxylation and increased drug clearance
time.
Drug Toxicity
definition
adverse drug reaction (ADR)
reaction which is harmful that occurs at a therapeutic dose
Principle of Pharmacology 32
, List the common types of drug toxicities and, where these are known, briefly outline
the underlying mechanisms
type A (augmented) ADRs
expected but exaggerated responses which are predictable
caused by increase drug conc due to defective metabolism/ excretion or
inappropriate dosing
dose dependent and should be avoidable
type B (bizarre) ADRs
unexpected or abnormal response
not dose dependent and cannot be predicted
e.g allergic and pseudoallergic reactions (reaction resemble allergic response
without immunological basis) → occur most commonly when inject IV
type C (chronic) ADRs
occur after prolonged use of drug
e.g. prednisolone in cushing’s disease
type D (delay) ADRs
occur at time remote from drug treatment
e.g. second cancer
type E (end of treatment) ADRs
when drug treatment halted abruptly
e.g. withdrawal seizures after termination of anti-convulsant drug; latrogenic
addison’s disease
Principle of Pharmacology 33
, type F(failure) ADRs
when expected response is not achieved, not due to primary failure of drug
might due to human error, should be avoidable
Describe, using examples, how alterations in drug pharmacokinetics can result in
toxic effects
Provide examples of species differences in susceptibility to the toxic effects of
drugs.
factors affecting type A ADRs
1. species: e.g. cats metabolised drug that depend on conjugation by
glucuronyl transferase
2. genetics: e.g. fluoroquinolone-induced retinal toxicity in cats, slow recovery
of greyhound thiopentone anasethesia
3. body weight; percentage fat: e.g. overdosing of large breed given metabolic
rate is measured by body surface area. overload when given poor lipid
soluble drug to obese and high lipid soluble drug to lean individuals
4. age: neonates metabolise drug slowly
5. gender: more common in women, drug affect foetus or neonate
6. pathology: e.g. cardiac, dehydration, GI tract disease
7. drug interaction
💡 higher potential for type A ADRs if
1. with organ dysfunction
2. young or elderly
3. obese or cachectic
4. on multiple drug therapy
5. safe use of drug has not established
Principle of Pharmacology 34
, Unit 2: Drug Targets
Intracellular Targets
Consolidate Knowledge of drug-receptor interaction
💡 the drug receptor interaction is characterised by 1) binding of drug to
reception(affinity) and 2) generation of response in a biological system
(efficacy)
4 types of receptors in transducer mechanisms
1. ligand gated ion channel receptor
2. G-protein coupled receptors (GPCRs)
3. Kinase-linked and related receptors
4. Receptors regulating gene expression (transcription factors, nuclear
factors)
Understand how transduction mechanisms (downstream signalling events) following
drug-receptor interaction indicates selectivity of targeting and safety
list the 4 targeting pathway to block GPCR activity via non-competitive agonism
Principle of Pharmacology 35
acetylate
2. quantitative: difference in the amount of enzyme present, result PK
difference, in clearance and elimination half-life
3. species difference in biotransformation:
a. drug being used safely providing the dosing interval is increased
b. drug used in one species is not safe to use in another
4. the important of enterohepatic recycling varies between species
breed differences
1. Half life → Beagles have shorter half lifes (faster metabolism) compared to
other dogs
2. Passage across the blood-brain barrier → Avermectins are more likely to
accumulate in the CNS of collie dogs result toxcity, caused by a defect in
the ACB1 efflux transporter located in the BBB
3. Evidence of breed difference in metabolism of the COX-2 inhibitor celecoxib
→ Two sub-populations of beagles have different elimiation for celecoxib
4. Breed difference in CYP isoenzyme activity → Lower activity of CYP2B11;
greyhounds recover more slowly from general anaesthetic propofol,
explained by reduced rate of hydroxylation and increased drug clearance
time.
Drug Toxicity
definition
adverse drug reaction (ADR)
reaction which is harmful that occurs at a therapeutic dose
Principle of Pharmacology 32
, List the common types of drug toxicities and, where these are known, briefly outline
the underlying mechanisms
type A (augmented) ADRs
expected but exaggerated responses which are predictable
caused by increase drug conc due to defective metabolism/ excretion or
inappropriate dosing
dose dependent and should be avoidable
type B (bizarre) ADRs
unexpected or abnormal response
not dose dependent and cannot be predicted
e.g allergic and pseudoallergic reactions (reaction resemble allergic response
without immunological basis) → occur most commonly when inject IV
type C (chronic) ADRs
occur after prolonged use of drug
e.g. prednisolone in cushing’s disease
type D (delay) ADRs
occur at time remote from drug treatment
e.g. second cancer
type E (end of treatment) ADRs
when drug treatment halted abruptly
e.g. withdrawal seizures after termination of anti-convulsant drug; latrogenic
addison’s disease
Principle of Pharmacology 33
, type F(failure) ADRs
when expected response is not achieved, not due to primary failure of drug
might due to human error, should be avoidable
Describe, using examples, how alterations in drug pharmacokinetics can result in
toxic effects
Provide examples of species differences in susceptibility to the toxic effects of
drugs.
factors affecting type A ADRs
1. species: e.g. cats metabolised drug that depend on conjugation by
glucuronyl transferase
2. genetics: e.g. fluoroquinolone-induced retinal toxicity in cats, slow recovery
of greyhound thiopentone anasethesia
3. body weight; percentage fat: e.g. overdosing of large breed given metabolic
rate is measured by body surface area. overload when given poor lipid
soluble drug to obese and high lipid soluble drug to lean individuals
4. age: neonates metabolise drug slowly
5. gender: more common in women, drug affect foetus or neonate
6. pathology: e.g. cardiac, dehydration, GI tract disease
7. drug interaction
💡 higher potential for type A ADRs if
1. with organ dysfunction
2. young or elderly
3. obese or cachectic
4. on multiple drug therapy
5. safe use of drug has not established
Principle of Pharmacology 34
, Unit 2: Drug Targets
Intracellular Targets
Consolidate Knowledge of drug-receptor interaction
💡 the drug receptor interaction is characterised by 1) binding of drug to
reception(affinity) and 2) generation of response in a biological system
(efficacy)
4 types of receptors in transducer mechanisms
1. ligand gated ion channel receptor
2. G-protein coupled receptors (GPCRs)
3. Kinase-linked and related receptors
4. Receptors regulating gene expression (transcription factors, nuclear
factors)
Understand how transduction mechanisms (downstream signalling events) following
drug-receptor interaction indicates selectivity of targeting and safety
list the 4 targeting pathway to block GPCR activity via non-competitive agonism
Principle of Pharmacology 35
