Flashcards in Drug toxicity Deck (34):
Define therapeutic index (TI)
balance between risk of harmful effects (patient, environment and owner) and the benefit the drug may bring to patient. Determined by risk benefit analysis.
What is predictable toxicity related to?
pharmacodynamic action of drugs (easy if acute dose)
How is drug toxicity assessed in vet med?
1.) margin of safety assessed in lab animals
- then target animal species safety studies undertaken (3-5 times therapeutic dose, for up to 3 times the dosing period, or up to 6 months if dose intended to be chronic)
- Food producing animals: require life-time safety studies in lab animals and 2 year safety studies in dogs. Also assess carcinogenicity, embryotoxicity and foetotoxicity
2.) field safety and efficacy study: all ADRs recorded and based on pre-clinical knowledge of drug and likely adverse signs
3.) Market authorisation (MA) granted
4.) MA holder is required to file periodic safety update reports over first 2 years to national pharmacovigilance scheme
Why does drug toxicity occur?
- off label use
- authorised for human but not animal use
- dealing with heterogenous population
- mistakes in dose, route of administration, storing, handling
- multiple diseases and multiple drugs
What is type A ADR?
predictable, from knowledge of mechanism of action of drug, when drug is administered as an overdose
Give 3 examples of type A ADR
- Beta-blocker - toxic to myocardium
- ACEI - acute renal failure
- Sulphonylurea (for tx of DM) - hypoglycaemia
What is a type B ADR?
reactions that are unrelated to the mechanism of action of drug. These may predictably occur when drug is taken in excessive dose or for prolonged time. Arise by biochemical mechanism unrelated to pharmacological effect of drug, often involving a chemically reactive metabolite. Within this group are also a subgroup called idiosyncratic reactions.
Examples - type B ADR
- Doxorubicin - toxic to myocardium
- Aminoglycoside ABs - kidney damage
- prednisolone - glycogen accumulation in liver
What are idiosyncratic reactions?
a subgroup of type B ADRs. There are rare conditions (1/2000), usually severe otherwise would be unrecognised. Existence important in establishing medicine safety. Detection of such problems requires comprehensive adverse reaction surveillance schemes by regulatory authorities.
Examples - idiosyncratic reactions (from human medicine)
- chloramphenicol - aplastic anaemia
- phenylbutazone - agranulocytosis
- phenytoin (AED) - hepatitis
How does suspected adverse effects surveillance scheme operate for vet uses of UK drugs?
yellow form reporting scheme through VMD
Which ADRs can vets predict?
should recognise potential for and avoid many type A ADRs and the dose-related well-recognised type B ADRs. by awareness of factors that may enhance likelihood of ADRs and by adjusting dose rates or avoiding particular drugs under these circumstances.
Factors that can enhance likelihood of ADRs
1. Physiological (age, breed/species, gender/ pregnancy)
2. disease status (hepatic, renal, cardiovascular)
3. Concomitant use of other drugs (interactions)
List physiological differences between neonates and adults which influence drug handling - 6
- decreased GIT motility
- underdeveloped gut flora
- immature mucosal enzymes
- increased total body water
- immature liver metabolic capacity (specific enzymes)
- decreased GFR and decreased renal tubular function
How do decreased GIT motility, underdeveloped flora and immature mucosal enzymes (neonates) affect drug handling?
--> decreased absorption of some drugs
How does increased total body water (neonates) affect drug handling?
Polar drugs have a large volume of distribution (lower plasma concentration)
How do immature liver metabolic capacity (neonates) affect drug handling?
less efficient biotransformation of some drugs - puppies deficient at birth, these enzymes rapidly increase in first 3-8 weeks. Herbivores tend to mature faster.
How do decreased GFR and decreased renal tubular function affect drug handling?
--> less effective renal clearance of drugs. Deficiences are present in puppies for first 8 weeks. Adult GFR reached in dogs at 3-6 months old.
Overall how do the differences between neonates and adults in drug handling affect neonates?
- increase risk of toxicity from drugs with low TI which rely on biotransformation or urine excretion for elimination and demand a different dosing strategy in some cases.
- pharmacokinetic info often not available for young animals of many species
If pharmacokinetic info is not available for neonatal companion animals, what is best course of action?
- avoid drug if possible
- choose drugs with high TI if drugs necessary
- choose formulation that allows accurate dosing
- weigh animal accurately
- avoid TCs and fluoroquinolones
How are fluoroquinolones toxic to immature animals?
damage articular cartilage
How are TCs toxic to immature animals?
Why is risk of ADRs in geriatrics higher than adults? 5
- smaller body size
- poor nutritional status
- presence of multiple disease processes
- altered compliance
- age-related changes in physiology and organ function (most commonly renal)
How common is kidney disease in cats?
30% cats 10 years + have subclinical kidney disease and therefore likely to have reduced GFR. Even subclinical reductions in GFR increase risk of toxicity from renally excreted drugs with low TIs (gentamicin, digoxin and procainamide)
How does decreased lean mm mass and decreased total body water in geriatrics affect drugs?
--> high plasma drug concentrations from polar drugs (cimetidine)
Define drug disposition
Drug disposition refers to all processes involved in the absorption, distribution metabolism and excretion of drugs in a living organism.
What are most species/ breed variations in sensitivity due to ?
differences in pharmacokinetics. Idiosyncratic reactions could be due to genetic polymorphisms with a low rate of occurrence.
Which species is monensin (an ionophore) toxic to?
Horses (supposed to be used in ruminants as a coccidiostat and has a postive effect on FCE and rumen fermentation)
CS - equine monensin toxicity
- neuronal, skeletal mm and cardiac mm effects of ionophores
- likely that the susceptibility is due to low first pass metabolism in horses compared to ruminants making systemic bioavailabilty of this drug much higher THAN in sheep.
What is pyrethrum toxic to and what is it?
- derived from chrysanthemum
- derivatives are synthetic pyrethroids (e.g. permethrin)
- toxic to cats (intended for insecticide tx in dogs) as an over the counter flea product
Outline pyrethrum toxicity in cats
- cats much more sensitive to the toxic effects of these products than dogs
- probably due to ineffective metabolism (they lack a glucoronidyl transferase enzymes)
- target of drug is voltage dependent sodim channel and it leads to repetitive neuron firing (animals show hyper-excitability--> convulsions)
- incidence of accidental toxicity in cats treated with these products is high despite the fact they are clearly labelled as being toxic to cats
Outline collie and collie-type dog toxcitiy to ivermectin
- PGP efflux pump for drugs is expressed in tumour cells (MDR1 gene)
- also expressed in other tissues including brain capillary endothelial cells (normally prevents entry to brain)
- deletion mutation of PGP product of MDR1 gene
- substrates for transporter: ivermectin, loperamide, vincristine, cyclopsporine A
What can happen to horses tx with potentiated sulphonamides?
- idiosyncratic reaction of cardiac arrhythmias as cardiac repolarisation affected
- horse may become ataxic, fall down to ground, paddle, stop breathing etc
- Case study: when given IV in combination with pheylbutazone anti-inflammatory. As both highly protein bound, both acidic so bound to same site on albumin. Consecutive admin --> increased free drug concentration. Increased likelihood of acute cardiac toxicity. Horse died.