adverse drug reactions 2 Flashcards
most clinically significant ADRs are due to what?
Most clinically significant ADRs are due to altered drug disposition in the target species !!
what species considerations should we take into account when administering a drug
Species differences….
o Makes extrapolating dosage regimens across species challenging
- GI tract
- Body composition
- Blood volume
> Cat (~70 mL/kg), Dog (~90 mL/kg)
Drug metabolism……
o Phase I reactions (oxidation, reduction, hydrolysis)
o Phase II reactions (conjugation)
- Glucuronide
- Glutathione
- Sulfate
- Acetyl group
- Amino acids
o Metabolism of some drugs produces toxic metabolites
- Acetaminophen in cats
what age factors should we take into account regarding dose-dependent ADRs? geriatrics vs neonates
In geriatrics:
- diminished organ function
-altered body composition (more fat, less water)
In neonates:
-overall increased bioavailability
-larger Vd
-slower elimination
Drugs capable of organ toxicity more likely to do so if what exists?
organ disease or significantly reduced organ function exists
Elderly patients with significant reduction in organ function and/or suffering from organ disease are more likely to have a problem with what?
drug disposition changes (PKs)
In relation to drug therapy, most profound changes in drug disposition are found with what?
decline in renal function
what kidney issues are related to age?
-Functioning nephron mass declines with age
-Chronic renal failure is common amongst aging individuals
why are the kidneys highly vulnerable to ADRs?
- Kidneys receive ~20-25% of the cardiac output
- Kidneys concentrate drugs and toxicants
- Kidneys have high metabolic activity
what part of the kidney is more commonly damaged and why?
Proximal tubule damage is more common due to high renal cortex blood flow
chronic renal failure is associated with what issues related to drugs?
-Reduced clearance of drugs by the kidney
- Uremia can reduce protein binding and hepatic metabolism some drugs
- Renal protein loss and dehydration affecting drug distribution
what should we do when choosing drugs if CRF is present?
Avoid the kidney if possible, when CRF is present
- Choose drugs not eliminated by the kidney
- Choose drugs that at not toxic to the kidney
- Use TDM and dosage adjustments when possible
Drugs capable of renal ADRs
Aminoglycosides (gentamicin, amikacin)
- NSAIDs
Primary or compensatory cardiovascular disturbances lead to…..
- Renal and sodium retention
-increased sympathetic nervous system output and blood redistribution
what effects on drug deposition does cardiovascular disease have?
Effects on drug disposition are difficult to predict
what drug administration changes should we make if a patient has cardiovascular disease?
-Critical drugs should be given IV
-Potentially toxic drugs given IV slowly
-TDM and dosage adjustments when possible
why is the liver highly vulnerable to ADRs?
q Liver also receives a high cardiac output %
q Liver is the “portal of entry” of most drugs
q Liver is the major site of metabolite formation
q Liver has very high metabolic activity
possible consequences of liver disease:
q Reduced enzyme function
q Increased fraction of plasma unbound drug
> Hypoalbumemia, bilirubinemia
q Reduced hepatic blood flow
reactive metabolites can cause liver related ADRs in this way:
hepatocellular injury
what changes in drug disposition can we see in patients with hepatic disease? how much liver disease do we need to see an ADR?
-it is more difficult to predict changes in drug disposition in patients with hepatic disease.
-Drugs metabolized and inactivated by the liver may achieve higher plasma levels with reduced hepatic function.
-Prodrugs requiring hepatic activation may see reduced plasma drug levels and therapeutic failure. –Generally significant liver disease or decline in function needs to be present before clinically relevant changes in drug disposition and risks of ADRs occur.
how can we avoid ADRs in patients with liver disease?
o Avoid the liver if possible, when significant liver disease is present
o Choose drugs eliminated primarily by extra-hepatic mechanisms if possible
o Use TDM and dosage adjustments when possible
drugs capable of hepatic ADRs:
*Corticosteroids (prednisolone, dexamethasone)
*Anticonvulsants (phenobarbital, primidone)
-Diazepam
-Carprofen
-Acetaminophen
what is a drug interaction?
change in the magnitude or duration of a pharmacologic effect of a drug due to the presence of another drug, food or environment factor
when can a drug interaction occur?
before or after the drug is absorbed by the host
the incidence of drug interactions increases with
number of drugs; polypharmacy
duration of drug use
The primary sequelae of drug interactions are……..
-Toxic ADRs
-Subtherapeutic (failure) pharmacologic effects; also an ADR
drug interactions are classified as:
Pharmaceutical, Pharmacokinetic or Pharmacodynamic in nature
pharmaceutical reactions have effects where? when? what do they affect and what do they rely on?
in vitro effects
Occur before the drug is absorbed by the host……
-Usually occur in the GI tract lumen following oral administration
-Affect total dose of drug available for absorption
-Rely on alterations in physicochemical properties of the affected drug
what is the most common type of pharmaceutical interaction? when is this most often seen?
drug-drug interaction
aka “drug incompatibilities
-Most often seen with addition of drugs to IV fluids
two less common types of pharmaceutical interactions?
Drug-Environment or Drug-Diet Syringes or containers, light, temperature
compounding of drugs without care could lead to this type of drug interaction
pharmaceutical
what type of effects do pharmokinetic interactions have
disposition effects
Most drug interactions of significance are due to what?
changes in drug pharmacokinetics (disposition)
4 types of phamacokinetic interactions
absorption, distribution, metabolism, excretion
pharmacokinetic absorption interactions can be due to:
-GI pH
-GI motility and regional blood flow
-P-glycoprotein (MDR-efflux pump), and GI CYP450’s
pharmacokinetic distribution interactions can be due to:
-Plasma protein binding or tissue protein binding
-Blood flow
pharmacokinetic distribution interactions can be due to:
-Plasma protein binding or tissue protein binding
-Blood flow
pharmacokinetic metabolism interactions can be due to:
-Metabolizing enzymes (CYP450); phase I Mixed Function
-Oxidase enzymes Hepatic blood flow
pharmacokinetic excretion interactions can be due to:
Urine pH
Tubular secretion
Renal blood flow
what kind of effects do pharmacodynamic intersctions have, generally
tissue response effects
when do Pharmacodynamic Interactions occur?
Occur when one drug directly alters the physiologic or cellular response to another drug
what are the types of pharmacodynamic interactions?
-Receptor interactions-same target site
-Post-receptor interactions-same cell
-Physiologic response interactions
what type of pharmacodynamic Receptor interactions at the same target site are there?
Agonist permissive effects
Antagonists, partial agonists
what type of pharmacodynamic Post-receptor interactions on the same cell are there?
Second messengers eg. cAMP levels
what type of pharmacodynamic Physiologic response interactions are there?
Differing or additive effects on the same physiologic response
6 ways to avoid an ADR?
- Choose drugs with wide therapeutic indices; use TDM when possible
- Adjust dose according to the stage of life and health of the patient
- Use drugs approved for target species in the disease of interest
4.Try to limit polypharmacy - Realize that most drugs do cause adverse effects; ALL drugs can potentially be associated with immunologic ADRs
- Never prescribe a drug without being aware of its potential adverse effects
