adverse drug reactions 1 Flashcards
4 goals of rational/successful drug therapy
The goal of successful drug therapy is to….
-achieve effective concentrations of an appropriate drug at the site of drug action in the individual ie the target site
-prevent, ameliorate or cure the disease with our drug therapy,
-avoid an unwanted adverse drug reaction (ADR)
-avoid violative drug residues in food producing animals
rational drug therapy includes consideration of:
drug, host, and disease factors
most drug therapies are based on what type of regimens?
fixed dose
what types of factors can influence plasma drug levels and the likelihood of therapeutic success, or an ADR, thus necessitating dosage regimen adjustments
host “physiologic” factors
drug factors- “interactions”
disease “pathophysiologic” factors
what Host “physiologic” Factors can influence plasma drug levels (and thus the likelihood of therapeutic success, or an ADR)
Neonatal patient
Geriatric patient
Pregnant/Lactating patient
Species/Breeds
what drug “interaction” Factors can influence plasma drug levels (and thus the likelihood of therapeutic success, or an ADR)
Pharmaceutical interactions
Pharmacokinetic interactions
Pharmacodynamic interactions
what Disease “pathophysiologic” Factors can influence plasma drug levels (and thus the likelihood of therapeutic success, or an ADR)
Renal disease
Hepatic disease
Cardiovascular disease
what is an ADR? what is their incidence?
adverse drug reaction
-Unintended and usually noxious response to a drug that is unwanted
-Occurs at drug doses used for prophylaxis, diagnosis or treatment
-Results in injury (toxicity) or lack of efficacy (therapeutic failure)
o What is the incidence of ADRs ??
- Estimated 3-5% of all hospitalized human patients admitted due to an ADR
Certain usage patterns are associated with higher incidences of ADRs, such as:
-Use of human-labeled drugs with little/no drug safety or efficacy data
-Irrational or trivial drug use
-Failure to set therapeutic goals or end-points
-Use of multiple drugs concurrently in a patient
-Failure to weigh the risk/benefits of drug use
-Use of drugs with a low therapeutic index
-Failure to educate owners on drug usage
o What are the most common drug classes to produce ADRs (6)
qNSAIDs
qVaccines (not classified as drugs)
qAntimicrobial drugs
qEctoparasiticides
qAnthelmintics
qAnesthetic agents
types of adverse drug reactions (7)
o Type A (Augmented)…..is avoidable!
> Pharmacological….”receptor-mediated”
> Intrinsic
o Type B (Bizarre)…..unavoidable!
> Immunological
> Idiosyncratic
what is the most common type of ADR?
type A (augmented)
characteristics of type A ADR
o Type A (Augmented)…..is avoidable!
n Most common type of ADR
n Dose-dependent and predictable
o Can occur in all patients
n Experimentally reproducible
n Mechanism responsible is known
n Altered plasma drug levels due to change in drug
disposition
o Elevated plasma drug levels and toxic effects
o Reduced plasma drug levels and therapeutic failure possible also !
what are the characteristics of a pharmacological “receptor mediated” ADR? what are the subcategories and what is an example?
n Exaggerated pharmacological effects of drug (metabolite)
on a cellular receptor
n “on intended target receptor”
- Propranolol (Inderal®, generic) induced bradycardia
- BZD/barbituate induced sedation
n “off target receptor”
- NSAIDs (Aspirin®, generic) induced GI ulcers
- Xylazine-induced emesis
- Propranolol-induced bronchospasm
examples of “on intended target receptor” pharmacological ADRs
-Propranolol (Inderal®, generic) induced bradycardia
-BZD/barbituate induced sedation
examples of “off intended target receptor” pharmacological ADRs
-NSAIDs (Aspirin®, generic) induced GI ulcers
-Xylazine-induced emesis
- Propranolol-induced bronchospasm
what do intrinsic ADRs depend on?
n Determined by drug’s physico-chemical
properties; non-specific binding to targets
n Frequently dependent on bioactivation
site of effects of an intrinsic ADR depends on what?
-cells tissues that accumulate drug
-localization of metabolizing NZs (enzymes?)
-susceptibility of various tissues
what happens in an ADR when a reactive metabolite binds non-specific targets in susceptible cells?
-disrupt membranes, organelles
-nucleic acids, proteins
characteristics of a type B ADR
o Type B (Bizarre)…..unavoidable !
n Dose-independent and unpredictable
n Host dependent > Genetic predisposition
n Usually not experimentally reproducible > Mechanism???
n Classification can be challenging
what are the characteristics of an immunological ADR? what is a common example?
-Major form of Type B ADR
-Drug (metabolite) can act as “haptens” binding to larger endogenous molecules—immunological response
> TypeI-IV reactions possible
> “Anaphylactic versus anaphylactoid” ADRs
n Penicillin-induced allergies in dogs
what are the characteristics of an idiosyncratic ADR? What are some important examples?
n Involvement of the immune system is not confirmed in all Type B ADRs
n Mechanism of action is usually not related to the drugs pharmacologic action, or is unknown
n Like intrinsic ADRs……
> Depends on chemical property of drug
> Typically involves bioactivation of the drug
n Oral diazepam in cats
n Carprofen in dogs
what are the signs of an ADR?
Clinical signs are often non-specific and rarely pathognomonic
what signs do we look to to diagnose an ADR?
o Temporal association
o Specificity and plausibility
o Repeatability and consistency
o Experimental evidence
o Biological gradient
o Predisposing patient factors
What therapies can we use to alleviate an ADR?
Drug withdrawal is the most important step!! Can we use the drug or agent again?
Treatment based on the clinical manifestation of the ADR, along with supportive care
-Clinical signs will depend on the affected organ
-Systemic effects often seen with Type B ADRs
-Specific antidotes possible!!
-Hastening elimination also recommended
Use of corticosteroids for idiosyncratic ADRs is poorly documented
Animals manifesting with neutropenia should be treated with a broad-spectrum prophylactic antibiotic
why do people fail to report ADRs in human medicine?
-Belief that ADRS were infrequent and that common ADRS were not worth reporting
-Apathy
-Too busy to fill out the paperwork!
