Exam 6/Final Material Flashcards
The study of adverse effects of chemical or physical agents on living systems
Toxicology
A poisonous substance produced by living cells
Toxin
A man-made chemical introduced into the environment that produces toxic effects on living cells
Toxicant
An area of focus in toxicology which is concerned with determining the toxic responses to agents
Descriptive toxicology
An area of focus concerned with determining why or how agents provoke a toxic response
Mechanistic toxicology
An area of focus in toxicology that is concerned with assessing the risks of toxic substances and determining how that risk is best managed
Regulatory toxicology
LOAEL
Lowest observable adverse effect level
NOAEL
No observable effect level
Seconds to hours
Immediate
Days to years
Delayed
Effect abates after stopping exposure
Reversible
Effect persists after stopping exposure
Irreversible
Source/environment, ingestion, inhalation, dermal
Exposure
Traveling through the body
Disposition
Cellular responses
Toxicodynamics
Three means by which toxic responses may be mitigated
Prevent/reduce exposure
Enhance elimination from body
Block/repair cellular effects
Three levels of risk benefit analysis
Accessibility, applicability, acceptability
Accessibility
FDA evaluates the benefits/risks for the population
Applicability
Provider evaluates benefits/risks for a patient
Acceptability
Patient evaluates benefits/risks in terms of personal values
Three elements needed for IND with the FDA
Animal pharmacology and toxicology, manufacturing information
Clinical protocol and investigator information
MRSD
Maximum recommended starting dose
Primary reason adverse drug events are not detected until after drug is approved
Rare effect in small amount of people
Five categories of preclinical studies
Acute, Repeated dose, Genetic toxicity, reproductive toxicity, carcinogenicity
Investigational New Drug Application
An application to begin administering a drug to human subjects
New drug applications
An application to receive approval to market a new drug
Generally recognized as safe
Compounds whose safety in humans has been established, if included toxicology data is not needed
Goal of preclinical studies
Determine nature of risk and minimize it
Effect of single dose in at least 2 species
Acute studies
Length depends on anticipated therapy in at least 2 species
repeated dose studies
Determine likelihood compound is mutagenic or carcinogenic
Genetic toxicity
Need depends on target population, multiple species
Reproductive toxicity
Only for compounds used in chronic or recurring conditions
Carcinogenicity
Off target response
Marginal impact on health
May impact patient compliance
Side effects
Extension of pharmacological effect
Dose dependent
May seriously impair health
Bradycardia with propanolol
Augmented responses
Not predicted from pharmacology of drug
Sometimes not dose dependent
Can seriously impact health
Carbamazepine induced liver injury
Toxic reactions
Four determinants of toxic drug responses
Individual susceptibility
Accessibility of drug to target
Compensatory mechanisms
Reactivity of drug with target
Diet, genetics, environment, underlying disease
Individual susceptibility
Compensatory mechanisms
blood pH compatible
Somatic cell damage outcome
Cancer
Germ cell damage outcome
Birth defects, childhood cancers
Developing embryo damage outcome
Miscarriages, still births, birth defects
Disruption of normal cellular functions that does not result in cell death
Cellular dysfunction
Dysregulation of cellular processes provoked by a toxicant resulting in the death of the cell
Cellular destruction
Damage to genetic material caused by external agent
Genotoxicity
Embryo death weeks
1-2 weeks
Major congenital anomalies weeks
3-8 weeks
Functional defects and minor anomalies weeks
Weeks 9-38
Malformations, exposure at specific stage of development, dose dependent effect
Criteria for teratogen classification
DES effects in women exposed in utero
Higher infertility rates
40x more chance of clear cell adenocarcinoma
Augmented response
Exaggerated response to a drug due to an excessive dose of greater than usual sensitivity
Damage to an organism that causes abnormality in development
Teratogenicity
An agent that causes damage to DNA
Mutagen
A low frequency serious adverse drug reaction with an immunological etiology to an otherwise safe and effective therapeutic agent
Drug induced hypersensitivity
A low mw chemical with propensity to bind irreversibly to protein. May or may not stimulate an immune response
Hapten
A substance that interacts with dendritic cells, stimulating maturation and possible polarization of an immune response
Costimulatory agent
A substance that stimulates an immune response having stimulatory capacity for the innate and adaptive immune systems
Immunogen
A substance that interacts with high affinity with immunologic receptors
Antigen
A rash that exhibits erythematous macules or papules most commonly initially appearing on the trunk
Exanthema
A rash that appears as flat distinct colored area less than 1 cm in area
Macule
A raised rash with distinct color overall size less than 1cm
Papule
DRESS
Drug reaction with Eosinophilia and Systemic Symptoms distinguished by involvement of internal organs and skin
Four key principles of DIHR
Rare, unpredictable, complex, potentially fatal
Reactions occur within one hour of last dose, Type 1 immunologically, IgE mediated
Immediate hypersensitivity
Reaction occurs more than 1 hour after last dose, type 4 or 3, T cell mediated
Delayed hypersensitivity
Hypersensitivity reactions require what phases
Sensitization and effector
Anaphylaxis consists of
Respiratory and cardiovascular manifestations, swelling of lips, tongue, or throat
Most patients with penicillin allergy lose sensitivity within how long
10 years
The action of a prescriber in selecting a drug for a particular patient is an example
of what element(s) of assessing the risk:benefit ratio for a drug?
Applicability
Acute preclinical toxicology studies are conducted in at least how many species?
2
The FDA does not require preclinical toxicology studies of non-drug components
(excipients) of a new drug as long as they are already included in
The GRAS list
The safety factor most commonly used for calculating the first dose in humans from
animal studies is
10
Which of the following toxic responses to a drug is most likely to be associated
with methemoglobinemia while taking the drug?
Cellular dysfunction
Patients receiving a tricyclic antidepressant frequently complain of a dry mouth due
to the anticholinergic effects of the drug. This is an example of a(n)
Side effect
Patients receiving some beta-blockers complain of experiencing frequent
nightmares. Some beta-blockers are less lipophilic and have a lower penetration
into the brain and, as a consequence, are rarely associated with nightmares. This
is an example of an adverse effect determined by
Accessibility of drug to target
The liver injury associated with acetaminophen is caused by a toxic metabolite. In
patients also taking a drug inhibiting the CYP450 responsible for this metabolism
would be expected to be at
Decreased risk for liver injury
Exposure of a pregnant woman to a teratogen in the 2 nd week of pregnancy is most
likely to result in what kind of impact?
Embryo death
RB received a dose of cephalexin and within 30 minutes developed wheezing and
a raised skin rash across her chest and face. This is most likely a reaction that is
IgE Mediated
DRESS is primarily differentiated from other DIHRs by
Internal organ involvement
Most people who claim to be allergic to penicillin can safely take the drug
True
Time frame at which most drug reactions occur
4-14 days or 1-3 weeks
