B4.010 Adverse Drug Effects Flashcards
toxicology
science that related hazardous effects of chemicals, including drugs to biological systems
acute toxicity
1 to 2 days; single or multiple exposures
subacute toxicity
repeated exposure; less than 3 months
chronic toxicity
repeated exposure; greater than 3 months
what is the individual dose response
dose response for each ‘toxic effect’ or molecular interaction’ will be different
what is the quantal (population) dose response
at a given dose there are responders or non-responders in a population
needs many doses and very large sample size
how is therapeutic index calculated
animals- TI=LD50/ED50
humans- TI=TD50/ED50
how is margin of safety calculated
animals- MS=LD1/ED99
humans- MS-TD1/ED99
how is risk defined
probability that injury will result from exposure to a substance under specified conditions of dose and route of admin
what is hormesis?
unusual dose response
lower doses have protective effects and higher doses have adverse effects
what are some substances that exhibit hormesis
vitamins
alcohol
radiation
oxidative stress
what are 3 types of adverse drug effects
toxicity
hypersensitivity
idiosyncrasies
toxicity
dose related toxicity due to non-immune mechanism
generally an overextension of the pharmalogical response
hypersensitivity
allergic reactions involving immune system
idiosyncrasies
abnormal responses not linked to immune system (mechanisms unclear)
what types of toxicities are typically dose limiting?
organ directed
aspirin induced GI tox
acetaminophen induced hep tox
doxorubicin induced cardio tox
benefit to risk ratio
expression of adverse effects that is more useful clinically than therapeutic index
what is the difference between direct fetal toxicity and teratogenicity
fetal toxicity acts on fetus directly
teratogenicity- physical defects in developing fetus due to drug exposure to the MOTHER during gestation
when are teratogenic effects most pronounced
during organogenesis
day 20 of gestation to the end of the first trimester
what are some examples of teratogens
thalidomide
alcohol
lithium
antifolates
what is the mechanism of a drug allergy
abnormal response resulting from previous sensitizing exposure activating immunologic mechanism
how do allergies differ from drug toxicity
- altered reactions occur in only a fraction of the pop
- dose-response is unusual (small amts can elicit severe rxn)
- manifestations of rxn are different from usual pharmacological and toxicological effects of drug
- primary sensitization
are most drugs immunogenic alone?
no
must bind covalently to self-macromolecule or alter structure of self-macromolecule to become immunogenic
4 types of drug induced hypersensitivities
anaphylactic (immediate)
cytotoxic (autoimmune)
arthus (immune complex)
cell mediated (delayed)
target organs of anaphylactic shock
GI
skin
lung
vasculature
clinical manifestations of anaphylactic shock
GI allergy
uticaria
asthma
anaphylactic shock
mechanism of anaphylactic shock
IgE
target organs of cytotoxic hypersens
circulating blood cells
clinical manifestations of cytotoxic hypersens
leukopenia
thrombocytopenia
hemolytic anemia
granulocytopenia
mechanism of cytotoxic hypersens
IgM, IgG
target organs of Arthus hypersens
blood vessels
skin
joints
kidney
clinical manifestations of arthus hypersens
serum sickness
vasculitis
arthritis
glomerular nephritis
mechanism of arthus hypersens
Ag-Ab complexes
target organs of cell-mediated hypersens
skin
lungs
CNS
clinical manifestations of cell mediated hypersens
contact nephritis
tuberculosis
allergic encephalitis
mechanism of cell mediated hypersens
sensitized T cells
describe the key concepts surrounding drug idiosyncrasies
untoward reactions to drugs that occur in a small fraction of patients and have no obvious relationship to dose or duration of therapy
does not involve immune rxn
what is frequently a cause of drug idiosyncrasies
genetic abnormalities in enzymes or receptors (pharmacogenomics differences)
what are some general mechanisms of adverse drug rxns
receptor-ligand interactions membrane functions cellular energy covalent binding to biomolecules calcium homeostasis non-lethal alterations in somatic cells ligand-activated transcription factors programmed cell death (apoptosis) GSH depletion and ROS
what are some major challenges when managing a poisoned patient?
no credible info on substance type, time of exposure, or dose of exposure
general stepwise approach in management of a poisoned patient
clinical stabilization
clinical evaluation
prevention of further toxicant absorption
enhancement of toxicant elimination
admin of antidote (if available)
supporting care, monitoring, and followup
ABCDTs
airway breathing circulation drugs temp
airway
should be cleared of vomit or any other obstruction and an airway or endotracheal tube inserted
breathing
assessed by observation and by measurement of arterial gases (pulse ox), intubate and mechanically ventilate if needed
circulation
monitor pulse, BP, and urinary output
start IV and draw blood for glucose and other labs
drugs
dextrose for altered mental status
thiamine for alcoholic and malnourished pts to prevent Wernicke-Korsakoff
lorazepam or diazepam for seizure control
temperature
tepid sponge bath and fan for cooling
example causes of death due to drug/chemical toxicity
CNS depression airway obstruction respiratory arrest hypotension cardiac arrhythmias hypoxia specific organ damage-necrosis
what is a toxidrome
constellation of clinical symptoms, that when taken together, are likely associated with exposure to a certain toxicological class of chemical
anion gap calculation and significant
gap = [Na+] - ([HCO3-]+[Cl-])
normally 12 +/- 2
INCREASED in metabolic acidosis
AT MUD PILES for conditions that can cause an increased anion gap
Alcohol Toluene Methanol Uremia DKA paraldehyde iron, isoniazid lactic acid ethylene glycol salicylates
osmolar gap calculation
osmolar gap = 2Na + (glucose/18) + (BUN/2.8)
normal = 285
MAE DIE for conditions that alter osmolar gap
methanol acetone ethanol diuretics isopropanol ethylene glycol
what is torsades de pointes?
prolonged QT intervals followed by ventricular tachycardia and a QRS that spirals around the isoelectric line
what types of drugs cause TdP?
quinidine (class IA & III antiarrhythmics) tricyclic antidepressants antipsychotics non sedating antihistamines cisapride
what causes the prolonged QT in TdP
b1 stimulation and intense SYM activation
factors that contribute to TdP
electrolyte imbalance
bradycardia
ischemia
hypoxia
treatment of TdP
magnesium sulfate- works by suppressing early afterdepolarizations (EADs) and terminating the arrhythmia
magnesium achieves this by decreasing the influx of calcium and lowering the amplitude of EADs
what are 2 ways to remove/eliminate toxin
gastric lavage using activated charcoal
induction of emesis using ipecac syrup
when is gastric lavage/emesis used?
is overdosed drug is suspected to be in stomach
downsides include aspiration (cant use with solvent chemicals)
how to prevent an inhaled substance from absorbing further?
remove from toxic environment and provide ventilation
how to prevent a topical substance from absorbing further?
remove contaminated clothing and wash with appropriate method
how to prevent an ingested substance from absorbing further?
much more involved induce emesis gastric lavage oral admin of activated charcoal whole-bowl irrigation (prevent further absorption via GI tract)
what are some methods of enhancing elimination of toxicant
alkalinization of urine hemodialysis hemoperfusion plasma exchange continuous hemofiltration multiple dose activated charcoal (MDAC)
what is ion trapping (alkalinization of urine)
change pH of urinate filtrate resulting in ionization of weak acids, thus trapping them in filtrate and preventing reabsorption
what is hemodialysis
drug removal based on concentration gradient
what is hemoperfusion
blood is passed over cartridge of adsorptive substance
what is hemofiltration
blood is filtered using specific filters and plasma ultrafiltrate is removed
necessary fluids and electrolytes are replaced
downside of antidotes
very limited and specific
ethylene glycol antidote
fomepizole
cyanide antidote
hydroxicobolamine
binds to cyanide ion and chelates it
organophosphate/ nerve gas antidotes
atropine
digoxin antidote
Fab fragments
what are metal chelators
used for heavy metal poisoning
bind to metals and chelate them
dimercaprol
arsenic, gold, mercury, acute lead
calcium disodium EDTA
lead
penicillamine
lead, copper
succimer
oral chelator for lead
