Drug Toxicology and Poisoning Flashcards
Homeostasis
normal physiological ranges that optimize the function of biological systems
Drugs and other chemicals at high concentrations produce toxicity by?
Disrupting homeostasis and causing physiological functions out of the normal range
Quantal dose
response curve based effective dosing and toxic effects
ED99
dose of drug required to produce a desired effect in 90% of the population
LD1
dose producing toxicity in 1% of the population
Margin of Safety
LD1/ED99
The larger the therapeutic index…
the safer the drug
The wider the margin of safety
the safer the drug
U-Shaped dose response curve
adverse effects at both high and low doses
examples: vitamins and essential metals
At low doses adverse effects occur due to?
a deficiency of nutrients to maintain homeostasis
At high doses there is risk for?
overdose toxicity
Types of pharmaceutical effects
desirable (therapeutic)
undesirable
Side effect
nondeleterious
Toxic Effects
deleterious types include pharmacological, pathological, and genotoxic
Allergic Reactions
an immunologically mediated (adverse reaction) to a foreign molecule resulting from prior exposure
What are the 4 types of allergic reactions
Type 1: Anaphylactic
Type 2: Cytolytic
Type 3: Arthur’s
Type 4: Delayed Hypersensitivity
Anaphylactic reactions
type 1
mediated by IgE antibodies
common targets: GI tract, skin, respiratory tract, blood vessels
releases mediators of inflammation
results in vasodilation, edema, and inflammation
Cytolytic Reactions
Type 2
mediated by IgG and IgM antibodies
activation of complement system
targets circulatory system
reaction subsidies within several months after removal of the agent
Hemolytic Anemia
anemia caused by red cell disruption
Arthus Reactions
Type 3
Mediated by IgG
associated with commonly used antibiotics and other drugs
results in antigen-antibody complexes that lodge in vascular endothelium resulting in serum sickness
affects skin, bone, and lymphatic systems
resolves 6-12 days after removal of agent
Serum sickness
uncommon clinical syndrome associated with exposure to animal serum
Delayed Hypersensitivity Reactions
mediated by sensitized T-lymphocytes and macrophages
poison ivy
causes a reaction to an oily resin called urushiol
idiosyncratic reactions
abnormal responses to drug exposures in an individual
What is the pharmacogenetic basis of idiosyncratic reactions?
variations in gene expression that makes patients more/less sensitive to substances through pharmacodynamic/pharmacokinetic mechanisms
What are the two types of cellular response to toxicity?
morphological adaptation
injury
Hypertrophy
increase in cell size
Hyperplasia
increase in the cell number
morphological adaptation
Atrophy
decrease in cell size
morphological adaptation
Metaplasia
change in cell type
morphological adaptation
Reversible cell injury
mild to moderate cellular damage
swelling and fatty change
Cellular swelling
due to cellular hypoxia that damages the sodium-potassium ATPase pump and increases intracellular fluids
reversible cell injury
Fatty Change
cell unable to metabolize fat, small vacuoles of fat accumulate within the cytoplasm and may disrupt cellular function
reversible cell injury
Irreversible cell injury leading to cell death
cell cannot restore homeostasis and function
What could cause irreversible cell injury?
oxygen deprivation
chemical agents
infectious agents
immunologic reactions
genetic defects
nutritional imbalances
physical agents
aging
What are the impacts of cell injury?
Depletion of ATP
Damage to Mitochondria
Influx of Calcium
Accumulation of Oxygen Derivedd Free Radicals
Defects in Membrane Permeability
Damage to DNA and Proteins
If ATP is depleted what could happen?
screwed up sodium pumps
anaerobic glycolysis -> lactic acidosis -> loss of cell function
influx of calcium
disruption of protein synthesis
If the mitochondria is damaged what could happen?
ATP is depleted
Formation of high conductance channel and release of cytochrome C (causes apoptosis)
If there is an influx of calcium what could happen?
Activation of
- phospholipids
- proteases - breakdown cell membrane
- endonucleases - breakdown DNA
- apoptosis - cell suicide
Free radicals are synthesized in response to?
redox reactions
radiation
enzymatic metabolism of endogenous chemicals
Effects of reactive oxygen species
lipid peroxidation of membranes
cross-linking of proteins
DNA fragmentation
What could happen if there are defects in membrane permeability?
decreased phospholipid synthesis
increased phospholipid breakdown
reactive oxygen species
lipid breakdown products
mitochondrial membrane damage
plasma membrane damage
injury to lysosomal membranes
What happens if DNA and proteins get damaged?
apoptosis
Autophagy
cellular repair mechanism
removes and degrades damaged cellular components
good for cardiac and skeletal myocytes
In autophagy, what dose a an autophagosome fuse with?
a lysosome
Which has an inflammatory response: Necrosis or Apoptosis?
necrosis
necrosis
nuclear shrinkage, fragmentation and dissolution
breakdown of plasma and organelle membranes
enzymatic digestion of cellular contents
inflammatory response
Apoptosis
programmed destruction of cells
seen in shrinkage of hormone dependent tissues upon hormone deprivation
cell loss in proliferating cell populations
cell death induced by T lymphocytes
What are some examples of pathological conditions that use apoptosis?
DNA damage
accumulation of misfolded proteins
certain infections
atrophy in parenchymal organs after duct obstruction
Mitochondrial Pathway of Apoptosis
Permeability of mitochondrial membrane
sensor activated- DNA damage, misfolded protein accumulation
cytochrome C released, activates caspace cascade
nuclear fragmentation
intrinsic path
Death Receptor Apoptosis
on cell surface
tissue necrosis factor
binding of activated T-lymphocytes
activation of caspaces
extrinsic path
What is activated by intrinsic and extrinsic apoptopic pathways?
initiator caspases
Executioner caspases
carry out apoptosis by cleaving cellular components
