Flashcards in Exam III Toxicity Deck (81):
What are the factors that relate to effectiveness and safety of drugs?
1) Biological variance
3) Drug idiosyncrasy
5) Pathological state
What is biological variation?
-defined as the range of response per dose
-an individual may require a higher/lower dose to produce the desired effect
What is hyper-susceptibility?
- a greater-than-normal reaction to a drug
-some patients may have a reaction to a drug that is greater than expected
-Ex: A small dose of a tranquilizer would be expected to provide a mild dedication but in a hyper susceptible patient it cause major motor incoordination
Response of the patient to the drug is _____ different from the usual or ________ response.
When some patients are given a _______ to sleep they stay awake all night. Other patients when given a stimulant to overcome dedication will _______. They are _________ responses
Many drugs must be given to _______ in doses that are _____ than the adult dose.
Doses are determined by the ___________
Dosing is bases on the ________ of the child
The poison prevention act of 1970 enacted to prevent _________ drug _______ in children
Prescription must be _________ in child_________ containers
-patients with arthritis who have difficult opening these safety caps
Geriatrics have ______ binding capacity (decreased plasma proteins), _________ metabolism (_______ liver function) and __________ renal function allow for _________ doses of drug to act at _________ levels in the geriatric patient.
Give a __________dose.
What is the pathological state of liver disease?
in most cases, drug metabolism is reduced du due to diminished function of the cytochrome P-450 system; doing must be REDUCED
What is the pathological state of renal disease?
Results in renal impairment of drug excretion doing must be modified on the basis of renal clearance values of the drug
Drug tolerance depends on what?
-increasing amounts of drug are required to produce consistent effect
-usually associate w/ drugs which cause physical dependence (addiction)
What is tachyphylaxis?
-a rapid development of tolerance
-tolerance develops rapidly after administration of only a few loses of drug (quick, successive dosing)
What is toxicology?
- The study deleterious effects of physical chemical or biological substance "toxins"
-study of the interaction between poisons and living organisms
-studies of toxicology predate the study of pharmacology
-Before the 20th century, most pharmacologically active agents were derived form poisons
What does toxicology encompasses today?
1) Occupational safety
-limit exposure to acceptable levels
3) Analytic toxicology
-Qualitative/quantitative eval of toxic substances
4) Forensic toxicology
What is short-term toxicity testing?
1) Testing in animals
2) general profile screen in mice
3) Determination of lethal dose LD 50 (kills 50% of total that received it)
4) Determination of effectiveness = ED 50
(causes an effect in 50% of numbers )
What is the margin of safety?
-LD 50 divided by the ED50
-If LD50 = 10 mg and ED50 = 2 mg, then the margin of safety is only 5 (lethal dose is only 5 X the effective dose)
-May be predictive of a low margin of safety in humans
-acceptable margin of safety is 2000 or more
What is the long-term toxicity studies?
-known as chronic toxicity studies
-daily doing to rats and dogs from 3 months to 2 yrs
-observe for toxicities, evaluate blood chemistries
-Sacrificed, then evaluate histopathology
-Many toxic effects appear only after repeated dosing over many months or years
What is the therapeutic window?
-Range of doses of a drug that elicits a therapeutic response without unacceptable side effects (toxicity) in a population of people
-blood plasma levels of a drug with a small therapeutic window must be monitored
What is the quantitative measure of the therapeutic window?
Therapeutic index = TD50/ED50
TD50= dose of the drug that causes a toxic response in 50% of the population
ED 50 = dose of the drug that is therapeutically effective in 50% of population
What does the Therapeutic index provide?
-a single # that quantifies the relative margin of safety of a drug in a population of people
-a large TI represents a large (wide) window
-a small TI = requires monitoring
The body cannot distinguish between _________ and ___________
therapeutic substances (drugs) and toxic foreign substances (xenobiotics)
Pharmacokinetics = ?
What is toxicokinetics?
-Study of absorption, distribution, metabolism and excretion of toxic parent compounds and metabolic products.
-Used to predict [ ] of toxin that reaches site of injury and the reusing damage
What is acute toxicity?
Occurs as a result of single, large exposure to the toxic agent
-effect = visible within minutes to hours
-occasionally signs of acute toxicity are not visible for weeks to months following the initial exposure.
What is chronic toxicity?
Effect of a toxic insult that occurs over a prolonged period of time
-often chronic toxicity is manifested after years of exposure
May also manifest ling aft=er the individual is now longer exposed to the toxin
How are toxins absorbed?
Toxins must cross an epic layer to be absorbed symmetrically
What are the 3 sites of absorption into the body?
2) Respiratory tract
Describe gastrointestinal absorption?
1) Ingested toxins
2) Contaminants in food
3) Majority of therapeutic agents (drugs)
4) Lead in dirt or paint
(kids can eat paint chips or contaminated dirt)
Descirbe respiratory tract absorption?
1) inhaled substances
(benzene, teterachloroethylene, asnestos)
-Against of chemical warfare (mustard gas, notogen gas)
Describe absorption through the skin
-Skin acts as a barrier= relatively impermeanle
-Toxins must diffuse through the 7 layers of skin to gain systemic exposure
-Caustic liquids = burn skin alert protective layer
-some can passively diffuse through the skin after prolonged contact (insecticides)
Regarding distribution most toxins pass through what ?
Through the circulation to exert their effects
-rapid= seconds to minute
-RATE of distribution to a particular tissue us related to the amount of bone flow to the issue
Organs with a lot of blood flow = __________, __________, _______________.
Organs with less blood flow =?
CONCENTRATION OF THE TOXIN IN EACH TISUE IS DETERMINED BY THE __________ OF THE TOXIN FOR THE TISSUE
_______ proteins in blood ______ toxin distraction by binding the toxins
How do toxins reach cells?
-cross cell membranes
-lipid soluble cross directly and water soluble crosses thru channels/pores thru receptor mediated mechanisms
-Toxins that are water soluble (polar) have difficulty crossing BBB
what is detoxification?
-A toxin may be metabolized to inert products occurs in the LIVER.
-Cytochrome P450 enzyme system is used to create water soluble molecules to allow for elimination
what is toxication?
-Nontoxic materials may be converted into toxic metabolites after undergoing metabolism in the liver
-Metabolite become the active substance!
-This is similar to how the body handles prodrugs(inert) until they pass thru the liver and become active drugs
What are the 3 changes toxins (just like drugs) can undergo?
1) Detoxication (active to inactive)
2) Toxication (inactive to active)
3) Toxins that undergo metabolism is converted into another toxin (active to active)
How are toxins eliminated?
-RENAL excretion of water-soluble molecules
-RESPIRATORY excretion of gases and volatile compounds
-Elimination kinetics = similar to drugs
-Some toxins can remain in the body much longer than drugs, because certain tissues (fat, bone) can store these molecules and release them slowly
What are 3 examples of toxins that are stored?
1) LEAD= stored in bones for decades
2) DDE= metabolite of the pesticide DDT stored in fat for years
3) inhaled particulates= phagocytes by PMNs by macrophages but may never be eliminated.
-Found in lung/ lymph nodes at autopsy
What are the mechanisms of Toxicity?
-Interference w/ cellular and molecular functions (gross physical interference w/ lipids, nucleus acids and proteins )
-Forming species that react with biological macromolecules
-Generating inflammatory/immune responses
What are examples of toxicity that is done by stimulating or inhibiting vital cellular processes mechanistically?
Toxins often act by more than ____ mechanisms.
Toxins may affect _______ and cause _____ tissue _______
How to toxins damage tissue?
-By altering structure of proteins, lipids, carbohydrates and nucleic acids so severely that cellular integrity is lost.
-damaging agents are NON-SPECIFIC = systems most commonly affected are one exposed to environment (SKIN, EYES, RESPIRATORY)
What are reactive species?
-they react chemically w/ biologic macromolecules and other chemicals
-More SPECIFIC in their site of action
-Most reactive species are metabolites of chemically inert compounds and cause damage in tissue which they are generated (may be distant from the site of exposure)
Describe the reactive species Carbon tetrachloride
1) Solvent used in cleaning products and in fire extinguishers
2) not hepatotoxic in itself
3) when metabolized by liver reacts w/ oxygen to form toxic organic free radicals
4) These free radicals cause toxicity (renal toxicity, hepatotoxicity, liver cancer)
what happens in the inflammatory response to tissue damage
Immune sys removes cells damaged by toxins and releases immune mediators that repair
How can the immune response itself be triggered?
1) Hypersensitivity rxns (allergic rxn)
2) Autoimmune rxn (body attacks itself)
How can many toxins alter metabolic pathways that are enzyme and receptor mediated?
By interacting w/ critical receptors like neurotransmission, cardiac rhythm, oxygen delivery, ATP generation or intracellular calcium balance
What is enzyme mediated toxicity?
-Nerve gases and pesticides are acetylcholinesterase inhibitors
-Causes excessive concentrations of acetylcholine in synaptic cleft: slowed heart rate, difficult breathing, swearing, diarrhea, salivation, vomiting, weakness, conclusions, pinpoint pupils
When CYANIDE binds to the heme iron in the active site of the __________ cytochrome C oxidase; inhibition of this enzyme prevents generation of ________
What is an example of receptor mediated toxicity?
Carbon monoxide binding strongly to the iron in the active sire of hemoglobin, preventing oxygen binding and reducing oxygen carrying capacity.
what is carcinogenesis?
-Transformation of a normal cell to a neoplastic cell.
-requires years/decades to complete
-involves multiple genetic changes some of which are associate w/ exposure to carcinogens
What are carcinogens?
a chemical, physical or biological substance that can cause transformation
Describe the development if cancer
-Inhibition- initiators damage DNA and interfere with replication and repair mechanism
-Most initiators are reactive species that modify DNA, and cause mutation
-Mutations affect genes that control cell cycle and cancer is initiated
Carcinogens can promote development of cancer by causing tissue damage in organs that are capable of what?
-Capable of regeneration like the liver
-Chronic consumption of alcohol leads to cirrhosis which can lead to liver cancer
-Occurs because of chronic regeneration and repair of liver tissues
What is a teratogen?
-Substance that can induce a birth defect
-Most are reactive species or metabolic inhibitors
Teratogenic effect is dependent on what?
Effect of any substance on the developmental timing of the exposure
Teratogens can inhibit/alter what?
-intracellular signals (potent teratogens)
-alter DNA or chromosomes
-exposure to fetus and mother = maternal toxicokinetics
-functional deficit to growth retardation to increasingly severe with defects to death
What is organ directed toxicity?
-Organs with regenerative capacity may recover after toxic exposure (liver)
-organs will limited/no regenerative fun lose fxn (heart, neuronal tissue)
-neurons are incapable of regeneration, so toxic exposure is permanent
-BBB prevents many toxins from entering
What is selective toxicity?
-Inhibits pathways or targets that are critical for the pathogen or cancer cell to survive and replicate
(Enzymes, receptors, metabolic pathways, proteins, structures)
What are the 3 methods of selective toxicity by drugs?
1) attack targets that are unique to the pathogen/cancer not PRESENT IN HOST
2) attack targets in pathogen or cancer cell that are similar but not identical to those in the host
3) Attacks targets in the pathogen/cancer cell that are shared by host but vary in importance between pathogen and host
(selective action more important to pathogen than host)
What are examples of selective toxicity?
-Targeting a protein that is unique to the pathogens survival
-Targeting differences in the cell cycle between a cancer cell and a normal host cell
Drugs exhibit the _______toxicity when they target a ________ between the pathogen/cancer cell and a normal host cell
Drugs exhibit the ______ toxicity when they ______ pathways shared by both pathogens/cancer cells and normal host cells
What is the ration of ht toxic dose to the therapeutic dose of a drug?
Indication of how ______ the drug is in producing the desired effects
A highly selective drug ______ is prescribed _____ because of the large difference between the therapeutic and toxic concentrations
Drugs that are __ selective into tier actions, meaning that they affect both the pathogens/cancer cells, are not as ____ : a _____ therapeutic index
Many cancer drugs for chemotherapy have a ____ therapeutic index: the therapeutic dose that kills the cancer cells cause ____ side effects from damage to normal host cells
What are the unique drug targets?
1) metabolic pathways
3) mutated genes
4) gene products
5) these unique targets are present in the pathogen or cancer cell, but are lacking in this host
What is an example of unique drug targets?
-antibacterial drugs (antibiotics) target bacterial cell wall synthesis
-the structure of the bacterial cell wall is unique to these pathogens: bacterial peptidoglycan
-antibiotics inhibit synthesis of peptidoglycan, which compromises integrity of cell wall: lysis occurs = bacterial death
Why do penicillin have minimal host toxicity? (safe)
Bc penicillin works against the unique target of the enzymes that make bacterial cell wall peptidoglycan
Which drugs are NOT good at selective targeting?
-Anti fungal drugs
-fungal organisms lack a cell wall and are enveloped by a lipid bilayer
-they alter cell membrane permeability can cause fungal death
-can also effect human cells as well = low therapeutic index = signifiant side effects
e.g. amphoteracin = ototoxicity
Many organisms have metabolic pathways that are ________ to the found in humans, but have a ______ enzymes or _______
These targets are slightly different, but are not ___________. (share some similarities).
Drugs that go after these targets have a therapeutic window that is usually _______ than those drugs with a _________ target
Give an example of selective inhibition of similar targets
-bacterial and human protein synthesis:
-binding mRNA ribosome decoding of mRNA synthesis of peptide chains, release of polypeptide from the ribosome
What is the difference between human and bacterial protein synthesis?
Difference sized ribosomes, different RNAs different proteins
Several classes of antibiotics, mactolides and ahminoglycosides, _____ bacterial _______ synthesis.
Battier cannot make _______ to operate its own ______ machinery = _______.
Macrolides= _______ emergence of the protein from the ________.
Amino glycosides = ______ decoding of mRNA
What are the common targets?
-When the host and pathogen/cancer cell share a common biochemical or physiologic pathway
-Drug produces an effect to a greater degree than on the host
-narrow therapeutic index
Cancer(target) cells arise from _____ cells that have been _________ by genetic mutations into cells with ________ growth.
cancer cells and normal cells utilize the _______ machinery for growth and _____.
Selective inhibition is very difficult because the machinery of both the cancer cell and normal cell are the _______.
Targets of inhibiting cancer cell growth often result in affecting the _______ of normal cells