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Pharm. II > Exam III Toxicity > Flashcards

Exam III Toxicity Flashcards

1
Q

What are the factors that relate to effectiveness and safety of drugs?

A

1) Biological variance
2) Hyper-susceptibility
3) Drug idiosyncrasy
4) Age
5) Pathological state
6) Tolerance
7) Tachyphylaxis

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2
Q

What is biological variation?

A
  • defined as the range of response per dose

- an individual may require a higher/lower dose to produce the desired effect

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3
Q

What is hyper-susceptibility?

Ex?

A
  • 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
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4
Q

Drug Idiosyncracy:

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

A
  • qualitatively
  • expected
  • hyponotic
  • sedation
  • unexpected
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5
Q

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

A

-children
manufacturer
-weight

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6
Q

The poison prevention act of 1970 enacted to prevent _________ drug _______ in children

Prescription must be _________ in child_________ containers
Exceptions include?

A
  • accidental
  • intoxication
  • dispenses
  • resistant

-patients with arthritis who have difficult opening these safety caps

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7
Q

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.

A
  • less
  • less
  • decreased
  • decreased
  • normal
  • overdose
  • lower
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8
Q

What is the pathological state of liver disease?

A

in most cases, drug metabolism is reduced du due to diminished function of the cytochrome P-450 system; doing must be REDUCED

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9
Q

What is the pathological state of renal disease?

A

Results in renal impairment of drug excretion doing must be modified on the basis of renal clearance values of the drug

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10
Q

Drug tolerance depends on what?

A
  • increasing amounts of drug are required to produce consistent effect
  • usually associate w/ drugs which cause physical dependence (addiction)
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11
Q

What is tachyphylaxis?

A
  • a rapid development of tolerance

- tolerance develops rapidly after administration of only a few loses of drug (quick, successive dosing)

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12
Q

What is toxicology?

A
  • 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
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13
Q

What does toxicology encompasses today?

A

1) Occupational safety

2) Environmental toxicology
- limit exposure to acceptable levels
- Analytic toxicology

3) Analytic toxicology
- Qualitative/quantitative eval of toxic substances

4) Forensic toxicology
- legal purposes

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14
Q

What is short-term toxicity testing?

A

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 )

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15
Q

What is the margin of safety?

A
  • 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
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16
Q

What is the long-term toxicity studies?

A
  • 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
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17
Q

What is the therapeutic window?

A
  • 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
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18
Q

What is the quantitative measure of the therapeutic window?

A

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

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19
Q

What does the Therapeutic index provide?

A

-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
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20
Q

The body cannot distinguish between _________ and ___________

A

therapeutic substances (drugs) and toxic foreign substances (xenobiotics)

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21
Q

Pharmacokinetics = ?

A

toxicokinetics

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22
Q

Pharmacodynamics= ?

A

toxicodynamics

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23
Q

What is toxicokinetics?

Use?

A
  • 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
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24
Q

What is acute toxicity?

A

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.
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25
Q

What is chronic toxicity?

A

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

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26
Q

How are toxins absorbed?

A

Toxins must cross an epic layer to be absorbed symmetrically

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27
Q

What are the 3 sites of absorption into the body?

A

1) Gastrointestinal
2) Respiratory tract
3) Skin

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28
Q

Describe gastrointestinal absorption?

A

1) Ingested toxins
2) Contaminants in food
-Mercury–> fish
-Pesticides–>produce
3) Majority of therapeutic agents (drugs)
4) Lead in dirt or paint
(kids can eat paint chips or contaminated dirt)

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29
Q

Descirbe respiratory tract absorption?

A

1) inhaled substances
-air pollution
-cigarette smoke
-industrial chemicals
(benzene, teterachloroethylene, asnestos)
-Against of chemical warfare (mustard gas, notogen gas)
-

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30
Q

Describe absorption through the skin

A
  • 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)
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31
Q

Regarding distribution most toxins pass through what ?

A

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

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32
Q

Organs with a lot of blood flow = __________, __________, _______________.
Organs with less blood flow =?

A

-brain
-liver
kidney

  • Fat
  • bone
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33
Q

CONCENTRATION OF THE TOXIN IN EACH TISUE IS DETERMINED BY THE __________ OF THE TOXIN FOR THE TISSUE

A

AFFINTIY

34
Q

_______ proteins in blood ______ toxin distraction by binding the toxins

A
  • plasma

- retard

35
Q

How do toxins reach cells?

A
  • by diffusion
  • 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
36
Q

what is detoxification?

A
  • 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
37
Q

what is toxication?

A
  • 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
38
Q

What are the 3 changes toxins (just like drugs) can undergo?

A

1) Detoxication (active to inactive)
2) Toxication (inactive to active)
3) Toxins that undergo metabolism is converted into another toxin (active to active)

39
Q

How are toxins eliminated?

A
  • 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
40
Q

What are 3 examples of toxins that are stored?

A

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

41
Q

What are the mechanisms of Toxicity?

A
  • 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
42
Q

What are examples of toxicity that is done by stimulating or inhibiting vital cellular processes mechanistically?

A
  • oxygen delivery
  • energy generation
  • ion sequestration
  • neurotransmission
  • gene expression
  • cellular replication
43
Q

Toxins often act by more than ____ mechanisms.

Toxins may affect _______ and cause _____ tissue _______

A
  • one
  • multiple
  • different
44
Q

How to toxins damage tissue?

A
  • 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)
45
Q

What are reactive species?

A
  • 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)
46
Q

Describe the reactive species Carbon tetrachloride

A

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)

47
Q

what happens in the inflammatory response to tissue damage

A

Immune sys removes cells damaged by toxins and releases immune mediators that repair

48
Q

How can the immune response itself be triggered?

A

By toxins:

1) Hypersensitivity rxns (allergic rxn)
2) Autoimmune rxn (body attacks itself)

49
Q

How can many toxins alter metabolic pathways that are enzyme and receptor mediated?

A

By interacting w/ critical receptors like neurotransmission, cardiac rhythm, oxygen delivery, ATP generation or intracellular calcium balance

50
Q

What is enzyme mediated toxicity?

A
  • 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
51
Q

When CYANIDE binds to the heme iron in the active site of the __________ cytochrome C oxidase; inhibition of this enzyme prevents generation of ________

A
  • enzyme

- ATP

52
Q

What is an example of receptor mediated toxicity?

A

Carbon monoxide binding strongly to the iron in the active sire of hemoglobin, preventing oxygen binding and reducing oxygen carrying capacity.

53
Q

what is carcinogenesis?

A
  • 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
54
Q

What are carcinogens?

A

a chemical, physical or biological substance that can cause transformation

55
Q

Describe the development if cancer

A
  • 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
56
Q

Carcinogens can promote development of cancer by causing tissue damage in organs that are capable of what?

A
  • 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
57
Q

What is a teratogen?

A
  • Substance that can induce a birth defect

- Most are reactive species or metabolic inhibitors

58
Q

Teratogenic effect is dependent on what?

A

Effect of any substance on the developmental timing of the exposure

59
Q

Teratogens can inhibit/alter what?

A
  • 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
60
Q

What is organ directed toxicity?

A
  • 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
61
Q

What is selective toxicity?

A

-Inhibits pathways or targets that are critical for the pathogen or cancer cell to survive and replicate

(Enzymes, receptors, metabolic pathways, proteins, structures)

62
Q

What are the 3 methods of selective toxicity by drugs?

A

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)

63
Q

What are examples of selective toxicity?

A
  • 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
64
Q

Drugs exhibit the _______toxicity when they target a ________ between the pathogen/cancer cell and a normal host cell

A
  • least

- unique difference

65
Q

Drugs exhibit the ______ toxicity when they ______ pathways shared by both pathogens/cancer cells and normal host cells

A
  • least

- target common

66
Q

What is the ration of ht toxic dose to the therapeutic dose of a drug?

A

TD50: ED50

67
Q

Therapeutic Idex:

Indication of how ______ the drug is in producing the desired effects

A

selective

68
Q

A highly selective drug ______ is prescribed _____ because of the large difference between the therapeutic and toxic concentrations

A
  • penicillin

- safely

69
Q

Drugs that are __ selective into tier actions, meaning that they affect both the pathogens/cancer cells, are not as ____ : a _____ therapeutic index

A

less
safe
narrow

70
Q

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

A

narrow

many

71
Q

What are the unique drug targets?

A

1) metabolic pathways
2) enzymes
3) mutated genes
4) gene products
5) these unique targets are present in the pathogen or cancer cell, but are lacking in this host

72
Q

What is an example of unique drug targets?

A
  • 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
73
Q

Why do penicillin have minimal host toxicity? (safe)

A

Bc penicillin works against the unique target of the enzymes that make bacterial cell wall peptidoglycan

74
Q

Which drugs are NOT good at selective targeting?

A
  • 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
75
Q

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

A 
similar
unique
receptors 
unique
smaller
unique
76
Q

Give an example of selective inhibition of similar targets

A
  • bacterial and human protein synthesis:

- binding mRNA ribosome decoding of mRNA synthesis of peptide chains, release of polypeptide from the ribosome

77
Q

What is the difference between human and bacterial protein synthesis?

A

Difference sized ribosomes, different RNAs different proteins

78
Q

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

A 
inhibit
protein 
proteins
intracellular
death 
prevent
ribosome
decoding
79
Q

What are the common targets?

A
  • 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
80
Q

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

A 
normal
transformed
dyregulated
same
replication
same 
growth
81
Q

How will targeting cancer cells with a drug that inhibits cell growth will affect other cells?

A

Causes:

  • hair loss
  • mouth sores (mucosal lining of mouth)
  • skin problems
  • gastrointestinal problems (diarrhea)
  • sex cells (infertility as a result)

Pharm. II (13 decks)

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