Toxicology 2 Flashcards
1
Q
If you wanted to try to prevent absorption of an orally ingested poison, which is the best choice of treatment? A. Emesis B. Gastric lavage C. Activated charcoal D. Catharsis
A
C. Activated charcoal (usually hydrophobic compounds and should be given within 3 hours of ingestion)
2
Q
What is the risky part about using emesis, gatric lavage, or activated charcoal?
A
aspiration
3
Q
What is the risk for catharsis?
A
ruptured of GI tract
4
Q
What is gastric lavage?
A
They put a slurry in your stomach and suck it out with a big boar tube.
5
Q
Methanol poisoning is treated:
A. By inhibiting alcohol dehydrogenase
B. With the administration of ethylene glycol
C. By inhibiting aldehyde dehydrogenase
D. With the administration of oxalic acid
A
A. By inhibiting alcohol dehydrogenase
with ethanol
6
Q
Stopping bioactivation is pharmacokinetics or pharmacodynamics?
A
pharmacokinetics (stopping or inhibiting metabolism)
7
Q
What type of treatments are pharmacodynamics?
A
bypassing inhibited pathway
receptor antagonist
receptor agonist
pulling a poison from an active sites
8
Q
What are the three basic approaches to treating a poisoned patient?
A
Toxicokinetic based
Inactivation of poison
Pharmacologically based
9
Q
What are the different toxic endpoints?
A
On and off target effects Non-organ specific toxicity Organ specific toxicity Idiosyncratic responses Allergic Reaction
10
Q
What organs are highly susceptible to toxicity?
A
Liver, kidney, nervous system, and lungs
11
Q
A compound with a half life that allows it to be cleared from the body before the next exposure can result in chronic adverse effects. How can that happen?
A
A multiple exposure where tissue damage can not be repaired before the next exposure.
12
Q
Which of the following is considered an area of specialty practice in the field of toxicology?
A
Clinical Toxicologist
13
Q
What is the spectrum of undesired effects?
A
Immediate vs Delayed Reversible vs Irreversible Local vs Systemic Interactions Tolerance Variations in Response
14
Q
What is an immediate response?
A
Those that occur rapidly after a single administration of a substance.
15
Q
What is a delayed effect?
A
Those that occur after the lapse of some time after administration of a substance.
16
Q
What are extreme examples of delayed effects?
A
Diethylstilbestrol (DES) and vaginal cancer - Generational delayed effect. Prescribed hormone used in the 50s for woman to hold on to pregnancy. Causes baby girls to develop cancer later in life and for boys to have problems with urinary tract.
Triorthocresylphosphate (TOCP) and neurotoxicity - organophosphate that binds to another enzyme Neuropathy Target Esterase (NTE) and inhibits it. You get tingly get lots of sensation a few days later. Expect SLUDE but this happens later.
17
Q
Some toxic effects are reversible and others are irreversible. T/F
A
True
18
Q
What determines if a toxic effect is reversible or irreversible?
A
The ability of a tissue to regenerate or not.
19
Q
Most injuries in the liver are irreversible or reversible?
A
Reversible due to the livers high ability to regenerate.
20
Q
Most injuries in the differentiated cells in the CNS are irreversible or reversible?
A
Irreversible due to the fact that the cells of the CNS cannot dived and be replaced.
21
Q
Cancer and birth defects are considered irreversible or reversible toxic effects?
A
Irreversible
22
Q
Where do local effects occur?
A
At site of first contact.
23
Q
What are some examples of local effects?
A
Chlorine Gas - damages peoples lungs, eyes, skin.
Poison Oak - damages skin
Reactive Acids - because they are reactive
24
Q
Where do systemic effects occur?
A
Require absorption at site of entry and distribution to site of action.
25
What are examples of systemic effects?
Most toxins unless they are highly reactive.
26
What poisons may have both local and systemic effects?
Tetraethyl lead - burns skin and can cause CNS damage
27
What poisons can cause indirect systemic effects?
Acid burns, Chlorine burns - you damage the skin so much that you cause problems in renal function due to fluid loss. Kidney failure
28
Interactions of different compounds that we are exposed to can do what?
Change the kinetics of it: absorption, protein binding, biotransformation and excretion of one or both interacting compounds.
29
What responses can you have when you have multiple chemical reactions?
Additive - add the effects
Synergistic - Sum of the effects is greater than each compound alone.
Potentiation - One chemical not toxic in itself will enhance the effects of another toxin.
Antagonism - Sum of the effects is less than what was expected
30
What is tolerance?
A decreased responsiveness to a toxic effect resulting from prior exposure to a chemical or a structurally related compound.
31
What are two major mechanisms for tolerance?
Dispositional tolerance: decreased amount of toxicant reaching site where toxic effect is produced.
Reduced responsiveness of tissue to a compound.
32
What is an example of dispositional tolerance?
Carbon tetrachloride - induces some of the enzymes metabolize it and help you clear it.
Cadmium 3 - induces expression of a carrier protein, metalathionine, will grab on to the metal and help increase the clearance for it.
33
What is an example of reduced responsiveness?
pharmacodynamics. Opioid down regulation.
34
What is selective toxicity?
lethal to one species but not to another
35
What is an example of selective toxicity?
chocolate and dogs
| Insecticides on the crops - kills off bugs but not plants
36
Why are there variations in toxic responses?
Selective Toxicity
Species differences
Individual Differences in Response
37
What is species differences?
One species is not affected to the same quantity or quality as another species. This raises questions of extrapolation of results between species like mice. Have to use the right animal
38
Why do individuals differ in their response?
Genetic differences, and possibly what we eat and our lifestyle
39
If different organs are being effected than the ______ is likely different.
Mechanism of Action
40
Toxic exposures may cause specific organ and non-specific physiological endpoints. T/F
True
41
Toxic exposures may see multiple specific organs and/or non-specific physiological responses for any given exposure. T/F
True
42
Why are there adverse effects when a drug hits an intended tissue on-target?
The dose is too high
| Chronic activation of inhibition effects
43
Why are there adverse effects when a drug hits an intended tissue off-target?
Incorrect receptor is activated or inhibited
44
Why are there adverse effects when a drug hits an unintended tissue on-target?
Correct receptor, but incorrect tissue
Dose too high
Chronic activation or inhibition effects
45
Why are there adverse effects when a drug hits an unintended tissue off-target?
Incorrect receptor is activated or inhibited
46
What can cause a dose at the receptor to be too high?
Deliberate or accidental dosing errors.
Changes in pharmacokinetics of drug.
Change in receptor number
Changes in pKA
47
What is an example of a drug that interacts with the correct receptor but in wrong tissue?
Benadryl when it causes sleepiness. Crosses the blood brain barrier and affects the H1 receptor in CNS
48
What is an example of an off-target side effect when it his the unintended receptor?
Arrhythmias with terfenadine (Seldane) - antihisimine
Desired effect: Peripheral H1 receptor antagonism
Undesired effect: Inhibition of cardiac potassium channel.
Causes heart to race.
49
What is an example of an off-target side effect when the enantiomer hits an unintended receptor?
Teragenesis with racemic thalidomide
Desired effect: R-enantiomer effective anti-nausea agent
Undesired effect: S enantiomer is a potent teratogen
causes bad birth defects
50
What is an example of an off-target side effects that causes activation of unintended receptor subtypes?
Asthma exacerbation with propranolol
Desired effect: Decrease in heart rate via inhibition of beta 1 adrenergic receptors in heart.
Undesired effect: Asthma exacerbation via inhibition of beta 2 adrenergic receptors located in airway smooth muscle. Makes it hard to breathe.
51
What is Fibrosis?
Fibrosis
Pathogenesis: Excessive deposition of collagen and extracellular matrix protein.
Causes loss of organ function as tissue is destroyed over time.
52
What drugs may causes pulmonary fibrosis?
Amiodarone (antiarrhythmic drug)
Bleomycin (Chemotherapeutic)
Paraquot (herbicide)
53
What may causes liver fibrosis (AKA cirrhosis)?
alcohol
54
What are the non-organ specific toxic endpoints?
Fibrosis, Genotoxicity, Cancer, Teratogenesis
55
What is the difference between Genotoxicity and Mutagenicity?
Genotoxicity is unscheduled DNA synthesis, sister chromatid exchanges, DNA strand breaks. Not transmissible from cell to cell or generation to generation.
Mutagenicity is transmissible genetic alterations.
56
What type of cells can genotoxicity occur in?
Somatic as well as germ cells.
57
What are the results of genotoxicity?
Cancer, Teratogenesis, Genetically based disorders.
58
What is the most common cancer?
Lung and bronchus then hormonal cancers like breast and prostate cancer.
59
What are the most common causes of cancer?
Tobacco use and adult dies/obesity
60
What are the two types of carcinogens?
Genotoxic
| Nongenotoxic
61
What is a Genotoxic carcinogen?
It interacts physically with DNA to damage or change is structure.
62
What is a nongenotoxic carcinogen?
Modifies gene expression but does not affect DNA structure; It may cause cell or tissue to be more susceptible to DNA damage from other sources.
63
What other sources can DNA damage occur from?
```
Nonmutagenic
Threshold, reversible
May function at tumor promotion stage
No direct DNA damage
Species, strain, tissue specificity.
```
64
What are the stages of cancer?
Initiation - Mutation in one or more genes that control key regulatory pathways of the cell.
Promotion - Enhancement of signal transduction pathways induced in the initiated cell and its progeny by continuous exposure to a promoting agent.
Progression - A second mutation in the cellular DNA (in addition to the original initiating event); makes the cell unstable and becomes malignant.
Complete carcinogen - Is capable of initiation, promotion, and progression.
65
What is Teratogenesis?
The induction of birth defects in the fetus.
Fetus is exposed with mother's exposure to the teratogen.
Fetal exposure is determined by maternal absorption, distribution, metabolism, and exretion, and whether or not the compound can cross the placenta. pKa can have an affect on whether a baby is born with problems.
66
One component may cause different deformities whereas multiple compounds can cause the same deformities. T/F
True
67
It probably takes more than one or more instance of genotoxicity to cause cancer and it may be under the influence of one of the nongenotoxic carcinogens that promotes its expression. T/F
True
68
What is it so hard to find the cause of cancer?
There can be a long latency period.
69
How are teratogenesis and cancer different when it comes to the dose that causes it?
It is thought that teratogenesis needs a threshold dose to cause birth defects where as cancer only needs the gene to be damaged by a carcinogen and doesn't depend on a certain dose.
70
What is the new regulations made by the FDA for pregnant and lactating patients?
The Final Rule - has to list pregnancy and lactation information (lactation is new). Also talks about the effects it may have in men with potential to have children.
71
What are the specific toxic endpoints?
Pulmonary Toxicity, Neurotoxicity, Hepatotoxicity, Nephrotoxicity
72
Why are lungs susceptible to toxins?
```
Oxidative Burden(Breathe in things that are oxidative)
Gas Exposures (Site of deposition and water solubility of gases)
Particle Exposures
```
73
Depending on the size of the particle where does it land in the pulmonary system?
Big particles stick to the nose or throat
Small particles usually get breathed out
Medium particles are the worst because they are more likely to get stuck to your lungs.
74
What are the acute responses to pulmonary toxicity?
```
Airway Reactivity (bronchoconstriction, Wheezing, coughing, chest tightness)
Pulmonary Edema (Acute exudative phase causing the thickening of the alveolar capillary barrier, abnormalities may persist)
```
75
What are the chronic responses to pulmonary toxicity?
Fibrosis
Emphysema
Asthma
76
What type of drugs taken systemically will cause pulmonary damage?
Bleomycin
Cyclophosphamide (chemo)
Monocrotaline (industrial)
Paraquat (herbicide)
77
Why is neurotoxicity unique?
You have to pass the blood-brain barrier (but its not always continuous and it doesn't catch everything)
78
Why is the nervous system susceptible?
High energy requirements
Axonal transport (very long)
Presence of myelin
Neurotransmission function
79
What are the specific injurys that can occur to specific neuron cells?
Neuronopathy (killed at the heart)
Axonopathy (damages transport)
Myelinopathy ( Schwann cells unwind)
Transmission Toxicity (Mess up Neurotransmitters and may be caused by organophosphates)
80
What is the liver susceptible?
```
Its Functions:
Uptake and concentration roles
Bioactivation and detoxification capabilities
Inflammatory and immune response in situ
Propensity for iodiosyncratic responses.
```
81
What is the liver immune cell?
Kupter cell that can cause inflammation.
82
The common bile duct, portal vein, and Hepatic artery form what?
The Portal Triad
83
Why are certain regions of the liver more susceptible than others?
Because Zone 1 is more oxygenated than Zone 2 or 3. Enzymes need oxygen for metabolism.
84
APAP needs P450 to be bioactivated. So what region of the liver is most affected by APAP overdose?
Zone 1 because it will have the most active P450 because of the oxygen and will therefore cause the most problems in zone 1.
85
What is important about in situ toxicity?
It's bio activated and toxicity is caused at the same site.
86
Why is the kidney susceptible to toxicity?
Receives large delivery of potential toxins in systemic circulation.
Processes for concentrating urine also concentrates potential poisons in renal tubule, enhancing their transport into renal tubular cells.
Renal transport, accumulation, and metabolism contributes significantly to probability of in situ toxicity.
Sensitivity of kidney to endogenous vasoconstrictors.
87
What is idiosyncratic toxicity?
Abnormal reactivity to a chemical due to genetics.
Qualitatively similar response compared to others, but extreme.
All reactions that occur with low frequency(not proper use of term)
88
What are allergic responses?
Drugs that may be recognized as foreign.
Small molecules may act as bound allergens (haptens).
Large drugs may directly activate the immune system.
89
What are the two main mechanisms drugs may activate immune responses?
```
Hypersensitivity
Autoimmune reactions (not allergic reactions)
```
90
The liver is very susceptible to drug toxicity because.... (choose all that apply)....
A. It expresses many drugs to toxic compounds.
B. It receives a large volume of blood via the portal circulation.
C. It is a large organ
D. It is able to uptake and concentrate xenobiotics.
E. It has its own immune cells to mount a quick inflammatory response.
A. It expresses many drugs to toxic compounds.
B. It receives a large volume of blood via the portal circulation.
D. It is able to uptake and concentrate xenobiotics.
E. It has its own immune cells to mount a quick inflammatory response.
91
Which statement is one reason for regional susceptibility to toxicity across the liver?
A. Relatively high oxygen content in Zone 1
B. Homogenous expression of P450s across the zones
C. Zone 2 has few Kupfer cells
A. Relatively high oxygen content in Zone 1
92
What is important when treating acutely poisoned patients in an emergency?
Eliminating further exposure.
Supportive care
Determine poisoning agent
93
How do you treat a patient after emergency care?
Toxic kinetic based
Inactivation of poison
Pharmacologically based
94
What are the different kinetic approaches to treatment?
Prevention of absorption
Inhibition of toxication (bioactivation)
Enhancement of metabolism (detoxication)
Enhancement of elimination
95
What is gastric lavage?
You put a tube down throat and suck it up but it could miss the lungs.
96
What is the risk of emesis?
Could aspirate
97
What is the risk of activated charcoal?
It is hard to swallow and then you have to get it back up which can cause aspiration.
98
What is advangatageous of multiple-dose activated charcoal?
It helps with hepatic recirclization
99
What is an example of trying to inhibit toxication or bioactivation?
Methanol and ethylene glycol(antifreeze) may be treated by inhibiting their alcohol dehydrogenase mediated metabolism using ethanol or fomepizole.
100
What is an example of enhancing the metabolism of a drug for treatment?
Can't induce enzymes because it takes too much time. Can accelerate metabolic actions by administering cofactors.
Treat cyanide and acetaminophen poisoning.
101
What are the three different antidotes for cyanide and what do they do?
```
Amyl nitrate and Sodium Nitrate (Methemoglobin inducers. Methemoglobin reversibly binds with cyanide to form cyanonmethemoglobin).
Sodium thiosulfate (Helps convert cyanide to thiocyanate, which is excreted renally) Methylene blue will return methemoglobin to its ferrous form.
```
102
What occurs in APAP overdose?
APAP turns into NAPQI which causes hepatotoxicity
103
What is the treatment for acetaminophen poisoning?
Give NAC (N-acetylcystiene) which then will make glutathione which will then bind to NAPQI and allow for excretion.
104
How can you enhance the elimination of a toxin?
ion trapping by alkalizing or acidifying urine
Hemodialysis, hemofiltation, hemoperfusion
Plasma exchange or exchange transfusion
105
Hemodialysis, hemofiltation, and hemoperfusion only work for what type of toxins and why?
toxins with small volumes of distribution so that removal of substance from blood does not leave a large, inaccessible reservoir in the body tissues.
106
What are pharmcodynamic ways to treat a poisoned patient?
Chelating
| Antivenoms and Antibody Binding
107
What is the mechanisms for inactivating poisons?
Inactivator binds to the toxin and prevents interaction of toxin with target tissues.
The toxin-inactivator complex is cleared.
Inactivators must have high affinity for the toxin
Complex must have low toxicity.
108
What is the ideal chelator?
Does not bind to bind to calcium
Binds lead, mercury, cadmium, iron, and copper
Small molecules with a nucleophilic electron donor to form a meal-ligand complex.
Must have higher affinity for binding metal than tissue macromolecules.
109
What is an orally bioavailable metal chealtor for iron?
Deferasirox
110
What are antivenoms?
Antibodies against a venom.
| Ex: Digoxin immune Fab
111
What are four categories of pharmacologically-mediated treatments?
Receptor Antagonist
Receptor Agonist
Removal of the poison from the active site
By-passes an inhibited pathway by stimulating downstream targets.
112
What is a receptor antagonist?
Blocks the effect of a toxin that acts as an agonist at a receptor or that potentiates the action of a receptor's endogenous ligand.
113
What is an example of receptor antagonists?
naloxone (opioid antagonist)
Flumazenil (GABAA Antagonist)
Atropine (organophosphate pesticides) - poison is not a direct agonist.
114
What is a receptor agonist?
Toxin is a competitive receptor antagonist.
| Treat with compound that enhances agonist activity.
115
Why is an example of receptor agonist?
Physostigmine (Blocks AChE to increase cholinergic tone)
116
What is an example of removing a toxin from an active site?
```
Cyanide poisoning
CO poisonings (treated with O2)
Organophosphates (pralidoxime)
```
117
What is an example of a treatment that involves metabolic pathway alternatives?
Warfarin which is treated with Vitamin K. Epoxide reductase reactivates Vitamin K which allows it to make clotting factors.
