Introduction to Toxicology (Lynn R. Panganiban, MD) Flashcards
(145 cards)
1
Q
It is the science of adverse effects of chemical, physical and biological agents on living organisms.
A
Toxicology
2
Q
What are the physical agents toxicology is concerned with?
A
Radiation and heat waves
3
Q
What are the biological agents toxicology is concerned with?
A
Parasites and infectious disease etiologic agents
4
Q
Define: Toxicity
A
Ability of a substance to cause harm in an organism
5
Q
T/F: Toxicity is an innate property of the substance.
A
True
6
Q
While we cannot control a drug’s toxicity, we can control its toxicity during (1).
A
Manufacture
7
Q
Define: Toxicodynamics
A
- Mechanisms of actions of chemicals
2. Extension of definition of pharmacodynamics
8
Q
Define: Toxicokinetics
A
ADME of substances in their toxic statess
i.e. changes from 1st order to 0 order
9
Q
Define: Poison
A
Any agent capable of producing a deleterious effect leading to injury or death
10
Q
What is the more medically acceptable term for “poison”?
A
Toxicant
11
Q
T/F: Toxins are artificial substances.
A
False
They are naturally occurring substances of endogenous plant or animal origin.
12
Q
What are used for substances that are synthetically manufactured?
A
Xenobiotics
13
Q
What is the state of being overdosed on drugs, medicaments, chemicals and biological substances?
A
Poisoning
14
Q
What is the difference between an adverse reaction and poisoning?
A
An adverse reaction always occurs within therapeutic doses.
15
Q
Enumerate the factors affecting responses to toxic agents
A
- Physical & chemical properties
- Exposure situation
- Individual factors
16
Q
Enumerate the important physical and chemical properties of toxic agents
A
- Physical state
- Solubility
- Vapor pressure
- Vapor density
- Reactivity
17
Q
What physical state is most toxic to humans?
A
Gas
18
Q
In terms of solubility, what toxicants are most harmful?
A
Fat-soluble, non-ionised substances
19
Q
What values of vapour pressure are considered most toxic?
A
Greater than or equal to 1 mmHg
20
Q
What values of vapour density are considered most toxic?
A
Greater than one (heavier than air)
Dangerous for people on the first floor!
21
Q
Toxicants with (1) and (2) are more deleterious.
A
(1) Charged particles
(2) Reactive oxygen species
22
Q
Define: Acute Exposure
A
- Exposure happens in less than 24 hours.
- Single dose
- Series of doses within 13hrs if administered orally
- Continuous for 4 hrs via inhalation
- Large volume of drugs
- Effects appear within 14 days
23
Q
Define: Subacute Exposure
A
- Repeated daily exposure for 21 ways via specific route
- No need for high dosage
- SSx manifest within 21 days.
24
Q
Define: Subchronic Exposure
A
- Repeated daily exposure for 90 days
2. Can be low dose
25
Define: Chronic Exposure
1. Lifetime exposure
2. Two years for rat and mice
3. Seventy years for humans
4. May result in transgenerational effects
26
What parameter is expressed in terms of exposures/time period?
Frequency
27
What parameter is critical to the concentration level of substance in biological fluids at the site?
Frequency
28
Enumerate the major routes by which toxic substances gain access to the body
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Ingestion
Inhalation
Dermal/Percutaneous
Parenteral
Mucosal
```
29
Rank the routes of entry in terms of descending effectiveness toxicity
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Parenteral
Inahalational
Intraperitoneal
Intramuscular
Subcutaneous
Intradermal
Oral & Dermal
```
30
What is the most critical factor determining whether the intrinsic property of a substance will be expressed?
Dosage
31
T/F: Dose should not be dependent on the weight of the individual.
False
It should be.
32
Which tenet may not necessarily apply in cases of toxicity?
The dose makes the poison
33
What are examples of endocrine disruptive agents?
```
Bisphenol A (found in plastics and can affect reproductive development of children)
DDT (affects reproductive development)
```
34
What substances can induce their effects in picograms?
Dioxins
35
What is the mechanisms of action of carcinogenic or genotoxic substances?
Disrepair of components of the central dogma
36
Enumerate the individual factors that contribute to toxicity
Age
Sex (pregnant women > women reproductive age group)
Genetic Background (toxicogenomics; G6P deficiency bleeding from nitrates)
Nutritional Status (low protein/albumin)
General Health Status (liver, kidney or heart disease)
ADME
37
T/F: Toxic action of drug is an exaggeration of its therapeutic action.
False
38
What happens when a person overdoses on paracetamol?
Develops liver problems
39
What is the mechanism of action of isoniazid?
Attacks the ribosomes of Mycobacterium
40
How does isoniazid overdose manifest?
Inhibition of GABA synthesis resulting in seizures and B6 deficiency
41
T/F: One toxicant may exert several mechanisms of toxic actions.
True
42
Toxicity may also affect the (1) not just the CNS. Give an example.
blood; lead toxicity
43
What does lead toxicity do to the body?
1. Breakdown of sulfhydryl molecules of myelin sheaths causing neuropathy
2. Interference with haemoglobin production by enzyme inhibition leading to multi-organ system effects
e. g. alcohol & tobacco
44
T/F: Toxic action can only be brought about by the parent compound.
False
45
What is a metabolite of diazepam that has the same potency as its parent compound?
Oxazepam
46
When metabolised, what is paracetamol converted to? Is it toxic?
NAPQI; yes
47
T/F: The mechanism of toxic action in acute exposure is no different from those in chronic exposure.
False
e.g. seizure as a result of acute exposure and cancer as a result of chronic exposure
48
What substances inhibit acetylcholinesterase?
Organophosphate
49
Enumerate the clinical signs of cholinergic manifestation
Salivation, diarrhoea, pupil dilation, sweating and bradycardia
50
Intensity of the toxic effect depends primarily on what properties of the ultimate toxicant?
Concentration and persistence
51
T/F: The effect of a chemical is dependent solely on the dose administered.
False.
It depends more on the concentration and disposition of the chemical in the target organ.
52
T/F: Drugs that are normally metabolised through first-order kinetics may change to zero-order kinetics during overdose.
True
53
Give examples of drugs that exhibit zero-order kinetics when overdosed.
Phenobarbital, theophylline and salicylate
54
T/F: During overdose, some drugs may change their volume of distribution
True
55
Enumerate the factors affecting kinetic processes.
1. Duration and concentration at the portal of entry.
2. Rate and amount of chemical absorbed
3. Distribution of the toxicant within the body
4. Efficiency of biotransformation and nature of metabolites
5. Ability of the chemical or its metabolites to pass through cell membranes and come into contact with specific cell components
6. Amount and duration of storage of the chemical or its metabolites in body tissues
7. Rate and site of excretion
56
T/F: The higher the concentration of the chemical at the portal of entry, the greater the damage
True
e.g. concentrated HCl causes greater damaged than diluted HCl
57
In terms of rate and amount of chemical absorbed, when will toxicity be low?
Slow absorption and small amount of absorption
58
T/F: Slowly released products have a wide margin of safety.
True
59
Where are toxicants most highly concentrated?
Brain, heart and kidneys
60
T/F: The organ where a chemical is most highly concentrated is where the most tissue damage occurs.
False
61
Describe: Lead as Storage Depot
95% of lead is stored in the bones for years, where it may reach the brain and cause effects to the hematologic and nervous systems.
62
Describe: DDT as Storage Depot
DDT is converted to DDE and stored in adipose tissue, bones, and plasma proteins for up to 8 years.
63
What is the half-life of lead?
20 years
64
T/F: A chemical may be converted into a metabolite that is more toxic than the parent compound.
True
65
What drugs undergo Michaelis-Menten kinetics at toxic concentrations?
1. Paracetamol
| 2. Alcohol (0 to begin with)
66
In what conditions will the blood-brain barrier not work?
Hypoglycemia and acidosis
67
T/F: Heavy metals can't pass through the placenta.
False
Heck, even nicotine can (fetal tobacco syndrome)
68
What is the half-life of DDT in the body? In the environment?
30; 100
69
What is the relationship between rate of excretion and toxicity?
Greater rate, less toxicity
70
What is responsible for delayed excretion of certain compounds via enterohepatic circulation?
Bacterial flora in distal ileum convert metabolites into lipophilic states
71
What compounds are recovered via enterohepatic circulation?
```
Carbamazepine (anti-convulsant)
Dapsone (anti-infective; leprosy)
Phenobarbital (anti-convulsant)
Quinine (for malaria)
Theophylline (asthma and lung problems)
```
72
What compounds are ionised in alkaline urine? acidic urine?
Weakly acidic drugs; weakly basic drugs
73
Enumerate the kinetic processes the body adapts to protect itself from toxicants.
Presystemic elimination
Distribution away from target site
Detoxification
Excretion
74
What is the process that prevents formation of ultimate toxic metabolites and enhances its elimination?
Detoxification
75
What agents are used in detoxification?
Antioxidants
Glutathione
Superoxide dismutase
76
What are the modes of excretion?
```
Liver
Kidney
Bile
GI tract
Breast milk
```
77
Enumerate the potential stages in development of toxicity after clinical exposure
1. Delivery
2. Interaction with target molecule
3. Cellular dysfunction & injury
4. Dysrepair
78
What are direct injuries usually caused by?
Caustic agents
79
Ethylene glycol is converted to (1) by (2), which produces (3) and (4), causing damage to (5) and (6).
(1) oxalic acid (potential acute kidney and lung injury)
(2) oxidation
(3) acidosis
(4) hypercalcemia
(5) kidney
(6) GIT
80
What are the two altered states of cell regulation? Of cell maintenance?
Dysregulation of gene expression
Dysregulation of ongoing cellular activity
Impaired internal maintenance
Impaired external maintenance
81
What are the forms of interaction with the target molecule?
Non-covalent binding
Covalent binding
Electron transfer (i.e. snake venom)
Enzymatic reactions
82
Which process is most affected by toxicity? What are its components?
Cellular regulation
Dysregulation of gene expression
Dysregulation of on-going cellular activity
83
Common endocrine disruptors affect?
Reproductive genes
Thyroid
Obesity
84
Give examples of compounds that produce transgenerational toxicity
Bisphenol A
DDT
Nonlyphenol
85
What compounds mimic endogenous estradiol?
Bisphenol A
DDT
Phthalate
86
What compounds produce inhibitory effect on the M2 and M3 receptors?
Atropine and atropine-like drugs
87
What causes "Alice in Wonderland" toxidrome?
Datura metel (Angel's trumpet plant or talampunay)
88
What are the components of Datura metel?
Scopolamine, atropine, hyoscine and calcium oxalate
89
Enumerate the manifestations of anticholinergic toxidrome present during the 1st to 6th hour
```
Mydriasis
Decreased bowel sounds
Urinary retention
Dry mouth
Hallucinations/agitation
Flushed skin
Tachycardia
Hyperthermia
Blind as bat
```
90
T/F: Exaggeration of benzodiazepine stimulation of GABA alpha-receptor leads to sedation and coma.
True
91
Amphetamine and other sympathomimetic drugs lead to?
Increased release of neurotransmitters
92
Differentiate anti-cholinergic and sympathomimetic
Sympathomimetic - no dryness of skin
| Anti-cholinergic - dry and hot skin and very high-grade fever
93
What compounds cause enzyme inhibition?
Lead
Organophosphate
Isoniazid
94
Describe: Isoniazid overdose
It causes seizures and inhibits GABA synthesis.
95
What enzymes does isoniazid inhibit?
Glutamic acid decarboxylase and pyridoxine phosphokinase
96
Can you treat isoniazid overdose with benzodiazepine?
No. Seizures will not stop.
97
What are examples of impaired internal maintenance?
Impaired ATP synthesis
Oxidative stress
Impaired membrane function
98
What cases fall under impaired ATP synthesis?
Impaired H+ delivery to ECT (fluoroacetate)
Inhibition of electron transport complexes (cyanide)
Inhibition of O2 delivery to ETC
Inhibition of ADP phosphorylation
99
Paracetamol undergoes (1) and (2) for metabolism and excretion.
(1) Glucuronidation
| (2) Sulfation
100
NAPQI is reduced to (1) by (2).
(1) Mercapturate
| (2) Glutathione
101
Paracetamol overdose manifests as...
Liver toxicity
102
T/F: Ethanol and organic solvents increased cell membrane fluidity.
True
103
T/F: Hydrocarbons destroy plasma membrane.
False
They destroy lysosomal membranes.
104
Describe: Impaired external maintenance by coumarin
Inhibits hepatic synthesis of coagulation factors
105
What are the different toxicity repair mechanisms?
Molecular (proteins, lipids and DNA)
Cellular
Tissue
106
How long does it take liver tissue to regenerate?
6 - 8 weeks
107
Give an example of a chemical allergy
Pyrethroids - insecticides
108
Refers to a genetically determined abnormal reactivity to a chemical
Chemical idiosyncrasy
109
Deficiency in NADH-methemoglobin reductase may lead to?
Cyanosis, CNS and GI effects
110
T/F: Immediate toxicity is acute toxicity, while delayed toxicity is chronic/subchronic toxicity
True
111
T/F: Neurotoxicity is an example of immediate toxicity caused by organophosphates.
False
Delayed!
112
Give examples of reversible and irreversible toxicity
Reversible - paracetamol injury
| Irreversible - alcoholic binge (2 million neurons lost!)
113
Give examples of systemic toxicity
Phenol a.k.a. lysol leading to kidney damage
| Oxalic acid leading to liver damage
114
What compound is capable of interrupting formation of NAPQI from paracetamol?
N-acetylcysteine (precursor of glutathione)
115
What is the antidote for isoniazid overdose?
GABA and exogenous vitamin B6
116
What are clinical applications in cases of toxicity?
Choose antidotal therapy
Determine magnitude and extent of toxicity
Make effective/adequate treatment plan to address kinetic & dynamic properties
Predict plasma drug concentration
117
What are the modifications in clinical responses of individual drugs with concurrent use of 2 or more drugs?
```
Adverse interaction (loss of efficacy)
Beneficial interaction (enhancement of efficacy)
```
118
T/F: Many drug interactions can be predicted by knowledge of pharmacokinetic & pharmacodynamic properties of the drugs.
True
119
T/F: Altered pharmacokinetics, pharmacodynamic, drug-induced disease or change in fluids and electrolyte balance may modify response to another drug.
True
120
T/F: Interactions demonstrated with certain drugs can be extrapolated to closely related drugs.
False
121
Give examples of drugs with a low therapeutic margin
```
Oral anticoagulants
Hypoglycemics
Cardiac glycosides
Anti-convulsants
Anti-cancer
Anti-hypertensives
```
122
T/F: Pharmaceutical drug interactions are typically in vitro.
True
123
T/F: IV fluid does not need to suit the drug.
False
124
T/F: Certain drugs may be broken down by polyvinyl chloride plastics.
True
125
T/F: Isoniazid can be converted to toxic forms if stored improperly.
True
126
When do pharmacodynamic drug interactions occur?
When interactant drug alters effect of object drug at site of action
127
What is the antidote for opiate overdose? What is the mechanism of action?
Naloxone; antagonism
128
T/F: Flumazenil and benzodiazepine exhibit antagonism.
True
129
What substances are used for potentiation of sedation?
Ethanol and CNS depressants
130
T/F: An antihistamine can enhance the hypotensive effect of an anti-hypertensive.
True
131
In indirect pharmacodynamic interactions, it is the (1) that interacts with the main drug.
Side effect
132
Enumerate drugs that cause potassium depletion
Diuretics
Amphotericin
Ampicillin
Carbenicillin
133
T/F: Furosemide can produce hypokalemia.
True
134
Give an example of an indirect pharmacodynamic interaction
Cardiac glycosides and potassium-depleting drugs
135
Define: Pharmacokinetic Drug Interaction
ADME is altered by the interactant drug
136
Antimuscarinic drugs (1) gastrointestinal motility.
(1) decrease
137
T/F: Food + isoniazid/penicillin/rifampicin would lead to increased absorption of the drugs.
False
Decreased!
138
What are the three factors affecting distribution?
Concentration in drug plasma
Relative binding affinity of the drug
Volume of distribution
139
T/F: Most drug interactions involving inhibition of metabolism occur in liver and are due to competitive inhibition.
True
140
List potent inducers of the microsomal enzyme system
```
Barbiturates
Imipramine
Phenytoin
Haloperidol
Carbamazpine
Rifampicin
```
141
List potent inhibitors of the microsomal enzyme system
```
Cimetidine
Isoniazid
Phenothiazines
Chloramphenicol
Metronidazole
TCADs
```
142
What are the factors involved in excretion drug interactions?
Competition for tubular secretion
| Change in urine pH
143
Define: Object Drugs
Narrow margin of safety
144
Define: Precipitant Drugs
Highly protein bound and affects metabolism of other drugs
145
What is the major limitation in interventions?
Cost
