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Medical Toxicology > Absorption, distribution, and excretion of toxicants > Flashcards

Absorption, distribution, and excretion of toxicants Flashcards

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1
Q

What is the basic unit of the cell membrane?

A

A lipid bilayer composed primarily of phospholipids, glycolipids, and cholesterol

The lipid bilayer is amphiphilic, consisting of a hydrophilic polar head and a hydrophobic lipid tail.

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2
Q

List the four major phospholipids found in mammalian cell plasma membranes.

A
  • Phosphatidylcholine
  • Phosphatidylethanolamine
  • Phosphatidylserine
  • Sphingomyelin

These phospholipids contribute to the structure and function of the cell membrane.

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3
Q

What is the thickness of the cell membrane?

A

About 7 to 9 nm

This thickness is essential for its structural integrity and function.

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4
Q

What drives the formation of membrane lipid bilayers?

A

Hydrophobic interactions

These interactions are crucial for the stability of the membrane structure.

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5
Q

How does the fluid character of membranes relate to unsaturated fatty acids?

A

The more unsaturated fatty acids present, the more fluid-like the membranes are

This fluidity facilitates rapid transport across the membrane.

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6
Q

What is the difference between passive processes and active processes in membrane transport?

A

Passive processes do not expend energy, while active processes require energy

Active transport often moves substances against their concentration gradient.

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7
Q

Define simple diffusion.

A

The movement of chemicals from regions of higher concentration to lower concentration without energy expenditure

This process follows Fick’s law.

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8
Q

What determines the lipid solubility of a compound?

A

The octanol/water partition coefficient (log P)

This coefficient is crucial for assessing potential membrane permeability.

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9
Q

What is the pKa of a weak organic acid?

A

The pH at which the acid is 50% ionized

pKa helps in understanding the ionization state of the acid at different pH levels.

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10
Q

What does the Henderson–Hasselbalch equation describe?

A

The derivation of pH as a function of pKa in a biological system

This equation is pivotal for understanding acid-base balance in biological systems.

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11
Q

At low pH, what is the ionization state of a weak organic acid like benzoic acid?

A

Largely nonionized

This affects its ability to cross cell membranes.

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12
Q

What is facilitated transport?

A

Carrier-mediated transport that does not require energy and does not move substances against a gradient

An example is glucose transport from the GI tract.

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13
Q

What characterizes active transport?

A
  • Movement against gradients
  • Saturability at high substrate concentrations
  • Selectivity for structural features
  • Competitive inhibition
  • Energy expenditure

Active transport is crucial for maintaining cellular homeostasis.

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14
Q

What are xenobiotic transporters?

A

Transport proteins that mediate the influx or efflux of xenobiotics

They are vital for the disposition of various compounds in the body.

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15
Q

What is the role of ATP-binding cassette (ABC) transporters?

A

Involved in the absorption and elimination of xenobiotics and maintaining barrier functions

This superfamily has at least seven subfamilies.

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16
Q

What is the significance of solute carriers (SLCs)?

A

They function predominantly as facilitative transporters and are vital for the disposition of endogenous compounds

There are 43 identified SLC gene families.

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17
Q

Define filtration in the context of membrane transport.

A

The process where solutes small enough pass through pores in a membrane along with bulk water flow

This differs from diffusion and is important in renal function.

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18
Q

What is the difference between log P and log D?

A

Log P is the partition coefficient for neutral forms, while log D considers all forms at a given pH

Log D is often used for predicting ADME properties.

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19
Q

What is the process by which toxicants cross body membranes to enter the bloodstream?

A

Absorption

Absorption occurs through the same processes as biologically essential substances.

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20
Q

What are the main sites of absorption for toxicants?

A

GI tract, lungs, and skin

These sites facilitate the entry of toxicants into the bloodstream.

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21
Q

What does enteral administration include?

A

Sublingual, oral, and rectal routes

Enteral administration pertains to routes involving the alimentary canal.

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22
Q

What does parenteral administration involve?

A

Intravenous, intraperitoneal, intramuscular, subcutaneous routes

Parenteral administration includes all routes other than the alimentary canal.

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23
Q

What is the significance of the GI tract in the context of toxicant absorption?

A

It is a tube where contents remain outside the body, and toxicants may cause damage only if absorbed

Toxicants can damage GI cells but usually do not result in systemic injury unless absorbed.

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24
Q

How can organic acids or bases be absorbed in the GI tract?

A

By simple diffusion in their lipid-soluble (nonionized) form

The pH in different areas of the GI tract affects their lipid solubility.

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25
Which equation helps determine the fraction of a toxicant in its nonionized form?
Henderson–Hasselbalch equations ## Footnote These equations estimate the rate of absorption from the stomach or intestine.
26
What factors influence the absorption of weak organic acids or bases?
* Surface area * Blood flow rate * Mass action law ## Footnote Absorption is proportional to surface area, and the small intestine's villi increase this area significantly.
27
What role do xenobiotic transporters play in the GI tract?
They increase or decrease the absorption of xenobiotics ## Footnote Important transporters include PEPT1, OATP2B1, and MDR1 (P-glycoprotein).
28
What is the typical absorption pathway for most toxicants in the GI tract?
Most enter by simple diffusion ## Footnote Lipid-soluble substances are absorbed more rapidly than water-soluble substances.
29
What is the relationship between particle size and absorption in the GI tract?
Absorption increases with decreasing particle diameter ## Footnote Large particles enter intestinal cells by pinocytosis.
30
What is presystemic elimination?
The removal of chemicals before they enter systemic circulation ## Footnote Also known as the first-pass effect.
31
What can influence GI absorption besides the chemical properties of the toxicant?
* pH * Presence of food * Digestive enzymes * Bile acids * Bacterial microflora * Motility and permeability of the GI tract ## Footnote These factors can affect absorption rates and the overall toxicity of compounds.
32
What effect does grapefruit juice have on GI absorption?
It increases absorption by inhibiting several transporters, including MDR1 ## Footnote This can lead to potential toxic or adverse reactions due to increased drug exposure.
33
What types of toxicants can be absorbed by the lungs?
Gases, vapors of volatile liquids, and aerosols ## Footnote Inhalation exposure can lead to toxic responses.
34
What is vapor pressure?
The pressure exerted by a vapor above its own liquid in a closed system ## Footnote Liquids with high vapor pressure tend to evaporate more readily.
35
What is the blood-to-gas partition coefficient?
It is the solubility ratio of a gas between blood and gas phase ## Footnote This ratio is unique for each gas and dictates absorption rates.
36
How does the solubility of a toxic chemical in blood affect its absorption?
The more soluble a toxic chemical is in blood, the more will be dissolved by the time equilibrium is reached ## Footnote High solubility gases take longer to equilibrate with blood.
37
What is steady state in the context of gas absorption?
It is when no net absorption of gas takes place as long as the exposure concentration remains constant ## Footnote At this point, equilibrium is reached between blood and tissues.
38
What determines the absorption of aerosols and particles?
Aerosol size and water solubility of any chemical present in the aerosol
39
Where do particles larger than 5 μm typically deposit in the respiratory tree?
Nasopharyngeal region
40
What happens to insoluble particles deposited in the nose?
They remain until removed by nose wiping, blowing, or sneezing
41
How are soluble particles processed after deposition in the nasal area?
They may dissolve in mucus and be carried to the pharynx or absorbed into the blood
42
What are fine particles and where are they primarily deposited?
Particles with diameters of approximately 2.5 μm, deposited mainly in the tracheobronchiolar regions
43
What is the mucociliary escalator?
A mechanism that clears particles by moving mucus in the ciliated portions of the respiratory tract
44
What is the size range of particles that penetrate to the alveolar sacs?
1 μm and smaller
45
What size are ultrafine particles or nanoparticles that have a high likelihood of depositing in the alveolar region?
Approximately 10 to 20 nm
46
List the three major mechanisms for the removal or absorption of particulate matter from the alveoli.
* Physical process via the mucociliary escalator * Phagocytosis by alveolar macrophages * Removal via lymphatics
47
What is the relationship between a compound's solubility in lung fluids and its removal rate?
The lower the solubility, the lower the removal rate
48
What is the role of alveolar macrophages in the lungs?
They phagocytize particles and migrate to clear them via the mucociliary escalator
49
What barriers does a chemical need to cross to be absorbed through the skin?
Stratum corneum and six other layers of the skin
50
What is the primary barrier to prevent fluid loss and absorption of xenobiotics in the skin?
Stratum corneum
51
What is the thickness of the stratum corneum on calloused areas like palms and soles?
400 to 600 μm
52
What factors influence the absorption of toxicants through the skin?
* Integrity of the stratum corneum * Hydration state of the stratum corneum * Temperature * Solvents as carriers * Molecular size
53
What is the typical molecular weight above which compounds exhibit poor dermal penetration?
Above 400 Da
54
How does the route of administration affect the absorption of chemicals?
Certain routes like intravenous introduce toxicants directly into the bloodstream
55
What is the first-pass effect?
The extraction and biotransformation of a compound by the liver before it reaches systemic circulation
56
What type of administration allows for rapid absorption due to the peritoneal cavity's blood supply?
Intraperitoneal injection
57
True or False: Subcutaneous and intramuscular injections generally result in faster absorption rates than intravenous injections.
False
58
What can be inferred about the toxicity of a compound based on different routes of administration?
Preliminary information on biotransformation and excretion can be derived from comparing toxic responses
59
What determines the rate of distribution of a toxicant to organs or tissues?
Blood flow and the rate of diffusion out of the capillary bed into the cells.
60
What is the Volume of Distribution (Vd)?
The volume in which the amount of drug would need to be uniformly dissolved to produce the observed blood concentration.
61
What are the three distinct compartments of total body water?
* Plasma water * Interstitial water * Intracellular water
62
If a chemical distributes only to the plasma compartment, what is its Vd?
Low Vd.
63
What factors affect the distribution of toxicants?
* Blood flow * Affinity for various tissues * Binding to storage sites (fat, liver, bone)
64
What is a storage depot in toxicology?
A compartment where a toxicant is concentrated but is not the major site of toxicity.
65
Which plasma protein is the major binding protein for drugs and xenobiotics?
Albumin.
66
What forces primarily drive protein-ligand interactions?
* Hydrophobic forces * Hydrogen bonding * Van der Waals forces
67
True or False: The fraction of a toxicant bound to plasma proteins is immediately available for distribution into the extravascular space.
False.
68
What can happen if a toxicant with a high degree of protein binding is displaced?
Increased free fraction of the toxicant in plasma may lead to severe toxic reactions.
69
What organs act as significant storage depots for many chemicals?
* Liver * Kidney
70
Why are fat and bone considered storage depots for toxicants?
* Fat: High stability and lipophilicity leads to long retention. * Bone: Exchange occurs between the bone surface and fluid in contact.
71
What is the function of the blood-brain barrier (BBB)?
To restrict access of toxic chemicals to the brain.
72
What primarily forms the blood-brain barrier?
Endothelial cells of blood capillaries in the brain.
73
What role do efflux transporters play in the BBB?
They move xenobiotics out of the capillary endothelial cells into the blood.
74
What is the blood-cerebral spinal fluid barrier (BCSFB)?
A barrier between circulating blood and cerebral spinal fluid in the brain.
75
What determines the rate of entry of a compound into the CNS?
* Lipid solubility * Degree of ionization
76
What are some substances that can cross the placenta?
* Nutrients * Viruses (e.g., rubella) * Cellular pathogens (e.g., syphilis spirochetes) * Globulin antibodies
77
What influences the movement of toxicants across the placenta?
* Degree of ionization * Lipophilicity * Protein binding * Molecular weight
78
What are syncytiotrophoblasts in the placenta responsible for?
Transporting nutrients and restricting distribution of toxicants to the fetus.
79
What factors affect the redistribution of xenobiotics in the body?
* Organ blood flow * Affinity for a xenobiotic
80
Fill in the blank: The initial phase of distribution is determined primarily by _______ to the various parts of the body.
[blood flow]
81
True or False: A well-perfused organ like the liver will not attain high initial concentrations of a xenobiotic.
False.
82
What is the primary prerequisite for the excretion of xenobiotics through urine?
Biotransformation to more watersoluble products ## Footnote This process enhances the elimination of toxicants from the body.
83
What are the three mechanisms by which toxic compounds are excreted in urine?
1. Glomerular filtration 2. Tubular excretion by passive diffusion 3. Active tubular secretion ## Footnote These mechanisms are essential for the removal of metabolic end products.
84
How does the pH of urine typically affect the excretion of toxicants?
Urine is usually slightly acidic (approximately 6 to 6.5) ## Footnote The pH influences the ionization and, consequently, the excretion of compounds.
85
True or False: Toxicants with a high lipid/water partition coefficient are efficiently excreted in urine.
False ## Footnote Such toxicants are typically reabsorbed into the bloodstream.
86
What role do transporters play in renal excretion of xenobiotics?
Transporters facilitate the uptake of toxicants from blood into renal proximal tubule cells and their efflux into tubular fluid ## Footnote Different families of transporters are involved in this process.
87
Fill in the blank: The two major pathways for the elimination of xenobiotics are _______ and fecal excretion.
urinary excretion
88
What is the significance of biliary excretion in the elimination of xenobiotics?
It allows for the removal of toxic chemicals from blood before they enter general circulation ## Footnote This process helps prevent systemic distribution of xenobiotics.
89
What are the two types of processes through which fecal excretion occurs?
1. Direct elimination of nonabsorbed compounds 2. Delivery to the GI tract via bile ## Footnote Both processes contribute to the elimination of xenobiotics.
90
What is enterohepatic circulation?
The cycle where a compound excreted into bile enters the intestine, can be reabsorbed, and returns to the liver ## Footnote This can lead to prolonged half-lives of xenobiotics.
91
Why is biliary excretion regulated by specific transporters?
Transporters on the canalicular membrane facilitate the transport of organic anions and other compounds into bile ## Footnote Key transporters include MRP2, BCRP, and MDR1.
92
What is the relationship between vapor pressure and the elimination of substances through the lungs?
The amount eliminated via the lungs is proportional to its vapor pressure ## Footnote This principle is applied in breath tests for substances like ethanol.
93
What role does cerebrospinal fluid (CSF) play in the elimination of toxic chemicals?
CSF allows compounds to leave the CNS through bulk flow and can also remove lipid-soluble toxicants at the blood-brain barrier ## Footnote Active transport systems also contribute to this process.
94
How do toxic compounds enter milk, and what implications does this have?
Toxic compounds are excreted into milk by simple diffusion, affecting nursing offspring and potentially entering the human food supply ## Footnote The acidic pH of milk can influence the concentration of certain compounds.
95
What is the significance of sweat and saliva in the excretion of toxic agents?
Excretion in these fluids is quantitatively minor and depends on the diffusion of nonionized, lipid-soluble forms ## Footnote Dermatitis can occur from substances excreted in sweat.

Medical Toxicology (13 decks)

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