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Archaeological Practice > Toxicology > Flashcards

Toxicology Flashcards

1
Q

Body Fluid Compartments - Female

A

45% Solids and 55%Fluids

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2
Q

Water within the body exists in three major fluid compartments and consitutes 50-70% body weight

A

Extracellular, Intercellular and Transcellular

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3
Q

Extracellular

A

Blood Plasma, Interstitial fluid and lymph

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4
Q

Intercellular

A

Fluid within all cells of the body

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5
Q

Transcellular

A

Cerebrospinal (the fluid that flows in and around the spinal cord etc.)

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6
Q

Intracellular makes up (ICF)

A

2/3 of the bodies fluids

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7
Q

Extracellular makes up (ECF)

A

1/3 of the bodies fluids

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8
Q

Extracellular is made up of

A

80% Interstitial fluid and 20% Plasma

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9
Q

Distribution of Drugs occurs in 4 patterns throughout the body

A

Only in Plasma. All body fluids homogenously, specific tissues and non-homogenous (non-uniform)

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10
Q

Only in Plasma

A

High-molecular weight (HMW), Dextran, Evans blue (dye) and Suramin

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11
Q

All body fluids homogenously

A

Small and non-ionized few molecules like alcohol, some sulfonamides

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12
Q

Concentration in specific tissues

A

Iodine in thyroid; chloroquine in liver; tetracylines in bones and teeth; high high lipophilic drugs in fat tissue

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13
Q

Non-homogenous (non-uniform)

A

Most of the drugs are distributed in this patter according to their abilities to pass through the cell membrans or affinities to different tissues

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14
Q

Uneven distribution of toxins in the body because of:

A

Toxicant Physio chemical properties:
*pKa
*Lipid Solubility
*Mollecular weight
*Protein/tissue binding

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15
Q

Volume of Ditribution

A

Blood flow (perfusion rate) mL/min/g
Barriers
*Placental barrier
*Blood-brain-barrier
*Walls of the capillary vessels in the circulatory system
*Cell membranes

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16
Q

As Molecular Weight (MW) increases

A

absorbtion decreases

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17
Q

Molecular Weight (MW)

A

The proper molecular weight of the drug is affecting its correct dosage range and it is importnat to avoid either being ineffective or creating an overdose even in use.

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18
Q

Molecular weight (MW)

A

If a higher proportion of the drug stays within the vascular space, due to binding to plasma protein or high molecular weight, the drug will have a lower volume of distribution.

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19
Q

Function of cell membranes

A
  • Act as a barrier to control transport of molecules
  • Structural support for the cell
  • Contain receptor sites for hormones and other extracellular enzymes
  • Contain cell markers for cell recognition
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20
Q

Membrane Permeability

A
  • Passive diffusion - During passive diffusion, a molecule simply dissolves in the phospholipid bilayer, diffuses across it, and then dissolves in the aqueous solution at the other side of the membrane.
  • Filtration - Membrane filtration process is a physical separation method characterized by the ability to separate molecules of different sizes and characteristics
  • Facilitated diffusion - Facilitated diffusion therefore allows polar and charged molecules, such as carbohydrates, amino acids, nucleosides, and ions, to cross the plasma membrane. Two classes of proteins that mediate facilitated diffusion are generally distinguished: carrier proteins and channel proteins.
  • Active transport - Active transport is the movement of dissolved molecules into or out of a cell through the cell membrane, from a region of lower concentration to a region of higher concentration. The particles move against the concentration gradient, using energy released during respiration.
  • Ion-pair - Ion pairing is shown to effectively increase the lipophilicity and transport rate of polar drugs across lipid membranes
  • Cells ingest fluid, molecules, and particles by endocytosis, in which localized regions of the plasma membrane invaginate and pinch off to form endocytic vesicles. Many of the endocytosed molecules and particles end up in lysosomes, where they are degraded.
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21
Q

Passive diffusion

A

Toxins dissolve and cross the cell membrane following concentration gradient.

Requires a:
* Concentration gradient
* Predominantly lipid soluable
* Uncharged (nonionised) toxin
* Lowe molecular weight (MW)
*Molecular size 50-600 Da (The dalton (symbol: Da), also known as an atomic mass unit, is a unit of mass that is equal to one twelfth of the mass of a free carbon-12 atom at rest. Its value is approximately equal to 1.660 x 10−27 kg.)

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22
Q

Rate of diffusion influence by the:

A
  • Difference in concentration gradient
  • Surface area and thickness of cell membrane
  • Lipid solubility of the toxin
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23
Q

Two types of Passive diffusion

A

1) Passive diffusion of non-electrolytes
2) Passive diffusion of electrolytes

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24
Q

Influence of pH and pKa

A

Weak acids are uncharged in acidic environment
Weak bases are uncharge in basic environment

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25
Q

Passive diffusion of non-electrolytes

A

Lipid-water partition coefficient (P) - the ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid (representing membrane) and an aqueous buffer (represnting the plasma).

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26
Q

P

A

= [drug] in lipid phase/[drug] in aqueous phase.

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27
Q

If the drug is more soluble in the lipid phase

A

P is higher

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28
Q

If the drug is more soluble in the aqeuous phase

A

P will be lower

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29
Q

Partition coefficient

A

a measure of relative affinity of a drug for the lipid and acqueous phases

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30
Q

One can control the P by modifying the side groups of the compound

A

The more C (carbon) and H (hydrogen) on the compound, the more lipid soluble, and thus the higher the P. The more O (oxygen) S () and the more water-soluble the compound, and the lower the P

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31
Q
A

Lipid solubility is an important and desired feature of most administered drugs that allows for the passive diffusion across cellular membranes. Lipophilic drugs are also difficult to excrete

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32
Q

Passive diffusion of electrolytes

A

The lower the P , the less lipid soluble, the slower the rate of transfer across biological membranes

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33
Q

pKa:

A

the pH at which half of the molecules are in the ionized form and one half are in the unionized form

34
Q

pKa

A

describes the acidity of a particular acid

35
Q

pKa

A

is a charcteristic of a toxin/drug

36
Q

Only Unionized forms of the drug or the uncharged drug

A

Can pass through or across the membranes (or is transferred) by passive diffusion.

37
Q

Un-ionized form

A

Acts like a nonpolar lipid soluble compound and can cross body membranes

38
Q

Ionized form

A

is less lipid soluble and cannot easily cross body membranes

39
Q

Controlling the pH of solution or the pKa of the drug/toxin

A

You can control the rate at which the drug/toxin is transferred

40
Q

All locla anesthetic agents

A

weak beses

41
Q

At physiologic pH

A

the lower the pKa, the greater the lipohilicity (the affinity of a drug for a lipid environment)

42
Q

Staurosporine

A

Like other fungal toxins, can enter cells by passive diffusion across the plasma membrane. It is a natural product originally isolated in 1977 from the bacterium Stretomyces staurosporeus.

43
Q

Staurosporine

A

It is a toxin that includes apoptotic cell death through at least two redundant parallel pathways.

44
Q

Staurosporine

A

is also a therapeutice agent that inhibits tumor cell growth by inducing cell death (via intrinsic apoptotic pathways)

45
Q

Apoptotic:

A

a type of cell death in which a series of molecular steps in a cell lead to its death. This is one
method the body uses to get rid of unneeded or abnormal cells. The process of apoptosis may be blocked
in cancer cells. Also called programmed cell death.

46
Q

Filtration

A

Passage of molecules through membrane pores or porous structures.

47
Q

Transports:

A
  • Polar (water soluble) molecules
  • Slightly larger molecules
48
Q

Requires a:

A
  • Concetration gradient
  • Transmembrane protein/specific carrier protein
49
Q

Filtration

A

The size of the compound and the size of pore is also affecting the rate of the filtration:

50
Q

Smaller compound

A

Transfer rapidly

51
Q

Larger compound

A

Retain

52
Q

Intermediate compound

A

Barrier

53
Q

In Biological systems:

A

Filtration is the transfer of drug/toxin across membrane the pores or through the spaces between cells:

  • Capillary endothelial membranes
  • Renal glomerulus
54
Q

Most substances (lipid-soluble or not)

A

Cross the capillary wall (filtration) - very fast

55
Q

Lipid soluble and unionized

A

Filtration and passive diffusion at the same time

56
Q

Facilitated diffusion

A
  • Carrier or receptor-mediated
  • Selective to specific molecules e.g. glucose
  • It can be saturated
  • Does not require ATP (Adenosine triphosphate)
  • Does not go against the concentration gradient
  • Bi-directional - no drug accumulation
  • Requires transmembrane protein/specific carrier protein
57
Q

Cyanide

A

Released from naural substances in foods and in certain plants such as cassava, lima beans and almonds. Pits and seeds of common fruits, such as apricots, apples and peaches, may have substantial amounts of chemicals which are metabolized to cyanide.

58
Q

Cyanide

A

Absorvs quickly through the respiratory tract and mucous membranes as well as the gatrointestinal tract and skin. It causes cell death by preventing the cell from using oxygen.

59
Q

Cyanide

A

Reversibly binds to the ferric ions cytochrome oxidase three within the mitochondria. This effectively haults callular respiration by blocking the reduction of oxygen to water. It is more harmful to the heart and the brain than other organs as they use a huge amout of oxygen.

60
Q

Transport of cyanide into cells has been presumed to be by passive diffusion.

A

Recently there have been reports that a large portion of CN, in the form of a n anion, may enter the cell by active or facilitated transport.

61
Q

Active transport

A
  • Goes against cancetration gradient
  • Requires energy (ATP) - (Adenosine triphosphate)
  • Mediated by transport carrier proteins
  • Drug combines with a transport protein in the membrane and the complex can move across the membrane
  • Selctivity - not for all molecules
  • One-way process - against concetration gradient resulting in toxin/drug accumulation
  • It can be saturated - Drug/receptor ratio - enzyme-catalyzed reactions
  • Can be inhibited - ATP (Adenosine triphosphate) inhibitors, structural analogous compounds.
62
Q

Transports

A
  • Polar molecules
  • Larger molecules
    ** Against a concetration gradient
63
Q

Requires

A

Energy ATP (Adenosine triphosphate)
Specific carrier protein

64
Q

Paraquat

A

A toxic chemical that is widely used as an herbicide (plant killer), primarily for weed and grass control.

65
Q

Primary effect Paraquat (PQ)

A

Toxicity is seen in the lungs, where PQ gets accumulated via a process of active transport in the Clara cells and alveolar type I and type II epithelial cells, leading initially to pulmonary edema, infiltration of inflammatory cells, and damage to the alveolar epithelium, and later progressing to lung fibrosis and respiratory failure.

66
Q

In addition:

A

PQ comes in direct contact with the oxygen in the lungs and generates toxic activated oxygen

67
Q

Endocytosis

A

the ingestion of large particles (such as bacteria) and the uptake of fluids or macromolecules in small vesciles.

  • Phagocytosis/Pinocytosis

Requires: ATP (Adenosine Triphosphate)

68
Q

Phagocytosis:

A

The process by which a cell engulfs and internalizes a large particle, such as bacterium, by extending it’s membrane around it.

69
Q

Pinocytosis

A

Similar to phagocytosis, but instead the cell engulfs droplets of extracelular fluid, taking in any dissolved substance within.

70
Q

Endocytosis works in three steps:

A

1) The cell membrane folds inward, forming a cavity that contains fluid, dissolved substances, food materials, foreign matter, microorganisms, and some other substances. This process is known as invagination (the action or process of being turned inside out or folded back on itself to form a cavity or pouch).

2) The cell membrane then folds back on itself until it forms a uniformly enclosed membrane around the trapped molecules, forming a vesicle.

3) The vesicle gets detached from the cell membrane, which is then processed by the cell.

71
Q

Phagocytosis form of Endocytosis works in five steps:

A

1) Detection: This is the first step during whichthe phagocyte idetifies the foreign substance, the antigen and moves towards the target cell.
2) Attachment: The phagocyte then makes contact and attaches to the target cell. This binding intiates the formation of pseudopodia, an extension of the cell membrane that helps to surround the target.
3) Ingestion: The surounded target cell gets enclosed within a vesicle when the membrane of pseudopodia fuses. This vescile enclosing the target is called a phagosome.
4) Fusion: The phagosome then gets fused with the hydrolytic enzymes of the lysosome in an animal cell, to form a structure called phagolysosome. Lysosomes thus help to digest the materials contained within the vesicle.
5) Elimination: This is the final step during which the digested foreign particle gets expelled from the cell.

72
Q

Example:

A

Immune cells such as white blood cells take up antigens such as viruses, bacteria, or dead cells, digest the content and move the digested material outside the cell.

73
Q

Pinocytosis

A

Also known as cell drinking, it is the process by which small particles such as fluids and dissolved nutrients are taken up within the cell.

74
Q

Pincytosis

A

follows the same basic steps of endocytosis involving vesicle formation and transport. Once inside , the vesicle either combines with the lysosome of the cell membrane. Lysosomes then degrade the trapped molecules within vesicles, thus releasing them into the cytoplasm. The cell undergoing pinocytosis is called a pinocyte.

75
Q

Receptor-mediated endocytosis (RME)

A

A much more specific uptake process

76
Q

RME

A

Drugs (peptide hormones, growth factors, antibodies, et al.) bind to their receptors on the cell surface in coated pits, and then the ligand and receptors are internalised, forming endosomes.

77
Q

Receptor-ligand complex may take four different pathways:

A

a) Receptor recycles, ligand degraded
b) Receptor and ligand recycle
c) Receptor and ligand degrade
d) Receptor and ligand transporter

78
Q

Example:

A

Uptake of cholesterol attached to lo-density lipoprotein (LDL) inside the cell.

79
Q

RME

A

It is a selective process used by all cell types to take up specific molecules with the help of membrane receptor proteins present in the cell membrane.

80
Q

Membrane receptors are coated with a special type of protein.

A

Clathrin

81
Q

Clathrin

A

Helps to trap the substance by forming a vesicle artound it. The vesicle then fuses with membrane-bound sacs called endosome that removes the clathrin coating from the vesicle, thus releasing the contents into the cytoplasm.

Archaeological Practice (2 decks)

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