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Clincal Toxicology EXAM I > Principles of Toxicology III > Flashcards

Principles of Toxicology III Flashcards

1
Q

A bodies natural method for detoxifying and/or removing foreign substances (xenobiotics) involves…

A

Biotransformation/metabolism

Excretion

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2
Q

What is a xenobiotic?

Most are..

A 
A foreign substance.
Most are..
-weak acids or bases
-Ionization depends on pH
-lipid soluble when unionized
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3
Q

****What are the organs MOST commonly involved in metabolism/biotransformation..

A

LIVER and GI

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4
Q

What are the advantages of the LIVER and GI for metabolism and biotransformation?

A
  • Receives the greatest fraction of total cardiac output after the lungs.
  • Contains the widest breadth of metabolic enzymes.
  • Liver has significant endothelial surface for filtration of blood.
  • Liver can distribute products to blood or bile for excretion via the kidneys or GI tract.
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5
Q

What organ in the body receives 100% of cardiac output?

A

LUNGS
Upper and lower respiratory tracts have also a large amount of surface area for absorption. Act to metabolize aerosolized xenobiotics. Thick nasal conchae but lungs as well- receives 100% of cardiac output.

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6
Q

What are phase I reactions?

A

3 types: oxidation, reduction and hydrolysis.
act to..
-increase the polarity of metabolites
-provide reactive sites for phase II enzymes

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7
Q

What are phase II reactions?

A

Conjugation reactions that couple xenobiotics to other molecules
act to..
-increase molecular weight (glutathione, methyl groups are added)
-increases polarity of metabolites

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8
Q

Both phase I and phase II reaction..

A

Modify the biological activity of parent compounds.

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9
Q

What are the ways that drugs can be changed in the body?

A
  • Once it is absorbed by an animal.. Can pass straight through to the urine or feces.
  • Can have a drug in-effected by phase I.. Conjugated by phase 2.
  • Most commonly* phase 1 changes the molecule, the products conjugated and eliminated.
  • Lipophilic molecule + enzymes => gets changed to hydrophilic and is excreted.
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10
Q

Chemical inactivation of a parent compound generally means…

A

loss of parent activity.

not the same as loss of ANY activity!

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11
Q

Biotransformation can..

A

REDUCE
ENHANCE or
COMPELETLY CHANGE biological activity.

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12
Q

Phase II conjugation reactions cause..

A

large changes (MW and polarity) usually resulting in the COMPLETE LOSS of activity.

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13
Q

Phase I reactions can…

A

create molecules with modified activity..

  • don’t increase the polarity as much as in phase II reactions.
  • modify reactive groups in a molecule instead of large MW changes.
  • metabolites are still capable of crossing membranes.
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14
Q

Cellular distribution of phase I and II enzymes can be… (2)

A

microsomal or non-microsomal

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15
Q

Cellular distribution of phase I and II enzymes

MICROSOMAL

A

Derived from the endoplasmic reticulum.

*Means the way the cells are processed. These detoxifying enzymes.

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16
Q

Cellular distribution of phase I and II enzymes

NON-MICROSOMAL

A

Derived from the cytoplasm

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17
Q

Phase I

Microsomal/ER

A 
Esterase's
Epoxide hydrolase (inducible)
Flavin monooxygenase (inducible)
Cytochrome P450s (inducible)
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18
Q

Phase I

Microsomal/ER

A

Glucuroniation (inducible)
Glutathione conjugation (inducible)
Glycine conjugation
Methylation

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19
Q

Phase I

Cytoplasmic

A 
Esterases
Epoxide hydrolase (inducible)
Peptidase
Alcohol dehydrogenase
aldehyde dehydrogenase
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20
Q

Phase II

Cytoplasmic

A

Sulfation
Glutathione Conjugation (inducible)
Acylation
Methylation

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21
Q

Phase I

Mitochondrial

A

Monamine oxidase

aldehyde dehydrogenase

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22
Q

Phase II

Mitochondrial

A

Glycine conjugation

acylation

23
Q

What is the physiological relevance of inducible enzymes/cytochrome p450?

A

Largest family of biotransformation enzymes.

  • Both with regard to number and family members
  • Diversity of enzymatic reactions.
  • *90% of phase I metabolism
  • *Phase I enzymatic activity, small changes of molecular weight,
  • *Phase I microsomal/ER
24
Q

Inducible enzymes/cytochrome p450 can be…

A

INDUCED by xenobiotic agents.

  • Xenobiotic agents inducing p450s may increase other inducible phase I enzymes because they act together in sequential reactions. Can lead to other phase one reactions…
  • Increased transcription
  • Stabilization of mRNA
  • Stabilization of protein (prevents destabilization)
  • Long-term changes that occur slowly.
25
Q

*****What drugs are p450/microsomal inducers?

A
  • Rifampin
  • Phenobarbital
  • Glucocorticoids
  • Tobacco smoke
  • Chronic ethanol
  • Fipronil
  • *These drugs ten to be given for long periods of time because long term changes occur slowly.
26
Q

*****What are p450/microsomal inhibitors?

A

Ketoconazole
Macrolide antibiotics
a-naphthoflavone
aminotriazole

27
Q

Inducible enzymes/cytochrome p-450s can be inhibited by…

A

xenobiotic agents

  • xenobiotic agents inhibiting p450s do not necessarily inhibit other biotransformation enzymes
  • mechanisms include…
  • -competitive inhibition and noncompetitive inhibition
  • Long and short term changes!*
28
Q

Both inhibiton and induction of inducible enzymes/cytochrome p450s..

A

can be caused by either parent xenobiotics or their metabolites
do not affect all p450s uniformly (each inhibitor/inducer acts on a subset of p450s.)

29
Q

Toxins may alter the effect of treatment and…

A

treatments may alter the effect of toxins!

30
Q

Biotransformation of paracetamol/acetaminophen;

In dogs phase II metabolism inactivates acetaminophen by..

A

GLUCURONIDATION (adding glucuronic acid)

SULFATION (adding a sulfate group)

31
Q

Biotransformation of paracetamol/acetaminophen;

In CATS phase II metabolism inactivates acetaminophen by..

A

Glucuronidation is DEFICENT

Sulfate donors are RAPIDLY DEPLETED

32
Q

When glucuroniation or sulfation pathways are missing or ineffective..

A

CYP3A4 activity is elevated

*This can be due to prolonged fipronil administration.

33
Q

What is NAPQI?

A

Metabolized glutathione conjugation. (GSH, Phase II)
GSH gets depleted.
NAPQI is a product of CYP3A4 and acetaminophen.
It forms a free radical that reacts with proteins, membranes and DNA.
Causes centriolobular hepatonecrosis.
Causes damage to the kidney medulla.
Converts Fe3+ to Fe2+ in RBC heme (Fe3+ does not bind to O2)

34
Q

What does NAPQI do inside the body?

A

NAPQI is a product of CYP3A4 and acetaminophen.

  • It forms a free radical that reacts with proteins, membranes and DNA.
  • Causes centriolobular hepatonecrosis.
  • Causes damage to the kidney medulla.
  • Converts Fe3+ to Fe2+ in RBC heme (Fe3+ does not bind to O2)
35
Q

Why does NAPQI cause oxidative stress in the body?

A

You can conjugate NAPQI to get rid of it with GSH, then you have a molecule that can be eliminated.
But you run low on GSH, increases oxidative stress because GSH is needed to control oxidative stress which leads to increased Fe2+ and Fe3+ and decreased O2 transport by RBCS.
That’s why this causes red blood cell damage in cats.
*METHEMOGLOBINEMIA

36
Q

Theoretically inducible enzymes/cytochrome p450…

A

can alter the effect of treatments
treatments may alter the effect of toxins
documented real word examples are sparse.

37
Q

Fipronil indications?

A 
Anti-flea medication
Used in dogs and cats
Administered topically every month
-INDUCES CYP3A4 and CYP1A1 (less so)
--CYP3A4 biotransforms acetaminophen
38
Q

What is the difference between dogs and cats when it comes to the glucuroniation pathway?

A

Dogs CAN

Cats CANT

39
Q

Cats are at greater risk of xenobiotics due to..

A

Prolonged presence of toxic xenobiotics resulting from slower biotransformation in the absence of glucuroniation.
Increased generation of toxic metabolites results from shifting in the biotranformative pathways used to compensate fro the absence of glucuroniation.

40
Q

GI excretion pathway

A
  • Direct route of excretion from the liver via the bile duct.
  • Xenobiotics undergoing phase II metabolism and with a molecular weight of more then 350 Da are eliminated this route (smaller urinary)
  • Xenobiotics can be reabsorbed following bacterial metabolism in the GI lumen.
41
Q

Kidneys excretion pathway..

A

The most vascular tissue in the body

Receives the second greatest portion of the cardiac output.

42
Q

Kidney

Filtration, diffusion and active transport..

A

Passive filtration of xenobiotics less then 40 kDA (except due to plasma protein binding)

  • In the PCT…
  • Charged xenobiotics can be actively transported into and out of the filtrate.
  • Neutral/lipid soluble xenobiotics will be reabsorbed via passive diffusion.
43
Q

Absorption, distribution and elimination are..

A

OVERLAPPING PROCESSES.

-Starts when the first molecule of a xenobiotic contacts the animal.

44
Q

Excretion of a drug implies..

A

physical removal of the drug from the body

45
Q

Elimination of a drug implies…

A

removal of a drug by ANY mechanism; excretion or metabolism.

-can be calculated using a 2-compartment model.

46
Q

What is the two compartment model?

A

The body has two compartments..
-Central = plasma
-Peripheral = tissues
Volume of distribution = sum of compartment volumes
Xenobiotics equilibrate between the plasma and periphery.

47
Q

****What is first order elimination?

A

Applies to many xenobiotics
Elimination follows exponential kinetics
the same PROPROTION of the agent is eliminated at a CONSTANT rate
-one half-life is when the amount of xenobiotic decreases by 50%
-half-life is constant only when elimination is first order!
*rate of elimination graph curves, proportional to the plasma drug concentration.

48
Q

****What is ZERO order elimination?

A

the SAME amount of agent is eliminated at a CONSTANT rate
occurs due to saturation of elimination processes
examples (for a 70kg animal)
-environmental toxicants
-alcohol
-aspirin
*CONSTANT amount is eliminated per unit of time (straight line)

49
Q

Aspirin toxicosis

TOXICITY:

A

pKa ~3.5 (an organic acid) sheds protons into the blood
large doses inhibit the respiratory center
causes respiratory and metabolic acidosis

50
Q

Aspirin toxicosis

METABOLISM

A

hydrolyzed to salicylate (pka ~3)

salicylate can be glucoronidated

51
Q

Aspirin toxicosis

excreted by the..

A

KIDNEYS

  • filtered by the glomerulus
  • transported by the organic acid transporter (per urate)
52
Q

Aspirin toxicosis

rate of elimination:

A

rates of filtration + active transport - rate of diffusion + active reabsorption

53
Q

Aspirin toxicosis

Pharmacological management?

A

NaHCO3
pKa = 10.3
Na+ + HCO3- is freely filtered by the kidney
In the blood and urine HCO3- ions absorb H+ from ASA keeping it in the A- state
Traps ASA in urine by reducing diffusion of HA
*Put it into the blood sucks out protons, will reverse the acidosis… will also freely filter out of the glomerulus. Urine bicarb looks like blood bicarb. Freely dumping base, radical shift in pH.
Aspirin can become more and more charged, increase the elimination rate of the drug.

Clincal Toxicology EXAM I (4 decks)

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