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MSII Pharmacology > Unit 1 - Biotransformation of toxicants > Flashcards

Unit 1 - Biotransformation of toxicants Flashcards

1
Q

what can biotransformation of toxicants affect?

A
  1. route of administration
  2. dose
  3. effectiveness
  4. toxicity, safety
  5. duration of effect
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2
Q

what are the 2 purposes of biotransformation?

A

it’s a method of clearing drug from the plasma, but rate depends on endogenous enzyme systems

  1. drug detoxification - change structure, thus change activity
  2. prepare drug for excretion - reduce drug characteristics that make it easy to absorb
    - make drug bigger
    - add positive/negative charges
    - make drug water solution (especially important)
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3
Q

what are the sites of biotransformation?

A 
liver
-on cellular structural components, SER, lipid environment (enhances equilibrium and accumulation with lipid soluble drugs)
-mitochondria
-cytoplasm
anywhere else in the body
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4
Q

hepatic microsomal drug metabolizing systems?

A

in the SER

  • both Phase I and Phase II processes
  • -inhibition - use a drug to block metabolism of another drug or endogenous compound
  • -induction - increase metabolism of primary drug or other drugs due to feedback to the nucleus; might be observed as increase in first pass metabolism
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5
Q

non-microsomal drug metabolizing systems?

A

other organs, plasma, and RBC that aren’t the liver

  • only Phase I
  • only inhibition b/c no nucleus to feedback to
  • acetyl cholinesterase, alcohol dehydrogenase
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6
Q

are enzyme systems specific of broad?

A

both, but more likely nonspecific with a broad range of activity for classes or types of molecules
-follow concept of mass action; accumulation of products from phase I become substrates of phase II

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7
Q

what are phase I reactions?

A

drug oxidations that add O2 or change proportion of O2 in the molecule
-very important and most common metabolic transformation

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8
Q

how does the ER and cytoplasm of liver cells, and the mitochondria of adrenergic nerves, oxidize drugs?

A

by adding O2

  1. ER: phenobarbital –> hydroxyphenobarbital
  2. cytoplasm: ethanol –> acetaldehyde
  3. mito: norephinephrine –> 3,4 dihydroxymandelic aldehyde
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9
Q

what are the components of the hepatic mixed function oxidase system and what do they usually do?

A
  1. NADPH
  2. cytochrome P450 reductase (flavoprotein)
  3. cytochrome P450 (hemoproteins)
  4. Mg++
  5. phospholipid
  6. O2
    usually metabolize lipid soluble drugs; drug as a [substrate] will concentrate in SER
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10
Q

what are the different groups of P450 in humans?

A

12 different ones

  • some for toxins, others for endogenous compounds
  • low specificity
  • very large genetic variations
  • catalyzes reductions and oxidations
  • thus if giving a different drug, make sure it’s metabolized by a different P450 system
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11
Q

go into more detail about CYP2D6

-how many drugs are metabolized by it?

A

type of P450 with the largest degree of identified genetic variations

  • about 70 nucleotide variations exist, resulting in inactive enzyme or reduced catalytic activity
  • 65 commonly used drugs metabolized
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12
Q

what are the 4 phenotypes of patients for metabolic activity, and variations by race?

A
  1. poor –> potential toxicity
  2. intermediate
  3. extensive
  4. ultrarapid –> potentially no effect due to high first pass metabolism

5-10% of Caucasians have poor metabolism, while 1-2% of SE Asians

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13
Q

how can there be slow metabolism in regards to the P450 enzymes?

A

potential drug interactions when various drugs are metabolized by the same type of cyt P450

  1. competition with inhibition causes potential toxicities
  2. induction –> decreased effectiveness for a given dose
    - this is why you should use a drug that uses a different P450 for metabolism
  3. disease factors (liver disease, liver perfusion)
  4. age and sex (fetal to geriatric)
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14
Q

what are 10 drug biotransformations carried out by hepatic mixed funciton oxidase system?

A
  1. aliphatic oxidations
  2. aromatic oxidations
  3. oxidative N-dealkylations
  4. oxidative O-demethylations
  5. oxidative S-dealkylations
  6. oxidative deaminations
  7. N-oxidations
  8. N-hydroxylations
  9. sulfoxide formations
  10. oxidative desulfurations
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15
Q

what are drug reductions? examples in the liver microsomes, and cytoplasm/mitcohondria of liver

A

add H or change proportion of H in the molecule

  1. reduction of aromatic nitro compounds and aromatic azo compounds in hepatic/liver microsomes
  2. reductions of aldehydes to alcohol in cytoplasm/mitochondria of liver
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16
Q

what are drug hydrolysis?

A

cleave a molecule by adding water

17
Q

how is activity in phase I reactions?

A

activities of drugs VS activities of metabolites

  • phase I may have variable results on activity
  • both in target tissue and on secondary receptors in other tissues - toxicity
18
Q

what are phase II reactions generally?

A

conjugation in liver; synthesize a new molecule by combining drug or metabolic product of Phase I with a molecule provided by the cell

  • metabolic energy is used and covalent bond is formed
  • resulting molecule is larger, charged, water soluble, and inactive
19
Q

what are 8 types of conjugation?

A
  1. glucuronide formation
  2. glycine conjugation
  3. glutamine conjugation
  4. acetylation, acylation
  5. sulfate conjugation
  6. methylation
  7. riboside and riboside phosphate formation
  8. mercapturic acid formation
20
Q

when are biotransformation enzyme systems rate limiting steps?

A
  1. when metabolism is more important than renal elimination (lipid soluble drugs)
  2. when enzyme is relatively slow
21
Q

first order VS zero order enzyme systems

A

first: [D] constant such that [D] &laquo_space;Km (efficient enzyme system)
- most are first order
zero: [D]&raquo_space; Km (inefficient enzyme system)
- at max, constant rate

22
Q

how do hepatic microsomal enzymes and non-microsomal enzymes differ?

A

microsomal has induction (increase metabolism by drug in question, or by other drugs), inhibition (decrease metabolism by another drug), and saturation

non-microsomal has only inhibition and saturation

23
Q

what is the most important route of elimination of drug or metabolites?

A

renal excretion

24
Q

what is the equation for amount of drug excreted?

A

excreted = amount entering tubule - amount reabsorbed

25
Q

what are the two methods drugs enter the nephron?

A
  1. glomerular filtration - only free drug molecules are filtered
    - amount filtered depends on glomerular blood flow and free drug concentration
  2. active tubular secretion - one system for acids, and one for bases (exists for endogenous compounds like uric acid or choline)
    - inhibition is usually competitive (some require lots of drug before effect begins)
    - saturation (can occur at therapeutic doses or with overdoses; changes from first order to second order)
26
Q

do all water or lipid soluble drugs have to be conjugated by the liver?

A

water-soluble drugs do NOT have to be conjugated, and can go straight to kidney filtration

lipid soluble drugs MUST be conjugated by the liver
-they can go to the kidney first, but they will have back-diffusion dependent on pH of tubulus fluid

27
Q

how are drugs reabsorbed in the kidney?

A
  1. passive reabsorption - especially for lipid soluble drugs
    - after free water absorption, these are concentrated in the LoH
    - reverse concentration gradient occurs
  2. active reabsorption - active transport, for endogenous compounds, works for some drugs (like glucoes)
28
Q

what is the equation for amount of drug excreted?

A

amount of drug excreted = glomerular filtration + active tubular secretion - passive reabsorption - active reabsorption

29
Q

how does one enhance renal excretion?

A
  1. forced diuresis
  2. manipulate pH of urine to trap ionized drug
    - usual urine pH is 5.5, so if alkalinize urine, increased clearance of acidic drugs
30
Q

explain biliary excretion

A

enters bile by secretion (active transport system with acids/bases) or passive diffusion

reabsorbed by passive diffusion and original absorption mechanism (enterohepatic cycling can occur)

31
Q

what is the use of activated charcoal?

A

given to overdose patients to drink, so it binds lipid soluble drugs in the stomach to facilitate clearance

32
Q

what are non-kidney/bile methods of elimination?

A

lung (exhaled air), sweat, saliva, tears, and breastmilk

33
Q

what is the main purpose of elimination of drugs from the site of action? what are the 3 steps?

A

decrease concentration of drug in the plasma

  1. redistribution - changes location of drug
  2. biotransformation - primarily hepatic, metabolically changes drug to metabolites, and causes clearance of drug from plasma
  3. excretion - primarily renal, produces clearance of drug from plasma and body
34
Q

what are 6 factors that influence clearance?

A
  1. body surface area
  2. protein binding
  3. cardiac output
  4. renal function
  5. hepatic function
  6. blood flow to systemic organs

MSII Pharmacology (43 decks)

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