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Pharm block 1 > ADME 3&4 -HG > Flashcards

ADME 3&4 -HG Flashcards

1
Q

Absorption and distribution combined action of these processes generally dictate what?

A

the onset of drug action and the peak intensity of the response.

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2
Q

the elimination (or removal) of drugs from the body is mediated by the processes? What do they contribute to?

A

metabolism and excretion

in general contribute to setting the duration of action by controlling the rate of termination.

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3
Q

What are primarily concerned with the accumulation of drug within the body and its movement to and from its site of action?

A

absorption and distribution

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4
Q

What is the chemical modification of xenobiotics by endogenous enzymes?

A

Biotransformation:

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5
Q

What is often used to refer exclusively to normal anabolic and catabolic reactions (protein, fat, carbohydrate, nucleic acids, hormones, and transmitters) ?

A

metabolism

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6
Q

What is often used to refer to the chemical transformation of both endogenous and exogenous agents?

A

metabolism

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7
Q

What is important about biotransformation and metabolism?

A

These reactions tend to convert active compounds into less active (or less toxic) compounds (inactivation or detoxification) and/or convert them to more polar and less lipid soluble that favor drug excretion

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8
Q

What may also catalyze the conversion of inactive parent compounds (prodrugs) to their active forms, as well as lead to the generation of toxic metabolites?

A

biotransformation

metabolism

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9
Q

T/F all biotransformation reactions are enzymatic in nature

Why is this imporant?

A

true

they are subject to the same constraints that exist for other enzymes.

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10
Q

What are the 5 properties of metabolic reactions?

A
    1. Obey Michaelis-Menton kinetics. V = Vmax[S]/(Km+[S])
    1. Reaction rate is proportional to the level of enzyme at saturating substrate concentrations.
    1. Reaction rate is proportional to substrate when substrate is limiting.
    1. Maximum rate achieved when enzyme saturated.
    1. They may be competitively or noncompetively inhibited by other substrates.
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11
Q

Define the 2 phases of metabolic reactions (brief)

A

Phase I reactions: usually convert the parent drug to an inactive metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH).

Phase II reactions: lead to covalent addition of a functional group (glucuronic acid, glutathione, amino acids, or acetate) onto the parent compound or the reactive product of a phase I reaction.

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12
Q

Why can phase I metabolites be readily excreted in the urine?

A

they are suffienciently polar

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13
Q

What is an important consequence of phase I rxns?

A

the resulting products of Phase I metabolic reactions are often highly reactive (free radicals) and potentially toxic

However, the resulting reactive metabolite may then productively take part in to phase II reactions.

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14
Q

What is the common result of the parent compound in phase II reactions? give example

A

These covalent modifications of the parent compound are generally inactive and readily excreted. Note: the 6- glucuronide metabolite of morphine is a more potent analgesic than morphine itself.

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15
Q

What are the 2 general locations of biotransformation? give specific locations of each

A

organs/tissues => liver (most common), GI tract, kidneys, lungs, brain (most tissues have metabolic capacity)

subcellular => ER (most common), cytosol and some in mitochondria, nuclear envelope, plasma membrane

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16
Q

How are microsomes made? What is necessary?

A

The endoplasmic reticulum fragments into microvesicles following homogenization and differential centrifugation.

Drug metabolizing enzymes associated are microsomal enzymes.

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17
Q

Where do most phase I reactions take place?

Where do most phase II conjugation reactions take place?

A

ER

cytosolic fraction

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18
Q

What are the 3 actions of Phase I reactions? describe them

A
  1. oxidation => addition of oxygen and/or the removal of hydrogen.
  2. reduction => Add a hydrogen or remove oxygen
  3. hydrolysis => Addition of water with breakdown of molecule.
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19
Q

What are common phase I reduction reactions?

A
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20
Q

Phase I oxidation reactions occur mostly where? Give common reactions in oxidation

A

Most oxidation steps occur in the endoplasmic reticulum

Alkyl group —-> alcohol
Aromatic ring —–> phenol

Oxidation at S or N, to generate the sulfoxide or nitroxide derivative,.

Modifications are common

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21
Q

Where do hydrolysis Phase I reactions take place? give a common example

A

performed in blood plasma and liver by esterases

Esters —> alcohol and acid

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22
Q

What are the 4 reactions in phase II conjugation? Give the result of phase II conjugation

A
  • glucorionidation (most common)
  • acylation (often less water soluble)
  • glycine addition
  • sulfoxidation
  • glutathione (GSH)

In most cases, the resultant metabolite is more water soluble, and less lipid soluble. Thus, less drug is reabsorbed from the kidney.

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23
Q

Describe the glucoronidation reaction of Phase II conjugation (location/substrates/enzyme)

A
  • location: occurs in the liver.
  • substrates: Aliphatic alcohols and phenols are commonly conjugated with glucuronide. Moreover, hydroxylated metabolites can also be conjugated. e.g. morphine.
  • enzyme: Catylyzed by UDP-Glucoronsyl transferases (UGTs)
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24
Q

What reaction of phase II conjugatioin is conjugation a tripeptide of (glutamate-cysteine-glycine) leads to a mercapturic acid metabolite?

A

glutathione (GSH)

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25
Q

Name the generaly location (nonmicrosomal/microsomal) of Type I and type 2 reactions

A

Type I

  • Oxidation: both
  • Reduction: primarily in microsome
  • Hydrolysis: primarily in microsome

TypeII conjugation

Majority of all reactions occur in the cytosol or nonmicrosomal

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26
Q

What is the major catalyst of Phase I drug biotransformation?

A

cytochrome P450 monooxygenase enzyme family

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27
Q

What are heme containing membrane proteins localized in the smooth endoplasmic reticulum of numerous tissues? Where are they in the highest concentrations?

A

cytochrome p450

highest [] in liver

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28
Q

T/F cytochrome p450 enzymes are very specific WRT to specificity and narrow in the range

A

false,

enzymes have broad and overlapping substrate specificity (i.e. non specific) they are often also referred to as the mixed function oxidase system

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29
Q

Which cytochrome p450 are represented in a majority of biotransformations?

A

CYP1, CYP2 and CYP3 encode the enzymes involved in the majority of biotransformations

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30
Q

What subfamily metabolizes many drugs during absorption from the GI- tract? What is the action?

A

CYP3A

decreases the bioavailability of many orally absorbed drugs.

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31
Q

Which isoforms are involved in the metabolism of ~50% drugs?

A

CYP3A4 and CYP3A5

32
Q

What are also involved in the metabolism of many drugs?

A

CYP2C and CYP2D6

33
Q

Describe what makes up the cytochrome p450 enzyme complex. Describe energy requirements and process of action

A
  • Cytochrome-P450 Enzyme
  • Cytochrome-P450 Reductase
  • O2, 1 oxygen is added to the drug and 1 atom of oxygen is reduced from H2O
  • NADPH: NADPH is the only energy source.
  • No ATP is required.
34
Q

What are the 8 factors affecting drug metabolism?

A
  1. species differences
  2. genetic differences or polymorphisms
  3. age differences
  4. sex
  5. diet
  6. disease
  7. drug induced changes in metabolism (induction)
  8. Drug-induced changes in metabolism (inhibition)
35
Q

What can cause an increase over time in liver enzyme activity? How does this affect metabolism?

A

A large number of drugs => Drug-induced changes in metabolism (induction)

This in turn can increase the metabolic rate of the same or other drugs.

36
Q

T/F induction is generally a reversible process.

What are the characteristics of induction?

A

true

    1. onset- 3-12 hours
    1. maximal- 1-5 days
    1. persistence- 5-12 days
37
Q

Drug metabolism being an enzymatic process can be subjected to what?

A

competitive inhibition

38
Q

What are the mechanisms of metabolic inhibition?

A
    1. Competition among substrates. (Ex. Cimetidine)
    1. Inactivation by formation of a tight complex with the heme. (Ex. Cobalt)
    1. Depletion of cofactors. generally more common with phase II reactions. (Ex. GSH depletion due to oxidative stress)
    1. Enzyme inhibitors. (Ex. MAOI)
    1. Increased degradation. (Ex. CCl4).
39
Q

What is the the genetic basis for differences among the population in drug responses (therapeutic or toxic)?

A

pharmacogenetics

40
Q

What is the application of genomic information towards the discovery/development of novel specific drugs?

A

pharmacogenomics

41
Q

drugs may be targeted for selective use among specific patient populations through what?

A

pharmacogenomics

42
Q

Variations in the DNA sequence of individuals can be propagated to the protein sequence and underlie what?

A

genetic polymorphism

43
Q

Name when differences between individuals will be expected in their response to the drug.

A

When structural changes occur in proteins that are important for a drug’s effect(s)

(either due to their pharmacodynamic effects or their disposition)

44
Q

Two of the most clear examples that illustrate the role of genetics in drug responses are

A

species-dependent

gender-dependent differences in drug metabolism

45
Q

Where can Genotypic polymorphisms between individuals be observed? How are they observed?

A

strictly in the sequence of DNA bases encoding specific proteins.

These differences can be readily observed by molecular biology techniques such as PCR, RFLP and can be mediated by changes a small as a single nucleotide (SNPs)

46
Q

pharmacogenomic differences are considered silent until the individual is appropriately challenged by a drug. The resulting response is seen where?

A

individuals phenotype

47
Q

What can be characterized by their frequency distribution patterns and be indicative of the number and extent of genotypic differences?

A

phenotypic variation

48
Q

Describe the difference in monogenic traits and polygenic traits wrt frequency of response and dose

A

monogenic => increase in response then a decrease followed by a stronger response

polygenic => 1 response that lasts much longer

49
Q

Common mechanisms by which genetics variations can control metabolism include what?

A
    1. complete loss of activity.
    1. reduced catalytic activity.
    1. enhanced catalytic activity
50
Q

What is the removal of drug from the body and is a component of drug elimination?

A

excretion

51
Q

What are the routes of drug excretion?

A
    1. Renal- urine
    1. liver /intestines -feces
    1. lungs – major route for inhaled agents
    1. sweat (minor)
    1. saliva (minor)
    1. breast milk
52
Q

The major organ for the excretion of drugs is what? What is the functionial unit that this takes place in?

A

kidney

53
Q

the nephron is where three major processes relevant to drug elimination occur. Name them

A

1) glomerular filtration
2) tubular secretion
3) tubular reabsorption

54
Q

T/F the kidney receives about 1/4 blood of cardiac output.

1/5 of cardiac blood enters what for filtration?

A

true

glomeruli

55
Q

Glomerular filtration is what type of process?

A

passive and nonsaturable process

56
Q

Desribe glomerular filtration rate (GFR).

How is it measured clinically?

A

amount of blood that enters the glomeruli

57
Q

In the glomerulus, what happens to all molecules of low molecular weight? give examples

A

are filtered out of the blood.

(ions, glucose and peptides, but not proteins)

58
Q

Most drugs are readily filtered from the blood unless what?

A

they are tightly bound to large molecules such as plasma protein

have been incorporated into red blood cells.

59
Q

How is the overall renal excretion controlled?

A

controlled by what happens in the tubules.

60
Q

How much of the filtrate is reabsorbed? What is normal urine output?

A

More than 90% of the filtrate is reabsorbed. (120 ml/min is ~170 L/day)

Normal urine output is about 1 to 2 liter per day.

61
Q

What occurs In the proximal tubule?

A

tubular secretion

there is reabsorption of water and active secretion of weak electrolytes (especially acids).

62
Q

The reabsorption of water and active secretion of weak electrolytes in the proximal tubule is what type of secretion? What will it require?

A

active secretion

requirements:

  • a transporter
  • supply of energy
63
Q

What is a significant pathway for the removal of organic anions and cations as well as drugs?

A

secretion

64
Q

What occurs in the distal tubules of the kidney?

A

tubular reabsorption

Nonionized (lipid soluble) forms of weak acids and bases which are present in the glomerular filtrate can be reabsorbed in the distal tubules by passive diffusion and returned to the general circulation

65
Q

filtered lipid soluble substances are extensively reabsorbed. Why?

A

The membrane is readily permeable to lipids

much of the water, in the filtrate, has been reabsorbed and therefore the concentration gradient for the drug now favors reabsorption

66
Q

Reabsorption of weak electrolytes is passive and therefore is dependent on what?

A

pH of urine

67
Q

What facilitates removal of basic drugs and metabolites?

What faciltates excretion of acidic compounds?

A

remove basic compounds => Acidification of urine (with NH4Cl)

remove acidic compounds => alkalinization (with NaHCO3)

68
Q

The renal excretion of drugs is quantified by what?

How is this calculated?

What can it be used for?

A

the renal clearance value for the drug

part of the total body clearance for a particular drug

investigate the mechanism of drug excretion

69
Q

If the drug is filtered but not secreted or reabsorbed, what is the renal clearance? How is the clearance related to the GFR?

A

renal clearance will be about 120 ml/min in normal subjects.

(CLr = GFR)

70
Q

If the renal clearance is less than 120 ml/min then drug show what? How is the clearance related to the GFR?

A

net reabsorption

(CLr < GFR)

71
Q

If the renal clearance is greater than 120 ml/min then tubular secretion must be doing what?

How does the clearance relate to the GFR?

A

contributing to the elimination process.

(CLr > GFR)

72
Q

Transport mechanisms similar to the proximal tubule of the kidney are also present where?

A

in the liver

73
Q

The transport mechanisms in the liver have processes that are similar to the kidney. Describe them

A

** actively secrete** drugs and metabolites along with bile acids and salts

released into the intestinal tract as part of the digestive process.

These may then ultimately be excreted in the feces

74
Q

reabsorption of drugs and metabolites may then also take place where?

A

in the intestinal epithelium

75
Q

Describe enterohepatic cycling

A

Conjugated byproducts of drugs previously metabolized by liver may also undergo hydrolysis back to the parent compound (or an active metabolite) in the intestines and be reabsorbed and directed to the liver by portal circulation

76
Q

What can prolong the presence of drug (and its effects) by reducing its elimination rate?

A

enterohepatic cycling

77
Q

What are factors affecting excretion?

A
    1. Drugs MW
    1. Volatility (for inhalation route)
    1. Lipid solubility
    1. Concentration
    1. Volume of distribution
    1. Protein binding
    1. Ionization
    1. Excretion mechanism
    1. Rate of metabolism
    1. Blood flow
    1. Disease states

Pharm block 1 (7 decks)

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