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CMOD Week 5 > ADME 2 > Flashcards

ADME 2 Flashcards

1
Q

____ and ____ 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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2
Q

The combined action of absorption and distribution generally dictate what two properties of a drug?

A

onset of drug action and the peak intensity of the response

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3
Q

In contrast, the elimination (or removal) of drugs from the body is mediated by the processes of ____ and ____.

A

metabolism and excretion

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4
Q

Metabolism and excretion contribute to setting what two properties of a drug?

A

duration of action by controlling the rate of termination

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5
Q

What is Biotransformation?

A

the chemical modification of xenobiotics by endogenous enzymes.

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6
Q

What is Metabolism?

A

normal anabolic and catabolic reactions (protein, fat, carbohydrate, nucleic acids, hormones, and transmitters) but is often used to refer to the chemical transformation of both endogenous and exogenous agents.

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7
Q

T or F. Biotransformation and Metabolism tend to convert active compounds into more active (or more toxic) compounds

A

F. They tend to convert them into less active and less toxic compounds.

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8
Q

How does biotransformation and metabolism convert active compounds into less active and less toxic compounds?

A

Inactivation or detoxification and/or

convert them to more polar and less lipid soluble that favor drug excretion.

However, these reactions may also catalyze the conversion of inactive parent compounds (prodrugs) to their active forms, as well as lead to the generation of toxic metabolites.*

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9
Q

T or F. All biotransformation reactions are enzymatic in nature

A

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

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10
Q

Biotransformation reactions all follow what characteristics?

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

Drug biotransformation reactions are classified either as phase I functionalization reactions or phase II biosynthetic (or conjugation) reactions. What are Phase I reactions?

A

These usually convert the parent drug to an inactive metabolite by introducing or unmasking a functional group (-OH, -NH2, -SH). Multiple modifications are common

However, in some instances activity is only modified, or increased (for ex. prodrugs).

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12
Q

What happens if If Phase I metabolites are sufficiently polar?

A

They may be readily excreted in the urine.

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13
Q

T or F. The resulting products of Phase I metabolic reactions are often highly reactive (free radicals) and potentially toxic.

A

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

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14
Q

What are Phase II reactions?

A

These 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.

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

Biotransformation takes place predominantly in the ____.

A

liver. However, virtually every tissue contains some of metabolic activity.

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16
Q

Where else is biotransformation readily observed?

A

The gastrointestinal tract, kidneys, and lungs.

The brain also possesses metabolic enzymes that are thought to play a role in the etiology of several neurodegenerative disorders and responses to environmental toxins

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17
Q

Most drug metabolizing enzymes are found in the ____ and the ____.

A

ER and the cytosol

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18
Q

Whee else are metabolic enzymes found in a cell?

A

Additional activity is found associated with the mitochondria, nuclear envelope, and the plasma membrane.

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19
Q

What are microsomal enzymes?

A

The endoplasmic reticulum fragments into microvesicles, referred to as microsomes, following homogenization and differential centrifugation. Drug metabolizing enzymes associated with this fraction are often called microsomal enzymes.

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20
Q

Most phase I reactions take place where in the cell?

A

in the endoplasmic reticulum.

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21
Q

Enzymes responsible for phase II conjugation reactions are primarily localized in the ____.

A

Cytosol

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22
Q

What are three main reaction types in Phase I reactions?

A

1) Oxidation
2) Reduction
3) Hydrolysis

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23
Q

What happens in an oxidation reaction?

A

the addition of oxygen and/or the removal of hydrogen.

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24
Q

Where do most oxidation reactions occur in a cell?

A

ER

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25
Q

What happens in a reduction reaction?

A

Add a hydrogen or remove oxygen

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26
Q

What happens in hydrolysis?

A

Addition of water with breakdown of molecule

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27
Q

Where is hydrolysis commonly performed?

A

Performed in blood plasma and liver by esterases

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28
Q

What are some common forms of Phase II conjugation reactions?

A

1) Glucuronidation
2) Acylation
3) Glycine Addition
4) Sulfoxidation
5) Glutathione (GSH) conjugation

29
Q

What is Glucuronidation?

A

This is the main conjugation reaction in the body

Aliphatic alcohols and phenols are commonly conjugated with glucuronide. Moreover, hydroxylated metabolites can also be conjugated. e.g. morphine.

30
Q

Where does glucuronidation occur in the body?

A

liver

31
Q

What catalyzes glucurindation reactions?

A

Catylyzed by UDP-Glucoronsyl transferases (UGTs). Responsible for most phase II reactions

32
Q

What compounds readily undergo acylation?

A

sulfonamides. Makes drugs more like to be absorbed in the kidney by adding a hydrophobic group and this extends the lifetime of the rug in the body- this is unique, most make the drugs more likely to be excreted

33
Q

What compounds readily undergo glycine addition?

A

nicotinic acid

34
Q

What compounds readily undergo sulfoxidation?

A

morphine and paracetamol

this is just adding SO4-

35
Q

What glutathione GSH conjugation result in?

A

conjugation a tripeptide of (glutamate-cysteine-glycine) leads to a mercapturic acid metabolite

36
Q

T or F. In most cases, the resultant metabolite of phase II reactions are less water soluble, and more lipid soluble.

A

F. the resultant metabolite is usually more water soluble, and less lipid soluble. Thus, less drug is reabsorbed from the kidney.

Note: acetylated metabolites are often less water soluble.

37
Q

What enzyme family is the major catalyst of Phase I drug biotransformation?

A

The cytochrome P450 monooxygenase enzyme family

38
Q

Describe cytochrome P450s. Location?

A

Cytochrome P450 enzymes are heme containing membrane proteins localized in the smooth endoplasmic reticulum of numerous tissues with the highest concentrations present in liver.

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

39
Q

Which members of cytochrome P450 family encode the enzymes involved in the majority of biotransformations?

A

CYP1, CYP2 and CYP3

40
Q

____ subfamily metabolizes many drugs during absorption from the GI- tract, where it decreases the bioavailability of many orally absorbed drugs.

A

CYP3A

  • CYP3A4 and CYP3A5 isoforms are involved in the metabolism of ~50% drugs.
  • CYP2C and CYP2D6 are also involved in the metabolism of many drugs
41
Q

Study The Cytochrome-P450 Enzyme Complex

A

Study The Cytochrome-P450 Enzyme Complex

42
Q

What are some factors that affect drug metabolism?

A

1) Species differences
2) Genetic
3) Age
4) Sex
5) Diet
6) Disease
7) Drug-induced changes to metabolism (Induction)
8) Drug-induced changes to metabolism (Inhibition)

43
Q

How can drugs change metabolism via induction? Ex.?

A

A large number of drugs can cause an increase over time in liver enzyme activity. This in turn can increase the metabolic rate of the same or other drugs.

Ex. Phenobarbital will induce the metabolism of itself and other drugs. Therefore, chronic administration can lead to a situation where there is a vicious cycle of dose escalation. Accumulation of toxic metabolites can also occur. Induction may be broad (Ex. Phenobarbital) or narrow (3-MC).

44
Q

T or F. Induction is generally a reversible process.

A

T.

45
Q

What is the general timeframe of induction?

A
  1. onset- 3-12 hours
  2. maximal- 1-5 days
  3. persistence- 5-12 days
46
Q

How can drugs change metabolism via inhibition? Ex.?

A

Drug metabolism being an enzymatic process can be subjected to competitive inhibition. Ex. warfarin inhibits tolbutamide elimination which can lead to the accumulation of drug and may require a downward adjustment of dose.

47
Q

Mechanisms of metabolic inhibition.

A
  1. Competition among substrates. (Ex. Cimetidine)
  2. Inactivation by formation of a tight complex with the heme. (Ex. Cobalt)
  3. Depletion of cofactors. generally more common with phase II reactions. (Ex. GSH depletion due to oxidative stress)
  4. Enzyme inhibitors. (Ex. MAOI)
  5. Increased degradation. (Ex. CCl4).
48
Q

What are Pharmacogenetics?

A

the genetic basis for differences among the population in drug responses (therapeutic or toxic).

49
Q

What are Pharmacogenomics?

A

application of genomic information towards the discovery/development of novel specific drugs. Such drugs may be targeted for selective use among specific patient populations.

In addition, pharmacogenetics/genomics aims to clarify the underlying basis for idiosyncratic drug responses. With this knowledge, the physician will be increasingly accountable for managing appropriate therapeutic strategies by tailoring drug dosage regimens towards individuals in register with their genetic profile.

50
Q

Common mechanisms by which genetics variations can control metabolism include:

A
  1. complete loss of activity.
  2. reduced catalytic activity.
  3. enhanced catalytic activity
51
Q

What is excretion?

A

removal of drug from the body and is a component of drug elimination which represents the combined action of metabolism and excretion. Drugs may be excreted as the parent compound or as a metabolite.

52
Q

What are the major routes of excretion?

A
  1. Renal- urine
  2. liver /intestines -feces
  3. lungs – major route for inhaled agents
  4. sweat (minor)
  5. saliva (minor)
  6. breast milk
53
Q

The major organ for the excretion of drugs is the ____.

A

kidney.

54
Q

The functional unit of the kidney is the nephron where three major processes relevant to drug elimination occur:

A

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

55
Q

How much blood does a normal kidney receive? Filter?

A

The kidney receives about 20-25% of caridac output (~650 ml/min). About 20% of the blood which enters the glomeruli is filtered (110 to 130 ml/min).

This represents the glomerular filtration rate (GFR).

56
Q

T or F. Glomerular filtration is a passive and nonsaturable process.

A

T. This filtration rate is often measured clinically by determining the renal clearance of creatinine.

57
Q

Are most drugs filtered in the kidneys?

A

In the glomerulus all molecules of low molecular weight (ions, glucose and peptides, but not proteins) are filtered out of the blood.

Most drugs are readily filtered from the blood unless they are tightly bound to large molecules such as plasma protein or have been incorporated into red blood cells.

However, the overall renal excretion is controlled by what happens in the tubules.

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.

58
Q

What happens in the proximal tubule?

A

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

Secretion is significant pathway for the removal of organic anions and cations as well as drugs

59
Q

Are the processes occurring in the proximal tubule active or process?

A

This process is an active secretion it requires a transporter

60
Q

What transporter is used in the proximal tubule?

A

MDR2 and a supply of energy.

61
Q

Nonionized (lipid soluble) forms of weak acids and bases which are present in the glomerular filtrate can be reabsorbed in the _____.

A

distal tubules

62
Q

Is reabsorption of nonionized forms of weak acids and bases in the distal tubules passive or active?

A

Passive. These are returned to the general circulation.

The membrane is readily permeable to lipids, so filtered lipid soluble substances are extensively reabsorbed. A reason for this is that much of the water, in the filtrate, has been reabsorbed and therefore the concentration gradient for the drug now favors reabsorption.

63
Q

Reabsorption of weak electrolytes is passive and therefore is dependent on the pH of the urine. Acidification of urine (with NH4Cl) facilitates removal of basic drugs and metabolites, while alkalinization (with NaHCO3) faciltates excretion of acidic compounds.

A

Reabsorption of weak electrolytes is passive and therefore is dependent on the pH of the urine. Acidification of urine (with NH4Cl) facilitates removal of basic drugs and metabolites, while alkalinization (with NaHCO3) faciltates excretion of acidic compounds.

64
Q

The renal excretion of drugs is quantified by the ____ for the drug.

A

renal clearance value

Renal clearance can be calculated as part of the total body clearance for a particular drug

If the drug is filtered, but not secreted or reabsorbed, the renal clearance will be about 120 ml/min in normal subjects. (CLr = GFR)
If the renal clearance is less than 120 ml/min, then drug show net reabsorption (CLr GFR)

65
Q

Biliary excretion

A

Transport mechanisms similar to the proximal tubule of the kidney are also present in the liver. These processes actively secrete drugs and metabolites, along with bile acids and salts, which are released into the intestinal tract as part of the digestive process. These may then ultimately be excreted in the feces

66
Q

What is enterohepatic cycling?

A

Reabsorption of drugs and metabolites from the biliary tract may then also take place in the intestinal epithelium.

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 then be reabsorbed and directed to the liver by portal circulation. This can prolong the presence of drug (and its effects) by reducing its elimination rate. Ex. Morphine and its glucoronide conjugate.

67
Q

Factors affecting excretion

A
  1. Drugs MW
  2. Volatility (for inhalation route)
  3. Lipid solubility
  4. Concentration
  5. Volume of distribution
  6. Protein binding
  7. Ionization
  8. Excretion mechanism
  9. Rate of metabolism
  10. Blood flow
  11. Disease states
68
Q

T or F. Drug-drug interactions cannot affect therapeutic window

A

T. First pass could affect the onset, and minimum effective concentration is only determined by the drug itself

CMOD Week 5 (16 decks)

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