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Pharmacology: Exam 1 > Unit 1. Lec 2-Pharmacokinetics II > Flashcards

Unit 1. Lec 2-Pharmacokinetics II Flashcards

1
Q

Define First Pass Effect

A

The combined action of bacterial and liver enzymes on drugs before reaching systemic circulation

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2
Q

Why do drugs get broken down before reaching systemic circulation when taken orally?

A

Because the drugs have to go through your GI tract and liver before entering systemic circulation. This is called First Pass Effect.

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3
Q

How much of a drug can you lose when taked orally (PO) due to first pass effect?

A

80%

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4
Q

How much of Nitroglycerin is lost due to first pass effect? And how it taken to bypass this outcome?

A
  • 100% is loss
  • Taken sublingually (under the tongue)-lipid soluble and cross epithelial cells
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5
Q

List the factors (4) that influence Drug Distribution

A
  • Blood Flow (most important)
  • Lipid Solubility of Drug
  • Molecular size
  • Protein binding
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6
Q

How does Blood Flow affect drug distrubtion?

A
  • The most highly perfused organs (liver, heart, lungs, kidney & brain) recieve most of the drug during the first few minutes after absorption
  • Slow Blood Flow: Delivery of drug to muscle, viscera, skin and fat
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7
Q

How does lipid solubility affect drug distribution?

A
  • More Lipid soluble drugs, better at crossing BBB
  • Lipid insoluble drugs, that cross the membrane poorly, are restricted in their distribution, and in their site of action
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8
Q

How does molecular size affect drug distribution?

A
  • Extremely large drugs are mainly confined to the plasma membrane compartment (e.g. heparin-anticoagulative drug)
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9
Q

How does protein binding affect drug distribution?

A
  • Distribution may be limited to drug binding to plasma protein (Reversable binding)
  • Only the unbound drugs cross the cell membrane
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10
Q

What are the binding proteins for acidic and basic drugs?

A-A
BG

A
  • Acidic: Serum Albumin
  • Basic: Alpha-one Glycoprotein
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11
Q

List Drug Reservoirs (4)

Reservoirs-place where substances collect

A
  • Plasma proteins
  • Fat
  • Bone
  • Cellular reservoirs
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12
Q

How are plasma proteins drug reservoirs?

A

Many drugs bind to plasma proteins (A-A, BG). This binding is predominately reversible

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13
Q

How is fat a drug reservoir?

A

Fat can act as a drug reservoir for highly lipophilic drugs

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14
Q

Explain cellular drug resevoirs

A

Some drugs may accumulate in the muscle or other cells at higher concentration than in extracellular fluids

Ex. antimalarial agent quinacrine in the liver

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15
Q

Describe the blood brain barrier (BBB) and what does it protect against

A
  • BBB is adaptive
  • Exclusion of foreign agents (xenobiotics) such as penicillin
  • Protects the CNS against severely toxic effects
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16
Q

What is a shortcoming of the BBB?

A
  • It is not absolute
  • So vary large doses of drugs (e.g. pencilllin) can produce seizures and other toxic effects
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17
Q

What method is being practiced to enhance the efficacy of chemotherapeutic agents of the brain?

A
  • Maneuvers to increase the permeability of the BBB of drugs used to treat infections or tumors localized in the brain

Negative side effects d/t the brain being so sensitive

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18
Q

Why is difficult for most drugs to cross the BBB?

A
  • No fenstrations in the brain, need to be lipid soluble to cross
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19
Q

True or False: Infants do not have a developed BBB and more can cross

A

True

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20
Q

True or False: Placenta is a barrier to drugs

A

False

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21
Q

Why is taking certain drugs while pregnant detrimental to the fetus?

A

Placenta is not a barrier to drugs so the fetus is to at least some extent exposed to essentiall all drugs taken by the mother.

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22
Q

Define Elimination

A

Combination of biotransformation and excretion. It is the process by which drugs are enzymatically altered (biotransformation) mainly in the liver and eventually excreted by the kidneys

23
Q

What does biotransformation do to drugs and why?

A

Increases the water solubilty of drugs so it can be readily excreted

24
Q

What is the most important organ for biotransformation?

A

LIVER

Biotransformation can occur in other organs as well

25
Q

List the relative Metabolic activity of different organs

Relative to the liver

A
  • Liver: 1.0
  • Lung:0.1-0.2
  • Kidney: 0.08
  • Intestine: 0.06
  • Placenta: 0.05
  • Adrenal: 0.02
  • Skin: 0.01
  • Brain: 0.01-0.002
  • Heart-?
26
Q

4 results of Biotransformation reaction

A
  1. Inactive metabolite
  2. Metabolite that retain similar activity
  3. Metabolite with altered activity
  4. Bioactived metabolites (prodrug)
27
Q

What is prodrug

A

Drug being adminstrated in its inactive form and turned to active drug upon adminstration

28
Q

What are the two main steps of Biotransformation?

A
  • Phase I (Oxidation, reduction and hydrolysis)
  • Phase II (Conjugation)

Not in order, do not have go through them sequentially

29
Q

Results of Phase I reactions (3)

A

Mainly degradative
1. Inactivation
2. Change in activity
3. Conversion of a pharmacologically inactive compound (prodrug) to active drug

30
Q

List the main Phase I reactions

A
  • Oxidation (most important)
  • Reduction
  • Hydrolysis
31
Q

What are Phase II reactions mainy invloved in?

A
  • Mainly: Coupling of the drug
  • Frequently its polar metabolite from Phase I reaction to endogenous substrate (e.g-glucuronate)

Think inactive

32
Q

What is the main reaction for Phase II?

A

Conjugation (via transferases)

33
Q

What enzyme system is most responsible for oxidation reaction?

A

Cytochrome P450 system (CYP)

34
Q

Where is the CYP system found?

A
  • Mainly in the LIVER
  • In microsomal fraction (smooth ER) of cells
  • Also in lung and kidney
35
Q

What are the 2 components of the CYP system

A
  • Cytochrome P450 oxidoreductase
  • Cytochrome P450
36
Q

What is requried for Cytochrome P450 oxidoreductase?

A

Oxygen (O2) & NADPH

37
Q

Explain why Cytochrome P450 are a family of isoenzymes w/ overlapping specificities

A
  • Family of isoenzymes d/t very similar AA’s sequences
  • Overlapping specificities occur b/c many different enzymes can interact w/ the same drug (compounds)
38
Q

What is the key step of oxidation?

A

Insertion of oxygen atom producing a non-stable intermediate which breaks down to yield the final product

39
Q

What are the 3 things oxidation can do?

A
  • Add O2
  • Remove electrons
  • Remove hydrogen
40
Q

List the main reactions (5) catalyzed by Oxidation

A
  • Dealkyation- (N, O, S)
  • Hydroxylation (Aromatic ring, side chain, N)
  • Sulfoxide formation
  • N-Oxidation
  • Deamination (or primary and secondary amines)
41
Q

Dealkylation (N,O,S) mechanism

(Oxidation rxn)

A

Removal of alkyl group, which can be DEMETHYLATION (CH3)

42
Q

Hydroxylation (aromatic ring, side chain, N) mechanism

(Oxidation rxn)

A

Adding a hydroxyl group (OH)

43
Q

Sulfoxide formation mechanism

(Oxidation rxn)

A

Adding an oxygen to sulfur

44
Q

N-Oxidation formation

(Oxidation rxn)

A

Adding oxygen to nitrogen

45
Q

Deamination mechanism

(Oxidation rxn)

A

Removal of amine group

46
Q

What the most important enzymes of the non-microsomal oxidation system? where are they located?

A
  • Alcohol dehydrogenase
  • Aldehyde dehydrogenase
  • Located in cytosol

Have polymorphisms

47
Q

What enzymes carry out hydrolysis reactions?

A
  • Esterases
  • Amidases
  • Peptidases
48
Q

List functions and locations: Esterases, Amidases, & Peptidases

(Hydrolysis rxn)

A
  • Esterases break down esters (acetylcholine, procaine)
  • Amidases breaks down amides (lidocaine, procainamide)
  • Pepttidases breaks down peptides
  • Mainly found in liver, plasma and GI tract
49
Q

Which enzymes is responsible for reduction rxn? and the mechanism?

A
  • Reductases
  • Catalyze the reduction of nitro group(e.g. chloramphenicol), azo, & carbonyl group (e.g. warfarin)
50
Q
  1. True or false:
    The glomerulus of the kidney plays a role in the first pass effect
A

False (It is involved in elimination)

First pass= biome+liver enzymes

51
Q

Cytochrome P450 is an enzyme system responsible for what type of reactions?
a. Reduction
b. Oxidation
c. Hydrolysis
d. Conjunction

A

b. Oxidation (P1)

Reduction (P1), Hydrolysis (P1), Conjunction (P2)

52
Q
  1. True or False:
    Fenestrations are a key component to keeping the Blood Brain Barrier protected from xenobiotics, and only drugs that are extremely lipid soluble can pass
A

False

Fenestrations: holes. NO holes in BBB

53
Q
  1. Which of the following is NOT true regarding Oxidation
    a. Requires Oxygen
    b. Requires NADPH
    c. Requires NADH
    d. Is a Phase 1 reactions
A

c. Requries NADH

54
Q
  1. All the following are examples of a Phase 1 reaction EXCEPT:
    a. Demethylation
    b. Methylation
    c. Reductase
    d. Esterase
A

b. Methylation

Pharmacology: Exam 1 (9 decks)

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