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Foundations of Disease > Exam 1: Pharmacokinetics > Flashcards

Exam 1: Pharmacokinetics Flashcards

1
Q

Pharmacokinetics

A

The absorption, distribution, metabolism, and excretion of a drug.

(What the body does to a drug)

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2
Q

Pharmacodynamics

A

The pharmacologic effect and clinical response of a given drug.

(What a drug dose to the body)

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3
Q

A drug can cross a cell membrane via…

A

carrier-mediated transport

or

passive diffusion

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4
Q

Carrier-mediated transport exhibits…

A

selectivity & saturability

Can also be inhibited by other compounds.

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5
Q

Predominant mechanism for absorption and distribution of drugs is via…

A

passive diffusion

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6
Q

Most drugs are…

A

weak acids or bases

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7
Q

The charged form of a drug is…

A

impermeant

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8
Q

The uncharged form of a drug is…

A

permeant

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9
Q

Balance between charged and uncharged forms depends on…

A

pH and pK of the compound

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10
Q

Henderson-Hasselbach

Equation

A
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11
Q

A weak acid is better absorbed at ___ in the ___.

A

acidic pH’s

stomach

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12
Q

A weak base is better absorbed at ___ in the ___.

A

basic pH’s

intestine

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13
Q

Aspirin Absorption

A
  • Acidic pH of stomach ⇒ uncharged permeant form predominants
    • [HA] = 1
  • Rapidly equilibrates across membranes of stomach
  • In plasma, most converted to charged impermeant form (A-)
    • Traps ASA in the plasma
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14
Q

Other Factors Affecting

Absorption

A
  • Solubility in aqueous solution
  • Dissolution rate (if solid)
  • Surface area of absorption site
  • Rate of blood flow
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15
Q

Bioavailability

A

The fraction of an administered dose that reaches systemic circulation in an unchanged form.

  • Reflects the efficiency of delivery
  • Accounts for metabolism and/or excretion before drug reaches general circulation
  • IV drug administration = 100% bioavailability
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16
Q

First-Pass Effect

A

The portion of a drug that is metabolized by the liver via portal system before it can reach systemic circulation.

Significantly affects bioavailability of drugs given PO.

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17
Q

Enteral Routes

A

Utilizes the GI tract:

  1. Oral
  2. Rectal
  3. Sublingual
  4. Buccal
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18
Q

Oral Route

A
  • Most common
  • Most economical and convenient
  • Disadvantages
    • GI irritation
    • Potential for first pass metabolism
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19
Q

Rectal Route

A
  • Delivered via suppository
  • Used for patients who are vomiting or unable to swallow pills
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20
Q

Sublingual Route

A
  • Absorbed via head/neck venous drainage
  • Avoids first-pass metabolism
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21
Q

Buccal Route

A
  • Dose placed in the cheek
  • Absorption similar to sublingual
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22
Q

Parenteral Routes

A

Avoids the GI tract:

  1. Intravenous
  2. Subcutaneous
  3. Intramuscular
  4. Topical/transdermal
  5. Pulmonary
  6. Intrathecal
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23
Q

IV route

A
  • Max bioavailability
  • Continuous infusion ⇒ constant drug level
  • Potential for irritation of vascular walls
  • Inc. risk of blood-borne infections
  • Difficult to reverse once given
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24
Q

Subcutaneous Route

A
  • Less painful than IV
  • Self-admin possible
  • Circulation at injection site important for delivery
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25
Q

Intramuscular Route

A
  • Site can serve as depot for slow delivery of drug
    • Not all of the drug absorbed instantly so get slow release
  • Depends on blood flow
    • Ex. exercising or anxiety ⇒ inc. blood flow ⇒ inc. delivery
  • Large volumes often feasible
  • Self-admin possible
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26
Q

Topical/Transdermal Route

A
  • Absorption depends on lipid solubility of drug or vehicle
  • Can be irritants
  • Can get slow absorption
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27
Q

Pulmonary Route

A
  • Technically a topical application
  • Usually see local affect with little systemic absorption
    • Ex. bronchodilators
  • With anesthesia, can finely control depth of anesthesia
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28
Q

Intrathecal Route

A
  • Admin of drug to CSF
  • Used to produce slelective spinal blockade
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29
Q

Routes of Administration

Summary

A
30
Q

Distribution

A

The movement of a drug from systemic circulation to other tissues.

31
Q

Elimination

A

The process of removing a drug from the systemic circulation by excretion or metabolism.

32
Q

Single Compartment Model

A

Body acts as a single compartment.

ka ⇒ rate of absorption

ke ⇒ rate of elimination

Assume instantaneous delivery and distribution ⇒ ka = ∞

33
Q

Elimination Rate

A

Proportional to drug concentration:

ke = elimination rate constant

Given in concentration per unit time e.g. (mg/ml)/hr

34
Q

Drug Time Course

A

Follows a single exponential time course.

C0 ⇒ concentration at t = 0

35
Q

Half-life

( t½ )

A

Time it takes for the concentration at any one time to get to 50% of that value.

36
Q

Volume of Distribution

( Vd )

A

The volume needed to account for the amount of a drug that reaches the plasma for a given amount of drug introduced.

Commonly normalized to body weight ⇒ l/kg

37
Q

Causes of High Vd

A

Drugs that accumulate in the tissue or fat have unrealistic Vd because majority is not in the plasma.

38
Q

Total body water =

A

0.6 L/kg

39
Q

Extracellular water =

A

0.2 L/kg

40
Q

Blood =

A

0.08 L/kg

41
Q

Plasma =

A

0.04 L/kg

42
Q

Fat =

A

0.2-0.35 L/kg

43
Q

Bone =

A

0.07 L/kg

44
Q

Body Compartment

Volumes

A
45
Q

Clearance

(CL)

A

Relates the rate of elimination to the plasma concentration.

Units of amount of drug per unit time e.g. mg/hr

46
Q

CL, Vd, and T½

Relationship

A
47
Q

Non-instantaneous Delivery

A

Absorption slow enough to measure.

ka ≠ ∞

ke can still be determined from the late decay phase.

Cannot extrapolate t=0 to get C0.

48
Q

Vd Definition

(Non-intantaneous delivery)

A

AUC ⇒ area under the concentration-time curve

(For single exponential decay, AUC = ke/C0)

49
Q

Constant Infusion

A

Dose needed to maintain a steady-stant concentration (Css).

Deliver rate = Elimination rate

ka = ke

50
Q

Generally, it takes ___ to reach steady state concentration.

A

4-5 half lives

51
Q

Two Compartment Model

A

Central compartment ⇒ plasma

Peripheral compartment ⇒ tissues that are in rapid equilibrium with the plasma

It takes time for a drug to be evenly distributed throughout the body.

Drug concentration falls more rapidly during distribution phase than during elimination phase.

52
Q

Two-Exponential Decay

Model

A

Half-life of a drug is determined from the slow phase.

Vd and CL can also be determined.

53
Q

Multiple Dosage Regimen

A

Need to maintain a therapeutic level:

  • Constant infusion
  • Infrequent large doses
    • Goes above toxic levels
    • Dips below therapeutic levels
  • Frequent small doses
    • Takes time to reach therapeutic levels
    • Steady state concentration stays between toxic and therapeutic levels ⇒ ‘safe zone’
54
Q

Biotransformation

A

Active, lipophiic molecules ⇒ less active, polar molecules

Two broad categories:

Phase I reactions

Phase II reactions

55
Q

Phase I Reactions

A

Parent drug ⇒ more polar metabolite via introduction/unmasking of a polar functional group

(-OH, -NH2, -SH)

  • ↑ polarity ⇒ ↑ water solubility
  • ∆ pharmacological activity
    • Usually means reduction or loss of activity
  • Some are inactive drugs converted to active metabolites ⇒ prodrugs
  • Some are non-toxic compounds ⇒ toxic compounds
56
Q

Enalapril

A

Enalapril ⇒ Enalaprilat

(inactive “prodrug” ⇒ active)

By de-esterification.

57
Q

Parathion / Malathion

A
  • Used as a pesticide
  • Converted to toxic intermediates via phase I reactions by desulfuration
  • Birds & mammals able to convert these to non-toxic substances via phase IL reactions
    • Insects are not
58
Q

Phase II Reactions

A

Phase I reaction ⇒ add polar group

Phase II reaction ⇒ conjugate to endogenous polar substrates

  • Glucuronic acid
  • Sulfuric acid
  • Acetic acid
  • Glycine

Produces highly polar compounds w/ high water solubility ⇒ increases excretion

Almost all conjugated products are inactive.

59
Q

Metabolism Sites

A

Liver is 1° site of biotransformation

Most phase I reactions catalyzed by SER enzymes ⇒ microsomes

60
Q

Microsomal Enzymes

A

Two play key roles in phase I reactions:

Cytochrome p450 (“CYP”) ⇒ oxidases

NADPH-cytochrome P450 reductase

61
Q

CYP

Induction

A

Repeated administration of some substances ⇒ inc. levels of CYP isoform that metabolizes compound

Results in acceleration of metabolism of all substrates for that isoform

Ex. Barbiturates ↑ [CYP2C9] ⇒ ↑ warfarin metabolism

62
Q

CYP

Inhibition

A

Some substrates can inhibit CYPs via:

  • Competitive inhibition
    • Ex. Erythromycin & Terfenadine both metabolized by CYP3A4
  • Covalent modification of enyme
    • Usually attacks heme moiety
63
Q

Two major routes of drug excretion are…

A

renal & biliary

64
Q

Renal Excretion

A

Major site of excretion.

3 transport mechanisms involved:

  1. Glomerular filtration
    • Factors that ∆ GFR ⇒ ∆ CL
    • % bound to plasma proteins ⇒ ∆ CL
  2. Active tubular secretion
    • Non-selective organic cation/anion transporters can move some compounds
  3. Passive tubular absorption
    • H2O reabsorption ⇒ ↑ [Drug]
    • Only uncharged drugs can be reabsorbed
    • pH of urine ∆ CL
65
Q

Biliary Excretion

A
  • Must undergo conjugation in the liver first
  • Products frequently excreted into biliary tract ⇒ bowel
  • May be excreted
  • Bowel flora can cleave off conjugate
  • Drug may be reabsorbed if lipid-soluble ⇒ enterohepatic recirculation
66
Q

Pharmacogenetics

A

Genetic differences ⇒ ∆ rate of drug metabolism

  • ∆ expression levels of enzyme
  • ∆ enzymatic activity
67
Q

Isoniazid

A
  • Slow acetylators
    • ↓ [enzyme]
    • ↑ plasma levels of drug
    • AR trait seen in 50% of blacks and whites in US & Europheans living @ high altitude
  • Fast acetylators
    • Usually Asians and Inuits
68
Q

CYP2D6

Pharmacogenetics

A
  • CYP2D6 metabolizes many medications
    • Flecanide, Metoprolol, Fluoxetine, Imipramine
  • Genetic polymorphisms
    • Gene duplication ⇒ ultrarapid metabolizers
    • Null nutation ⇒ poor metabolizers
  • Exam ratio of debrisoquin : 4-hydroxydrisoquin in urine
    • Determine activity of CYP2D6
      • Ratio < 0.1 ⇒ ultrarapid
      • Ratio > 10 ⇒ poor
    • Compound is inert in the body
69
Q

Thiopurine Methyltransferase (TPMT)

Pharmacogenetics

A
  • TPMT metabolizes thiopurine drugs
  • Patients w/ low or absent TPMT activity @ inc. risk for drug induced bone marrow toxicity
  • Test for abnormal TPMT*3A allele before treatment
70
Q

Influence of Disease

A
  • Liver function
    • Hepatitis
    • Cirrhosis
  • Hepatic blood flow
    • Affects “flow-limited” metabolism drugs most
      • Metabolism so fast that it is limited by rate of delivery to liver
      • Ex. Amitriptyline & imiprimine
71
Q

Influence of Age

A

Generally, very old and very young more sensitive to drugs.

Can be due to many factors:

  • Renal clearance
  • Body fat content
  • End-organ responsiveness
  • Drug metabolism
  • Reduced rate of hepatic metabolism ⇒ most significant determinant

Foundations of Disease (46 decks)

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