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Block 2 > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

Two methods of elimination

A
  1. Metabolism 2. Excretion
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2
Q

Excretion vs. metabolism

A

Excretion = The drug is removed in its intact form; Metabolism = the drug is chewed up and inactivated

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3
Q

Enteral drug administration

A
  • Originate in the GI tract
  • Oral
  • Rectal
  • Sublingual
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4
Q

Parenteral drug administration

A
  • Everything other than enteral routes of administration
  • IV
  • Intramuscular
  • Subcutaneous
  • Inhalation
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5
Q

Advantages and Disadvantages of IV drug administration

A
  • Pros: Rapid onset, can dissolve drug in a large volume of flouid if that’s required to get it into solution; can give drugs that are chemical irritants that patients couldn’t otherwise tolerate
  • Cons: Costly, invonvenient; irreversible; risks of fluid overload, infection, embolism extravasation
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6
Q

What are the barriers to absorption for IV drug administration?

A

None

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7
Q

What are the barriers to absorption for intramuscular or Subcutaneous drug administration?

A
  • Capillary walls (i.e. very little)
  • Water-soluble drugs get absorbed more quickly than lipid-soluble drugs in this case
  • This is b/c drugs do not need to diffuse across membranes with this method, but they need to be soluble in blood
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8
Q

What determines the rate of absorption for IM or SubQ drug administration?

A
  • Water soluble has greater rate of absorption than lipid-soluble
  • Perfusion of tissue
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9
Q

Advantages and disadvantages of IM/SubQ drug administration

A
  • Pros: If drugs cannot be given via IV but they’re poorly soluble (i.e. need to just place it straight into bloodstream); If you need absorption to be slow.
  • Cons: Uncomfortable, inconvenient, risk of injury/bleeding
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10
Q

Barriers to absorption for enteral drug administration

A
  • Epithelial lining - drug needs to cross membranes to get into portal system
  • Destruction of drug by
    • stomach acid
    • enzymes in the small intestine
  • First pass metabolism - liver
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11
Q

What factors affect rate/extent of enteral drug absorption?

A
  1. Surface area of absorptive organs
  2. Drug ionization (ionized cannot cross membranes, so cannot get absorbed as easily)
  3. Chemical interactions (i.e. acid-sensitive drugs may be fully degraded in acidic environment of stomach)
  4. Drug formulation (ex: can use enteric coating to protect from stomach acid)
  5. Gastric emptying time
  6. First pass metabolism
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12
Q

Bioavailability

A
  • A number between 0 and 1 reflecting how much of a drug reaches general circulation (is absorbed)
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13
Q

How does surface area of absorptive organs affect drug absorption following oral drug administration?

A
  • More surface area = more absorption
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14
Q

How does drug ionization affect drug absorption following oral drug administration?

A
  • Ionized form cannot cross membranes
  • Acid/base properties will impact where in the body a drug can cross membranes
  • Weak acid stays protonated in stomach and small intestine. Can get absorbed in both places.
  • A weak base is protonated in the acidic environment of the stomach –> cannot get absorbed in the stomach, but only in small intestine
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15
Q

How do chemical interactions affect drug absorption following oral administration?

A
  • Acid-sensitive drugs may be fully degraded in acidic environment of the stomach
  • Drugs can form complexes with metal ions in the stomach and then become completely insoluble –> cannot be absorbed
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16
Q

How does drug formulation impact absorption following oral drug administration?

A
  • Drugs can be formulated with an enteric coating
    • This coating protects them from degradation by stomach acid
    • They get degraded in small intestine
  • Drugs can be formulated for a slow release
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17
Q

How does gastric emptying time affect drug absorption following oral administration?

A
  • Taking drug on empty stomach –> drug is emptied more quickly into small intestine –> drug is absorbed faster
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18
Q

How does first pass metabolism affect drug absorption following oral drug administration?

A
  • Drug can be absorbed by enzymes in both the small intestine and the liver
  • Usually first pass refers to the liver
  • Everything gets metabolized in liver before reaching general circulation
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19
Q

Concept of apparent volume of distribution

A
  • Because drugs have different chemical properties, they get distributed to tissues differently
  • Because some drugs can get to more places in the body, it APPEARS that different drugs are dissolved in different volumes of fluid in the body
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20
Q

Low apparent volume of distribution

A
  • Drug that stays in the plasma and cannot get distributed to tissues very well
  • This will have a really high initial drug concentration but a low volume of distribution
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21
Q

High apparent volume of distribution

A
  • A drug that distributes throughout the body
  • This will have a low initial drug concentration, but a high apparent volume of distribution
  • You can infer that a drug with a high apparent volume of distribution is sequestered in the tissues
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22
Q

Volume of distribution when drug is only in plasma

A
  • 5 L/70 kg
  • 0.07 L/kg
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23
Q

Volume of distribution when drug is in extracellular water

A
  • 5-20 L/70 kg
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24
Q

Volume of distribution when drug is in total body water

A
  • 20-40 L/70 kg
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25
Q

Volume of distribution when drug is in tissue

A
  • More than 40 L/70 kg
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26
Q

How does relative perfusion of tissue affect distribution?

A
  • More perfused organs get the drug first
  • Assuming IV drug injection so you’re not dealing with first pass metabolism
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27
Q

What types of drugs can cross the blood-brain barrier?

A
  • Lipid soluble drugs
  • Hydrophilic drugs must have a special transporter
28
Q

How does drug binding to albumin impact drug distribution?

A
  • Drug cannot escape general circulation when it is bound to albumin
  • Drug is likely to have a relatively low volume of distribution because it’s trapped in the blood
29
Q

Is drug distribution reversible? Is drug elimination reversible?

A

Yes

No

30
Q

Main modes of drug metabolism

A
  • Phase 1 metabolism
  • Phase 2 metabolism
31
Q

Phase 1 metabolism

A
  • Hydroxylation to make drug more polar
32
Q

Phase 2 metabolism

A
  • Conjugation
33
Q

Most prominent enzymes for hepatic drug metabolism

A

p450

34
Q

CYP2D6 polymorphisms

A
  • CYP2D6 is a p450 enzyme
  • There is polymorphism in the population that generates:
    • Ultra rapid metabolizers
    • Extensive metabolizers
    • Intermediate metabolizers
    • Poor metabolizers
  • Has clinical significance based on whether the drug is being eliminated or activated by CYP2D6
35
Q

How is fluoxetine impacted by CYP2D6? What does CYP polymorphism imply for this drug?

A
  • Fluoxetine is metabolized by CYP2D6
  • Rapid metabolizers will eliminate fluoxetine faster –> may need to give a higher dose
  • Poor metabolizers need to be careful of fluoxetine overdose b/c they don’t clear it quickly
36
Q

How is codeine impacted by CYP2D6? What does this imply for polymorphisms of CYP2D6?

A
  • Codeine is activated by CYP2D6
  • Rapid metabolizers will get codeine quickly after administration. Watch for overdose.
  • Poor metabolizers may not achieve therapeutic levels. May need to give more drug.
37
Q

Where does renal excretion occur?

A
  • Filtration (glomerulus)
  • Secretion (proximal tubule)
  • Resorption (occurs everywhere in tubule)
38
Q

What does filtration in glomerulus do to the drug?

A
  • Removes drug from blood
39
Q

What does secretion in proximal tubule do to drug?

A
  • Removes drug from blood
40
Q

What does resorption do to drug?

A
  • Puts drug back in the blood
41
Q

Net Renal excretion

A

= (filtration + secretion) - resorption

42
Q

How can you test filtration rate of kidney?

A
  • Measure creatinine in the urine
  • (Creatinine is never reabsorbed)
43
Q

Key features of renal secretion

A
  • Active transport
  • Saturable –> can set up drug-drug interactions
44
Q

Key features of resorption

A
  • This is a passive process
  • Ionized drug will not be reabsorped well
45
Q

Overview of elimination

A
46
Q

What is biliary excretion and enterohepatic cycling

A
  • Drugs that have been inactivated can get reactivated and put back into general circulation
47
Q

Assumptions made with IV bolus injection

A
  • There is no absorption process - the drug goes straight into general circulation
  • No distribution - this is a “one compartment” model where we assume that after the drug is given, it equilibrates to the same concentration in all tissues
48
Q

In IV bolus injection model, how do you predict the intial drug concentration?

A
  • Note: initial drug concentration for continuous infusion model is assumed to be 0
49
Q

Clearance

A
  • The amount of plasma that is cleared of drug in a certain amount of time
  • Measured in volume (of blood) per unit time
50
Q

What do you need to know to predict how drug concentration varies with time in the IV bolus model?

A
  • Dose
  • Volume of distribution
  • Clearance
51
Q

What is first order elimination?

A
  • The drug’s elimination is proportional to the drug concentration
  • The AMOUNT of drug eliminated drops as the drug concentration drops
  • The FRACTION of drug eliminated stays the same
  • The drug’s elimination is due to its half life
52
Q

What determines a drug’s half life?

A
  • volume of distribution
  • Clearance
53
Q

How do changes in clearance or Vd affect a drug’s half life?

A
  • Higher Vd –> longer half life
    • Because it takes more time to clear a larger volume than a smaller volume, the drug sticks around longer
  • Higher clearance –> shorter half life
    • Because the drug is cleared from the system faster
54
Q

Explain this equation

A
  • t 1/2 = drug’s half life
  • ke = elimination rate
    • Clearance/Vd
55
Q

Key assumptions for continuous IV infusion model

A
  • One-compartment model
  • first order elimination rate (elimination according to half life)
56
Q

What is Css

A
  • Steady state concentration
  • Parameter of continuous IV infusion
57
Q

What is the relationship between input rate, Css, and clearance in continuous IV infusion model?

A
  • The steady state concentration depends on input rate and clearance
  • Higher infusion rate –> higher steady state concentration
  • Lower clearance –> higher steady state concentration
58
Q

Explain this equation

A
  • Use to determine steady state drug concentration in continuous IV infusion model
  • R0 = infusion rate
  • Css = steady state concentration
  • Cl = clearance
59
Q

What determines the time to reach steady state concentration in the continuous IV infusion model?

A
  • Half life
    • Curves reach half of steady state concentration after 1 half life
  • ***It is understood that after 4 half-lives worth of infusion, we consider the drug concentration to be at steady state
60
Q

Explain this graph

A
  • This is for continuous IV infusion model
  • The drug concentration rises rapidly at first because elimination is proportional to drug concentration. Since there’s little drug in the system at first, there is little elimination.
  • Elimination when pump is turned off occurs just as it would if the drug had been placed there instantaneously via bolus injection. (According to first order elimination).
61
Q

Explain this graph

A
  • Drug concentration varying with time for ORAL drug administration
  • Phase 1 (black) = absorption only, very little elimination
  • Phase 2 (blue) = absorption and elimination both occurring
  • Phase 3 (red) = elimination only
  • Purple = incomplete absorption
62
Q

How is repetitive dosing via IV bolus different from continuous IV infusion? And the same?

A
  • Different b/c you see sawtooth pattern
  • Same b/c you still reach a steady state concentration
63
Q

What happens in repetitive dosing IV model when dosing interval is much greater (longer) than half life?

A
  • The drug is fully eliminated before the next dose is given
  • The graph looks just like the IV bolus model - a high initial concentration with elimination according to first order kinetics
64
Q

What happens in repetitive dosing IV model when dosing interval is equal to the half life?

A
  • You get a zigsaz pattern
  • When dose is given, you have Cmax
  • Elimination –> Cmin
  • Caverage exists
65
Q

What happens in repetitive dosing IV model when dosing interval is less than the drug’s half life?

A
  • You still see a sawtooth pattern to the graph, but it’s smoother than when dosing interval = half life
  • You reach a plateau similar to continuous infusion model
66
Q

What is a loading dose?

A
  • Used if you need your drug to get to a steady state concentration quickly but your drug has a long half life
  • You don’t have time to wait for drug to reach steady state concentration via IV infusion
  • Give an IV bolus injection as the loading dose and start them on a continuous infusion at the same time

Block 2 (5 decks)

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