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PDA Block 1 > Pharmacokinetics I > Flashcards

Pharmacokinetics I Flashcards

1
Q

What determines passive diffusion

A

Passive diffusion is determined by the partition coefficient of the drug into oil from water AND its concentration gradient across the membrane

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2
Q

What types of compounds can diffuse readily through the membrane?

A

Hydrophobic or lipophilic

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3
Q

Weak acid equilibrium

A

HA ↔ A- + H

HA is not charged and therefore will likely passively diffuse through cell membranes

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4
Q

[HA]/[A-] is determined by:

A

1) The pH of the environment

2) The pKa of the drug

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5
Q

Henderson-Hasselbach equation:

A

Log ([protonated]/[unprotonated]) = pKa - pH

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6
Q

Plasma pH:

Stomach pH:

A

Plasma pH: 7.4

Stomach pH: 1.4

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7
Q

Weak base equilibrium

A 
B + H+ ↔ BH+
The unprotonated (B) form is uncharged and therefore likely to pass through membranes
B is predominant when the pH is high
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8
Q

Henderson Hasselbach for bases

A

Log ([BH+]/[B]) = pKa - pH

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9
Q

Ion Trapping

A

Acidic drugs accumulate on the side of the membrane that is more basic
Basic drugs accumulate on the side of the membrane that is more acidic

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10
Q

How can morphine (a weak base) be detected in the stomach following intravenous overdose.

A

Although BH+ dominates in the blood, enough B is present that it will diffuse down its gradient into the stomach. Once there, it is protonated and trapped

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11
Q

Base with pKa of 8.4 in stomach

A

Log ([BH+]/[B]) = 8.4 - 1.4
Log ([BH+]/[B]) = 7
[BH+]/[B] = 10,000,000/1 (so uncharged to charged is 1/10 million)

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12
Q

Acid with pKa of 4.4 in stomach

A

Log ([HA]/[A-]) = 4.4-1.4
Log ([HA]/[A-]) = 3
[HA]/[A-] = 1000/1; or 1/0.001

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13
Q

Movement via passive diffusion is:

A

Bidirectional

Driven by the concentration gradient (movement “down hill” is energetically favored)

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14
Q

Carrier Mediated Transport

A

Transport of a molecule (solute) across a barrier is mediated by binding of the solute to a protein transporter

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15
Q

Purposes of Carrier Mediated Transport (3)

A

1) Can move hydrophilic molecules through the bilayer
2) Can move molecules against their concentration gradient
3) Provides specificity

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16
Q

Facilitated diffusion

A

Carrier mediated
Concentration-gradient driven
No requirement for the input of energy

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17
Q

Active transport

A

Carrier mediated
Moves solute against its concentration gradient
Therefore, requires energy

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18
Q

P-glycoprotein

A

An ABC (ATP binding cassette) carrier or pump

  • Primarily binds to liphophilic drugs that have entered cells via passive diffusion and mediates their efflux from the cell
  • Energy from ATP
  • Is encoded by the multi-drug resistance gene
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19
Q

Secondary Active transport

A

Carrier mediated; move two different solutes in the same (symport) or opposite (antiport) directions
Most often, couple solute movement against its concentration gradient to the movement of sodium or hydrogen with their concentration gradients

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20
Q

Bioavailability (F)

A

Fraction of the administered dose of drug that reaches the circulation
By definition, an intravenously administered drug would have an F=1
Orally administered drugs are almost never completely bioavailable

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21
Q

First pass effect

A

Enterohepatic cycling
Drug is metabolized by the liver or excreted back into the intestine through biliary excretion during its “first pass” through the liver
Never reaches the systemic circulation

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22
Q

Bioequivalence between two preparations means:

A

Same drug
Same route of administration
Same amount of drug enters the circulation
Drug enters the circulation at the same rate

23
Q

Orally administered drugs

A

Absorbed from the GI tract
Mostly via passive diffusion
Favors the absorption of unionized drugs
HA form and B form absorbed preferentially

24
Q

Absorptive surface area of the upper intestine

A

200m^2 (due to villi)

25
Q

Relationship between gastric emptying and drug absorption

A

Increased gastric emptying will increase the rate of drug absorption

26
Q

Dissolution of solid drug preparation:

A

Affects the rate of absorption

Is affected by how the drug is formulated

27
Q

Advantages and Drawbacks to controlled release preparations

A

Advantages: slower absorption results in decreased frequency of dosing; more uniform concentration of drug in the blood
Drawbacks: Greater variability among patients AND toxicity if all the drug is released at once

28
Q

Enteric Coatings

A

Protect the drug from the stomach acid AND the stomach from the drug
Better taste
Do not want the coating to be completely impervious, it will retard or result in variable absorption in the intestine

29
Q

Other routes of entry
Sublingual:
Buccal:

A

Under the tongue and Between the gum and cheek

30
Q

Rectal administration

A

Useful if patient cannot or won’t swallow
50% less first pass than orally administered agents
Disadvantages: variable absorption; can be incomplete; irritating to the rectal mucosa; uncomfortable

31
Q

Transdermal administration (and examples)

A 
Through the skin
Epidermis is a nearly complete barrier to non-lipophilic substances
Permeable to lipophilic drugs
Best if hydrated
Nicotine, estrogen/progesterone
32
Q

Parenternal injection

A 
"Without the intestine"
Intravenous: no absorption needed
Subcutaneous and intramuscular
- Injection results in a depot of the drug that is placed either in the dermis or muscle
- Drug diffuses to nearby capillaries
33
Q

Lipophilic drugs: Rate of Absorption

A

Depends on:
Drug solubility in interstitial fluid
Area of capillary bed in the vicinity

34
Q

Large hydrophilic drugs

A

Pass through large, aqueous channels in the capillaries

35
Q

How do proteins enter the circulation

A

Enter the circulation slowly via the lymphatic system

36
Q

Lung absorptive properties

A

Large capillary bed
Metabolic enzymes that can transform the drug
Filters particulates
Volatile agents can diffuse into the expired air
Lipophilic agents can accumulate; redistribute

37
Q

Intravenous injection/infusion

A

Completely bioavailable (F=1)
Achieve immediate action (Anesthetics; emergency treatments)
Drug delivery can be highly controlled
Irritating agents are diluted by the entire blood volume

38
Q

Advantages of intravenous injection

A

Control over the dose; adjust based upon patient response

Control over the rate of administration

39
Q

Disadvantages of IV injection

A

Route of no return-once the drug is in the circulation, it is very difficult to remove
Needs close monitoring, patent vein, experienced medical staff

40
Q

Subcutaneous

A

Into the skin
Drugs must be non-irritating; not painful or damaging to tissue
Can add vasoconstrictors to delay absorption

41
Q

Intramuscular

A

Into the muscle

Depends on blood flow to the muscle

42
Q

Administration to the airway for pulmonary absorption

A

Used to deliver volatile agents; rapid access to circulation

Drugs to treat airway

43
Q

Topical application of drugs

A

Mucous membranes

Eye

44
Q

Drug eluting stents

A

Placed into blood vessels, blood flows through and elutes drug

45
Q

Novel methods of drug delivery

A

Drug eluting stents
Targeting of drugs using antibodies
Activation of drugs at the site of action

46
Q

Phases of drug delivery by blood flow

A

First phase: highly perfused organs receive most of the drug; equilibration is rapid
Second phase: More poorly perfused organs; equilibration is very slow

47
Q

Capillary permeability of a drug

A

Endothelial junctions are loose; allow for paracellular movement of most drugs out of the circulation into the tissues
Driving force is hydrostatic pressure
Not in the brain

48
Q

Drug binding to plasma proteins

A

Albumin for acidic drugs

alpha 1-acid glycoprotein for basic drugs

49
Q

Binding law of mass action

A

Drug + Protein ↔ DrugProtein

[DP] = [Total protein] x [Drug]/(KD + [Drug])

50
Q

Consequences of Protein binding to Drug

A
  1. Protein binding prevents the drug from leaving the circulation
  2. Drug responses, toxicity , metabolism are all a function of the drug that is free
  3. At equilibrium is perturbed if:
    - Plasma protein concentrations suddenly change
    - There are changes in exogenous or endogenous competitors for the binding sites
51
Q

Extent of protein binding can be affected by disease states that alter plasma binding proteins long term

A

Liver disease - reduced albumin and reduced protein binding; might need to decrease dose of drug
Immune activation can increase alpha1 acid glycoprotein; might need to increase the dose of drug

52
Q

Tissues serve as slowly releasing reservoirs

A

Lipophilic drugs can be stored for long periods in fat

Drugs that bind divalent cations and heavy metals can accumulate in bone

53
Q

What can lead to the local bone destruction?

A

Toxins within the bone can result in:

reduced bone blood flow and even slower redistribution of the toxins out of the bone

PDA Block 1 (13 decks)

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