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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
Relationship between gastric emptying and drug absorption
Increased gastric emptying will increase the rate of drug absorption
26
Dissolution of solid drug preparation:
Affects the rate of absorption | Is affected by how the drug is formulated
27
Advantages and Drawbacks to controlled release preparations
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
Enteric Coatings
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
Other routes of entry Sublingual: Buccal:
Under the tongue and Between the gum and cheek
30
Rectal administration
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
Transdermal administration (and examples)
``` Through the skin Epidermis is a nearly complete barrier to non-lipophilic substances Permeable to lipophilic drugs Best if hydrated Nicotine, estrogen/progesterone ```
32
Parenternal injection
``` "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
Lipophilic drugs: Rate of Absorption
Depends on: Drug solubility in interstitial fluid Area of capillary bed in the vicinity
34
Large hydrophilic drugs
Pass through large, aqueous channels in the capillaries
35
How do proteins enter the circulation
Enter the circulation slowly via the lymphatic system
36
Lung absorptive properties
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
Intravenous injection/infusion
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
Advantages of intravenous injection
Control over the dose; adjust based upon patient response | Control over the rate of administration
39
Disadvantages of IV injection
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
Subcutaneous
Into the skin Drugs must be non-irritating; not painful or damaging to tissue Can add vasoconstrictors to delay absorption
41
Intramuscular
Into the muscle | Depends on blood flow to the muscle
42
Administration to the airway for pulmonary absorption
Used to deliver volatile agents; rapid access to circulation | Drugs to treat airway
43
Topical application of drugs
Mucous membranes | Eye
44
Drug eluting stents
Placed into blood vessels, blood flows through and elutes drug
45
Novel methods of drug delivery
Drug eluting stents Targeting of drugs using antibodies Activation of drugs at the site of action
46
Phases of drug delivery by blood flow
First phase: highly perfused organs receive most of the drug; equilibration is rapid Second phase: More poorly perfused organs; equilibration is very slow
47
Capillary permeability of a drug
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
Drug binding to plasma proteins
Albumin for acidic drugs | alpha 1-acid glycoprotein for basic drugs
49
Binding law of mass action
Drug + Protein ↔ DrugProtein | [DP] = [Total protein] x [Drug]/(KD + [Drug])
50
Consequences of Protein binding to Drug
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
Extent of protein binding can be affected by disease states that alter plasma binding proteins long term
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
Tissues serve as slowly releasing reservoirs
Lipophilic drugs can be stored for long periods in fat | Drugs that bind divalent cations and heavy metals can accumulate in bone
53
What can lead to the local bone destruction?
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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