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PharmSci Exam 1 > Lecture 4: ADME > Flashcards

Lecture 4: ADME Flashcards

1
Q

Absorption

A

Drug transfer from its site of administration to the general circulation

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2
Q

Distribution

A

Drug molecules carried by blood to site of action

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3
Q

Metabolism

A

Transformation from one drug product to anotehr

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4
Q

Excretion

A

Removal of the drug product from the body

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5
Q

What is the overall goal of drug therapy?

A

For the drug to travel from its site of administration to its target site at desirable concentrations and at desirable time frame

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6
Q

Local administration

A

The site of action is localized around the site of administration

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7
Q

Systemic administration

A

Site of action is far from the site of administration

Drug must be transported between the two sites via the bloodstream

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8
Q

Before the drug is absorbed through the GI walls, what should it be available as?

A

Molecules solubilized in the intestinal fluids

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9
Q

What do solid oral pharmaceutical dosage forms undergo disintegration followed by?

A

Dissolution before they are available for absorption

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10
Q

What do liquid oral pharmaceutical dosage forms undergo before they are available for absorption?

A

Dissolution

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11
Q

What is a common route of drug administration?

A

Extravascular (especially oral)

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12
Q

What is the optimum site for most drugs for drug absorption after oral administration?

A

Upper portion of small intestine or duodenum region

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13
Q

Where can drugs be absorbed and by what process?

A 
Alimentary canal
Sublingual 
Buccal
GI 
Rectal absorption

By passive diffusion

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14
Q

What type of drugs can be absorbed by the stomach?

A

Fat-soluble, acid stable

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15
Q

What is efficiently absorbed already in the stomach?

A

Ethanol because it is completely miscible with water and easily crosses cell membranes

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16
Q

Colon anatomy

A

Lacks vili
Limited drug absorption
Lack of SA, blood flow
Viscous semisolid nature of lumen contents

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17
Q

Duodenal region anatomy

A

High SA
Large network of capillaries
Helps maintain concentration gradient

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18
Q

Gastrointestinal motility

A
  • absorption window
  • transit time of drug affected by many factors
  • migrating motor complex during interdigestive (fasted state)
  • irregular contractions followed by regular high amplitude contractions in fasted state
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19
Q

What is the duration of fasted state I and what are the characteristics?

A

30 - 60 minutes

  • quiescence
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20
Q

What is the duration of fasted state II and what are the characteristics?

A

20 - 40 minutes

  • irregular contractions
  • medium amplitude
  • bile secretion begins
  • onset of gastric discharge of administered fluid of small volume usually occurs before particle discharge
  • onset of mucus and particle discharge
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21
Q

What is the duration of fasted state III and what are the characteristics?

A

5 - 15 minutes

  • regular contractions with high amplitudes
  • mucus discharge continues
  • particle discharge continues
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22
Q

What is the duration of fasted state IV and what are the characteristics?

A

0 - 5 minutes

  • irregular contractions
  • medium descending amplitude
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23
Q

What is the duration of the fed state and what are the characteristics?

A

As long as food is present

  • regular, frequent contractions
  • amplitude is lower than phase III
  • 4-5 contractions/min
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24
Q

What is gastric emptying delayed by/

A

High fat meals
Cold beverages
Anticholinergic drugs

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25
Q

What does a delay in gastric emptying tend to slow?

A

The rate of drug absorpion

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26
Q

What drugs degrade if gastric emptying is delayed?

A

Unstable drugs

Liquids and particles are not retained in the stomach

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27
Q

How long are large particles (tablets and capsules) delayed for by presence of food in the stomach and why?

A

3 - 6 hours

Retained and subjected to more mixing and trituration until size is reduced

Indigestible solids empty slowly, mainly during interdigestive phase

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28
Q

Small intestine characteristics

A
  • peristaltic movement (CNS)
  • independent of solid particle size or fed status
  • retention time is about 3 - 4 hours
  • high SA
  • gradient bacterial content duodenum-ileum
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29
Q

Large intestine characteristics

A
  • takes 53 hours from time something is ingested by mouth until excreted in feces
  • unabsorbed drug molecules spend 90% of time in large intestine and in rectum where absorption is minimum
  • highest bacterial content (anaerobic)
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30
Q

Bioavailability

A

Rate and extent to which an active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of action

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31
Q

Absolute bioavilability

A

Fraction of the administered dose which reaches the systemic circulation relative to an intravenous dose (F)

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32
Q

Bioavailability graph

A

Displayed by concentration time curve of the administered drug in an appropriate tissue system

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33
Q

What does the bioavailability data help determine?

A
  • amount of drug absorbed from dosage form
  • rate at which drug was absorbed
  • duration of drug’s presence in biologic fluid or tissue
  • relationship between drug blood levels and clinical efficacy and toxicity
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34
Q

FDA bioavailability requirements

A
  • NDA
  • abbreviated NDA
  • supplemental application if there is a:

Change in manufacturing process
New indication for use of drug
New or additional dosage regimen for a special patient population

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35
Q

Parameters for assessment of bioavailability

A
  • peak height concentration (Cmax)
  • Time of peak concentration (Tmax)
  • Area under the blood concentration time curve (AUC)
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36
Q

Cmax

A
  • rates of absorption and elimination are equal
  • Conventional dosage forms usually have one max
  • amount of drug expressed as concentration in a specific volume of blood
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37
Q

MEC

A

Minimum effective concentration

Concentration must be achieved for the patient to exhibit adequate response

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38
Q

MTC

A

Minimum toxic concentration

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39
Q

Tmax

A
  • reflects the rate of absorption from a formulation, which determines the time needed for the MEC to be reached and to maintain it
  • changes in the rte of drug absorption change the values of both Cmax and T max
  • when the rate of absorption is decreased, the Cmax is lowered and T max occurs at the same time
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40
Q

AUC

A
  • Measure of the total amount of drug absorbed into the circulation following the administration of a single dose of drug
  • equivalent doses of a drug, when fully absorbed, produced the same AUC
  • two curves with different Cmax and Tmax may have similar AUC
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41
Q

If equivalent doses of drug in different formulations provide different AUC values then…

A

= differences in the extent of absorption

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42
Q

What are oral dosage strengths based on?

A

Considerations of the proportion of the dose administered that is expected to be absorbed

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43
Q

What is the absolute bioavailability following oral dosing compared to?

A

Intravenous dosing

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44
Q

Calculating F

A

Extent of availability is usually assessed by measuring AUC

AUCpo x Doseiv / AUCiv x Dosepo

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45
Q

When F is less than 1 what happens to oral doses?

A

Must be larger than iv doses to provide the same concentration of drug in the plasma

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46
Q

Consequences of low bioavailability

A

Gastroointestinal toxicity

As bioavailability worsens, the variability from patient to patient tends to increase

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47
Q

Factors influencing oral bioavailability

F = Fa x Fi x Fh

What does Fa stand for?

A

fraction of the administered dose that is not destroyed in the gut or lost in the feces

% of dose available to permeate gut wall

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48
Q

Factors influencing oral bioavailability

F = Fa x Fi x Fh

What does Fi stand for?

A

Fraction of the dose that escapes metabolism in the intestinal wall

49
Q

Factors influencing oral bioavailability

F = Fa x Fi x Fh

What does Fh stand for?

A

Fraction of the dose that escapes metabolism on first-pass through the liver

50
Q

Passive transport

A
  • diffusion (no external energy)
  • molecules diffuse randomly in all directions
  • net diffusion from the high concentration side to low concentration side
  • flux = rate of transfer
51
Q

Fick’s law of diffusion

A

Molecules diffuse from a region of high concentration to a region of low concentration

Drug distributes rapidly into a large volume after entering the blood

Concentration of drug in the blood is low relative to the concentration at the site of drug absorption

Cgi&raquo_space; Cp

52
Q

Passive transport

dQ/dt meaning

A

Rate of diffusion

D is constant

53
Q

Passive transport

P

A

Permeability coefficient

54
Q

Passive transport

k

A

Lipid-water partition coefficient of drug

Higher K favors absorption

Drugs that are more lipid soluble have a larger value of K

55
Q

Passive transport

A

A

Higher A favors absorption (duodenum)

56
Q

Where does the most rapid drug absorption occur?

A

Duodenal area of the small intestine

57
Q

PH-partition hypothesis

If the pH on one side of a barrier differs then

A
  1. Drug will ionize to different degrees on either side
  2. Total drug concentrations on the two sides will be unequal
  3. The side where the drug is more ionized will contain greater portion of the drug
58
Q

Weak acid and absorption

A

Will be rapidly absorbed from stomach

59
Q

Weak base absorption

A

Poorly absorbed from stomach

60
Q

What are the rules for drug molecules that would improve the chance for oral absorption?

A
  • molecular weight <500 Da
  • Not more than 5 H bond donors
  • not more than 10 H bond acceptors
  • octanol-water partition coefficient, log P ,5.0

Rules are not applicable to drugs whose absorption involves transporters

61
Q

After a drug is absorbed, how are the drug molecules distributed throughout the body?

A

Systemic circulation

62
Q

What are dependent on the drug’s properties and individual patient characteristics?

A

Location extent and degree of distribution

63
Q

Intracellular water volume

A

27 L

64
Q

Interstitial water volume

A

12 L

65
Q

Plasma water volume

A

3 L

66
Q

Extracellular water volume

A

15 L

67
Q

Blood water volume

A

4.5 - 5 L

68
Q

Blood cell water volume

A

2 L

69
Q

What does the passage of drug molecules across a cell membrane depend on?

A

Drug and cell membrane

70
Q

Do hydrophoboic drugs or hydrophilic drugs diffuse more easily across cell membranes?

A

Hydrophobic

71
Q

Do small drug molecules or large drug molecules diffuse more rapidly across cell membranes?

A

Small drug molecules

72
Q

Hydrostatic pressure

A

Represents the pressure gradient between the arterial end of the capillaries entering the tissue and the venous capillaries leaving the tissue

73
Q

Capillary hydrostatic pressure (CHP)

A

Pressure exerted by blood against the wall of a capillary

Drives fluid out of capillaries and into tissues

74
Q

Interstitial fluid hydrostatic pressure (IFHP)

A

Opposes hydrostatic presse

75
Q

Which is higher arterial CHP or IFHP?

A

CHP

Absorption of fluids by lymphatic vessels

Fluid moves out of the capillary and into the interstitial fluid

76
Q

Osmotic pressure

A

Net pressure that drives the movement of fluid from the interstitial space back into the capillaries

77
Q

Blood colloidal osmotic pressure (BCOP)

A

Pressure created by the concentration of colloidal proteins in the blood

Effect on capillary exchange accounts for the reabsorption of water

78
Q

BCOP and interstitial fluid colloidal osmotic pressure

A

BCOP is always higher because interstitial fluid contains few proteins

79
Q

Net filtration pressure (NFP)

A

Difference between CHP and BCOP

80
Q

Hydrostatic or filtration pressure

A

At the arterial end, as the blood newly enters the capillary, the pressure of the capillary blood is slightly higher than that of tissue, causing fluid to leave the capillary and enter the tissues

81
Q

Absorptive pressure

A

Venules have lower pressure than tissue fluids allowing the filtered fluid to return to the venous capillary

82
Q

Drug affinity

A

Partitioning and accumulation of a drug in the tissue or organ

83
Q

How is the time for drug distribution generally measured?

A

By the distribution half life or tie for 50% distribution

84
Q

Rate of distribution relationship with Q

A

Increasing Q leads to decreased distribution time

85
Q

distribution time relationship with V

A

Increasing V leads to increased distribution time

86
Q

What is the accumulation of drugs in the tissues dependent on?

A

Blood flow

Affinity of the drug for the tissue

87
Q

Affinity to tissues may be due to

A 
Solubility
Binding to tissue proteins
Low binding to plasma proteins
Chelation
Active transport
Complexation with cellular DNA
88
Q

Volume of distribution (VD)

A

Concentration of drugs in the plasma or tissues depends on the amount of drug systemically absorbed and the volume in which the drug is distributed

True volume is not known, just estimated

89
Q

Drugs with large Vd

A

Dispersed or distributed to extravascular tissues

Less concentrated intravascularly

90
Q

What can lead to high Vd?

A

Factors leading to high affinity to peripheral compartment and low affinity to central compartment

Solubility
Transporters
Peripheral metabolism
Tissue binding
Low plasma protein binding
91
Q

Vd equation

A

Amount of drug added to system/ drug conc in system after equilibrium

92
Q

What is the tissue drug concentration influenced by?

A

Partition coefficient

Tissue protein binding

93
Q

Drugs with high Vd and affinity and albumin

A

Generally have high tissue affinity or low binding to serum albumin

94
Q

Vd and hydrophillic drugs

A

Polar or hydrophilic drugs tend to have Vd similar to the volume of extracellular water

95
Q

Applications of Vd

A
  • anticipate initial drug plasma concentration
  • estimate residual amount of drug in the body
  • calculate doses/loading doses
  • predict fluctuation of plasma concentrations in a multiple dosing regimen
  • anticipate usefulness of dialysis as a detoxification procedure
96
Q

Where is the principal sit of metabolism?

A

Liver

97
Q

Mixed-function oxidases (MFOs)

A

Enzymes responsible for oxidation and reduction of drugs and certain natural metabolites

98
Q

What do MFOs contain?

A 
Constitute electron transport system
NADPH
Molecular oxygen
CYPs 
Phospholipid
99
Q

CYPs

A

Heme protein
Iron protoporphyin IX as prosthetic group
Responsible for >70% of drugs

Major source of drug-drug and drug-food interactions

100
Q

Prodrugs

A

Inactive

Must be biotransformed in the body to metabolites that have pharmacologic activity

101
Q

Purpose of prodrugs

A

Improve drug stability
Increase systemic drug absorption
Prolong duration of activity

102
Q

Phase I reactions

A

Asynthetic reactions

Oxidation, reduction, hydrolysis

Expose functional group

103
Q

Phase II reactions

A

Synthetic

Conjugation

Use conjugating reagents
Transferase enzyme

104
Q

What may phase II reactions activate?

A
  • active, high energy form of conjugating agent

- drug may be activated to high energy compound that reacts with conjugating agent in presence of transferase enzyme

105
Q

Drug elimination

A

Refers to the irreversible removal of drug from body by all routes of elimination

106
Q

Drug excretion

A

Removal of the intact drug

107
Q

Biotransformation or drug metabolism

A

Process by which the drug is chemically converted in the body to a metabolite

108
Q

Kidney functions

A
  • secretion of renin, regulates blood pressure

- secretion of erythropoietin, stimulates RBC production

109
Q

Renal blood flow (RBF)

A

Volume of blood flowing through the renal vasculature per unit time

Exceeds 1.2 L/min

110
Q

Renal plasma flow (RPF)

A

Renal blood flow minus volume of RBCs present

111
Q

Glomerular filtration rate (GFR)

A

120 mL

112
Q

Filtration fraction

A

GFR/RPF

113
Q

RBF and GFR relationship

A

Remain relatively constant even with large difference in mean systemic blood pressure

114
Q

What helps keep constant blood flow and filtration fraction fairly constant?

A

Autoregulation

115
Q

What is filtered through the glomerulus from the plasma?

A

Only unbound small molecules

116
Q

What type of drugs are eliminated by renal excretion

A
  • nonvolatile
  • water soluble
  • low MW
  • slowly transformed by liver
117
Q

What processes may drugs be excreted by kidney?

A

Glomerular filtration
Active tubular secretion
Tubular reabsorptioin

118
Q

For a weak acid drug, is the extent of dissociation more affected by changes in the urinary pH if the pKa is 5 or 3?

A

More affected if pKa if 5

PKa <2 are slightly affected

119
Q

Drug clearance

A

Elimination from body without identifying mechanism of process

Considers the entire body as a single drug eliminating system from which many unidentified elimination processes may occur

PharmSci Exam 1 (4 decks)

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