Ch 4: Pharmacokinetics Flashcards
(101 cards)
1
Q
What are the four phases of pharmacokinetics?
For the bonus, what is another term used to describe the combination of 2 of the phases?
A
Absorption, distribution, metabolism, and excretion
Sometimes the term elimination is used to describe the combination of metabolism plus excretion
(p. 22)
2
Q
What is drug metabolism?
A
Enzymatically mediated alteration of drug structure. a.k.a. biotransformation
(p. 22)
3
Q
The factors that determine the passage of drugs across ________ _________ have a profound influence on all aspects of ________________.
A
biologic membranes
pharmacokinetics (p. 23)
4
Q
What are the 3 most important ways by which drugs cross cell membranes?
Which is most common?
A
- Passage through channels or pores (applies to very few drugs)
- Passage with the aid of a transport system (all of which are selective)
- Direct penetration of the membrane itself
(#3 is the most common) (p. 23)
5
Q
Where is the P-glycoprotein (multidrug transporter protein) present and what does it do?
A
The liver, kidney, placenta, intestine, and capillaries of the brain. It transports a wide variety of drugs OUT of cells.
(p. 24)
6
Q
Membranes are composed primarily of lipids, therefore, to directly penetrate membranes a drug must be…
A
…lipid-soluble (lipophilic).
p. 24
7
Q
What kinds of molecules cannot penetrate membranes?
A
polar molecules and ions (except for very small molecules)
p. 24
8
Q
Although polar molecules have an uneven distribution of charge, they have…
A
…no net charge.
p. 24
9
Q
Polar molecules will dissolve in _____ ________, but not in ________ ________.
A
polar solvents (such as water) nonpolar solvents (such as oil)
(p. 25)
10
Q
Ions are defined as molecules that have a…
A
…net electrical charge.
p. 25
11
Q
Quaternary ammonium compounds are molecules that contain…
A
…at least one atom of nitrogen and carry a positive charge at all times. Because of the charge, these compounds are unable to cross most membranes.
(p. 25)
12
Q
Name an example of a quaternary ammonium compound.
A
tubocurarine
p. 25
13
Q
Whether a weak acid or base carries a charge is determined by…
A
…the pH of the surrounding medium.
p. 25
14
Q
Many drugs are either weak…
A
…organic acids or weak organic bases.
15
Q
Name an example of a polar drug. (p. 24-25)
A
Gentamicin
16
Q
An acid can be thought of as a…
A
…proton donor
p. 26
17
Q
A base can be thought of as a…
A
…proton acceptor.
p. 26
18
Q
Acids tend to ionize in…
A
…basic (alkaline) media.
p. 26
19
Q
Bases tend to ionize in…
A
…acidic media.
p. 26
20
Q
The process whereby a drug accumulates on the side of a membrane where the pH most favors its ionization is referred to as…
A
…ion trapping or pH partitioning.
p. 26
21
Q
Name an example of the use of ion trapping in medicine.
A
Treatment of poisoning. By manipulating urinary pH, we can employ ion trapping to draw toxic substances from the blood into the urine which accelerates their removal.
(p. 26)
22
Q
The literal definition of parenteral is…
A
…outside the GI tract (p. 27)
23
Q
What is the rationale for injecting IV drugs over the course of one minute?
A
All the blood in the body is circulated about once every minute, therefore injecting the drug over this time frame dilutes it in the largest volume of blood possible.
(p. 28)
24
Q
Solutions intended for subcutaneous administration are ____________, solutions intended for intravenous administration are ______.
A
concentrated
dilute (p. 29)
25
Intravenous administration of concentrated epinephrine could...
...overstimulate the heart and blood vessels, causing severe hypertension, cerebral hemorrhage, stroke, and death. (p. 29)
26
When a drug is injected IM, the only barrier to absorption is...
...the capillary wall (p. 29)
27
Since little harm will come from depositing a suspension of undissolved drug in the interstitial space of muscle tissue, the IM route is...
...acceptable for drugs whose water solubility is poor.
| p. 30
28
What is a depot preparation?
a preparation of drug which is absorbed slowly over an extended time.
(p. 30)
29
IM injections cannot be used for patients receiving...
...anticoagulant therapy.
| p. 30
30
Where does the abbreviation PO come from?
The Latin phrase "per os" which means by way of the mouth.
| p. 30
31
What are the barriers to absorption for PO administration?
1. Layer of epithelial cells that line the GI tract
2. The capillary wall
(p. 30)
32
To pass the layer of epithelial cells in the GI tract, drugs must pass...
....through cells rather than between them.
| p. 30
33
There are 6 factors which cause the rate and extent of absorption of PO drugs to be highly variable. What are they?
1. solubility and stability of the drug
2. gastric and intestinal pH
3. gastric emptying time
4. food in the gut
5. coadministration of other drugs
6. special coatings on the drug preparation
(p. 30)
34
PO drugs must pass through...
...the liver via the portal blood.
| p. 30
35
Why can't insulin be taken orally?
Because it would be destroyed by digestive enzymes
| p. 30
36
What is the first pass effect?
A phenomenon in which certain drugs undergo extensive inactivation as they pass through the liver
(p. 30)
37
Because of variable absorption, oral administration does not permit...
...tight control of drug levels.
| p. 31
38
Why can many anticancer drugs not be administered by mouth?
Some of them would cause severe local injury if given by mouth (p. 31)
39
Explain chemical equivalence.
two drug preparations are considered chemically equivalent if they contain the same amount of the identical chemical compound (drug) (p. 31)
40
Explain bioavailability.
Preparations are considered to be equal in bioavailability if the drug they contain is absorbed at the same rate and to the same extent.
(p. 31)
41
What is a tablet?
a mixture of a drug plus binders and fillers
| p. 31
42
Why can the absorption of enteric-coated preparations be even more variable than with tablets?
Because gastric emptying time can vary from minutes up to 12 hours! Furthermore, enteric coatings sometimes fail to dissolve.
(p. 32)
43
How do sustained-release capsules work?
These formulations are capsules filled with tiny spheres that contain the actual drug. The individual spheres have coatings that dissolve at variable rates.
(p. 32)
44
What is drug distribution?
The movement of drugs throughout the body.
| p. 32
45
What 3 factors determine drug distribution?
1. Blood flow to tissues
2. Ability of a drug to exit the vascular system
3. Ability of a drug to enter cells
(p. 32)
46
Why is distribution an issue with treating abscesses and tumors?
Both of these condition involve low regional blood flow.
Abscesses have no blood supply, so antibiotics cannot reach the bacteria within.
With tumors, blood flow decreases progressively toward the core.
(p. 32)
47
Why do drugs leave the bloodstream so readily within capillary beds?
Drugs pass between capillary cells rather than through them. (p. 32)
48
How does the blood-brain barrier work?
The anatomy of capillaries in the CNS is unique. Rather than spaces, there are tight junctions between cells, which prevent the passage of many drugs. (p. 32)
49
What kind of drugs can cross the blood-brain barrier?
Those drugs which are lipid-soluble or have a transport system (p. 32)
50
Why are neonates especially vulnerable to CNS toxicity and sensitive to drugs which act on the brain?
Because the blood-brain barrier is not fully developed at birth (p. 33)
51
Why is it important to know if a drug can bind with albumin?
Because it is the most abundant protein in the plasma. In addition, if a drug is bound to albumin, it cannot leave the vascular system. (p. 34)
52
Because of its size, albumin always...
remains in the bloodstream. It is too large a molecule to fit through pores in the capillary wall (p. 34)
53
What is the molecular mass of albumin compared with the average drug?
Albumin measures 69,000 daltons; in comparison, the average drug is only 300 - 500 daltons (p. 34)
54
Why can protein binding be a source of drug interactions?
One drug can displace another from albumin, causing the concentration of the displaced drug to rise. (p. 34)
55
Most drug metabolism is performed by...
...the hepatic microsomal enzyme system, and known as the cytochrome P450 system (p. 34)
56
What is cytochrome P450?
A group of 12 closely related enzyme families (p. 34)
57
Which of the cytochrome P450 families metabolize drugs?
CYP1, CYP2, and CYP3 (p. 35)
58
What do the other 9 cytochrome P450 families metabolize?
Endogenous compounds (e.g. steroids, fatty acids)
| p. 35
59
Drug metabolism can result in the synthesis of a molecule that is...
larger than the parent drug. (p. 36)
60
What are the 6 possible (significant) consequences of drug metabolism?
1. Accelerated renal excretion of drugs
2. Drug inactivation
3. Increased therapeutic action
4. Activation of "prodrugs"
5. Increased toxicity
6. Decreased toxicity (p. 36)
61
The most important consequence of drug metabolism is...
...promotion of renal drug excretion. (p. 36)
62
The kidneys are unable to excrete drugs that are...
...highly lipid soluble. (p. 36)
63
How can the metabolic conversion of highly lipid soluble drugs be accelerated?
By converting lipid-soluble drugs into more hydrophilic (water-soluble) forms.
(p. 36)
64
Name two metabolic transformations which enhance renal excretion.
1. Simple structural change with the addition of a hydroxyl group can convert some drugs into a more polar form (less lipid-soluble) form.
2. Glucuronidation is a process in which a hydrophilic glucose derivative (glucuronic acid) is attached to a drug molecule, rendering it much more water-soluble. (p. 36)
65
Metabolism can increase the effectiveness of some drugs. In fact, with codeine, the formation of _______ may account for virtually all the pain relief that occurs following codeine administration.
morphine
| p. 36
66
What is a prodrug?
A compound that is pharmacologically inactive as administered and then undergoes conversion to its active form via metabolism. (p. 36)
67
The liver does not develop its full capacity to metabolize drug until...
about 1 year after birth. (p. 36)
68
What does it mean for a drug to be a P450 substrate?
It means that these drugs are metabolized by P450 hepatic enzymes. (p. 36)
69
What does it mean for a drug to be a P450 enzyme inducer?
It means that these drugs act on the liver to increase rates of drug metabolism. (p. 36)
70
What does it mean for a drug to be a P450 enzyme inhibitor?
It means that these drugs act on the liver to decrease rates of drug metabolism. (p. 36)
71
What is the consequence if a drug is both a P450 inducer and a P450 substrate?
By stimulating the liver to produce more drug-metabolizing enzymes, the drug can increase the rate of its own metabolism, thereby necessitating an increase in its dosage to maintain therapeutic effects. (p. 36)
72
What is the first pass effect?
rapid hepatic inactivation of certain oral drugs (p. 36)
73
Why is sublingual administration of nitroglycerin effective?
Because it permits the drug to be absorbed directly into the systemic circulation and carried to its sites of action prior to passage through the liver. (p. 37)
74
Describe the process of enterohepatic recirculation.
It is a repeating cycle in which a drug is transported from the liver into the duodenum (via the bile duct) and then back to the liver (via the portal blood). (p. 37)
75
What is the consequence of enterohepatic recirculation and which drugs are affected?
It can cause drugs to remain in the body much longer than they otherwise would.
This process affects only those drugs which have undergone glucuronidation.
76
Urinary excretion of drugs is the net result of what 3 processes?
1. Glomerular filtration
2. Passive tubular reabsorption
3. Active tubular secretion
(p. 37)
77
Glomerular filtration moves drugs...
...from the blood into the tubular urine. (p. 37)
78
Why are drugs bound to albumin not filtered in the glomerulus?
Because large molecules (and the drugs bound to them) are not filtered, and remain behind in the blood. (p. 37)
79
Drugs that are lipid soluble undergo...
...passive reabsorption from the tubule back into the blood. (p. 38)
80
What are the two primary classes of active transport systems (pumps) in the kidney tubules?
One for organic acids, and one for organic bases (p. 38)
81
Because ions are not lipid soluble, drug that are ionized at the pH of tubular urine will...
...remain in the tubule and be excreted. (p. 38)
82
What happens if we administer two drugs at the same time which both use the same renal tubular transport system?
Excretion of each will be delayed by the presence of the other. (p. 38)
83
Why do we adjust plasma levels of a drug when what really matters is the concentration of that drug at its sites of action?
Because there is a direct correlation between therapeutic and toxic responses and the amount of drug present in plasma.
(p. 39)
84
We can determine plasma drug concentrations that, in turn, are highly predictive of...
...therapeutic and toxic responses.
| p. 39
85
The minimum effective concentration (MEC) is defined as...
...the plasma drug level below which therapeutic effects will not occur.
(p. 39)
86
Acetaminophen has a relatively wide therapeutic range. The toxic concentration is how many times greater than the MEC?
30 times greater
| p. 39
87
Name a drug with a very narrow therapeutic range.
| The toxic concentration is how many times greater than the MEC?
Lithium
3 times greater
(p. 39)
88
What are the primary determinants of how long drug effects will persist?
Metabolism and excretion
| p. 39
89
Drug half-life is defined as...
...the time required for the amount of drug in the body to decrease by 50%.
(p. 40)
90
What is the half-life of morphine?
approximately 3 hours
| p. 40
91
The half-life of a drug determines the...
...dosing interval.
| p. 40
92
At what point will average drug levels remain constant? (In other words, when will plateau be reached?)
When the amount of drug eliminated between doses equals the dose administered.
(p. 40)
93
What a drug is administered repeatedly in the same dose, plateau will be reached in...
...approximately four half-lives.
| p. 40
94
As long as dosage remains constant, the time required to reach plateau is...
...independent of dosage size.
| p. 41
95
What 3 techniques can be used to reduce fluctuations in drug levels?
1. Administer drugs by continuous infusion.
2. Administer a depot preparation, which releases the drug slowly and steadily.
3. Reduce both the size of each dose and the dosing interval, keeping the total daily dose constant.
(p. 41)
96
What can be done to reach plateau quickly when using drugs that have a long half-life?
A large initial dose (loading dose) can be given, followed by smaller maintenance doses.
(p. 41)
97
When drug administration is discontinued, most (94%) of the drug in the body will be eliminated over...
...an interval equal to about four half-lives.
| p. 41
98
The concept of half-life does not apply to the elimination of all drugs. Name a notable example and its pattern of elimination.
Ethanol (alcohol) leaves the body at a constant rate.
| p. 41
99
Absorption of drugs is enhanced by what 4 factors?
1. Rapid drug dissolution
2. High lipid solubility of the drug.
3. A large surface area for absorption
4. High blood flow at the site of administration
(p. 42)
100
Enteric-coated oral formulations are designed to...
....release their contents in the small intestine -- not in the stomach.
(p. 42)
101
Sustained-release oral formulations are designed to...
....release their contents slowly, thereby permitting a longer interval between doses.
(p. 42)
