L3- Pharmacokinetics Flashcards
Pharmacokinetics
The process by which drugs are Absorbed, Distributed within the body, Metabolized, and Excreted.
“What the body does to the drug”
What determines whether a drug will cross membranes by passive diffusion?
- Lipid Solubility
- Ionization
- Drug must be NON-POLAR to cross the cell membrane, also must be POLAR because it needs to be water-soluble for excretion.
- AND If drug was COMPLETELY non-polar, it would pass through body unabsorbed by the GI tract.
- Weak bases and weak acids are in their ionic form (Protonated base/acid = can’t cross membrane as easily)
- Henderson-Hasselbalch equation can determine the proportion of a substance that is ionized at given pH.
- (pKa > pH means unionized form predominates)
What are the two most important factors in drug distribution?
1. Membrane Permeability
- Drugs can be membrane limited
- Can affect rate of drug across barriers/different aqueous volumes (plasma, ISF, ICF)
2. Blood Flow
- Distribution is “flow limited”
- Blood flow different in diff organs.
PRODRUG
An inactive drug dosage form that is later converted to an active metabolite
- Can overcome problems with drug delivery
ACTIVE METABOLITE
A prodrug (inactive drug) that is metabolized to be pharmacologically active
What are the general purpose of Phase I and Phase II metabolism?
To build-up and break down of substances by enzymes to inactive drug to make easier to excrete.
- DECREASE LIPID SOLUBILITY!!
Phase I: Make drug more reactive in order for it to be conjugated
Phase II: Conjugate (add substituent) to reactive drug to INACTIVE (can be easily excreted now).
- Makes drug MORE POLAR.
FORMULA:
Rate Constant of Elimination (Ke)
Ke= CL/Vd or Ke= 0.693/t1/2
On a log concentration vs. time curve → the slope of the line indicates Ke
FORMULA:
Elimination (>90%) a drug-using half life
(Practice Question: How long does it take to eliminate (>90%) a drug that has a t1/2 of 7 hours?)
Time it takes for drug to be over 90% eliminated:
4 x (t1/2)
Practice Question:
→ 4 x 7 = 28 hours
Rule of Thumb for Elimination:
1 t1/2 = 50% eliminated
2 t1/2 = 75% eliminated
3 t1/2 = 87.5% eliminated
4 t1/2= 93.75% eliminated
5 t1/2= 96.88% eliminated
How long does it take to eliminate (>90%) a drug with a Ke of 0.07 hr-1?
t(<sub>1/2</sub>) = 0.693/K<sub>e</sub> t(<sub>1/2</sub>) = 0.693/0.07 t(<sub>1/2</sub>) = 9.9
4 x t<sub>1/2</sub> = 4 x (9.9) =
39.6 hours
FORMULA:
Volume of Distribution (Vd)
Vd = DOSE / Co
What might it mean that a drug as Vd = 200 liters?
The APPARENT volume of the drug in the body/concentration in the blood is 200L
- This is HIGH volume of distribution = drug concentration is more sequestered in unknown tissue outside the blood (than in the vascular compartment)
- High Vd can indicate high concentration in the extracellular tissue, peripheral tissue, or partitioned into body fat (with lower blood-plasma concentration)
- (The drug will first be in the blood, then in the extracellular environment and then lastly in the tissue.)
- High Vd also indicates drug is lipophilic.
FORMULA
Bioavalibilty
F = AUCoral / AUCIV
Formula:
Clearance
The volume (of the Vd) from which drug is completely removed per unit time.
- It can determine the maintenance dose required to achieve desired steady-state concentration.
CL = Vd* Ke
Formula:
Maintenance Dosing Rate
(IV and ORAL)
IV: CL x CSS
ORAL: (CL x CSS)/F
Formula:
Loading Dose
Co x Vd
*The absorption of a drug across a cell membrane is influenced most strongly by
a. How lipid-soluble the drug is
b. The ability of the drug to be metabolized by CYP enzymes
c. The blood flow to specific organs
d. Phase II enzymes
e. The Clearance of the drug
a. How lipid soluble the drug is
*A prodrug is
A. A drug that crosses membranes easily and quickly gets to its site of action
B. A drug that is inactivated by phase I or phase II enzymes
C. A Drug that has a low bioavailability
D. A drug that needs to be metabolized to become active
E. A drug taken by the Redskins or other pro team
D. A drug that needs to be metabolized to become active
*A drug that is metabolized in a first-order process
a. Has its metabolic enzymes saturated
b. Typically has a large volume of distribution
c. Has a measurable half-life
e. Will decrease its plasma concentration linearly with time
f. None of the above
C. Has a measurable half-life
*A drug with a t1/2 of 8 hours
a. Will be mostly cleared from the plasma 8 hours after discontinuation
b. Will take more than a day to be mostly cleared after discontinuation
c. Will come to a steady state in about 8 hours if administered as a constant I.V. drip
d. Will typically have a large volume of distribution
e. None of the above
b. Will take more than a day to be mostly cleared after discontinuation
If the t1/2 of a drug is 48 hours it will mostly (~94%) be eliminated in:
A. 3 Days
B. 4 days
C. 6 Days
D. 8 days
E. Too little information is given to determine an answer
D. 8 Days
Why are most drugs eliminated with first-order kinetics?
A. Because most drugs saturate the metabolic enzymes involved in their degradation.
B. Because the kidney can excrete only a certain volume per day.
C. Because most drugs are sequestered in fat stores
D. Because most drugs are both water and lipid soluble.
E. Because most drugs do not saturate the metabolic and excretory processes in the body.
E. Because most drugs do not saturate the metabolic and excretory processes in the body.
If a drug has a Vd of 300 liters, it could mean that
A. the drug is metabolized rapidly
B. the drug will not pass the blood-brain barrier easily
C. The drug is very water soluble
D. the drug may be sequestered in fat
E. the drug will be eliminated in the urine
D. the drug may be sequestered in fat
If a drug has a clearance of 2L/hr and you want to achieve a steady state concentration of 5 ug/L, what dosage regimen (how much drug per time) would you use?
A. 2.5 ug/hr
B. 2 ug/hr
C. 5 ug/hr
D. 10 ug/hr
E. 20 ug/hr
D. 10 ug/hr
What is the most common method of absorption of drugs?
a. Passive diffusion
b. Diffusion through an aqueous channel
c. Assisted diffusion with a carrier molecule
d. Endocytosis
a. Passive diffusion
Drug transport:
a. Very hydrophilic drugs may not be well-absorbed
b. Excessively lipid-soluble (hydrophobic) drugs may not be soluble enough to cross a water layer near the cell membrane
c. Both A and B
d. None of the above
c. Both A and B
The primary site for drug metabolism:
a. Stomach
b. Small intestine
c. Kidney
d. Muscle
e. Liver
e. Liver
During phase 2 of drug metabolism,
a. Drugs undergo oxidation and deamination
b. The structures of the drugs are changed to make the compound more reactive
c. Groups are added to the drug to make the metabolite more polar so it can be excreted more easily.
d. Drugs are metabolized while slightly nonpolar and polar
e. Drugs are at their maximum potency.
c. Groups are added to the drug to make the metabolite more polar so it can be excreted more easily.
Most drugs follow nonlinear pharmacokinetics.
a. True
b. False
a. True
Clearance determines
a. The time to reach steady-state
b. The loading dose required to achieve the desired steady-state concentration.
c. The maintenance dose required to achieve the desired steady-state concentration.
d. The dosage intervale.
e. A and D
c. The maintenance dose required to achieve the desired steady-state concentration.
What determines whether a drug will cross membranes by passive diffusion?
Must be nonpolar
(but if it’s completely nonpolar, it will pass right through body)
How can you manipulate a drug’s ability to cross membranes by passive diffusion?
Molecule’s polarity can be manipulated by pH
- Polarity can be dependent upon pH and the molecule’s pKa
- For a base, protonated = charged
(doesn’t cross membranes easily).
Explain why a drug must be both polar and non-polar and what would happen if a drug is only non-polar.
A drug must be non-polar in order to cross the cell membrane and must be polar because it needs to be water-soluble (important for excretion).
If a drug was only non-polar it would simply pass through the GI tract unabsorbed
