EXAM #1: PHARMACOKINETICS Flashcards
What is absorption?
Movement of the agent from the site of administration into the circulation
What is the difference between enteral and parenteral administration?
Enteral= drug delivery via the GI tract
Parenteral= non-GI drug delivery
What are the four routes of enteral administration?
1) Oral
2) Sublingual
3) Buccal
4) Rectal
What are the pros of oral administration?
Highest levels of compliance
What is the con of oral administration?
- GI tract breaks down drug
- enters portal circulation
- liver breaks down drug
Thus, delivery can be a challenge
What are the disadvantages of sublingual and buccal administration?
Mucosal irritation
What are the advantages of sublingual and buccal administration?
Drug is delivered directly into the venous system, BYPASSING the liver
What is the disadvantage to rectal administration?
- Inconvenient
- Non-compliance
- Incomplete absorption in rectal tissue can make it difficult to predict dosing
What are the advantages of rectal administration?
- Unconscious patients
- 50% of drug goes to liver, partially bypassing first-pass metabolism
What are the general cons of enteral administration?
1) Must pierce the skin, leading to non-compliance
2) Break in skin increases risk of infection
What is the advantage of IV drug administration?
Bypass metabolism b/c the entire dose is placed directly into the blood/ circulation
What is the disadvantage of IV drug administration?
If a mistake is made in dosing, the drug cannot be “recalled” i.e. can’t correct the mistake
*****Margin of error significantly reduced
What are the pros of IM & subcutaneous injections?
- Dosing is less frequent
- Slow diffusion from tissuee that mirrors taking the medical regularly
What are the cons of IM & subcutaneous injections?
- Pain that leads to poor compliance
- Especially for subcutaneous tissue, change in tissue composition with repeated administration
Where is an intrathecal administration delivered?
Subarachnoid space
What are the advantages of intrathecal and epidural administration?
Bypass the BBB and delivery of drug directly into the CNS
What are the disadvantages of intrathecal and epidural administration?
The CNS is a very delicate tissue that is prone to damage
What types of drugs are best given transdermally?
Lipophillic drugs b/c they need to pass through the lipid membrane of the epidermis
What is the con of transdermal drugs?
Skin is a difficult barrier to bypass
What is the pro of inhalation?
- Direct administration into lungs
- Very rapid absorption
What are the cons of inhalation?
1) Irritation of lung tissue
2) Direct delivery of drug to the heart following inhalation, which is especially detrimental if the drug is cardiotoxic
Which form of drug is able to cross barriers, ionized or unionized?
Unionized
What form should weak acid and bases be in to best cross a lipid membrane?
Weak acid= protonated= unionized
Weak base= unprotonated= unionzed
Why? These forms are UNIONIZED
Write the Henderson-Hasselbach equation.
N/A
What is the pKa?
pH at which 50% if the drug is ionized, 50% is unionzed
If the pH is greater than pKa , what form will the drug be in?
pH > pKa= DEPROTONATED
If the pH is less than pKa, what form will the drug be in?
pH
Where is the body are weak acids and weak bases favored for absorption?
Stomach= low pH= protonated= weak acids more readily absorbed
Intestine= high pH= unprotonated= weak bases more readily absorbed
What pH favors absorption of Salicylic acid, pKa = 3?
Less than 3
*****Protonated and unionized
What pH favor absorption of Amphetamine, pKa= 10?
Greater than 10
*****Unprotonated and unionized
How much salicylic acid, pKa=3, will be absorbed from the small intestine, which has a pH of 7?
N/A
See ppt.
In the stomach (at pH=2), what is the ratio of unionized to ionized ASA?
N/A
See ppt.
At a pH of 8, what is the ratio of unionized to ionized amphetamine (pKa=10)?
N/A
See ppt.
What is the antilog of -4?
0.0001
What is the antilog of -3?
0.001
What is the antilog of -2?
0.01
What is the antilog of -1?
0.1
What is the antilog of 0?
1
What is the antilog of 1?
10
What is the antilog of 2?
100
What is the antilog of 3?
1,000
What is the antilog of 4?
10,000
What is distribution?
Process by which a drug leaves the circulation and enters the tissues perfused by the blood
What are the four general factors that affect drug distribution?
1) Cardiovascular factors
2) Tissue binding
3) Drug molecule size
4) Lipid solubility
What are the four cardiovascular factors that affect drug absorption?
1) CO
2) Regional blood flow
3) Capillary permeability
4) Binding to plasma proteins
What is drug metabolism?
Biotransformation–making a drug more soluble for elimination from the body
What is Phase I of biotransformation?
Generation of a more polar molecule by exposing a functional group
What is Phase II of biotransformation?
Conjugation of a drug to yield a more water soluble product to be excreted
What enzymes mediate Phase I biotransformation?
Cytochrome P450’s or “CYPs”
What are the most common reactions of Phase II biotransformation?
Glucuronidation
Sulfation
Acetylation
Know that these are conjugation processes that are making the drugs more polar and water soluble for excretion.
What are the key sites of biotransformation?
GI Lungs Skin Kidneys Brain
What is the “first-pass” effect?
Entrance into the portal circulation and initial metabolism of a drug by the liver
What is the primary mechanism of drug elimination? Secondary?
Primary= renal excretion
Secondary= fecal via hepatic secretion into bile
What are the factors that alter renal excretion of a drug?
- GFR (glomerular filtration rate)
- Binding to plasma proteins
- Urine pH
What is the “Volume of Distribution (V)?”
Measure of the space in the body available for the drug
Amount of drug in body/ Concentration of drug in blood or plasma
What is “Clearance (CL)?”
Measure of the ability of the body to eliminate a drug
Rate of elimination/ concentration of drug
Generally, what does a large V mean?
Greater extent to which the drug distributes to the extravascular tissue
What does a V similar to the blood volume mean?
Majority of the drug is located in the vasculature
What does a V 100x the volume of the blood mean?
Majority of the drug is located in the extravascular tissue e.g. fat
What is zero-order elimination?
A specific amount of drug is eliminated of a specific period of time INDEPENDENT of drug concentration
E.g. 20mg of drug eliminated per 2 hours
When is zero-order kinetics/ elimination observed?
When the body’s capacity to eliminate the drug is saturated
Draw an example of zero-order elimination graphically.
N/A
What is first-order elimination?
A constant fraction of drug is eliminated per unit time b/c the system is NOT saturated
E.g. Half the drug is eliminated from the body per 2 hours
Draw an example of first-order elimination graphically.
N/A
What is capacity-limited elimination?
A point at which the concentration of drug has saturated the elimination capacity of the system
Zero-order process
What is flow-dependent elimination?
When the system to eliminate drug is NOT saturated, the limiting factor in elimination is how fast blood can get to the organ/system
E.g. how fast can you get blood to the liver?
What is the consequence of continuous dosing with a drug that undergoes capacity-limited elimination?
Dangerous toxic levels of drug will accumulate
What drugs are associated with capacity-limited elimination?
Phenytonin
ASA
Alcohol
What drug is associated with flow limited elimination?
Propanolol
What is the half-life of a drug?
Time required for the plasma concentration of a drug to decrease by 50%
What is the half-life a drug dependent on?
- Volume of distribution (V)
- Clearance (CL)
After two half-lives, how much drug has been eliminated?
75%
How many half-lives does it take for a drug to be “fully eliminated?”
4-5 half-lives
What happens to the half-life of a drug if you reduce the clearance of the drug e.g. from renal insufficiency/failure?
Half-life INCREASES
How does increasing the Volume of Distribution (V) impact the half-life of the drug?
Increases the half-life
How is the initial plasma concentration calculated?
- Plot drug plasma concentration vs. time (semi-log)
- Slope= rate of elimination
- Extrapolate the line of best fit to find the y-intercept, the Cp0
Note that Cp0= Dose/V
What is the impact of calculating the initial plasma concentration in a one compartment vs. a two compartment model?
- B/c Cp0= Dose/V, the method works well for a one compartment model with a LOW volume of distribution V
- In the two-compartment model, Cp0 is much HIGHER than the Cp0 in a one-compartment model
If you use a one compartment model to give a loading dose, you could give a toxic/lethal initial dose
What is an accumulation factor?
= 1/fraction of drug lost in one dosing interval
A factor used to predict the ratio of steady-state concentrations to the dose seen following the first dose
When does accumulation of a drug become detectable?
If the dosing interval is shorter than 4 half-lives
What is bioavailability? What is the equation for bioavailability?
The amount of drug that reaches the systemic circulation
F= f x (1-ER)
f= extent of absorption from gut
What is the bioavailability of a drug given IV? How does this compare to a drug given PO?
IV= 100% PO= much less
What is the extraction ratio (ER)?
Effect of first-pass metabolism on bioavaliability
What are the determinants of the extraction ratio?
ER= Hepatic Clearance/ Hepatic Blood Flow
What is the TC?
Target concentration
What is the MEC?
Minimum effective concentration
What is the Css?
“Steady State concentration”
= Dosing Rate/Clearance
The point at which elimination of a drug is equal to the bioavaliability i.e. in and out are balanced
How long will it take to reach the Css?
4-5 half-lives
What is the therapeutic window?
Concentration range between the MEC for the desired effect and the MEC for the toxic effect
If the clearance of a drug decreases from renal insufficiency or failure, what happens to the Css?
Css INCREASES
What is the effect of an increased dosing rate of the Css?
Css INCREASES
What is a maintenance dose?
The dose needed to maintain the Css (Steady State Concentration)
What value do you need to calculate first to determine the maintenance dose?
Dosing rate at steady state
Dosing Ratess= CL x TC
What is the equation for maintenance dose?
Dosing rate x dosing interval
What is a loading dose?
An initial dose that can be given to reach target concentrations (TC) rapidly
= V x TC/F
What are the advantages of a loading dose?
Useful when it would take a long to reach steady state, but you need to rapidly reach the TC
- E.g. in a drug with a long half-life
What are the disadvantages of a loading dose?
- Abrupt high concentration may be v.toxic
- Calculation takes into final volume of distribution, but inital dose is restricted to the blood
