Exam 3: Oral dosing Flashcards
The Importance of Pharmacokinetics
Drug concentration does not reach toxic levels
• Drug concentration is in the therapeutic range
• The duration of effect leads to practical dosing
Which modes of diffusion are saturable?
Facilitated diffusion
Active transport
Which modes of diffusion are unsaturable?
Passive diffusion
An orally administered drug must be absorbed
into the systemic circulation from the GI tract
How does an orally administered drug get absorbed
if in a solid form, it must first be released from its dosage form (tablet, capsule, etc.) – (liberation)
• Then dissolve in body fluids
There are physicochemical considerations to liberation and dissolution
pH
• Presence of food
• Dilution with liquids, etc
kinetic considerations to liberation and dissolution
- Immediate/controlled release formulations
- Gastric emptying time
- Small intestine transit time
- whether the drug is taken up by saturable or not saturable mechanisms
- Blood flow, surface area, etc
At the peak, the rate of drug absorption equals
the rate of elimination
- according to graph
In the graph, once plasma drug conc. declines, the rate of elimination becomes
greater than the rate of absorption
A drug is not absorbed until
it reaches systemic circulation
rate of elimination formula
Ke * [C]
where [C] is conc.
Rate of absorption formula
Ke * [C]
The absorption rate constant is important for
extravascular routes of administration
After administration, what happens to plasma conc.
the plasma concentration rises until it reaches a
peak
When the drug is being absorbed it is also
being eliminated simultaneously
Kinetics of oral dosing
When we first administer an oral
dose,
the rate of absorption is
greater than the rate of
elimination
ka[C]GI>ke[C]plasma
more drug in GI than Urine
Kinetics of oral dosing
Rate of drug entering = Rate of drug leaving
ka[C]GI=ke[C]plasma
Equal amount of drug in GI and urine
Kinetics of oral dosing
Then, as the drug in the
stomach/small intestine is
depleted,
the rate of elimination is
greater than the rate of
absorption
ka*[C]GI
A greater Ke means
faster elimination
shorter half life
A greater Ka means
faster absorption
most likely higher Cmax
If Drug A has a larger ke than Drug B, which drug will be eliminated first?
A. Drug A
B. Drug B
Drug A
As clearance decreases, conc. at steady state
increases
A drug with a high Ka will
reach it’s conc. much faster
What is tmax
the time required to reach max plasma drug conc.
tmax formula
tmax = ln (Ka) - ln (Ke) / Ka - Ke
Onset of effect /Latency
- Time between dosing and start of therapeutic effect
• Time to reach the MEC
(AUC)
Area Under the Curve
AUC
Monitor concentration of plasma [drug] over time
• Time
• Drug concentration
is indicative of the body’s actual exposure to the drug
Greater AUC means
greater systemic exposure
- greater therapeutic effect
- also potential for toxicity
Trapezoidal rule
- method of finding AUC
- Measure concentration at multiple time points
- Area = ((C2+C1)/2)*(t2-t1)
How is AUC done?
- AUC is often done from t=0 to infinity AUC0-inf - AUC is sometimes done to the last measurable time point AUC0-t - For steady state, AUC is usually done over the dosing interval AUC0-τ
AUC formula
Dose administered / Cl
units are mg/ L/ hr
Clearance formula
Ke * Vd
units are L/ hr
If our clearance increases, our AUC will
decrease
Larger clearace means
lower AUC
Lower AUC means
less exposure to drug
Lower clearance
high AUC, more exposure to drug
A dosage form with slow absorption could yield plasma concentrations
to low to yield a therapeutic effect
A dosage form with rapid absorption could
yield plasma concentrations
in the toxic range
All of dose administered intravenously reaches
systemic circulation
Bioavailability
amount of drug reaching systemic circulation versus the total amount of drug
administered
represented by F
Bioavailability formula
amount of drug reaching circulation / dose administered
Oral route of administration characteristics
- Incomplete dissolution
- Acidic pH
- Destruction by digestive enzymes
- Metabolism by intestinal enzymes
- Biliary excretion to feces
- Metabolism by the liver
Other doses of administration may not reach systemic circulation bc:
- Diffusion down concentration gradient
• Limited by surface area
• Limited by solubility
Oral bioavailability is usually due to
to poor absorption or significant 1st pass
effect
First pass metabolism
drug is metabolized before it reachers systemic circulation
Routes when it comes to bioavailability
IV is 100 % by definition
Intramuscular and subcutaneous - 75-100%
Oral - 5-100% bc of 1st pass effect
Rectal 30-100%- less 1st pass effect than oral
AUCiv
amount of drug in plasma if 100% had been
absorbed
Total amount of drug administered directly into the systemic
circulation
• Dose bypassing absorption (
If a drug is administered by IV, which part of ADME is skipped
Absorption
AUCroute
actual amount of drug that gets into plasma
• Mass after absorption
Massafter absorption =
Mtotal mass administered * Froute
Greater bioavailability(F) means
- more potential for toxic effects
- most likely higher Cmax
The AUC for IV is
dose/clearance
The AUC for other routes of administration
has to take into account bioavailability
dose *F / Cl other
Bioequivalence
- A generic drug must have the same quality, strength, and safety as its brand name equivalent
- Lack of significant difference in the rate and extent to which the active ingredient of a drug
becomes available at the site of action when administered at the same dosage and under the
same conditions
In-vivo performance
- PK studies
- Bioavailability
In-vitro performance
- Dissolution rate
- Drug release rate
Cmax indicative of
rate of absorption
Peak exposure
• May vary depending on ka
The peak concentration is known
as Cmax
The trough concentration is known
as Cmin
The dosing interval (τ)
is the time which we allow to elapse between doses
For orally administered drugs, dosing intervals are typically every
6, 8, 12, or 24 hours
The fewer number of times a drug has to be taken per day
the more likely the patient will be to stick with the
regimen
Appropriate dosing intervals are dependent on the half-life of a drug and the therapeutic range
If your drug has a half-life of 8 hours, a patient’s symptoms may return if taken only once daily
• If your drug has a half-life of 24 hours, a patient may experience symptoms of toxicity if taken 3x daily
IV administration, plasma drug concentrations will also reach a steady state
Css = (dose*F)/(Cl * τ)
IV administration, plasma drug concentrations will be dependent
on the dose, bioavailability, clearance, and dosing interval
Calculating Drug Accumulation
The concentration remaining after the 1st dose is additive with the concentration of the second dose
Cmax2 = Cmax1*(1+e-k τ
)
Cmax2= Cmin1 + Cmax1
When a steady state concentration is reached
the equivalent of one dose is removed every dosing interval
If dosing interval=half life
the plasma concentration of
drug fluctuates 2-fold over the dosing interval
Rate of administration formula
Ra = dose / time
