Exam 3: Oral dosing Flashcards by Angelise Hicks

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

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Which modes of diffusion are saturable?

Facilitated diffusion

Active transport

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Which modes of diffusion are unsaturable?

Passive diffusion

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An orally administered drug must be absorbed

into the systemic circulation from the GI tract

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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

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There are physicochemical considerations to liberation and dissolution

pH
• Presence of food
• Dilution with liquids, etc

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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

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At the peak, the rate of drug absorption equals

the rate of elimination

according to graph

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In the graph, once plasma drug conc. declines, the rate of elimination becomes

greater than the rate of absorption

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A drug is not absorbed until

it reaches systemic circulation

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rate of elimination formula

Ke * [C]

where [C] is conc.

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Rate of absorption formula

Ke * [C]

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The absorption rate constant is important for

extravascular routes of administration

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After administration, what happens to plasma conc.

the plasma concentration rises until it reaches a

peak

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When the drug is being absorbed it is also

being eliminated simultaneously

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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

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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

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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

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A greater Ke means

faster elimination

shorter half life

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A greater Ka means

faster absorption

most likely higher Cmax

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If Drug A has a larger ke than Drug B, which drug will be eliminated first?
A. Drug A
B. Drug B

Drug A

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As clearance decreases, conc. at steady state

increases

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A drug with a high Ka will

reach it’s conc. much faster

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What is tmax

the time required to reach max plasma drug conc.

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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