ICPP - Pharmacokinetics Flashcards
What are the four main processes in pharmokinetics?
Absorption, distribution, metabolism and elimination
Summarise the drug administration routes.
ENTERAL (oral, sublingual, rectal) and PARENTERAL (intravenous, subcutaneous, intramuscular)
Where does most drug absorption occur in the oral route?
Most is absorbed from small intestine
What is the typical transit time of the small intestine?
3-5 hours, but motility varies 1-10 hours
What is passive diffusion?
The mechanism by which lipophilic drugs and weak acids/bases diffuse directly down concentration gradient into GI capillaries.
What are SLCs?
Solute Carrier transport, which move anions and cations through the GI epithelia. It is a passive process driven by electrochemical gradient.
Give some examples of factors in the GI tract that can affect drug absorption?
- GI length
- Density of SLC expression
- Blood flow to GI
- Motility of GI
- Whether there is food present/ pH
What are phase I and II enzymes?
Enzymes found in the liver that metabolise enzymes. Phase I = cytochrome P450s.
Phase II = conjugating
What is “first pass” metabolism?
When drugs pass through the liver, which reduces the availability of the drug reaching systemic circulation.
What is bioavailability?
The fraction of a defined dose which reaches its way into a specific body compartment.
Why is the circulatory compartment a common reference compartment?
Because an IV bonus has 100% delivery to veins
How is oral bioavailability (F) calculated?
F = amount reaching systemic circulation (area under curve on oral graph) / total IV drug given (area under curve on IV graph)
F is between 0 and 1, and informs choice of administration route
What are the three varying levels of capillary permeability?
- continuous
- fenestrated
- sinusoid
If a drug is lipophilic, is it easy or difficult to move across the membrane barriers?
Easy
If a drug binds to plasma/tissue proteins, can it bind to the target site?
Not initially, as it must be free to bind. However, bound drug often acts as a “reservoir”, so it would be able to dissociate and bind to target site.
What are the three model body fluid compartments?
Plasma water (3 litres), interstitial water (11 litres) and intracellular water (28 litres). Drugs move from plasma to interstitial to intracellular.
What is apparent volume of distribution?
A (made up) concept that the main body fluid compartments can be grouped together.
Vd = drug dose / [plasma drug] at time=0. Units are litres or litres/kg
Smaller Vd values = less penetration of intracellular fluid compartment, higher Vd values = more penetration
Can the Vd change from person to person?
Yes - it is affected by many factors, for example pregnancy, pediatrics, geriatrics, renal failure
What is the evolutionary advantage of recognising xenobiotics?
They are potential toxins
Which reactions do CYP450 (phase I) enzymes catalyse, and where are they found?
Redox, dealkylation and hydroxylation.
Found on external face of ER.
What are pro-drugs?
A precursor to drugs which must be activated in order to work, eg codeine to morphine
Where are phase II enzymes found and what do they do?
In the cytosol, they enhance hydrophilicity by further increasing ionic charge which allows better renal elimination.
What are the three super families of cytochrome P450 enzymes?
CYP 1, 2 and 3. Six of these isozymes metabolise around 90% of prescription drugs.
Give some factors affecting speed of drug metabolism in humans.
- age
- sex
- general heath/dietary/disease
What is CYP450 induction?
Certain drugs can induce CYP450, leading to faster metabolism of other drugs.
Give an example of CYP4450 inhibition.
Grapefruit juice inhibits CYP3A4, which metabolises Verapimil which is used to treat high blood pressure. Consequence can be much reduced BP and fainting.
Do CYP450s show genetic variation?
Yes - some may not be expressed, or are overexpressed. Eg 1% of Caucasians and Africans are unable to metabolise NSAIDs.
What is the main route of drug excretion?
Via kidneys. Other routes include bile, lung, breast milk, sweat, tears, genital secretions, saliva.
Which sort of drug molecules are NOT filtered out by the kidneys?
Lipophilic, unionised molecules. These leave the tubule due to solute conc being higher inside than outside. Hydrophilic, ionised drug is filtered out and excreted in urine.
In the proximal tubule, anions and cations are actively transported in. Give some examples of these.
OATs: urate, penicillin, NSAIDs, antiviral
OCTs: morphine, histamine, chlorpromazine
What is clearance?
The volume of plasma that is completely cleared of the drug per unit time. Units are ml/min
Total body clearance = hepatic clearance + renal clearance
What can clearance (CL) and Vd indicate when combined?
They predict how long the drug will stay in the body.
What is drug half life?
The amount of time over which the concentration of a drug in plasma decreases to one half of the concentration value it had when it was first measured.
T1/2 = 0.693xVd / CL
The curve of plasma half-life decreases exponentially, so what happens if we plot concentration on a log axis?
It becomes linear
What happens when elimination processes become saturated?
They become rate limited and cannot go any faster. They are known as zero order. In this situation, a graph of [drug] against time would be a straight line.
Why is it better to avoid drugs having zero-order kinetics?
All processes are saturated, so more likely to result in ADRs/toxicity as. Relatively small dose changes can cause huge plasma [drug] changes. Half-life is not easily calculable so cannot predict dosage regimes.
