Pharmacokinetics Flashcards
What are the 4 stages of pharmacokinetics?
Absorption, distribution, metabolism, elimination
Where does the most drug absorption take place?
Most in SI: 6-7m, 3-5 hrs, pH 6-7. SA ~ 30-35m2
In the absorption stage how does facilitated diffusion take place?
Solute carrier (SLC) transport = either OATs or OCT = organic anion/cation transporters. Ionic +ve or –ve charge carried across
When is passive diffusion used in pharmacokinetics?
Common mechanism for absorption for lipophilic drugs weak acids/ bases: Lipophilic drugs e.g. steroids diffuse directly down conc gradient into GI capillaries, Weak acids/bases protonated/deprotonated species can diffuse
What are the factors affecting absorption?
Physicochemical factors = drug lipophilicity, pKa, density of SLC.
GI physiology = blood flow, motility, pH
What is bioavailability and how is it calculated?
fraction of a defined dose which reaches its way into a specific body compartment. IV = 100%.
For other routes we compare against IV.
oral = Area under curve oral / AUC IV (answer in decimal)
How are drugs distributed?
Bulk flow = large distance, via arteries
Diffusion = capillaries (diff levels of permeability) - interstitial fluid - cell membrane – target
What is Vd?
Volume of distribution
represents degree to which a drug is distributed in the body tissue rather than the plasma
= drug dose / [plasma drug]t=0 (smaller value = lower penetration)
What are the factors affecting distribution?
Vd
Drug molecule lipophilicity/hydrophilicity = if lipophilic it can move across plasma membrane.
Degree of binding to plasma/tissue proteins = only free drugs can bind targets, binding plasma decreases availability – plasma/tissue act as drug reservoir
What happens in phase I metabolism?
enzyme cytochrome p450, metabolise wide range, increase ionic charge of drug = increase renal elimination. Can activate pro-drug = codeine to morphine
What happens in phase II metabolism?
cytosolic enzymes – more rapid kinetics, further increase ionic charge = increase renal elimination
What is cytochrome p450?
3 superfamilies’ CYP 1, 2, 3, six isoenzymes met ~90% prescription drugs.
Can be induced = plasma levels decrease, can be inhibited = plasma levels increase
What are the factors affecting metabolism?
age, sex (alcohol met slower in F), general health (especially hepatic disease), CYP450 inhibition, genetic variation of enzymes (poor, normal/high, ultrarapid metabolisers)
Where does drug metabolism take place?
Liver
Where does the majority of drug elimination take place?
kidney
What can the drug elimination stage remove?
Removes both exogenous (introduced from outside) and endogenous (originate within) molecule species. Recognises xenobiotics = foreign chemical substance
What are the three stages of drug elimination?
1) Glomerular Filtration –> 20% renal blood.
2) Active tubular secretion –> Proximal tubular secretion = 80% blood = High OAT/OCTs, active transport of ionised molecules out.
3) Passive tubular reabsorption –> Distal tubular reabsorption = passive reabsorption of unionised drugs, OAT/OCTs
What is total body clearance and how is it calculated?
CL: volume of plasma that is completely cleared of the drug per unit time = hepatic clearance + renal clearance.
Predicts how long drug will stay in the body. Plasma can never be fully cleared
Define drug half-life
t1/2 = amount of time over which the conc of a drug in the plasma decreases to one half of that conc value it had when it was first measured
What is drug half-life dependent on?
Vd and CL
What is pharmacokinetics?
what the body does to the drug
What are the 2 types of drug administration?
enteral and parenteral
What is enteral drug administration?
oral, sublingual, rectal
What is parenteral drug administration?
IV, subcutaneous, intramuscular
What are the 3 methods for drug absorption?
passive diffusion, facilitated diffusion, active transport
What is first pass metabolism?
drugs travel to liver via hepatic portal vein, metabolised before reaching systemic circulation
It is the fraction of drug lost during the process of absorption which is generally related to the liver and gut wall
What genetic factor do CYP enzymes show?
genetic polymorphism
some CYP enzymes are expressed more than others in differing nationalities
When does zero kinetics occur?
when there is full saturation of CYPs or transporters
Unequal half-life
What does polypharmacy lead to?
zero kinetics as there is more competition for active sites
In pharmacokinetics what type of graph shows linear kinetics?
log graph of time vs drug conc in plasma
In pharmacokinetics what is the advantage of linear graphs?
can determine half-lives easier
How does CYP450 metabolise drugs?
Oxidation, hydrolysis, hydroxylation
