ICPP 16 - Pharmacokinetics 1 Flashcards
Define “pharmacokinetics”
What the body does to the drug.
What are the 4 main processes of drug therapy?
Which processes are involved in “drug in” and which ones involves in “drug out”?
- Absorption, Distribution, Metabolism, Excretion (ADME)
- A & D = Drug in
- M & E = Drug out
What 2 classes can drug administration routes be divided into, and what administration routes do they encompass?
1) Enteral - anything that is delivered via the GI tract, e.g.: oral, rectal or sublingual
2) Parenteral - all other routes, e.g.: IV, IM, SC.
Why does the majority of drug absorption occur in the small intestine rather than the stomach.
The surface area of the SI (due to villi & microvilli) is much larger (30-35m^2) compared to that of the stomach (0.75-1m^2) - therefore majority of absorption occurs in the SI.
What are the 3 methods of drug absorption?
Which one is the most common, and which drugs can be absorbed in this way?
1) Passive diffusion
2) Facilitated diffusion
3) Secondary active transport
- Passive diffusion is the most common for lipophilic drugs and weak acids & bases - it is the protonated versions of bases, and deprotonated version of acids that can diffuse due to their polarity/neutral charge.
Which drugs can be absorbed via facilitated diffusion and how?
- Drugs will a net ionic charge can be carried via facilitated diffusion across the gut epithelia (this is a passive process)
- Via OAT’s/OCT’s - which are highly expressed in the GI, hepatic and renal epithelia
How are drugs absorbed via secondary active transport?
OAT’s and OCT’s once again transport molecules down the existing electrochemical gradient along with another ion - this does NOT require the direct utilisation of ATP.
- E.g.: Penicillins co-transported via OAT with H+ ion.
What are the physiochemical and GI physiology factors that affect drug absorption?
Physiochemical =
- GI length & SA
- Drug lipophilicity
- Density of OAT/OCT expression in the GI tract
GI physiology =
- Blood flow - increases post meal
- GI motility = slows post meal
- Food/pH = Food can reduce or increase absorption
What is the main factor that affects absorption/bioavailability of a drug?
- The 1st pass metabolism effect via the GI tract and mostly the liver - CYP450 enzymes involved in phase 1 and conjugation reactions occur in phase 2. This reduces the availability of the drug reaching the systemic circulation.
What is “bioavailability” and how is oral bioavailability calculated?
- Bioavailability is the fraction of a defined dose that reaches the required body compartment (most commonly the cardiovascular circulation).
- By comparing bioavailability to IV route (which is 100%) using area under the curve
- AUC(oral)/AUC(IV) = F (bioavailability) - given as a number between 0-1.
Define drug distribution, and describe the main stages of drug distribution.
- Drug distribution is the journey of drugs through the body after absorption to reaching its target and target tissues.
1) Bulk flow - blood carrying drug around circulation to target capillaries
2) Diffusion - across capillaries into interstitial fluid to cell membranes
3) Barriers to diffusion - e.g.: permeability or non-target binding - e.g.: to plasma proteins.
How does the permeability of different capillaries affect drug distribution?
This depends on the type of capillary - i.e.: continous, fenestrated or sinusouid - which increase in permeability thus increasing distribution/diffusion to cell membranes.
- NB: capillaries also contain OCT’s/OAT’s for charged drugs to cross.
What are the major factors that affect drug distribution?
1) Drug lipophilicity - if drugs are lipophilic they can freely move across membrane barriers however if they are charged they must rely on capillary permeability, drug pKa or presence of OCT’s/OAT’s in capillary and target tissue membranes.
2) Binding to plasma/tissue proteins - e.g.: albumin or lipoproteins - they reversibly bind thus creating a “dynamic reservoir” of drug in the plasma, AND decreases free plasma drug concentration (only unbound form can reach target tissue)
What are the effects of increasing drug penetration into interstitial and then intracellular fluid compartments on plasma drug concentration and volume of distribution (Vd)
- Plasma drug concentration decreases (more entering interstitial fluid and moving into cells)
- Vd increases, and there is less drug in the total body water.
Use slide 44 on pharmacokinetics 16 to help here
What determines whether a drug can move freely into a cell or has to utilise OCT/OAT’s?
- It’s lipophilicity - only lipophilic drugs can pass through the plasma membrane, e.g.: steroids.
