Flashcards in topic 2 Deck (27):
Movement of drug into blood from site of application
Movement of drug from blood to its site of action
What role do biological membranes play in drug absorption and distribution? What kinds of transport across them are there?
Drug must pass many semi-permeable membranes (Lipoprotein barriers containing pores) before getting to site of action.Examples of transport across membranes include:
Simple diffusion (passive transport)
Facilitated diffusion (carrier mediated)
Active transport (carrier mediated)
Diffusion through pores (rare for drugs)
Pinocytosis (rare for drugs)
Basics of Simple Diffusion. What is flux and what factors affect it?
No carrier proteins. Must pass through lipids. Polar molecules don't readily pass, but non-polar molecules can't be contained in blood.
Flux determined by lipid solubility, temperature, surface area and thickness of the membrane, the concentration gradient, the size of the drug, and the pKa of drug compared to pH of solution.
J=Flux, rate of movement across membrane
D=diffusion coefficient, which is proportional to the temperature and lipid permeability (which is linearly related to partition coefficient (lipid solubility and drug size)
A=Surface area of membrane
dC=change in concentration
dx=thickness of membrane
Lipid soluble drugs have high partition coefficients and easily pass through membrane. However, drugs must be water soluble enough to dissolve in aqueous solution. Thus, week acids or bases are used.
Anything >1000 Da must do pinocytosis. Anything less than that will follow Fick's law (proportional to gradient).
How do pKa and pH affect flux?
Only the ionized form of a drug can pass through a membrane
In an acidic solution, an acid will largely be unionized and can pass through better.
In a basic solution, a base will be largely unionized and can pass through better.
Henderson Hasselbach. What does pKa signify?
Acid: pH=pKa +log (A-/HA)
Base: pH=pKa + log (B/BH+)
pKA is the pH value at which 50% of the drug is ionized.
Only the unionized form can pass through a membrane and thus the unionized form on both sides will reach equilibrium
Considering an weak acid drug, HA. If side 1 has a lower pH than side 2, the weak acid will be less ionized on side 1 than side 2. Therefore, when HA reaches side 2, it will become ionized as A-, which means that less HA will be on side 2 so more HA from side 1 will pass and the same will happen and you end up with more of the drug on side 2 trapped in the form of A-.
Summary of passive diffusion
Increases as partition coefficient increases
Goes from higher to lower concentration
Increases with membrane surface area.
It is non-saturable (more drug given, more drug absorbed=no upper limit)
The greater the surface area of the membrane, the greater the flux. Small intestine is large with many folds and villi. Most food and drugs pass through here.
Commonalities in carrier mediated transport
Bind to protein carriers and are translocated
Can be saturated (limited number of carriers)
They can be inhibited or compete with other molecules that bind to their carrier
Can't go against gradient; follows Fick's law
Can go against gradient; requires energy
Can be inhibited by taking away energy source.
Carrier mediated vs. Passive transport
Carrier faster than passive
Carrier can be saturated
Carrier can be competitively inhibited.
Factors affecting oral administration
Most drugs absorbed in small intestine (even in passive transport)
Presence or absence of food. Gastric emptying. Solid foods slow down movement from stomach to intestine. Therefore, most drugs are better taken on empty stomach with liquids.
Ion Trapping. pH of solution affects how well the drug is transported. Acids do better in acidic, bases in basic.
Drug formulation. How quick tablets dissolve, if they dissolve in acid, etc.
What is a Hematocrit? How does it mean? what is the water content in cells and in plasma?
Blood put into centrifuge to separate plasma from cells.
0.45 would mean that the blood volume is 45% cells and 55% plasma.
Water content of cells is 70%. Water content of plasma is 100%
Calculating plasma concentration of drug
Total concentration in blood= (fraction of blood that is serum x serum water content x concentration of drug in plasma) + (fraction of blood that is cells x cell water content x concentration of blood in cells)
Drug Distribution Types
Within Vascular system
Concentrated in one or more tissue
Factors that determine distribution
Where a drug goes depend on:
1) Rate of distribution
Plasma protein binding
2) Extent of distribution
This is where drugs exit from circulation. Can be continous, fenestrated, and discontinous.
Most capillaries will allow small molecules to leave < 60,000 MW, but larger ones cannot. Therefore, molecules bound to albumin stay in circulation.
Exceptions to rule are liver, bone marrow, spleen (discontinous) and BBB (super tight).
In general, rates of delivery:
***In this class, we'll consider all capillaries to be fenestrated***
Effect of albumin
Major plasma protein. Many molecules bind to it b/c it carries a net negative charge at pH=7.4 and has non specific sites and sites for lipids (drugs with high partition coefficients)
Only the free concentration of these molecules is important b/c the others can't do anything.
It might take longer to clear a molecule once you stop taking it b/c its stuck in albumin.
Albumin and multiple drugs
If two drugs bind tightly to albumin, one might bind tighter and if both are given, the one that binds less tightly will be in greater unbound concentration in the blood than normal which could have toxic effects.
Also, when one is taken away, the other might become more bound and have less effect than normal.
Binding and body fat
Some drugs with a very high partition coefficient can end up in the fat at equilibrium.
This is limited by the fact that most drugs don't have that and that there is low blood supply to fat tissue so equilibrium might not be reached.
This increases with more fat in one's body.
Blood perfusion to different organs
Blood is perfused to different organs at different rates.
Brain, heart, liver, and kidneys>>skeletal muscle and skin>>Adipose tissue.
However, there is some variability.