Solubility and partitioning of drugs Flashcards
What are the barriers that a drug has to cross before it becomes effective?
GIT
BBB
Why are biological membranes hydrophobic in nature?
Because they are composed of phospholipids containing long hydrobcarbon chains
What must a drug do to succeed in its mission?
Pass from the aq solution of the EXTRACELLULAR fluid to the aq solution of the INTRACELLULAR fluid by crossing the lipid membrane
What are the properties of some organic solvents (e.g. n-octanol, cyclohexane) thought to resemble?
Similar properties of a lipid bilayer membrane. This suggests that distribution of drugs into hydrophobic organic media stimulates their ability to passively diffuse across biological membranes
What is partitioning?
The movement (or redistribution) of organic compounds from one liquid to another
What happens if an excess of an organic compound is added to a mixture of two immiscible liquids?
It will partition itself between the two liquids so that each becomes saturated
What happens if the amount of compound added is not enough to saturate the solutions?
It will be distributed between the two immiscible liquids according to a definite concentration ratio:
Corg -> Caq
What is the partition coefficient (P)?
A constant, which is the ratio of concentration of compound in organic phase to the concentration in aq phase at EQUILIBRIUM
What is the equation for P?
P = Corg/Caq
What is the TRUE partition coefficient?
The partition coefficient of UNIONISED drug
What does it mean if Ptrue > 1?
Then Corg > Caq and the compound is HYDROPHOBIC (lipophilic)
What does it mean if Ptrue < 1?
then Corg < Caq and the compound is HYDROPHILIC (lipophobic/polar)
What does LogP = 1 means?
P = 10 and Corg:Caq = 10:1
What does LogP = 0 mean?
P=1 and Corg:Caq = 1:1
What does P= -1 mean?
P= 0.1 and Corg:Caq = 1:10
What can P be used to predict?
the absorption, distribution and elimination of drugs within the body
What is the Hansch-Fujita parameter?
They describe the contribution of various functional groups to the lipophilicity of a compound
What are the hydrophobic functional groups (+)?
Aromatic hyrdocarbons
Aliphatic hydrocarbons
Halogens
What will happen to P if there is a predominance of hydrophobic (+) groups?
Increase - making molecule more lipid soluble and more able to pass through the lipid membrane
What are the hydrophilic (-) functional groups?
Hydroxyl groups Carboxyl groups Amines Ether Amide
What will happen to P if there is a predominance of hydrophilic groups (-)?
Decrease - making molecule less lipid soluble and less able to pass through the lipid membrane
How does the permeability of a drug in the unionised form differ from that of the ionised form?
Permeability of the unionised form of a drug across a phospholipid membrane by passive diffusion is 10^8 higher
Should a drug be in the ionised or unionised form at the membrane surface to permeate the membrane by passive diffusion?
Uncharges (i.e. unionised)
What effects the concentration of the compound passing through the membrane barrier?
The % of the compound that is unionised
What controls the % of the unionised compound?
pKa of compound and pH of solution
For weak acids and bases, how does P vary?
Varies depending upon the pH at which it is measured (APPARENT P)
Papparent is sometimes referred to as what?
D or Distribution coefficient
What is Papparent dependent on?
the proportion of unionised form of the drug present in solution
How is Papparent calculated?
Papp = Ptrue x funionised
What is funionised?
The fraction of the total amount of drug unionised at a certain pH
What does is mean if funionised = 1?
Then Papp = Ptrue
What is funionised dependent upon?
The pH of the aq solution and the pKa of the drug
If drug is only absorbed in the small intestine there will be a delay in onset of action. Why?
Because the drug has to pass through the stomach first
When should patients take antihistamines for travel sickness?
At least one hour before travelling
Drugs can be _______ in the kidneys rather than excreted.
reabsorbed
How is it possible to control reabsorption of drugs from the kidney tubule and accelerate excretion?
If the reabsorption happens through passive diffusion via unionised drug form, the same partitioning rules can be applied
Acidic drugs are reabsorbed best from _______ urine
Acidic
If the drug taken in overdose is a weak acid then the reabsorption can be minimised by _______ the urine
basifying
What happens to acidic drugs in forced base diuresis in terms of reabsorption and clearance?
The reabsorption decreases and the clearance is more rapid
Basic drugs are reabsorbed best from _______ urine
Alkaline
If the drug taken in overdose is a weak base reabsorption can be minimised by _______ the urine
acidifying
What happens to basic drugs in forced acid diuresis in terms of reabsorption and clearance?
decrease in reabsorption and more rapid clearance
