PCOL Prelims Lecture 4 Drug as a Weak Acid

Permeation
Movement of drug molecules within the biologic
environment from one area to another
In the body we have several compartments that separate A neutral molecule that can reversibly dissociate into an
it with a lipid membrane anion (- charged molecule) and a proton (+ charged
Factors: molecule)
o Lipid layer Proton acceptor

Drug as a Weak Base

A neutral molecule that can form a cation by combining

with a proton
Aqueous Diffusion Proton donor
Movement of molecules:
1. Across epithelial membrane tight junctions Ionization and Lipid Solubility
2. Endothelial lining of blood vessels through aqueous pores
There must be a passageway, pore, or tight junction for
the molecule from the aqueous compartment to cross the
lipid barrier
A form of passive diffusion (no energy or carrier needed)
Governed by a concentration gradient
A. The protonated form of a weak acid is the neutral, more
From concentration to concentration for it
lipid-soluble form
to equilibrate
If a weak acid is protonated (in its neutral from)
more lipid soluble faster movement
Ficks Law
A weak acid in its neutral form is more lipid soluble
Anion (weak acid/aspirin)) tries to get a positive
charge (proton) from the environment to become
neutral
More of a weak acid will be in the lipid-soluble form
C1 C2 is the concentration gradient at acid pH
Area of the tissues, compartments, etc
Permeability coefficient is usually given

All passive diffusion is governed by Ficks law

Directly proportional to the area
How fast a molecule moves from one area to another
B. The unprotonated form of a weak base is the neutral form
Area is larger faster movement of molecules from one
If its unprotonated, its in its neutral form
compartment to another (Area and Movement of
It wont accept a proton (+ charge) but instead
molecules are directly proportional)
releases/donates it
Barrier is thicker slower movement of molecules from
If a weak base is in its neutral form more lipid
one compartment to another (inversely proportional to
soluble movement across lipid barrier is faster
area)
More of a basic drug will be in the lipid soluble form
Which organ facilitates permeation faster, brain or
at alkaline pH
intestines?
Answer to quiz:
INTESTINES have greater area, thus the flux of
In an acidic environment (low pH more positive), weak acid
molecules is faster
has a lot of positive charges in the environment tries to
Lungs or Skin?
accept the positive charges to become more protonated
LUNGS because it is thinner
more lipid soluble movement is faster
Area is not applicable because the structure of
Methamphetamine is a weak base alkaline pH more
the organs are not the same
donation of positive charges more unprotonated more
lipid soluble faster movement faster absorption
Lipid Diffusion
Sodium bicarbonate is also basic. If a drug (methamphetamine)
Movement of molecules through membranes and other
is basic and exposed to a weak base releasing more positive
lipid structures
charges becomes unprotonated lipid soluble more
Governed by Ficks Law Passive diffusion
reabsorbed
It is the most important limiting factor for drug
SODIUM BICARBONATE DOES NOT HELP BECAUSE IT WILL KEEP
permeation because of the large number of lipid barriers
METHAMPHETAMINE WHEN FILTERED; NEEDS AMONIUM
that separate the compartments of the body
CHLORIDE (ACIDIC) SO IT CAN BE EXCRETED BECAUSE ITS
Drugs should be lipid soluble
REPELLED FROM REABSORPTION WHEN THE ENVIRONMENT IS
LAPC (Liquid : Aqueous Partition Coefficient) Determines ACIDIC & THE DRUG IS BASIC
how readily (the rate) the molecule moves between the
aqueous and the lipid compartment

Henderson-Hasselbach Equation
pH of the surrounding environment affects the movement
of the molecules
Describes the derivation of pH as a measure of acidity in
biological and chemical systems
A drug molecule can exist as a weak acid or a weak base
 In an acidic environment
Weak acid = kuha ng proton, LIPID SOLUBLE,
movement is faster
Weak base = di maglabas ng positive charge, less
lipid soluble, unprotonated, not reabsorbed
(TRAPPING or repelled from reabsorption)
In alkaline environment
Weak acid = less lipid soluble, not absorbed,
slower movement
Weak base (meth) = releases positive,
unprotonated, more lipid soluble, faster
absorption

LIPID DIFFUSION IS GOVERNED A FICKS LAW

For a weak acid, which is faster: Lungs or Skin?
In physiologic pH walang pakialam ang pH here, so
simply apply Ficks Law
LUNGS still because thinner
Physiologic pH, use Ficks Law
If theres a change in pH, then consider Ficks Law AND the
pH

Special Carriers
For substances that are important for cell function
For too large and too insoluble lipid to diffuse passively
1. Special carriers are selective
2. Special carriers are saturable (limited)
3. Special carriers are inhibitable (can disrupt the function of
the special carrier)

Endocytosis (cell eating) and Exocytosis

For substances that are so large or so impermeant
If it cannot be carried by the special carriers
Barriers are the ones being engulfed
Substance is
1. Bound at a cell-surface receptor
2. Engulfed by the cell membrane
3. Carried into the cell by pinching of the newly
formed vesicle inside the membrane