diffusion of drug and its parameters

1. 1
Diffusion factors
u.sai kumar

2. Diffusion: is the movement of drug molecules in
to & within the biological environment. It involves
several processes of drug transport across the
cell membranes.
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3. • Generally the drugs are administered
away from their site of action .
• To reach their site of action they are
permeate from one compartment to
another by crossing the different barriers.
• So the drugs have to cross the cell
membranes.
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4. Cell membrane:
Fluid bi-layer of phospholipids.
• Scattered membrane protein molecules
embedded in bi-layer serve as
– Receptors--- selective targets for drug action
– Ion channels
– Transporters
• Lipid molecules are capable of lateral
movement.
• It is flexible
• Has high electrical resistance
• Relatively impermeable to highly polar
molecules
• Highly permeable to lipid soluble drug molecules12/10/2019 L24

5. Main Mechanisms Of Drug Permeation /
diffusion
1. Passive diffusion
Lipid diffusion
Aqueous diffusion
2. Carrier mediated transport /diffusion
Active transport
Facilitated diffusion
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6. Passive Diffusion
Drugs cross the cell membranes along the concentration and
electrical gradient without expenditure of energy according to
Fick’s Law.
Fick’s first Law of diffusion: the drug molecules diffuse
from a region of higher concentration to one of lower
concentration until equilibrium is attained.
rate of diffusion is directly proportional to the conc.
gradient across the membrane
dQ/dt= DAK (Cgit-C)
h
dQ/dt= rate of diffusion (amount per unit time)
D = diffusion Coefficient (area /time)
A = surface area
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7. K m/w =Partition Co-efficient
(Cgit-C)= concentration gradient
h = thickness of membrane
Lipid diffusion
The most important mechanism for transport of majority of
drugs in the body. It is the passive movement of lipid soluble
molecules through membranes or other lipid structures.
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8. Characteristics of Lipid Diffusion:
• Passive process, governed by Fick’s Law.
• Along a concentration gradient.
• Only lipid soluble drug molecules can cross.
• It occurs through the cells, by dissolving in the lipid
matrix of the membrane.
• Energy not required.
• Not saturable or capacity limited
• Not inhibitable by other substances.
Example: Most of the drugs
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9. Aqueous Diffusion
(Intracellular/ Paracellular diffusion/ filtration)
• Passive diffusion
• Through the aqueous pores
• Along a concentration gradient
• Small water soluble drug molecules in solution
form (M.W up to 20,000 – 30, 000)
• If the drug is charged, its flux is also influenced
by electrical fields (e.g. the membrane
potential, transtubular potential)
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10. Facilitated Diffusion: A mechanism to enhance
diffusion of drugs with low lipid solubility.
• Along a concentration gradient
• Carrier mediated:
Carrier increases lipid solubility of drug →↑rate of
diffusion
• Not energy dependent
• Saturable
• Competitive inhibition
e.g. Glucose entry into the cell by Glucose transporters-GLUT1-
GLUT5
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11. Carrier Mediated Transport
• Important for drug molecules too large or too
insoluble in lipid to diffuse passively through
membranes.
• Carriers are trans-membrane proteins. The drug
molecules chemically related to naturally occurring
peptides , amino-acids , or sugars can use these
carriers.
• Carrier binds one or more molecules or ions ,
changes conformation & releases them on the
other site of membrane.
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Drug (A)
Administration
Diffusion
Free drug [A]
Systemic circulation A + P AP
Plasma protein-bound drug (AP)
Protein-drug complex
Excretion
Site of action
AR A + R
Other storage tissues
AT A + T
Unchanged
A
Drug metabolite (A’)
A’
Distribution
Distribution
Pharmacological
effects
Metabolism
plasma

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Mechanisms of drug diffusion
• Drug administration
– Solid to solution
• Drug absorption
– membarne
• Drug distribution
– Protein binding
• Drug elimination – excretion

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15. 15
1. Passive diffusion
1) Passive diffusion of non-electrolytes
Mechanisms of Drug Transport
The higher the Kp, the more lipid soluble, the faster
the rate of transfer across biological membranes

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1. Passive diffusion
2) Passive diffusion of electrolytes
Electrolytes: tend to ionize in physiological solutions.
Two main categories – weak acids and weak bases.
Weak acids: HA H+ + A- R-COOH, R-OH and R-SH
Weak bases: BH+ B + H+ R-NH2
Most drugs are either weak acids or weak bases.
Mechanisms of Drug Transport

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2. Filtration
- Passage of molecules through pores or porous structures.
The rate of filtration
a. Driving force: The pressure gradient in both sides.
a. The size of the compound relative to the size of the pore.
i. Smaller compound – transfer rapidly
ii. Larger compound – retained
iii. Intermediate compound – barrier
Mechanisms of Drug Transport
Lipid soluble – passive diffusion
Water soluble – filtration

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5. Ion-pair transport
+
_
+
_
+
_
+
_
Mechanisms of Drug Transport
Highly ionized
Carrier
Passive diffusion

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Diffusion of Drugs
1. Sites of Diffusion through the GI tract
1) Mouth:
a. Small amount of surface area but good blood flow – best for
potent drugs.
b. Transfer by passive diffusion – good for lipid soluble drugs.
c. pH = 6. Weak base drugs have better Diffusion.
Nicotine pKa 8.5
Mouth GI tract
pH 6 1-5
Ionization more less
Diffusion 4 times faster
d. Can bypass first pass effect.

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1. Sites of Diffusion through the GI tract
2) Stomach:
a. Moderate surface area – more than mouth, less than small intestine.
b. Good blood supply.
c. Drugs absorbed in the stomach will experience first pass effect.
d. Transfer by passive diffusion.
e. Low pH (1-2) – ionization - Drugs that are weak acids will be
absorbed better than weak base drugs.
f. Ion trapping: Accumulation of weak base drugs in the stomach.
Diffusion of Drugs

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1. Sites of Diffusion through the GI tract
3) Small intestine
a. The primary site for most drugs.
b. Large surface area - Folds, villi and microvilli and high
blood perfusion rate.
c. pH = 5-8.
d. Passive diffusion.
e. Diffusion can also take place by active transport,
facilitated diffusion, endocytosis and filtration.
Diffusion of Drugs

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1. Sites of Diffusion through the GI tract
4) Large intestine
a. Not important for drug Diffusion, if the drug is absorbed
effectively in small intestine.
b. Can be a site of Diffusion for incompletely absorbed drugs.
c. Less Diffusion then small intestine – less area and solid nature
of contents.
d. Rectum can be used for drug administration.
For drugs that cause irritation to the stomach
After GI surgery
Children
Partially avoids liver first pass effect: The half of blood flow goes into
liver, the half of blood flow enters the systemic circulation directly.
Diffusion of Drugs

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Parameters that affect diffusion
1) Drug solubilization
2) Formulation factors
3) Concentration of drug at the Diffusion site
4) Blood flow at the Diffusion site
5) Surface area of Diffusion
6) Route of administration
7) Gastric emptying
8) Food
9) Intestinal motility
10) Metabolism of drug by GI tract
Diffusion of Drugs

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2. Factors that modify Diffusion in the GI tract
Hydrophilic drugs - poorly absorbed - inability to cross the lipid-rich cell membrane.
Hydrophobic drugs - poorly absorbed - insoluble in the aqueous body fluids - cannot
gain access to the surface of cells.
- largely hydrophobic yet have some solubility in aqueous solutions
Diffusion of Drugs

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2. Factors that modify Diffusion in the GI tract
1) Drug solubilization – breaking drugs into smaller, more
absorbable particles
Solid Granules fine particles:
Solution
disintergration deaggregation
Diffusion of Drugs

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2. Factors that modify Diffusion in the GI tract
2) Formulation factors – materials added to the drug during processing
can affect the solubilization of the drug.
a. Fillers – add bulk to the tablet
b. Disintegrators – cause tablet to break down into granules
c. Binders – hold tablet together
d. Lubricants – prevent tablet from sticking to machinery
Formulation factors - not clinically important if the drug is absorbed effectively and may
have important influence on drug Diffusion for these drugs which are not effectively
absorbed in the GI tract - influence drug’s bioavailability.
Diffusion of Drugs

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2. Factors that modify Diffusion in the GI tract
3) Concentration of drug at the Diffusion site
Passive diffusion
Driving force – the concentration gradient.
The higher the concentration of the drug, the faster the rate of Diffusion.
Diffusion of Drugs

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2. Factors that modify Diffusion in the GI tract
4) Blood flow at the Diffusion site
- maintain concentration gradient – driving force
Blood
Membrane
Diffusion of Drugs

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2. Factors that modify Diffusion in the GI tract
5) Surface area of Diffusion
small intestine
Diffusion of Drugs

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2. Factors that modify Diffusion in the GI tract
6) Route of administration
GI tract – first pass effect
Diffusion of Drugs

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2. Factors that modify Diffusion in the GI tract
7) Gastric emptying
small intestine – primary site of drug Diffusion
Anything that delays/accelerates gastric emptying will
decrease/increase drug Diffusion.
For all drugs - acidic, basic or neutral substances.
Diffusion of Drugs

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2. Factors that modify Diffusion in the GI tract
8) Food
High fat food – delay gastric emptying – slow Diffusion
Diffusion of Drugs

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2. Factors that modify Diffusion in the GI tract
9) Intestinal motility
– depends on whether the drug is completely absorbed under
normal condition.
a. Completely absorbed early upon entry into the small intestine,
increasing intestinal motility will not significantly affect Diffusion.
b. Not completely absorbed before entry into the small intestine,
increasing/decreasing intestinal motility will slow down/facilitate
drug Diffusion.
Diffusion of Drugs

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2. Factors that modify Diffusion in the GI tract
10) Metabolism of drug by GI tract
a. Drug metabolizing enzymes in the GI tract
b. Proteases in the GI tract
c. Microbes in the GI tract - metabolize certain drugs
- Drug metabolites are not usually absorbed.
Diffusion of Drugs