ROUTES OF DRUG ADMINISTRATION The route of administration (ROA) that is chosen has a large impact on how fast the drug is taken up and how much of it arrives at its destination in an active form. MEMBRANE PHYSIOLOGY The cell membrane also known as the plasma membrane or cytoplasmic membrane is a biological membrane that separates the interior of all cells from the outside environment. GSTERO-INTESTINAL PHYSIOLOGY AGE

1. PHYSIOLOGIC FACTORS
RELATED TO DRUG
ABSORPTION
BY
NADIKATLAANUSHA
M.Pharm

2. CONTENTS
ROUTES OF DRUG ADMINISTRATION
a. PARENTRAL
I. INTRAVENOUS(IV)
II. INTRAMUSCULAR INJECTION(IM)
III. SUBCUTANEOUS INJECTION(SC)
b. ENTERAL ROUTES
I. BUCCAL OR SUBLINGUAL(SL)
II. ORAL(PO)
III. RECTAL(PR)
c. OTHER ROUTES
I. TRANSDERMAL
II. INHALATION
ANUSHA NADIKATLA

3. MEMBRANE PHYSIOLOGY
a. NATURE OF CELL MEMBRANE
b. TRANSPORT PROCESSES
1. PASSIVE DIFFUSION
2. CARRIER MEDIATED TRANSPORT
A) Active transport
B) Facilitated transport
3. VESICULAR TRANSPORT
A) Pinocytosis
B) Phagocytosis
4. PORE TRANSPORT
5. ION PAIR FORMATION
ANUSHA NADIKATLA

4. GASTERO-INTESTINAL PHYSIOLOGY
a. GASTRIC EMPTYING RATE
b. INTESTINAL MOTILITY
c. DRUG STABILITY IN GIT
d. pH AND SURFACE AREA OF GIT
e. INTESTINAL TRANSIT
f. SPLANCHNIC BLOOD FLOW
g. EFFECT OF FOOD AND NUTRIENTS
AGE
ANUSHA NADIKATLA

5. ROUTES OF DRUG ADMINISTRATION
• The route of administration
(ROA) that is chosen has a large
impact on how fast the drug is
taken up and how much of it
arrives at its destination in an
active form.
• The route of administration is
determined by the physical
characteristics of the drug, the
speed at which the drug is
absorbed, as well as the need to
bypass hepatic metabolism and
achieve high conc. at particular
sites.
ROUTES WHICH
BYPASS
ABSORPTION
ROUTES
INVOLVING
ABSORPTION
Intra-cardiac Intra-dermal
Intra-arterial Subcutaneous
Intra-venous Intra-muscular
Intra-thecal Intra-peritoneal
Intra-ventricular
ANUSHA NADIKATLA

6. ORAL: Drug is taken orally.
Features: Absorption takes place along the whole length of GIT (i.e.
large surface area).
Absorption site: Gastrointestinal epithelia.
BUCCAL/SUBLINGUAL: Drug is placed in mouth or under the
tongue.
Features: Rapid absorption avoiding first-pass effect. Drugs which are
highly lipid-soluble and subject to high first-pass effect if swallowed are
given through this route (e.g. Nitroglycerine).
Absorption site: Buccal/Sublingual mucosa. ANUSHA NADIKATLA

7. INHALATION: The drug is inhaled and absorbed through the lungs.
Features: large surface area and rapid absorption.
Avoids first pass metabolism.
Volatile and gaseous drugs are given in this route.
Absorption site: Alveoli of lung.
INTRANASAL: drug is given into the nasal cavity.
Absorption site: Nasal membrane.
RECTAL: Drug is given into rectum e.g. suppositories.
Feature: absorption process avoids first-pass metabolism.
Absorption site: epithelia of rectal wall.
ANUSHA NADIKATLA

8. PARENTERAL ROUTES
Biotechnology-derived drugs (e.g. insulin, erythropoietin, somatotropin)
are given through parenteral route because they are too labile in GIT to
be given orally.
Intravenous (IV): placing a drug directly into the blood stream.
Features: no absorption required, 100% bioavailable, rapid onset of
action.
Intramuscular (IM): drug injected into skeletal muscle; absorption is
faster then SC but slower than IV.
Absorption site: Striated muscle fiber.
Subcutaneous (SC): Absorption of drugs from the subcutaneous
tissues.
Absorption site: Subcutaneous tissue.
ANUSHA NADIKATLA

9. No single method of drug administration is ideal for all drugs in all
circumstances.
The oral route is the most popular route of administration of drugs
because of its:
Large surface area for absorption.
Compartments with different pH that accommodate the drugs of
different solubility.
Convenient, easy and efficient route compared to other routes.
ANUSHA NADIKATLA

10. ROUTE BIOAVAILABILITY ADVANTAGES DISADVANTAGES
PARENTRAL
INTRAVENOUS
(IV)
Complete(100%)
systemic drug
absorption.
• Drug is given for
immediate or
controlled effect.
• Can inject large fluid
volumes.
• Suitable for irritating
drugs.
• Increased chance for
adverse reactions
• Possible anaphylaxis.
• Requires skill in insertion
of infusion set.
• Tissue damage at site of
injection.
INTRAMUSCUL
AR INJECTION
(IM)
Rapid absorption from
aqueous solutions.
Slow absorption from
non aqueous (oily)
solutions.
• Easier to inject than
intravenous injection.
• Larger volumes may
be used compared to
subcutaneous
solutions.
• Irritating drugs may be
very painful.
• Variable rates of
absorption depending
upon muscle group
injected and blood flow.
SUBCUTANEOU
S INJECTION
(SC)
Rapid absorption from
aqueous solutions.
Slow absorption from
depot formulations.
• Generally used for
vaccines and drugs
not absorbed orally.
• Eg:insulin
• Rate of drug absorption
depends upon blood flow
and injection volume.
ANUSHA NADIKATLA

11. ROUTE BIOAVAILABILITY ADVANTAGES DISADVANTAGES
ENTERAL ROUTES
BUCCAL OR
SUBLINGUAL
(SL)
Rapid absorption of
lipid soluble drugs.
No presystemic
metabolism.
Some drug may be
swallowed .Not for most
drugs or drugs with high
doses.
ORAL
(PO)
Absorption may vary.
Generally slower
absorption rate
compared to IV bolus
or IM injection.
Safest and easiest route
of drug administration.
Suitable for both
immediate realese and
modified release drug
products.
Some drugs are unstable in
Git,or undergo presystemic
metabolism or show erratic
absorption.
RECTAL
(PR)
Absorption may
vary.generally slower
absorption rate to IV
bolus or IM injection.
Useful when patient
cannot swallow
medication.
Used for local and
systemic effects.
Absorption may be
erratic.Suppository may
migrate to different
position.
Some patient discomfort.
ANUSHA NADIKATLA

12. ROUTE BIOAVAILABILITY ADVANTAGES DISADVANTAGES
OTHER ROUTES
TRANSDERM
AL
Slow
Absorption rate may
vary.
Increased
absorption with
occlusive dressings.
Transdermal delivery
system is very easy to use
and withdraw.
Continuous release for a
specified period.
Used for lipid soluble
drugs with low dose and
low MW.
Some irritation by patch or
drug.
Permeability of skin
variable with
condition,anatomic site,age
and gender.
Type of cream or ointment
base affects drug realease
and absorption.
INHALATION
Rapid absorption.
Total dose absorbed
is variable
May be used for local or
systemic effects.
Particle size of drug
determines anatomic
placement in respiratory
tract
Some drug may be
swallowed.ANUSHA NADIKATLA

13. MEMBRANE PHYSIOLOGY
NATURE OF CELL MEMBRANES
CELL MEMBRANES
The cell membrane also known as
the plasma
membrane or cytoplasmic
membrane is a biological membrane
that separates the interior of all cells
from the outside environment.
The characteristic feature of cell
membranes is that it allows only
certain substances to pass through.
Cell membranes can be artificially
reassembled.
ANUSHA NADIKATLA

14. STRUCTURE OF CELL MEMBRANES
The cell membrane is made up of two layers and these layers are composed
of phospholipids.
The bilayer is formed by the arrangement of phospholipids in a manner that
their head regions (which are hydrophilic) face external environment as well
the internal cytosolic environment.
The (hydrophobic) tails of these phospholipids face each other. This peculiar
arrangement of hydrophilic and hydrophobic layers doesn't allow nucleic
acids, amino acids, proteins carbohydrates and ions to pass through the
bilayer.
ANUSHA NADIKATLA

15. For a drug to be absorbed and distributed into organs and tissues and
eliminated from the body, it must pass through one or more biological
membranes/barriers at various locations, such a movement of drug
across the membrane is called as DRUG TRANSPORT.
The cellular membrane consist of a double layer of amphiphillic
phospholipid molecules arranged in such a fashion that their
hydrocarbon chains are oriented inwards to form a hydrophobic or
lipophillic phase and their polar heads oriented to form the outer and
inner hydrophillic boundaries of the cellular membrane that face the
sorrounding aqueous environment.
Globular protien molecules are associated on either side of these
hydrophillic boundaries and also interpersed within the membrane
structure.
The hydrophobic core of the membrane is responsible for the relative
impermeability of polar molecules.
Aqueous filled pores or perforations of 4to10A in diameter are also
present in the membrane structure through which inorganic ions and
small organic water soluble molecules like urea can pass.
ANUSHA NADIKATLA

16. In general biomembranes acts like a semipermeable barrier permitting
rapid and limited passage of some compounds while restricting that of
others.
The GI lining constituting the absorption barrier allows most nutrients
like glucose, amino acids, fattyacids, vitamins etc.,to pass rapidly into the
systemic circulation but prevents the entry of certain toxins and
medicaments. Thus for a drug to get absorbed after oral administration, it
must first pass through this biological barrier.
FUNCTIONS OF CELL MEMBRANES
Basic function of cell membrane is to protect cell from its surroundings.
These are involved in a variety of cellular processes such as cell
adhesion, Ion conductivity and cell signaling.
It retains the contents of the cell and acts as a permeability barrier.
It allows only certain substances to enter or leave the cell and the rate of
entry is strictly controlled.
Provide anchoring sites for filaments.
Provide a binding site for enzymes. ANUSHA NADIKATLA

17. MACROMOLECULES FOUND IN CELL MEMBRANES
Lipids
Phospholipid bilayer
Cholesterol
Proteins
Integral proteins
peripheral proteins
Recognition proteins
Carbohydrates
Oligosaccharides on glycoproteins
ANUSHA NADIKATLA

18. FUNCTIONS OF MEMBRANE MACROMOLECULES
LIPID
Phospholipid bilayer
Forms boundary to isolate cell contents from environment.
Restricts passage of hydrophilic substances across the membrane.
Cholesterol
Increases bilayer strength, flexibility.
Reduces membrane fluidity.
Reduces permeability to water-soluble substances.
PROTEINS
Transport proteins
Regulate movement of water soluble substances.
Channel proteins have pores that allow passage of ions and small
water-soluble molecules.
Carrier proteins bind to molecules and change shape for delivery
across membrane. ANUSHA NADIKATLA

19. PHOSPHOLIPID BILAYER
Phospholipids are the most abundant lipid in the plasma membrane.
Phospholipids are amphiphilic molecules, containing hydrophobic and
hydrophilic regions.
The fluid mosaic model states that a membrane is a fluid structure
with a “mosaic” of various proteins embedded in it.
ANUSHA NADIKATLA

20. Phospholipids are compounds of
glycerol(propane-1,2,3-triol)in which
two of the alcohol groups joined to fatty
acids, and the third to phosphoric acid.
The resultant molecule has two oily
tails, usually of 12-24 carbon atoms and
hydrophilic regions around the charged
phosphate esters, called the head group.
Common head group molecules are
choline, ethanolamine, serine and
inositol and resulting phospholipids are
termed as phosphatidylcholine and
phosphatidylserine respectively.
Bilayer exists as a sheet in which the
hydrophobic regions of phospholipids
are protected from the aqueous
environment, while hydrophilic regions
are immersed in water
ANUSHA NADIKATLA

21. DYNAMIC BEHAVIOUR OF MEMBRANES
The most important factor in determining the dynamic behaviour of
the membrane is the transistion temperature of the bilayer.
The transistion is often thought as a gel-liquid melting of the bilayer
and in fluid state the lipid molecule mobile to lateral diffusion.
They diffuse at a speed of several microns a second.
As the temperature is raised, little movements takes place until the
transition temperature is reached.
ANUSHA NADIKATLA

22. The most important dynamic process are:
LATERAL DIFFUSION
TRANSVERSE DIFFUSION(OR)FLIP-FOP
The transistion temperature mainly depends on:
Structure of fatty acid chains attached to glycerol backbone.
Unsaturated chains causing low transistion temperature (below 0⁰c).
Saturated chains having high transistion temperature.
LATERAL
ANUSHA NADIKATLA

23. MEMBRANE MODULATION OF FLUIDITY MODELS BY PROTEINS
Cell membrane fluidity can be regulated by altering the phospholipid
fattyacid content.
Some proteins in the plasma membrane can drift within the bilayer.
Proteins are much larger than lipids and move more slowly.
The temperature at which a membrane solidifies depends on the types of
lipids.
Membranes rich in unsaturated fatty acids are more fluid than those rich in
saturated fatty acids.
Membranes must be fluid to work properly; they are usually about, as fluid
as salad oil.
ANUSHA NADIKATLA

24. MODULATION OF MEMBRANE FLUIDITY BY
STEROLS
The steroid cholesterol has different effects on membrane fluidity at
different temperatures.
At warm temperatures (such as 37°C), cholesterol restrains movement
of phospholipids.
At cool temperatures, it maintains fluidity by preventing tight
packing.
In the absence of sterols the bilayer melts over a small temperature
range causing the sharp peak.
In the presence of cholesterol the melting transistion is much boarder
ANUSHA NADIKATLA

25. EPITHELIA
All internal and external body surfaces are covered with epithelium.
Epithelial cells are said to be polarized due to the asymmetric
distribution of transport proteins on the opposite ends of their plasma
membrane.
TYPES OF EPITHELIA:
SIMPLE SQUAMOUS EPITHELIUM
SIMPLE COLUMNAR EPITHELIUM
TRANSITIONAL EPITHELIUM
STRATIFIED SQUAMOUS EPITHELIUM
ANUSHA NADIKATLA

26. SIMPLE SQUAMOUS EPITHELIUM
This forms a thin layer of flattened cells and it is permeable. This type of
epithelium lines in most of blood vessels
SIMPLE COLUMNAR EPITHELIUM
A single layer of columnar cells is found in the epithelium of organs such
as stomach and small intestine
TRANSITIONAL EPITHELIUM
This is composed of several layers of cells of different shapes and it
lines epithelia which are required to stretch
STRATIFIED SQUAMOUS EPITHELIUM
These membranes are several cells thick. In the skin the outer cells
become filled with keratin and is termed as keratinized. It provides a
major permeability barrier as well as protection from the environment
ANUSHA NADIKATLA

27. TRANSPORT ACROSS CELL MEMBRANES
Many drugs need to pass through one or more cell membranes to
reach their site of action.
There are a number of possible mechanisms for transport across
membranes.
Substances may simply diffuse across , or be carried by a range of
more selective processes ,depending on the substance involved.
Illustration of Different Transport Mechanisms
ANUSHA NADIKATLA

28. PRINCIPLE MECHANISMS OF TRANSPORT OF
DRUG MOLECULES ACROSS THE CELL
MEMBRANE
1. PASSIVE DIFFUSION
2. CARRIER MEDIATED TRANSPORT
A) Active transport
B) Facilitated transport
3. VESICULAR TRANSPORT
A) Pinocytosis
B) Phagocytosis
4. PORE TRANSPORT
5. ION PAIR FORMATION
ANUSHA NADIKATLA

29. PASSIVE DIFFUSION
Most (many) drugs cross biologic membranes by passive diffusion.
Passive diffusion is the process by which molecules spontaneously
diffuse from a region of higher concentration to a region of lower
concentration.
Drug diffuses across the membrane in an attempt to equalize the drug
concentration on both sides of the membrane.
This process is passive because no external energy is expended.
ANUSHA NADIKATLA

30. ANUSHA NADIKATLA

31. If the drug partitions into the lipid membrane a
concentration gradient can be established.
Lipophilic drug may pass through the cell or go around it.
If the drug has a low molecular weight and is lipophilic, the
lipid cell membrane is not a barrier to drug diffusion and
absorption.
The unionized form of a drug is lipid-soluble and diffuses
easily by dissolution in the lipid bilayer.
ANUSHA NADIKATLA

32. Diagram of passive transport with a concentration gradient
FICK'S FIRST LAW, RATE OF DIFFUSION: The rate of transport of
drug across the membrane can be described by Fick's first law of
diffusion:-
ANUSHA NADIKATLA

33. The parameters of this equation are:-
D: diffusion coefficient. This parameter is related to the size and lipid
solubility of the drug and the viscosity of the diffusion medium, the
membrane. As lipid solubility increases or molecular size decreases then
D increases and thus dM/dt also increases.
A: surface area. As the surface area increases the rate of diffusion also
increase. The surface of the intestinal lining (with villae and microvillae)
is much larger than the stomach. This is one reason absorption is
generally faster from the intestine compared with absorption from the
stomach.
x: membrane thickness. The smaller the membrane thickness the quicker
the diffusion process. As one example, the membrane in the lung is quite
thin thus inhalation absorption can be quite rapid.
(Ch -Cl): concentration difference. Since V, the apparent volume of
distribution, is at least four liters and often much higher the drug
concentration in blood or plasma will be quite low compared with the
concentration in the GI tract. It is this concentration gradient which
allows the rapid complete absorption of many drug substances.
ANUSHA NADIKATLA

34. Normally Cl << Ch then
Thus the absorption of many drugs from the G-I tract can often appear to
be first-order.
ANUSHA NADIKATLA

35. pH PARTITION THEORY
It explains about the passage of the drug molecules through biological
membranes, it states that the process of absorption is governed by :
The dissociation constant (pKa) of the drug.
The lipid solubility of the unionized drug.
The pH at the absorption site.
For weak acids: pH = pka + log (ionized) / (unionized)
For weak bases: pH = pka + log (unionized) / (ionized)
A perfect hydrophilic-lipophilic balance should be there in the
structure of the drug for optimum bioavailability. ANUSHA NADIKATLA

36. LIMITATIONS OF pH PARTITION THEORY
Presence of virtual membrane pH.
Absorption of ionized drugs.
Influence of GI surface area and residence time of drug.
Presence of aqueous unstirred diffusion layer.
Hence modified pH partition theory came in to existence.
ANUSHA NADIKATLA

37. CARRIER MEDIATED TRANSPORT
Some polar molecules cross the membrane more readily than can be
predicted from their concentration gradient and partition coefficient
values.
This suggests the presence of some specialized transport mechanisms
without which many essential water-soluble nutrients like
monosaccharides, amino acids and vitamins will be poorly absorbed.
The mechanism is thought to involve a component of the membrane
called as the carrier that binds reversibly or noncovalently with the
solute molecules to be transported.
In the intestine, drugs and other molecules can go through the
intestinal epithelial cells by either diffusion or a carrier-mediated
mechanism.
Numerous specialized carrier-mediated transport systems are present
in the body, especially in the intestine for the absorption of ions and
nutrients required by the body. ANUSHA NADIKATLA

38. Carrier-Mediated
Transport Process
Characteristics of Carrier
Mediated Transport
ANUSHA NADIKATLA

39. ACTIVE TRANSPORT
Active transport is a carrier-mediated transmembrane process that
plays an important role in the gastrointestinal absorption and in renal
and biliary secretion of many drugs and metabolites.
Active transport moves substances against their concentration
gradient.
The drug is transported from a region of lower concentration to a
region of higher concentration.
Active transport requires energy, usually in the form of ATP.
In addition, active transport is a specialized process requiring a carrier
that binds the drug to form a carrier–drug complex that shuttles the
drug across the membrane and then dissociates the drug on the other
side of the membrane.
ANUSHA NADIKATLA

40. Active transport is performed by specific proteins embedded in the
membranes.
The fixed number of active transport binding sites may be subject to
competition or saturation.
Energy can be supplied either directly to the ion pump, or indirectly
by coupling pump-action to an ionic gradient that is actively
maintained.
The sodium-potassium pump is one type of active transport system
The body has a number of specialized mechanisms for transporting
particular compounds; for example, glucose and amino acids.
Endogeneous substances that are transported actively include Sodium
(Na+), potassium (K+), calcium (Ca++), iron (Fe++) in ionic state;
certain amino acids and vitamins like niacin, pyridoxine and ascorbic
acid.
A few lipid-insoluble drugs that resemble natural physiologic
metabolites (such as 5-fluorouracil) are absorbed from the
gastrointestinal tract by this process. ANUSHA NADIKATLA

41. ANUSHA NADIKATLA

42. FACILITATED DIFFUSION
Facilitated diffusion is also a carrier mediated transport system but it
moves along a concentration gradient (i.e from higher to lower
concentration) and hence it does not require any energy.
e.g. vitamin B12 transport.
ANUSHA NADIKATLA

43. Acetylcholine (ligand) binds to certain synaptic membrane and opens
Na+ channels and initiate a nerve impulse.
Gamma amino butyric acid (GABA) binds to GABAA receptors and
the chloride channel opens.
This inhibits the creation of a nerve impulse.
ANUSHA NADIKATLA

44. P-GLYCOPROTEIN
P-glycoprotein transporters (PGP, MDR-1) are present throughout the
body including liver, brain, kidney and the intestinal tract epithelia.
They appear to be an important component of drug absorption acting
as reverse pumps generally inhibiting absorption.
This is an active, ATP-dependent process which can have a significant
effect on drug bioavailability.
P-glycoprotein works against a range of drugs (250 - 1850 Dalton)
such as cyclosporin A, digoxin, β-blockers, antibiotics and others.
This process has been described as multi-drug resistance (MDR).
Additionally P-glycoprotein has many substrates in common with
cytochrome P450 3A4 (CYP 3A4) thus it appears that this system not
only transports drug into the lumen but causes the metabolism of
substantial amounts of the drug as well (e.g. cyclosporin).
ANUSHA NADIKATLA

45. Clinically significant substrates of PGP include digoxin, cyclosporine,
fexofenadine, paclitaxel, tracrolimus, nortriptyline and phenytoin.
A number of compounds can act as PGP inhibitors including
atorvastatin (digoxin AUC increased), cyclosporine (increased
paclitaxel absorption), grapefruit juice (increased paclitaxel
absorption) and verapamil.
Rifampin and St. John's wort have been reported to induce PGP
expression.
The distribution of PGP polymorphism varies by race.
The 'normal' 3435C allele is found in 61% African American and 26%
in European American.
The clinically important 3435T polymorph is found in 13% of African
American and 62% of European American.
The 3435T allele has been associated with reduced PGP expression
(concentration) and consequently higher absorption.
Digoxin levels were higher in healthy subjects with the 3435T allele
compared with results in subjects with the 3435C allele. ANUSHA
NADIKATLA

46. VESICULAR TRANSPORT
 Vesicular transport is an
example of exocytosis is the
transport of a protein such as
insulin from insulin-producing
cells of the pancreas into the
extracellular space.
 The insulin molecules are first
packaged into intracellular
vesicles, which then fuse with
the plasma membrane to
release the insulin outside the
cell.
ANUSHA NADIKATLA

47. Vesicular transport is the process of engulfing particles or dissolved
materials by the cell.
a) Pinocytosis
b) Phagocytosis
Larger particles are not able to move through membranes or interstitial
spaces so other processes must be available.
These processes involve the entrapment of larger particles by the cell
membrane and incorporation into the cell, cytosis.
Vesicular transport is the proposed process for the absorption of orally
administered Sabin polio vaccine and large proteins.
Transport of proteins, polypeptides like insulin from insulin producing
cells of the pancreas into the extracellular space.
Active process for movement of large molecules and organisms.
Substance is taken in by vesicle formed from cell membrane
ANUSHA NADIKATLA

48. PINOCYTOSIS
Liquid droplets in vesicle
A spontaneous incorporation of a small amount of extracellular fluid
with solutes is called pinocytosis.
ANUSHA NADIKATLA

49. PHAGOCYTOSIS
Solid substance in vesicle.
Phagocytosis is a process involving the incorporation of larger
particles.
Examples include Vitamin A, D, E, and K, peptides in newborn.
ANUSHA NADIKATLA

50. PORE TRANSPORT
Very small molecules (such as urea, water, and sugars) are able to
rapidly cross cell membranes as if the membrane contains channels or
pores.
Although such pores have never been directly observed by
microscopy, the model of drug permeation through aqueous pores is
used to explain renal excretion of drugs and the uptake of drugs into
the liver.
Small drug molecules move through this channel by diffusion more
rapidly than at other parts of the membrane.
A certain type of protein called transport protein may form an open
channel across the lipid membrane of cell.
ANUSHA NADIKATLA

51. ANUSHA NADIKATLA

52. ION PAIR FORMATION
Strong electrolyte drugs are highly ionized or charged molecules, such
as quaternary nitrogen compounds with extreme pKa values.
Strong electrolyte drugs maintain their charge at all physiologic pH
values and penetrate membranes poorly.
When the ionized drug is linked up with an oppositely charged ion, an
ion pair is formed in which the overall charge of the pair is neutral.
This neutral drug complex diffuses more easily across the membrane.
For example, the formation of ion pairs to facilitate drug absorption
has been demonstrated for propranolol, a basic drug that forms an ion
pair with oleic acid, and quinine, which forms ion pair with
hexylsalicylate.
ANUSHA NADIKATLA

53. ANUSHA NADIKATLA

54. GSTERO-INTESTINAL PHYSIOLOGY
GASTRIC EMPTYING RATE
INTESTINAL MOTILITY
DRUG STABILITY IN GIT
pH AND SURFACE AREA OF GIT
INTESTINAL TRANSIT
SPLANCHNIC BLOOD FLOW
EFFECT OF FOOD AND NUTRIENTS
a
c
b
d
f
e
g
ANUSHA NADIKATLA

55. CHARACTERISTICS OF GI PHYSIOLOGY AND
DRUG ABSORPTION
ORGANS PH MEMBRANE
BLOOD
SUPPLY
SURFAC
E AREA
TRANSIT
TIME
BUCCAL approx 6 thin
Good, fast
absorption
with low
dose
small
Short unless
controlled
ESOPHAGUS 6-7
Very thick
no absorption
- small
short, typically a
few seconds,
except for some
coated tablets
ANUSHA NADIKATLA

56. STOMACH
1.7-4.5
decomposition
, weak acid
unionized
normal good small
30 min (liquid) -
120 min (solid
food), delayed
stomach emptying
can reduce
intestinal
absorption
no
DUODENUM
5 - 7
bile duct,
surfactant
properties
normal good very large
very short (6"
long), window
effect
no
SMALL
INTESTINE
6 -7 normal good
very large 10
- 14 ft, 80 cm
2 /cm
about 3 hours no
LARGE
INTESTINE
6.8 – 7 - good
not very large
4 - 5 ft
long, up to 24 hr
lower
colon,
rectum
yesANUSHA NADIKATLA

57. GASTRIC EMPTYING AND MOTILITY
Rapid gastric emptying increases bioavailability of a drug.
For better dissolution and absorption, gastric emptying can be
promoted by taking the drug on empty stomach.
Generally drugs are better absorbed in the small intestine (because of
the larger surface area) than in the stomach, therefore quicker stomach
emptying will increase drug absorption.
For example, a good correlation has been found between stomach
emptying time and peak plasma concentration for acetaminophen.
The quicker the stomach emptying (shorter stomach emptying time)
the higher the plasma concentration.
Also slower stomach emptying can cause increased degradation of
drugs in the stomach's lower pH; e.g. L-dopa.
ANUSHA NADIKATLA

58. Several parameters are used to quantify gastric emptying such
as:
GASTRIC
EMPTYING
RATE
GASTRIC
EMPTYING
TIME
GASTRIC
EMPTYING
HALF-LIFE
ANUSHA NADIKATLA

59. GASTRIC EMPTYING RATE
Gastric emptying rate is the speed at which the stomach contents
empty into the intestine.
Anatomically, a swallowed drug rapidly reaches the stomach.
Eventually, the stomach empties its contents into the small intestine.
Because the duodenum has the greatest capacity for the absorption of
drugs from the GI tract, a delay in the gastric emptying time for the
drug to reach the duodenum will slow the rate and possibly the extent
of drug absorption, thereby prolonging the onset time for the drug.
Some drugs, such as penicillin, are unstable in acid and decompose if
stomach emptying is delayed.
Other drugs, such as aspirin, may irritate the gastric mucosa during
prolonged contact.
Gastric emptying rate is faster in case of solution & suspensions than
solid & non-disintegrating dosage forms.
ANUSHA NADIKATLA

60. GASTRIC EMPTYING TIME
Gastric emptying time which is the time required for the gastric
contents reach the Small intestine.
The time taken for stomach contents to be passed into the duodenum
influenced by gastric motility, activity of pyloric sphincter etc.
If acidic drugs remain for long time into stomach, they get absorbed at
a faster rate.
And if basic drug remains for a short time in stomach and being more
time in small intestine, they get easily absorbed.
For acidic drug gastric emptying time should be more and for basic
drug less.
Example: penicillin is unstable in acid and decomposes if stomach
emptying is delayed.
Other drugs, such as aspirin, may irritate the gastric mucosa during
prolonged contact. ANUSHA NADIKATLA

61. GASTRIC EMPTYING HALF-LIFE
Gastric emptying half-
life is the time taken for
half the stomach
contents to empty.
Dependence of peak
acetaminophen plasma
concentration as a
function of stomach
emptying half-life
ANUSHA NADIKATLA

62. FACTORS INFLUENCING GASTRIC EMPTYING
Gastric Emptying volume :
The larger the starting volume, the greater the initial rate of emptying,
after this initial period, the larger the original volume, the slower the rate
of emptying.
Type of meal:
Reduction in rate of emptying to an extent directly dependent upon
concentration of carbohydrate, lipid and protein type food.
Osmotic pressure:
Reduction in rate of emptying to an extent dependent upon concentration
for salts and nonelectrolytes.
Physical state of gastric contents:
Solutions or suspensions of small particles empty more rapidly.
ANUSHA NADIKATLA

63. Body position:
Rate of emptying is reduced in a patient lying on left side.
Viscosity:
Rate of emptying is greater for viscous solutions.
Emotional states:
Aggressive or stressful emotional states increase stomach contractions
and emptying rate; depression reduces stomach contraction and
emptying.
Disease states:
Rate of emptying is reduced in some diabetics and in patients with local
pyloric lesions and hypothyroidism; gastric emptying rate is increased in
hyperthyroidism.
Drugs:
Anticholinergics, narcotic analgesics etc., decrease emptying.
ANUSHA NADIKATLA

64. FACTORS AFFECTING GASTRIC EMPTYING
VOLUME OF
INGESTED MATERIAL
As volume increases initially an increase then a decrease.
Bulky material tends to empty more slowly than liquids.
TYPE OF MEAL Fatty food Decrease
Carbohydrate Decrease
TEMPERATURE OF
FOOD
Increase in temperature, increase in emptying rate
BODY POSITION
Lying on the left side decreases emptying rate.
Standing versus lying (delayed)
DRUGS
Anticholinergics (e.g. atropine), Narcotic (e.g.
morphine, alfentanil), Analgesic (e.g. aspirin)
Decrease
Metoclopramide, Domperidone, Erythromycin,
Bethanchol.
Increase
ANUSHA NADIKATLA

65. GASTROINTESTINAL MOTILITY
It tends to move the drug through the alimentary canal. This movement helps
drug particle to come in contact with mucosa and get absorbed. The excessively
rapid movement of GIT impairs absorption.
Gastrointestinal Motility Disorders
• Achalasia
• Gastroesophageal Reflux Disease (GERD)
• Functional chest pain
• Gastroparesis / Delayed gastric emptying
• Rapid gastric emptying
• Idiopathic vomiting / Cyclic vomiting syndrome
• Functional dyspepsia
• Constipation
• Diarrhoea
• Irritable bowel syndrome
• Faecal incontinence ANUSHA NADIKATLA

66. INTESTINAL MOTILITY
Normal peristaltic movements mix the contents of the duodenum,
bringing the drug particles into intimate contact with the intestinal
mucosal cells.
The drug must have a sufficient time (residence time) at the absorption
site for optimum absorption.
In the case of high motility in the intestinal tract, as in diarrhea, the
drug has a very brief residence time and less opportunity for adequate
absorption.
It mix the contents of the duodenum, bringing them into intimate
contact with the mucosal cells.
The drug must have a sufficient time at the absorption site for
optimum absorption.
In case of high motility(e.g diarrhea) the drug has a very brief
residence time and less opportunity for adequate absorption.
ANUSHA NADIKATLA

67. a. Physical activity
b. Food
c. Emotional condition
d. Age, gender
e. Disease state,drug etc
Intestinal motility is very
important in absorption and
bioavalability of SRDFs, enteric
coated dosage forms and drugs
which are absorbed by carrier
mediated transport systems of
small intestine.
Intestinal pseudo-obstruction
Irritable bowel syndrome
Fecal incontinence
Constipation
FACTORS AFFECTING
INTESTINAL MOTILITY
INTESTINAL MOTILITY
DISORDERS
ANUSHA NADIKATLA

68. DRUG STABILITY IN GIT
Metabolism or degradation by enzymes or chemical hydrolysis may
adversely affect the drug absorption.
Destruction in gastric acid (e.g. penicillin).
Metabolism or degradation by enzymes or chemical hydrolysis may
adversely affect the drug absorption and thus reduces B.A.
Generally a problem with orally administered drugs.
ANUSHA NADIKATLA

69. pH AND SURFACE AREA OF GIT
GASTROINTESTINAL pH
The GI pH increases gradually from stomach to the colon and rectum.
The disintegration of some dosage forms is pH sensitive.
A large number of drugs are either weak acids or weak bases whose
solubility is affected by pH.
Weakly acidic drugs dissolve rapidly in the alkaline pH of the
intestine whereas basic drugs dissolve in the acidic pH of the stomach.
Depending upon the drug pKa and whether its an acidic or a basic
drug, the GI pH influences drug absorption by determining the
amount of drug that would exist in the un-ionised form at the site of
absorption.
ANUSHA NADIKATLA

70. ANUSHA NADIKATLA

71. GI fluid ph affects in several ways:
Disintegration: The Disintegration of some drugs is pH sensitive with
enteric coating the coat dissolves in only the intestine at specific PH.
Dissolution : A large no of drugs whose solubility is greatly affected by
pH are either weak acids or weak bases. Weakly acidic drugs dissolves
rapidly in alkaline pH of the intestine whereas basic drugs dissolve in the
acidic pH of the stomach.
Stability :GI pH also affect the chemical stability of drugs .
EX – the acidic stomach pH gives a degradation of penicillin G and
erythromycin. So such drugs to be formulated by preoaring prodrugs.
Ex - Carindacillin and erythromycin estolate or in any other way .
Depending upon the pKa and weather it is an acidic or basic drug the
amount of drug that would exist in the unionized form at site of
absorption. This was covered in pH partition hypothesis.
ANUSHA
NADIKATLA

72. ORAL CAVITY:
Saliva is the main secretion of the oral cavity.
pH 7.
Contains ptyalin which digests starch.
e.g fentanyl citrate, nitroglycerin etc (lipid soluble drug)
ESOPHAGUS:
It connects the pharynx and the cardiac orifice of stomach.
pH 5-6.
Very little drug dissolution occurs in it.
STOMACH:
Fasting pH 2-6.
pH in presence of food is 1.5-2.
Intrinsic factor enhances vitamin B-12 absorption & gastric enzymes initiate
digestion.
Basic drugs are solubilized rapidly in presence of acid.
pH may be increased due to certain drugs e.g. omeprazole.
Ethanol easily crosses cell membrane & efficiently absorbed from the
stomach.
e.g. ibuprofen, aspirin etc. absorbed here
ANUSHA NADIKATLA

73. INTESTINE:
pH 5-8.
Large area for drug absorption.
pH is optimum for enzymatic digestion of protein and peptide containing
food.
Hence protein type drug (e.g. insulin) can’t be administered orally.
The influence of absorptive surface area is much prominent than pH.
e.g. vitamin, diazepam, quinidine etc. absorb here.
COLON AND RECTUM:
pH 5.5-7
Colon promotes melting of oily drugs to form emulsion.
e.g. In crohn’s disease prednisolone, hydrocortisone for inflammatory bowel
disease.
Rectums pH is 7 and virtually has no buffer capacity.
Oral SRDF are well absorbed in colon (e.g. theophylline).
Suppositories are well absorbed in rectum.
ANUSHA NADIKATLA

74. IONIZATION OF DRUG
Acidic drugs are absorbed faster in acidic pH as they remain
unionized in acidic medium of stomach.
So they can be absorbed through lipidic cell membrane. e.g. aspirin,
ibuprofen.
Basic drugs are not absorbed well in acidic pH because they ionized
in acidic medium.
Basic drugs remain unionize in basic medium (small intestine) and
can be easily absorbed. e.g. codein.
Acidic drugs ionize in basic medium so can’t be absorbed. Highly
acidic or basic drug ionize at all pH hence poorly absorbed in GIT.
e.g. disodium cromogylate, guanethidine etc
ANUSHA NADIKATLA

75. INTESTINAL TRANSIT
Long intestinal transit time is desirable for complete absorption of
drug.
e.g. for enteric coated formulation & for drugs absorbed from specific
sites in the intestine.
Peristaltic contraction promotes drug absorption by increasing the
drug membrane contact and by enhancing dissolution especially of
poorly soluble drugs.
Influenced by food, disease and drugs.
EX- metoclopramide which promotes intestinal transit &thus enhance
absorption of rapidly soluble drugs while anticholinergic retards
intestinal transit and promotes the absorption of poorly soluble drugs.
ANUSHA NADIKATLA

76. Since, intestinal transit time is the major site of absorption of most of
drugs, long intestinal transit time is desirable for complete absorption
of drugs.
Transit time for contents from different regions of intestine
Intestinal transit time is influenced by various factors such as food,
diseases and drugs.
e.g. metoclopramide which promotes intestinal transit, enhance
absorption of rapidly soluble drugs.
While, anticholinergic retards intestinal transit and promotes the
absorption of poorly soluble drugs.
Intestinal region Transit time
Duodenum 5 minutes
Jejunum 2 hours
Ileum 3 to 6 hours
Caecum 0.5 to 1 hour
Colon 6 to 12 hours
ANUSHA NADIKATLA

77. SPLANCHNIC BLOOD FLOW
• The GIT is extensively supplied by blood capillary network and blood
flow rate to GIT (splanchnic circulation) is 28% of the cardiac output.
• Therefore, it helps in maintaining sink conditions and concentration
gradient for drug absorption by rapidly removing drug from the site of
action.
• The high perfusion rate of GIT ensures that once the drug has crossed
the membrane, It is rapidly removed from the absorption site thus
maintaining the sink conditions and concentration gradient for
continued drug absorption.
ANUSHA NADIKATLA

78. TABLE : INFLUENCE OF BLOOD FLOW EFFECT ON
VARIOUS TYPES OF DRUGS
DRUGS EFFECT ON BLOODFLOW
For highly lipid soluble drugs
More
For many lipophilic drugs
such as ethanol, glycerol, etc.
Intermediate
Polar compounds such as ribitol
Less
ANUSHA NADIKATLA

79. Some drugs are achieving higher plasma conc. after food, this is
because food increase splanchnic blood flow.
E.g. propranolol, chloramphenicol, lithium carbonate.
The absorption of some drugs is reduced due to presence of food (e.g
ampicillin, aspirin, L-dopa)
In hypovalemic state, the splanchnic blood flow is reduced. So
absorption of the drug is also decreased.
Once the drug is absorbed from the small intestine, it enters via the
mesenteric vessels to the hepatic-portal vein and the liver prior to
reaching the systemic circulation.
Any decrease in mesenteric blood flow, as in the case of congestive
heart failure, will decrease the rate of drug removal from the intestinal
tract, thereby reducing the rate of drug bioavailabilityANUSHA NADIKATLA

80. GIT has higher perfusion rate because it is extensively supplied by
blood capillary network.
Therefore help in maintaining sink conditions &concentration gradient
for drug absorption by rapidly removing the drug from site of action.
Blood flow is important for actively absorption of drugs.
Highly permeable drugs or drugs that absorbed through pores –GI
perfusion is rate limiting while the drugs with poor permeability GI
perfusion is not important.
Perfusion increases after meals & persist for few hours but absorption
is not affected.
ANUSHA NADIKATLA

81. GRAPH REPRESENTING THE ABSORPTION RATE OF
VARIOUS DRUGS AFFECTED BY INTESTINAL BLOOD FLOW.
ANUSHA NADIKATLA

82. EFFECT OF FOOD
Food can effect the rate of gastric emptying.
For example fatty food can slow gastric emptying and retard drug
absorption.
Generally the extent of absorption is not greatly reduced.
Occasionally absorption may be improved, for example, Griseofulvin
absorption is improved by the presence of fatty food.
Apparently the poorly soluble griseofulvin is dissolved in the fat and
then more readily absorbed.
The presence of food in the GI tract can affect the bioavailability of
the drug from an oral drug product.
Digested foods contain amino acids, fatty acids, and many nutrients
that may affect intestinal pH and solubility of drugs.
The effects of food are not always predictable and can have clinically
significant consequences.
ANUSHA NADIKATLA

83. The presence of food in the GI tract affects the bioavailability of
oral drugs. Some effects of food on the bioavailability of the oral drugs
include:
Delay in gastric emptying time.
Stimulation of bile flow.
Change in the pH of GI tract.
Increase in splanchnic blood flow.
Change in luminal metabolism of drug substances.
Physical/chemical interaction of metal with drug substances.
The nutrient and caloric contents of the meal, meal volume, meal
temperature etc., affect drug product transit time, luminal dissolution,
drug permeability and systemic availability. Thus it affects drug
absorption. Absorption of some antibiotics decreases when administered
with food (e.g. penicillin, tetracycline)
ANUSHA NADIKATLA

84. Absorption of some lipid soluble drugs increases when administered
with food. e.g.: metazalone. The presence of food in the GI lumen
stimulates the flow of bile which increases the solubility of fat soluble
drugs by forming micelle. The presence of food in the stomach lowers
the pH which causes rapid dissolution and absorption of basic drugs
with limited aqueous solubility. e.g.: cinnarizine.
Drugs irritating to GI mucosa (e.g.: erythromycin, aspirin, NSAIDs
etc.) given with food to reduce the irritation by decreasing the rate of
drug absorption. In the presence of food, enteric coated and non
disintegrating drug products can not reach the duodenum rapidly, thus
they delay drug release & systemic drug absorption.
Food can also affect the integrity of dosage form which causes an
alteration in the release rate of the drug. e.g. theophylline. Timing of
drug administration is important as taking a medication either 1hr
before or 2hrs after meals, avoid any delay in drug absorption.
ANUSHA NADIKATLA

85. Effect of Fasting versus Fed on Propranolol
Concentrations
Propranolol plasma concentrations are larger after food than in
fasted subjects. This may be an interaction with components of the
food.
ANUSHA NADIKATLA

86. 1) FOOD- DRUG INTERACTIONS :
presence of food will affect absorption in following way
a) Delay absorption: ex. Aspirin, paracetamol, diclofenac ,
nitrofurantoin , digoxin etc.
b) Decreased absorption: ex. Penicillin, erythromycin, ethanol,
tetracycline, levodopa etc.
c) Increased absorption: grieseofulvin, diazepam, vitamins etc.
in some cases it do not affect. ex. methyldopa, propylthiouracil etc.
The absorption of some antibiotics, such as penicillin and tetracycline, is
decreased with food; whereas other drugs, particularly lipid-soluble
drugs such as griseofulvin and metazalone, are better absorbed when
given with food containing a high fat content. ANUSHA NADIKATLA

87. 2) FLUID VOLUME:
Administration of a drug with large fluid volume results in better
dissolution, rapid gastric emptying and enhanced absorption, for ex.
erythromycin is better absorbed when taken with a glass of water under
fasting condition than when taken with meals.
3) INTERACTION OF DRUG WITH NORMAL GI
CONSTITUENTS:
The GIT contains a number of normal constituents such as mucin–which
is a protective mucopolysaccharides that lines the GI mucosa, interact
with streptomycin. Bile salts which affect the absorption of lipid soluble
drugs like grieseofulvin and vitamins.
4) DRUG-DRUG INTERACTIONS:
They can either be physiological or physiochemical.
ANUSHA NADIKATLA

88. EFFECT OF NUTRIENTS ON DRUG
ABSORPTION
Absorption of water soluble vitamins (e.g. B- 12, folic acid) in the
stomach are facilitated by forming complex with intrinsic factors.
Absorption of calcium in the duodenum is facilitated by vita-D by
increasing calcium binding protein which binds calcium in the
intestinal cell & transfer it to the blood circulation.
Grape juice contains various flavonoids e.g. naringin which inhibits
cytochrome P-450 enzymes. Thus it inhibits absorption of some drugs.
ANUSHA NADIKATLA

89. AGE
In infants, the gastric pH is high and intestinal surface and blood flow
to the GIT is low resulting in altered absorption pattern in comparison
to adults.
In elderly persons, causes of impaired drug absorption include altered
gastric emptying, decreased intestinal surface area and GI blood flow,
higher incidents of achlorhydria and bacterial over growth in small
intestine.
ANUSHA NADIKATLA

90. REFERENCE
1. Brahmankar D.M., Jaiswal S.B., First edition, “Absorption
of Drugs” Biopharmaceutics and Pharmacokinetics – A
treatise, Vallabh Prakashan, Delhi 1995, Page No. 5-75.
2. Shargel L., Andrew B.C., Fourth edition “Physiologic
factors related to drug absorption” Applied
Biopharmaceutics and Pharmacokinetics, Prentice Hall
International, INC., Stanford 1999. Page No. 99-128.
3. Pharmaceutics , the Science of Dosage form Design By
M.E. Aulton.
4. Swarbrick J., Boylan J.C., “Absorption” Encyclopedia of
Pharmaceutical Technology, Marcel Dekker, INC., New
York 1988:1:1-32.
ANUSHA NADIKATLA