absorbtion of drugs 2

1. ABSORPTION OF DRUGS
II
1
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2. Diagram Representing Absorption, Distribution, Metabolism and
Excretion
The ultimate goal is to have the drug reach the site of action in
a concentration which produces a pharmacological effect.
No matter how the drug is given (other than IV) it must pass
through a number of biological membranes before it reaches the
site of action.
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3. MOVEMENT OF SUBSTANCES ACROSS
CELL MEMBRANES
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4. Factors influencing Drug Absorption and
Bioavailability
1. PHARMACEUTICAL FACTORS
- a. Physicochemical Properties of drug substance
- b. Dosage form characteristics & Phr Ingredients
• PATIENT RELATED FACTORS
- a. Biological factors
- b. Physiological factors
- c. Pathological factors
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5. BIOLOGICAL FACTORS:
 Penetration Of Drugs Through Gastro-intestinal Tract
 Penetration Of Drugs Through Blood Brain Barrier
 Penetration Of Drugs Through Placental Barrier
 Penetration Of Drugs Through Across The Skin
 Penetration Of Drugs Through The Mucous Membrane Of The Nose,
Throat, Trachea, Buccal Cavity, Lungs ,Vaginal And Rectal Surfaces
PHYSIOLOGICAL FACTORS:
 Age
 Gastrointestinal (GI) Physiology
 Influence Of Drug Pka And GI pH On Drug Absorption
 GIT Blood Flow
 Gastric Emptying
 Intestinal transit time
 Disease States
 Gastrointestinal content
 Presystemic metabolism
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6. PENETRATION OF DRUGS THROUGH
GASTRO-INTESTINAL TRACT
The GIT barrier that separates the lumen of the stomach and intestine
from systemic circulation and is composed of lipids, proteins and
polysaccharides.
GIT mucosa is a semi permeable membrane across which various
nutrients like Carbohydrates, Amino acids, Vitamins and foreign
substances are transported and absorbed into the blood by various
mechanisms like:
1. Passive diffusion
2. Pore transport
3. Facilitated transport
4. Active transport
5. Pinocytosis
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7. 1. PASSIVE DIFFUSION
• Major process for absorption of more than 90% of drugs
• Diffusion follows Fick’s law:
– The drug molecules diffuse from a region of higher
concentration to a region of lower concentration till
equilibrium is attained.
– Rate of diffusion is directly proportional to the
concentration gradient across the membrane.
• Factors affecting Passive diffusion:
– Diffusion coefficient of the drug
• Related to lipid solubility and molecular wt.
– Thickness and surface area of the membrane
– Size of the molecule
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9. 2. PORE TRANSPORT
• It involves the passage of ions through Aq. Pores (4-40 A0)
• Low molecular weight molecules (less than 100 Daltons) e.g.
urea, water, sugar are absorbed.
• Also imp. In renal excretion, removal of drug from CSF and
entry of drugs into liver.
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10. 3. FACILITATED DIFFUSION
• Carrier mediated transport (downhill transport)
• Faster than passive diffusion
• No energy expenditure is involved
• Not inhibited by metabolic poisons
• Important in transport of Polar molecules and charged ions
that dissolve in water but they can not diffuse freely across
cell membranes due to the hydrophobic nature of the
phospholipids.
Eg. 1. entry of glucose into RBCs
2. intestinal absorption vitamin B1 ,B2
3. transport of amino acids through permeases
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3. FACILITATED DIFFUSION

12. 4. ACTIVE TRANSPORT
• Carrier mediated transport (uphill transport)
• Energy is required in the work done by the carrier
• Inhibited by metabolic poisons
• Endogenous substances that are transported actively include
sodium, potassium, calcium, iron, glucose, amino acids and
vitamins like niacin, pyridoxin.
• Drugs having structural similarity to such agents are absorbed
actively
Eg. 1. Pyrimidine transport system – absorption of 5 FU
and 5 BU
2. L-amino acid transport system – absorption of
methyldopa and levodopa
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14. 5. PINOCYTOSIS
Pinocytosis ("cell-drinking")
• Uptake of fluid solute.
• A form of endocytosis in which small particles are brought
into the cell in the form of small vesicles which subsequently
fuse with lysosomes to hydrolyze, or to break down, the
particles.
• This process requires energy in the form of (ATP).
• Polio vaccine and large protein molecules are absorbed by
pinocytosis
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15. PENETRATION OF DRUGS THROUGH BLOOD BRAIN
BARRIER
• A stealth of endothelial cells lining the capillaries.
• It has tight junctions and lack large intra cellular pores.
• Further, neural tissue covers the capillaries.
• Together , they constitute the so called BLOOD BRAIN BARRIER
• Astrocytes : Special cells / elements of supporting tissue found at
the base of endothelial membrane.
• The blood-brain barrier (BBB) is a separation of circulating blood
and cerebrospinal fluid (CSF) maintained by the choroid plexus in
the central nervous system (CNS).
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17. Since BBB is a lipoidal barrier,
It allows only the drugs having high o/w partition
coefficient to diffuse passively where as moderately
lipid soluble and partially ionised molecules penetrate
at a slow rate.
Endothelial cells restrict the diffusion of microscopic
objects (e.g. bacteria ) and large or hydrophillic
molecules into the CSF, while allowing the diffusion of
small hydrophobic molecules (O2, hormones, CO2).
Cells of the barrier actively transport metabolic
products such as glucose across the barrier with
specific proteins.
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Various approaches to promote crossing the BBB by
drugs:
• Use of Permeation enhancers such as dimethyl
sulfoxide (DMSO)
• Osmotic disruption of the BBB by infusing internal
carotid artery with mannitol
• Use of Dihydropyridine redox system as drug
carriers to the brain
( the lipid soluble dihydropyridine is linked as a
carrier to the polar drug to form a prodrug that
rapidly crosses the BBB )

19. PENETRATION OF DRUGS THROUGH
PLACENTAL BARRIER
• Placenta is the membrane separating fetal blood from the
maternal blood.
• It is made up of fetal trophoblast basement membrane and
the endothelium.
• Mean thickness (25 µ) in early pregnancy and reduces to (2 µ)
at full term
• Many drugs having mol. wt. < 1000 daltons and moderate to
high lipid solubility e.g. ethanol, sulfonamides , barbiturates,
steroids , anticonvulsants and some antibiotics cross the
barrier by simple diffusion quite rapidly .
• Nutrients essential for fetal growth are transported by carrier
mediated processes
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21. PENETRATION OF DRUGS THROUGH ACROSS THE SKIN
• Skin is composed of three primary layers:
• the epidermis , which provides waterproofing and serves as a
barrier to infection;
• the dermis , which serves as a location for the appendages of
skin; and
• the hypodermis (subcutaneous adipose layer).
The stratum corneum is the outermost layer of the epidermis and is
composed mainly of dead keratinised cells (from lack of oxygen and
nutrients). It has a thickness between 10 - 40 μm.
The dermis is the layer of skin beneath the epidermis. It contains the hair
follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic
vessels and blood vessels.
Hypodermis - Its purpose is to attach the skin to underlying bone and
muscle as well as supplying it with blood vessels and nerves. The main cell
types are fibroblasts, macrophages and adipocytes (the hypodermis
contains 50% of body fat).
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23. ROUTES OF PENETRATION
– Through follicular region
– Through sweat ducts
– Through unbroken stratum corneum
FACTORS IN SKIN PERMEATION
1. Thickness of the skin layer:
(Thickest on palms and soles & thinest on the face)
 Skin condition: permeability of skin is affected by age, disease state
or injury.
 Skin temp.: permeability increases with increase in temp.
 Hydration state
APPROACHES TO ENHANCE SKIN PERMEATION
 Induction
 Iontophoresis
 Sonophoresis
 Magnetophoresis 23

24. Penetration Of Drugs Through The Mucous Membrane Of The
Nose, Throat, Trachea, Buccal Cavity, Lungs ,Vaginal And Rectal
Surfaces
• The barrier for the drug absorption is the capillary
endothelial membrane which is lipoidal and consists of pores
.
• Thus, lipid soluble drugs can easily penetrate by diffusion and
smaller drug molecules can penetrate by pore transport.
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25. PHYSIOLOGICAL FACTORS:
 Age
 Gastrointestinal (GI) Physiology
 Influence Of Drug Pka And GI pH On Drug
Absorption
 GIT Blood Flow
 Gastric Emptying
 Intestinal transit time
 Disease States
 Gastrointestinal content
 Presystemic metabolism
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26. Age
• In infants: gastric pH is high and intestinal
surface and blood flow to GIT is low resulting
in altered absorption
• In elderly: altered gastric emptying, decreased
intestinal surface area, and GI blood flow,
higher incidents of achlorhydria and bacterial
overgrowth in small intestine
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27. pH Membrane Blood
Supply
Surface
Area
Transit
Time
By-pass
liver
BUCCAL approx 6 thin Good, fast
absorption
with low dose
small Short unless
controlled
yes
ESOPHAGUS 6 Very thick, no
absorption
- small short -
STOMACH 1 – 3 Normal
Lipophilic,
acidic and
neutral drugs
good small 30 - 40
minutes,
reduced
absorption
no
DUODENUM 5 – 7 Normal
Mainly
lipohilic and
neutral drugs
good large very short (6"
long)
no
SMALL
INTESTINE
6 -7 Normal
All types of
drugs
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 yes
Gastrointestinal (GI) Physiology
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28. SMALL INTESTINE
• Major site for absorption of most drugs due to its large surface area
(0.33 m2 ).
• It is 7 meters in length and is approximately 2.5-3 cm in diameter.
• The Folds in small intestine called as folds of kerckring, result in 3 fold
increase in surface area ( 1 m2).
• These folds possess finger like projections called Villi which increase
the surface area 30 times ( 10 m2).
• From the surface of villi protrude several microvilli which increase the
surface area 600 times ( 200 m2).
• Blood flow is 6-10 times that of stomach.
• PH Range is 5–7.5 , favourable for most drugs to remain unionised.
• Peristaltic movement is slow, while transit time is long.
• Permeability is high.
All these factors make intestine the best site for absorbtion of most drugs.
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29. INFLUENCE OF DRUG pKa AND GI pH ON DRUG
ABSORBTION
Drugs Site of absorption
Very weak acids (pKa > 8.0) Unionized at all pH values
Absorbed along entire length of GIT
Moderately weak acids (pKa 2.5 – 7.5) Unionized in gastric pH
Ionized in intestinal pH
Better absorbed from stomach
Strong acids (pKa <2.5) Ionized at all pH values
Poorly absorbed from GIT
Very weak bases (pKa < 5) Unionized at all pH values
Absorbed along entire length of GIT
Moderately weak bases (pKa 5 – 11 ) Ionized in gastric pH
Unionized in intestinal ph
Better absorbed from intestine
Strong bases (pKa >11) Ionized at all pH values
Poorly Absorbed from GIT
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30. GIT BLOOD FLOW
• It plays an imp. role in drug absorption by continuously
maintaining the conc. Gradient across the epithelial
membrane
• Polar molecules that are slowly absorbed show no
dependence on blood flow
• The absorption of lipid soluble drugs and molecules that are
small enough to easily penetrate through Aq. pores is rapid
and highly dependent on rate of blood flow
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31. GASTRIC EMPTYING
• The process by which food leaves the stomach and enters the
duodenum.
• It is a rate determining step in drug absorption.
• Rapid Gastric Emptying Advisable when :
– Rapid onset of action is desired eg. Sedatives
– Dissolution occurs in the intestine eg. Enteric coated
tablets
– Drugs not stable in GI fluids eg. penicillin G
– Drug is best absorbed from small intestine eg. Vitamin
B12
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32. GASTRIC EMPTYING
• Gastric emptying is delayed by co-administration of food
because unless the gastric contents are fluid enough or the
size of the solid particles is reduced below 2mm, its passage
through the pylorus into the intestine is not possible.
• Delay in Gastric Emptying recommended when:
– Food promotes drug dissolution and absorption eg.
Gresiofulvin
– Disintegration and dissolution is promoted by gastric
fluids
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33. • Gastric emptying is first order process
1. Gastric emptying rate is the speed at which the
stomach content empty into intestine
2. Gastric emptying time is the time required for the
gastric content to empty into small intestine
3. Gastric emptying t1/2 is the time taken for half of
the stomach content to empty
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GASTRIC EMPTYING

34. 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 Gastric emptying rate:
carbohydrates > proteins > fats
Temperature of
Food
Increase in temperature, increase in emptying rate
Body Position Lying on the left side decreases emptying rate and right
side promotes it
GIT PH Retarded at low stomach pH and promoted at higher
alkaline PH
Emotional state Anxiety promotes where as depression retards it
Disease states gastric ulcer, hypothyroidism retards it, while duodenal
ulcer, hyperthyroidism promotes it.
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35. Intestinal transit time
Since Small Intestine is the major site for
absorption of most drugs, long intestinal
transit time is desirable for complete drug
absorption
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Intestinal region Transit time
Duodenum 5 min
Jejunum 2 hr
Ileum 3-6 hr
Cecum 0.5-1 hr
Colon 6-12 hr

36. • The mixing movement of the intestine that
occur due to peristalsis promote drug
absorption, firstly, by increasing the drug
intestinal membrane contact, and secondly,
by enhancing drug dissolution esp of poorly
soluble drugs, through induced agitation
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Intestinal transit time

37. • Delayed intestinal transit is desirable for:
1. Drugs that dissolve or release slowly from
their dosage form (sustained release
products)
2. Drug that dissolve only in intestine (enteric
coated formulations)
3. Drugs absorbed from specific site in the
intestine (several B vitamins)
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Intestinal transit time

38. DISEASE STATES
• CHF decreases blood flow to the GIT, alters GI pH, secretions
and microbial flora.
• Cirrhosis influences bioavailability mainly of drugs that
undergo considerable 1st pass metabolism eg. Propranolol
• GIT infections like cholera and food poisoning also result in
malabsorption.
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39. Gastrointestinal content
1. Food-drug interactions: presence of food
may either delay, reduce, or may affect drug
absorption
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Delay Decrease Increase Unaffected
Aspirin Penicillins Griseofulvin Methyldopa
Paracetamol Erythromycin Diazepam Propylthiouracil
Diclofenac Ethanol Water soluble vitamins Sulfasomidine
Nitrofurantoin Tetracycline
Digoxin Levodepa
Iron

40. 2. Fluid volume: Administration of drug with large fluid
volume result in better dissolution, rapid gastric
emptying, and enhanced absorption. E.g.
Erythromycin taken with water under fasting
condition is better absorbed than taken with meal
3. Interaction of drug with normal GI constituents:
Mucin- interact with streptomycin and retard their
absorption. Mucin also act as barrier to diffusion of
drugs
Bile salts- Aid solubilization and absorption of lipid
soluble drugs like griseofulvin and vitamins A,D, E, K
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Gastrointestinal content

41. Presystemic metabolism
1. Lumenal enzymes: These are enzymes present in gut
fluid and contains enzymes from intestinal and pancreatic
secretions. Hydrolase- hydrolize ester drugs like
chloramphenicol, Peptidase- split amide linkage and
inactivate proteins/polypeptide drugs
2. Gut wall enzymes: Also called mucosal enzymes, present
in stomach, intestine and colon. Alcohol Dehydrogenase, is
an enzyme of stomach mucosa that inactivate ethanol.
3. Bacterial enzymes: GI microflora less present in stomach
and small intestine but predominant in colon. They render
drug more active or toxic on biotransformation-
Sulfasalazine (drug used in ulcerative colitis) is hydrolyzed to
Sulfapyridine and 5-amino salicylic acid
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