Absorption of drugs

1. Pharmacokinetics
DRUG
T h e U n t o l d S t o r y
D i r e c t e d b y :
J a i n e e l D h a r o d
D e p t . o f P h a r m a c o l o g y
JD’sPharmacology

2. Pharmacokinetics
• It deals with, what the body does to a drug.
• It primarily covers ADME
• ADME = (Absorption, Distribution, Metabolism and Elimination)
• These processes are initiated as soon as drug enters the human body
• Here in this chapter all these processes will be discussed in detail.
• So here we go…

4. ABSORPTION
IT IS THE PROCESS OF A DRUG MOVING FROM ITS SITE OF
DELIVERY INTO THE BLOODSTREAM.

5. Absorption Bioavailability
• Movement from site of
administration to blood
stream
• Absorption is defined as
movement of drug across
the outer mucosal
membranes of the GI tract.
• Rate and Extent of drug
reaching to the site of
action
• Amount of unchanged
Drug reaching to site of
action by blood stream

6. Mechanisms of Drug Absorption (GIT)
1. Passive Diffusion
2. Carrier Mediated diffusion
a. Facilitated Diffusion
b. ActiveTransport
3. Phagocytosis and Pinocytosis
4. Endocytosis
5. Filtration

7. 1. Passive Diffusion
• Movement of drug molecules across membranes
from a region of high concentration to a region of
lower concentration
• Most drugs are absorbed through this mechanism
• No carrier involved
• Non saturable

8. 2. Carrier Mediated Transport
• Drugs always require a carrier molecule to enter the system
• It may not require energy in Facilitated transport
• It may require energy in Active transport

9. a. Facilitated Diffusion
• Entry to the cell through specialized
transmembrane carrier proteins
• Movement occurs from the area of the high
concentration to the area of low concentration
• Does not require energy
• Can be saturated and inhibited by compounds
that compete for the carrier

10. b. Active Transport
• Involves specific carrier proteins
• Requires energy
• Moves the drugs against the concentration
gradient (from low concentration to high
concentration regions)
• Selective
• Saturable, can be inhibited by cotransported
substances

11. 3. Phagocytosis and Pinocytosis
• Phagocytosis: Cell Eating
• Pinocytosis: Cell Drinking

12. 4. Endocytosis
• Specifically seen in case of drugs acting on
nuclear receptors. As they have to travel
to nuclear membrane.

13. 5. Filtration
• Drugs with very low molecular weight and
size are entered into system by filtration.
• They simple pass through the pores
present between plasma membranes.

14. SITES OF ABSORPTION
Absorption via:
1. GIT (Oral [buccal & sublingual], stomach, Intestine, Large intestine, Rectal)
2. Parenteral sites
3. Lungs
4. Topical Sites

15. AbsorptionviaGIT
AbsorptionviaGIT

16. Parenteral Site of Absorption
• Drug administered intravenously are completely absorbed and rapidly
distributed.
• Because they directly go into the blood stream without crossing any
membrane.
• The also bypass the first pass metabolism of Liver, so the amount that will
reach to site of action will be 100% BA.
• In case of IM and SC injections, Drug passively diffuse into bloodstream
hence no first pass metabolism takes place.
• Extent of absorption: IV > IM > SC

17. Absorption by lungs
• Lipid soluble drugs, when given in vaporized form (General anesthetics), or
aqueous solution spray (Salbutamol) are absorbed by pulmonary epithelial
cells and mucous membrane of trachea and lungs.
• Absorption is rapid because of the large surface area and high vascularity.
• First pass metabolism is avoided.

18. Absorption by Topical Sites
• Absorption of most of drug through intact skin is of course poor as the
keratinized epidermis behaves as a barrier to permeability.
• However, dermis is permeable to many lipid soluble drugs, hence significant
absorption can occur.
• Drugs undergoing transdermal absorption include (Nitroglycerine,
scopolamine, clonidine, etc.)
• Drugs given in ophthalmic form are absorbed through cornea

19. BIOAVAILABILITY
RATE AND EXTENT OF DRUG REACHING TO THE SITE OF
ACTION

20. BIOAVAILABILITY (%) = AUC (ORAL) / AUC (IV)
AUC
CMAX
TMAX
T90
Terms

21. Factors influencing Absorption & Bioavailability
1. Pharmaceutical Factors
2. Pharmacological Factors

22. 1. Pharmaceutical Factors
A. Physicochemical Properties: Drug solubility and dissolution rate, Particle
size and effective surface area, Polymorphism and amorphism, Salt form of
the drug, Lipophilicity of the drug, Drug stability, Stereochemical nature of
the drug
B. Formulation Factors: Disintegration time, manufacturing variables, nature
and type of dosage form, pharmaceutical ingredients (excipients), product
age and storage conditions

23. 2. Pharmacological Factors
Age, gastric emptying time, intestinal transit time, gastrointestinal pH, GIT
diseased states, blood flow through the GIT, gastrointestinal contents, drug-
drug interaction, drug-food interaction, fluids, other normal G.I contents, pre-
systemic metabolism, enzymes.

24. Pharmaceutical
Factors

25. Drug solubility and dissolution rate :
For Hydrophobic drugs:
Dissolution is rate
limited step.
Eg: griseofulvin,
spironolactone.
For Hydrophilic drugs:
Permeation is rate
limited step.
Eg: Cromolyn sodium,
neomycin.

26. Particle size and effective surface area of drug
• Smaller the particle size (by micronization) greater is the effective surface
area more intimate contact b/w solid surface and aqueous solvent higher is
the dissolution rate increase in absorption efficiency.
• Particle size reduction has been used to increase the absorption of a large
number of poorly soluble drugs, such as bishydroxycoumarin, digoxin,
griseofulvin, nitrofurantoin, and tolbutamide.

27. Polymorphism and Amorphism:
• Many compounds form crystals with different molecular arrangements, or
polymorphs.
• These polymorphs may have different physical properties, such as
dissolution rate and solubility.
• 40 % of all organic compounds – exist in various polymorphic forms.
• 70%of barbiturates & 65% of sulphonamides exhibit polymorphism.

28. Polymorphism and Amorphism:
Amorphous form:
• These have greater aqueous solubility than the crystalline forms because
the energy required to transfer a molecule from crystal lattice is greater
than that required for non-crystalline solid .
• Eg: amorphous form of novobiocin
• 10 times more soluble than crystalline form.
• Solubility = amorphous > metastable> stable

29. Salt form of drug
• The dissolution rate of a particular salt is usually different than that of the
parent compound.
• Salts of weakly acidic drugs are highly water soluble.
• Hence gives faster dissolution rate and enhanced bioavailability
• Eg: Tolbutamide sodium and Phenytoin sodium are more soluble than
Tolbutamide and Phenytoin.

30. Salt form of drug
Amount of drug that exist in unionized form and in ionized form is a function of
pKa of drug & pH of the fluid at the absorption site and it can be determined by
Henderson-Hasselbalch equation:
• For Acidic drugs:
pH = pKa + log [ionized form] / [Unionized form]
• For Basic drugs:
pH = pKa + log [unionized form] / [Ionized form]

31. Lipophilicity and drug absorption
• Ideally for optimum absorption,
• a drug should have sufficient aqueous solubility to dissolve in fluids at
absorption site and
• Lipid solubility high enough to facilitate the partitioning of the drug in the
lipoidal bio membrane
• i.e. drug should have perfect HLB for optimum Bioavailability.

32. Disintegration
• Rapid disintegration is important to have a rapid absorption so lower
Disintegration Time is required.
• And one thing should be remembered that in vitro disintegration test gives
no means of a guarantee of drugs bioavailability because if the
disintegrated drug particles do not dissolve then absorption is not possible.

33. Compression force of Tablet
• Higher compression force yields a tablet with greater hardness and reduced
wettability & hence have a long D.T. but on other hand higher compression
force cause crushing of drug particles into smaller ones with higher effective
surface area which in decrease in D.T.
• So effect of compression force should be thoroughly studied on each
formulation

34. Nature and type of dosage form

35. Pharmaceutical ingredients / Excipients
• More the no. of excipients in dosage form, more complex it is & greater the
potential for absorption and Bioavailability problems.
• Changing an excipient from calcium sulfate to lactose and increasing the
proportion of magnesium silicate, increases the activity of oral phenytoin.
• Systemic availability of thiamine and riboflavin is reduced by the presence
of Fuller’s earth.
• Absorption of tetracycline from capsules is reduced by calcium phosphate
due to complexation.

36. Pharmacological
Factors

37. Gastric emptying
• Apart from the dissolution of drug and its permeation through the bio
membrane, the passage from stomach to small intestine, called as gastric
emptying, can also be a rate limiting step in absorption because the major
site of drug absorption is intestine.
• It is advisable where:
• Rapid onset of drug is desired eg: sedatives
• Drug not stable in gastric fluids eg: penicillin G
• Dissolution occurring in intestine eg: enteric coated forms

38. Gastric emptying is first order process. Several parameters used to quantify
are:
• Gastric emptying rate: speed at which stomach contents empties into
intestine.
• Gastric emptying time: time required for gastric contents to empty into
small intestine.
• Gastric emptying t1/2 : time taken for half of the stomach contents to
empty.

39. Factors affecting Gastric emptying
• Volume of meal: larger the bulk of meals, longer the gastric emptying time.
carbohydrates > proteins> fats
• Delayed gastric emptying with fatty meal, is beneficial for the absorption of
poorly soluble drugs like griseofulvin.
• Physical state and viscosity of meal
• Disease state: like gastroenteritis, gastric ulcer, pyloric stenosis retard
gastric emptying rate.

40. Intestinal transit
• Since small intestine is the major site for absorption of most drugs, long
intestinal transit time is desirable for complete drug absorption.
Intestinal region Transit time
Duodenum 5 min
Jejunum 2 hrs
Ileum 3 to 6 hrs
Caecum 0.5 to 1hr
Colon 6 to 12 hrs

41. Pre-systemic Metabolism (First Pass)
• For a drug administration orally, the 2 main reasons for its decreased
bioavailability are:
1. Decreased absorption and
2. First pass metabolism
• The loss of drug through biotransformation by such eliminating organs
during its passage to systemic circulations called as first pass or pre-
systemic metabolism.

42. Gastrointestinal Disease
• Altered GI motility:
• Gastrointestinal diseases and infections: Two of the intestinal disorders
related with malabsorption syndrome that influence drug availability are
celiac disease and Crohn’s disease.
• Crohn’s disease that can alter absorption pattern are altered gut wall
microbial flora, decreased gut surface area and intestinal transit rate.
• GI infections like shigellosis, gastroenteritis, cholera and food poisoning
also result in malabsorption.

43. • Gastrointestinal surgery: Gastrectomy can result in drug dumping in the
intestine, osmotic diarrhea and reduced intestinal transit time.
• Cardiovascular diseases: Several changes associated with congestive
cardiac failure influence bioavailability of a drug.
• Hepatic diseases: Disorders such as hepatic cirrhosis influence
bioavailability mainly of drugs that undergo considerable first-pass hepatic
metabolism.

44. Gastrointestinal Contents
• Fluid Volume and temperature: administration of drug with more volume of
fluid and slight warm fluid can enhance the absorption.
• Mucous: Enhances absorption except for streptomycin and quaternary
ammonium compounds

45. Drug – Drug Interaction
Decreased GI transit:
• Anticholinergics like propantheline retard GI motility and promote
absorption of drugs like ranitidine and digoxin & delay absorption of
paracetamol and sulphamethoxazole.
Increased gastric emptying:
• Metoclopramide promotes GI motility and enhances absorption of
tetracycline, levodopa.

46. Food – Drug Interaction
Acetaminophen +Alcohol = Liver toxicity
Tetracycline + Dairy products = reduce absorption of drug
Griseofulvin + High Fat meal = increases absorption of drug

47. Age
• In the elderly there is a reduction in gastric pH which, in the case of some
drugs, affects the solubility and thus will influence the rate of absorption.
• Furthermore, there is a reduction in intestinal blood flow, which would tend
to delay or reduce drug absorption

48. To be
continued…