Absorption of DrugsNIKITA ANIMESH BHAVIKA SHAFAT GYAN PUSHKAR

DRUG:• A drug is injected

intravascularly (iv or ia)

directly enters into systemic

circulation.

• Majority of drugs are

administered extravascularly

(generally orally).

• Such drugs can exert the

pharmacological action only

when they come into

systemic circulation from

their site of administration .

• Thus, absorption is an important prerequisite step

Definition of Absorption• The process of movement of unchanged drug from the

site of administration to systemic circulation

• The effectiveness of a drug can only be assessed by its

concentration at the site of action.

• It is difficult to measure the drug concentration at such

site.

• Instead, the concentration can be measured more

correctly in plasma

• As there always a correlation between the plasma

concentration of a drug & therapeutic response

Cell Membrane Structure & Physiology

CELL MEMBRANE

• Cell membrane separates living cell from nonliving

surroundings

• thin barrier = 8nm thick

• Controls traffic in & out of the cell

• selectively permeable

• allows some substances to cross more easily than others

• hydrophobic vs hydrophilic

• Made of phospholipids, proteins & other macromolecules

• Proteins determine membrane’s specific functions– cell membrane & organelle membranes

each have unique collections of proteins

• Membrane proteins:– peripheral proteins

• loosely bound to surface of membrane• cell surface identity marker (antigens)

– integral proteins • penetrate lipid bilayer, usually across whole

membrane • transmembrane protein transport proteins

– channels, permeases (pumps)

Physiological factors affecting oral absorption (outline)

• Passage of drugs across membranes

1.Active transport

2.Facilitated diffusion

3.Passive diffusion

4.Pinocytosis

5.Pore transport

6.Ion pair formation

• Main factors affecting oral absorption

• Physiological factors • Physical-chemical factors

• Formulation factors

MECHANISMS OF DRUG ABSORPTION

I. Passive Diffusion

Diffusion Movement from high

low concentration• Major process for absorption

of more than 90% of drugs• Non ionic diffusion• Driving force – concentration

or electrochemical gradient• Difference in the drug

concentration on either side of the membrane

• Drug movement is a result of kinetic energy of molecules

Mathematically(Fick’s First law of diffusion)

.................IdQ/dt = rate of drug diffusion (amount/time)

D = diffusion coefficient of the drug

A= surface area of the absorbing membrane for drug diffusion

Km/w = partition coefficient of drug between the lipoidal

membrane & the aqueous GI fluids

(CGIT – C) = difference in the concentration of drug in the GI

fluids & the plasma (Concentration Gradient)

h = thickness of the membrane

Characteristics of Passive diffusion:

Energy independentGreater the area & lesser the thickness of the membrane, faster the diffusion

The process rapid over for short distancesConcentration equal on both the sides of the membrane - Equilibrium is attained

Greater the PC of the drug faster the absorption

But this is not the case……

The passively absorbed drug enters blood, rapidly

swept away & distributed into a larger volume of

body fluids

Hence,

The concentration of drug at absorption site CGIT is

maintained greater than the concentration in the

plasma. Such a condition is called as sink

condition for drug absorption.

Under usual absorption conditions,

D, A, Km/w & h are constants, the term DAKm/w /h can be

replaced by a combined constant P called as

permeability coefficient

Permeability - ease with which a drug can permeate or

diffuse through a membrane.

Due to sink conditions, the C is very small in

comparison to CGIT.

……………..II

Equation II is an expression for a first order

process.

Thus, passive diffusion follows first order kinetics.

II. PORE TRANSPORT

• It is also called as convective transport, bulk flow or

filtration.

• Mechanism – through the protein channel present in

the cell membrane.

• Drug permeation through pore transport – renal

excretion, removal of drug from CSF & entry of drug

into the liver

The driving force – hydrostatic or osmotic pressure differences

across the membrane. Thus, bulk flow of water along with the

small solid molecules through aqueous channels. Water flux

that promotes such a transport is called as solvent drag

The process is important in the absorption of low molecular

weight (<100D), low molecular size (smaller than the diameter

of the pore) & generally water soluble drugs through narrow,

aqueous filled channels or pores e.g. urea, water & sugars.

Chain like or linear compounds (upto 400D)- filtration

III. ION-PAIR TRANSPORT

Responsible for absorption of compounds which

ionizes at all pH values. e.g. quaternary ammonium,

sulphonic acids

Ionized moieties forms neutral complexes with

endogenous ions which have both the required

lipophilicity & aqueous solubility for passive diffusion.

E.g. Propranolol, a basic drug that forms an ion pair

with oleic acid & is absorbed by this mechanism

CARRIER MEDIATED Transport

• Involves a carrier which reversibly binds to the solute molecules and forms a solute-carrier complex.

• This molecule transverse across the membrane to the other side and dissociates, yielding the solute molecule.

• The carrier then returns to the original site to accept a new molecule.

• There are two type of carrier mediated transport system

1) Facilitated diffusion

2) Active transport

FACILITATED DIFFUSION

• Facilitated diffusion is a form of carrier transport that does not require the expenditure of cellular energy.

• Carriers are numerous in number & are found dissolved in cell membrane .

• The driving force is concentration gradient, particles move from a region of high conc to low conc.

Contd…• The transport is aided

by integral membrane proteins.

• Facilitated diffusion mediates the absorption of some simple sugars, steroids, amino acids and pyrimidines from the small intestine and their subsequent transfer across cell membranes.

ACTIVE TRANSPORT

• Requires energy, which is provided by hydrolysis of ATP for transportation.

• More commonly, metabolic energy is provided by the active transport of Na+, or is dependent on the electrochemical gradient produced by the sodium pump, Na+/K+ ATPase (secondary active transport).

This transport requires energy in the form of ATP

PRIMARY ACTIVE TRANSPORT• Direct ATP requirement• The process transfers only one ion or molecule & only in

one direction. Hence, called as UNIPORT • E.g. absorption of glucose• ABC (ATP binding Cassette) transporters

Secondary active transport

• No direct requirement of ATP• The energy required in transporting an ion aids transport

of another ion or molecule (co-transport or coupled transport) either in the same direction or opposite direction.

• 2 types:• Symport (co-transport)• Antiport (counter transport)

symportantiport

ATP ATP

Antiport and Symport

ENDOCYTOSIS

• It is a process in which cell absorbs molecules by engulfing them.

• Also termed as vesicular transport.

• It occurs by 3 mechanisms:

PhagocytosisPinocytosisTranscytosis

PHAGOCYTOSIS

TRANSCYTOSIS• It is the process through

which various macromolecules are transferred across the cell membrane.

• They are captured in vesicles, on one side of the cell and the endocytic vesicle is transferred from one extracellular compartment to another.

• Generally used for the transfer of IgA and insulin.

PINOCYTOSIS

• It is a form of endocytosis in which small particles are brought to the cell, forming an invagination.

• These small particles are suspended in small vesicles.

• It requires energy in the form of ATP.

• It works as phagocytosis, the only difference being, it is non specific in the substances it transports.

• This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients

FACTORS AFFECTING RATE OF ABSORPTION

DRUG SOLUBILITY AND DISSOLUTION RATE

• MAXIMUM ABSORBABLE DOSE (MAD)

• Ka = intrinsic absorption rate constant

• SGI = the solubility of the drug in the GI fluid

• VGI = the volume of the GI fluid

• tr = residence time of the drug in the GI

CLASS

SOLUBILITY

PERMIABILITY ABSORPTION PATTERN

RATE LIMITING STEP

EXAMPLE

1 HIGH HIGH WELL ABSORBED

GASTRIC EMPTYING

DILTIAZEM

2 LOW HIGH VARIABLE DISSOLUTION

NIFEDEPINE

3 HIGH LOW VARIABLE PERMIATION

INSULIN

4 LOW LOW POORLY ABSORBED

CASE BY CASE

TAXOL

PARTICLE SIZE AND SURFACE AREA

• Particle size 1/surface area• Absolute surface area• Effective surface area• Larger the surface area higher the dissolution rate• Decrease in particle size can be accomplished by micronisation.

• hydrophobic drugs

- The hydrophobic surface of the drug adsorbs air

onto their surface which inhibits their wettability

- The particles re-aggregate to form larger

particles due to their high surface free energy.

- Electrically induced agglomeration owing to

surface charges prevents intimate contact of the

drug with the dissolution medium.

REMEDIES• -Use of surfactant as wetting agent

Decreases the

interfacial tension

Displaces the adsorbed

air with the solvent2. Adding hydrophilic diluents

which coat the surface

of hydrophobic drug particles & render them

hydrophilic. E.g. PEG, PVP

• Particle size reduction & subsequent increase in the surface area & dissolution rate is not advisable for-

• - When the drugs are unstable & degrade in the

• solution form e.g. penicillins, erythromycin.

• - When drugs produce undesirabe effects (gastric

• irritation caused by nitrofurantoin).

• - When a sustained effect is desired.

Polymorphism and Amorphism

• A substance exists in more than one crystalline form, the different forms are designated as polymorphs & the phenomenon as polymorphism.

• Enantiotropic polymorph: sulphur

• Monotropic polymorph: glyceryl stearate

• Depending on their relative stability, one of the several polymorphic forms will be physically more stable than the others.

• Stable polymorphs

- lowest energy state

- highest MP

- least aqueous solubility• Metastable polymorphs

- higher energy state

- low MP

- high aqueous solubility

• Chloramphenicol Palmitate - A, B & C.• E.g. Riboflavin has 5 polymorphs- I, II, III, IV & V

• Only 10% of the pharmaceuticals are present in metastable

forms.

• Aging of dosage forms containing metastable forms usually

result in formation of less soluble, stable polymorph.

• E.g. More soluble crystalline form II of cortisone acetate

converts to less soluble form V in aqueous suspension

resulting in caking of solid.

• Amorphism:

• Amorphous forms: having no internal crystal structure

• The highest energy state

• 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

(amorphous) solid.

• E.g. the amorphous form of novobiocin is 10 times more

soluble than the crystalline form.

Salt form of drug

• Most drugs are either weak acids or weak bases.

• Solubilization technique – salt formation of drugs• Weakly acidic drugs- strong base salt• Weakly basic drugs- strong acidic salt

Drug pKa & GI pH

• The pH partition theory – the process of drug absorption from the GIT & its

distribution across GI membrane.

• Many drugs are either Was or WBs

• The drugs primarily transported across the biomembrane by passive

diffusion, is governed by –

1. The dissociation constant

2. The lipid solubility of the unionised drugs

3. The pH at absorption site

• Drug pKa & GI pH

• Unionised form of drug = Function of dissociation constant of the drug &

pH of fluid at the absorption site

Drug Lipophilicity Lipophilicity & Drug Absorption:

Ideally a drug should have

• Sufficient aqueous solubility to dissolve in the fluids at

absorption site

• Sufficient lipid solubility to facilitate the partitioning of the drug

in lipoidal membrane

• A perfect hydrophilic-lipophilic balance should be there in the

structure of the drug for optimum bioavailability.

Drug Permeability

• Three major drug properties which affects drug permeability –

1. Lipophilicity

2. Polarity of the drug

3. Molecular size of the drug

Drug Stability

• A drug for oral use may destabilize either during its

shelf life or in the GIT

• Reasons:

• Degradation of the drug into inactive form

• Interaction with one or more different component either

of the dosage form or present in the GIT to form

complex which is poorly absorbable or is unabsorbable

FORMULATION FACTORS

DISINTEGRATION TIME• Is of particular importance in case of solid dosage forms

like tablets and capsules • Rapid disintegration-important in the therapeutic success

of solid dosage form• Sugar coated tablets have long DT

• DT is directly related to the amount of binder present and the compression force of a tablet

• After disintegration-granules deaggregate into tiny particles-dissolution faster

MANUFACTURING VARIABLES

Method of granulation:• Wet granulation was thought to be the most conventional

technique

• Direct compressed tablets dissolve faster

• Agglomerative phase of communition-superior product

Compression force:• Higher compression force-

increased density and hardness-decreased porosity and penetrability-reduced wetability -inturn decreased DR

• Also causes deformation,crushing-increased effective surface area-increased DR

• Intensity of packing of capsule contents:

• Tightly filled capsules-diffusion of GI fluids-high pressure-rapid bursting and dissolution of contents

• Opposite also possible-• poor drug release due

to decreased pore size and poor penetrability of GI fluids

DOSAGE FORMS• Different Types• Solution• Suspension• Tablets• Capsules• Coated Tablets• Enteric Coated Tablet• Powders

ORDER OF ABSORPTION• Solutions>Emulsions>Suspensions>Capsules> Tablets>

Coated Tablets>Enteric Coated Tablet>Sustain Release Tablet

• Mechanism

• Factors

Product age and storage conditions

Aging and alteration in storage condition change the physiochemical properties of a drug ---adversely affect Bioavailability

During storage• Metastable form stable form• Change in particle size• Tablet harden

soften

Eg

Prednisone tablet containing lactose as a filler ,high temp& high humidity resulted in harder tablet that disintegrated and dissolve slowly

PATIENT RELATED FACTORS

GI pH

i) disintegration: some dosage forms is Ph sensitive , with enteric coating the coat dissolves only in in intestine.

ii) Dissolution: A large no. of drugs whose solubility is affected by pH are weak acidic and weak basic drugs.

W.A drugs dissolve rapidly in the alkaline medium whereas W.B drugs dissolve in acidic medium.

iii) Absorption : Depending on drug pKa and whether it is acidic or basic , absorption depends on the amount of unionised form at site of absorption.

iv) Stability: GI pH affects chemical stability of drug. Eg. Acidic pH of stomach degrades Penicillin G and

erythromycin. Hence they are administered as prodrugs namely carindacillin and erythromycin estolate.

Blood flow through GIT

-GIT extensively supplied by blood capillary network .Therefore it helps in maintaining the sink condition for continued drug absorption.

DRUG BLOOD FLOW EFFECT(A) For highly lipid soluble drug More(B) For lipophilic drug Intermediate(C)For polar drugs No effect

GASTROINTESTINAL CONTENTS I) Food

Influence of food on drug absorption. Delayed Decreased Increased Unaffected Aspirin Penicillins Griseofluvins Methyldopa Paracetamol Erythromycin Diazapam Propylthiouracil Diclofenac Tetracyclines Delayed or decreased drug absorption could be due to a)Delayed gastric emptying b) Formation of poorly soluble , unabsorbable complex.c) Increased viscosity due to food therby preventing drug dissolution.

Increased drug absorption could be due to:a) Increased time for dissolution of a poorly soluble drug.b) Enhanced solubility due to GI secretions.c) Prolonged residence time Eg. Vitamins.

II Fluid volumeLarge food volume results in better dissolution and enhanced drug absorptionEg. Erythromycin is better absorbed when taken with a glass of water under fasting condition.

III Interaction with normal GI constituents.-mucin , a protective mucopolysaccharide that lines GI mucosa interacts with streptomycin and certain quaternary ammonium copmpounds and retards their absoprtion-Bile salts aid to solubilisation of drugs like Vitamin A,D,E and K -Enzymes.

IV)Drug-drug interaction in the GIT:They can be physicochemical.

V) Physicochemical D-D interaction can be due to :

a) Adsorption : Antidiarrhoeal preparation contain adsorbant like kaolin-pectin retard absorption of co-administerd drugs like promazine and lincomycin.

b) complexation: formation of unabsorpable complexes.Eg. Tetracyclinesc)pH change

• In infants – incomplete development of biological system -

the gastric pH is high & intestinal surface area & blood flow

to GIT is less – results in altered absorption pattern

• Elderly patients – impaired biological system like altered

gastric emptying, decreased intestinal surface area,

decreased blood flow to GIT, higher incidence of

achlorhydria & bacterial overgrowth in small intestine.

AGE

INTESTINAL TRANSIT

Defined as, the residence time of drug in small intestine.

Delayed intestinal transit is desirable for:

1. Sustained release dosage forms.

2. Drug that only release in intestine ie ,enteric coated formulations,

3. Drugs absorbed from specific sites in intestine, eg; several B vitamins .

4. Drugs which penetrate intestinal mucosa very slowly

5. Drugs with minimal absorption from colon.

DISEASE STATE

Several disease state may influence the rate and extent of drug absorption.

Three major classes of disease may influence bioavailability of drug.

• GI diseases• CVS diseases• HEPATIC diseases

GI diseases

A. GI Infections

1. Celiac diseases:(characterized by destruction of villi and microvilli) abnormalities associated with this disease are increased gastric emptying rate and GI permeability, altered intestinal drug metabolism.

2. Crohn’s disease: altered gut transit time and decreased gut surface area and intestinal transit rate.

B. GI surgery: Gastrectomy may cause drug dumping in intestine, osmotic diarrhoea and reduce intestinal transit time.

CVS diseases:

In CVS diseases blood flow to GIT decrease causing decreased drug absorption.

HEPATIC diseases:Disorders like hepatic cirrhosis influences bioavailability of drugs which under goes first pass metabolism.

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