DRUG: • A drug is injected • Thus, absorption is an important intravascularly (iv or ia) prerequisite step 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 .
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• 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 • Main factors across membranes affecting oral 1.Active transport absorption 2.Facilitated diffusion • Physiological factors 3.Passive diffusion 4.Pinocytosis • Physical-chemical 5.Pore transport factors 6.Ion pair formation • Formulation factors
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 ofdiffusion) .................IdQ/dt = rate of drug diffusion (amount/time)D = diffusion coefficient of the drugA= surface area of the absorbing membrane for drug diffusionKm/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 diffusionThe process rapid over for short distancesConcentration equal on both the sides of the membrane - Equilibrium is attainedGreater 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 fluidsHence,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 coefficientPermeability - 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.
……………..IIEquation 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 dragThe 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 TRANSPORTResponsible for absorption of compounds which ionizes at all pH values. e.g. quaternary ammonium, sulphonic acidsIonized 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 • The carrier then which reversibly returns to the original binds to the solute site to accept a new molecules and forms molecule. a solute-carrier • There are two type of complex. carrier mediated• This molecule transport system transverse across the 1) Facilitated membrane to the diffusion other side and 2) Active transport dissociates, yielding the solute molecule.
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)
TRANSCYTOSIS • It is the process • Generally used for the through which various transfer of IgA and macromolecules are insulin. 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.
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
DRUG SOLUBILITY ANDDISSOLUTION 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
CLAS SOLUBILIT PERMIABILIT ABSORPTION RATE EXAMPLES Y Y PATTERN LIMITING STEP HIGH HIGH WELL GASTRIC DILTIAZEM1 ABSORBED EMPTYING LOW HIGH VARIABLE DISSOLUTI NIFEDEPINE2 ON HIGH LOW VARIABLE PERMIATIO INSULIN3 N LOW LOW POORLY CASE BY TAXOL4 ABSORBED CASE
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 • Particle size reduction & subsequent increase in the Decreases the surface area & dissolution rate is not advisable for- interfacial tension • - When the drugs are unstable & degrade in the Displaces the • solution form e.g. penicillins, erythromycin. adsorbed air with the • - When drugs produce undesirabe effects (gastric solvent • irritation caused by nitrofurantoin). 2. Adding hydrophilic diluents which coat the surface • - When a sustained effect is desired. of hydrophobic drug particles & render them hydrophilic. E.g. PEG, PVP
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 constant2. The lipid solubility of the unionised drugs3. 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. Lipophilicity2. Polarity of the drug3. 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
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 VARIABLESMethod 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: • Intensity of packing of• Higher compression force- capsule contents: increased density and • Tightly filled capsules- hardness-decreased diffusion of GI fluids-high porosity and penetrability- pressure-rapid bursting reduced wetability -inturn and dissolution of contents decreased DR • Opposite also possible-• Also causes • poor drug release due deformation,crushing- to decreased pore size increased effective surface and poor penetrability of area-increased DR GI fluids
ORDER OF ABSORPTION• Solutions>Emulsions>Suspensions>Capsules> Tablets> Coated Tablets>Enteric Coated Tablet>Sustain Release Tablet• Mechanism• Factors
Product age and storage conditionsAging 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 softenEg Prednisone tablet containing lactose as a filler ,high temp& high humidity resulted in harder tablet that disintegrated and dissolve slowly
GI pHi) 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 CONTENTSI) Food Influence of food on drug absorption. Delayed Decreased Increased Unaffected Aspirin Penicillins Griseofluvins Methyldopa Paracetamol Erythromycin Diazapam Propylthiouracil Diclofenac TetracyclinesDelayed or decreased drug absorption could be due toa)Delayed gastric emptyingb) 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 fastingcondition.III Interaction with normal GI constituents.-mucin , a protective mucopolysaccharide that lines GI mucosa interacts withstreptomycin 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.
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 slowly5. Drugs with minimal absorption from colon.
DISEASE STATESeveral 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 diseasesA. GI Infections1. 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 GITdecrease causing decreased drug absorption.HEPATIC diseases:Disorders like hepatic cirrhosisinfluences bioavailability of drugswhich under goes first passmetabolism.