DRUG ABSORPTION

Dr. Chandane R. D. Asst Professor Dept of Pharmacology Govt Medical College, Akola

Pharmacokinetics, Overview

Pharmacokinetics: the study of the movement of drugs in the body, including the processes of absorption, distribution, localization in tissues, biotransformation and excretion

Learning pharmacokinetics is of great practical importance in the choice and administration of a particular drug for a particular patient, e.g., one with impaired renal function

INTRODUCTION TO ABSORPTION Passage of drug through cell

membranes to reach its site of action.

Definition :The process of movement of

unchanged drug from the site of administration to systemic circulation.

There always exist a correlation between the plasma concentration of a drug & the therapeutic response & thus, absorption can also be defined as the process of movement of unchanged drug from the site of administration to the site of measurement.

i.e., plasma.

Is the passage of drug through cell membranes to reach its site of action.

Mechanisms of drug absorption1. Simple diffusion = passive

diffusion.2. Filtration3. Facilitated diffusion.4. Active transport.5. Pinocytosis (Endocytosis).

CELL MEMBRANE

CELL MEMBRANE Also called the plasma membrane, plasmalemma

or phospholipid bilayer. The plasma membrane is a flexible yet sturdy

barrier that surrounds & contains the cytoplasm of a cell.

Cell membrane mainly consists of: 1. Lipid bilayer-

-phospholipid-Cholesterol-Glycolipids.

2. Proitens--Transmembrane proteins-Lipid anchored proteins-like G protein-Peripheral Proteins

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water soluble drug (ionized or polar) is readily absorbed via aqueous channels or pores in cell membrane.

Lipid soluble drug (nonionized or non polar) is readily absorbed via cell membrane itself.

Characters common. Occurs along concentration

gradient. Non selective Not saturable Requires no energy No carrier is needed Depends on lipid solubility. Depends

pka of drug - pH of medium.

Drugs exist in two forms ionized (water soluble & nonionized forms (lipid soluble) in equilibrium.

Drug ionized + nonionized

Only nonionized form is absorbable. Nonionized / ionized fraction is determined

by pH and pKa according to

Henderson-Hasselbach

pH=pKa+log Conc of ionized drug / Conc of unionized drug

PKa of the drug(Dissociation or ionization constant):pH at which half of the substance is ionized & half is unionized.

pH of the medium

Affects ionization of drugs. Weak acids best absorbed in stomach.Aspirin, Phenobarbitone, penicillin v Weak bases best absorbed in intestine.

Atropine, ephedrine, Chloroquine

2. PORE TRANSPORT/ FILTRATION

It involves the passage of ions through Aq. Pores (4-40 A0)

Low molecular weight molecules (less than 100 Daltons) eg- 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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Occurs along concentration gradient.

Requires carriers Selective. Saturable. No energy is required.

Relatively unusual.Occurs against concentration

gradient.Requires carrier and energy.Specific Saturable. Iron absorption.Uptake of levodopa by brain.

ACTIVE TRANSPORT

Primary Active transport- Energy derived directly by hydrolysis of ATP. ATP binding cassettee (ABC) transporter have ATPase activity at intracellular loop. This mediate only efflux

Secondary Active transport- this is effected by another set of SLC transporter, energy to pump one solute is derived from downhill movement of another solute. When conc gradient of both solute moves in same direction ,it is called symport or cotransport but when they moves in opposite direction, is termed as antiport or exchange transport. This mediate both uptake and efflux of drug.

Carrier-mediated facilitated diffusion

Active transport

along concentration gradient

(From high to low)

Against concentration gradient

(From low to high)

Needs carriers Needs carriers

Selective, saturable Selective, saturable

No energy is required Energy is required

Active transport Passive transport

against concentration gradient

(From low to high)

Along concentration gradient

(From high to low)

Needs carriers No carriers

Selective, saturable Not selectiveNot saturable

energy is required No energy

Mechanism Direction Energy required Carrier Saturable

Passive diffusion Along gradient No No No

Facilitated diffusion Along gradient No Yes Yes

Active transport Against gradient Yes Yes Yes

ENDOCYTOSIS

It involves engulfing extracellular materials within a segment of the cell membrane to form a saccule or a vesicle (hence also called as corpuscular or vesicular transport) which is then pinched off intracellularly.

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In endocytosis, there are three process:

A) Phagocytosis

B) Pinocytosis

C) Transcytosis- It is a phenomenon in which endocytic vesicle is transferred from one extracellular compartment to another.

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A) PHAGOCYTOSIS

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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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B) PINOCYTOSIS

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

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Plasma level curve

Cmax = maximal drug level obtained with the dose. tmax = time at which Cmax occurs. Lag time = time from administration to appearance in blood. Onset of activity = time from administration to blood level reaching minimal

effective concentration (MEC). Duration of action = time plasma concentration remains greater than MEC. Time to peak = time from administration to Cmax.

1- Absorption It is the process of entry of drug from site of administration into

systemic circulation.

Factors influencing absorption A- Factors related to drug

a) Physicochemical properties:1-Degree of ionization: highly ionized drugs are poorly absorbed.2-Degree of solubility: High lipid/water partition coefficient increases

absorption.3-Chemical nature: inorganic iron is better absorbed than organic

iron.4-Valency: ferrous salts are more absorbed than ferric,

-so vitamin C increases absorption of iron.

b) Pharmaceutical form of drug:Absorption of solutions is better than suspensions or tablets.

1- Absorption, Factors Influencing Absorption, contd

B- Factors related to the patient:1-Route of administration:

absorption is faster from i.v. > inhaled > i.m. > oral > dermal administration

2-Area and vascularity of absorbing surface: absorption is directly proportional to both area and vascularity. Thus absorption of the drug across the intestine is more efficient than across the stomach, as intestine has more blood flow and much bigger surface area than those of the stomach

3-State of absorbing surface: e.g. atrophic gastritis and mal-absorption syndrome decrease rate of absorption of drugs.

4-Rate of general circulation: e.g., in shock, peripheral circulation is reduced and I.V. route is used.

5-Specific factors and presence of other drugs: e.g. intrinsic factor of the stomach is essential for vitamin B12 absorption from lower ileum and adrenaline induces vasoconstriction so delay absorption of local anesthetics.

seconds minutes hours

PHYSIO-CHEMICAL FACTORS

PHYSICAL FACTORS

PHYSIO-CHEMICAL FACTORS

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PHYSICAL FACTORS1.PARTICLE SIZE

Smaller particle size, greater surface area then higher will be dissolution rate, because dissolution is thought to take place at the surface area of the solute( Drug).

This study is imp. for drugs that have low aqueous solubility. Absorption of such drugs can be increased by increasing particle size by Micronization.

ex. Griseofulvin, active intravenously but not effective when given orally.

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To poor soluble drug, disintegration agents and surface active agents may be added .• ex. Bioavailability of Phenacetin is increased by tween 80.

Micronization also reduces the dose of some drugs• ex. the dose of griseofulvin is reduced to one half while the dose of spironolactone is reduced to one twentieth.

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1.PARTICLE SIZE

Lesser particle size is always not helpful

Ex. Micronization of Aspirin, phenobarbital, lesser effective surface area and hence lesser dissolution rate

Reasons:

On their surface, hydrophobic drugs absorb air and reduce their wettability

Particle having size below 0.1 micron reaggregate to form large particle

Particle having certain micro size get electrical charge which preventing contact with wetting medium 32

Finally drug size reduction and subsequent increase in surface area and dissolution rate is always not useful.

Ex. of such drugs are Penicillin G & ErythromycinThese Drugs are unstable and degrade quickly in solution.

Sometime, reduction in particle size of nitrofurantoin and piroxicam increase gastric irritation

These problem can be overcome by Microencapsulation. 33

2. Crystal Form

Substance can exist either in a crystalline or amorphous form. When substance exist in more than one crystalline form, the different form are called polymorphs and the phenomena as polymorphism .

Two types of Polymorphism 1) Enantiotropic polymorph ex. Sulfur2) Monotropic polymorph ex. Glyceryl Stearates

Polymorphs have the same chemical structure but different physical properties such as solubility, density, hardness etc.ex. Chlormphenicol has a several crystal form, and when given orally as a suspension, the drug concentration in the body was found to be dependent on the percentage of β - polymorph in the suspension. The form is more soluble and better absorbed.

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One of the several form of polymorphic forms is more stable than other. Such a stable form having low energy state and high melting point and least aqueous solubility

The remaining polymorphs are called as metastable forms which have high energy state, low melting point and high aqueous solubilities. About 40% of all organic compounds exhibit polymorphism.

Some drug exists in amorphous form which have no internal crystal structure. Such drugs have high energy states than crystal form hence they have greater aqueous solubility than crystalline form.Ex. Novobiocin, cortisone acetate.

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3. Solvates And Hydrates

Many drugs associate with solvent and forms solvatesSolvent is water then it is called as hydrate eg. Anhydrous form of caffeine and theophylline dissolve more rapidly than hydrous form of these drugs.

Solvate form of drugs with org. solvent may dissolve fast in water than non solvated form. eg. Fluorocortisone

4. ComplexationThis property can influence the effective drug concentration in gi fluids. Complexation of drug and gi fluids may alter the rate and extent of absorption

eg. Intestinal Mucin form complex with Streptomycin and Dihydro Streptomycin.

In some cases, Poor water soluble drugs can be administered as water soluble complexes. eg. Hydroquinone with Digoxin.

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5.AdsorptionIt is a physical and surface phenomena where the drug

molecules are held on the surface of some inert substances by vanderwall’s forces.

ex. Charcoal used as an antidote; When it is co-administered with promazine, then it reduces the rate and extent of absorption Cholestyramine reduces the absorption of warfarin.

6.Drug Stability And Hydrolysis In GITDrugs undergoes various reactions due to wide spectrum of ph and enzymatic activity of GI fluid namely acid and enzymatic hydrolysis.

eg. T½ of Penicillin G= 1 min. at pH 1 T½ of Penicillin G= 9 min. at pH2So it means Penicillin G is stable at less acidic pH Erythromycin and its esters are unstable at gastric fluid (T½=Less than 2 min.)

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Certain salts also may have low solubility and dissolution rate.

7. Salts

Na or K salts of weak acid dissolves rapidly than free acid.

ex. Na salts of Novobiocin shows improved bioavailability

ex. Al salts of weak acid and pamoate salt of weak base

8. Presence Of SurfactantUse of wetting agent and Solubilizing agent improve the Dissolution rate & absorption of drugs.Ex. Tween 80 increase the rate & extent of absorption of Phenacetin.

9. DissolutionDisintegration is the formation of dispersed granules from an intact solid dosage form whereas the dissolution is the formation of solvated drug molecules from the drug

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SOLID DRUG

DRUG AT ABSORPTIONSITE

DRUG IN SYSTEMIC

CIRCULATION

DISSOLUTION

ABSORPTION

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NOYES AND WHITNEY’S EQUATION

dc/dt = KS(CS-C)Where,

dc/dt = Rate constant, K = constant, S = surface area of the dissolving solid, Cs=solubility of the drug in the solvent, C=concentration of drug in the solvent at time t.

Constant K=D/h

Where, D is the diffusion coefficient of the dissolving material and h is the thickness of the diffusion layer

Here, C will always negligible compared to Cs

So,

dc/dt=DSCs/h

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PHYSICOCHEMICAL FACTORS

1) pH PARTITION THEORY (Brodie) :

It explain drug absorption from GIT and its distribution across biomembranes.

Drug(>100 daltons) transported by passive diffusion depend upon:

dissociation constant, pKa of the drug lipid solubility, K o/w pH at absorption site. Most drugs are either weak acids or weak bases whose degree of ionization is depend upon pH of biological fluid.

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For a drug to be absorbed, it should be unionized and the unionized portion should be lipid soluble.

The fraction of drug remaining unionized is a function of both Dissociation constant (pKa) and pH of solution.

The pH partition theory is based on following assumption:

GIT acts as a lipoidal barrier to the transport of the drug The rate of absorption of drug is directly proportional to its fraction of unionised drug Higher the lipophilicity of the unionised degree, better the absorption.

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HENDERSON HASSELBATCH EQUATION For acid, pKa - pH = log[ Cu/Ci ] For base, pKa – pH = log[ Ci/Cu ] Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will have > 99%of unionized form so gets absorbed in stomach

Weak base quinine (pKa=8.5) will have very negligible unionization in gastric pH so negligible absorption

Several prodrugs have been developed which are lipid soluble to overcome poor oral absorption of their parent compounds.

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eg. Pivampicilin, the pivaloyloxy-methyl ester of ampicilin is More lipid soluble than ampicilin.

Lipid solubility is provided to a drug by its partition coefficient between An organic solvent and water or an aq. Buffer (same pH of ab. Site) E.g. Barbital has a p.c. of 0.7 its absorption is 12% Phenobarbital ( p.c = 4.8 absorption=12%) Secobarbital (p.c =50.7 absorption=40%)

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2)DRUG SOLUBILITY The absorption of drug requires that molecule be in solution at absorption site.

Dissolution, an important step, depends upon solubility of drug substance.

pH solubility profile:

pH environment of GIT varies from Acidic in stomach to slightly Alkaline in a small intestine. soluble 1)Basic drug 1) Acidic medium( stomach)2)Acidic drug 2) basic medium( intestestine)

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Improvement of solubility:

Addition of acidic or basic excipientEx: Solubility of Aspirin (weak acid) increased by addition of basic excipient.

For formulation of CRD , buffering agents may be added to slow or modify the release rate of a fast dissolving drug.

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PHARMACEUTICAL FACTORS MEANS Absorption rate depends on the dosage Form which is administered, ingredients used, proceduresUsed in formulation of dosage forms. The availability of the drug for absorption from the dosage forms is in order.

Solutions > Suspensions > capsules > Compressed Tablets > Coated tablets.

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BIOAVAILABILITY The term bioavailability is defined as the rate and extent of absorption of

unchanged drug from its dosage form. It is the fraction of drug that reaches systemic circulation in an

unchanged form and becomes available for biological effect following administration by any route. It is 100% after IV administration.

It is calculated by comparison of the area under the plasma concentration time curve (AUC) after IV dose of a drug with that observed when the same dose is given by another route e.g. oral.

Area under the curve (AUC) oral x 100 Oral bioavailability =

Area under the curve (AUC) I.V.

Oral bioavailability depends on amount absorbed and amount metabolized before reaching systemic circulation (first pass metabolism) Bioequivalence:

Bioequivalence occurs when two formulations of the same compound have the same bioavailability and the same rate of absorption

BIOAVAILABILITY

Dose

Destroyed in gut

Notabsorbed

Destroyed by gut wall

Destroyedby liver

tosystemiccirculation

Factors Affecting Bioavailability:

Molecular weight of drug. Drug Formulation (ease of dissolution).

(solution > suspension > capsule > tablet) Drug solubility of the drug Chemical instability in gastric pH

(Penicillin & insulin ) First pass metabolism reduces bioavai

Factors Affecting Bioavailability (BAV):

Blood flow to absorptive site

Greater blood flow increases bioavailability Intestine has greater blood flow than stomach

Surface area available for absorption. Intestinal microvilli increases it

Rate of gastric emptying rapid gastric emptying fast transit to

intestine pH of gut

Intestinal motility (Transit Time) Diarrhea reduce absorption

Drug interactions Food

slow gastric emptying generally slow absorption Tetracycline, aspirin, penicillin V