PHARMACEUTICAL CHEMISTRYPRESENTED BY: GROUP NO. 4

• KANIZ FATIMA

• FATIMA HAYAT

• SHAZIA NASIM

• SYEDA MAIRA HAMID

• SHERBANO

• SMAIRA AFZAL

• TUBA ALVI

PRESENTED TO: Dr. SOBIA

TOPIC: DRUG ABSORPTION

DATE: 4TH MAY, 2015

WHAT IS DRUG?Drug is any chemical or biologic substance that affects the body and its processes. ORA substance used as medication or in the preparation of medication.

Its MOL.WT should be less than 500.

PHARMACOKINETICSIt describes how the body handles a drug and accounts for the process of:

•Absorption•Distribution•Metabolism•Excretion

We will discuss Drug Absorption

DRUG ABSORPTION

•Drug absorption is the movement of a drug into the bloodstream after administration.

•Absorption affects bioavailability____•How quickly and how much of a drug reaches its target of action.

Drug absorption is determined by:

1) Drug’s physicochemical properties2) Formulation3) Route of administration(oral, buccal, inhalation,parenteral, topical).

Regardless the route, drug must be in solution to be absorbed.

BIOLOGICAL MEMBRANE

Biological membranes consist of a lipid bilayer separating different compartments, with protein molecules acting as enzymes, channels or carrier proteins.

Drugs have to cross the biological membranes to get absorbed.

RULE OF FIVEThe medicinal chemist Christopher Lipinski and his colleagues analysed the physico-chemical properties of more than 2,000 drugs, and concluded that a compound is more likely to be membrane permeable and easily absorbed by the body if it matches the following criteria:•Molecular weight of drug should be less than 500.•Less than 5 hydrogen bond donor.•Less than 10 hydrogen bond acceptor.•Pka value should be less than 5.

PROCESSES DETERMINING ABSORPTION

•PASSIVE TRANSPORT

•ACTIVE TRANSPORT

•ENDOCYTOSIS

•TRANSCYTOSIS

•ORAL ADMINISTRATION

•PARENTERAL ADMINISTRATION

•PORE TRANSPORT

•ION PAIR TRANSPORT

PASSIVE TRANSPORT

PASSIVE TRANSPORT IS A MOVEMENT OF BIOCHEMICAL AND OTHER ATOMIC OR MOLECULAR SUBSTANCES ACROSS CELL MEMBRANES. SO THE DRUG CAN CROSS CELL MEMBRANES USING PASSIVE TRANSPORT IN THREE WAYS :

• SIMPLE DIFFUSION

• FILTRATION/ AQUEOUS DIFFUSION

• BULK FLOW

SIMPLE DIFFUSION• MOST OF THE DRUGS ARE ABSORBED BY SIMPLE DIFFUSION, WHICH IS THE

MOVEMENT OF MOLECULES DOWN THE CONCENTRATION GRADIENT I.E. FROM HIGHER CONCENTRATION (GI FLUIDS) TO LOWER CONCENTRATION (BLOOD).

• THIS TYPE OF TRANSPORT OCCURS MOSTLY FOR THE LIPID SOLUBLE DRUGS.

• DIFFUSION RATE IS DIRECTLY PROPORTIONAL TO THE GRADIENT BUT ALSO DEPENDS ON THE MOLECULE’S LIPID SOLUBILITY, SIZE, DEGREE OF IONIZATION, AND THE AREA OF ABSORPTIVE SURFACE.

NON-SPECIFIC:

• THIS TYPE OF TRANSPORT IS NON-SPECIFIC I.E. NO CARRIER PROTEINS ARE REQUIRED.

ENERGY EXPENDITURE:

• NO ENERGY IS REQUIRED FOR THIS TYPE OF TRANSPORT.

FILTRATION

• FILTRATION INVOLVES THE AQUEOUS CHANNELS OR PORES THROUGH WHICH HYDROPHILIC DRUGS CAN PASS.

• FILTRATION OCCURS IN THE JEJUNUM AND PROXIMAL TUBULES OF KIDNEYS.

• IT IS ABSENT IN THE STOMACH AND THE LINING OF THE URINARY BLADDER.

• ONLY CERTAIN IONS LIKE NA+ AND DRUGS OF LOW MOLECULAR WEIGHT, LIKE ETHANOL AND GLYCEROL CAN UNDERGO FILTRATION.

BULK FLOW• THE DRUG IN THIS PROCESS PASSES THROUGH THE PORES BETWEEN

CAPILLARY ENDOTHELIAL CELLS.

• THE PASSAGE IS INDEPENDENT OF WATER AND LIPID SOLUBILITY.

• BULK FLOW IS THE PHENOMENON MOSTLY SEEN WITH THE INTRA MUSCULAR AND SUBCUTANEOUS INJECTIONS. DRUG IS INJECTED IN BULK FORM INTO THE MUSCLE. DRUG MOLECULES ALONG WITH THE AQUEOUS MEDIUM PASS THROUGH THE PORES OF ENDOTHELIUM, AND DIFFUSE INTO THE BLOOD.

• BULK FLOW DOES NOT OCCUR IN BRAIN BECAUSE OF ABSENCE OF PORES.

• BULK FLOW IS DEPENDENT ON THE BLOOD FLOW, MORE THE BLOOD FLOW, MORE RAPID IS THE ABSORPTION. THIS IS WHY THE AREA IS RUBBED AFTER INTRA MUSCULAR INJECTIONS TO INCREASE THE BLOOD FLOW.

ACTIVE MEMBRANE TRANSPORT

Active membrane transport is for the drugs which cannot cross the lipid membrane and require transport proteins.

It involves the penetration of the drug molecule in the lipid bilayer membrane from lower concentration to the higher concentration of solutes against the concentration gradient

• with the expenditure of energy and

• with the help of special transport protein.

“

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FEATURES OF ACTIVE TRANSPORT•Relatively unusual

•Selective

•Saturable

•Requires Energy Expenditure in the form of ATP

•Limited to drugs structurally similar to endogenous substances e.g: ions, vitamins, sugars, amino acids

•Uptake of Levo Dopa by brain which utilize amino acid transporting mechanism. 

Primary Active Transport

When the substance moves against the concentration gradient by the expenditure of energy.

It transfers only one ion or molecule & only in one direction, hence called UNIPORT.

e.g: absorption of glucose

Secondary Active Transport

When the substance moves against the concentration gradient by the energy stored by a substance moving down the concentration gradient, the process is called secondary transport.

ENDOCYTOSIS

Endocytosis is a process in

which a substance gains

entry into cell by formation

of intracellular vesicle by

virtue of invagination of

plasma membrane and

membrane fusion takes

place.

e.g. at soluble vitamins,

protein molecule, folic acid

ENDOCYTOSIS:

PHAGOCYTOSIS PINOCYTOSIS

RECEPTOR-MEDIATED ENDOCYTOSIS

PHAGOCYTOSIS:

Cellular process of engulfing the solid particle

Vesicular internalization by the cell membrane itself to form the internal phagosome

Vesicle = >0.75 µm in diameter Phagocytosis is mediated by

‘actin-myosin contractile system’.

Ingestion of particle ∞ size of particle

This type of transport is utilized by large molecular weight drugs.

PINOCYTOSIS

The endocytosis in which particles or liquid is brought into cell by forming an invagination or vesicle called lysosomes.

Requires a lot of energy in form of ATP.

Can be in form of; Micropinocytosis with vesicle

(<0.1µm) Macro pinocytosis with vacuole

(0.5-5.0 µm). On average 2% of plasma

membrane internalized per minute.

RECEPTOR MEDIATED ENDOCYTOSIS:

Also term as CLATHRIN MEDIATED

ENDOCYTOSIS.

Process by which cells internalize

molecules by the inward budding of

plasma membrane vesicles containing

protein with receptor site specific to

molecule wit receptor.

Important in absorption across tight

junction of blood brain barrier (BBB).

E.g. therapeutic proteins with large

molecular weight.

Vesicle have coat made up of complex of protein mainly:

• Cytosolic protein clathrin• Coat protein(COP I, II)

Clathrin coated vesicle (CCVs) form domains of plasma

membrane - clathrin coated pits.

concentrate large receptor responsible for receptor mediated endocytosis.

For example; uptake of cholesterol by binding of LDL to LDL receptors associated with

clathrin coated pits.

First identified by MATT LION & P. GEORGE.

Hormone receptor (insulin), Transferrin receptor, Antibodies,

Growth factors

TRANSCYTOSIS: Process by which various

macromolecules are transported across the interior of a cell .

Macromolecules are captured in vesicles on one side of the cell, drawn across the cell and ejected on the other side.

Movement of receptor bound macromolecule through the cell, employing both endocytosis and exocytosis.

Therapeutic drugs, IgA, IgG, transferrin,

Blood capillaries are well known sites for the transcytosis.

Including neuron, osteoclasts, cell of intestine.

Absorption by Oral Administration

To be absorbed, an oral drug encounters:

Absorption of oral drugs involves transport across epithelial cells of the GI tract.

Low pH,

GI secretions

Degrading enzymes.

Absorption in Mouth :The oral mucosa has a thin epithelium and rich

vascularity, which favors absorption.A drug placed between gums and cheeks (bucal

administration) or under the tongue (sublingual administration) retain longer and enhances the absorption.

Examples: Nitroglycerine IsoprenalineClonidine

Absorption in stomach : Large epithelial surface but thick mucous layer limit absorption.

Food especially fatty food slows down the drug absorption. e.g: Parasympatholytic drugs are taken on an empty stomach.For poorly soluble drugs, e.g: Griseofulvin food may enhance the drug absorption.

Absorption in small intestine:Larger surface area. Its membrane is more permeable than stomach.pH ranges 4 to 5 in duodenum and approaches 8 in ileum.For these reasons, most drugs are absorbed faster in the

small intestine than in the stomach. But the decreased blood flow and microflora may

reduce absorption in small intestine by passive diffusion.

PARENTERAL ABSORPTION

parenteral absorption isthe taking up of substances within the body by structures ot

her than the digestive tract.outside the alimentary, commonly means ”the injection routes only.”

Need of Parenteral absorption:To get rapid and systemic effect of the drugTo provide the needed effect when the patient

(unconscious/ trauma patient)is unable to swallow drug due to surgical alterations.

To give nourishment when it cannot taken by mouth.

Parenteral routes

Absorption Drugs given IV enter the systemic circulation directly.

However, drugs injected IM or SC must cross one or more biologic membranes to reach the systemic circulation. If protein drugs with a molecular mass > 20,000 g/mol are injected IM or SC, movement across capillary membranes is so slow that most absorption occurs via the lymphatic system.

Perfusion (blood flow/gram of tissue) greatly affects capillary absorption of small molecules injected IM or SC. Thus, injection site can affect absorption rate. Absorption after IM or SC injection may be delayed for salts of poorly soluble bases and acids.

Pore transporto It is also known as connective transport or

filtration.

o Mechanism _ through the protein channels present in the cell membrane.

o The driving force for the passage of drug through

pore transport is hydrostatic or osmotic pressure differences across the membrane.

o Thus bulk flow of water along with small solid molecules through aqueous channels. Water fluxthat promote such a transport is called as solventdrag.

o The process is important in the absorption of lowmolecular weight (< 100D) , low molecular size (smallerthan the diameter of the pore) and generally watersoluble drugs through narrow , aqueous filled channelsor pores.

Ion pair transporto It is another mechanism to explain the absorption of such drugs which ionize at all pH conditions e.g.quaternary ammonium, sulphonic acid.

o Although they have low partition coefficient valuesthey will penetrate the membrane by forming reversible neutral complexes with endogenous ionse.g. mucin of GIT

o Such neutral complexes have both the required lipophilicity as well as aqueous solubility for passive diffusion.

e.g. propranolol, a basic drug that forms an ion pair with oleic acid and absorbed by this mechanism.

FACTORS AFFECTING ABSORPTION OF

DRUGS

1. Molecular size:•Smaller the molecular size of the drug rapid is the absorption.• Those with a large molecular size undergo endocytosis or facilitated diffusion, while those with smaller molecular sizes undergo diffusion or lipid channels.

2.Degree of Ionization:•Different drugs are either acidic or basic and are present in ionized or unionized form, which is given by their pKa values. And it depend upon the pH of the body .•Acidic drugs are unionized in the acidic medium and basic drugs are unionized in the basic medium. •Acidic drugs are better absorbed from the acidic compartment.

3. Physical Forms: •Drugs exist as solids, liquids or gases. •Gases (anesthesia) are rapidly absorbed than the liquids, while the liquids (syrup or suspension form) are rapidly absorbed than the solids (tablets or capsules).

4. Chemical Nature:•Chemical nature is responsible for the selection of the route of administration of drug.•Drugs in inorganic or salt form are better absorbed than organic forms.

5. Concentration:•According to Fick’s law, higher the concentration more fluctuation occurs across the membrane. The rate is less affected than the extent of absorption.

6. Dosage Forms:Dosage forms also affect the rate and extent of absorption. It include to process disintegration and dissolution .When these two processes occur rapidly, the rate of absorption increases.a. Disintegration:•Breaking up the dosage form into smaller particles. b. Dissolution:•After disintegration, the drug dissolves in the gastric juices, is called dissolution.

7. pH:•Acidic pH favors acidic drug absorption while basic pH is better for basic drugs.

8. Presence of other Substances:Foods or other chemical may increase or decrease the rate of absorption. Especially for the drugs given orally. E.g.•Vitamin C enhances the absorption of iron.•Milk decreases the absorption of tetracycline.•Calcium salts when given with iron salts or tetracycline interfere with their absorption

9. GI Mobility:•GI mobility must be optimal for absorption of oral drugs. It should be neither increased nor decreased which may affect the rate or extent of absorption.10. Particle size• Larger is the particle size, slower will be the absorption.