Absorption of drugs by Passive Diffusion.

 

Passive Diffusion

• Also called non-ionic diffusion, it is the major process for absorption of more than 90% of the drugs. 

• The driving force for this process is the concentration or electrochemical gradient. It is defined as the difference in the drug concentration on either side of the membrane.

• Drug movement is a result of the kinetic energy of molecules. Since no energy source is required, the process is called passive diffusion. 

• Passive diffusion is best expressed by Fick's first law of diffusion which states that the transfer of drug molecules takes place from a region of higher concentration to lower concentration until equilibrium is attained and that the rate of diffusion is directly proportional to the concentration gradient across the membrane.

•  It can be mathematically expressed by the following equation:

where,

• dQ/dt = rate of drug diffusion (amount/time). It also represents the rate of appearance of drug in blood

• D = diffusion coefficient of the drug through the membrane (area/time)

• A = surface area of the absorbing membrane for drug diffusion (area)

• Km/w = partition coefficient of the drug between the lipoidal membrane and the aqueous GI fluids (no units) 

• (CGIT-C) = difference in the concentration of drug in the GI fluids and the plasma, called as the concentration gradient (amount/volume)

• h = thickness of the membrane (length)

Characteristics of passive diffusion: 

1. The drug moves down the concentration gradient indicating downhill transport.

2. The process is energy-independent and non-saturable.

3. The rate of drug transfer is directly proportional to the concentration gradient between Gl fluids and the blood compartment.

4. Greater the area and lesser the thickness of the membrane, faster the diffusion; thus, more rapid is the rate of drug absorption from the intestine than from the stomach.

5. The process is rapid for short distances and slower for long distances.

6. Equilibrium is attained when the concentration on either side of the membrane becomes equal.

7. Rate of transfer of unionized species is 3 to 4 times the rate for ionized drugs.

8. Greater the membrane/water partition coefficient of drug, faster the absorption; since the membrane is lipoidal in nature, a lipophilic drug diffuses at a faster rate.

9. The drug diffuses rapidly when the volume of GI fluid is low; conversely, dilution of GI fluids decreases the drug concentration in these fluids (CGrr) and lower the concentration gradient (CGIT C). 

10. The process is dependent, to a lesser extent, on the square root of the molecular size of the drug. The diffusion generally decreases with increase in the molecular weight of the compound. exceptions-for example, cyclosporin A, 

11. Initially, when the drug is ingested, CGIT >> C and a large concentra gradient exists thereby acting as the driving force for absorption. As equilibrium approaches, the drug diffusion should stop and consequently large fraction of drugs may remain unabsorbed. But this is not the case; the passively absorbed drug enters blood, it is rapidly swept away and distributed into a much larger volume of body fluids and hence, the penetration of drug at the absorption site, CGIT, is maintained with greater concentration of drug in plasma. Such a condition is called a Sink condition for drug absorption.

Commonly asked questions.

1. Write a short note on “Absorption of drugs by Passive diffusion”.

2. What is Fick’s first law of diffusion, explaining characteristics of passive diffusion of drugs.

Introduction to Absorption of Drugs.

 

Definition:

• Movement of drug molecules from site of administration to systemic circulation in the unchanged from.

• The rate and extent at which the drug gets absorbed determines its therapeutic success rate.

Major routes of Drug Administration:

1. The Enteral Route:

• This includes peroral i.e. gastrointestinal, sublingual/buccal and rectal routes. 

• The GI route is the most common route of administration.

2. The Parenteral Route:

• This  includes all routes of administration through or under one or more layers of skin. 

• In case of intravenous route as drug is being poured directly in blood there is no question of absorption but,, it is necessary for extravascular parenteral routes like the subcutaneous and the intramuscular routes.

3. The Topical Route:

• This includes skin, eyes or other specific membranes. 

• The intranasal, inhalation, intravaginal and transdermal routes may be considered enteral or topical according to different definitions.

Gastrointestinal Absorption of Drugs.

• GIT represents the most commonly used route of absorption of drugs.

Mechanisms of Drug Absorption:

• Transport mechanisms involved in absorption of drugs can be broadly divided into three categories like,

• Transcellular / Intracellular transport.

• Paracellular / Intercellular Transport.

• Vesicular Transport.

1. Transcellular / Intracellular transport:

• It is defined as the passage of drugs across the GI epithelium. 

• It is the most common pathway for drug transport. 

• The 3 steps involved in transcellular transport of or rugs are 

• (i) Permeation of GI epithelial cell membrane, a lipoidal barrier -this is the major obstacle to drug absorption.

• (ii) Movement across the intracellular space (cytosol).

• (iii) Permeation of the lateral or basolateral membrane-this is of secondary importance. 

• The various transcellular transport processes involved in drug absorption are:

1. Passive Transport Processes: 

• These transport processes do not require energy to pass through the lipid bilayer. 

• Passive transport processes can be further classified into following types

• (a) Passive diffusion.

• (b) Pore transport.

• (c) Ion-pair transport.

• (d) Facilitated- or mediated-diffusion.

2. Active Transport Processes: 

• These transport processes require energy from ATP to move drug molecules from extracellular to intracellular and opposite. 

• They are of two types

• 1) Primary active transport. 

• 2) Secondary active transport-this process is further subdivided into two

• (i) Symport (co-transport)

• (ii) Antiport (countertransport)

2. Paracellular / Intercellular Transport:

• It is defined as the transport of drugs through the junctions between the GI epithelial cells.

• Two types,

• 1. Permeation through tight junctions of epithelial cells: this process basically occurs through openings which are little bigger than the aqueous pores. Compounds such as insulin and cardiac glycosides are taken up by this mechanism.

• 2. Persorption is the permeation of drugs through temporary openings formed by shedding of two neighboring epithelial cells into the lumen.

• Paracellular transport differs from pore transport.

3. Vesicular or Corpuscular Transport (Endocytosis): 

• Like active transport, these are also energy dependent processes.

• Since the mechanism involves transport across the cell membrane, the process can also be classified as transcellular. 

• Vesicular transport of drugs can be classed into two categories

• 1. Pinocytosis: Drinking of cells.

• 2. Phagocytosis: Eating of cells.

Commonly asked questions.

1. Define the process of drug absorption.

2. Define absorption and discuss various mechanisms of drug absorption.

Introduction to Biopharmaceutics.

 

Important Definitions.

1. Biopharmaceutics:

• It is the branch of pharmacy that deals with the study of factors influencing the rate and amount of drug that reaches the systemic circulation and use of this information to optimize the therapeutic efficacy of the pharmaceutical products.

2. Absorption:

• Movement of unchanged form of  drug molecule from site of administration to the systemic circulation is called  absorption.

3)       Bioavailability:

• Rate and extent of drug molecules reaching systemic circulation in intact form.

4) Drug Disposition:

• Collective phenomenon of drug distribution and elimination of drug following absorption is called Drug Disposition.

5) Drug Distribution:

• The movement of drug molecules across the body compartments (Blood and extravascular tissues) is called drug distribution.

6) Drug Elimination:

• It is defined as the process of removal of drug from body termination of its action, it can be achieved by two processes as,

• Biotransformation: Drug metabolism modification of drug action.

• Excretion: Removal of drug molecule.

7) Pharmacodynamics: 

• Study of actions of drugs on the body simply means what drugs do to our body.

8) Pharmacokinetics:

• Study of movement of drugs inside the body simply means what our body does to the drug.

Super Centrifuge.

 Super Centrifuge.

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Centrifuge:

• The equipment used for the process of centrifugation is called a Centrifuge.

• The centrifuges are of two types as following,

1. Sedimentation centrifuge:L

• It is a centrifuge that produces sedimentation of solids based on the difference in the densities of two or more phases of the mixture. 

2. Filtration centrifuge:

•  It is a centrifuge in which solids pass through the porous medium based on the difference in the densities of the solid and liquid phases.

Super Centrifuge. 

•  Super Centrifuge is a continuous centrifuge used for separating two immiscible liquid phases.

Principle:  

• It is a sedimentation centrifuge. 

• The separation is based on the difference in the densities between two immiscible liquids. 

• Centrifugation is done in the bowl of a small centrifuge. 

• During centrifugation, the heavier liquid is thrown against the wall, while the lighter liquid remains as an inner layer. 

• The two layers are simultaneously separated using modified weirs. 

Construction:  

• It consists of a long hollow cylindrical bowl of small diameter. 

• It is suspended from a flexible spindle at the top and guided at the bottom by loose-fit bushing. 

• Two liquid outlets are provided at different heights at the top of the bowl, for simultaneous recovery of the separated liquids using modified weirs.  

Working:  

• The centrifuge is allowed to rotate on its longitudinal axis at a high frequency usually about 2000 revolutions per minute with the help of drive-assembly. 

• The feed is introduced from the bottom of the centrifuge using a pressure system. 

• During centrifugation, two liquid phases separate based on the difference in their densities. 

• The heavier liquid is thrown against the wall, while the lighter liquid forms an inner layer. 

• Both liquids rise to the top of the vertical bowl. 

• The liquid-liquid interface (the so-called neutral zone) is maintained by a hydraulic balance. 

• These two layers are simultaneously separately removed from different heights through modified weirs. 

• Thus the super centrifuge can work for continuous separation of immiscible liquid phases.

Uses:  

1. It is used for separating liquid phases of emulsions in food and pharmaceuticals. 

Commonly Asked Questions.

1. Write a short note on Super Centrifuge.

Non-Perforated Basket Centrifuge.

 

Centrifuge:

• The equipment used for the process of centrifugation is called a Centrifuge.

• The centrifuges are of two types as following,

1. Sedimentation centrifuge:L

• It is a centrifuge that produces sedimentation of solids based on the difference in the densities of two or more phases of the mixture. 

2. Filtration centrifuge:

•  It is a centrifuge in which solids pass through the porous medium based on the difference in the densities of the solid and liquid phases.

Non-Perforated Basket Centrifuge.

Principle:  

• This is a sedimentation centrifuge. 

• The separation is based on the difference in the densities of solid and liquid phases without a porous barrier. 

• The bowl contains a non-perforated side-wall. 

• During centrifugation, solid phase is retained on the sides of the basket, while the  liquid remains at the top, which is removed by a skimming tube.

Construction:  

• It consists of a basket, which may be made of steel or any other suitable metal. 

• The basket is suspended on a vertical shaft and is driven by a motor using a suitable power system. 

Working:  

• The suspension is fed continuously into the basket. 

• During centrifugation, the solid phase is retained on the sides of the basket, while liquid remains on the top. 

• The liquid is removed over a weir or through a skimming tube. 

• When a suitable depth of solids has been deposited on the walls of the basket, the operation is stopped. 

• The solids are then scraped off by hand or using a scraper blade.   

Uses:  

1. Non-perforated basket centrifuge is useful when the deposited solids offer high resistance to the flow of liquid.  

Commonly Asked Questions.

1. Write a short note on Non-Perforated Basket Centrifuge.