Physiologic Factors Related to Drug Absorption

Question 1

The drug absorption process can be defined as?

Answer 1

It is the movement of drugs from the application site into the bloodstream via the physiological membrane or barrier.

Question 2

What is the eventual goal of the absorption process?

Answer 2

It is to make the drug available at the specific site of action in a fitting concentration to produce the desired pharmacological action.

Question 3

What happens with the drug in systemic applications?

Answer 3

In this case, the drug is available completely and consistently at the site of action in the appropriate concentration and therefore does not have any physiological barrier towards the absorption.

Question 4

What occur in extended release drug formulation?

Answer 4

Here the drug has to be positioned near the site of application for slow release and thereby leads to slow absorption.

Question 5

Topical or local applications?

Answer 5

It is desirable to minimize the systemic absorption to avoid severe systemic side effects.

Question 6

What factors are important for successful absorption of the drug from its formulation?

Answer 6

The anatomy and physiology of the physiological barriers

Question 7

What does the design of the dosage form of a drug depend on?

Answer 7

Many times depends on the routes of applications, such as oral, parenteral, topical, intranasal, pulmonary, ocular, vaginal, and uterine routes. However, all the routes have their own physiologic conditions including nature of cell membrane, pH differences, differences in splanchnic blood flow, transport processes.

Question 8

Oral route of administration (characteristics and limitations):

Answer 8

• It is one of the utmost sensitive and complex routes of drug application.
• The oral route is considered safe, convenient, and dosage forms
• The foremost constraints for the efficacious drug absorption at the site of action are the gastric emptying time, gastrointestinal motility, pH, and presence of food and nutrients.

Question 9

Give some examples of oral drug dosage form?

Answer 9

• tablet,
• capsule
• sirup
• suspension
• emulsion

Question 10

The major disadvantage of oral route administration?

Answer 10

The major disadvantage is the slow onset of action of drug due to diminished absorption process.

Question 11

What causes unpalatable drugs in patients? And give some expamples:

Answer 11

Usually have lesser patient compliance and can cause nausea and vomiting to the patients.
Examples: quinine, clarithromycin, flucloxacillin.

Question 12

What is the first-pass metabolism?

Answer 12

The first pass effect or first-pass metabolism or presystemic metabolism is another major drawback of oral administration that can lead to excessive biotransformation (of drug) and thereby cause diminished biological activity

Question 13

What about buccal and sublingual routes of administration?

Answer 13

Buccal and sublingual routes have great absorption rate and permeability of drugs, but the physicians recommend only small doses because of the limited surface area of mucosa.

Question 14

Rectal route:

Answer 14

It is the better choice for the administration of drugs in unconscious patients but is marred with irregular or incomplete absorption and also causes irritation to the rectal mucosa.

Question 15

Parental drug administration?

Answer 15

Advantage: This route shows rapid onset of action of drug molecule as the drug is injected directly into the bloodstream and also makes the drug 100% available.

Limitation: the major demerit of the route is the withdrawal of drugs from the body of patient is not possible, and it may also induce hemolysis, thrombophlebitis of the vein, and necrosis of adjoining tissues.

Question 16

Topical administration?

Answer 16

Topical drug delivery provides a constant plasma drug profile of the administered drug with the easy option to withdraw drug therapy by removing the transdermal patches or other formulations.

Question 17

What is a prerequisite condition during drug formulation design?

Answer 17

It is the selection of an appropriate administration route, which needs extensive knowledge of the biopharmaceutical properties of drug molecules. It is important to consider the physiological barriers that can affect the drug absorption from the site of application and overall can alter the biopharmaceutical aspects of the drug candidate.

Question 18

Nonmucosal Barrier to Drug Absorption

The skin was designed to:

Answer 18

Allow very little entry, since other tissues like permeable epithelia of the GI tract and lung, offer the prime means of regulated entry into the body.

Question 19

Skin prevents:

Answer 19

Excessive loss of water and other bodily constituents.

Question 20

What is stratum corneum?

Answer 20

It is the thin outer epidermis layer that provides the skin’s remarkable barrier properties.

Question 21

What is the major component of stratum corneum?

Answer 21

The stratum corneum consists of corneocytes which are surrounded by an extracellular milieu of lipids organized as multiple lamellar bilayers.

Question 22

The extracellular milieu of lipids only allow the entry of:

Answer 22

Lipid soluble and low molecular weight drug molecules, prevent excessive loss of water from the body and likewise, block entry of most topically applied drugs.

Question 23

How is the skin as a barrier?

Answer 23

Skin keeps microorganisms and noxious chemicals out and body water in.

Question 24

What about TOPICAL drugs?

Answer 24

• It is the first line of treatment in dermatology.

- Here the percutaneous absorption will be minimal and systemic side effects will be negligible.

Question 25

Nail as a barrier: | What is the most commonly administered drug for the treatment of nail disease?

Answer 25

It is an orally administered drug and they are systematically distributed and subsequently reach the infected site of the nail bed.

Question 26

NAIL BED | What happens with antifungal drugs exerting an effect on nail infections?

Answer 26

When this type of drug is administered through systemic administration, it is obstructed due to the limited blood circulation in the affected nail bed, resulting in low transport of the drug.

Question 27

NAIL PLATE | What happens with the administration of the drug in the nail plate?

Answer 27

The nail plate creates a much longer diffusional pathway due to its thickness to deliver a drug. The restriction of the drug penetration is due to the stable disulfide bonds (which are the reasons behind the hardness of nail).

Question 28

NAIL AS A BARRIER?

Answer 28

The nail acts as a hydrophilic gel rather than lipophilic making it convenient for drug delivery systems across other body tissues having a bilipid membrane.

Question 29

What is the reason of long treatment time and lack of efficacy of topical formulations for nail diseases?

Answer 29

It is due to the differences in the stratum corneum and nail plate.

Question 30

What is the importance of drug transporters?

Answer 30

Drug transporters play a crucial role in achieving the desired intracellular concentration of drugs. The outcomes of coordinated events and of several effluxes and uptake transporters facilitated the movement of drugs across the biological membrane.

Question 31

What are the carrier membrane transporters?

Question 32

What are the carrier membrane transporters?

Answer 32

Are large, membrane-bound proteins expressed in tissues such as epithelia of major organs of secretion and absorption like intestine, liver, and kidney as well as brain, testes, and placent.

Question 33

Carrier-mediated transporters are classified in:

Answer 33

1. solute carrier superfamily 2. uptake transporters 3. ATP binding cassete (ABC) transporter superfamily 4. efflux transporters

Question 34

ATP-Binding Cassette (ABC) Transporters

Answer 34

t is a prominent class of multidomain integral membrane proteins which relies on ATP hydrolysis to translocate solutes like amino acids, ions, proteins, peptides, sugars, choles- terol, toxins, and metabolites across cellular membranes and implicated in resistance to pathogenic microbes to drugs and cancers

Question 35

How is also known the ABC transporters?

Answer 35

They are also known as primary active transporters which restrict the intracellular drug content by inhibiting the influx and facilitated the efflux.

Question 36

What is the classification of ABC transporters?

Answer 36

They are classified into: - P-glycoprotein (ABCB1, MDR1, P-up) - multidrug resistance-associated proteins (MRPs) including nine members (MRP1 (ABCC1) - MRP2 (ABCC2), MRP3 (ABCC3), MRP4 (ABCC4), MRP5 (ABCC5), MRP6 (ABCC6), MRP7 (ABCC10), MRP8 (ABCC11), MRP9 (ABCC12)) - breast cancer resistance protein (ABCG2, BCRP).

Question 37

What is the role of MRPs (multidrug resistance-associated proteins)?

Answer 37

It plays a significant role in the intestinal drug absorption. Althoug several transporters are found to be expressed in the enterocytes.

Question 38

What are enterocytes?

Answer 38

They are intestinal absorptive cells. Epithelial cells which line the inner surface of large and small intestines.

Question 39

Where are found the MRP2, BCRP and P-gp?

Answer 39

They are most commonly found on the brush border membrane of the intestinal epithelia.

Question 40

Where are found the MRP3?

Answer 40

Drug encounter this receptor expressed on the basolteral membrane.

Question 41

What is BCRP?

Answer 41

It is. the breast cancer receptor protein that depends on ATP and is implicated in resistance to pathogenic microbes to drugs and cancers.

Question 42

P-GLICOPROTEIN (P-GP): CHARACTERISTICS AND MORE

Answer 42

- It is a polypeptide that confers protection to tissues from endogenous metabolites and toxic xenobiotics. - It transporter influences the uptake and distribution of drugs. - It is also responsible for shuttling the structurally dissimilar hydrophobic amphipathic compounds as well as peptides, therapeutic drugs, and lipid-like compounds. - It is widely distributed across the blood brain barrier, pancreatic ducts, intestine, proximal kidney tubules, bile ducts, adrenal gland and it is overexpressed in most of the human cancers, contributing to the cancer chemotherapy resistance. - The protein comprises of two domains: two transmembrane domains (TMD) and two cytosolic nucleotide-binding domains (NBD). - It is reported that two ATP molecules bind between the NBDs at the respective binding sites where hydrolysis of ATP takes place providing energy for efflux of substrate through binding to TMD

Question 43

P-GLYCOPROTEIN (P-GP)

Answer 43

- The drug present in the intracellular environment binds to the inner-faced conformation from the membrane cytosolic side (TMD). - Following which, using the energy derived from ATP hydrolysis (catalyzed by NBD), the membrane switches to the outer-faced conformation thereby reorienting the binding site to the extracellular side, which results in drug expulsion -

Question 44

What are the two models to describe drugP-gp interaction?

Answer 44

First model: outwardly directed drug/lipid flippase model Second model: hydrophobic vacuum cleaner model.

Question 45

Explain the flippase model:

Answer 45

1. The drug first partitions into the membrane, following which it spontaneously translocates to the inner leaflet and interacts with the P-gp substrate-binding pocket. 2. After that, the drugs are projected to the leaflet of outer membrane where it rapidly undergoes passive diffusion into the extracellular aqueous phase.