Physiologic Factors Related to Drug Absorption Flashcards
The drug absorption process can be defined as?
It is the movement of drugs from the application site into the bloodstream via the physiological membrane or barrier.
What is the eventual goal of the absorption process?
It is to make the drug available at the specific site of action in a fitting concentration to produce the desired pharmacological action.
What happens with the drug in systemic applications?
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.
What occur in extended release drug formulation?
Here the drug has to be positioned near the site of application for slow release and thereby leads to slow absorption.
Topical or local applications?
It is desirable to minimize the systemic absorption to avoid severe systemic side effects.
What factors are important for successful absorption of the drug from its formulation?
The anatomy and physiology of the physiological barriers
What does the design of the dosage form of a drug depend on?
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.
Oral route of administration (characteristics and limitations):
- 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.
Give some examples of oral drug dosage form?
- tablet,
- capsule
- sirup
- suspension
- emulsion
The major disadvantage of oral route administration?
The major disadvantage is the slow onset of action of drug due to diminished absorption process.
What causes unpalatable drugs in patients? And give some expamples:
Usually have lesser patient compliance and can cause nausea and vomiting to the patients.
Examples: quinine, clarithromycin, flucloxacillin.
What is the first-pass metabolism?
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
What about buccal and sublingual routes of administration?
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.
Rectal route:
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.
Parental drug administration?
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.
Topical administration?
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.
What is a prerequisite condition during drug formulation design?
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.
Nonmucosal Barrier to Drug Absorption
The skin was designed to:
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.
Skin prevents:
Excessive loss of water and other bodily constituents.
What is stratum corneum?
It is the thin outer epidermis layer that provides the skin’s remarkable barrier properties.
What is the major component of stratum corneum?
The stratum corneum consists of corneocytes which are surrounded by an extracellular milieu of lipids organized as multiple lamellar bilayers.
The extracellular milieu of lipids only allow the entry of:
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.
How is the skin as a barrier?
Skin keeps microorganisms and noxious chemicals out and body water in.
What about TOPICAL drugs?
- It is the first line of treatment in dermatology.
- Here the percutaneous absorption will be minimal and systemic side effects will be negligible.
Nail as a barrier:
What is the most commonly administered drug for the treatment of nail disease?
It is an orally administered drug and they are systematically distributed and subsequently reach the infected site of the nail bed.
NAIL BED
What happens with antifungal drugs exerting an effect on nail infections?
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.
NAIL PLATE
What happens with the administration of the drug in the nail plate?
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).
NAIL AS A BARRIER?
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.
What is the reason of long treatment time and lack of efficacy of topical formulations for nail diseases?
It is due to the differences in the stratum corneum and nail plate.
What is the importance of drug transporters?
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.
What are the carrier membrane transporters?
What are the carrier membrane transporters?
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.
Carrier-mediated transporters are classified in:
- solute carrier superfamily
- uptake transporters
- ATP binding cassete (ABC) transporter superfamily
- efflux transporters
ATP-Binding Cassette (ABC) Transporters
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
How is also known the ABC transporters?
They are also known as primary active transporters which restrict the intracellular drug content by inhibiting the influx and facilitated the efflux.
What is the classification of ABC transporters?
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).
What is the role of MRPs (multidrug resistance-associated proteins)?
It plays a significant role in the intestinal drug absorption. Althoug several transporters are found to be expressed in the enterocytes.
What are enterocytes?
They are intestinal absorptive cells. Epithelial cells which line the inner surface of large and small intestines.
Where are found the MRP2, BCRP and P-gp?
They are most commonly found on the brush border membrane of the intestinal epithelia.
Where are found the MRP3?
Drug encounter this receptor expressed on the basolteral membrane.
What is BCRP?
It is. the breast cancer receptor protein that depends on ATP and is implicated in resistance to pathogenic microbes to drugs and cancers.
P-GLICOPROTEIN (P-GP): CHARACTERISTICS AND MORE
- 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
P-GLYCOPROTEIN (P-GP)
- 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
What are the two models to describe drugP-gp interaction?
First model: outwardly directed drug/lipid flippase model
Second model: hydrophobic vacuum cleaner model.
Explain the flippase model:
- 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.
- After that, the drugs are projected to the leaflet of outer membrane where it rapidly undergoes passive diffusion into the extracellular aqueous phase.
