Bench to bedside Flashcards
What are the physicochemical barriers to drug delivery?
Poor aqueous solubility
pH dependent solubility
Extensive ionisation at GI pH range
Extreme lipophilicity
High molecular weight
Susceptibility to pH mediated degradation
What are the physiological barriers to drug delivery?
Mucus barrier
Diverse pH range of the GI tract (1.2-7.4)
Rapid gastric emptying
Gastric and intestinal motility
First-pass metabolism
Presence of digestive enzymes
GI microflora and their secretions
What are the biopharmaceutical barriers to drug delivery?
Poor drug permeability
Pre-systemic metabolism in the GI tract
Presence of drug efflux transporters
pH and mucosal layer thickness variations in the GI tract depending upon the location
What are the clinical barriers to drug delivery?
Fed and fasted state variability in drug absorption
Inter/Intra individual differences in oral bioavailability
Difference in gastric emptying time and GI transit time
Disease state
What does the mucus barrier do?
Protect cell surface from pathogens and harm and allow passage of substance, the absence of this can lead to colitis in the GI tract, dry eyes and when mucus is overproduced can cause CF in respiratory which leads to inflammation and infection
How is the mucus barrier formed?
Mucins are thick extended glycoprotein polymers which have sugar side chains. They are made in the endoplasmic reticulum and transported to the golgi and glycosylated.
What part of the intestine has a large dense layer and bacteria cannot penetrate it?
Large intestine
What art of the intestine has one layer which bacteria can penetrate it easily?
Small intestine
How do drugs get across the intestinal mucosa?
-Stop concentration gradient just outside the point of absorption
-Careful control of release of the drug
Where do fast release drugs stay?
Doesn’t reach epithelium stays in the lumen
Where do slow release drugs stay?
Concentration gradient is too shallow and does not cross the epithelium, therefore not absorbed.
What are the two ways in which we can deliver drugs across the mucus barrier?
1) Mucoadhesive
2) Mucopenetrant
What are mucoadhesive drugs?
-Drug/carrier which sticks to mucus and is then carried along the GIT an the drug is released along the way, the drug is then retained for a lifetime of mucus transit and has to pass through mucus which goes agasint the flow.
PRO of mucoadhesive drugs?
Doesn’t get maintained in the lumen
CON of mucoadhesive drugs?
Drug has to go against the mucus
How do Mucopenetrant drugs work?
Drug/carrier which penetrate though the mucus to get to the epithelium.
PRO of mucopenetrant drugs?
Gets to epithelium
CONs of mucopenetrant drugs
Difficult to avoid muco-adhesion, therefore need to have a nano-sized vehicle with a ‘stealth’ coating, such as PEG
What are the 5 routes to drug absorption across mucosae?
1) Transcellular route - passive diffusion
2) Paracellular route (passive diffusion)
3) Transcellular route (Active transporter utilisation)
4) Lipid absorption via micelles/bile salts
5) Particulate absorption via GALT
What is the mechanism of transcellular route for drugs to cross the mucosae?
- Mechanism: Passive diffusion (Fick’s law)
- High concentration on apical side of the cell
-Low conentration inside the cell
-Molecule diffuses into the cell and out the other side into the blood
Tries to equalise
What drugs use the transcellular route?
-Most drug molecules
-Neutral molecules (un-ionised)
-logP is important, as it needs to partition into the membrane, need to be reasonably high
What is the mechanism of the paracellular route?
Absorption through tight junctions
What is the pore size in paracellular route?
Jejunum and small intestine 0.8nm, ileum and colon 0.3nm
What drugs use the paracellular route?
Small hydrophobic molecules of molecular diameter less than 1.15nm. Example: Mannitol, PEG 400, Lactulose
