Routes Of Admin Lec 1 PDB Flashcards
An epithelium with one layer is a _____ epithelium.
Give 3 examples of types of these epithelia and where they can be found in the body…
Simple e.g Squamous epithelium such as Alveoli Columnar epithelium in GI or Nasal cav Cuboidal epithelium not involved in abs
Transcellular pathway goes across or between cells?
Across cells
Between = paracellular
An epithelium with more than one layer is a _____ epithelium. This type of epithelium must be able to withstand large amounts of wear and tear. Where is it found?
Stratified
E.g Stratified squamous epithelium like cornea, skin, mouth
The Paracellular pathway is a minor pathway - which of the following is rate limiting in this path…
Tight junctions
Adherens junctions
Desmosomes
Gap junctions
Tight junctions are membranes of neighbouring cells fused by connections between cell surface proteins, forming a band around the entire cell.
Allows passage of small, hydrophilic molecules generally
Desmosomes are the most common cell junction - what are they?
Fibrous proteins that cross the gap between cells and anchor keratin filaments in the cytoskeletons together
-less of a barrier for molecules to cross
Gap junctions are sits of intracellular information exchange. Do they have hydrophobic or hydrophilic pores?
Hydrophilic pores
Membranes close but not fused
Small molecules (AA,sugars,nucs,vits) pass between neighbouring cells
Adherens junctions connect what filaments in cytoskeletons of neighbouring cells together?
Actin filaments
Is the lipid bilayer a minor or major barrier to drug absorption?
Major - it’s hydrophobic nature prevents passage of most polar and charged (water soluble) molecules
Transcellular abs = major pathway
Passive diffusion is the minor or main pathway of drug absorption?
What must they do to get into the cytoplasm?
MAIN - diluted diffuse into cells down a conc grad. Must partition into lipid bilayer and then out into cytoplasm
Aqueous pores are involved in transcellular absorption and allow transport of what?
Small neutral solutes such as urea and glycerol - drugs are normally too large to be absorbed in this way
Is facilitated diffusion selective?
Yes - carrier mediated trans of drug down conc grad
Endocytosis = minor pathway that can be split into Pinocytosis and phagocytosis
Pinocytosis is what?
Cell drinking that occurs constantly
- small solute or fluid engulfed.
Absorptive or receptor mediated
What is Endocytosis?
Internalisation of plasma mem which engulfs extracellular fluid
Phagocytosis not relevant for soluble drug abs.
What is it and what does it?
Engulfment of particles by monocytes and macrophages
Endosomes may fuse with ______ and contents are then degraded by ______ enzymes. Drugs may escape ______ degradation and released through basolateral membrane in process called transcytosis. E.G ABS OF NGF, EGF, VACCINES (This could be useful in absorption of higher molecular weight drugs - proteins)
Lysosomes, lysosomal, lysosomal
Tight junctions allow the passage of what?
Allows passage of small, hydrophilic molecules generally
What type of molecules do gap junctions allow to pass directly between neighbouring cells?
- Small molecules
- e.g amino acids, sugars, nucleotides and vitamins
- ALSO enables direct cell to cell electrical conductance
Out of the following, which are less of a barrier to molecules wishing to pass?
Desmosomes
Adherents junctions
Tight junctions
Gap junctions
- Adherens junctions
- Gap junctions
- Desmosomes
REMEMBER: Tight junctions are membranes of neighbouring cells fused by intimate connections between cell surface proteins, forming a band around the entire cell and are RATE LIMITING for PARACELLULAR PATHWAY
Drugs can be absorbed by transcellular absorption by active transport. What is active transport?
- Selective, carrier mediated transport of a drug down or against a concentration gradient.
- It requires energy import (ATP)
Passive diffusion is the main pathway of drug absorption.
The ___ a system from equilibrium, the ____ it moves towards equilibrium
This is the reason behind passive diffusion
- The FURTHER the system from equilibrium, the FASTER it moves towards equilibrium
What is the equation for Fick’s first law of diffusion?
J (flux) = A * D * K * change in C / h
A = Area D = Diffusivity K = Partition coefficient Change in C = Conc grad across membrane h = membrane thickness
What drug properties are proportional to flux?
- Change in concentration across membrane
- Partition coefficient
What drug AND membrane property is proportional to flux?
- Diffusivity
Drugs administered orally must cross the __ __ epithelium to be absorbed and enter the systemic circulation.
GI tract epithelium
What do goblet cells secrete?
Mucus
What is the role of mucus?
Protectant and lubricant
Drugs must ___ though mucus barriers in order to be absorbed
diffuse
The phospholipid bilayer prevents water soluble components of cells from being lost as it is impermeable to most ___ and ___ molecules.
Polar and charged
Broadly speaking which type of drugs tend to be abs by…
1) Paracellular route
2) Transcellular passive diffusion
3) Endocytic processes
4) Transcellular carrier mediated mechanisms (fac/act diff)
1) Small, low mol weight, hydrophillic molecules
2) Lipid soluble drugs
3) Macromolecules (EGF, NGF, Large proteins)
4) Drugs bearing structural similarities to endogenous nutrients e.g L-DOPA
Name the following parameters of the Stokes-Einstein equation:
D = KB * T / 6pi nr
D = diffusivity KB = Boltzman constant (relates temp to energy) T = Temp n = Membrane viscosity r = Particle radius
In the Stokes-Einstein equation, what parameters can we control?
n = Membrane viscosity r = Particle radius (make smaller so inc diff) T = temp (inc temp, inc diff)
LogP (oil/water partition coefficient) is analogous to K (partition coefficient quantifying distribution of drug between aq phase and membrane)
How is P determined?
What is the equation for determining P?
1) Add oil to a drug in water
2) Shake it and leave it to settle
3) The solute will have partitioned
4) Separate and analyse to see how much of the drug is in the aq phase and how much is in octane phase
P = C oil/C water
What drug properties make it more soluble in oil?
- Non-polar
- Hydrophobic properties e.g benzene ring
- Unionised (not charged)
Lipid soluble drugs have a LogP value of greater than or less than 0?
- Greater than 0
P value of greater than 1
Drugs that are equally distributed between oil and water have a P value of WHAT?
1
LogP value of 0
Hydrogen bonds must be ___ before the drug can enter the lipophilic plasma membrane
BROKEN
Change H bond donor groups such as OH for groups which don’t H bond e.g __ to improve lipophilicity so drug absorption can be improved
Cl
What is Lipinski’s rule of 5?
- MW less than 500
- Log P less than 5
- 5 or less H bond donors (OH or NH)
- 10 or less H bond acceptors (O or N)
