Routes Of Admin Lec 1 PDB

Question 1

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…

Answer 1

Simple 
e.g 
Squamous epithelium such as Alveoli
Columnar epithelium in GI or Nasal cav
Cuboidal epithelium not involved in abs

Question 2

Transcellular pathway goes across or between cells?

Answer 2

Across cells

Between = paracellular

Question 3

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?

Answer 3

Stratified

E.g Stratified squamous epithelium like cornea, skin, mouth

Question 4

The Paracellular pathway is a minor pathway - which of the following is rate limiting in this path…

Tight junctions
Adherens junctions
Desmosomes
Gap junctions

Answer 4

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

Question 5

Desmosomes are the most common cell junction - what are they?

Answer 5

Fibrous proteins that cross the gap between cells and anchor keratin filaments in the cytoskeletons together
-less of a barrier for molecules to cross

Question 6

Gap junctions are sits of intracellular information exchange. Do they have hydrophobic or hydrophilic pores?

Answer 6

Hydrophilic pores
Membranes close but not fused
Small molecules (AA,sugars,nucs,vits) pass between neighbouring cells

Question 7

Adherens junctions connect what filaments in cytoskeletons of neighbouring cells together?

Answer 7

Actin filaments

Question 8

Is the lipid bilayer a minor or major barrier to drug absorption?

Answer 8

Major - it’s hydrophobic nature prevents passage of most polar and charged (water soluble) molecules

Question 9

Transcellular abs = major pathway
Passive diffusion is the minor or main pathway of drug absorption?

What must they do to get into the cytoplasm?

Answer 9

MAIN - diluted diffuse into cells down a conc grad. Must partition into lipid bilayer and then out into cytoplasm

Question 10

Aqueous pores are involved in transcellular absorption and allow transport of what?

Answer 10

Small neutral solutes such as urea and glycerol - drugs are normally too large to be absorbed in this way

Question 11

Is facilitated diffusion selective?

Answer 11

Yes - carrier mediated trans of drug down conc grad

Question 12

Endocytosis = minor pathway that can be split into Pinocytosis and phagocytosis

Pinocytosis is what?

Answer 12

Cell drinking that occurs constantly
- small solute or fluid engulfed.
Absorptive or receptor mediated

Question 13

What is Endocytosis?

Answer 13

Internalisation of plasma mem which engulfs extracellular fluid

Question 14

Phagocytosis not relevant for soluble drug abs.

What is it and what does it?

Answer 14

Engulfment of particles by monocytes and macrophages

Question 15

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)

Answer 15

Lysosomes, lysosomal, lysosomal

Question 16

Tight junctions allow the passage of what?

Answer 16

Allows passage of small, hydrophilic molecules generally

Question 17

What type of molecules do gap junctions allow to pass directly between neighbouring cells?

Answer 17

• Small molecules
• e.g amino acids, sugars, nucleotides and vitamins
• ALSO enables direct cell to cell electrical conductance

Question 18

Out of the following, which are less of a barrier to molecules wishing to pass?

Desmosomes
Adherents junctions
Tight junctions
Gap junctions

Answer 18

• 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

Question 19

Drugs can be absorbed by transcellular absorption by active transport. What is active transport?

Answer 19

• Selective, carrier mediated transport of a drug down or against a concentration gradient.
• It requires energy import (ATP)

Question 20

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

Answer 20

• The FURTHER the system from equilibrium, the FASTER it moves towards equilibrium

Question 21

What is the equation for Fick’s first law of diffusion?

Answer 21

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

Question 22

What drug properties are proportional to flux?

Answer 22

• Change in concentration across membrane

- Partition coefficient

Question 23

What drug AND membrane property is proportional to flux?

Answer 23

• Diffusivity

Question 24

Drugs administered orally must cross the __ __ epithelium to be absorbed and enter the systemic circulation.

Answer 24

GI tract epithelium

Question 25

What do goblet cells secrete?

Answer 25

Mucus

Question 26

What is the role of mucus?

Answer 26

Protectant and lubricant

Question 27

Drugs must ___ though mucus barriers in order to be absorbed

Answer 27

diffuse

Question 28

The phospholipid bilayer prevents water soluble components of cells from being lost as it is impermeable to most ___ and ___ molecules.

Answer 28

Polar and charged

Question 29

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)

Answer 29

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

Question 30

Name the following parameters of the Stokes-Einstein equation:

D = KB * T / 6pi nr

Answer 30

D = diffusivity
KB = Boltzman constant (relates temp to energy) 
T = Temp
n = Membrane viscosity 
 r = Particle radius

Question 31

In the Stokes-Einstein equation, what parameters can we control?

Answer 31

n = Membrane viscosity 
r = Particle radius (make smaller so inc diff) 
T = temp (inc temp, inc diff)

Question 32

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?

Answer 32

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

Question 33

What drug properties make it more soluble in oil?

Answer 33

• Non-polar
• Hydrophobic properties e.g benzene ring
• Unionised (not charged)

Question 34

Lipid soluble drugs have a LogP value of greater than or less than 0?

Answer 34

• Greater than 0

P value of greater than 1

Question 35

Drugs that are equally distributed between oil and water have a P value of WHAT?

Answer 35

1

LogP value of 0

Question 36

Hydrogen bonds must be ___ before the drug can enter the lipophilic plasma membrane

Answer 36

BROKEN

Question 37

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

Answer 37

Cl

Question 38

What is Lipinski’s rule of 5?

Answer 38

• 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)