Transportation of drugs

Question 1

Models of Transportation across membranes

Answer 1

-Davison and Daniells model: hydrophilic part at the bottom and top -> a bilayer lipid bilayer in the middle -> doesn’t explain the transport of hydrophilic molecules and water

-Singer and Nicolson fluid mosaic model explains the transport of water/polar molecule transport across membranes through transmembrane proteins (ion channels) -> in addition to the diffusion of lipophilic molecules through the membrane

-today: membranes also have glycoproteins providing cell membranes an antigenic character (identifies them as a specific cell membrane)

Question 2

Mechanism of drug transport across the membrane:

Answer 2

-Transcellular transport across the membrane: lipophilic molecules (triglyceride)
-Osmosis: semipermeable cell membrane -> hypotonic at one side and hypertonic at the other side, allowing water to move
-carrier-mediated through transporter: changing confirmation when binding the solute -> active transport (against gradient with ATP) and facilitated (passive and with the gradient)
-Paracellular transport: squeeze between the cells (not often)

Question 3

What is the driving force of passive diffusion?

Answer 3

-Concentration gradient: flow from low concentration to the high concentration
-The concentration gradient is maintained bc the blood flushes away the drug

Question 4

Ficks Law and diffusion across the membrane

Answer 4

Ficks law: the rate at which a molecule moves through a membrane is proportional to the concentration gradient and inversely proportional to the thickness of the membrane

D = diffusion co-efficient (property of the drug molecule)
A = surface of the membrane
K = partition coefficient (log P)
h = membrane thickness
C(GI) - C(P) = concentration difference between the GI and the plasma -> MAIN DETERMANT

Question 5

What is the Kinetic behind passive diffusion?

Answer 5

-The rate of diffusion is proportional to the concentration gradient

Question 6

How does water cross the membrane?

Answer 6

-Through channels (aquaporins)
-small molecules (<200D) like urea, ions (potassium or sodium), and hydrophilic small molecules

Question 7

What are the carrier-mediated transport mechanisms?

How is Glucose being transported into the body?

Answer 7

-Facilitated: passive and with the gradient, no ATP required
->GLUT1 (Vitamin B12 and glucose transport, SGLT2 (transport of glucose from renal tubes)

-Active transport: against the gradient, with ATP
-> Na-K ATPase (antiporter)

Question 8

Why is carrier-mediated transport a zero-order process?

Answer 8

Because once the transporter is saturated, the rate doesn’t increase anymore

Question 9

What is the pseudo-order reaction?

Answer 9

-reaction rate is dependent on 2 reactants
-but here the concentration of one reactant is so high, that the reactant in excess is ignored (f.e. amoxicillin in water)

-also in carrier-mediated transport: initially, it looks like a first-order process but once the transporter is saturated the rate becomes constant -> zero-order

Question 10

How do transporter affect Absorption?

Answer 10

-many transporters are present in the GI tract, mediating drug uptake and drug expulsion
-transporter are specific for different substrates: nutrients, sugars, amino acids, vitamins -> drugs compete for substrate site

-SLC transporter: solute carrier -> drug UPTAKE
-ABC: ATP binding cassette transporters -> drug EXPULSION

Question 11

What is a way to overcome the efflux of drugs?

Answer 11

-Increase the dose -> saturate the transporter responsible for the efflux -> whatever amount is left over will be absorbed

-Inhibit the efflux-transporter: f.e. PGB in cancer cells

Question 12

Why should Grapefruit intake be avoided for certain drugs?

Answer 12

-Flavanoids in grapefruit block transporter for drug uptake: too little drug in the body

-Flavanoids interfere with Cyp3A4 -> less drug metabolism -> too much drug in the body

Question 13

What are the effects of Probenecids transporter modulation?

Answer 13

-OAT transporter secretes Penicillin from the blood into the renal tube -> Blockage of the OAT transporter can increase the concentration of penicillin

-URAT transporter reabsorbs uric acid from the urine into the renal tube -> by blocking URAT, the excretion of uric acid can be increased -> reduce Gout build-up in the joints

Question 14

What are enteral routes of administration?

Answer 14

-Buccal or sublinugal
-Rectal
-Oral
-Buccal
-Transdermal
-Inhalation

Question 15

Which route is enteral but not oral?

Answer 15

Sublingual: under the tongue
-rich in blood vessel
-bypasses the first pass (portal circulation)
-Cyclobenzaprine -> first pass creates a psychoactive metabolite
-fast onset, f.e. Nitroglycerin for angina (chest pain)

Question 16

What criteria are required for sublingual drugs?

Answer 16

-Lipophilic
-Soluble
-potent -> small dose

Question 17

Advantages of rectal administration:

Answer 17

-absorption of orally administered drugs work similarly; the rectal is not optimized for absorption and doesn’t have as many villi -> absorption is somewhat slower and less efficient

-bypass first-pass only through the inferior (lower) and middle hemorrhoidal vein; the superior vein will go into the portal circulation and will undergo first pass

Question 18

What determines successful pulmonary drug delivery?

Answer 18

Particle size -> optimum size is 1-2µm

large particles (>5µm) would be impacted by the bronchioles and don’t reach the lung
very small (>1µm) particles will be exhaled before absorption
most inhalers only deliver 10-20% of the administered dose to the lung

Question 19

Intraarterial administration:

Answer 19

-works locally bc the arteries go towards the tissues to provide oxygen-rich blood -> later it will go to the heart and systemically, so it takes more time to work systemically compared to IV
-Bioavailabilty = 100%

-used for diagnostics, imaging, cancer chemotherapy

Question 20

Intrathecal administration

Answer 20

-goes to the spinal cord and the brain
-administrated into the lower back and to the brain (meninges = 3 layers -> Dura mater, Arachnoid, Pia mater) -> given below dura mater so that it can easily enter the CNS
-Bioavailability = 100&

Question 21

Why are intradermal injections not the best way to administer a drug?

Answer 21

-into the the skin between dermal and epidermal layer
-not much space -> only low volume possible
-slow absorption

-mostly used for immunological tests (tuberculin), some vaccines (BCG), allergy tests

Question 22

Subcutaneous route

Answer 22

-administered to connective and adipose tissue
-good for lipophilic drugs
-up to 1 ml
-good blood supply
-aqueous solutions are rapidly absorbed, and suspension and oily material slowly (extended period of exposure)

Question 23

Intramuscular administration

Answer 23

-rich supply of blood vessels -> rapid absorption
-avoids the first pass
-large volume (up to 10ml)
-aqueous solutions rapidly absorbed, oily material slowly
-can administer mildly irritant agents