Drugs and the CNS (Prof. Smart)

Question 1

What is the most common molecular structure for local anesthetics (LAs) ?

Answer 1

• an aromatic group
• and amide or ester
• a basic side chain (2ary or 3ary amine)
  These three groups are connected by ester linkages, which can easily be broken down by esterases

Question 2

What suffix allows us to distinguish LAs from other molecules ?

Answer 2

The suffix -caine e.g. procaine or lignocaine (more stable)

Question 3

What is the pKa of LAs ?

How are they charged at physiological pH ?

Answer 3

pKa(LA) = 8-9

They are thus positively charged at physiological pH (=7.2-7.4)

Question 4

Are LAs active in their charged or uncharged form ?

What does this imply for the LAs diffusion across the membrane ?

Answer 4

In their charged form.

Thus, LA crosses the membrane and picks up a proton (LA+).

Question 5

How do LAs work ?

What are the 2 pathways LAs use ?

Answer 5

LAs block Na+ channels to prevent sodium from rushing into the neuron.
They can use either:
- the hydrophilic pathway: get inside the neuron, pick up a H+ and block the channel from the inside
- the hydrophobic payhways: diffuse into the membrane, travel towards the channel, pick up a H+ and block it

Question 6

What are the 4 main ways of administrating a LA ?

Answer 6

1. Topical (T) –> skin, cornea, oropharynx
2. Infiltration (I) (intradermal + subcutaneous) –> injection around nerve ending (e.g. dentistry)
3. Peripheral nerve block (PNB) –> injection around sensory nerve trunk (e.g. anesthesia of entire leg/arm)
4. Central nerve block (CNB) –> spinal anesthesia (injection into CSF of sub-arachnoid space in lumbar region) and epidural anesthesia (injection into arachnoid, specific for 1 nerve route –> used 99% for “painless childbirth”)

Question 7

Why are anesthetic injection done in the lumbar region of the spinal cord ?

Answer 7

Because the spinal cord in thinner and very fibrous in this region.

Question 8

Give a few examples of LAs, their molecular structure (A or E), how they are used and how long they last.

Answer 8

Cocaine: E, not used, short (<30mins)
Procaine: E, infiltration, PNB, CNB, short
Lignocaine: A, all uses, inertmediate (2-3hrs)
Prilocaine: A, all uses, intermediate
Amethocaine: E, topical, long (>3hrs)
Bupivocaine: A, PNB or CNB, long
Benzocaine: E, topical, long

Question 9

To which ions is the nAChR permeable ?

Answer 9

To Na+, K+, and to a lesser extent Ca2+ –> lets Na+ come in and K+ get out.

Question 10

How long does ACh stay in the synaptic cleft ?

Answer 10

10-15ms

Question 11

How many receptors are situated on the post-synaptic neuron ?

Answer 11

50-100

Question 12

How many molecules of ACh can each nAChR bind ?

Answer 12

2

Question 13

How many molecules of ACh in each vesicle ?

Answer 13

~10 000 molecules of ACh/vesicle

Question 14

Why is there a huge error margine for the activation of the nAChRs ?

Answer 14

Because hundreds/thousands of vesicles, each containing about 10,000 molecules of ACh must excite 50-100 nAChRs (each able to bind 2 ACh molecules) –> only between 100 and 200 molecules of ACh necessary to excite all the receptors on the post-synaptic neuron ==> HUGE error margine

Question 15

How large is the synaptic cleft ?

Answer 15

About 20nm.

Question 16

How is ACh broken down ?

Which element of ACh is recycled and why ?

Answer 16

ACh is broken down by ACLE (Acetylcholinesterase).

Acetyl diffuses away and choline is recycled in the nerve terminal because in it more synthetically valuable.

Question 17

How is ACh synthesized in the nerve terminal ?

Answer 17

The mitochondria convert acetate to acetyl, which associates w/ CoA, forming AcetylCoA.
Choline enters the terminal via the chloine transporter (which uses the Na+ gradient to transport choline into the neuron).
Choline acetyltransferase converts AcetylCoA + CoA into ACh, which is stored into a secretory vesicle.

Question 18

What are the 3 ways in which drugs can affecting NM transmission ?

Answer 18

1. Act on NT synthesis (He. and TEC)
2. Act to inhibit NT release
3. Act post-synaptically, blocking ion channels/GPCRs

Question 19

How does He. (Hemicholinium) work ?

Answer 19

He. = choline uptake inhibitor

Question 20

How does TEC (triethylcholine) work ?

Answer 20

Part of the TEC molecules can enter the neuron via the choline transporter, are attached to AcetylCoA and stored into vesicles. This leads to the release of a “false transmitter” = ATEC

Question 21

How can we act to inhibit NT release ?

Answer 21

• LAs (Na+ blockers)
• use divalent cations (transition metals: Mg2+, Cd2+, Co2+, Mn2+) to block Ca2+ entry
• toxins e.g. botulinium toxin (botox) = protease that destroys nerve terminal (nerve grows back after 6 weeks) or beta-bungarotoxin (from snake) = inhibits NT release
  Other toxins: steptomycin, neomycin, fanomycin

Question 22

How can we increase NT release ?

Answer 22

By blocking K+ channels –> repolarization will take much longers (will only occur because of Na+ inactivation) –> increased NT release

Question 23

How can we act post-synaptically to decrease NM transmission ?

Answer 23

By using:

• non-depolarizing competitive blockers
• depolarizing, non-competitive blockers

Question 24

How do non-depolarizing competitive blockers work ?

Can these blockers be ruled out ? If yes, how ?

Answer 24

The blocker binds to the nAChR instead of ACh.
This blocker can be ruled out if we increased the effective concentration of ACh in the synaptic cleft (e.g. by inhibiting ACLE).

Question 25

How do depolarizing non-competitive blockers work ?

Can these be ruled out ? If yes, how ?

Answer 25

At first, the blocker binds to the receptor, whih is followed by a brief depolarization.
Another blocker molecule then binds to the pore of the receptor channel, preventing the mvnt of Na+ in and K+ out. At later stages, the blocker molecule in the pore leaves and the channel closes (receptor desensitization because the blocker is there too long).
This cannot be ruled out, we must either destroy the blocker or wait for it to leave.

Question 26

Give a few examples of non-depolarizing blockers, potency as well as their duration of action.

Answer 26

• tobocurarine: potency 1, med/long (20-30mins)
• pancuronium: potency 5, med
• gallumine: potency 0.2, med
• alcuronium: potency 1, med/long
• vancuronium: potency 3, short/med (<20mins)
• atracurium: potency 0.9, med

Question 27

GIve a few examples of depolarizing non-competitive drugs.

Answer 27

• Suxamethonium (like to ACh molecules put together) –> used only for intubation (surgery)
• decamethonium
• suxethonium