Lecture 39 (Cut off for Exam 3)

Question 1

Tubocurarine

Answer 1

• First identified NM blocker
• Quat. ammonium and tertiary amine (protonated at pH = 7.4)
• 2 tetrahydroisoquinoline rings linked by a phenoxylether
• From curarine poison used by S.A. indians

Question 2

Tubocurarine v.s. ACh

Answer 2

• Both have positive nitrogens
• No ester bond like ACh has
• SIGNIFICANTLY larger than ACh

Question 3

SAR: d-Tubocurarine

Answer 3

• Two positive nitrogen centers at specifically 1.15 nm apart (rigid pharmacore)
• Two binding sites: anionic
• Two binding sites need to be occupied
• Very strong interaction which makes up for lack of ester

Question 4

Designing New Compounds

Answer 4

Clinical Use:

• NM blocker for surgery
• Tubocurarine has SE like histamine release
• Permits for lower and safer levels of gen. anesthesia

Question 5

Depolarizing NM Blockers

Answer 5

• Decamethonium Bromide and Succinylcholine Chloride

- Simplified tubocurarine

Question 6

SAR: Depolarizing NM Blockers

Answer 6

• Two quat. ammonium

- 10-12 unsubstituted methylene groups in between for maximum blocking effect

Question 7

Decamethonium

Answer 7

• Flexible
• Capable of lots of conformations
• Full extension is most stable and places N centers 1.4 nm away
• More folded conformations plane N at ~1.14 nm away, more closely resembles tubocurarine
• Long lasting, long recovery times
• SE: heart effects

Question 8

Succinylcholine Chloride

Answer 8

• Suxamthonium
• Depolarizing NM Blocker
• Dimer of ACh, bound alpha carbons by ester
• Rapidly hydrolyzed in vivo and in vitro, so must make solutions fresh from dry powder
• Short duration, 6-8 minutes, useful in tracheal intubation assistance
• SE: autonomic ganglia

Question 9

Depolarization

Answer 9

• All drugs in this category first depolarize the membrane

- Undesirable, so research has focused mainly on non-depolarizing agents

Question 10

Non-depolarizing NM Blockers

Answer 10

• More rigid structure with positive, quat. heads being part of bulky groups
• Include ACh skeleton

Question 11

Ideal NM Blocker

Answer 11

Non-depolarizer that is metabolically inactivated and rapidly eliminated.

Question 12

Aminosteroid NM Blockers

Answer 12

• All end in curonium
• Ammonium substituted at R1 (2) and R2 (16)
• Separated by hydrophobic center (Steroid)
• One N must be quat. at least
• Cis = active, trans = inactive
• Acyl groups added at positions 3 & 17 to increase affinity for receptor sites

Question 13

Pancuronium and Vecuronium

Answer 13

• Pan - R-ME
• Vec - R = H
• Steroid acts as spacer for quat. centers (1.09 nm)
• Acyl groups introduced to mimic ACh cytoskeleton
• Faster onset than tubocurarine, slower than succinyl.
• Longer duration than succinylcholine (45 min)
• No effect on BP and few SE

Question 14

Pancuronium

Answer 14

• Two quat. ammoniums
• Hydrolysis of acetate groups by liver esterases
• Active pancuronium metabolite and 2 inactive metabolites formed
• Long acting, duration 2-3 hours, renally excreted

Question 15

Vecuronium

Answer 15

• Tertiary ammonium at 2 and quat. ammonium at 16
• Hydrolysis of acetate groups by liver esterases
• Active vecuronium metabolite and 2 inactive metabolites formed
• Intermediate acting, duration ~1/2 hour, renally excreted

Question 16

Rocuronium

Answer 16

• Acyl group added to mimic ACh
• No acetate at position 3
• Non-depolarizing NM Blocker
• Rapid onset, intermediate duration
• Terminated by administration of Sugammedex (cyclodextrin)

Question 17

Sugammedex

Answer 17

• Chemically inert and binds to no receptor
• Modified by adding 8 carboxyl thioethers, 8 side chains, and negatively charged carboxyl to increase binding to rocuronium
• Drug “open” in solution, durg enters and thioethers interact and the carboxylate “locks” rocuronium in place by interacting with the positive nitrogen
• Binding of guest and host molecules occur due to vdW, hydrophobic, and electrostatic interactions
• Additional non-covalent interactions hold it in place

Question 18

THIQ

Answer 18

• Tetrahydroisoquinoline
• Name ends in acurium
• Contains 2 substituted THIQ molecules
• Hydrolysis terminates action
• SAR: same two quat. ammonium with hydrophobic link

Question 19

Atracurium

Answer 19

• Based on tubocurarine and suxamethonium
• No cardiac SE
• Administered via I.V. drip
• Rapidly broken down in blood chemically and metabolically
• Self destructs, limiting lifetime to 30 minutes
• Avoids patient’s variation in enzyme
• Two quart. ammonium with substituted THIQ
• Flexibility in link allow N to react at the right distance
• Ester hydrolysis and Hofmann elimination occurs, the latter yields an inactive metabolite

Question 20

Is inactivation by Hofmann elimination dependent on renal function?

Answer 20

No, drugs eliminated this way are good for patients with renal disease.

Question 21

What feature of drugs is necessary for Hofmann elimination?

Answer 21

2 carbon separation between quat. nitrogen and carbonyl

Question 22

Self Destruction Drugs

Answer 22

• Stable in one set of conditions but degrades in another
• Helps avoid patient enzyme variation problems
• Atracurium - stable in acid but not in slightly alkaline blood (why it is given in an continuous IV drip)

Question 23

1R-cis, 1’R-cis

Answer 23

• One stereoisomer of atracurium
• Highest efficacy and least amount of side effects
• Cisastracurium (Nimbex), most widely used in surgery, better than the racemic mixture
• 80% is metabolized by Hofmann elimination

Question 24

Mivacurium

Answer 24

• Sufficiently flexible linker with one double bond
• Short duration: 10-20 minutes, hydrolyzed by plasma ChE
• NO HOFMANN ELIMINATION (more than a two carbon separation)
• Use has decreased in favor of drugs with better profiles