Lecture 39 (Cut off for Exam 3) Flashcards
Neuromuscular Blockers - Feng
1
Q
Tubocurarine
A
- 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
2
Q
Tubocurarine v.s. ACh
A
- Both have positive nitrogens
- No ester bond like ACh has
- SIGNIFICANTLY larger than ACh
3
Q
SAR: d-Tubocurarine
A
- 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
4
Q
Designing New Compounds
A
Clinical Use:
- NM blocker for surgery
- Tubocurarine has SE like histamine release
- Permits for lower and safer levels of gen. anesthesia
5
Q
Depolarizing NM Blockers
A
- Decamethonium Bromide and Succinylcholine Chloride
- Simplified tubocurarine
6
Q
SAR: Depolarizing NM Blockers
A
- Two quat. ammonium
- 10-12 unsubstituted methylene groups in between for maximum blocking effect
7
Q
Decamethonium
A
- 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
8
Q
Succinylcholine Chloride
A
- 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
9
Q
Depolarization
A
- All drugs in this category first depolarize the membrane
- Undesirable, so research has focused mainly on non-depolarizing agents
10
Q
Non-depolarizing NM Blockers
A
- More rigid structure with positive, quat. heads being part of bulky groups
- Include ACh skeleton
11
Q
Ideal NM Blocker
A
Non-depolarizer that is metabolically inactivated and rapidly eliminated.
12
Q
Aminosteroid NM Blockers
A
- 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
13
Q
Pancuronium and Vecuronium
A
- 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
14
Q
Pancuronium
A
- 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
15
Q
Vecuronium
A
- 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
16
Q
Rocuronium
A
- 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)
17
Q
Sugammedex
A
- 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
18
Q
THIQ
A
- Tetrahydroisoquinoline
- Name ends in acurium
- Contains 2 substituted THIQ molecules
- Hydrolysis terminates action
- SAR: same two quat. ammonium with hydrophobic link
19
Q
Atracurium
A
- 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
20
Q
Is inactivation by Hofmann elimination dependent on renal function?
A
No, drugs eliminated this way are good for patients with renal disease.
21
Q
What feature of drugs is necessary for Hofmann elimination?
A
2 carbon separation between quat. nitrogen and carbonyl
22
Q
Self Destruction Drugs
A
- 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)
23
Q
1R-cis, 1’R-cis
A
- 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
24
Q
Mivacurium
A
- 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
