skeletal muscle relaxants acting on the neuromuscular junction

Question 1

Possibilities to relax skeletal
muscles

structure of skeletal muscle relaxants.

Answer 1

1. Centrally acting muscle relaxants – decrease the tone of the skeletal muscles (spasmolytics)
2. Peripheral muscle relaxants – paralyze the skeletal
   muscles (total relaxation)
3. A. Presynaptically acting drugs
4. A.A. Toxins: botulinumtoxin, -conotoxin (full relaxation)
5. A.B. Certain antibiotics: aminoglycosides, tetracyclines.

2.B. Postsynaptically acting drugs
 Curare derivatives
 Depolarizing muscle relaxants
 Ryanodine antagonists

Blockers act either as antagonists (non-depolarizing type of neurmuscular blockers) or as agonists (depolarizing type).

Structurally similar to Ach, and also contain 2 quaternary nitrogen which makes them pretty much impermeable to the CNS.

Question 2

indications of peripheral muscle

relaxants

Answer 2

Indications of peripheral muscle
relaxants
1. Providing muscle ralxation during surgical narcosis
2. Relaxing the muscles of artificially respired patients (eg. severe COPD)
3. Electroshock
4. Intubation- very important
5.Tetanus
6. Epileptic seizure (convulsion) not responding to
antiepileptics
7. Intoxication (overdose) with certain medicines
(theophyllin, amphetamin)

Question 3

Curare type peripheral muscle

relaxants

Answer 3

derivatives of d-tubocurare
 Competitive antagonist of the NM acetylcholine
receptors in the neuromuscular junction
 Structure: bisquaternary ammoniumbases (Ø
central effect!)
 Intravenously administered.

Mechanism of action: The drug act predomininantly at the nicotinic receptor site by competing with acetylcholine, preventing binding of Ach and thus preventing depolarization of the muscle cell membrane.

Their action can be overcome by increasing the conc. of Ach in the synaptic clef (e.g. administration of AchE inhibitors such as pyridostigmine and neostigmine).
due to lack of selectivity the drug may also block prejuncitonal sodium channels, intefering with mobilization of acetylcholine at the nerve ending. They may also activate mast cells to release histamine-> vasodialation and bronchoconstriction.

Question 4

Time order of the curare induced

muscle paralysis

Answer 4

Time order of the curare (d-tubocurarine) induced
muscle paralysis
Outer eye muscles
Facial muscles
Pharyngeal muscles
Extremities
Truncal muscles
Respiratory muscles (diaphragm)
Full paralysis within 2 to 6 minutes

the muscles recover in the reverse manner, with the diaphragm recovering first.

Question 5

Structural classification of curare

drugs

Answer 5

Structural classification of curare
drugs
1. Izoquinolines
D-tubocurarine
Doxacurium
Atracurium
Cisatracurium
Mivacurium

2. Steroids
Pancuronium
Pipecuronium
Vecuronium
Rocuronium

Question 6

mivacurium (isoquinolines)

Answer 6

short acting (15~mins)- 
Moderate histamine release.
Eliminated by pseudocholinestrase. 
duration prolonged in imparied renal function.

Question 7

Atracurium (Izoquinolines)

Answer 7

intermediate acting (20-35mins~).
slight histamine release.
elimination- spontaneous (Hoffmann-elimination)
metabolite may cross BBB and cause seizures.

Question 8

Rocuronium (steroid)

Answer 8

intermediate acting (20-35mins~).
 (dose-dependent: 15-110 minutes) 
Metabolized mainly by liver.

Question 9

 Cisatracurium (isoquinoline)

 Vecuronium (steroid)

Answer 9

 Intermediate acting (20-40 minutes):

cisatracurium is metabolized spontaneously and vecuronium is metabolized by the liver.

Question 10

Pancuronium
pipecuronium
both steroids

Answer 10

 Long acting (60-180 minutes):

eliminated mainly by kidney

Question 11

Doxacurium

Answer 11

long acting

Question 12

Adverse effects of curare

derivatives

Answer 12

1. Recurarization- After suspending the effect a reappearing muscle weakness (reason unknown)
   2, Ganglion blockade (d-tubocurarine, pancuronium)
2. hypotension, tachycardia
3. Histamine release (isoquinolines: atracurium, mivacurium)- leading to itching, bronchospasm, hypotension
4. M2 receptor blockade (pancuronium) leading to tachycardia
5. Norepinephrine releaser and re-uptake inhibitor (pancuronium)-> tachycardia
6. The metabolite of atracurium (laudanosin) may cause
   muscle spasm - convulsions

Question 13

Suspending / terminating the curare effect

Answer 13

neostigmine/ pyridostigmine and sugammadex.
sugammadex is a selective relaxant binding agents which binds to rocuronium and vecuronium (chemical antagonist?)

Acetylcholinesterase inhibitors
neostigmine, distigmine
Coadministered with atropin in order to
antgonize their parasympathomimetic effects
Sugammadex
Neutralizes the steroid structures in the plasma

Question 14

Factors infulencing the curare

effects

Answer 14

Enhancing the effects
1. General anesthetics - important 
2/ Aminoglycosides, tetracyclines
3/ Local anesthetics
4/ Myasthenia gravis (autoimmune disease, antibodies
against the NMJ)

Attenuating the effetcs

1. Acetylcholinesterase inhibitors
2. Motoneuron lesions

Question 15

depolarizing skeletal muscle agents

Answer 15

Depolarize the NM similar to Ach but are more resistant to degradation by AchE and can thus more persistenly depolarize the muscle fibers.

Question 16

Succynylcholine (suxamethonium)

Answer 16

MEchanism: Provides depolarizing blockade that cannot be antagonized by acetylcholinesterase inhibiotors

Kinetics:
 Duration of action: after iv. admnistration 5 to 10 minutes

 Metabolism: pseudocholinesterase in the blood then in the liver.

 Indications: short surgical interventions; intubation;
electroshock; short, invasive diagnostic procedures (e.g. bronchoscopy). Important in the induction of anesthesia when rapid endotracheal intubation is required.

Question 17

mechanism of succynylcholine

Answer 17

phase 1: attaches to nicotinic receptor-> membrane depo-> initial discharge that produces transient fasciulations followed by flaccid paralysis (voltage gated Na remains in the inactive state.

phase 2: membrane repolarizes but receptor is desensitized to the effect of Ach.

lecture:
 In the beginning short time muscle fasciculations
 Due to the longer stimulus of the receptor Na+
influx is higher resulting the depolarization of the surrounding membrane
 In the surrounding depolarized membrane the voltage gated Na+ -channels cannot return to the resting closed state instead they remain in inactive state
 action potential generation stops, the muscle becomes paralyzed
 This paralysis cannot be antagonized by acetylcholiesterase inhibors in the beginning.

2nd phase: desensitization block
Succynylcholine diffuses quckly out of the NMJ
 continous receptor stimulation ends
The muscle restores the normal ion balance
(see Na+ /K+ -ATP-ase)
The muscle can be stimulated with high amount
of acetylcholine for a while
Reason: desensitization of the NM receptors

Question 18

Adverse effects of succynylcholine

Answer 18

Muscle pain (postoperative, fatigue fever like
pain – muscle strain)
Arrythmia – mainly bradycardia.
Hyperkalemia – nicotinic receptor conducts
outward K+ current-> K efflux from the cell.
Vomiting
Higher intraocular pressure (contraction of the
myofibers or dilation of choroidal vessels)
MALIGNANT HYPERTHERMIA!!!-> treat with dantrolene quickly.

Question 19

Malignant hyperthermia: reason

and symptoms

Answer 19

Genetic disorder – affects ryanodin receptors
For unknown reason (idiosynchrasia)
succynilcholine makes ryanodin activation
permanent, continously high amount of Ca++
flows out of the sarcoplasmic reticule
Continuous muscle shivering heat production
 hyperthermia
Lactacidosis
Myoglobinaemia, myoglobinuria, acute renal
failure

Question 20

teatment to malignant hyperthermia

Answer 20

Treatment of malignant hyperthermia
– dantrolene
Dantrolene
Ryanodin receptor antagonist, inhibits Ca++
release in the skeletal muscle
Main indication: malignant hyperthermia
Most dangerous side effect: hepatotoxicity (1- 2%), when develops lethality is 20-30%

Other
Bicarbonate infusion to acidosis
Physical cooling of the patient

Question 21

adverse effects of muscle relaxants:

Answer 21

Recurarization