Depolarizing neuromuscular blockers 

- AchE inhibitors 

- increase levels of Ach

- directly stimulate the nicotinic receptors on the skeletal muscle endplate, producing depolarization of the endplate 

Succinylcholine 

- depolarizing neuromuscular blockers 

- acts by producing initial contraction followed by a paralysis of the skeletal muscle, which cannot be activated through the Nm receptor 

- still used therapeutically

Nondepolarizing neuromuscular blockers 

- D-tubocurare

- antagonize the effects of Ach at the Nm receptor 

- the endplate region of skeletal muscle remains polarized 

-competitive Nm receptor antagonists

- produce flaccid paralysis

Direct-acting agents 

- act directly on the skeletal muscle

to produce relaxation 

Neuronal acting agents

- act at the motor neuron to interfere with Ach release

 - Hemicholinium which inhibits Ach synthesis

- Botulinus toxin 

Depolarizing neuromuscular blocker

- Decamethonium 

- not used therapeutically 

Nondepolarizing neuromuscular blockers

2 groups:

- the benzylisoquinolinium compounds

- the aminosteroid compounds  

Benzylisoquinolinium compounds 

- D-tubocurare

- metocurine

- alcuronium

- atracurium

- mivacurium

- placed at the skeletal muscle endplate region (lollipop)

Aminosteroid compounds 

- Pancuronium

- Vecuronium

- Rocuronium

- more potent

- they are competitive Nm receptor antagonists

- placed at the skeletal muscle endplate region (lollipop)

Depolarizing neuromuscular blockers 

- produce a persistent (long-acting) depolarization

of the skeletal muscle endplate 

- produce transient fasciculations

-they desensitize the skeletal muscle to Ach

(Ach will bind and produce no effect)

Vagal stimulation

- Succinylcholine, it seems to mimic

the effects of Ach

- it stimulates the vagal nerve, and you

get bradycardia as a potential effect

Succinylcholine works in 2 phases:  

Phase 1, the skeletal muscle membrane

depolarizes, you get a transient fasciculation

and flaccid paralysis. (normal agonist effect)  

Phase 2, the membrane repolarizes,

but the membrane still will not respond to Ach

(is still desensitized to Ach); the effect

like the inverse agonist.

Adverse CV effects  of NM Blockers

Ganglionic block: Tubocurarine, Metocurine, Alcuronium

Histamine release: Tubocurarine, Metocurine, Alcuronium, Succinylcholine

Vagal stimulation:Succinylcholine

Sympathetic stimulation: Pancuronium

Ganglionic blockade

- will cause hypotension

- it is blocking sympathetic ganglia

(less vasoconstriction)

- can be produced by Tubocurarine, Metocurine, Alcuronium

Ganglionic blocker on the heart

- would produce tachycardia because in

the heart, you have dual innervation and

the predominant tone to the

heart is parasympathetic, and it

will be blocked the most.

So you have unopposed sympathetic stimulation. 

Histamine release     

- dangerous for asthmatics (should be pre-treated with a H-1 receptor antagonist)

-can produce bronchoconstriction, vasodilation, hypotension

Bronchiole smooth muscle

- has naked histamine receptors,

- has naked muscarinic receptors 

- it has naked beta 2 receptors 

Arterioles

- predominant tone is sympathetic 

Sympathetic stimulation  

Pancuronium 

Adverse effects of succinylcholine 

- increased intraoccular pressure- caution in glaucoma!!

- post-operative muscle pain (because of the fasciculations, which cause the contraction of the skeletal muscle)

- hyperkalemia - because of the muscle contractility

 - Malignant hyperthermia and succinylcholine apnea

Succinylcholine apnea 

- idiosyncratic response due to the abnormal pseudocholinesterase 

Hyperkalemia

 - compatible with normal cardiac function

- can result in dangerous electrolyte

imbalances, so avoid using succinylcholine

when you have soft tissue trauma 

Malignant hyperthermia 

- occurs with halogenated hydrocarbons and succinylcholine, it’s an idiosyncratic response

- excessive calcium release from the sarcoplasmic reticulum that leads to rigidity of the muscle

- also associated with hyperthermia, increased muscle metabolism, resulting metabolic acidosis, and it can result in death. 

Disposition of neuromuscular blockers 

Hepatic and renal: d-tubocurare, pancuronium, rocuronium, vecuronium, are metabolized by the liver and eliminated through the kidneys.

Plasma cholinesterase is important with succinylcholine!!! 

Plasma cholinesterase 

Succinylcholine apnea, succinylcholine-induced malignant hyperthermia, along with the halogenated hydrocarbon anaesthetics and cyclopropane – these are agents which have this unique characteristic to it. 

Succinylcholine 

- metabolized by the pseudocholinesterase

in the plasma 

- given to patients with renal or liver problems

Mivacurium

- metabolized by the pseudocholinesterase and

degraded spontaneously  

- given to patients with renal or liver problems 

Peripherally acting skeletal

muscle relaxant drug uses

- used as adjuncts to general anaesthesia, as

adjuncts to electroshock therapy 

Dantrolene (Dantrium)  

Direct-acting agent, increases the binding of calcium to the sarcoplasmic reticulum and

it inhibits the movement of calcium in response to membrane depolarization 

It doesn't interfere with voluntary contractions; it

interferes with tiny contractions which depend

on initial release of calcium from

the sarcoplasmic reticulum.

Dantrolene

Dantrolene adverse effects:

- transient drowsiness: avoid CNS

depressants / driving;

- hepatotoxicity;

- respiratory depression with impairement of central control of respiration (in people with cervical/ high cervical lesions, or brainstem lesions) 

Neuronal acting agent

Botulinum toxin (Type A) Botox: given locally; works by inhibiting Ach release and causing relaxation of the skeletal muscle responsible for producing the wrinkle 

Botulinum toxin (Type B) Myoblock

Also used for: blepharospasms, strabismus, and

cervical dystonia 

Adverse effects and precautions of botulinum toxin:  

- aminoglycoside antibiotics and curare-like drugs can potentiate their effects 

Curare-like drugs, by blocking the nicotinic

receptors, will potentiate the effects of

drugs which inhibit the release of Ach!!

Xerostomia and dysphagia!!!

Hemicholinium 

- potentiates the effect of d-tubocurare