Neuromuscular blockers Flashcards
What are the types of skeletal muscle relaxants?
1) Neuromuscular blockers: Used during surgical procedures & in intensive care units to cause paralysis
2) Spasmolytics/antispasmodics: centrally acting, used to reduce spasticity in neurological conditions (except for dantrolene which has no significant central effects)
What are the drugs that are considered as neuromuscular blockers (skeletal muscle relaxants)?
1) Nondepolarizing:
- Tubocurarine (long action)
- Mivacurium (short action)
2) Depolarizing:
- Succinylcholine
What are the drugs considered spasmolytics (skeletal muscle relaxants)?
1) Chronic use:
- Action on CNS:
1) Baclofen
2) Diazepam
3) Tizanidine - Muscle action:
1) Dantrolene
2) Acute use:
1) Cyclobenzaprine
What is the normal function of the neuromuscular?
1) Two Ach molecules combine with nicotinic receptors on the motor end plate opening the Na+ channel
2) The influx of Na+ will excite the postsynaptic potential (EPSP) depolarizing the muscle membrane
3) The Action potential generated will travel along the sarcolemma (muscle fiber) causing muscle contraction
4) Acetylcholinesterase (AChE) in the extracellular will degrade the ACh
What are the different mechanisms by which the end-plate function is blocked?
1) Competition with ACh: preventing depolarization (nondepolarizing subgroup like tubocurarine)
2) Excess of depolarizing agonist (depolarizing blocking drug is succinylcholine)
Describe the function and mechanism of non-depolarizing blocking drugs
- Tubocurarine is the prototype, producing a competitive blockade inhibition
- The mechanism of action is competitive antagonism
- d-Tubocurarine is an antagonist to ACh preventing it from depolarizing the muscle at the neuromuscular junction, having an affinity to the ACh receptor
What is the procedure if you mistakenly give a high dose of tubocurarine to a patient?
By boosting ACh via blocking the action of acetylcholinesterase (cholinesterase inhibitors) like neostigmine and edrophonium
We do not give ACh directly as it has a very short half-life and it’s not available in the market, thus we increase the effectiveness of the endogenous ACh
What are some antibiotics that interfere with the neuromuscular transmission?
1) Aminoglycosides
2) Tetracyclines
3) Polypeptide antibiotics (actinomycin, bacitracin, colistin, polymyxin)
- Clinically they are not used as muscle relaxants but they can act synergistically with muscle relaxants
What are some examples of drugs that are non-depolarizing blockers?
1) Mivacurium (short life)
2) Atracurium (intermediate)
3) Vecuronium (intermediate)
4) Tubocurarine (long)
5) Pancuronium (long)
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- The duration of action is determined by the strength of the drug’s affinity
- Most of them contain the word -cur-
What are the clinical uses of non-depolarizing blockers?
1) Modifies/adjunct, for general anesthesia producing satisfactory skeletal; muscle relaxation
2) Facilitates endotracheal intubation
Which drug is considered a depolarizing blocker?
Succinylcholine
- Two molecules of acetylcholine joined together
What is a depolarizing blocker?
- Succinylcholine is an agonist of acetylcholine
- It will continuously depolarize the muscle, contracting the muscle to a point it is so tired that it cannot contract anymore
- They are used for normal muscles, not the ones that have spasms
What is the mechanism of action of depolarizing blocker (succinylcholine)?
Phase I (prolonged depolarization “Paralysis will occur here”):
1) They will stimulate nicotinic receptors opening ion channel, depolarizing the motor end plate
2) This will cause fasciculations of the muscle (brief muscle contraction/twitching)
These modifications are caused by succinylcholine which cannot be broken down by acetylcholinesterase in the synaptic cleft
Phase II (desensitization & repolarization):
Depolarization will continue until the nicotinic receptors are desensitized meaning that they are tired of responding and thus they will shut down allowing the motor end plate to repolarize the muscle to relax
Describe the pharmacokinetics of succinyl-cholinesterase
1) It has a brief duration of action (5-10 minutes), rapidly hydrolyzes by plasma cholinesterase (pseudocholinesterase)
2) It might be prolonged in patients with abnormal variants of plasma cholinesterase of genetic origin
What are the clinical manifestations of non-depolarizing block drugs?
- Tubocurarine & Ataracurium
1) Hypotension due to the liberation of histamine
2) Ganglionic blockade in large doses
What are the clinical manifestations of depolarizing block drugs?
- Various cardiac arrhythmias
effects seen only with depolarizing blockade:
1) Hyperkalemia
2) Increased intraocular pressure
3) Increased intragastric pressure (emesis)
4) Muscle pain
What is meant by spasticity?
It is characterized by an increase in tonic stretch reflexes & flexor muscle spasms together with muscle weakness often associated with cerebral palsy, multiple sclerosis and stroke damaging the descending pathways and causing hyperexcitability of alpha motor neurons (a-MNs) in the spinal cord
- a-MNs innervating the head and neck are found in the brainstem, the remaining a-MNs that innervates the rest of the body is found in the spinal cord
What are some examples of drug interactions between non-depolarizing and depolarizing drugs?
1) Inhaled anesthetics increase neuromuscular blockade from non-depolarizing agents
2) Local anesthetics: Increases block from both non-depolarizing and depolarizing muscle relaxants
3) Depolarizing muscle relaxants are antagonized by non-depolarizing blockers
4) Non-depolarizing muscle relaxants are antagonized by ACh
What is the mechanism of action of spasmolytic drugs?
- GABA “Gamma-aminobutyric acid” - is an inhibitory neurotransmitter
- Glutamate is excitatory neurotransmitter
so relaxants would :
1. either potentiate GABA
- Baclofen acts on GABA B in presynaptic and postsynaptic nerves
- Benzodiazepines acts on Gaba A
- Tizanidine is an alpha-2 agonist (presynaptic)
- Block glutamate
some act directly on muscles (dantrolene)
What are the drugs for chronic muscle spasms?
1) Diazepam
2) Baclofen
3) Idrocilamide
4) Riluzole
5) Dantrolene
6) Tizanidine
7) Clonidine
What is the importance of diazepam?
1) Acts on all GABA-A synapses
2) The site of action is at least partly in the spinal cord
3) Can be used for muscle spasms in any region
4) Its major limitation is sedation
What is the use of baclofen?
1) Postsynaptic inhibition (inhibits AP) as it is an Agonist at GABA-B (found in both pre- and post- synapse) receptors causing hyperpolarization (it increases the conductance of K+)
2) Presynaptic inhibition (inhibits glutamate) by decreasing Calcium influx, leading to a decrease in the release of excitatory transmitters in both the brain and spinal cord
3) Causes much less sedation
4) causes drowsiness and increases seizure activity
5) Withdrawl must be done slowly
Describe the use of idrocilamide and riluzole
- New drugs that treat amyotrophic lateral sclerosis (ALS)
- Has spasm-reducing effects possibly through the inhibition of glutamatergic transmission in the CNS
What is the use of clonidine?
It is an antihypertensive drug that has been shown to reduce muscle spasms by its activity on the central nervous system
What is the importance of tizanidine?
1) a2-adrenergic receptor agonist (present pre-synaptic)
- Alpha 2 are regulatory receptors, which means when there is more agonist released in the body having its effect on alpha 2 receptors there will be negative feedback to break the release of more neurotransmitter
2) Reduces spasticity at doses that result in less hypotension than clonidine
3) Depresses excitatory feedback from muscles that would normally increase muscle tone, minimizing spasticity
4) Similar efficacy to spasmolytic agents such as diazepam and baclofen with a different spectrum of adverse effects
Describe dantrolene
1) The sarcoplasmic reticulum in skeletal muscles is the site of action of dantrolene, and not in the CNS
2) Decreases the release of activator calcium via sarcoplasmic reticulum calcium channel
3) One of its special applications is malignant hyperthermia (a rare disorder that can be triggered by general anesthesia & neuromuscular blocking drugs)
What are the drugs for acute muscle spasms?
There are many drugs like cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine, these drugs are promoted for the treatment of acute spasms resulting from muscle injury
- Most of these drugs are sedatives or acts on the brain stem
- None of these drugs used for acute spasm are effective in muscle spasm resulting from cerebral palsy or spinal cord injury
What is the importance of cyclobenzaprine?
- Acts on the brain stem by interfering with the polysynaptic reflexes which maintain the skeletal muscle tone
- This drug is activated by the oral route and has marked sedative and antimuscarinic actions
- It might cause confusion and visual hallucinations
