NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS
description
Transcript of NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS
![Page 1: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/1.jpg)
NEUROMUSCULAR BLOCKERS and CENTRAL
MUSCLE RELAXANTS
DR.ABDUL LATIF MAHESARPHARMACOLOGY
Dr.Alia Al-Shanawani
December 17,2011References: Basic and clinical pharmacology 11th edition
Bertram G.Ktzang
![Page 2: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/2.jpg)
• Learning issues and objectives• A brief review of NM junction and its function• Mechanism and purpose of its block• Drugs used for this block• Indications for these drugs• Their adverse effects• How to over come the overdose effects
![Page 3: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/3.jpg)
Neuromuscular Junction• 1: Cholinergic motor neurone,2: motor end-
plate, 3: vesicles, 4: NMR, 5: mitochondrion
![Page 4: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/4.jpg)
• Skeletal muscle contraction is evoked by nicotinic cholinergic transmission.
• Blockade of this transmission is clinically useful in producing muscle relaxation.
• This is required for surgical relaxation and control of ventilation.
![Page 5: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/5.jpg)
Neuromuscular transmission
Initiation of impulse release of acetylcholine activation of nicotinic receptors at motor end plate
opening of ion channel, passage of Na+ depolarization of end plate Muscle contraction.
Neuromuscular blocking agents used in clinical practice interfere with this process.
![Page 6: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/6.jpg)
• Skeletal muscle relaxation can also be produced by the drugs which act CNS and directly at intracellular contractile apparatus itself like
• Diazepam through GABAA receptors
• Baclofen through GABAB receptors
• Dantrolene inteeferes with excitation contraction coupling
![Page 7: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/7.jpg)
CLASSIFICATION1. Peripherally acting (Neuromuscular blockers)
a) Non-depolarizing blockers: Cholinergic antagonists (Tubocurarine, Atracurium, Mivacurium , Pencuronium others)
b) Depolraizing blockers: Cholinergic agonists ( Succinylcholine ) 2. Centrally acting skeletal muscle relaxants (Diazepam , Baclofen)
3. Direct acting skeletal muscle relaxants (Dantroline)
![Page 8: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/8.jpg)
Peripherally acting
A) Presyneptic NMB a)Inhibit acetylcholine synthesis e.g Triethylcholine , Hemicholiniumb)Inhibit acetylcholine release e.g.Aminoglycosides ,Botulinum toxin(not clinically used)
B) Post synaptic NMB a) Competetive ( non depolarizing blockers b) Depolarizing blockers
![Page 9: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/9.jpg)
Classification(non depolarizing agents) based on chemical nature
• ISOQUINOLINE DERIVATIEVES• Tubocurarine• Atracurium• Doxacurium• Mivacurium (shortest duration immediately inactivated by plasma cholinestrase)• cisatracurium• STEROID DERIVATIVES• Pancuronium• Vecuronium• Pipecuronium• Rocuronium•
![Page 10: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/10.jpg)
• B) Centrally acting• Diazepam ( act through GABA A) receptors)• Baclofen (GABA B) receptors
• C) Directly acting)• Dantroline ( act directly by interfering release of calcium
from sarcoplasmic reticulum)• Note:• these drugs are used to control spastic muscle tone as in
spinal injury, cerebral palsy, multiple scelerosis, and stroke.
![Page 11: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/11.jpg)
• d-Tubocurarine is the prototype of this group. It is a quaternary alkaloid.
• At low doses these drugs combine with nicotinic receptors and prevent acetylcholine binding, thus prevents depolarization at nicotinic end-plate. In this way contraction and relaxation of skeletal muscles is inhibited.
![Page 12: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/12.jpg)
NOTE: their action can be overcome by increasing conc. of acetylcholine in the synaptic gap by e.g. Neostigmine cholinestrase inhibitors ( this inhibits choline estrase)
At High dose :these drugs block ion channel at the end plate and leads to further weakening of the transmission ,and it becomes difficult to overcome the block by acetylcholinestrase inhibitors
![Page 13: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/13.jpg)
Pharmacokinetics:
• Administered intravenouly
• Cross blood brain barrier poorly
• Tubocurarine, mivacurine and metocurine are not metabolized in liver ,their action is terminated by redistribution.
• Excreted in urine unchanged
• Mivacurium is degraded by plasma cholinestrase rapidly ,it has shortest duration of action than others.
![Page 14: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/14.jpg)
• They differ in onset , duration and recovery (see table )
• USES:• As adjuvant to general anesthetics during surgery
especially intrabdominal ,and intrathorasic.
• Tracheal intubation
• Control of ventilation( to reduce chest wall reistatnce)
![Page 15: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/15.jpg)
Adverse effects
• Bronchospam due to release of Histamine
• Hypotension due to ganglion block may also be due to histmaine release
• Tachycardia ( by pancuronium) due to
blockade of muscarinic receptors in heart
![Page 16: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/16.jpg)
DEPOLARIZING NEUROMUSCULAR BLOCKERS
• SUCCINYLECHOLINE:• These drugs act like acetylcholine but persist at the synapse
at higher concentration and for longer duration and constantly stimulate the receptor.
(there is inhibition of repolarization) and the receptor become insensitive
• First opening of the Na+ channel occurs resulting in depolarization, muscle twitching occurs , continued binding of drug make the receptor incapable of transmitting the impulses PARALYSIS OCCURS.
![Page 17: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/17.jpg)
• Therapeutic uses:• When rapid endotracheal intubation is required• Electroconvulsive shock therapy
![Page 18: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/18.jpg)
Pharmacokinetics
• Administered intravenously • It can also be used in continuous infusions
( due to rapid inactivation)• its duration of action is 5-10 minutes• In low doses it causes negative ionotropic and
chronontropic effects and • In high doses positive ionotropic and
chronotropic effect may occur
![Page 19: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/19.jpg)
Adverse effects:• Bradycardia preventable by atropine
• Hyperkalemia in patients with trauma or burns this may cause dysrhythmia or even cardiac arrest.
• Increased intraocular pressure due to contracture of extra ocular muscles applying pressure to the eye ball.
• Increased intragastric pressure which may lead to emesis and aspiration of gastric content
• Muscle pain
• Malignant hyperthemia: due to a rare inherited condition probably caused by Ca++ release channel of sarcoplamic reticulum implicated by succinylcholine and treated by DANTROLENE (a direct acting muscle relaxant)
![Page 20: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/20.jpg)
Characteristics of neuromuscular-blocking drugs
![Page 21: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/21.jpg)
Some properties of neuromuscular blockers
Drug Elimination Approximate potency relative to Tubocurarine
Atracurium spontaneous 1.5Doxacurium kidney 6Mivacurium Plasma cholinestrase 4Metocurine Kidney 40% 4Tubocurarine Kidney 40% 1Panacurium Kidney 80% 6Rocuronium Liver 70-80%,kidney 0.8vecuronium Liver 75-90%,kidney 6pipecuronium Kidney ,liver 6Rapacuronium liver 0.4
![Page 22: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/22.jpg)
CENTRALY ACTING DRUGS
• These spasmolytic drugs do not resemble Acetylcholine in structure or effect.
• They act in CNS or in skeletal muscle cell and used to overcome the spasticity.
• Spasticity is characterized by increase in tonic stretch reflexes and flexor muscle spasm, muscle tone is increase, it is often associated with cerebral palsy ,muscle sclerosis and stroke.
![Page 23: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/23.jpg)
• DIAZEPAM:• Facilitates the GABA receptors in CNS .It can be
used in the patients with muscle spasm of almost any origin, including local muscle trauma.
• It is a drug of choice to overcome and abolish if the convulsion are continuous and persistent such as in epilepsy ( if there are continuous and persistent convulsions ) called status epilepticus.
![Page 24: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/24.jpg)
• BACLOFEN:• It is structurally related to GABA and possess
GABAB agonist activity.• It causes hyperpolarization by increasing
potassium conductance reducing calcium influx• It reduces pain in patients with spasticity • It is administered orally• It has a half life of 3-4 hours
![Page 25: NEUROMUSCULAR BLOCKERS and CENTRAL MUSCLE RELAXANTS](https://reader036.fdocuments.in/reader036/viewer/2022081800/56816465550346895dd649f0/html5/thumbnails/25.jpg)
DANTROLENE
• It acts directly on muscle by interfering with excitation –contraction coupling in the muscle fiber and prevents the release of calcium from sarcoplasmic reticulum .It is not useful in surgery
• Used in malignant hyperthermia ( a rare heritable disorder triggered by volatile anesthetics and depolarizing neuromuscular blocker Succinylcholine. There is rise in temperature and massive muscle contraction due to impairment in ability of SR to sequester calcium
• It can be administered orally and parentrally• Has a half life of 8-9 hours