MUSCLE RELAXANTS: NEUROMUSCULAR BLOCKING DRUGS & SPASMOLYTIC DRUGS (Nbd-S) DLHSI-CM PHARMACOLOGY (DOC DEO) BATCH 2014

Transcribed and Edited by: Zafril Salvador and Emily Fernando

I. INTRODUCTION
Muscle relaxents are highly specialized drugs Block the transmission of impulses at the neruomuscular junction causing paralysis Accomplished by acting: PREsynaptically: inhibits the synthesis or release of acetylcholine from the axons [ex. Botulinum toxin] POSTsynaptically: blocking the action of acetylcholine at the acetylcholine receptors. [Majority of Nbd-S are post] Clinical Uses: Adjunct to Anesthesia: given with analgesic since patients still feel the pain Induce Paralysis Surgical Importance. Surgery c an be carried out without difficulty due to decreased muscle tone May also paralyze the muscle of breathing important for mechanical ventilation to maintain adequate respiration (otherswise, patient will die of apnea) Ventilation control Treatment of convulsions Nbd-S affect the skeletal muscle function and decreases muscle tone Alleviate symptoms such as muscle spasms, pain and hyperreflexia [there is NO analgesia] Two major therapeutic groups:

NEUROMUSCULAR BLOCKING DRUGS

Produce muscle paralysis to facilitate surgery or artificial intervention Ex. Pxs in the ICU, who needs artificial ventilation, will be hook to a mechanical ventilator and be administered IV w/neuromuscular blockers for the machine to operate easier and for the px to breathe easier Has no therapeutic effect Structurally related to Acetylcholine and can act as acetylcholine and cause paralysis or the decrease or relaxation of the structures of muscle Drugs that are adjuncts (used as adjuncts for anesthesia ,surgical procedure especially abdominal surgery to relax the muscles for easy intervention) Fig.1 Legend: 1- Axon 2- Neuromuscular junction 3- Muscle 4- myofibrils

SPASMOLYTIC DRUGS
Centrally Acting [means that they act on the nerves within the central nervous system; spinal cord or brain stem] Some may be Peripherally Acting Therapeutic Drugs among neuromuscular blockers which seeks to reduce the elevated muscle tones that can be seen in spasticity It Alleviate muscle spasms and pain of neurologic muscle disease [not all; analgesics are still needed]

Fig.2 Neuromuscular Junction Legend: 1- Presynaptic terminal 2- Sarcolema 3- Synaptic Vesiclescontain Ach neurotransmitter

I. NEUROMUSCULAR BLOCKING DRUGS

NON-DEPOLARIZING
FUNCTION Antagonist Block the binding of Ach to the Ach receptor Directly block the ionotropic activity of acetylcholine receptors

DEPOLARIZING
Agonist Act by depolarizing the plasma membrane of skelatal muscles, NOT on the receptors Perisistent depolarization makes the skeletal muscle more resistant to futher stimulation by Ach SUCCINYLCHOLINE* Short-acting Single agent used as depolarizing neuromuscular blocker ONLY depolarizing drug used An adjunct to Local Anesthesia Ideal for endotracheal intubation

PROTOTYPE*

CLASSIFICATIO N

TUBOCURARINE* Slow onset [>5mins], long duration Cannot be used in endotracheal intubation Must paralyze the anterior neck muscles using drugs w/ shorter onset Side effect: Hypotension [release of histamine] Block 70-80% Ach receptors before effective neuromuscular blockade can occur Eliminated in urine According to Chemical Structure ISOQUINOL STEROIDAL ONES Tubocurarine Pancuronium* * Vecuronium Atracurium Pipecuronium Doxacurium Rocuronium Mivacurium Rapacuronium [new] Acccording to Duration of Action LONG INTERMEDIATE [20SHORT [10[>35min] 40min] 20min] Tubocurarine Atracrunium Mivacurium Pancuronium Cisatracurium Rapacuronium Pipecuronium Vecuronium Doxacunium Rocuronium MEtocurine *this is the reason how Anesthesiologist will chooses the correct neuromuscular blockers for the correct procedure Ex. For General Anesthetic procedure which only entails for an hour, then you can use INTERMEDIATE neuromuscular blockers; but for long hours procedures, use LONG acting

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neuromuscular blockers which can last up to a maximum of 2 hours

MECHANISM OF ACTION

CompetitiveBlocker Compete with Ach at Nicotinic receptor sites Surmountable / Reversible Giving cholinesterase [enzymes that metabolize Ach] inhibitors which will result to accumulation of ACH Same with non depolarizing blockers, your acetylcholinesterase inhibitors will cause accumulation of acetylcholine & will displace the Non-depolarizing neuromuscular blockers. Ion Channel Blocker Exhibit Tetanic Fade Post Anesthesia: if doctors still want to find out if patient is still paralzyed, ther stimulate muscles with high frequency tetanic stimulatoin If patient exhibits tetanic fade, there is still some amount of NMB present

PHARMACOKINE TICS

Administration: IV [Not given orally because it is metabolized in the gastric acid] Distribution Rapid initial distribution into the highly perfused area [brain, muscles] Highly Ionized Limited Volume of distribution: 80-140 ml/kg Metabolism and Excretion [correlates with duration of action] Mivacurium: is short acting because it is metabolized by the Plasma cholinesterases Vecuronium, Rocuronium: it undergoes enterohepatic circulation and excreted at the bile therefore having an intermediate action Doxacurium, Pancuronium, Tubocurarine: takes for a while before it is excreted in the kidneys therefore having a LONG duration of action [contraindicated in patients w/ renal problems]

Ach like effects when it occupies the ACH receptors Phase I Block: DEPOLARIZING Reacts with nicotinic receptor depolarization spread muscle contraction Muscle remains depolarized as long as succinylcholine is occupying the receptor site which will cause Flaccid paralysis- muscle tone is highly decreased (see fig.4 at the last page for picture and explanation) Phase II Block: DESENSITIZING Continued exposure to a drug Decrease in depolarization repolarization but desensitized Excess Succinylcholine in receptors accounts for desensitization Can be explained by neuromuscular fatigue Ion Channel Blockade: prolonged blocked state Late Phase II: Nondepolarizing block Tetanic Fade Reversed by acetylcholinesterase inhibitors Structure: 2 acetylcholine molecules Metabolism Plasma Cholinesterases Short acting because it is hydrolyzed by Butyrylcholinesterase / Pseudocholinesterase: synthesizes succinylcholine Duration: 5-10 mins. [if >15mins = overdose] Termination: diffusion away from the neuromuscular junction Prolonged Blockade: abnormal genetic variant Dibucaine number Test for differentiation of atypical pseudocholinesterases (active/inactive succinylcholine) Normal enzyme: 75 and above Heterozygous Atypical Pseudocholinesterase: 40-70 Homozygous Atypical Pseudocholinesterase: less than 20

PHARMACOLOGI C EFFECTS

Atracuium- has the ability to be spontaneously degraded; no enzyme degrades it but it degrades in the plasma by itself spontaneously which is called Hoffman Elimination *Adverse effects: Causes production of metabolite: Laudanosine which affects the kidneys Skeletal Paralysis Motor weakness Flaccid skeletal muscles inexcitable to stimulus In Paralysis, small skeletal muscle are first to be paralyzed, then trunk, then the diaphragm In Recovery, diaphragm is the first to recover then so on CVS Hypotension [main CVS effect], caused by: Tubocurarine, Metocurine, Mivacurine, Atracurium Histamine release vasodilation Ganglionic blockade Tachycardia caused by Pancuronium Increase in cardiac output due Pancuronium [tachycardia]

DRUG INTERACTIONS

Anesthetics Augmentation of Nmblockade Isoflurane > Sevoflurane > Desflurane > Halotane Antibiotics Augmentation of paralysis Aminogylcosides [streptomycin, gentamicin, etc.] Local Anesthetics / Anti-arryhtmics - can cause augmentation also Neuromuscular blockers - for ventilation control, treatment for convulsions

Skeletal Paralysis Onset: 1min, Duration: 5-10min Transient muscle fasciculations [chest and abdomen] In Paralysis, arms and leg muscle are first to be paralyzed follwed by the facial/pahryngeal and then respiratory muscles. In Recovery, respiratory muscles first then so on. CVS Stimulates: ALL autonimic cholinoreceptors [symptom: increased salivation, etc] Nicotinic receptors [sympathetic and parasympathetic ganglia] Muscarinic receptors found in the sinus node Low dose: (-) ionotropic and chronotropic effects High dose: (+) ionotropic and chronotropic effects Bradychardia in pediatric patients *one usually would alson adminster: Ephedrine: vasoconstriction to correct the hypotension Atropine: stimulate the heart [effects: blind as a bat, red as a beet, mad as a hatter, dry as a bone] Other effects: Hyperkalemia Increase IntraOcular Pressure [contraindicated in patients w/ glaucoma or eye injuries] Increase intragastric pressure [vomitting; asphyxiation due to aspiration] Muscle pain

I. SPASMOLYTIC DRUGS
a. Classification

CENTRALLY-ACTING SPASMOLYTICS [BRAIN AND SPINAL CORD]

PERIPHERALLY-ACTING SPASMOLYTICS [MUSCLES]

Baclofan Dantrolene sodium Diazepam Tizanidine Cyclobenzapine b. Therapeutic Uses Muscle spasm in muscle strain or inflammatory joint disease Spasticity [increase in muscle tone] due to degenerative disease: multiple sclerosis, cerebral palsy Spasticity resulting from spinal cord injury, stroke Baclofen and Diazepam mostly used drug a. Prototype Drugs

BACLOFEN
SITE OF ACTION THERAPEUTIC USE Spinal cord and Supraspinal Centrally acting Multiple sclerosis Lou Gehrigs Disease [Amyotrophic Lateral Sclerosis]

DIAZEPAM
Spinal cord and Brainstem Centrally acting

DANTROLENE
Peripheral acting Malignant Hyperthermia Hypermetabolic state Other treatment: low dose of succinylcholine Not recommended for treatment of skeletal muscle spasms due to rheumatic disease Blocks release of calcium from the sarcoplasmic reticulum Inhibit excitation-contraction coupling mechanism of muscle fibers Relaxation of skeletal muscles IV or oral Excretion through kidneys

MECHANISM OF ACTION

Bind to and activate GABAB receptors [GABA: an inhibitory neurotransmitter] Inhibit release of excitatory neurotransmitters Oral: well-absorbed from the GIT Peak plasma concentration: 2-3hrs 30% plasma protein binding Half-life: 3-4hrs 70-85% excreted unchanged through kidneys

Bind to Benzodiazepine receptor Allsoteric change in GABAA receptor Enhanced binding of GABA to GABA receptor Increased chloride conductance Hyperpolarization of neruonal membrane[inhibition]

PHARMACOKINET ICS

ADVERSE EFFECTS

I.

Diarrhea General malaise, weakness, fatigue Drowsiness, dizziness Hepatocellular disease Muscle pain Muscle weakness most dominant -----------------------------------------------------------------------------------FIGURES----------------------------------------------------------------------------------Introduction

CNS: drowsiness, dizziness, weakness, fatigue, confusion, headache, insomia GIT: nausea, anorexia, constipation

Sedation, confusion, lethargy Impaired mental and psychomotr function Delayed reaction time

Fig. 3. Simple diagram on how it occupies your receptors displacing the Ach but as we said it is romatable if you give your cholinesterase inhibitors then that nondepolarizing blockers will be displaced and ach will occupy the receptor, again, it causes a blockade which is what we call a Closed ion channel blockade. Si doc deo nasgabi nun sa taas. Magulo. Hahaha romatable daw. Hahaha Anyway, it goes like this: A non-depolarizing blocker, for example rocuronium, prevents the opening of the channel when it binds to the receptors.

Fig.4 The diagram shows the Mechanism of Action of Succinylcholine in the Ion Channels. The Open normal channel is the receptor, you have an Agonist (black triangle) occupying the receptor, lets say the black triangle is the Ach, so when Ach occupies the receptor it opens, which is its normal way to open. So if you change the black triangle into succinylcholine, it will act as an agonist and there will be no depolarization and will be called depolarizing blocker because it occupies the receptors and some of the molecules of the ion channels. The ion channel is open but it is blocked by the succinylcholine. Para mas maintindihan:

Yung Open Normal channel ay yung RECEPTOR, yung black triangle ay yung ACH. Kapag nag attach yung Ach sa Open normal channel, (RECEPTOR) mag oopen siya, which is un ung normal way nya mag open. Pero pag pinalitan mo yung black triangle ng Succinylcholine at pag nag attach siya sa Open normal channel, magiging BLOCKED na yung open normal channel which will be now called DEPOLARIZING BLOCKER. Take note na bukas ung Ion channel kaso nakaharang ung succinylcholine kaya blocked na siya

Comparison of a Typical Nondepolarizing MuscleRelaxant (Rocuronium) and a Depolarizing Muscle Relaxant (Succinylcholine). Rocuronium Succinylcholine Phase I Phase 2 Administration of Additive Antagonistic Augmented Tubocuraine Administration of Antagonist Additive Augmented Succinylcholine Effects of Antagonistic Augmented Antagonistic Neosigmine Initial excitatory effect on skeletal None Fasciculations None muscle Response to tetanic Unsustained Sustained Unsustained stimulus Post tetanic Yes No yes Facilitaion Rate of Recovery 30-60 mins 4-8 mins >20 mins

II.

Spasmolytic The spinal cord and muscles showing the action of muscle relaxants and spasmolytics. If in the spinal cord, we call it centrally acting Spasmolytics: ex. Baclophen and diazepam- under benzodiazepine, it acts on your GABAa receptors. Benzodiazepine will act first on benzodiazepine receptors( it cannot act on your GABAa receptors ) , it will cause a change in your receptors and will inhibit the production of the action potential. Same goes with Baclofen, it occupies GABAb receptors or glutamate receptors. In the peripherals theres only 1 spasmolytic and that is dantrolene it acts directly on the muscles Black lines in arrow heads represent chemicals or actions that enhance the target of the lines. Baclofen GABAB receptor Benzodiazepines GABAA receptor Dantrolene muscle

Here you have your Calcium affecting the sarcoplasmic reticulum causing your actin, myosin muscle fibers to intercalate and act to one another resulting to muscular contraction. In the reflex arc you have cutaneous afferents and stimulus from the skin and it goes into the dorsal root then stimulus is transmitted to the spinal cord into the ventral roots to your efferent nerves and efferents causing stimulus in the muscle

Postulated sites of spasmolytic action of tizanidine ( 2), benzodiazepines (GABAA), and baclofen (GABAB) in the spinal cord. Tizanidine may also have a postsynaptic inhibitory effect. Dantrolene acts on the sarcoplasmic reticulum in skeletal muscle. Glu, glutamatergic neuron. A variety of pharmacologic agents described as depressants of the spinal "polysynaptic" reflex arc (eg, barbiturates [phenobarbital] and glycerol ethers [mephenesin]) have been used to treat these conditions of excess skeletal muscle tone. However, as illustrated in the figure above, nonspecific depression of synapses involved in the stretch reflex could reduce the desired GABAergic inhibitory activity, as well as the excitatory glutamatergic transmission. Currently available drugs can provide significant relief.

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