Neuromuscular Blockers and Other Skeletal Muscle Relaxants PDF

PHARMACOLOGY | TRANS # 11 LE Neuromuscular Blockers and Other Skeletal 02 Muscle Relaxants TERESITA A. BAT...

PHARMACOLOGY | TRANS # 11 LE Neuromuscular Blockers and Other Skeletal 02 Muscle Relaxants TERESITA A. BATANES, MD, MSc, DPBA, FPSA | Lecture Date (OCT/08/2024) | Version 1 OUTLINE I. SKELETAL MUSCLE RELAXANTS I. Skeletal Muscle Relaxants VI. Clinical Pharmacology of Drugs that affect skeletal muscle function II. Cholinergic Transmission NMBs Can be divided into 2 main groups: A. Normal Neuromuscular VII. Spasmolytics & → Neuromuscular Blockers Function Antispasmodics ▪ Produce muscle paralysis B. Cholinergic Receptor VIII. Review Questions ▪ May be used in the ICU and surgical procedures III.Neuromuscular Blockers IX. Formative Quiz IX. Appendix → Spasmolytics and Antispasmodics A. Basic Pharmacology IV. Depolarizing ▪ Reduce spasticity in a variety of painful conditions Neuromuscular Blockers A. Pharmacokinetics B. Prolonged Succinylcholine block C. Mechanism of Action D. Pharmacodynamics E. Drug Interactions V. Nondepolarizing Neuromuscular blockers A. Classification B. Pharmacokinetics C.Mechanism of Action D.Pharmacodynamics E. Drug Interactions Must Lecturer Book Previous Youtube Figure 1. Categories of Skeletal Muscle Relaxants [Synchronous ❗️ Know 💬 📖 📋 Trans Video 🔺 Presentation] SUMMARY OF ABBREVIATIONS ❗ Allcholinergic, II. CHOLINERGIC TRANSMISSION preganglionic efferent autonomic fibers nicotinic (N) are ACh Acetylcholine → Secrete acetylcholine (ACh) as a neurotransmitter AChE Acetylcholinesterase → Bind with nicotinic acetylcholine receptors, AP Action Potential specifically of the neuronal subtype (NN) CP Cerebral Palsy → NN: neuronal type of nicotinic receptor made up of 5 IV/IM Intravenous/Intramuscular subunits nAChR Nicotinic Acetylcholine Receptor ▪ Pentameric structure in ANS usually have ⍺- and ꞵ- 📋 NMB Neuromuscular Blocking Drugs type subunits only NMJ Neuromuscular Junction Found in CNS, dendrites, some presynaptic N Nicotinic cholinergic terminals, and in postganglionic cell NN NM Nicotinic, neuronal Nicotinic, muscle type ❗ bodies Somatic motor fibers to skeletal muscle are nicotinic (N) MG Myasthenia Gravis MAOIs Monoamine Oxidase Inhibitors → Also has ACh as its neurotransmitter SCh Succinylcholine → Binds with nicotinic receptors of the muscle subtype SR Sarcoplasmic Reticulum (NM) ▪ 5 subunits: 2𝛼, 𝛽, 𝛾 and 𝛿 RYR Ryanodine Receptor ✔ LEARNING OBJECTIVES Describe cholinergic blockade in the neuromuscular 📋 ▪ Found on motor end plates Most parasympathetic postganglionic fibers are muscarinic ✔ junction Characterize the 2 main groups of neuromuscular blockers and differentiate their pharmacokinetics, 📋 → Cardiac smooth muscle, Gland cells, Nerve terminals Few sympathetic postganglionic fibers → Sweat glands pharmacodynamics, clinical uses ✔ Identify the reversal agents used to overcome neuromuscular blockade ✔ Classify and characterize the spasmolytics and antispasmodics Space intentionally left blank LE # 2 TG # 11 | J. Santiago, C. Santos, J. Santos, TE | M. Reyes, C. Sanchez AVPAA | J. Tudtud PAGE 1 of 11 TRANS # 11 K. Santos, R. Santos VPAA | D. Patajo PHARMACOLOGY | LE 2 Neuromuscular Blockers and Other Skeletal Muscle Relaxants | Teresita A. Batanes, MD, MSc, DPBA, FPSA Figure 2. Cholinergic Transmission to Effector Organs[Lecture Figure 3. Normal Neuromuscular Function[Lecture PPT] 📋 PPT] ACETYLCHOLINE Primary transmitter at ANS ganglia, somatic 📋NICOTINIC RECEPTOR BLOCKERS Ganglionic blockers: neuromuscular junction, and parasympathetic → Competitive antagonists to ACh at NN of both ❗ postganglionic nerve endings Excitatory to smooth muscles and secretory cells in enteric nervous system parasympathetic and sympathetic ganglia NMBs or skeletal muscle relaxants → Block nicotinic receptors at the muscle side or at the All available neuromuscular blockers have a structure muscle end plate. similar to ACh → Agents that act against NM A. NORMAL NEUROMUSCULAR FUNCTION → Only given in a controlled setting; NOT given when 1. Arrival of an action potential (AP) in the nerve respiration cannot be controlled 2. Influx of calcium into the sarcoplasm of the nerve → Parenteral forms (IV/IM) are available → NMBs cause skeletal paralysis 📋terminal The increased intracellular calcium causes fusion of vesicles with the surface membrane. ▪ Muscles of respiration including diaphragm, intercostal muscles, and larynx are paralyzed 3. Release of ACh from its storage vesicles into synaptic ▪ Must be given only by physicians with specific cleft by exocytosis training 4. Released ACh will bind to the nicotinic receptor located B. CHOLINERGIC RECEPTORS 📋at the motor end plate Binding of two ACh molecules elicits a conformational 📋 MUSCARINIC RECEPTORS G-protein coupled receptors (GPCRs) change of the ion channel. Subclassified into M1, M2, M3, M4, and M5 5. Upon binding, there will be opening of Na+ and K+ channels NICOTINIC RECEPTORS → Initially Na+ channel will open → influx of Na+, and Ligand-gated ion channels later on the exit of K+ Skeletal muscle type of nicotinic receptors (NM) 6. Na+ influx → depolarization → motor AP → Two ACh binding sites: 7. Motor AP will spread throughout the muscle and cause ▪ 𝛼-𝛽 and 𝛿-𝛼 interphases muscle contraction When ACh binds with the 2 binding sites, there will be 8. ACh is removed from the end plate by enzymatic opening of the nicotinic receptor and influx of Na+ degradation by acetylcholinesterase (AChE) located at → Binding of ACh in one binding site will increase the 📋the postsynaptic area AChE splits ACh into choline and acetate thereby terminating the action of the neurotransmitter. affinity of the receptor to another ACh molecule → Binding of another ACh with the second binding site in the nicotinic receptor will increase chance for the 📋 receptors to open and allow the passage of Na+ ions 📋 Resulting in conductance Or lack of conductance with the use of NMB Two additional types of ACh receptors in the neuromuscular junction (NMJ): → Presynaptic motor axon terminal Space intentionally left blank ▪ Activation will cause release of additional ACh ▪ Located presynaptically → Extrajunctional cells/receptors ▪ Not usually involved in NM transmission ▪ Proliferate during prolonged immobilization (bedridden, post-stroke, etc.), thermal burns PHARMACOLOGY Neuromuscular Blockers and Other Skeletal Muscle Relaxants PAGE 2 of 11  PHARMACOLOGY | LE 2 Neuromuscular Blockers and Other Skeletal Muscle Relaxants | Teresita A. Batanes, MD, MSc, DPBA, FPSA COVID-19 INTUBATION Since COVID-19 is still not over, in COVID-19 intubation there is a special use for the NMBs Important considerations during intubation under then COVID-19 protocol → Prevent aerosolization to avoid spread of the virus → Deep sleep → Deep and rapid neuromuscular blockade ▪ Accomplished by giving the full intubating dose of a paralytic agent of a NMB → full paralysis → Most experienced intubator (anesthesiologist) ▪ To make sure a single attempt to intubate the patient will be successful Figure 4. Adult nicotinic acetylcholine receptor[Lecture PPT] → Specialized equipment ▪ Video laryngoscope where the patients larynx can III. NEUROMUSCULAR BLOCKERS be observed in a monitor while intubation is done A. BASIC PHARMACOLOGY ▪ Proper use of personal protective equipment RESEMBLANCE TO ACETYLCHOLINE All neuromuscular blockers (NMB) have some CONCEPT CHECKPOINT resemblance to ACh in its structure 1. An excess of the agonist neurotransmitter, Ex. Succinylcholine acetylcholine, at the NMJ will result in 📋 → Looks like 2 molecules of ACh joined together a. Strong contraction Quaternary skeletal muscle relaxant prepared in its b. Weak contraction bromide, chloride, or iodide salt c. No Contraction d. Any of the above 2. The mechanism of action of depolarizing NMB a. Competes with acetylcholine at the NMJ b. Acts as agonist in excess at the NMJ c. Stays in the plasma to prevent contraction d. Degrades acetylcholine ANS: 1. C. It will result in excess binding of the acetylcholine neurotransmitter and there will be no subsequent contraction. Figure 5. Chemical structure of Succinylcholine vs. 2. B. It will bind with the nicotinic receptor at the muscle Acetylcholine[Lecture PPT] end plate but it will cause no contraction because of the 📋 Causes paralysis → Used in the following scenarios: excess agonist effect. IV. DEPOLARIZING NEUROMUSCULAR BLOCKERS ▪ Intraoperative muscle relaxation ▪ Intubation for general anesthesia ❗ A. PHARMACOKINETICS There is only one available in clinical practice: ▪ Intubation under COVID-19 airway management protocol ▪ Controls the positioning of body parts 💬 Succinylcholine (Suxamethonium) Decamethonium is only used in the laboratory → Acts peripherally, hence no central activity ROUTE OF ADMINISTRATION ▪ Effects in CNS are absent Parenteral (IV or IM) ▪ No drowsiness, dizziness, or increased intracerebral All neuromuscular blockers are administered only activity parenterally → It does not have good oral absorption PRESENCE OF 1 OR 2 QUATERNARY NITROGEN/S Poorly lipid soluble: the quaternary nitrogens make them METABOLISM polar Succinylcholine is metabolized into Succinylmonocholine Limits entry into CNS by: Limited volume of distribution (80-140 mL/kg) → Pseudocholinesterase in the plasma ▪ Undergoes rapid hydrolysis before reaching the NMJ ▪ Only a portion of the administered dose reaches the site of action to binds with the nicotinic receptor → Butyrylcholinesterase in the liver Succinylmonocholine is an active metabolite → Has the property of the parent compound → Also causes paralysis → Final metabolism to succinic acid and choline TERMINATION OF ACTION AND EXCRETION Diffusion from motor end plate: termination of Figure 6. Chemical Structure of Tubocurarine (L) and action/paralysis Rocuronium (R)[Lecture PPT] Excretion: via urine from the kidneys as polar metabolite PHARMACOLOGY Neuromuscular Blockers and Other Skeletal Muscle Relaxants PAGE 3 of 11  PHARMACOLOGY | LE 2 Neuromuscular Blockers and Other Skeletal Muscle Relaxants | Teresita A. Batanes, MD, MSc, DPBA, FPSA Refer to Table 1 → If the Dibucaine no. is high (such as 70-80): ▪ Normal type of pseudocholinesterase, Homozygous typical ▪ Normal duration of succinylcholine block ▪ High proportion of pseudocholinesterase has been Figure 7. Metabolism of Succinylcholine (SCh)[Lecture PPT] inhibited by dibucaine → If the dibucaine is lower in number (50-60): ❗ Among B. PROLONGED SUCCINYLCHOLINE BLOCK all NMBs, whether depolarizing or nondepolarizing, succinylcholine has the: ▪ Atypical atypical pseudocholinesterase, heterozygous ▪ Duration of block will increase by 50-100%, Instead → Most Rapid Onset of Action: 60-90 seconds of 5-10 minutes, it will be 10-20 minutes → Shortest Duration of Action: 5-10 minutes → When the dibucaine no. is 20-30: There are certain situations when there is prolonged ▪ Homozygous atypical succinylcholine block ▪ Duration of succinylcholine block is increased to 4-8 → During cases of ↓ Pseudocholinesterase levels hours DECREASE IN PSEUDOCHOLINESTERASE LEVEL C. MECHANISM OF ACTION Decrease in the enzyme that degrades succinylcholine PHASE I BLOCK (DEPOLARIZING BLOCK) Can be observed in: Usual or normal block produced by succinylcholine → Conditions: pregnancy, burns, oral contraceptives, Succinylcholine binds with the nicotinic acetylcholine monoamine oxidase inhibitors (MAOIs) receptor (nAChR) located at the motor end plate → → Diseases: liver disease, neoplastic diseases depolarization (opening of the nicotinic receptor) → influx ▪ Pseudocholinesterase is synthesized in the liver of sodium and eventual muscle contraction → Concurrent Medications: anticholinesterases, → Seen as fasciculations (disorganized depolarization) echothiophate, cytotoxic drugs, → Flaccid paralysis tetrahydroaminoacridine, hexafluorenium Excess of depolarizing agonist or excess acetylcholine that DRUG INTERACTION binds with the nAChR Mechanism: Succinylcholine will have a prolonged block when given → Succinylcholine undergoes slower hydrolysis than with neostigmine acetylcholine → membrane remains depolarized for a → (+) Neostigmine longer period of time ▪ Inhibit pseudocholinesterase = longer duration of ▪ Unresponsive to impulses block ▪ No repolarization and repetitive firing ATYPICAL FORM OF PSEUDOCHOLINESTERASE: ▪ No excitation-contraction coupling GENETIC VARIANT ▪ No subsequent contraction Rare familial genetic condition Dibucaine → Local anesthetic → Inhibits normal pseudocholinesterase much more than it inhibits the atypical pseudocholinesterase 📋 ▪ N enzyme >>> abN enzyme Used to determine if there are pseudo abnormal or atypical pseudocholinesterase Dibucaine number of a patient 📋 → Percentage of pseudocholinesterase inhibited Measures the ability of a patient to metabolize 📋 succinylcholine High Dibucaine Number: High presence of normal 📋 pseudocholinesterase inhibited Low Dibucaine Number: High presence of variant of abnormal form Table 1. Types of Pseudocholinesterase. Dibucaine Duration Pseudo- Incidence No. (% of Sch cholinesterase inhibited) Block Homozygous Normal 70-80 Normal Typical Heterozygous 1/480 50-60 ↑ by Atypical ~50-100% Homozygous 1/3200 20-30 ↑ to 4-8 Atypical hours Figure 8. Depolarizing block[Lecture PPT] PHARMACOLOGY Neuromuscular Blockers and Other Skeletal Muscle Relaxants PAGE 4 of 11 PHARMACOLOGY | LE 2 Neuromuscular Blockers and Other Skeletal Muscle Relaxants | Teresita A. Batanes, MD, MSc, DPBA, FPSA PHASE II BLOCK (DESENSITIZING BLOCK) E. DRUG INTERACTIONS Continuous exposure of the end plate to succinylcholine Increase duration of Succinylcholine block → Happens when high doses of SCh is given or when → SCh + Neostigmine (cholinesterase inhibitor) given by infusion by a long period of time ▪ Partly due to inhibition of pseudocholinesterase Depolarized (manifested as fasciculations) → Increase dose requirement of Succinylcholine 💬 Repolarized → Desensitized Even though there will be ACh that will bind to the nicotinic receptor, the membrane is desensitized so → SCh + Nondepolarizing blocker ▪ INC dose requirement of SCh by about 50% → Why do we give nondepolarizing NMB with depolarizing there will be no effect, no muscle contraction NMB? Behaves like a nondepolarizing neuromuscular block ▪ Small dose of nondepolarizing NMB is given before (NMB) later in duration the block succinylcholine to prevent fasciculations D. PHARMACODYNAMICS CONCEPT CHECKPOINT EFFECTS ON CARDIOVASCULAR SYSTEM C. Who among the following patients may safely Depolarizing Drug: Succinylcholine receive succinylcholine? 💬 1. Cardiac Arrhythmias (Succinylcholine + Halothane) Halothane: Volatile (inhalation) anesthetic a. With a family history of unexplained deaths following exposure to inhaled anesthetic 💬 ▪ Not frequently used anymore May present as: ▪ Sinus Bradycardia, nodal (junctional rhythm) b. With burn injury sustained more than 24 hours c. Diagnosed angle closure glaucoma d. With no known comorbidities 📋 ▪ Ventricular Arrhythmias Due to: ▪ Direct myocardial effects ANS: 3. D. A healthy patient can receive any drugs. ▪ Increased muscarinic stimulation Patients with burn injury may have rhabdomyolysis 📋 ▪ Increased ganglionic stimulation Prevention: ▪ Atropine (widely used) and there are also diseases in extrajunctional receptors that develop. They should not be given succinylcholine. ▪ Ganglionic blockers With a family history of unexplained deaths following − Can be given prior to administration of exposure to inhaled anesthetic → May be because of antimuscarinic atropine malignant hyperthermia 💬 2. Hyperkalemia Transient increase in serum K+ (0.5-0.7 mEq) → Maybe clinically insignificant if the patient has normal Angle closure glaucoma → transient increase in intraocular pressure V. NONDEPOLARIZING NEUROMUSCULAR 💬 serum potassium In patients with burns, trauma, nerve damage, neuromuscular disease, renal failure, metabolic BLOCKERS A. CLASSIFICATION acidosis → Serum potassium levels may already be ACCORDING TO STRUCTURE increased Table 2. Classification according to structure ▪ The additional transient increase in serum potassium CLASSIFICATION STRUCTURE may be fatal and cause cardiac arrest, due to very 1. Steroidal Derivatives high potassium levels. “-curonium” → SUCCINYLCHOLINE SHOULD NOT BE GIVEN to Have steroid in the these patients and patients with already high levels of core of their 💬 potassium In about 5 minutes, the plasma potassium levels will go back to normal structure ❗ Examples: Rocuronium (eg. Esmeron) OTHER EFFECTS → Vecuronium 💬 1. Increased Intraocular Pressure Onset: 35 mins Tubocurarine → Spontaneous degradation in plasma Short Duration → Can be used in patients with liver and kidney → Mivacurium pathologies ▪ May cause bronchospasm. Removed from the US Laudanosine can accumulate when there is high dose or market prolonged use of Isoquinoline derivatives ▪ Still long compared to the duration of action of → Has a long elimination half-life (T½: 150 min) Succinylcholine (5-10 mins) → Can cross the CNS/BBB − SCh still have the shortest duration ▪ During prolonged surgery, it can cost increased Intermediate Duration anesthetic requirements → Atracurium, Vecuronium, Rocuronium, Cisatracurium → Most commonly used NMBs nowadays 📋 ▪ Causes excitatory effects in the brain (e.g. seizure) It can accumulate if Atracurium is used for several days → Most surgeries last for the duration of these agents ▪ If the procedure is longer, additional NMB can be 📋 📋 as infusion in the ICU for ventilatory / movement control Atracurium is the older agent Cisatracurium is an improvement given Long Duration → Less dependent on hepatic metabolism → Pancuronium, Tubocurarine → Less Laudanosine is produced → Tubocurarine is not used anymore → Less histamine is released ▪ There are other agents that are effective with less side effects 📋 → More commonly used in practice Gantacurium 📋 D-TUBOCURARINE Tubocurarine from curare → An experimental NMB still not clinically available → Metabolism is non-enzymatic → Histamine release may cause hypotension at a dose of → Prototypical nondepolarizing neuromuscular blocker ED95 MOA: Competitive blocking of nicotinic receptors at the neuromuscular junction Long Acting (more than 35 minutes) ❗ Competitive receptor C. MECHANISM OF ACTION antagonism with Acetylcholine at nicotinic Release histamine causing bronchospasm and hypotension due to peripheral vasodilation → Only one binding site occupied is enough to inhibit No significant effects on myocardium opening of the receptor-ion channel High Doses = Ganglionic block Blocks pore of ion channel in large doses May block prejunctional Na+ channels B. PHARMACOKINETICS → Interferes with mobilization and release of Ach ❗ ABSORPTION AND DISTRIBUTION Highly Polar → Polar due to the presence of Quaternary Nitrogens → Inactive if taken orally; only parenteral preparation is available Space intentionally left blank → Does not cross membranes well → Has limited volume distribution Rapid initial distribution phase Slower elimination phase PHARMACOLOGY Neuromuscular Blockers and Other Skeletal Muscle Relaxants PAGE 6 of 11 PHARMACOLOGY | LE 2 Neuromuscular Blockers and Other Skeletal Muscle Relaxants | Teresita A. Batanes, MD, MSc, DPBA, FPSA 💬 Patients with CVS pathology: Patients with previous MI, Coronary Artery Disease, Ischemia, Congenital Heart 💬 Disease, Hypertension, etc. Atracurium: Only available presently for clinical use → 💬 May cause hypotension due to Histamine release Pancuronium: Long acting, nondepolarizing NMB [Not used in patients who are tachycardic and hypertensive OTHER EFFECTS: HISTAMINE RELEASE Some NMB cause release of histamine which can result in: → Flushing → Hypotension → Bronchospasm → Tachycardia Figure 11. Non-Depolarizing NMBs as Competitive Inhibitors. Nondepolarizing blockers that cause histamine release ACh (Green) and Non-depolarizing NMB (Red). [Lecturer’s PPT] 💬 (Benzylisoquinoline derivatives) When one non-depolarizing NMB binds to one or two binding sites in the nicotinic receptors → inhibits the opening of nicotinic receptor → No passage of Na+ ❗ → Decreasing order of degree of release: d-Tubocurarine (most histamine release) >> Metocurine > Atracurium, Mivacurium > Cisatracurium ions (least histamine release) 💬 ▪ Cisatracurium is best to use − Newly developed drug with all the advantages of Atracurium, minus the disadvantages such as the release of histamine and the consequent hypotension and tachycardia Steroidal type of NMB DO NOT cause release of Histamine (e.g. Rocuronium, Vecuronium, and 💬 Pancuronium) Patients who have asthma or those who have many Figure 12. Normal agonist ACh opening channel [Lecturer’s PPT] allergies does not use d-tubocurarine → Cisatracurium or the steroidal type of nondepolarizing blockers are used instead E. DRUG INTERACTIONS Augment/Enhance Neuromuscular Block → Anesthetics ▪ Isoflurane (most) > Sevoflurane, Desflurane, Halothane, Nitrous Oxide (least) → Antibiotics ▪ Aminoglycosides: Streptomycin, Gentamicin, Figure 13. Competitive antagonism of NMB at nicotinic Amikacin receptors [Lecturer’s PPT] ▪ Macrosides: Erythromycin 💬 ACh will not be able to bind with its binding site in the → Local Anesthetics ▪ High Doses → Local anesthetics block receptor and the receptor will remain closed → No influx neuromuscular transmission of Na+ → No depolarization EFFECTS OF DISEASE / AGE D. PHARMACODYNAMICS Myasthenia Gravis (MG) EFFECTS ON THE CARDIOVASCULAR → Cause: (+) IgG antibodies vs nicotinic ACh receptors → Table 5. Cardiovascular Effects Less number of responsive receptors CV Effects Nondepolarizing Remarks → Less number of functional receptors, MG patients will Drugs be: Minimal Vecuronium Best in patients ▪ Less susceptible to depolarizing NMB Rocuronium with CVS ▪ More susceptible to nondepolarizing NMB pathology → Enhanced neuromuscular blockade Hypotension due to Tubocurarine Attenuated by → Remember: MG patients already have weak muscular Histamine release Metocurine antihistamine contraction especially of the respiratory muscles Mivacurium Elderly (>70y/o) Atracurium → Prolonged duration due to ↓ clearance from the liver Ganglionic Tubocurarine Tubocurarine: and kidneys blockade Metocurine not being used → Should ↓ Dose (large doses) anymore Severe Burns, Upper Motor Neuron Disease ↑HR, ↑CO Pancuronium** Vagolytic action → Resistance to nondepolarizing blockers due to presence ±↑Systemic release of NE & of extrajunctional receptors Vascular block reuptake of ▪ Proliferates only in certain conditions with prolonged Resistance NE at synaptic immobilization (e.g. Stroke, burns) site → Should ↑ Dose PHARMACOLOGY Neuromuscular Blockers and Other Skeletal Muscle Relaxants PAGE 7 of 11  PHARMACOLOGY | LE 2 Neuromuscular Blockers and Other Skeletal Muscle Relaxants | Teresita A. Batanes, MD, MSc, DPBA, FPSA VI. CLINICAL PHARMACOLOGY OF NMBs Clinical uses of NMBs for Skeletal Muscle Paralysis → Relaxation for intubation of the trachea → Intraoperative relaxation of the skeletal muscles necessary to expose operative field ▪ Relaxation of the abdominal muscles to expose the contents of the abdominal cavity more easily → ICU: Important to control mechanical ventilation ▪ To synchronize the mechanical ventilation with the ❗ patient No Central Activity: it does NOT cross the BBB → No dizziness, headache, sedation ASSESSMENT OF NEUROMUSCULAR BLOCKADE To monitor effects of NMB: before intubation, intraoperatively, and recovery Nerve stimulator 📋 → Transdermal electrical stimuli Gold standard in assessing NM function in anesthesia is by nerve stimulation of the ulnar nerve–function of Figure 15. Train of Four Stimulation on Adductor Pollicis[Lecturer’s PPT] 📋 adductor pollicis muscle. Volar surface of the forearm along the course of the ulnar nerve is stimulated ⇒ elicit contractions from the REVERSAL OF BLOCKADE FROM NONDEPOLARIZING BLOCKERS Recall: MOA of Non-depolarizing blockers are due to adductor pollicis muscle ⇒ manifested as adduction competitive antagonism with Ach at the NMJ of the thumb that can be measured Counteracted by cholinesterase inhibitors Ulnar nerve: superficial nerve stimulated → ↓degradation of Ach → ↑ Ach at neuromuscular junction Adductor pollicis muscle ▪ Displaces the non-depolarizing blocker from the 📋 → Contractions in the thumb are measured Other nerves that can be stimulated → Posterior tibial nerve ❗ binding site of the nicotinic receptor Neostigmine, Pyridostigmine → Inhibits cholinesterase → Facial nerve → Increase release of Ach from motor nerve ending Edrophonium: short acting; used for the diagnosis of Myasthenia Gravis 📋 Structure: SUGAMMADEX (BRIDION) Modified γ-cyclodextrin New agent: rapid reversal of neuromuscular blockade → Ex: Rocuronium, Vecuronium, Pancuronium Used for steroidal type non-depolarizing blockers → CANNOT be used with isoquinoline derivatives 18x faster onset vs Neostigmine to TOF ratio of >90% Figure 14. Transdermal Electrical Stimuli [Lecturer’s PPT] 1:1 tight binding w/ Rocuronium: → Sugammadex- Rocuronium complex in plasma 📋 Four TRAIN OF FOUR STIMULATION successive supramaximal electrical stimuli at 0.5 sec interval at 2Hz → Sugammadex pulls Rocuronium from NMJ into the plasma and binds with it ▪ Enhanced concentration gradient between → Four twitches of the adductor pollicis (thumb) Rocuronium in plasma and rocuronium in NMJ Administration of Rocuronium (Nondepolarizing NMB) − There is higher concentration of rocuronium in the → FADE: decreasing amplitude of the 4 twitches NMJ than in the plasma → TOF Count: no. of Responses (twitches seen) → Sugammadex-rocuronium complex is excreted in urine → TOF Ratio (TOFR): ratio of the relative magnitude of within 24 hours the 4th twitch to the 1st twitch (4/1) → Caution in patients with severe renal impairment (longer excretion time) Table 6. TOFR Ratios Ratio Indication TOFR = 1.0 No neuromuscular blockade (baseline) TOFR = 0.5 (50%) Height of amplitude of the 4th twitch (0.5) to the 1st twitch (1.0) is 50% TOFR = 0.8 (80%) 4th twitch amplitude to 1st twitch amplitude ratio is 0.8 ❗ TOFR of >90% is a sign of neuromuscular blockade (paralysis) recovery from Figure 16. Sugammadex-Rocuronium Complex. Reaction favors formation of the Sugammadex-Rocuronium Complex, ▪ Breathing is normal, no sign of paralysis but some (rare) situations favor separation of the complex [Lecturer’s PPT] PHARMACOLOGY Neuromuscular Blockers and Other Skeletal Muscle Relaxants PAGE 8 of 11 PHARMACOLOGY | LE 2 Neuromuscular Blockers and Other Skeletal Muscle Relaxants | Teresita A. Batanes, MD, MSc, DPBA, FPSA ADVERSE EFFECTS Hypersensitivity: nausea, pruritus, urticaria Anaphylaxis (rare) Bradycardia → Cardiac Arrest (rare) ❗ Coagulopathy May also inhibit other steroids → Progesterone-based contraceptives ▪ Binds with the contraceptive = missed 1-2 doses ▪ Use alternative non-hormonal contraceptive for 7 days after Sugammadex → Selective estrogen receptor modulator Toremifene ▪ Binds with Toremifene − Used in cancer treatment − Displaces rocuronium form sugammadex-rocuronium complex thus, a prolonged NM blockade − Decreased efficacy of toremifene Figure 17. Sites of action of some Spasmolytics [Lecturer’s PPT] VII. SPASMOLYTICS AND ANTISPASMODICS OTHER CENTRALLY-ACTING SPASMOLYTIC DRUGS A. SPASMOLYTICS Gabapentin (Neurontin) Available orally, unlike NMBs → Antiseizure drug: antagonist at voltage gated Ca++ Treats spasticity from: channel -as 1° action → Upper motor neuron lesions → Spasmolytic effect → Involuntary muscle contractions ▪ Especially in patients with Multiple Sclerosis → Hyperactivity α-motor neurons Pregabalin (Lyrica) Some have central side effects (sedation, dizziness) → Antiseizure drug Relief from painful muscle spasms → Analog of gabapentin Not much improvement in function (moving about, Progabide and Glycine working) → Progabide is GABAA and GABAB agonist ❗ TableCentrally-acting 7. Spasmolytics Peripherally-acting → Glycine is an inhibitory amino acid neurotransmitter → Readily pass through the BBB Idrocilamide and Riluzole Diazepam (Valium) Dantrolene Sodium → Inhibition of glutamatergic transmission (Dantrium) ▪ Glutamate - excitatory neurotransmitter Baclofen (Lioresal) Eperisone HCl (Myonal) → Newer drugs for Amyotrophic lateral sclerosis Tizanidine Phenyramidol (Bragal) (ALS) CENTRALLY-ACTING PERIPHERALLY-ACTING DIAZEPAM DANTROLENE SODIUM MOA: binds with component of GABAA receptor MOA: inhibits Ca2+ release from the sarcoplasmic → GABA receptors are the main inhibitory NT in the reticulum (SR) by direct action on skeletal muscles CNS → Prevents excitation-contraction coupling Adverse effects: drowsiness, dizziness, weakness, ▪ May bind with Ryanodine receptor (RYR1) mental confusion − Channel for Ca2+ release from SR Dependence: Withdrawal Syndrome ▪ Cardiac smooth muscle (RYE2 ryanodine receptor Tolerance: increase the dose to attain the same effect isoform) after prolonged use − Depressed only slightly Adverse effects BACLOFEN MOA: agonist at GABAB receptor → Presynaptic inhibition: ↓ release of excitatory ❗ → Muscle weakness, sedation, occasional hepatitis Drug of Choice for MALIGNANT HYPERTHERMIA neurotransmitter BOTULINUM TOXIN → Causes less sedation than Diazepam MOA: prevents release of transmitter (ACh) from cholinergic vesicles (VAMPs and SNAPs) TIZANIDINE (SIRDALUD TAB) Local injection for treatment of generalized spastic Congener of Clonidine (antihypertensive) disorders MOA: significant α2-adrenoceptor agonist effects → Benefits lasts for weeks to months Side Effects: drowsiness, hypotension, dry mouth, asthenia ❗ Most clinical studies: administration in one or two limbs Utilize Type A Botulinum Toxin Space intentionally left blank Space intentionally left blank PHARMACOLOGY Neuromuscular Blockers and Other Skeletal Muscle Relaxants PAGE 9 of 11 PHARMACOLOGY | LE 2 Neuromuscular Blockers and Other Skeletal Muscle Relaxants | Teresita A. Batanes, MD, MSc, DPBA, FPSA B. ANTISPASMODICS III. REVIEW QUESTIONS Treatment of acute local muscle spasm 1. Among all neuromuscular blockers whether → Peripheral Musculoskeletal Conditions depolarizing or nondepolarizing, which drug has the ▪ Tissue trauma or muscle strain (e.g. whiplash injury) most rapid onset of action? → Drugs not listed in PNF, 2017–NOT available locally a. Atracurium Central-acting: Brainstem b. Succinylcholine → Cyclobenzaprine (prototype) c. Decamethonium → Carisoprodol d. Diazepam → Chlorphenesin 2. A 23 year old female with a history of allergies to → Chlorzoxazone several food items and medications will undergo → Metaxalone general anesthesia for an abdominal surgery. Which → Orphenadrine of the following neuromuscular blockers is best → Methocarbamol (Robaxin) avoided in this patient? a. Succinylcholine CYCLOBENZAPRINE (FLEXERIL) PROTOTYPE b. Cisatracurium Structurally related to the tricyclic antidepressants c. Atracurium (+) Antimuscarinic side effects d. Rocuronium → Sedation, transient visual hallucinations, confusion 3. Which of the following is NOT an effect of Contraindications and AE depolarizing NMB? → NOT for Upper Motor Neuron (UMN) conditions a. Cardiac arrhythmia ▪ E.g. Spinal Cord Injury, Cerebral Palsy, Multiple b. Muscle pains Sclerosis c. Decreased intraocular pressure Abuse potential d. Transient hyperkalemia Drug interaction: 4. What Train Of Four Ratio (TOFR) is a sign of recovery → Serotonin Syndrome from neuromuscular blockade or paralysis? ▪ Agitation, sweating, tremors, seizures, hyperthermia, a. More than 90% coma b. More than 80% → Concomitant Intake c. More than 95% ▪ Selective serotonin reuptake inhibitors (SSRIs), 5. What are spasmolytics used for? serotonin/norepinephrine reuptake inhibitors (SNRIs), a. Spasticity from upper motor neuron lesions tricyclic antidepressants (TCAs), tramadol, b. Spasticity from lower motor neuron lesions bupropion, meperidine, verapamil, MAO inhibitors c. Spasticity peripheral musculoskeletal conditions ANS: 1. B. Among all NMBs, whether depolarizing or nondepolarizing, succinylcholine has the most rapid onset of action at 60-90 seconds and shortest duration of action at 5-10 minutes. 2. C. Atracurium has an effect on histamine release. 3. C. There will be an increase in intraocular pressure. Succinylcholine should not be used in patients with glaucoma. 4. A. >90% Train Of Four Ratio (TOFR) is a sign of recovery from neuromuscular blockade or paralysis 5. A. Spasmolytics. C. Antispasmodics are used to treat spasms from peripheral musculoskeletal conditions. V. REFERENCES Batanes, T. (2024). Skeletal Muscle Relaxants Figure 18. Pharmacology view at motor end plate [Lecturer’s PPT] Kruidering-Hall, M, Campbell, M. (2021). Skeletal Muscle Relaxants. In B.G. Katzung (Ed.), Basic and Clinical Pharmacology 16th Ed, 2023. International Edition, USA, McGraw-Hill Education Additional reference for COVID-19 update in relation to NMB: CanadiEM. (2020). Recommendations for COVID-19 Intubation: an Infographic. https://canadiem.org/recommendations-for-covid-19-intubation-an-infograph ic/ 2026 Trans 2025 Trans PHARMACOLOGY Neuromuscular Blockers and Other Skeletal Muscle Relaxants PAGE 10 of 11 PHARMACOLOGY | LE 2 Neuromuscular Blockers and Other Skeletal Muscle Relaxants | Teresita A. Batanes, MD, MSc, DPBA, FPSA VI. FORMATIVE QUIZ Question & Choices Answer & Rationale For questions 1 and 2, please refer to this case presentation: A healthy patient for surgery was given a neuromuscular blocker intravenously 1. If fasciculations were observed after drug Small dose of nondepolarizing NMB is given before administration, what NMB was given? succinylcholine to prevent fasciculations. A. Atracurium C B. Succinylmonocholine C. Succinylcholine D. Decamethonium 2. If the train of four (TOF) tracing showed “fade”, what "Fade" in the Train of Four (TOF) monitoring is indicative of a NMB was given non-depolarizing neuromuscular blockade (NMB) such as Rocuronium (nondepolarizing NMB) A. Decamethonium B B. Rocuronium C. Succinylmonocholine D. Succinylcholine 3. The bioavailability at the NMJ of an intravenously Succinylcholine undergoes rapid hydrolysis before reaching administered succinylcholine is the NMJ so only a portion of the administered dose reaches the site of action. A. Less than the amount given A B. Cannot be quantified C. More than the amount given D. 100% 4. The reason for the use of neostigmine to reverse Neostigmine is a cholinesterase inhibitor. neuromuscular block is Decreasing the degradation of Ach increases Ach at neuromuscular junction. It displaces the non-depolarizing A. Decrease in binding of the depolarizing blocker from the binding site of the nicotinic receptor. neuromuscular blocker to its receptor due to decrease in affinity B. Increase in the binding of 2 acetylcholine neurotransmitter molecules to muscarinic receptors C due to increase amount of acetylcholine C. Increasing the amount of acetylcholine due to inhibition of its degradation D. Decreasing the amount of nondepolarizing neuromuscular blocker due to increase in its metabolism 5. Sugammadex is useful in reversing neuromuscular Sugammadex is responsible for rapid reversal of block from which NMB neuromuscular blockade. It cannot be used with isoquinoline derivatives such as atracurium and cisatracurium. It is used for A. Atracurium B steroidal types of non depolarizing blockers such as B. Rocuronium Rocuronium, Vecuronium, and Pancuronium. C. Cisatracurium D. Succinylcholine 6. A patient who is receiving which drug will be affected Intake of Toremifene displaces Rocuronium from by the administration of sugammadex Sugammadex-Rocuronium complex, leading to prolonged NM blockade. This will cause a decrease in efficacy of the drug A. Toremifene A Toremifene B. Dantrolene C. Ibuprofen D. Methotrexate 7. Which condition is an indication for dantrolene? Dantrolene sodium is the drug of choice for malignant hyperthermia. A. Intense fever B. Malignant hyperthermia B C. Whiplash injury D. Stiff neck 8. A patient with spastic type of cerebral palsy who Baclofen treats spasticity with less sedation. wishes not to be too much sedated may be given which spasmolytic? A. Eperisone B B. Baclofen C. Tizanidine D. Diazepam PHARMACOLOGY Neuromuscular Blockers and Other Skeletal Muscle Relaxants PAGE 11 of 11