Pharmacology of Muscle Relaxants Fall 2024 PDF

PHM 736 Fall 2024 Lunawati Bennett MS; PhD; PharmD; FACN When you lie down, you will not be afraid; when you lie down, your sleep will be sweet- Proverbs 3:24  nAChR-nicotinic acetylcholine  MS-multiple sclerosis receptor  NTs-neurotransmitters  ACh- acety...

PHM 736 Fall 2024 Lunawati Bennett MS; PhD; PharmD; FACN When you lie down, you will not be afraid; when you lie down, your sleep will be sweet- Proverbs 3:24  nAChR-nicotinic acetylcholine  MS-multiple sclerosis receptor  NTs-neurotransmitters  ACh- acetylcholine  BBB-blood brain barriers  AChE- acetylcholine esterase  ALS-amyotrophic lateral sclerosis  MOA-mechanism of action  AP- action potential  ADRs-adverse drug reactions  CS-controlled substance  DDI-drug drug interactions  CNS- central nervous systems  IOP-intraocular pressure  H-histamine  ICU-intensive care unit  Generic Name Trade Name Type Gabapentin Neurontin® Anticonvulsant Cyclobenzaprine Flexeril ®, Amrix ® Muscle relaxants Pregabalin Lyrica ® Analgesic, anticonvulsant Carisoprodol Soma® Muscle relaxant Baclofen Lioresal ® Muscle relaxant Tizanidine Zanaflex® Muscle relaxant Cisatracurium Nimbex  Neuromuscular blocking agent You are responsible for underlined ADRs, drug names of each class, and brand names of top prescriptions At the end of this lecture and after studying the material, the student should be able to: 1. Identify the MOA and ADR of a drug that works as depolarizing neuromuscular agent 2. Identify the MOA, names of the drugs that work as non-depolarizing neuromuscular agents. Which one is better in patients with ARS 3. Identify MOA and ADRs of centrally acting spasmolytic drugs: baclofen, cyclobenzaprine, diazepam, carisoprodol, and tizanidine. 4. Identify important counseling point when using spasmolytic drugs 5. Identify the names of other drugs that can be useful as spasmolytics 6. Identify specific characteristics of Cisatracurium 1. Neuromuscular blocking drugs ✓ Used during surgical procedure and ICU to produce muscle paralysis ✓ Interfere with transmission at the neuromuscular end plate, so there is no CNS activity. ✓ Used with general anesthesia to ensure adequate ventilation, prolonged relaxation during surgical procedure, relaxation of respiratory muscle ✓ Also useful for treatment of status epilepticus 2. Spasmolytics ❖ Used to reduce spasticity in a variety of painful condition ❖ Also called “centrally acting” muscle relaxant to treat chronic pain, painful fibromyalgia, or acute spasm due to muscle injury or due to inflammation in stroke, multiple sclerosis, cerebral palsy patients  Neuromuscular transmission at the motor end plate is due to influx of Ca 2+ and release of ACH (ACH diffuses across the synaptic cleft to activate the nAChR located on the motor end plate. The binding of Ach to nAChR causes opening of the channel). Ach is removed from the end plate through diffusion and enzymatic degradation by enzyme AChE.  Movement of Na+ and K+ causing depolarization of the end plate membrane  If the potential is small, the permeability and the end plate potential return to normal without an impulse being propagated.  If the potential is large, muscle membrane is depolarized, and AP will propagate along the entire muscle fiber. Muscle contraction is then initiated by excitation –contraction coupling.  Katzung BG, 2021  The Cause fewer receptors for ACH to bind Drugs MOA Effects Others info Succinylcholine Agonist of nAChR at Initial depolarization cause Hydrolysis by plasma AChE (Anectine ®) neuromuscular transient contraction, then Time onset: 1-1.5 min junction. May stimulate cause prolonged flaccid Duration: 5-8 min ganglionic or cardiac paralysis during ADRs: arrhythmias, hyperkalemia, nAChR. repolarization post operative muscle pain, IOP Depolarizes the motor end plate Extracted from Katzung 2021 and Goodman and Gillman 2023 Drugs MOA Effects Others info D-tubocurarine Competitive Prevent depolarization by Ach, Renal elimination. Liver clearance antagonist of nAChR cause flacccid paralysis, Duration:80-120 min. Onset 4-6 min at neuromuscular release Histamine ADRs: apnea, hypotension junction Mivacurium (Mivacron ®) Same as D Same as D tubocurarine Hydrolysis by plasma ChE. tubocurarine Some release of H, less Duration 12-18 min. Onset 2-4min antimuscarinc effect ADRs: less than D-tubocurarine 4x potency of D-tubocurarine Rocuronium (Zemuron® ) Same as D Same as mivacurium Hepatic metabolism tubocurarine Duration 20-35 min. Onset 1-2 min ADRs : like mivacurium 0.8 X potency of D-tubocurarine Vecuronium (Norcuron ®) Same as D Same as mivacurium Liver metabolism, renal eliminate tubocurarine Duration 60-90 min. Onset 2-4 min ADRs: like mivacurium 6x potency of D-tubocurarine Cisatracurium Same as D  histamine release, -May improve mortality in patients with moderate (Nimbex®) tubocurarine less laudanosine ( seizure), or severe acute respiratory syndrome (ARS) less dependence on renal -Metabolism via Hofmann elimination-does not hepatic inactivation require renal & hepatic function. Degrade spontaneously - ADR: flushing, bradycardia, hypotension  Drugs are highly polar, inactive orally, must be given as IV Non-depolarizing relaxant drugs (Antagonist):  Rapid initial distribution phase, follow by slower elimination phase  Drugs do not readily cross cell membrane, not bound to peripheral tissue  Drugs that are eliminated by kidney , tend to have longer t1/2 and longer duration of action (> 60 mins)  Drug that are eliminated by liver, tend to have shorter t 1/2 and shorter duration of action  Metabolites of the drug is 40-80% as potent as the parent drugs, with minimal neuromuscular blocking properties. However, prolonged use (ICU) may cause paralysis due to metabolite accumulation  Intermediate acting (vecuronium and rocuronium) more common used than long acting (pancuronium and pipecuronium)  Drug can block prejunctional Na channel can cause tetanic stimulation, by releasing large amount of Ach (reversible) Spasticity:  tonic stretch reflexes and flexor muscle spasms , muscle weakness. Due to spinal injury, cerebral palsy, multiple sclerosis, stroke. Mechanism of spasticity appear to be due to: 1. to stretch reflex arc 2. CNS (upper motor neuron lesion), with damage to descending pathway in the spinal cord→ causing hyper-extrality of the  motor neurons in the spinal cord  Most of the drugs modify hyperactive stretch reflex arc by ↓ the activity of Ia fibers (excite the primary motor neurons), the activity of the inhibitory internuncial neurons Spasmolytic action of tizanidine (2). May also have postsynaptic inhibitory effect Benzodiazepine (GABAA) Baclofen (GABAB) Dantrolene acts on the sarcoplasmic reticulum in skeletal muscle Katzung BG,2021 Drugs MOA Effects Other info. Also see DDI Baclofen (Lioresal®) GABAB agonist, spinal Pre and post synaptic Oral, intrathecal inhibition of motor inhibition of reflex motor ADRs: sedation, weakness neurons output Cyclobenzaprine Inhibit muscle stretch ↓hyperactive muscle reflexes Hepatic metabolism, (Flexeril®) reflex in spinal cord Anti-muscarinic effect Duration 4-6 hr ADRs: anti-muscarinic, sedation Diazepam GABAergic transmission  Interneuron inhibition of Hepatic metabolism (Valium ®) in the CNS motor afferents in spinal Duration 12-24 hr GABAA agonist cord ADR: depressant, dependence, sedation Tizanidine 2 agonist in spinal cord Pre and post synaptic Renal and hepatic elimination ( Zanaflex®) inhibition of reflex motor Duration:3-6 hr output ADRs: weakness, sedation, hypotension Chlorphenesin, metacarbamol (Robaxin ®), orphenadrine (Norflex®)- similar to cyclobenzaprine with varying degrees of anti-muscarinic action From Katzung 2021 MOA: not clear, act as CNS depressant  For musculoskeletal : muscle spasm, back pain, relief acute pain.  Standard dose: 350 mg 3-4 x/day. Potential abuse like other class IV. Prototype of muscle relaxants  ADRs: tolerance, dependence, withdrawal symptoms , drowsiness, tremor, agitation, headache, depressive disorder  One of the most diverted drugs and abused use, CS IV as of Jan 2012  Metabolized to meprobamate (substance with barbiturate-like properties)  Pregnancy C  DDI: ethanol ( depressant effects), CYP2C19 Caution when use with CNS depressants (alcohol, benzodiazepines, opioids) causing additive sedation, dizziness, confusion  Avoid alcohol, sleeping pills, antihistamines, sedative, pain pills and tranquilizers, except under supervision of the doctor  Avoid use of tizanidine with ciprofloxacin and fluvoxamine (can cause  tizanidine level)  Gabapentin: anticonvulsants, also useful as spasmolytic in MS  Pregabalin: anticonvulsants, relieved painful disorder  Progabide : act as GABA A and GABA B agonist,  spasticity  Glycine: inhibitory NT that can pass BBB,  spasticity  Idrocilamide and Riluzole: for treatment of ALS that have spasmolytic effect. Works by inhibiting glutaminergic transmission MOA: block RyR1 Ca 2+ channel in the sarcoplasmic reticulum of skeletal muscle ▪ Effect: ↓ actin-myosin interaction, weakens skeletal muscle contraction Drug: Dantrolene (Dantrium ®) Use for: IV-malignant hyperthermia, or overdose of amphetamine ▪ Rare heritable disorder trigger by general anesthetic and succinylcholine. If one of the trigger agents was used, there is a sudden and prolonged release of Ca, with massive muscle contraction, lactic acid,  body temp. ▪ Treatment: control: body temp, lactic acidosis, or use dantrolene to ↓ Ca release  PO-spinal cord injury, cerebral palsy, multiple sclerosis ADRs: muscle weakness, sedation 1. People going on surgery may be given _______________ (name drugs:__________, _________); while a person experience cerebral palsy may be given ____________ (name drugs : _____________, ______________, _______________, _______________) 2. Dantrolene works by ______of ____calcium channel. It is useful for : _________due to amphetamine, or ___________ during anesthetic. It is a ______________________ 3. Cisatrocurium is __________________ neuromuscular blocker. It’s advantage are __________________, _________ laudanosine which decrease seizure episodes, ____ hepatic elimination 4. GABAB agonist is _________ ( ), alpha 2 agonist in spinal cord is __________ (Zanaflex ®), ____________ ( ) inhibit muscle stretch reflex in spinal cord  Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 14th edition Editors: Brunton, Hilal-Dandan, Knollmann. Publisher: McGraw-Hill, 2023 Katzung BG et al. Basic & Clinical Pharmacology. 15th ed. 2021