Pharmacology II Skeletal Muscle Relaxants - Lecture Notes PDF

PM 719 Pharmacology II Chapter 27 Skeletal Muscle Relaxants Lecture Notes Background ========== \(a) two different groups of drugs that effect skeletal muscle function \(1) neuromuscular blockers (used in surgery and ICU to induce muscle paralysis) \(2) drugs to reduce spasticity (spasmolytics...

PM 719 Pharmacology II Chapter 27 Skeletal Muscle Relaxants Lecture Notes Background ========== \(a) two different groups of drugs that effect skeletal muscle function \(1) neuromuscular blockers (used in surgery and ICU to induce muscle paralysis) \(2) drugs to reduce spasticity (spasmolytics) \(b) Neuromuscular blocking drugs interfere with transmission \(c) Spasmolytics thought to act centrally used to treat chronic back pain, painful fibromyalgic conditions etc. **[Neuromuscular Blocking Drugs]** History ======= \(a) native South Americans used **curare** as an arrow poison to bring down small game \(b) active agent in **curare** is **d-tubocurarine** \(c) The MOA of d-tubocurine is block of Ach receptors at the neuromuscular junction. Normal Neuromuscular Function ============================= \(a) Normal neuromuscular function \(1) arrival of electrical action potential at terminal of neuron causes Ca influx \(2) **Ach** vesicles fuse with neuron membrane \(3) Ach released from storage vesicles \(4) Ach binds to muscle nicotinic receptor \(5) Na flows into muscle \(6) Na mobilizes intracellular Ca which activates muscle fibers \(7) muscle fires (contracts) \(8) Ach is hydrolyzed by AchE \(b) two ways to block the motor end plate \(1) block Ach at the muscle receptor \(a) nondepolarizing neuromuscular blocking drugs \(b) **d-tubocurarine** is prototype example \(2) excess Ach causes blockade \(a) **succinylcholine** is prototype example \(b) drugs and **organophosphate** **pesticides** that inhibit Basic Pharmacology ================== Chemistry ========= \(a) all neuromuscular blocking drugs resemble Ach in structure \(b) **succinylcholine** is two **Ach** molecules linked together end-to-end \(c) many have two quaternary nitrogens which make them poorly lipid soluble Pharmacokinetics ================ Nondepolarizing Relaxant Drugs ============================== \(a) non-depolarizing neuromuscular blocking drugs \(1) isoquinolines \(a) **d-tubocurarine** \(b) **atracurium** \(c) **doxacurium** \(d) **cisatracurium** \(e) **mivacurium** **"curium" =** the stem except for (a) above \(2) steroids \(a) **pancuronium** \(b) **vecuronium** \(c) **pipecuronium** \(d) **rocuronium** **"nium" =** the stem \(b) most common drug used in clinical practice is **cisatracurium** \(c) **mivacurium** is shortest acting of all drugs Depolarizing Relaxant Drugs =========================== \(a) only **succinylcholine** in this class \(b) **succinylcholine** removed by plasma cholinesterase with half life of \(c) plasma cholinesterase genetic polymorphisms have been identified which take longer than 10-15 min to hydrolyzed succinylcholine \(1) molecular variants identified by the **dibucaine number** \(2) 80% inhibition of plasma cholinesterase by **dibucaine** = normal \(3) 20% inhibition of plasma cholinesterase by **dibucaine** = variant \(d) molecular variant results in longer patient recovery time, prolonged Mechanism of Action =================== Nondepolarizing Relaxant Drugs ============================== \(a) **d-tubocurarine** prototype neuromuscular blocker \(b) compete with Ach at nicotinic receptor at neuromuscular end plate \(c) AchE inhibitors (**neostigmine, edrophonium, pyridostigmine**) Depolarizing Relaxant Drugs =========================== \(a) Phase I Blocking (depolarizing) \(1) **succinylcholine** only drug in this class \(2) **succinylcholine** binds to nicotinic receptor and opens the channel and motor end plate depolarizes \(3) muscle contracts \(4) **succinylcholine** not rapidly removed and channel remains \(5) flaccid paralysis results \(6) **AchE inhibitor drugs** enhance this Phase I Blocking (good question) \(b) Phase II Blocking (desensitizing) \(1) membrane finally becomes repolarized \(2) receptor can not be repolarized (made to fire) because it has become desensitized by the prolonged actions of Clinical Pharmacology ===================== Skeletal Muscle Paralysis ========================= \(a) skeletal muscle relaxant drugs produce deep muscle relaxation and prevent having to use higher doses of **inhaled anesthetics** to produce the same levels muscle relaxation Neuromuscular Transmission ========================== \(a) peripheral nerve stimulation devices used during surgery to monitor neuromuscular blockade and recovery (Katzung pg 460) Nondepolarizing Relaxant Drugs ============================== \(a) time to onset of action and duration of action are the two most important properties of the nondepolarizing drugs Depolarizing Drugs ================== \(a) **succinylcholine** iv transient muscle fasciculations occur over \(b) paralysis develops in \< 90 sec \(c) AchE hydrolyzes the drug slowly and recovery occurs in about 10 min Cardiovascular Effects ====================== \(a) most have minimal cardiovascular effects \(b) **pancuronium, atracurium, mivacurium** produce cardiovascular effects mediated by autonomic or histamine receptors \(c) histamine release produces lowered BP \(d) **succinylcholine** given with **halothane** can cause arrhythmias Other Effects ============= \(a) Hyperkalemia \(a) **succinylcholine** can cause release of K in certain conditions \(b) Increased Intraocular Pressure \(a) **succinylcholine** \(c) Increased Intragastric Pressure \(a) risk of regurgitation from **succinycholine** \(d) Muscle Pain \(a) **succinycholine** induced myalgia Drug Interactions ================= Inhaled Anesthetics =================== \(a) inhaled anesthetics potentiate the actions of nondepolarizing blockers \(b) factors involved in this interaction \(1) depression of CNS proximal to peripheral neuron blockade \(2) increased muscle blood flow (gas cause peripheral dilation) \(3) decreased sensitivity of the postjunctional membrane to Antibiotics =========== \(a) **aminoglycosides** enhances neuromuscular blockade Use of AchE Inhibitors To Reverse Drug Actions ============================================== \(a) **neostigmine,** **pyridostigmine** inhibit AchE and increase Ach at the Uses Of Neuromuscular Blocking Drugs ==================================== \(a) tracheal intubation \(b) control of ventilation \(c) treatment of convulsions Spasmolytic Drugs ================= \(a) often associated with spinal injury, cerebral palsy, multiple sclerosis, and stroke \(b) mechanism involves stretch reflex arc and higher centers in the CNS Diazepam ======== \(a) increases **GABA** activity but induces sedation at 60 mg/d doses required for muscle relaxation Baclofen ======== \(a) **baclofen** (p-chlorophenyl-GABA) \(b) drug is agonist at **GABA~B~** receptors which are K conductance receptors, K outward flow blocks neuron firing K inside neuron \~115 mmol/L outside neuron 5.0 mmol/L \(c) causes less sedation compared to **diazepam** \(d) drug delivery through a catheter in the subarachnoid space also used \(e) normal dosing is po Tizanidine ========== \(a) congener of **clonidine** an alpha 2 agonist \(b) alpha 2 agonist inhibits the release of NE \(c) reduces spasticity with fewer cardiovascular effects compared to clonidine Dantrolene ========== \(a) derivative of **phenytoin** \(b) **dantrolene** blocks the release of Ca from the SR stores in skeletal muscle and inhibits muscle contraction. Botulinum Toxin =============== \(a) treatment for spastic condition lasts from weeks to several months Chapter 27 Required Drugs in **Bold** along with all the drugs in the above text. **[Neuromuscular Blocking Drugs]** **[Depolarizing Drugs]** **succinylcholine** agonist at nicotinic receptors **[Nondepolarizing Drugs]** receptors **cisatracurium** " " (cis a tra KYOO ree um) **rocuronium** " "(roe kyoor OH nee um) **vecuronium** " " **pancuronium** " " (pan kyoo ROE nee um) **[CNS Acting Spasmolytic Drugs]** **baclofen** GABA~B~ agonist in spinal column **cyclobenzaprine** inhibits muscle stretch reflex in spinal **diazepam** GABA~A~ agonist **tizanidine** alpha~2~ agonist in spinal cord **botulinum toxin** blocks release of Ach **carisoprodol** similar to cyclobenzaprine (kar eye soe PROE dole) **gabapentin** " **[Direct Muscle Relaxants]** **dantrolene** blocks release of Ca from SR stores in skeletal muscle Diagram Description automatically generated **[Neuromuscular Blocking Drugs]** **[Depolarizing Drugs]** succinylcholine agonist at nicotinic receptors **[Nondepolarizing Drugs]** tubocurarine competitive antagonist at nicotinic receptors cisatracurium " " (cis a tra KYOO ree um) rocuronium " "(roe kyoor OH nee um) mivacurium " " vecuronium " " atracurium " " pancuronium " " (pan kyoo ROE nee um) **[CNS Acting Spasmolytic Drugs]** baclofen GABA~B~ agonist in spinal column cyclobenzaprine inhibits muscle stretch reflex in spinal chlophenesin " " methocarbamol " " orphenadrine " " diazepam GABA~A~ agonist tizanidine alpha~2~ agonist in spinal cord botulinum toxin blocks release of Ach carisoprodol similar to cyclobenzaprine (kar eye soe PROE dole) chlorzaxazone " gabapentin " metaxalone " riluzole inhibits actions of glutamate in CNS **[Direct Muscle Relaxants]** dantrolene blocks release of Ca from SR stores in skeletal muscle