Med305 Neuromuscular Blockers PDF

MED305 Neuromuscular Blockers Said KALKIŞIM, MD PhD School of Medicine, Department of Medical Pharmacology [email protected] muscle relaxants neuromuscular blockers Spasmolytics and Antispasmotics In surgeries and intensive care units To reduce muscle spasm and pain Neuromuscular Blo...

MED305 Neuromuscular Blockers Said KALKIŞIM, MD PhD School of Medicine, Department of Medical Pharmacology [email protected] muscle relaxants neuromuscular blockers Spasmolytics and Antispasmotics In surgeries and intensive care units To reduce muscle spasm and pain Neuromuscular Blockers (NMB) • They prevent the passage of stimuli at the neuromuscular junction. • They are applied with general anesthesia in surgeries and intensive care units. Each muscle fiber contains only one terminal button • Muscle relaxation or muscle paralysis can be created by affecting the following stages. • Somatic pathway in CNS • Myelinated nerve cells • Nonmyelinated motor nerve terminal • Nicotinic acetylcholine (ACh) receptor • Motor end plate • Muscle membrane • Contraction mechanisms within the cell Nicotinic Receptors • Nicotinic receptors are divided into two main groups. • Muscle-type nicotinic acetylcholine receptor: NM • Nerve-type nicotinic acetylcholine receptor: NN • The acetylcholine (ACh) receptor, located presynaptically at the motor nerve end , has an effect when stimulated, causing ACh vesicles to come closer to the synapse for the next stimulus. • Rarely, nicotinic receptors present outside the neuromuscular junction (extrajunctional). Although they have no function in normal functioning muscles, the number of these receptors increases rapidly in situations such as burns or immobilization . Depolarized and non-depolarized • Blocking the neuromuscular junction can be achieved by two methods. • 1. Excessive stimulation of the acetylcholine receptor that makes the muscle unable to respond  Depolarizing drugs.  The prototype of this group is succinylcholine. • 2. Preventing acetylcholine from binding to the receptor  non- depolarizing drugs  In this case, the muscle cannot depolarize because acetylcholine couldn’t not bind to the receptor.  The prototype of this group is d-tubocurarine. Curare • In the 16th century, European explorers discovered that indigenous people living in the Amazon River basin were using a muscle relaxant called curare. • They paralyzed and killed the animal they wanted to hunt by putting curare on the tips of their arrows. • tubocurarine, a synthetic analogue of curare NMB Pharmacokinetics • All neuromuscular drugs are drugs of high polarity. Therefore, they are administered parenterally. • Due to their high polarity, it is difficult to pass through membranes. Tissue distributions are low. nicotine receptor Depolarized NMB • Succinylcholine is a depolarizing neuromuscular blocker (NMB) that is used in clinical settings. • Typically, it is administered during induction and is not used for maintenance purposes. • The effect of succinylcholine lasts for about 5-10 minutes. When administered, there is a short contraction during the first attachment. However, succinylcholine does not leave the receptor, and no new stimulation can pass through. • As a result, the muscle relaxes, and this condition is called depolarization block. • Transient contractions may occur in the abdominal and thoracic muscles during the first 30 seconds. However, the effect can be reduced by the NMB effect of general anesthesia and low-dose nondepolarizing blockers that can be applied beforehand. • PHASE I • It stimulates the muscle with an acetylcholine-like effect. However, the duration of action of succinylcholine is higher than that of acetylcholine and it continues to occupy the receptor. • During the first attachment, there is a short contraction, but the muscle relaxes because there is no new stimulus. • This condition is called a depolarization block. • For the excitation-contraction coupling of the muscle to work, the cell must be repolarized again • For this reason, flaccid paralysis occurs in the muscle. • With a cholinesterase inhibitor, this may increase the effectiveness of the drug. Depolarizing NMB • PHASE II • There may be a transition to Phase II in the prolonged effect. • It is an undesirable situation. • In this phase, the muscle cell has repolarized, and succinylcholine is still bound to the receptor. • However, despite repolarization, it cannot be stimulated easily. This situation is called desensitization. • The last period of Phase II shows similar features to the non-depolarizing block. Nondepolarizing NMBs • Short Large muscles are more resistant to nondepolarizing block. • Medium The diaphragm muscle is affected last. First, the blockage in the diaphragm ends. The effect of d-tubocurarine administered IV continues for 45-60 minutes. For intubation process neuromuscular blockade is needed. The fastest-acting drug among nondepolarizing blockers is rocuronium (60-120 seconds). acting (~20min)  mivacurium     Effect (~45 min ) rocuronium atracurium cis-atracurium vecuronium • Long Acting (~90 min )  pancuronium  d-tubocurarine Nondepolarizing NMBs Onset Effect duration Elimination Notes Short Acting mivacurium 2-4 min 15-25 min 90% enzymatic <10% hepatic Medium Effective rocuronium 1-3 min 60-90 min 70% Hepatic 30% renal Used for rapid onset of action when the patient is contraindicated to succinylcholine Does not release histamine Bind to sugammadex. atracurium 2-3 min 45-60 min 60% Enzymatic hydrolysis 30% Hoffman reaction May be preferred in patients with liver and kidney failure Releases histamine Cisatracurium 3-5 min 45-60 min similar to atracurium May be preferred in patients with liver and kidney failure No histamin release vecuronium 2-3 min 60-90 min 70% Hepatic 30% renal It is recommended for patients with cardiovascular disease. Bind to sugammadex pancuronium 3-5 min 90-120 min 70% Renal 30% Hepatic Used when 1 hour+ NMB is needed Cardiovascular side effects are common. Tubocurarine 5 min 60-120 min 75% Renal 25% Hepatic Respiratory side effects are common. It is not used today. Long Acting Effects of NMBs in other tissues Succinylcholine / Adverse effects  Malignant hyperthermia  Hyperkalemia – In patients with trauma or extensive burns, nicotinic receptors begin to form outside the neuromuscular junction. Administering succinylcholine in such patients may lead to hyperkalemia. Therefore, succinylcholine is contraindicated in this patient group.  It may cause bradycardia, especially when used together with halothane.  High doses cause tachycardia  Especially in well-built patients, it may increase the intragastric pressure due to the muscle fasciculations and may cause regurgitation.  It may cause a sudden increase in intraocular pressure. Contraindicated in narrow-angle glaucoma Histamine-releasing NMBs 1. d-tubocurarine 2. atracurium 3. succinylcholine Malignant Hyperthermia • Autosomal Dominant inherited disease • There is a mutation in ryanodine receptors • It may develop with succinylcholine and volatile general anesthesia. • Ca++ is released from the sarcoplasmic reticulum, Intracellular Ca++ ↑ • Uncontrolled contraction and rigidity in striated muscles • Increased metabolism, increased body temperature • Treatment: Dantrolene Termination of NMB effect • Neostigmine and Pyridostigmine • By applying anticholinesterase, the amount of acetylcholine in the synaptic gap is increased. Thus, NMB is removed from the receptor. • These drugs are often administered together with atropine (anti-muscarinic) because of their undesirable effects on muscarinic receptors. (ANS Pharmacology will be instructed in the following committee) • Sugammadex • It binds to rocuronium and vecuronium in plasma, reducing the free amount of these drugs in plasma. Thus, the drugs in the synaptic gap are drawn into the plasma NMB Use Cases • 1- Surgeries • 2- Endotracheal intubation • 3- Ventilator use • 4- Epilepsy and Electroconvulsive therapy • 5- In orthopedic operations  Especially in surgeries in the abdominal and thoracic region, muscle contraction makes the operation difficult.  Reflexive contraction of the striated muscles in the larynx and pharynx makes intubation difficult.  In patients who are monitored in the intensive care unit and are dependent on a ventilator, blocking the striated muscles reduces the resistance exerted by the chest wall and synchronization is achieved. ( Thoracic compliance)  These drugs do not pass into the CNS. It is used only to reduce muscle spasms.