Pharmacology-1 PHL 211 Twelfth Lecture By Abdelkader Ashour, Ph.D. Phone:

Nicotinic Antagonists, Skeletal Muscle Relaxants, I. Neuromuscular blockers  Since skeletal muscle contraction is elicited by nicotinic (N M ) cholinergic mechanisms, it has similarities to nicotinic neurotransmission at the autonomic ganglia  Neuromuscular blockers interfere with transmission at the neuromuscular end plate and lack CNS activity  Two different kinds of functional blockade may occur at the neuromuscular endplate, and hence clinically used drugs fall into two categories: A.Non-depolarizing blocking agents: antagonists at the nAChR (i.e. they act by blocking nAChR B.Depolarizing blocking agents: agonists at the nAChR (i.e., they act by stimulating the nAChR) A. Non-depolarizing neuromuscular blocking drugs:  They act as competitive antagonists at the ACh receptors of the endplate  Tubocurarine is a prototype for this class of drugs  Blockade by these agents (such as tubocurarine and pancuronium) can be reversed by increasing the amount of ACh in the synaptic cleft, for example, by the administration of a cholinesterase inhibitor  Drugs that affect skeletal muscles fall into two major therapeutic groups: I.Neuromuscular blockers II.Spasmolytics I.Neuromuscular blockers: Drugs used during surgical procedures and in intensive care units to cause paralysis

B. Depolarizing neuromuscular blocking drugs:  They stimulate the nicotinic endplate receptor to depolarize the neuromuscular endplate  This initial depolarization is accompanied by transient twitching of the skeletal muscle (fasciculation)  With continued agonist effect, the skeletal muscle tone cannot be maintained, and, therefore, this continuous depolarization results in a functional muscle paralysis (flaccid paralysis; muscles are weak and have little or no tone)  Thus, the effects of a depolarizing neuromuscular blocking agent move from a continuous depolarization (phase I) to a gradual repolarization (as the sodium channel closes) with resistance to depolarization (phase II)  Succinylcholine (suxamethonium) is a prototype for this class of drug. It has a short half-life (5-10 minutes) and must be given by continuous infusion if prolonged paralysis is required  An important aspect of succinylcholine is its hydrolysis by pseudocholinesterase  In patients with pseudocholinesterase deficiency, succinylcholine half-life is greatly prolonged, and such patients may suffer from prolonged apnoea and they may regain control of their skeletal muscles slowly after a surgical procedure. This is the most serious complication of pseudocholinesterase deficiency Nicotinic Antagonists, Skeletal Muscle Relaxants, I. Neuromuscular blockers

 Comparison of non-depolarizing neuromuscular blocking drugs and Depolarizing neuromuscular blocking drugs  Cholinesterase inhibitors are effective in overcoming the blocking action of the competitive agents (non-depolarizing neuromuscular blockers). In contrast, depolarization block is unaffected, or even increased, by AChE inhibitors  The fasciculation seen with depolarizing neuromuscular blocking drugs as a prelude to flaccid paralysis does not occur with competitive drugs  Clinical Significance: The most important application of the neuromuscular blockers is in facilitating surgery…..How?  Before the introduction of neuromuscular blocking drugs, profound skeletal muscle relaxation for intracavitary operations could be achieved only by producing deep levels of anaesthesia that was often associated with profound depressant effects on the cardiovascular and respiratory systems  The adjunctive use of neuromuscular blocking drugs makes it possible to achieve adequate muscle relaxation for all types of surgical procedures without the cardiorespiratory depressant effects of deep anaesthesia Nicotinic Antagonists, Skeletal Muscle Relaxants, I. Neuromuscular blockers (Comparison & Clinical Significance)

II.Spasmolytics: Drugs used to reduce spasticity in a variety of neurologic conditions  These drugs have traditionally been called "centrally acting" muscle relaxants. However, at least one of these agents (dantrolene) has no significant central effects  Spasmolytic drugs are used in the treatment of muscle spasm and immobility associated with strains, sprains, and injuries of the back and injuries to the neck  Spasmolytic drugs are of two types: I.Peripheral: act directly on muscle II.Central: act indirectly by depressing nerves I.Peripheral: Dantrolene is an example:  It reduces muscle tension through a direct effect at a site proximal to the contractile mechanism. In skeletal muscle, dantrolene dissociates the excitation-contraction coupling, by interfering with the release of Ca 2+ from the sarcoplasmic reticulum  It does not affect neuromuscular transmission.  Dantrium is indicated in controlling the manifestations of clinical spasticity resulting from upper motor neuron disorders (e.g., spinal cord injury) Nicotinic Antagonists, Skeletal Muscle Relaxants, II. Spasmolytic Drugs II.Central:  There are a number of anti-anxiety agents ( e.g., diazepam, chlordiazepoxide) that also have a significant ability to reduce nerve stimulation of the muscles

Cholinesterase Inhibitors (Indirect Cholinomimetics)  The muscarinic and nicotinic agonists mimic acetylcholine effect by stimulating the relevant receptors themselves  Another way of accomplishing the same thing is to reduce the destruction of ACh following its release  This is achieved by cholinesterase inhibitors, which are also called the anticholinesterases  They mimic the effect of combined muscarinic and nicotinic agonists.  Mechanism: By inhibiting acetylcholinesterase and pseudocholinesterase, these drugs allow ACh to build up at its receptors. Thus, they result in enhancement of both muscarinic and nicotinic agonist effect  Cholinesterase inhibitors are either reversible or irreversible

Cholinesterase Inhibitors, Reversible & Irreversible  " Reversible" cholinesterase inhibitors are generally short-acting. They bind AChE reversibly. They include physostigmine that enters the CNS, and neostigmine and edrophonium that do not  Physostigmine enters the CNS and can cause restlessness, apprehension, and hypertension in addition to the effects more typical of muscarinic and nicotinic agonists  Neostigmine is a quaternary amine (tends to be charged) and enters the CNS poorly.  It is used to stimulate motor activity of the small intestine and colon, as in certain types of non-obstructive paralytic ileus  It is useful in treating atony of the detrusor muscle of the urinary bladder  It is useful in myasthenia gravis, and sometimes in glaucoma  Edrophonium is a quaternary amine used as a clinical test for myasthenia gravis  If this disorder is present, edrophonium will markedly increase strength. It often causes some cramping, but this only lasts a few minutes  Ambenonium and pyridostigmine are also used to treat myasthenia gravis  Long-acting or "irreversible" cholinesterase inhibitors are those that bind AChE irreversibly. Example: organophosphates  Irreversible cholinesterase inhibitors are especially used as insecticides. Cholinesterase inhibitors enhance cholinergic transmission at all cholinergic sites, both nicotinic and muscarinic. This makes them useful as poisons