Pharmacology-1 PHL 211

Twelfth Lecture

By

Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

Nicotinic Antagonists, Skeletal Muscle Relaxants, I. Neuromuscular blockers

Since skeletal muscle contraction is elicited by nicotinic (NM) 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 drugsBlockade 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 blockersII.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 Ca2+ 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