Download Pharmacology

Pharmacology-1 PHL 211
Twelfth Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Nicotinic Antagonists, Skeletal Muscle Relaxants,
I.
Neuromuscular blockers
 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
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 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
Nicotinic Antagonists, Skeletal Muscle Relaxants,
I.
Neuromuscular blockers
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 & Clinical Significance)
 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,
II. Spasmolytic Drugs
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)
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