Download 313 Pharmacology PSNS 6th Lecture S

Pharmacology-1 PHL 313
Sixth Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Nicotinic Antagonists, Skeletal Muscle Relaxants,
(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
Skeletal Muscle Relaxants,
Spasmolytic Drugs
 Drugs that affect skeletal muscles fall into two major therapeutic groups:
1. Drugs used during surgical procedures and in intensive care units to cause paralysis
(i.e., neuromuscular blockers). They interfere with transmission at the neuromuscular
end plate and lack CNS activity...Why?
2. Drugs used to reduce spasticity in a variety of neurologic conditions (i.e.,
spasmolytics). 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)
Skeletal Muscle Relaxants,
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 … How?
 Binding to the benzodiazepine binding site on GABAA receptor (ligandgated ion channel) enhances the binding of gamma aminobutyric acid
(GABA), an inhibitory neurotransmitter in the central nervous system 
opening of the channel  flow of Cl- into the cell
 This action results in a negative change in the transmembrane potential,
usually causing hyperpolarization
 Glycine, like GABA, is an important CNS inhibitory amino acid
neurotransmitter
• Glycine acts by binding to a ligand-gated ion channel that is selectively
permeable to chloride
• The opening of ion channels allows the flow of Cl- into the cell
• This action results in a negative change in the transmembrane potential,
usually causing hyperpolarization
• Effects of glycine are antagonized by strychnine, which may cause
hypersensitivity to stimuli and eventually convulsions
Ligand-gated Ion Channels
GABAA Receptor
Hyperpolarization
 Binding to either the benzodiazepine (e.g. diazepam) or barbiturate (e.g.
pentobarbitone) binding site, enhances the binding of GABA and
increases either the rate or duration of channel opening
Cholinesterase Inhibitors
 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
 "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 widely 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 sometimes also used to treat
myasthenia gravis
Cholinesterase Inhibitors,
Irreversible
 Cholinesterase Inhibitors bind AChE irreversibly. Example:
organophosphates (e.g., phosphorothionates)
 Long-acting or "irreversible" cholinesterase inhibitors (organophosphates)
are especially used as insecticides. Cholinesterase inhibitors enhance
cholinergic transmission at all cholinergic sites, both nicotinic and
muscarinic. This makes them useful as poisons
 Cholinergic neurotransmission is especially important in insects, and it was
discovered many years ago that anticholinesterases could be effective
insecticides, by “overwhelming the cholinergic circuits”
 Many phosphorothionates, including parathion and malathion undergo
enzymatic oxidation that can greatly enhance anticholinesterase activity
 The reaction involves the substitution of oxygen for sulphur
 Thus, parathion is oxidized to the more potent and more water-soluble
paraoxon
Cholinesterase Inhibitors,
Irreversible
 Differences in the hydrolytic and oxidative metabolism in different
organisms accounts for the remarkable selectivity of malathion.
 In mammals, the hydrolytic process in the presence of carboxyesterase leads
to inactivation. This normally occurs quite rapidly, whereas oxidation leading
to activation is slow.
 In insects, the opposite is usually the case (hydrolysis is slow and activation is
quick), and those agents are very potent insecticides.
 Another example of irreversible cholinesterase inhibitors is sarin gas (a war
nerve gas)