313 Pharmacology PSNS 6th Lecture S

7/28/2019 313 Pharmacology PSNS 6th Lecture S

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Pharmacology-1 PHL 313

Parasympathetic Nervous System

Sixth LectureBy

Abdelkader Ashour, Ph.D.Phone: 4677212 Email: [email protected]


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Skeletal Muscle Relaxants,Spasmolytic DrugsDrugs 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 immobilityassociated 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

Dantrolene is indicated in controlling the manifestations of clinical spasticity resultingfrom upper motor neuron disorders (e.g., spinal cord injury)


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Skeletal Muscle Relaxants,Spasmolytic Drugs

II. Central:

There are a number of anti-anxiety agents ( e.g., diazepam,

chlordiazepoxide) that have a significant ability to reduce nerve

stimulation of the muscles How?

Binding to the benzodiazepine binding site on GABAA receptor (ligand-

gated 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 cellThis 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 selectivelypermeable 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 causehypersensitivity to stimuli and eventually convulsions


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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

Ligand-gated Ion ChannelsGABAA Receptor

Hyperpolarization


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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


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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 treatmyasthenia gravis


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Cholinesterase Inhibitors,Irreversible

Cholinesterase Inhibitors that 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 wasdiscovered 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


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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)

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313 Pharmacology PSNS 6th Lecture S