Pharmacology-1 PHL 313

Parasympathetic Nervous System

Sixth Lecture
By

Abdelkader Ashour, Ph.D.

Phone: 4677212 Email: aeashour@ksu.edu.sa

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 Dantrolene 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 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 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 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)