Pharmacology-1 PHL 351, Parasympathetic Nervous System

Abdelkader Ashour, Ph.D.

6th Lecture

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. 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

Nicotinic Antagonists, Skeletal Muscle Relaxants,

(Comparison)

Skeletal Muscle Relaxants, Spasmolytic Drugs

Neuromuscular blocking agents produce general relaxation of all skeletal muscles. Thus, they are not useful for specific muscle relaxation.

Furthermore, they have to be administered parenterally. Therefore, there is a great need for specific muscle relaxants, which can be used in spastic states associated with trauma and inflammation

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

Peripheral: Dantrolene is an example:

It is the only muscle relaxant which reduces muscle tension through a direct effect at a site proximal to the contractile mechanism.

It reduces the release of activator calcium from the sarcoplasmic reticulum

It does not affect neuromuscular transmission.

Skeletal Muscle Relaxants, Spasmolytic Drugs

Central:

There are a number of anti-anxiety agents that also have a significant ability to reduce nerve stimulation of the muscles (diazepam, chlordiazepoxide, carisoprodol, meprobamate).

Glycine, like gamma-aminobutyric acid (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 negatively-charged chloride ions 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.

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)