Pharmacology-1 PHL 351, Parasympathetic Nervous System Abdelkader Ashour, Ph.D. 6 th 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)