Pharmacological Properties

The pharmacological properties of anti-ChE agents can be predicted by knowing where ACh is released physiologically by nerve impulses, the degree of nerve impulse activity, and the responses of the corresponding effector organs to ACh (see Chapter 6). The anti-ChE agents potentially can produce all the following effects: (1) stimulation of muscarinic receptor responses at autonomic effector organs; (2) stimulation, followed by depression or paralysis, of all autonomic ganglia and skeletal muscle (nicotinic actions); and (3) stimulation, with occasional subsequent depression, of cholinergic receptor sites in the CNS.

In general, compounds containing a quaternary ammonium group do not penetrate cell membranes readily; hence, anti-ChE agents in this category are absorbed poorly from the gastrointestinal (GI) tract or across the skin and are excluded from the CNS by the blood-brain barrier after moderate doses. On the other hand, such compounds act preferentially at the neuromuscular junctions of skeletal muscle, exerting their action both as anti-ChE agents and as direct agonists. They have comparatively less effect at autonomic effector sites and ganglia.

The more lipid-soluble agents are well absorbed after oral administration, have ubiquitous effects at both peripheral and central cholinergic sites, and may be sequestered in lipids for long periods of time. Lipid-soluble organophosphorus agents also are well absorbed through the skin, and the volatile agents are transferred readily across the alveolar membrane.

The therapeutically important sites of action of anti-ChE agents are the CNS, eye, intestine, and the neuromuscular junction of skeletal muscle; other actions are of toxicological consequence.

EYE When applied locally to the conjunctiva, anti-ChE agents cause conjunctival hyperemia and constriction of the pupillary sphincter muscle around the pupillary margin of the iris (miosis) and the ciliary muscle (block of accommodation reflex with resultant focusing to near vision). Miosis is apparent in a few minutes and can last several hours to days. The block of accommodation generally disappears before termination of miosis. Intraocular pressure, when elevated, usually falls as the result of facilitation of outflow of the aqueous humor (see Chapter 63).

GASTROINTESTINAL TRACT Neostigmine enhances gastric contractions, increases the secretion of gastric acid, and stimulates the lower potion of the esophagus. In patients with marked achalasia and dilation of the esophagus, the drug can cause a salutary increase in tone and peristalsis.

Neostigmine augments GI motor activity; the colon is particularly stimulated. Propulsive waves are increased in amplitude and frequency, and movement of intestinal contents is thus promoted. The effect of anti-ChE agents on intestinal motility probably represents a combination of actions at the ganglion cells of Auerbach's plexus and at the smooth muscle fibers (see Chapter 37).

NEUROMUSCULAR JUNCTION Most of the effects of potent anti-ChE drugs on skeletal muscle can be explained by their inhibition of AChE at neuromuscular junctions. However, there is good evidence for an accessory direct action of neostigmine and other quaternary ammonium anti-ChE agents on skeletal muscle.

The lifetime of free ACh in the nerve-muscle synapse (-200 ,usec) is normally shorter than the decay of the end-plate potential or the refractory period of the muscle. After inhibition of AChE, the residence time of ACh in the synapse increases, allowing for lateral diffusion and rebinding of the transmitter to multiple receptors and a prolongation of the decay time of the endplate potential. Asynchronous excitation and fasciculations of muscle fibers occur. With sufficient inhibition of AChE, depolarization of the endplate predominates, and blockade owing to depolarization ensues (see Chapter 9). The anti-ChE agents will reverse the antagonism caused by competitive neuromuscular blocking agents but not that caused by depolarizing agents (e.g., succinylcholine), whose depolarization will be further enhanced by AChE inhibition (see Chapter 9).

ACTIONS AT OTHER SITES Secretory glands that are innervated by postganglionic cholin-ergic fibers include the bronchial, lacrimal, sweat, salivary, gastric (antral G cells and parietal cells), intestinal, and pancreatic acinar glands. Low doses of anti-ChE agents augment secretory responses to nerve stimulation; higher doses actually produce an increase in the resting rate of secretion.

Anti-ChE agents increase contraction of smooth muscle fibers of the bronchioles and ureters. The cardiovascular actions of anti-ChE agents are complex, since they reflect both ganglionic and postganglionic effects of accumulated ACh on the heart and blood vessels and actions in the CNS. The predominant effect on the heart from the peripheral action of accumulated ACh is bradycardia, resulting in a fall in cardiac output. Higher doses usually cause a fall in blood pressure, often due to effects of anti-ChE agents on medullary vasomotor centers of the CNS. Anti-ChE agents augment vagal influences on the heart. At the ganglia, accumulating ACh initially is excitatory on nicotinic receptors, but at higher concentrations, ganglionic blockade ensues as a result of persistent depolarization. Excitation of parasympathetic ganglion cells reinforces diminished cardiac function, whereas enhanced function results from the action of ACh on sympathetic ganglion cells. Excitation followed by inhibition also is elicited by ACh at the central medullary vasomotor and cardiac centers. These effects are complicated further by the hypoxemia resulting from the bron-choconstrictor and secretory actions of increased ACh on the respiratory system; hypoxemia, in turn, can reinforce both sympathetic tone and ACh-induced discharge of epinephrine from the adrenal medulla. Hence, it is not surprising that an increase in heart rate is seen with severe ChE inhibitor poisoning. Hypoxemia probably is a major factor in the CNS depression that appears after large doses of anti-ChE agents. Atropine antagonizes CNS-stimulant effects, although not as completely as muscarinic effects at peripheral autonomic effector sites.

ABSORPTION, FATE, AND EXCRETION Physostigmine is absorbed readily from the GI tract, subcutaneous tissues, and mucous membranes. The conjunctival instillation of solutions of the drug may result in systemic effects if measures (e.g., pressure on the inner canthus) are not taken to prevent absorption from the nasal mucosa. Parenterally administered physostigmine is largely destroyed within 2 hours, mainly by hydrolytic cleavage by plasma esterases; renal excretion plays only a minor role in its elimination.

Neostigmine and pyridostigmine are absorbed poorly after oral administration, such that much larger doses are needed than by the parenteral route (effective parenteral dose of neostigmine, 0.5-2 mg; equivalent oral dose, 15-30 mg or more). Neostigmine and pyridostigmine are destroyed by plasma esterases, with half-lives of 1-2 hours.

Organophosphorus anti-ChE agents with the highest risk of toxicity are highly lipid-soluble liquids; many have high vapor pressures. Agents used as agricultural insecticides (e.g., diazinon, malathion) generally are dispersed as aerosols or dusts that are absorbed rapidly through the skin and mucous membranes following contact with moisture, by the lungs after inhalation, and by the GI tract after ingestion. Absorbed organophosphorus compounds are hydrolyzed by plasma and liver esterases to the corresponding phosphoric and phosphonic acids, which are excreted in the urine. Young animals are deficient in these esterases (carboxylesterases and paraoxonases), which could contribute to toxicity in neonates and children.

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