Pharmacology DOR 101 Abdelkader Ashour, Ph.D. 5 th Lecture

Drugs Acting on the Parasympathetic Nervous System, Responses to parasympathetic activation

Nicotinic Agonists  Nicotine is the most commonly encountered nicotinic agonist.  It is a tertiary amine found in the leaves of the tobacco plant.  It is sufficiently lipid-soluble to be absorbed across the skin.  It is responsible for the addicting properties of tobacco.  Nicotine has a greater affinity for neuronal than for skeletal muscle nicotinic receptors  Nicotine's actions are complex:  At low dosages it stimulates ganglionic nicotinic receptors, thus enhancing both sympathetic and parasympathetic neurotransmission In the case of the cardiovascular system, the effects of nicotine are chiefly sympathomimetic on blood vessels (vasoconstriction), and parasympathomimetic on the heart (slow heart rate and decreased cardiac output) In the GI and urinary tracts, the effects are largely parasympathomimetic  As nicotine dosages increase, there is stimulation of nicotinic receptors in many other sites  At high dosages, nicotine possesses some antagonist effect at nicotinic receptors  In large concentrations, nicotine induces tremor and emesis. At still higher levels, nicotine causes convulsions, which may terminate in fatal coma  The lethal effects on the central nervous system, and the fact that nicotine is readily absorbed, form the basis for the use of nicotine as an insecticide

Nicotinic Antagonists  Nicotinic antagonists include skeletal muscle relaxants (drugs that block neuromuscular transmission) and ganglion blockers (not used clinically)  Since skeletal muscle contraction is elicited by nicotinic cholinergic mechanisms, it can be inhibited by drugs that act as competitive antagonists at the ACh receptors at the neuromuscular junction of skeletal muscle.  Skeletal muscle relaxants (neuromuscular blockers) are used during surgical operations to produce temporary paralysis of skeletal muscles…WHY??  General anesthetics can cause muscle paralysis but at doses that depress the heart and respiration  Doses of general anesthetics are reduced when used in combination with skeletal muscle relaxants, and thus the patient is protected from the depressant effects of the anesthetic  Examples: tubocurarine and pancuronium  The action of these drugs can be reversed by increasing the amount of ACh in the neuromuscular junction for example, by the administration of a cholinesterase inhibitor  Tubocurarine is now rarely used because of its side effects (bronchoconstriction and hypotension)  Pancuronium is widely used. It is approximately 5-fold more potent than tubocurarine, with a longer duration of action and better side-effect profile  Succinylcholine (suxamethonium) is another skeletal muscle relaxant that works via a different mechanism

Indirect Parasympathomimetics, 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  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.  They mimic the effect of combined muscarinic and nicotinic agonists  Cholinergic neurotransmission is especially important in insects, and it was discovered many years ago that anticholinesterases could be effective insecticides.

Cholinesterase Inhibitors, Reversible & Irreversible  Cholinesterase inhibitors are either: 1.Reversible “generally short-acting”:  They bind AChE reversibly.  They are used for treatment of myasthenia gravis. They may be used as antidotes in the treatment of atropine poisoning, and to reverse neuromuscular blocking agents  Examples: physostigmine, neostigmine and edrophonium  Physostigmine enters the CNS and can cause restlessness and hypertension in addition to the effects more typical of muscarinic and nicotinic agonists  Neostigmine enters the CNS poorly; its effects are therefore almost exclusively those of muscarinic and nicotinic stimulation  Edrophonium is a quaternary amine widely used as a clinical test for myasthenia gravis If this disorder is present, edrophonium will markedly increase strength 2.Irreversible " long-acting" cholinesterase inhibitors (organophosphates):  They bind AChE irreversibly  They are especially used as insecticides  Examples: organophosphates (e.g., parathion and malathion)