Pharmacology-1 PHL 313 Sixth Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

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 (cause marked activation of these nicotinic receptors and initiate action potentials in postganglionic neurons) thus enhancing both sympathetic and parasympathetic neurotransmission The initial response therefore often resembles simultaneous discharge of both the parasympathetic and the sympathetic nervous systems. In the case of the cardiovascular system, the effects of nicotine are chiefly sympathomimetic on blood vessels, and parasympathomimetic on the heart 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 Prolonged exposure results in depolarizing blockade of the ganglia

Nicotinic Agonists, Ganglion Stimulants Most nicotinic receptor agonists affect both ganglionic and motor end plate receptors, but nicotine and lobeline (a plant derivative similar to nicotine) affect ganglia preferentially In spite of the smaller ratio of nicotinic to muscarinic receptors in the brain, nicotine and lobeline have important effects on the brainstem and cortex. The mild alerting action of nicotine absorbed from inhaled tobacco smoke is the best-known of these effects At larger concentrations, nicotine induces tremor, emesis, and stimulation of the respiratory center. At still higher levels, nicotine causes convulsions, which may terminate in fatal coma The lethal effects on the CNS, and the fact that nicotine is readily absorbed, form the basis for the use of nicotine as an insecticide Ganglion stimulants are not used clinically, but only as experimental tools. They cause complex peripheral responses associated with generalized stimulation of ALL autonomic ganglia (sympathetic & parasympathetic)

Nicotinic Antagonists, Ganglionic Blockers The primary receptors at ganglia are cholinergic receptors of the nicotinic (NN) type. Nearly all effects are predictable from the knowledge that ganglionic blockers reduce transmission in all autonomic ganglia, both sympathetic and parasympathetic. In some sites, sympathetic activation seems to predominate over parasympathetic, while in other sites, the opposite is true Ganglionic blockade thus "uncovers" the predominant system This class of drugs is now rarely used Example: trimetaphan Mediators and Effects of Ganglionic Blockade on Organ Systems Tissue Predominant System/Ganglionic Blockade Effect Arterioles Sympathetic/(Vasodilation Veins Sympathetic/Vasodilation Heart Parasympathetic/Tachycardia Iris Parasympathetic/Mydriasis Ciliary muscle Parasympathetic/Cycloplegia Gastrointestinal tract Parasympathetic/Hypomotility Urinary bladder Parasympathetic/Urinary retention Salivary glands Parasympathetic/Xerostomia Sweat glands Sympathetic cholinergic/Anhidrosis

Nicotinic Antagonists, Skeletal Muscle Relaxants (drugs that block neuromuscular transmission) Since skeletal muscle contraction is elicited by nicotinic (NM) cholinergic mechanisms, it has similarities to nicotinic neurotransmission at the autonomic ganglia Two different kinds of functional blockade may occur at the neuromuscular endplate, and hence clinically used drugs fall into two categories: Non-depolarizing blocking agents: antagonists at the nAChR (i.e. they act by blocking nAChR Depolarizing blocking agents: agonists at the nAChR (i.e., they act by stimulating the nAChR) Non-depolarizing neuromuscular blocking drugs: They act as competitive antagonists at the ACh receptors of the endplate Tubocurarine is a prototype for this class of drugs Blockade by these agents (such as tubocurarine and pancuronium) can be reversed by increasing the amount of ACh in the synaptic cleft, for example, by the administration of a cholinesterase inhibitor

Nicotinic Antagonists, Skeletal Muscle Relaxants (drugs that block neuromuscular transmission) Depolarizing neuromuscular blocking drugs: They stimulate the nicotinic endplate receptor to depolarize the neuromuscular endplate This initial depolarization is accompanied by transient twitching of the skeletal muscle (fasciculation) With continued agonist effect, the skeletal muscle tone cannot be maintained, and, therefore, this continuous depolarization results in a functional muscle paralysis (flaccid paralysis; muscles are weak and have little or no tone) Thus, the effects of a depolarizing neuromuscular blocking agent move from a continuous depolarization (phase I) to a gradual repolarization (as the sodium channel closes) with resistance to depolarization (phase II) Succinylcholine (suxamethonium) is a prototype for this class of drug. It has a shorter half-life (5-10 minutes) and must be given by continuous infusion if prolonged paralysis is required An important aspect of succinylcholine is its hydrolysis by pseudocholinesterase In patients with pseudocholinesterase deficiency, succinylcholine half-life is greatly prolonged, and such patients may suffer from prolonged apnoea and they may regain control of their skeletal muscles slowly after a surgical procedure. This is the most serious complication of pseudocholinesterase deficiency

Nicotinic Antagonists, Skeletal Muscle Relaxants, (Comparison) 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