Download 351 Pharmacology PNS 5th Lecture F

Pharmacology-1 PHL 351,
Parasympathetic Nervous System
Abdelkader Ashour, Ph.D.
5th Lecture
Muscarinic agonists
Drug
Structure
Receptor specificity
Hydrolysis by
AChE
Clinical uses
Musc
Nic
Acetylcholine
+++
+++
+++
None
Carbachol
++
+++
-
None
Methacholine
+++
+
++
None
Bethanechol
+++
-
-
Bladder* and Gl
hypotonia
Muscarine
+++
-
-
None†
Pilocarpine
++
-
-
Glaucoma
Oxotremorine
++
-
-
None
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.
 In 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 central nervous system, and the fact that nicotine
is readily absorbed, form the basis for the use of nicotine as an insecticide.
 These drugs 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:
A. Non-depolarizing blocking agents: antagonists at the nAChR (i.e. they act by
blocking nAChR
B. Depolarizing blocking agents: agonists at the nAChR (i.e., they act by
stimulating the nAChR)
A. 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, pancuronium, and
doxacurium) 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)
B. 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