Pharmacology of Autonomic Nervous System Munir Gharaibeh, MD, PhD, MHPE mgharaib@ju.edu.jo Pharmacology of Autonomic Nervous System

Anatomic and neurotransmitter features of autonomic and somatic motor nerves.

Anatomy of the Autonomic Nervous System Sites of Origins Length of Preganglionic and Postganglionic neurons. Ratio of preganglionic: postganglionic

Direct Effects of Autonomic Nerve Activity on some Organs Systems Direct Effects of Autonomic Nerve Activity on some Organs Systems. Drug effects are similar but not identical.

Direct Effects of Autonomic of Nerve Activity on some Organs Systems Direct Effects of Autonomic of Nerve Activity on some Organs Systems. Drug effects are similar but not identical.

Direct Effects of Autonomic Nerve Activity on some Organs Systems Direct Effects of Autonomic Nerve Activity on some Organs Systems. Drug effects are similar but not identical.

Direct Effects of Autonomic Nerve Activity on some Organs Systems Direct Effects of Autonomic Nerve Activity on some Organs Systems. Drug effects are similar but not identical.

Direct Effects of Autonomic Nerve Activity on some Organs Systems Direct Effects of Autonomic Nerve Activity on some Organs Systems. Drug effects are similar but not identical

Direct Effects of Autonomic Nerve Activity on some Organs Systems Direct Effects of Autonomic Nerve Activity on some Organs Systems. Drug effects are similar but not identical

Steps in Autonomic Transmission: Effect of Drugs

Steps in Autonomic Transmission: Effect of Drugs

Effects of Sympathetic and Parasympathetic Activity Function Sympathetic Parasympathetic Heart rate Increased Slowed Blood vessels Constricted Dilated Stomach and intestine Decreased activity and secretions Increased activity and secretions Salivary and bronchial glands Decreased secretion Increased secretion Urinary bladder Body relaxed, sphincter constricted Body contracted, sphincter relaxed Bronchial muscle Relaxed Contracted Blood sugar Raised Eye Pupils dilated Pupils constricted, accommodation for near vision Munir Gharaibeh

Schematic illustration of a generalized cholinergic junction

Life Cycle of Acetylcholine Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (ChT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from choline and acetyl Co-A (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle-associated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Munir Gharaibeh

Life Cycle of Acetylcholine Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft. This step can be blocked by botulinum toxin. Acetylcholine's action is terminated by metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. Munir Gharaibeh

Nicotinic transmission at the skeletal neuromuscular junction Munir Gharaibeh

Nicotinic transmission at the skeletal neuromuscular junction ACh released from the motor nerve terminal interacts with subunits of the pentameric nicotinic receptor to open it, allowing Na+ influx to produce an excitatory postsynaptic potential (EPSP). The EPSP depolarizes the muscle membrane, generating an action potential, and triggering contraction. Acetylcholinesterase (AChE) in the extracellular matrix hydrolyzes ACh.

Diagram of the intestinal wall and some of the circuitry of the enteric nervous system.

Diagram of the intestinal wall and some of the circuitry of the enteric nervous system (ENS). The ENS receives input from both the sympathetic and the parasympathetic systems and sends afferent impulses to sympathetic ganglia and to the central nervous system. Many transmitter or neuromodulator substances have been identified in the ENS. AC: absorptive cell CM: circular muscle layer EC: enterochromaffin cell EN: excitatory neuron EPAN: extrinsic primary afferent neuron IN: inhibitory neuron IPAN: intrinsic primary afferent neuron LM: longitudinal muscle layer MP: myenteric plexus NP: neuropeptides SC: secretory cell SMP: submucosal plexus

Cholinergic Receptors

The major groups of cholinoceptor-activating drugs, receptors, and target tissues.

Cholinergic Agonists or Parasympathomimetcs Definition: Drugs which produce effects similar to those observed during the stimulation of postganglionic parasympathetic nerve fibers or have actions similar to acetylcholine.

Cholinergic Agonists or Parasympathomimetcs Choline Esters. Alkaloids. Cholinesterase Inhibitors or Anticholinesterases. Munir Gharaibeh

Cholinergic Agonists or Parasympathomimetcs Choline Esters: Acetylcholine: Naturally released ACh from the cholinergic nerve endings. Very short acting because of rapid hydrolysis by AChase enzyme. Used only in experimentation. Munir Gharaibeh

Carbachol: not used clinically because of nicotinic activity Methacholine: Used in in the diagnosis of bronchial asthma ”Methacholine Challenge” Carbachol: not used clinically because of nicotinic activity Bethanechol: Works mainly on M3( smooth muscles and glands), but weak at M2, so minimal cardiac effects. Synthetic, long acting, used orally or s.c.. Used in gastric and bladder atony, when there is no obstruction. Causes flushing, sweating, colic.

Molecular structures of four choline esters

Cholinergic Agonists or Parasympathomimetcs Choline Esters. Alkaloids: produce similar actions to ACH but inconsistent Muscarine: present in some species of mushroom (Amanita muscaria), can cause poisoning. Pilocarpine: not hydrolyzed by cholinesterase works mainly on M3 receptors. used topically in glaucoma. Nicotine Munir Gharaibeh

Nicotine Uses: Non medical use( smoking and as an insecticide) and medical use in smoking cessation Kinetics: Rapidly absorbed through skin, lungs, and gut For smoking cessation, used orally as a gum or topically as a patch. Works on the ganglia, parasympathetic, sympathetic, motor end plate, CNS). Dependence: due to activation of nicotinic receptors on neurons in the brain’s dopaminergic reward pathway(venrtal tegument area). Nm stimulation can lead to fasiculations, spasms, and depolarizing blockade. Nn stimulation can lead to: High heart rate Vsoconstriction High gastric motility and secretions. Increased respiratory rate, due to chemoreceptor activation. Medullary emetic chemoreceptor stimulation, so nausea and vomiting.

Varnicline(Chantix) Partial nicotinic agonist. Highly effective in supporting smoking cessation. May be associated with psychiatric symptoms, including suicidal ideation.

Structures of some cholinomimetic alkaloids

Cholinergic Agonists or Parasympathomimetcs Choline Esters. Alkaloids. Cholinesterase Inhibitors or Anticholinesterases: Reversible Alcohols: e.g. Edrophonium Carbamic acid esters: e.g. Neostigmine, Carbaryl. Irreversible( Organophosphates): e.g. Echothiophtae, Soman, Malathion Munir Gharaibeh

Cholinest Cholinesterase Inhibitors or Anticholinesterases erase Inhibitors or Anticholinesterases Mechanism of Action: Inhibit cholinesterase enzyme leading to accumulation of acetylcholine at neuromuscular junctions and synapses

Organophosphate Poisoning Very potent agricultural insecticides and lethal war weapons. Very easily absorbed through all parts of the skin. Inhibit the enzyme and cause accumulation of ACh at all sites. Munir Gharaibeh

Organophosphate Poisoning Tissue or System Effects Skin Sweating Visual Lacrimation, miosis, blurring, spasm Digestive Salivation, increased secretions, tone, and motility (cramps, vomiting, diarrhea, and defecation) Urinary Frequency and incontinence Respiratory Increased secretions, bronchoconstriction, weakness of muscles Skeletal muscle Fasiculation, weakness, paralysis Cardivascular Bradycardia, decreased cardiac output, hypotension. CNS Tremor, anxiety, restlessness, confusion, convulsions, coma Munir Gharaibeh

Treatment of Organophosphate Poisoning Stop the exposure, wash extensively, very lipid soluble. Atropine, a parasympatholytic drug, in very large doses, until the appearance of Atropine Poisoning. Pralidoxime, when given very early after the poisoning, can regenerate the enzyme. Munir Gharaibeh