(1/22) Beck Lecture: Autonomic Pharmacology The Autonomic Nervous System (ANS) is one branch of the Efferent Peripheral Nervous System (PNS). It is further defined by the parasympathetic and sympathetic circuits. Generally, the ANS is the primary regulator of the constancy, or homeostatic nature, of the internal environment of the organism.

- Parasympathetic: Cranial and Spinal Nerves o Long axons synapse with nicotinic ganglia o Nicotinic ganglia synapse to muscarinic receptors o At both synapses, ACh is the NT

- Sympathetic: Thoracic and Lumbar Nerves o Short axons synapse with nicotinic ganglia

§ Some extend to adrenal medulla o Nicotinic ganglia synapse to both adrenergic

(E>NE) and muscarinic (ACh) receptors - The ANS neuronal inputs modulate the activity of smooth

muscle, cardiac tissue, and secretory glands. The sympathetic ANS has shorter axons closer to the spinal cord, and are more related to regulating the activity of the visceral organs. All in all, ACh is the key NT in the ANS

- Cholinergic drugs, in general, alter the relative activity of ACh. Due to the diffuse distribution of muscarinic receptors and widespread utilization of ACh as the chemical messenger, cholinergic drugs are capable of affecting the Sympathetic, Parasympathetic, and Enteric Nervous System of the Peripheral Nervous System.

Neurochemical Transmission - The transmission of chemical signals relies upon, and is affected by: Axonal conduction, release of the NT, post-

junctional activity (IPSP, EPSP), destruction or dissipation of the transmitter, and non-electrogenic functions such as enzyme activity and receptor turnover.

- Cholinergic Transmission o Cholinergic neurochemical activity relies upon the successful synthesis

and storage of ACh, ACh release upon stimulation, and ACh reception and signal transduction by post-synaptic receptors

o Nicotinic (Nn) Receptors: Ligand-gated ion channels. (Ligand is ACh) § Signal: Ion movement generates electrical impulses

o Muscarinic (M) Receptors: G-protein coupled receptors (GPCR) § Signal: Intracellular signaling cascade

- Adrenergic Transmission o Adrenergic neurochemical activity depends upon catecholamine synthesis

of NE and E from Tyr, and their activity at the adrenergic neuroeffector junction. These NT only operate in the sympathetic ANS, and we will discuss them further in Dr. Schlemmer’s section

Cholinomimetic & Cholinesterase-Inhibiting Drugs: These compounds elicit effects related to the increasing of [ACh] or its related analogs/agonists at the post-synaptic muscarinic receptors, thereby increasing conduction of nerve impulses

Direct-Acting Stimulant/Agonists (1)- Choline Esters (ex: bethanechol) (2)- Cholinomimetic Alkaloids (ex: pilocarpine)

Indirect-Acting Stimulant/’Agonists’ (1)- Reversible Cholinesterase Inhibitors

(ex: physostigmine) (2)- Irreversible/Organophosphate Ch-I

(ex: parathion)

These are cholinergic agonists, physiologically speaking, think Ýsecretions, Ýgut motility, etc

Direct-Acting Cholinoreceptor Stimulants/Agonists

- Choline Esters: A class of direct-acting stimulants at the postsynaptic junction. The prototype agonist is ACh, though it is not a ‘druggable’ compound due its short T1/2. Synthetic compounds were made with longer durations of action, such as:

o Methacholine o Carbachol o Bethanechol

- Cholinomimetic Alkaloids: Also direct-acting stimulants, the alkaloids refer to Muscarine, Nicotine and their analogues. Their discovery led to the naming and discovery of their receptor!

o Drug Examples: Pilocarpine, Lobeline - Direct-acting stimulant (agonist) effect at organs

o Eye: Stimulate the sphincter muscle to contract (miosis, pinpoint), Ciliary muscle to contract (near-vision)

o Heart: SA Node (Rateß), Atria (ßContractile strength+refractory period), AV Node (ßConduction velocity, Ýrefractory period), and the Ventricles experience a minor ß in refractory strength

o Blood Vessels: Arteries and Veins dilate at therapeutic doses in response to EDRF (epitheial-derived relaxing factor), but will constrict at high doses.

o Lungs: Stimulation induces bronchoconstriction (this is not a good idea for asthmatics), bronchial gland secretion

o GI Tract: Overall, cholinoreceptor stimulants increase gut motility through the relaxation of sphincters and stimulation of secretion. Cholinergic Agonist? à Diarrhea

o Urinary Bladder § Detrusor Muscle: Contraction § Trigone & Sphincter: Relaxation

o Other Glands: Sweat, saliva, lacrimal fluid, and nasopharyngeal discharge ,,,, secretions increased! Indirect-Acting Cholinomimetic Stimulants/Agonists: This class of compounds, although not direct-acting like the previous two groups discussed, are also agonists. The indirect-acting cholinomimetics are majorly comprised of Cholinesterase Inhibitors. These compounds block ACh degradation, allowing for a longer ACh resonance time

- Reversible Cholinesterase Inhibitors: Neostigmine, Physostigmine, Carbaryl, Endrophonium - Irreversible Cholinesterase Inhibitors: The organophosphates!

o Echothiophate: Long-acting (T1/2 ~100h), used to treat glaucoma o Sarin Nerve Gas o Insecticides: Parathion (bioactivatedà Paraoxon)

§ Malathion (bioactivatedà Malaoxon) - Therapeutic Use: *Think! – these are agonists, so relative [ACh]Ý

§ Neostigmine: Myasthenia gravis (skeletal muscle weakness), Ileus (bowel paralysis)

§ Physostigmine: Anticholinergic Poisoning Echothiophate: Glaucoma Cholinoceptor Antagonists: Also known as Muscarinic/Nicotinic receptor antagonists, these compounds block the action of ACh. For the purposes of this class, we will only focus on Muscarinic antagonists, as nicotinic are less useful

- Atropine: Much like ACh being the prototype agonist of cholinergic receptors, Atropine is the prototype antagonist. A belladonna alkaloid historically used for eye-dilation (mydriasis) properties

- Clinically Useful Muscarinic Receptor Antagonists (used to treat) o Scopolamine: Motion Sickness, N, V, Post-op nausea o Dicyclomine: IBS, Minor cases of diarrhea. o Atropine: Used in retinal exams and for the prevention of Synechiae following eye surgery

§ It is a mandatory antidote for severe cholinesterase-inhibitor poisoning o Pralidoxime: The more common antidote for early-stage (<48h) cholinesterase-inhibitor poisoning. It

works to regenerate live AChE and relieve the skeletal muscle end plate block. o Ipratropium/Tiotropium: To decrease or prevent bronchospasm in asthmatics/COPD patients o Oxybutynin: Decreases Detrusor muscle tone and reduces spasms, helping to treat urge incontinence and

post-op spasms that are common following anesthesia administration § Tolterodine: Exhibits greater selectivity for M3 receptors

- Anticholinergic effect on organs – to be aware of o Eye: Induces pupil dilation à mydriasis through cycloplegia (paralysis of the ciliary muscle) o Lungs: Decreases or prevents bronchospasms o GI Tract: Decreases smooth muscle activity and gut secretion activity, calms down the intestines o Urinary Bladder: Decreases detrusor smooth muscle tone, decreases spasms o Exocrine Glands: Anticholinergics block muscarinic excess

§ Also at the heart and smooth muscle o Secretions: Majorly decreased

- Recognizing Anticholinergic Poisoning *Phrases: 1950s Movie, South Pacific, Blood Mary ate bad nuts. o Hot as a Hare: Hyperthermia o Blind as a Bat: Blurred Vision o Dry as a Bone: Dry Mouth/Skin (Disclaimer: many anticholinergics induce xerostomia, this isn’t

a symptom to call 911 about, just consider full body hydration and thermal regulation) o Red as a beet: Flushed Skin o Mad as a hatter: Confusion o Full as a Flask: Urinary Retention

Learning Objectives: Set 2: Cholinergic Pharmacology – Know the use and toxicities of muscarinic agonists, antagonists, agents that inhibit AChE, and block neuromuscular junction. Katsung, Chapter 7 summary table (2018)

Cholinergic Agonist~Stimulant DRUG Sub-Class Effect Indication àToxicityß

Bethanechol Direct-acting muscarinic agonist A choline ester

Stimulates M1, M2, and M3 receptors in peripheral tissues inducing secretion, smooth muscle contraction, and changes in heart rateÝ

Post-operative and neurogenic Ileus Urinary Retention

Does not enter CNS Excessive parasympathomimetic effects – such as bronchospasm in asthmatics

Pilocarpine Direct-acting muscarinic agonist Cholinomimetic alkaloid

Stimulates M1, M2, and M3 receptors in peripheral tissues inducing secretion, smooth muscle contraction, and changes in heart rateÝ

Glaucoma, Sjoegren’s Syndrome

Does not enter CNS Excessive parasympathomimetic effects – such as bronchospasm in asthmatics

Nicotine Direct-acting nicotinic agonist Pure substrate

Stimulates NN and NM receptors, activating both ANS sympathetic and parasympathetic neurons in the CNS and skeletal muscle NMJ

Smoking cessation Insecticides

Acutely increased GI activity, NVD, ÝBP Excessive dose may cause seizure Long-term GI and cardiovascular risk factor

Neostigmine Indirect-acting reversible cholinesterase inhibitor

Forms a covalent bond with AChE that is readily hydrolyzed and released. It produces an intermediate duration effect of amplification ACh, increasing parasympathetic activity

Myasthenia gravis, post-operative and neurogenic ileus, Urinary retention

Does not enter CNS May produce excessive parasympathomimetic effects

Anticholinergics~Antagonist

DRUG Sub-Class Effect Indication àToxicityß Scopolamine Muscarinic

Anticholinergic

Tropine Alkaloid

Its mechanism in the CNS is not well understood, but it reduces vertigo and post-operative nausea

Prevention of motion sickness

and post-operative N,V

Toxicities include: Tachycardia, blurred vision, xerostomia, delirium (Sounds like Bloody Mary!)

Dicyclomine Muscarinic Anticholinergic Competitive Antagonist

A competitive antagonist specifically at M3 receptors, dicyclomine reduces smooth muscle and secretory activity in the gut.

IBS, Minor diarrhea

Toxicities include: Tachycardia, urinary retention, increased intraocular pressure

Oxybutynin Muscarinic Anticholinergic

Selective Antagonist

Acting as an antagonist slightly selectively at the M3 receptor, Oxybutynin reduces detrusor smooth muscle tone, stopping and reducing spasms.

Urge incontinence, post-operative spasms

Toxicities include: Tachycardia, constipation, increased intraocular pressure, xerostomia

Pralidoxime Antidote, Phosphorous-loving

Pralidoxime is capable of regenerating active AChE by performing nucleophilic attack on pre-aged organophosphate-AChE complexes

Early-stage organophosphate poisoing, Cholineesterase-inhibitor poisoning

May cause muscle weakness in cases of overdose