Autonomic Nervous System Drugs

• The presentation focuses on drugs affecting the autonomic nervous system, specifically cholinomimetics and anticholinergic drugs.
• When studying pharmacology, pay attention to classifications, doses, effects, pharmacokinetics, and pharmacodynamics.

Autonomic Nervous System

• The autonomic nervous system consists of the sympathetic and parasympathetic systems.
• The sympathetic system dilates pupils, inhibits salivation, relaxes bronchi, accelerates heartbeat, inhibits peristalsis and secretion, stimulates glucose production and release, triggers secretion of adrenaline and noradrenaline, inhibits bladder contraction, and stimulates orgasm.
• The parasympathetic system constricts pupils, stimulates saliva flow, constricts bronchi, slows heartbeat, stimulates peristalsis and secretion, stimulates bile release, and contracts the bladder.

Biochemistry of Acetylcholine

• Acetylcholine (ACh) is synthesized locally in cholinergic nerve endings.
• Choline is actively taken up and acetylated with ATP and coenzyme-A by choline acetyl transferase (ChAT) in the axoplasm.
• ACh release from nerve terminals occurs in small quanta upon membrane excitation and Ca2+ channel activation.
• After release, ACh is hydrolyzed by cholinesterase, and choline is recycled.
• Two types of cholinesterase exist: true cholinesterase at cholinergic sites and pseudocholinesterase in plasma and liver.
• True cholinesterase hydrolyzes ACh instantaneously, while pseudocholinesterase hydrolyzes ACh slowly and metabolizes ingested esters.

Synaptic Transmission

• Action potentials arrive at the axon terminal, opening voltage-gated Ca2+ channels.
• Ca2+ enters the cell, signaling vesicles to move to the membrane.
• Docked vesicles release neurotransmitter (ACh) by exocytosis.
• Neurotransmitter diffuses across the synaptic cleft and binds to receptors on the postsynaptic cell.
• Binding of neurotransmitter opens ligand-gated Na+ channels in the postsynaptic membrane, allowing Na+ ions to diffuse into the postsynaptic bulb.
• Sufficient Na+ ions in the postsynaptic bulb can trigger another action potential at the axon hillock.

Cholinoceptors

• Muscarinic (M1-M5) and Nicotinic (NN, NM) cholinoceptors have various locations.
• Muscarinic M1 receptors are in CNS neurons and sympathetic postganglionic neurons.
• Muscarinic M2 receptors are in the myocardium and smooth muscle.
• Muscarinic M3 receptors are in exocrine glands and vessels.
• Muscarinic M4 receptors are in CNS neurons.
• Muscarinic M5 receptors are in vascular endothelium.
• Nicotinic NN receptors are in postganglionic neurons.
• Nicotinic NM receptors are in skeletal muscle neuromuscular end plates.

Physiological Effects of Acetylcholine

• Cardiovascular effects include vasodilation, decreased heart rate, decreased atrioventricular conduction, and decreased cardiac output.
• Respiratory effects include bronchoconstriction and increased synthesis of glandular mucus.
• Urinary effects include detrusor muscle constriction leading to urination and stimulation of peristalsis of ureters.
• Gastrointestinal effects include increased synthesis of HCl and increased peristalsis of intestines.
• Eye effects include miosis, decreased intraocular tension, and accommodative spasm.
• It causes increased secretion for exocrine glands
• Central nervous system effects include overall excitation but no penetration of the blood-brain barrier.

Cholinomimetics

• Cholinomimetics are categorized by cholinergic agonists (N-cholinergic agonists and M-cholinergic agonists) and anticholinesterases.

N-Cholinergic Agonists

• Nicotine is used to stop tobacco abuse, impacting central and peripheral n-cholinoceptors, irritating the respiratory and vasomotor center of medulla oblongata.
• In small doses, nicotine stimulates n-cholinoceptors of the adrenal gland, releasing epinephrine, while large doses suppress it and can be excreted in breast milk.
• Lower dose nicotine delivery methods includes gum, dermal patches, nasal spray, or inhalator.
• Nicotine patches are better tolerated than gum due to consistent nicotine release; coffee and carbonated drinks can influence nicotine absorption.
• Nicotine treatment is nearly twice as effective as placebo for sustained withdrawal from smoking.
• Bupropion, varenicline, cytisine, and lobelin are used for smoking cessation. Cytisine and lobelin are also used intravenously to stimulate respiratory function.

M-Cholinergic Agonists

• Muscarine is found in poisonous mushrooms like Amanita muscaria and Inocybe species and has only muscarinic actions.
• Pilocarpine causes sweating, salivation, and other secretions. Systemic injection is dangerous due to AcH-related effects.
• Pilocarpine, applied to the eye, penetrates the cornea to cause miosis, ciliary muscle contraction, and relaxation of suspensory ligaments.
• It lowers intraocular tension for 4-8 hours and is used in glaucoma 0.5-4.0% eye drops to improve drainage and reduce intraocular tension.
• Pilocarpine can also be used to treat xerostomia.

Anticholinesterases

• These agents inhibit cholinesterase, protecting ACh from hydrolysis, and potentiating cholinergic effects in vivo and in vitro.
• Anticholinesterases actions resemble direct cholinoceptor stimulants, affecting smooth muscles and glands in the gastrointestinal, respiratory, urinary tracts, and eyes.
• Lipid-soluble tertiary amines (physostigmine, galantamine, ipidacrine, donepezil) have marked muscarinic and CNS effects.
• Lipid-insoluble quaternary ammonium salts (neostigmine, pyridostigmine) affect skeletal muscles more but have fewer muscarinic effects and no central effects.
• Anticholinesterases treat myasthenia gravis, prevent atonia of the intestines and bladder postoperatively, treat Alzheimer's disease, and act as antidotes in poisoning by myorelaxants.
• Neostigmine and physostigmine eye drops treat glaucoma, but galantamine is not recommended due to edema risk.
• For intoxication by anticholinesterases, use pralidoxime or atropine.

Anticholinesterases - Types

• Reversible anticholinesterases: Carbamates (physostigmine, neostigmine, pyridostigmine, rivastigmine). Non-carbamates (edrophonium, tacrine, donepezil, galantamine)
• Irreversible anticholinesterases: Carbamates (carbaryl, propoxur); Organophosphates (Dyflos (DFP), Echothiophate, Malathion, Diazinon, Tabun, Sarin, Soman)

Anticholinergic Drugs

• Categories of anticholinergic drugs are M-cholinoblockers (antimuscarinic drugs), N-cholinoblockers (antinicotinic drugs), ganglion-blocking drugs, and neuromuscular blocking drugs of peripheric action

M-Cholinergic Antagonists (Blockers)

• Muscarinic antagonists also known as parasympatholytic block parasympathetic autonomic discharge.
• Atropine is a prototype drug is highly selective for muscarinic receptors, and blocks all receptor subtypes.
• Low doses of CNS stimulation occur in medullary centers along with vestibular center suppression and helps in the basal ganglia. High doses cause cortical excitation, disorientation, hallucinations, respiratory depression, and coma..
• Cardiovascular system effects include tachycardia with facilitated A-V conduction, PR-interval shortening, and no blood pressure effect unless vasodilatation occurs in large doses.
• Eye effects from topical instillation cause mydriasis, light reflex abolition, cycloplegia, photophobia, blurred near vision, and potential intraocular tension elevation.
• Smooth muscle relaxation include peristalsis suppression including GIT and stomach, along with intestinal suppression and may result in constipation.
• Higher doses can cause increased body temperature.
• Glands will have decreased sweat, salivary, tracheobronchial, and lacrimal secretion.
• Dose is 0.6-1.2 mg by mouth at night or 0.6 mg i.v., repeated up to 3 mg/day. It is easily absorbed in the GIT and almost does not penetrate the BBB.

Anticholinergic Drugs - Types

• Natural Alkaloids: Atropine, Hyoscine (Scopolamine).
• Semisynthetic Derivatives: Atropine methonitrate, Homatropine, Hyoscine butyl bromide, Ipratropium bromide, Tiotropium bromide.
• Synthetic Compounds:
  • Mydriatics: Cyclopentolate, Tropicamide.
  • Vasicoselective: Oxybutynin, Flavoxate, Tolterodine, Darifenacin, Solifenacin.
  • Antiparkinsonian: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden.
  • Antisecretory-antispasmodics: Quaternary Comps. (Propantheline, Oxyphenonium, Clidinium, Cimetropium bromide, Isopropamide, Glycopyrrolate) and Tertiary Amines (Dicyclomine, Valethamate, Pirenzepine).

Mechanism of Action, Indications and Side Effects of Anticholinergic Drugs

• Anticholinergic drugs block acetylcholine from binding to muscarinic receptors and block signaling pathways.
• This alters parasympathetic functions, leading to increased heart rate, and decreased smooth muscle motility, exocrine gland secretion.
• Indications for anticholinergic drugs include overactive bladder syndrome, irritable bowel syndrome, bradycardia, motion sickness, Parkinson's disease, peptic ulcers, and respiratory conditions.
• Side effects include dry mouth, sore throat, tachycardia, urinary retention, obstipation, blurred vision, light sensitivity, mood changes, hallucinations, confusion, and disorientation.

Antimuscarinic Drugs

• Scopolamine is similar to atropine but a CNS depressant causing calmness and sleep. It better targets the eyes and exocrine glands and has better BBB penetration.
• Homatropine and tropicamide are mydriatic and cycloplegic, with quicker action than atropine.
• Ipratropium is an inhaled bronchodilator for asthma and COPD, not depressing mucociliary clearance.
• Tiotropium is another alternative to ipratropium, but only for chronic COPD patients.
• Dicyclomine has smooth muscle relaxant and antiemetic properties and treats menstrual issues, IBS and motion sickness.
• Glycopyrronium is used as a premedicant to reduce salivary secretion during anesthetics and it causes less tachycardia than atropine.
• Antimuscarinic drugs should be used with caution in patients that have prostate hypertrophy and glaucoma.

Uses of Antimuscarinic Drugs

• Some anticholinergic medications like trihexyphenidyl and orphenadrine are used against rigidity and tremors of Parkinson's disease.
• Atropine, homatropine and cyclopentolate are used topically in ophthalmology to dilate the pupil and to paralyze ocular accommodation.
• Antimuscarinic drugs like atropine and hyoscine may be used in aesthetic premedication to block the vagus nerve.
• Ipratropium is used in the respiratory tract as a bronchodilator to treat chronic obstructive pulmonary disease (COPD).
• Anticholinergic drugs may aid in the gut to treat muscle spasms and hypermotility against colic.
• Flavoxate, oxybutynin, propiverine, tolterodine, trospium and propatheline can be used in the urinary tract.
• Atropine is useful to bradycardia following myocardial infarction.
• To treat cholinergic poisoning, atropine is given.

Summary of Info

• Acetylcholine (ACh) is a neurotransmitter in the brain, peripheral nervous system, autonomic ganglia, skeletal muscle, and other effector cells, mainly glandular or smooth muscle.
• The body terminates the effector response via enzymatic destruction by acetylcholinesterase.
• Outside the CNS, acetylcholine has two main receptor classes: those on autonomic ganglia and skeletal muscle stimulated by nicotine, and others stimulated by muscarine.
• Drugs like pilocarpine and atropine mimic and oppose acetylcholine and have several uses.
• Neuromuscular junction drugs relax muscle in anesthesia or inhibit acetylcholinesterase in diseases like myasthenia gravis.