Autonomic nervous system Cholinergic agonists CHOLINOMIMETICS Ph D

Autonomic nervous system Cholinergic agonists (CHOLINOMIMETICS) Ph. D. A. V. Aleksandrova www. company. com

Functional divisions within the nervous system www. company. com

What are the differences between the somatic and the autonomic nervous system? • Somatic N. S Autonomic N. S • • Control internal viscera Involuntary autonomic nerve is two fibers (Preganglionic & Postganglionic) Control skeletal muscles Voluntary Somatic nerve is one fiber www. company. com

Efferent neurons of the autonomic nervous system www. company. com

Sympathetic ANS • The 1 st neuron of sympathetic division is located in the thoracolumbar region of the spinal cord (T 1 -L 3) and the 2 nd is disposed either in the paravertebral, or in the prevertebral ganglia. Postganglionic non-myelinated nerve fibres arising from neurones in the ganglia, innervate most organs of the body • The neurotransmitter released by sympathetic nerve endings is noradrenaline. www. company. com

Parasympathetic system • The 1 st neuron of parasympathetic system is located in the brain stem and in the sacral region of the spinal cord. The preganglionic fibres leave the central nervous system in the III, VII, IX and X pairs of cranial nerves and the third and fourth sacral spinal roots. • Ganglia are located either in the tissue of effector organ or near it. The nerve endings of the postganglionic parasympathetic fibres release neurotransmitter acetylcholine. All the preganglionic nerve fibres (sympathetic and parasympathetic; ) are myelinated and release acetylcholine from the nerve terminals which depolarizes the ganglionic neurones by activating nicotinic receptors. www. company. com

Parasympathetic Nervous System (craniosacral outflow) www. company. com

Cholinergic nervous fibres are: 1) preganglionic (sympathetic and parasympathetic); 2) all postganglionic parasympathetic; 3) postganglionic sympathetic which supply sweat glands and vessels of skeletal muscles; 4) somatic nerves; 5) nerves which supply adrenal medulla and carotic sinuses; 6) neurons of CNS Adrenergic nervous fibres are: 1) postganglionic sympathetic, except those which supply sweat glands and vessels of skeletal muscles; 2) neurons of CNS www. company. com

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Cholinergic transmission Main NT is Acetylcholine (Ach). A large number of peripheral ANS fibers which synthesize & release Acetylcholine are called CHOLINERGIC fibers. They include: • All pre-ganglionic efferent autonomic fibers. • Somatic motor fibers to skeletal muscles. • Most parasympathetic post ganglionic fibers. • A few sympathetic post ganglionic fibers– to sweat glands. Some parasympathetic post ganglionic fibers utilize nitric oxide or peptides for transmission. www. company. com

Fate of acetylcholine released by cholinergic fiber • ACh is released from the nerve into the synaptic cleft and binds to ACh receptors on the postsynaptic membrane, relaying the signal from the nerve. • Ach-esterase, located on the post-synaptic membrane, terminates the signal transmission by hydrolyzing ACh. • The liberated choline is reuptaken by the presynaptic membrane and used for resynthesis of ACh. www. company. com

Cholinergic synapse • Nerve terminal of cholinergic fibre contains numerous vesicles with neurotransmitter acetylcholine (ACh) that is released from presynaptic membrane. • Release of acetylcholine depends on sufficient influx of Ca 2+, which occurs under the influence of action potential. ATP negative feedback ATP www. company. com

Cholinergic receptor types • Two cholinergic receptor subtypes have been identified by selective agonists: muscarinic (M-cholinoceptors) and nicotinic (Ncholinoceptors). At M 1 least 5 subtypes of muscarinic receptors (M 1 – M 5) have been distinguished. • There are 3 main classes of N- cholinoceptors: the muscle, ganglionic, and CNS classes. MUSCARINIC M 2 M 3 M 4 v Eye v Heart v Smooth muscles v Exocrine glands v CNS NICOTINIC M 5 NM NN v Ganglions v Carotid sinus v Skeletal muscles v Adrenal glands v CNS www. company. com

Muscarinic receptors • High affinity to muscarine • M 1 – gastric parietal cells, saliva, CNS • M 2 - cardiac cells, smooth muscle, CNS Amanita muscaria • M 3 - bladder, exocrine glands, smooth muscle, eye, CNS • M 1&M 3 – Gq • M 2 - Gi www. company. com

Nicotinic receptors • High affinity to nicotine • NM- neuro-muscular junction • NN – ganglion, adrenal gland CNS, carotid sinus www. company. com

Mechanisms of impulse transmission • Muscarinic receptors belong to G-protein coupled receptors. Transmission of impulses through M 1, M 3, M 5 cholinoceptors is realized by phospholipase C, inositol triphosphate and diacylglycerol • Stimulation of M 2 and M 4 cholinoceptors results in inhibition of adenylate cyclase and decrease in intracellular c. AMP. • N- cholinoceptors are ion channel coupled. Their stimulation results in opening of Na+ channels that causes depolarization. www. company. com

Muscarinic receptors M 1 M 3 www. company. com

M-cholinoceptors Receptor M 1 Excitatory Locations CNS gastric parietal cells M 2 Inhibitory Heart M 3 Excitatory Exocrine glands Smooth muscles Vascular endothelium M 4 & M 5 CNS Pharmacological actions CNS excitation Gastric acid secretion Cardiac inhibition (Bradycardia) • Secretion of glands • Smooth muscle contraction • Vasodilatation (via nitric oxide) memory, arousal, attention and www. company. com

N-cholinoceptors Cholinoc Localization eptors Effects of stimulation NN Autonomic Increase in parasympathetic and ganglia sympathetic reactions (parasympatheti c and sympathetic) NN Adrenal medulla Increase in adrenaline release, increase in BP NM Skeletal muscle Increase in tone, contraction Carotid sinus Reflex respiratory centre stimulation CNS Stimulation NN www. company. com

Nicotinic receptors Central cholinoceptor Muscarinic receptors Peripheral cholinoceptor Ion channel linked receptors G protein linked receptors Autonomic ganglia (sympathetic & parasympathetic) stimulation ( Nn ) On all peripheral organs that receive postganglionic parasympathetic fibers Adrenal medulla (Nn) release of catecholamines (Adrenaline & Noradrenaline) Heart (M 2) inhibition exocrine glands (M 3) contraction Skeletal muscle (Neuromuscular junction) (Nm) Contraction Almost excitatory Smooth muscles (GIT, urinary tract, bronchial muscles) (M 3) contraction Excitatory or inhibitory www. company. com

Nicotinic actions Skeletal muscles: • Low conc. of nicotine muscle contraction • High conc. of nicotine persistent depolarization & relaxation. Ganglia: stimulation of sympathetic& parasympathetic ganglia. Adrenal medulla release of catecholamines (A & NA). www. company. com

Muscarinic actions Organs Eye Cholinergic actions Contraction of circular muscle of iris (miosis)(M 3) Contraction of ciliary muscles for near vision (M 3) Decrease in intraocular pressure Heart bradycardia ( heart rate ) (M 2) endothelium Release of NO (EDRF) Lung Constriction of bronchial smooth muscles Increase bronchial secretion M 3 GIT Increase motility (peristalsis) Increase secretion Relaxation of sphincter M 3 Urinary Contraction of muscles bladder Relaxation of sphincter M 3 - Urination Exocrine glands Increase of all secretions sweat, saliva, lacrimal, bronchial, intestinal secretions M 3 www. company. com

Cholinomimetics • • • I. Direct acting 1. Muscarinic agonists (Mcholinomimetics) Pilocarpine Oxothermorine Aceclidine 2. Nicotinic agonists Lobeline Dimethylphenylpiperazinum (DMPP) 3. Muscarinic and nicotinic agonists Acethylcholine Carbachol II. Indirect acting (muscarinic and nicotinic agonists – anticholinesterase agents) 1. Reversible Neostigmine (Proserinum) Physostigmine • • • • • • • • Pyridostigmine Edrophonium Ambenonium chloride (Oxazylum) Galanthamine 2. Irreversible (Organophosphates) Echotiophate Isoflurophate Arminum Drugs used in poisoning with organophosphates 1. Reactivators of acetylcholine esterase Pralidoxime Dipiridoxinum Izonitrozinum Obidoxime 2. M-cholinoblockers Atropine www. company. com

Pharmacological effects • • • Bradycardia, decrease in blood pressure Raising the tone of smooth muscles of internal organs Stimulation of intestinal motility Reducing sphincter of alimentary canal and bladder Increased secretory activity of the exocrine glands Constriction of the pupil of the eye (miosis) spasm of accommodation Reducing intra ocular pressure Relief of pulses in mionevralnomu skeletal muscle synapse, strengthening their contractility (anticholinergic drugs) • Stimulation of the central nervous system (means of penetrating the blood-brain barrier) www. company. com

Main clinical usage • 1. Glaucoma (Pilocarpine, Physostigmine, Armine) • 2. Infants (Neostigmine) • 3. Postoperative atony of the intestines and bladder (Neostigmine) • 4. Paralysis, paresis, neuritis, polyneuritis (Neostigmine) • 5. Dusturbances of skeletal muscle contractile function after cranial trauma, polio and stroke (Galanthamine hydrobromide) • 6. Belladonna poisoning (Neostigmine, Physostigmine, Galanthamine) • 7. Overdose nondepolarizing muscle relaxants (Neostigmine) • 8. Xerostomia (Pilocarpine) • 9. Respiratory depression (Cititon, Lobeline) www. company. com

Side effects of cholinomimetics • • • 1. Bradycardia 2. Bronchospasm 3. Intestinal cramps, colic, diarrhea 4. Hypersalivation 5. Blurred vision www. company. com

Contraindications • • • 1. Bradycardia, A-V block 2. Asthma 3. Gastric ulcer and 12 duodenal ulcer 4. Epilepsy (Neostigmine) 5. Pregnancy (Neostigmine) www. company. com

Direct acting cholinergic agonists ACETYLCHOLINE www. company. com

Direct acting cholinergic agonists ACETYLCHOLINE 1. Decrease in heart rate and cardiac output 2. Decrease in blood pressure www. company. com

Direct acting cholinergic agonists ACETYLCHOLINE 3. Other actions 4. Clinical use very rare: eye drops to obtain miosis Muscarinic and nicotinic agonist not used clinically because Ach is not selective (N, M) Has short duration of action. Why? Due to rapid metabolism by acetycholinesterase www. company. com

Direct acting cholinergic agonists 1. Stimulation of atonic bladder 2. Nonobstructive urinary retention 3. Neurogenic atony 4. Megacolon Ophthalmology www. company. com

Direct acting cholinergic agonists PILOCARPINE 1. Tertiary nitrogen 2. Good adsorbtion 3. Penetrate BBB www. company. com

Direct acting cholinergic agonists PILOCARPINE Natural alkaloids Tertiary amine lipophilic Pharmacokinetics It is well absorbed Good distribution Cross BBB (has central effects). Long duration of action Direct muscarinic agonist (mainly on eye & secretion). Jaborandi (Pilocarpus pennatifolius) www. company. com

Direct acting cholinergic agonists PILOCARPINE www. company. com

Pilocarpine • Uses: • Xerostomia (dry mouth). • Drug of choice in emergency glaucoma applied as eye drops. • • • Adverse effects: Profuse sweating Salivation Bronchoconstriction Diarrhea CNS effects www. company. com

Aceclidinum • a synthetic preparation; • administered SC, IM, or topically (eye drops); not toxic; • does not penetrate CNS; • M-cholinomimetic; • used for the treatment of atonia of the intestine and urinary bladder, as well as for glaucoma. www. company. com

Mushroom poisoning § Miosis § Hyper salivation § Excessive sweating, lacrimation § Cold, wet skin § Bradycardia § Polyuria § Diarrhea § Convulsions Atropine www. company. com

N-CHOLINOMIMETICS • They stimulate N-cholinoreceptors in zona carotis and initiate a reflexive increase • in the activity of the respiratory and vasomotor centers resulting in the short stimulation of breathing and elevation of BP. • They also stimulate N-cholinoreceptors in the adrenal medulla, increase the secretion of epinephrine, which causes vasoconstriction and the elevation of BP www. company. com

NICOTINE • It is a tobacco alkaloid with a dose-dependent action on N-cholinoreceptors. • Effects of nicotine are manifested in tobacco smoking. • Nicotine causes dependence that leads to abuse of tobacco and results in the development of cardiovascular and lungs pathology. www. company. com

Physiological effects of nicotine at CNS NN receptors • • ↑Emesis (vomiting) due to actions on chemoreceptor trigger zone of medulla oblongata • • Dependence (i. e. makes it hard to quit smoking) • • Respiratory depression (only at very high doses) due to actions on medulla oblongata - also contribution from blockade of diaphragm and intercostal muscles • • Tremors + convulsion (only at very high doses) www. company. com

Physiological effects of nicotine at peripheral NN receptors • Many Effects of Nicotine Involve Ganglia • • ↑GI motility (nausea, diarrhea, vomiting) – Stimulation of parasympathetic ganglia • • ↑Heart rate, ↑blood pressure – Stimulation of sympathetic ganglia innervating heart and blood vessels – Release of EPI from adrenal medulla – Stimulation of chemoreceptors → reflex ↑heart rate, vasoconstriction www. company. com

Lobeline • is an alkaloid; is administered IV and acts during 3 -5 min; • stimulates N-cholinoreceptors; • is used for emergency help in the respiratory arrest, asphyxia, asphyxia of newborns; is used to treat tobacco abuse in the form of combined tablets • is not used for collapse due to its ability to provoke transitory a decrease in BP resulting from the stimulation of n. vagus center. www. company. com

Cytitonum • the name of a cytizine solution; • administered IV, acts 3 -5 min; • stimulates N-cholinoreceptors; reflexly stimulates respiration and increases BP; • used for emergency help in respiratory arrest and collapse; • an ingredient of combined tablets against tobacco abuse. www. company. com

Indirect acting cholinergic agonists Reversible Irreversible Edrophonium Neostigmine Physostigmine Rivastigmine Galantamine Echothiophate Organophosphates Arminum www. company. com

Mechanism of action: Anticholinesterases prevent hydrolysis of Ach by antagonizing cholinesterase thus increase Ach concentrations and actions at the cholinergic receptors (both nicotinic and muscarinic). www. company. com

Pharmacological effects of anticholinesterases q q q Muscarinic actions Nicotinic actions CNS actions: Excitation, convulsion, respiratory failure, coma only for lipid soluble anticholinesterases physostigmine & phosphate ester except Ecothiophate. www. company. com

Reversible Physostigmine • • • Reversible anticholinesterase Tertiary ammonium compound Non polar (lipid soluble) Good lipid solubility Good oral absorption Has muscarinic & nicotinic actions • cross BBB (has CNS effects) Calabar Bean www. company. com

Reversible Physostigmine Indications 1. Atony of intestine 2. Atony of bladder 3. Glaucoma 4. Overdose of ATROPINE, ANTIPSYCOTICS, ANTIDEPRESSANTS Side effects 1. Convulsions 2. Bradycardia 3. Paralysis of skeletal muscle www. company. com

Reversible Neostigmine 1. 2. 3. 4. Quatenary nitrogen Poor adsorbtion Not penetrate BBB Reversible anticholinesteras 5. Has muscarinic & nicotinic actions (prominent on GIT & urinary tract). www. company. com

Reversible Neostigmine Indications Side effects 1. Paralyzes 2. Myastenia gravis 3. Antidote of neuromuscular blocker TUBOCURARINE 1. Salivation 2. Flushing 3. Decreased BP 4. Abdominal pain 5. Diarrhea 6. Bronchospasm www. company. com

Contraindications Neostigmine 1. Bronchial asthma 2. Intestinal inflammation, obstruction 3. Bladder obstruction 4. Peritonitis www. company. com

Galantamine • • • an alkaloid from Galanthus Woronowi; administered SC, IM; penetrates into CNS; has a reversible anticholinesterase action; used for the treatment of paralysis, neuritis, early stages of Alzheimer’s disease and other neurological diseases; • is not used in glaucoma due to its irritative action. www. company. com

Reversible Edrophonium 1. 2. 3. 4. 5. Quatenary nitrogen Poor adsorbtion Not penetrate BBB Fast elimination Duration 10 -20 min www. company. com

Reversible Edrophonium 1. Diagnosis of myasthenia gravis 2. Antidote of neuro-muscular blocker www. company. com

Reversible Rivastigmine 1. Tertiary nitrogen 2. Good adsorbtion 3. Penetrate BBB www. company. com

Reversible Rivastigmine Alzheimer disease www. company. com

Irreversible Echothiophate Mechanism -Irreversible anticholinesterase -Binds to cholinesterase by strong covalent bond. -Have very long duration of action -Aging make bond extremely stable -Used for glaucoma. www. company. com

Toxicology Organophosphates www. company. com

Toxicology Salivation Lacrimation Urination Defecation Gastrointestinal motility Emesis Miosis Death is caused by breath insufficiency, bronchospasm and lungs edema www. company. com

Toxicology 1. Reactivation of acetylcholinesterase • PRALIDOXIME üNot enter BBB 2. M-cholinoblocker • ATROPINE ü Antimuscarinic only 3. Anticonvulsant • DIAZEPAM www. company. com

Pralidoxime (PAM) cholinesterase reactivator • Acts by regeneration of cholinesterase enzyme. • reactivates recently inhibited enzymes before aging. Uses I. V. over 15 -30 min for organophosphate intoxication. www. company. com

Summary for cholinomimetics & their uses Eye : treatment of glaucoma Pilocarpine (direct muscarinic agonist) Physostigmine -Ecothiophate (indirect cholinomimetics) Urinary retention and paralytic ileus Bethanechol (direct) Neostigmine (indirect) Myasthenia gravis (only indirect cholinomimetics) Pyridostigmine, Neostigmine, Ambenonium Xerostomia Pilocarpine –Cevimeline (Sjogren’s syndrome) Alzheimer’s disease: Rivastigmine, Donepezil www. company. com

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