Autonomic nervous system Cholinergic agonists (CHOLINOMIMETICS) Cholinergic antagonists (CHOLINOBLOCKERS)

Functional divisions within the nervous system

Efferent neurons of the autonomic nervous system

Sympathetic and parasympathetic actions

Sympathetic ANS The 1st neuron of sympathetic division is located in the thoracolumbar region of the spinal cord (T1-L3) and the 2nd 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.

Parasympathetic system The 1st 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.

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.

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

Fate of acetylcholine released by cholinergic fiber ACh is released from the nerve into the synaptic cleft and binds to ACh receptors on the post-synaptic 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 pre-synaptic membrane and used for resynthesis of ACh.

Cholinergic receptor types Two cholinergic receptor subtypes have been identified by selective agonists: muscarinic (M-cholinoceptors) and nicotinic (N-cholinoceptors). At least 5 subtypes of muscarinic receptors (M1 – M5) have been distinguished. There are 3 main classes of N- cholinoceptors: the muscle, ganglionic, and CNS classes. MUSCARINIC NICOTINIC M1 M5 NM NN M2 M3 M4 Ganglions Carotid sinus Skeletal muscles Adrenal glands CNS Eye Heart Smooth muscles Exocrine glands CNS

Muscarinic receptors High affinity to muscarine M1 – gastric parietal cells, saliva, CNS M2 - cardiac cells, smooth muscle, CNS M3 - bladder, exocrine glands, smooth muscle, eye, CNS M1&M3 – Gq M2 - Gi Amanita muscaria

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

Mechanisms of impulse transmission Muscarinic receptors belong to G-protein coupled receptors. Transmission of impulses through M1, M3, M5 cholinoceptors is realized by phospholipase C, inositol triphosphate and diacylglycerol Stimulation of M2 and M4 cholinoceptors results in inhibition of adenylate cyclase and decrease in intracellular cAMP. N- cholinoceptors are ion channel coupled. Their stimulation results in opening of Na+ channels that causes depolarization.

Muscarinic receptors M1 M3

M-cholinoceptors Cholinoceptors Localization Effects of stimulation M2 Heart Smooth muscle Bradycardia, decrease in conduction, decrease in force of atrial contraction Relaxation M3 Smooth muscles Increase in tone, increase in peristalsis, decrease in sphincter tone and removal of content, bronchoconstriction M1-M3 Exocrine glands Secretion Eye miosis spasm of accommodation decrease in intraocular tension M1-M5 CNS Stimulation

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

Cholinomimetics 1. Muscarinic agonists (M-cholinomimetics) Pilocarpine I. Direct acting 1. Muscarinic agonists (M-cholinomimetics) 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

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)

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)

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

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

Direct acting cholinergic agonists ACETYLCHOLINE

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

Direct acting cholinergic agonists ACETYLCHOLINE 3. Other actions 4. Clinical use very rare: eye drops to obtain miosis

Direct acting cholinergic agonists Stimulation of atonic bladder Nonobstructive urinary retention Neurogenic atony Megacolon Ophthalmology

Direct acting cholinergic agonists PILOCARPINE Tertiary nitrogen Good adsorbtion Penetrate BBB

Direct acting cholinergic agonists PILOCARPINE Secretagoge (sweat, tears, saliva) Jaborandi - what causes slobbering Sjögren’s syndrome Dry mouth, lack tears Glaucoma Jaborandi (Pilocarpus pennatifolius)

Direct acting cholinergic agonists PILOCARPINE

Atropine Mushroom poisoning Miosis Hyper salivation Excessive sweating, lacrimation Cold, wet skin Bradycardia Polyuria Diarrhea Convulsions Atropine

Indirect acting cholinergic agonists Reversible Irreversible Edrophonium Neostigmine Physostigmine Rivastigmine Galantamine Echothiophate Organophosphates Arminum

Mechanism of action

Reversible Tertiary nitrogen Good adsorbtion Penetrate BBB Physostigmine Tertiary nitrogen Good adsorbtion Penetrate BBB Calabar Bean

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

Reversible Quatenary nitrogen Poor adsorbtion Not penetrate BBB Neostigmine Quatenary nitrogen Poor adsorbtion Not penetrate BBB

Reversible Neostigmine Indications Side effects Paralyzes Salivation Myastenia gravis Antidote of neuro-muscular blocker TUBOCURARINE Salivation Flushing Decreased BP Abdominal pain Diarrhea Bronchospasm

Reversible Neostigmine Bronchial asthma Intestinal inflammation, obstruction Bladder obstruction Peritonitis

Reversible Quatenary nitrogen Poor adsorbtion Not penetrate BBB Edrophonium Quatenary nitrogen Poor adsorbtion Not penetrate BBB Fast elimination Duration 10-20 min

Reversible Edrophonium Diagnosis of myasthenia gravis Antidote of neuro-muscular blocker

Reversible Tertiary nitrogen Good adsorbtion Penetrate BBB Rivastigmine Tertiary nitrogen Good adsorbtion Penetrate BBB

Reversible Rivastigmine Alzheimer disease

Irreversible Echothiophate Glaucoma

Toxicology Organophosphates

SLUDGEM Toxicology Salivation Lacrimation Urination Defecation Gastrointestinal motility Emesis Miosis SLUDGEM

Toxicology Reactivation of acetylcholinesterase PRALIDOXIME Not enter BBB M-cholinoblocker ATROPINE Antimuscarinic only Anticonvulsant DIAZEPAM

CHOLINERGIC BLOCKERS

Classification of cholinoblockers I. M-cholinoblockers (Muscarinic antagonists) Natural agents Atropine Hyoscine /Scopolamine/ Plathyphylline Semisynthetic and synthetic Homatropine Propantheline Methacinum Ipratropium bromide /Atrovent/ Cyclopentolate Pirenzepine

Classification of N-cholinoblockers 1. Ganglion blocking drugs Hexamethonium /Benzohexonium/ Hygronium Mecamylamine Pempidine tosilate Trimethaphan 2. Neuromuscular blockers a) Nondepolarizing Atracurium Pancuronium Tubocurarine Vecuronium b) Depolarizing Succinylcholine Dithylinum

Mechanism of action

Parasympatholythics Eye inability to focus for near vision, mydriasis, IOP ↑ Saliva xerostomia Bronchi bronchodilation, secretion ↓ Heart Rate ↑ GIT secretion, peristalsis ↓ sphincter tone ↑ Bladder detrusor ↓ sphincter tone ↑

Clinical uses of M-cholinoblockers A-V block – Atropine Colic, abdominal cramps – Atropine, Plathyphylline Urinary frequency - Oxybutinin Preanesthetic medication – Atropine, Hyoscine Peptic ulcer – Pirenzepine (selective M1 cholinoblocker) Bronchial asthma - Ipratropium bromide

Clinical uses of M-cholinoblockers Therapeutic uses in ophthalmology: in iritis, keratitis and other inflammatory diseases and trauma of eye - Atropine Diagnostics in ophthalmology – Atropine, Homatropine, Cyclopentolate Prevention of motion sickness - Hyoscine Muscarinic poisoning – Atropine Organophosphate poisoning - Atropine

Pharmakokinetics Tertiary nitrogen Good adsorbtion Penetrate BBB ATROPINE Tertiary nitrogen Good adsorbtion Penetrate BBB Atropa belladonna

Dose-dependent effects of atropine Main effects ATROPINE Smooth muscle relaxation Antisecretory Dose-dependent effects of atropine

Therapeutic uses ATROPINE Ophtalmological tests Spasmolythic (as an antispasmodic agent to relax the GIT and bladder) Antisecretory (during dental operations, tuberculosis, to block secretions in the upper and lower respiratory tracts prior to surgery) Mushroom poisoning Organophosphates poisoning Heart block, bradycardia Resuscitation (asystole)

Adverse effects ATROPINE

Contraindications ATROPINE Narrow-angle glaucoma Pyloricstenosis Prostatichypertrophy Drivers

Belladonna poisoning Dry mouth, difficulties in swallowing and talking Dilated pupil, photophobia, blurred vision Dry, flushed and hot skin Difficulties in micturation Constipation Hypotension, weak and rapid pulse Excitement, psychotic behavior,delirium, hallucination ANTICHOLINESTERASE DRUGS ARE ANTIDOTES

Pharmakokinetics Tertiary nitrogen Good adsorbtion Penetrate BBB SCOPOLAMINE Tertiary nitrogen Good adsorbtion Penetrate BBB Solanaceae family

Therapeutic uses SCOPOLAMINE

Therapeutic uses TROPICAMIDE Eye examination

Therapeutic uses IPRATROPIUM Bronchial asthma COPD

Therapeutic uses TRIHEXYPHENIDYL Parkinson’s disease

Nicotine Dose-dependent effect

Ganglion blocking drugs Hexamithonium Hygronium Mecamylamine Trimethaphan Interfere with postsynaptic transmission of Ach Block action of Ach on nicotinic receptors Used rarely severe adverse effects: Orthostatic (postural) hypotension, tachycardia, dry-mouth, GIT atony, urine retention, digestive problems, sexual dysfunction: failure of erection and ejaculation

Nondepolarizing (competitive) Neuromuscular Blocking Drugs Depolarizing (non-competitive) Nondepolarizing (competitive) Atracurium Pancuronium Tubocurarine Succinylcholine Dithylinum

Tubocurarine

Clinical uses of nondepolarizing myorelaxants In surgery General anesthesia to produce paralysis, to permit intubation of the trachea, To optimize the surgical field by inhibiting spontaneous ventilation, and causing relaxation of skeletal muscles. Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm), mechanical ventilation should be available to maintain adequate respiration.

Side effects of nondepolarizing myorelaxants Stimulation of histamine release, Hypotension, Flushing, Tachycardia Arrest of breathing. Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm), mechanical ventilation should be available to maintain adequate respiration.

Succinylcholine

Succinylcholine It has a rapid onset (30 seconds) but very short duration of action (5–10 minutes) because of hydrolysis by various cholinesterases (such as butyrylcholinesterase in the blood). Used in short lasting surgical invasions It cause side effects: fasciculations (a sudden twitch just before paralysis occurs). post-operative pain

TOXICITY RESPIRATORY PARALYSIS - neuromuscular blockers induce a respiratory paralysis. If mechanical ventilation is not provided, the patient will asphyxiate. 2. MALIGNANT HYPERTHERMIA - Malignant hyperthermia susceptibility, an autosomal dominant disorder of skeletal muscle, is one of the main causes of death due to anesthesia. Depolarizing neuromuscular blocking drugs (succinylcholine) can trigger malignant hyperthermia. Malignant hyperthermia is a result of excessive release of Ca2+ from sarcoplasmic reticulum. The clinical features of malignant hyperthermia are hyperthermia, metabolic acidosis, tachycardia, accelerated muscle metabolism and contructures.