www.company.com autonomic nervous system cholinergic agonists (cholinomimetics) cholinergic...
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Autonomic nervous system
Cholinergic agonists (CHOLINOMIMETICS)
Cholinergic antagonists (CHOLINOBLOCKERS)
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Functional divisions within the
nervous system
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Efferent neurons of the autonomic nervous system
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Sympathetic and parasympathetic actions
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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.
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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.
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Cholinergic transmission
Main NT is Acetylcholine (Ach). Main NT is Acetylcholine (Ach).
A large number of peripheral ANS fibers which A large number of peripheral ANS fibers which synthesize & release Acetylcholine are called synthesize & release Acetylcholine are called CHOLINERGIC fibers. They include:CHOLINERGIC fibers. They include:
• All pre-ganglionic efferent autonomic fibers.All pre-ganglionic efferent autonomic fibers.• Somatic motor fibers to skeletal muscles.Somatic motor fibers to skeletal muscles.• Most parasympathetic post ganglionic fibers.Most parasympathetic post ganglionic fibers.• A few sympathetic post ganglionic fibers– to A few sympathetic post ganglionic fibers– to
sweat glands.sweat glands.
Some parasympathetic post ganglionic fibers utilize Some parasympathetic post ganglionic fibers utilize nitric oxide or peptides for transmission.nitric oxide or peptides for transmission.
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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.
negative feedback
ATP
ATP
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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.
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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
M1M2 M3 M4
M5
EyeHeartSmooth musclesExocrine glandsCNS
NM NN
GanglionsCarotid sinusSkeletal musclesAdrenal glandsCNS
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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
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Nicotinic receptors
• High affinity to nicotine
• NM- neuro-muscular junction
• NN – ganglion, adrenal gland
CNS, carotid sinus
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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.
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Muscarinic receptors
M1
M3
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M-cholinoceptors
Cholinoceptors
Localization Effects of stimulation
M2 Heart
Smooth muscle
Bradycardia, decrease in conduction, decrease in force of atrial contractionRelaxation
M3 Smooth muscles Increase in tone, increase in peristalsis, decrease in sphincter tone and removal of content, bronchoconstriction
M1-M3 Exocrine glands Secretion
Eye a)miosisb)spasm of accommodationc)decrease in intraocular tension
M1-M5 CNS Stimulation
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N-cholinoceptors
Cholinoceptors
Localization Effects of stimulation
NN Autonomic ganglia(parasympathetic and sympathetic)
Increase in parasympathetic and sympathetic reactions
NN Adrenal medulla Increase in adrenaline release, increase in BP
NM Skeletal muscle Increase in tone, contraction
Carotid sinus Reflex respiratory centre stimulation
NN CNS Stimulation
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Cholinomimetics• I. Direct actingI. 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 II. Indirect acting (muscarinic and
nicotinic agonists – nicotinic agonists – anticholinesterase agents)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
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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)
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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)
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Side effects of cholinomimetics
• 1. Bradycardia • 2. Bronchospasm • 3. Intestinal cramps, colic, diarrhea • 4. Hypersalivation • 5. Blurred vision
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Contraindications
• 1. Bradycardia, A-V block • 2. Asthma • 3. Gastric ulcer and 12 duodenal ulcer • 4. Epilepsy (Neostigmine) • 5.Pregnancy (Neostigmine)
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Direct acting cholinergic agonists
ACETYLCHOLINE
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Direct acting cholinergic agonists
1. Decrease in heart rate and cardiac output 2. Decrease in blood pressure
ACETYLCHOLINE
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Direct acting cholinergic agonists
ACETYLCHOLINE
3. Other actions
4. Clinical use very rare: eye drops to obtain miosis
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Direct acting cholinergic agonists
1. Stimulation of atonic bladder2. Nonobstructive urinary retention3. Neurogenic atony4. Megacolon
Ophthalmology
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Direct acting cholinergic agonists
PILOCARPINE
1. Tertiary nitrogen2. Good adsorbtion3. Penetrate BBB
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Direct acting cholinergic agonists
Jaborandi (Pilocarpus pennatifolius)
1. Secretagoge (sweat, tears, saliva)
• Jaborandi - what causes slobbering
2. Sjögren’s syndrome• Dry mouth, lack tears
3. Glaucoma
PILOCARPINE
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Direct acting cholinergic agonistsPILOCARPINE
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Mushroom poisoning
Miosis Hyper salivation Excessive sweating, lacrimation Cold, wet skin Bradycardia Polyuria Diarrhea Convulsions
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Indirect acting cholinergic agonists
Reversible Irreversible
EdrophoniumNeostigmine
PhysostigmineRivastigmineGalantamine
EchothiophateOrganophosphates
Arminum
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Mechanism of action
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Reversible
Physostigmine
Calabar Bean
1. Tertiary nitrogen2. Good adsorbtion3. Penetrate BBB
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Reversible
Physostigmine
1. Atony of intestine2. Atony of bladder3. Glaucoma4. Overdose of ATROPINE, ANTIPSYCOTICS, ANTIDEPRESSANTS
1. Convulsions2. Bradycardia3. Paralysis of skeletal muscle
Indications
Side effects
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Reversible
Neostigmine
1. Quatenary nitrogen2. Poor adsorbtion3. Not penetrate BBB
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Reversible
Neostigmine
1. Paralyzes2. Myastenia gravis3. Antidote of neuro-
muscular blocker TUBOCURARINE
Indications Side effects
1. Salivation2. Flushing3. Decreased BP4. Abdominal pain5. Diarrhea6. Bronchospasm
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Reversible
Neostigmine
1. Bronchial asthma2. Intestinal inflammation,
obstruction3. Bladder obstruction4. Peritonitis
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Reversible
Edrophonium
1. Quatenary nitrogen2. Poor adsorbtion3. Not penetrate BBB 4. Fast elimination5. Duration 10-20 min
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Reversible
Edrophonium
1. Diagnosis of myasthenia gravis2. Antidote of neuro-muscular
blocker
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Reversible
Rivastigmine
1. Tertiary nitrogen2. Good adsorbtion3. Penetrate BBB
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Reversible
Rivastigmine
Alzheimer disease
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Irreversible
Echothiophate
Glaucoma
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Toxicology
Organophosphates
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Toxicology
SalivationLacrimationUrinationDefecationGastrointestinal motility EmesisMiosis
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Toxicology
1.Reactivation of acetylcholinesterase• PRALIDOXIME
Not enter BBB2.M-cholinoblocker
• ATROPINEAntimuscarinic only
3.Anticonvulsant• DIAZEPAM
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CHOLINERGIC BLOCKERS
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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
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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
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Mechanism of action
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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 ↑
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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
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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
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Pharmakokinetics
ATROPINE
1. Tertiary nitrogen2. Good adsorbtion3. Penetrate BBB
Atropa belladonna
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Main effectsATROPINE
• Smooth muscle relaxation• Antisecretory
Dose-dependent effects of atropine
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Therapeutic uses
ATROPINE
1. Ophtalmological tests2. Spasmolythic (as an
antispasmodic agent to relax the GIT and bladder)
3. Antisecretory (during dental operations, tuberculosis, to block secretions in the upper and lower respiratory tracts prior to surgery)
4. Mushroom poisoning5. Organophosphates poisoning6. Heart block, bradycardia7. Resuscitation (asystole)
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Adverse effects
ATROPINE
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Contraindications
ATROPINE
1. Narrow-angle glaucoma2. Pyloricstenosis3. Prostatichypertrophy4. Drivers
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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
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Pharmakokinetics
SCOPOLAMINE
Solanaceae family
1. Tertiary nitrogen2. Good adsorbtion3. Penetrate BBB
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Therapeutic uses
SCOPOLAMINE
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Therapeutic uses
TROPICAMIDE
Eye examination
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Therapeutic uses
IPRATROPIUM
1. Bronchial asthma2. COPD
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Therapeutic uses
TRIHEXYPHENIDYL
Parkinson’s disease
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Nicotine
• Dose-dependent effect
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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
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Neuromuscular Blocking Drugs
Nondepolarizing (competitive)
Depolarizing(non-competitive)
AtracuriumPancuroniumTubocurarine
SuccinylcholineDithylinum
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Tubocurarine
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Clinical uses of nondepolarizingmyorelaxants
• 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.
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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.
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Succinylcholine
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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
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TOXICITY
1. 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.
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