PARASYMPATHETIC NERVOUS SYSTEM Department of Pharmacology Copyright notice The presentation is copyrighted work created by employees of Masaryk university. Students are allowed to make copies for learning purposes only. Any unauthorised reproduction or distribution of the presentation or individual slides is against the law. Cholinergic nervous system - pharmacological interventions cholinotropics cholinomimetics cholinolytics direct indirect NN M indirect direct NN M parasympathomimetics acetylcholine analog. ACHE inhibitors parasympatholytics ganglioplegics muscle relaxants NM gangliomimetics Θ ⊝Θ •Cholinomimetics - ↑ activity at cholinergic synapses –direct – ACh and its analogues – they imitate ACh effects on M and N receptors –indirect - ACHE inhibitors – always non-selective »short-term effect - edrophonium »intermediate and long-term effect - carbamates („stigmins“) »very long effect - organophosphates » •Parasympathomimetics - they imitate ACh effect on M rc. –direct (mostly non-selective effect) –stimulatory agents selective to M receptors for ACh • Terminology: - agents blocking acetylcholine receptors Parasympatholytics - M receptor blockers - without any effect on nicotinic receptors Ganglioplegics - NN-receptor blockers Peripheral muscle relaxants (non-depolarizing) – - NM-receptor blockers Terminology: Cholinolytics - direct: - indirect: e.g. presynaptic inhibition of ACh release acetylcholine (ACh) choline acetyl CoA + choline acetyltransferase (CHAT) Acetylcholine synthesis choline in a lecithin form is a dietary supplement lecithin acts as a precursor to ACh Acetylcholine degradation acetylcholine choline acetate hydrolysis + acetylcholinesterase (ACHE) Cholinotropic agents •- according to the chemical structure we distinguish: •agents with quaternary ammonium cation –quaternary amines, e.g. muscarine – with low GIT absorption (they do not cross BBB) – •tertiary amines, e.g. natural alkaloids – (nicotine, physostigmine) – – – Cholinomimetics - cholinergic agonists - pharmacological effects: •CVS - negative chronotropic effect - heart depression - generalized vasodilation •GIT - increased motility of smooth muscles •respiratory tract - bronchoconstriction ↑ bronchial secretion •eye - miosis, ↓ intraocular pressure • ↑ lacrimation •↑ sweating, ↑ salivation •CNS - tremor, increased locomotion •acetylcholine •rapid biodegradation by ACHE → not used in clinics • 5-20 s effect after i.v. administration •limited absorption after oral / s.c. administration •does not penetrate BBB • •- other choline esters: •carbachol •poor absorption from GIT •agonist of M and N Rc •not hydrolyzed by cholinesterase → long duration of action •I: ophthalmology - miosis •cevimeline •selective M agonist - parasympathomimetic •I: xerostomia (dry mouth) Acetylcholine and its analogues •↑ postganglionic neuronal activity •↑ neuromuscular signal transduction •↑ activity of parasympathetic effectors •↑ sympathetic stimulation of sweat glands - pharmacological effects: l¯ BP, bradycardia, danger of heart arrest lnauzea, cough, dyspnoe lvascular dilation: NO release lsalivation, lacrimation, ↑ mucosal gland secretion lexcessive sweating • Acetylcholine and its analogues •pilocarpine (Pilocarpus) •non-selective M receptor agonist •good absorption from GIT •BBB crossing (→CNS excitation) •stimulates gland secretion •stimulates m. sphincter pupilae (eyedrops) •I: miotic agent used in ophthalmology 2-4%, Sjögren's syndrome • •muscarine (Inocybe, Clitocybe, Amanita muscaria/phalloides) •M receptor agonist, quaternary amine • •arecoline (Areca catechu) •CNS stimulant, tertiary amine •M and N receptor agonist Cholinomimetics - natural alkaloids ACHE inhibitors short-term (REVERSIBLE) long-term (IRREVERSIBLE) competitive enzyme inhibition complex inhibitor + enzyme COVALENT INHIBITION Indirect cholinomimetics medicinal use toxicology •General indications: •glaucoma •GIT atony •urinary retention •antidotes of non-depolarizing muscle relaxants •myasthenia gravis (use quaternary amines) •Alzheimer‘s disease (use tertiary amines) •intoxication with organophosphates •poisoning associated with the central anticholinergic syndrome (atropine) • • Indirect cholinomimetic agents Reversible ACHE inhibitors •Side effects: •miosis •increased glandular secretion •nausea, diarrhea •heart depressants (negative chronotropic effect) •CNS – stimulation followed by depression •neuromuscular junction - fasciculation and twitching (overdose - depolarization blockade) •overdosing = cholinergic crisis – depolarization blockade - muscle paralysis • Indirect cholinomimetic agents Reversible ACHE inhibitors •neostigmine, (edrophonium) •short-term effect •I: diagnosis of myasthenia gravis •„decurarization“, antidotes of competitive muscle relaxants • •pyridostigmine, ambenonium •longer effect than neostigmine, slower onset of action •weaker muscarinic effect - less GIT side effects •I: myasthenia gravis • •distigmine •long-acting reversible ACHE inhibitor •I: myasthenia gravis, atonic the urinary bladder, uterine atony, postoperative GIT atony, paralytic ileus Indirect cholinomimetics Reversible ACHE inhibitors - CNS effects of drugs, that can cross the blood-brain barrier physostigmine I: antidote in acute intoxications with central anticholinergic syndrome galantamine, rivastigmine, donepezil I: dementias of the Alzheimer´s type •galantamine has a positive allosteric effect on ACh binding on N rec. Indirect cholinomimetics Reversible ACHE inhibitors •- effects: nausea, vomitus, sweating, CVS collapse, • breath depression, fasciculation and twitching → muscle paralysis, CNS convulsions •- agents: organophosphates •insecticides (malathion, parathion) •chemical weapons such as nerve gas sarin or VX, soman, tabun •- their antidotes: obidoxime, trimedoxime, pralidoxime • Indirect cholinomimetics Irreversible ACHE inhibitors Therapy of organophosphate itoxication: 1. reduce further neurotoxine absorption 2. mechanical ventilation 3. atropine i.v. in high doses 2 mg every 5 min until a slight overdose (in mass-casualty settings s.c.) 4. ACHE reactivators : obidoxime, (pralidoxime) 5. therapy of muscle convulsions i.v. benzodiazepines 6. high doses of reversible ACHE inhibitors 7. bioscavengers Irreversible ACHE inhibitors Indirect cholinomimetics Parasympatholytics tertiary amines quaternary amines blockade of M receptors blockade of M >N receptors atropine scopolamine tropicamide, cyklopentolate oxybutynine tolterodine, fesoterodine solifenacin, darifenacin procyklidine, biperiden (pirenzepine, telenzepine) (homatropine) butylscopolamine phenpiverine, propiverine otilonium, glycopyrrolate ipratropium, tiotropium aclidinium, umeclidinium trospium (oxyfenonium),(poldin) •General indications: •spasmolytics •bronchodilating agents •antiarrhythmics •mydriatics •premedication prior to GA •antiemetics •antiparkinson agents •antidotes of pilocarpine, ACHEI poisoning (physostigmine) • Parasympatholytics direct antimuscarinic agents •Side effects: •dry mouth (xerostomia) •dry eyes (xerophthalmia) •loss of accommodation (cycloplegia) •heart palpitations •constipation •urinary retention •CNS: seizures, severe dyskinesias, hallucinations, agitated delirium, respiratory depression, coma • Parasympatholytics direct antimuscarinic agents PL with tertiary N •atropine, tropicamide, cyclopentolate, homatropine •mydriasis (stimulation of m. sphincter pupilae) •cycloplegia (paralysis of the ciliary muscle of the eye) •I: for diagnostic and therapeutic mydriasis • •scopolamine (hyoscine) TTS, supp. •I: therapy of kinetosis, CNS depression • •oxybutinine •orally, TTS •pharmacokinetics: high 1st pass effect •I: antispasmodic agent used for overactive urine bladder • •Selective parasympatholytics: • •darinefacin, solifenacin •M3 uroselective antagonists •I: symptomatic therapy of overactive urinary bladder • •(pirenzepine) •gastric M1 receptor selective antagonist •former indication: gastroduodenal ulcers • PL with tertiary N PL with quaternary N (LAMA) * long acting muscarinic antagonists (LAMA) short acting muscarinic antagonists (SAMA) • •1. Centraly acting •2. Peripheral effect on neuromuscular junctions • •nondepolarizing depolarizing •- NM antagonists - NM agonists •- antag. by ACHEI - decamethonium •- tubocurarine - suxamethonium •- mivacurium •- atracurium, cisatracurium •- rocuronium, pipecuronium •- (pancuronium, vecuronium) • •indirect muscle relaxants: dantrolene, botulinum toxin • Skeletal muscle relaxants decamethonium - not registered