PARASYMPATHETIC NERVOUS SYSTEM Cholinergic drugs elicit their effect: 1)via the parasympathetic synapses of effector organs 2)via synapses of the autonomic nerve ganglia 3) via synapses of neuromuscular junctions 4) via synapses in CNS - influence synapses, where acetylcholine (ACh) acts as their neurotransmitter Výsledek obrázku pro acetylcholin 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), Sjögren’s syndrome 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