Notes for Pharmacology I Practicals This study material is exclusively for teachers of general medicine and dentistry in Pharmacology I course. It contains only basic notes of discussed topics, which should be completed with more details and actual information during practical courses to make a complete material for teaching J. Dept. of Pharmacology, Faculty of Medicine, Masaryk University PARASYMPATHETIC NERVOUS SYSTEM hemicholine ACHE inhibitors https://www.youtube.com/watch?v=dkpohXE06pg 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 - they can influence synapses, where acetylcholin (ACh) acts as their neurotransmitter Výsledek obrázku pro acetylcholin • parasympathomimetics acetylcholine analog. acetylcholine esterase (ACHE) inhibitors parasympatolytics ganglioplegics muscle relaxants NM gangliomimetics 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 https://www.youtube.com/watch?v=k7YX9kuWrxA »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 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 their chemical structure we distinguish: •agents with quaternary ammonium cation - quaternary amines with low GIT absorption (they do not cross BBB), e.g. muscarine • •tertiary amines, e.g. natural alkaloids (nicotine, physostigmine) – – – Strukturní vzorec nikotinu Strukturní vzorec https://upload.wikimedia.org/wikipedia/commons/thumb/2/21/Acetylcholine.svg/208px-Acetylcholine.svg .png acetylcholine muscarine nicotine 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 Choline analogues (M and N receptor agonists) Léčivo Sensitivita k ACHE M Rc N Rc acetylcholine + + + + + + + + + (metacholine) + + + + + + karbachol 0 + + + + + betanechol 0 + + + 0 cevimeline 0 + + + 0 Cholinomimetika acetylcholine •- effects: ¯ BP, bradycardia, heart arrest –vasodilation: NO release (indirect effect) –nausea, coughing, dyspnoe, ↑GIT motility –miosis, sweating, salivation, lacrimation, mucosal glands secretion Choline analogues (M / N receptor agonists) Léčivo Sensitivita k ACHE M Rc N Rc acetylcholine + + + + + + + + + metacholine * + + + + + + carbachol 0 + + + + + bethanechol ♦ 0 + + + 0 Cholinomimetics * metacholine - cholinergic agonist - not used in Czech rep. ♦ bethanechol, cevimeline - parasympathomimetics •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 •↑ adrenaline and noradrenaline (NA) release from adrenal glands •↑ 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 1280px-Pilocarpine_Structural_Formulae Výsledek obrázku Jaborandi (Pilocarpus jaborandi) Mother tincture 125ml pilocarpine •non-selective M receptor agonist I: glaucoma, xerostomia, Sjögrenův sy •2% or 4% eyedrops HVLP combined with timolol •KI: asthma bronchiale, COPD sinus bradycardia, heart failure Cholinomimetics - natural alkaloids • arecoline from Areca catechu L. Cholinomimetics - natural alkaloids Antiglaucoma agents - miotics •pilocarpine •carbachol •physostigmine • • •atropine •scopolamine • ACHE inhibitors short-term (REVERSIBLE long-term (IRREVERSIBLE) competitive enzyme inhibition complex inhibitor + enzyme COVALENT INHIBITION Indirect cholinomimetics medicinal use toxicology ACHE inhibitors • increase ACh concentration at its synapses and postganglionic receptors • different duration and reversibility of their effect • • A) reversible/short or intermediate effect - therapy B) irreversible inactivation/long acting - toxicology Indirect cholinomimetic agents Image37 Image39 Image41 Image38 Image40 Indirect cholinomimetics Acetylcholinesterase binding •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 • •neuromuscular junction - longer and stronger effect of ACh NT – → stronger muscle contraction, fasciculations video •fasciculations - adverse effects of ACHEI •physostigmine - https://www.youtube.com/watch?v=YYMZFvJEO6I –at high doses – tremor, muscle paralysis –Ondra: •edrophonium in dog (diagnosis of myasthenia gravis) •https://www.youtube.com/watch?v=k7YX9kuWrxA •Google Tensilon test (human) – 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 receptors Indirect cholinomimetics Reversible ACHE inhibitors •physostigmine - alkaloid from Physostigma venenosum •- CNS effect, specific therapeutic programe •antidote in case of overdose • with parasympatholytics •antidote for central • anticholinergic poisoning •miotic - antiglaucoma agent • •https://www.youtube.com/watch?v=YYMZFvJEO6I https://upload.wikimedia.org/wikipedia/commons/5/5a/Physostigmine_Structural_Formulae.png alternativní popis obrázku chybí Indirect cholinomimetics Reversible ACHE inhibitors ). •effects: nausea, vomitus, sweating, CVS collapse, breath depression, fasciculation and twitching →muscle paralysis, CNS convulsions •insecticides (malathion, parathion • chemical weapons such as nerve gas sarin or VX, soman, tabun •antidotes: obidoxime, trimedoxime, pralidoxime • Indirect cholinomimetics Irreversible ACHE inhibitors Oxidační desulfurace malathionu Intoxication symptoms: miosis, dyspnoe, bronchospasm, vomiting, sweating, salivation, lacrimation, diarrhea, neuromuscular paralysis CNS: convulsions → coma, late neurological toxicity (demyelinization, polyneuritis, vision impairment) Irreversible ACHE inhibitors Indirect cholinomimetics 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 solifenacin, darifenacin procyclidine, biperiden (pirenzepine, telenzepine) (homatropine) butylscopolamine phenpiverine, propiverine otilonium, glycopyrrolate ipratropium, tiotropium aclidinium, umeclidinium trospium (oxyphenonium),(poldin) • • • • Tertiary amines •homatropine, tropicamide, oxybutynine, cyclopentolate, darifenacin, tolterodine, biperiden •CNS effects (antihistamines, neuroleptics, antidepressants) •used in ophthalmology • • • Quaternary amines •ipratropium, tiotropium, butylscopolamine, trospium, otilonium •more peripheral effects and less CNS effects Antimuscarinic semisynthetic and synthetic derivatives tropic acid base •- effects of reversible M receptors antagonists: •glandular secretion •CVS •eye •GIT •bronchi •CNS • Parasympatholytics direct antimuscarinic agents •- clinical use: •spasmolytics •bronchodilators •antiarrhythmics •mydriatics •premedication prior to GA •antiemetics •antiparkinsonics •antidotes for pilocarpine •antidotes for 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 • alkaloids from Solanaceae family (Solanum nigrum) (Datura stramonium) •Selective parasympatholytics: • •darinefacin, solifenacin •M3 selective antagonists •symptomatic therapy of overactive urinary bladder • •(pirenzepine) •gastric M1 Rc 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) Anticholinergic effects of other drugs •Antidepressants (amitriptyline) •Antipsychotics (chlorpromazine) •Antiemetics (thiethylperazine) •Antiparkinson agents (procyclidine, biperiden) •Antihistaminics (cyproheptadine, orphenadrine) •Central muscle relaxant • orphenadrine inj. anticholinergic, muscle relaxant with antihistamine effects I: vertebrogenic pain syndrome, neurosurgery (CNS effects) • •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