1 ANTICHOLINERGIC DRUGS, GAGLION BLOCKING AGENTS AND Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and ToxicologyANTICHOLINERGIC DRUGS,GAGLION BLOCKING AGENTS ANDNEUROMUSCULAR BLOCKING AGENTSAssoc. Prof. I. Lambev
2 ANTICHOLINERGIC DRUGS (Muscarinic Receptor Antagonist,Parasympatholytics,Atropinic Drugs,Cholinolytics)Atropine, the prototype drug of this class,is highly selective blocking agent for pre-and postmuscarinic receptors, but someof its synthetic derivatives have significantnicotinic blocking proparty in addition.
3 Atropine Presynaptic receptors in adrenergic synapse ()Presynaptic receptors in adrenergic synapseand their role in the regulative negative andpositive feedback
8 Action of atropineCNS. Atropine has an overall stimulant action. Its sti-mulant effects are not appreciable at low doses whichproduce peripheral effects because of restricted entryinto the brain. Hyoscine produces central depressanteffects even at low doses.Atropine stimulates many medullar centers –vagal, respiratory and vasоmotor.By blocking the relative cholinergic overactivity in ba-sal ganglia, it suppresses tremor and rigidity in par-kinsonism.High doses cause cortical excitation, rest-lessness, disorientation, hallucinations and deliriumfollowed by respiratory depression and coma.
9 CVS. Atropine causes tachycardia, due to blockade of M2-receptors on SA node through which vagal tonedecreases HR. The tachycardia is more marked inyoung adults than in children and elderly. Atropineabbreviates refractory period of AV conduction, spe-cially if it has been depressed by high vagal tone.Atropine does not influence BP. Itblocks vasodepressor action of cholinergic agonists.Eye. Topical instillation of atropine (0.1%) causesmydriasis, abolition of light reflex and cycloplegia,lasting 7–10 days. This results in photophobia andblurring of near vision. The intraocular tension rises,specially in narrow angle glaucoma, but conventionalsystemic doses produce minor ocular effects.
11 Smooth muscles. All visceral smooth muscles with parasympathetic inervation are relaxed (M3-blokade).Tone and amplitude of GIT are reduced. Spasm maybe reduced, constipation may occur. Peristalsis isonly incompletely suppressed because it is primarilyregulated by local reflexes and other neurotrans-mitter (serotonin, encephalin etc.).Atropine causes bronchodilation and reduced airwayresistance, specially in asthma patients. Inflammatorymediators (histamine, PGs and kinins) increase vagalactivity in addition to their direct action on bronchialmuscle and glands. Atropine attenuates their actionby antagonizing the reflex vagal component.It has a relaxant action of ureter and urinary bladder.Urinary retention can occur in older man with prostatichyperplasia.
12 Glands. Atropine decreases sweat, salivary, tracheo- brochial and lacrimal secretion (M3-blockade). Skinand eyes becomes dry, talking and swallowing my bevery difficult.Atropine decreased less the secretion of acid and pep-sin and more of the mucus in the stomach. It is lesseffective than H2-blockers in reducing acid secretion.Intestinal and pancreatic secretion are not significantlyreduced. Bile and milk secretion is not undercholinergic control, so not affected by atropine.Body temperature. Rise in body temperature occurs athigher doses, is due to both inhibition of sweating aswell as stimulation of temperature regulating centre inthe hypothalamus. Children are highly susceptible.
13 saliva, sweat, bronchial secretion > eye > Local anaesthetic action. Atropine has a mildanaesthetic action on the cornea.The sensitivity of different organs and tissuesto atropine varies and can be graded as(Tripathy, 2003):saliva, sweat, bronchial secretion > eye >bronchial muscles > heart > intestinal andbladder smooth muscles > gastric glandsand gastric smooth muscles
14 Pharmacokinetics Atropine and hyoscine are rapidly absorbed from GIT. Applied to eyes they penetrate cornea.Passage across BBB is somewhat restricted. 50%of atropine is metabolized in liver and excretedunchanged in urine. It has t1/2 3–4 h. Hyoscine ismore completely metabolized and has better BBBpenetration. Some rabbits have a specific atropineesterase which degrade atropine very rapidly.
15 Unwanted effects: Dry mouth, difficulty in swallowing and talking; dry, flushed and hot skin (specially over face andneck); fever; difficulty in micturition; a scarlet rashmay appear; dilated pupils, photophobia, blurring ofnear vision; palpitation; excitement, psychotic behavior,ataxia, delirium, hallucinations; hypotension, week andrapid pulse, cardiovascular collapse with respiratorydepression; convulsion and coma (in very high doses).Diagnosis: 1 mg neostigmine s.c. fails to inducetypical M-effects.Treatment: Gastric lavage with tannic acid (KMnO4 isineffective in oxidation of atropine). The patient mustbe kept in a dark quiet room. Galantamine or physo-stigmine (1-3 mg s.c./i.v.), diazepam against convulsion.
17 They remove tremor and hypersa- livation. Atripine-like side effects! CentralМ-cholinolytics:BiperidenTrihexyphenidylAtropa belladonna L.Indications:Drug induced(e.g. neuroleptics)parkinsonismSpastic paralysisThey remove tremor and hypersa-livation. Atripine-like side effects!
19 Anticholinergics in asthma Ipratropium Tiotropium Primarily sites of bronchodilation action of inhaled β2-adrenergicagonists is mainly bronchiolar smooth muscle. Atropinic drugscause bronchodilation by blocking cholinergic constrictor tone,act primarily in large airways.
21 Main interactions of anticholinergic drugs Absorption of more drugs is slowed because atropinedelays gastric empting. As a result the dose of levo-dopa, needed to control parkinsonism may have tobe increased. But the extent of digoxin and tetracy-clines absorption my be increased.Antacids interfere with absorption of anticholinergics.Antihistaminics, tricyclic antidepressants, pheno-thiazines, pethidine etc. have anticholinergic property:additive side effects with atropinic drugs are possible.MAO inhibitors interfere with metabolism of centralantiparkinsonian drugs (biperiden and others):delirium may occur.
22 Ganglionblockingagents- many side effecs- out of date
23 Skeletal muscle relaxants act peripherally NEUROMUSCULAR BLOCKING AGENTSSkeletal muscle relaxants act peripherallyat neuromuscular junction. According totheir action they divide into follow groups.Nondepolarizing (competitive) agentsor curare like drugsDepolarizing (hyperdepolarazing) agents
26 Competitive (curare like) blocking agents N+… 14 Å … N+ GI resorption BBB
27 Curare is plant extract from Chondrodendron tomentosum,Strychnos toxifera etc. It isused by South America tribalsas arrow poison for gamehunting. The animals got pa-ralyzed even if not killed bythe arrow. Muscle paralyzingactive principles of curareare alkaloids tubocurarine,toxiferine etc.
28 The competitive blockers have affinity for the nicotinic (NM) cholinoceptors at the muscle end-plate, but nointrinsic activity.The NM-receptoris a macroprotein with5 subunits, which arearrange like rosettesurrounding the Na+channel. The two alphasubunits carry two AChbinding sites with nega-tively charged groupswhich combine with thecationic group of AChand open Na+ channel.
29 Competitive (nondepolarizing) block Most of competitive blockers have two or more quarter-nary N+ atoms which provide the necessary attractionto the same site, but the bulk of the antagonist moleculedoes not allow conformational changes in the subunitsneeded for opening the channel. Competitive blockersgenerally have thick bulky molecules and were termedPachycurare by Bovet (1951). ACh esterase releasedfrom motor nerve endings is not able to combine withits NM-receptors to generate end-plate potential (EPP).
31 Depolarizing blockSuccinylcholine (SCh) and decamethonium have affinityas well as submaximal intrinsic activity at theNM-cholinoceptors. They depolarize muscle end-plates by opening Na+ channels (just as ACh does)and initially produce twitching and fascilations. Thesedrugs do not dissociate rapidly from the receptor,induce prolonged partial depolarization of the regionaround muscle end-plate and inactivation of Na+channels.Depolarizing agents also have two quaternary N+atoms but there molecule is long, slender and flexible.They are termed Leptocurare by Bovet (1951).
32 Effects of neuromuscular blocking drugs Depolarizing agents produce dual mechanism neuro-muscular blockade which can be divided in two phases:Phase I block. It is rapid in onset, results from persis-tent depolarization of muscular end-plate and hasfeatures of depolarization blockade.Phase II block. It is slow in onset and results fromdesensitation of the NM-receptor to ACh. It superficiallyresembles block produced by tubocurarine.Effects of neuromuscular blocking drugsSkeletal muscles. Intravenous injection of competitiveblockers rapidly produces muscle weakness, fol-lowed by flaccid paralysis. Small fast response muscles(fingers, extraocular) are affected first. Paralysisspreads to hands, feet, arm, leg, neck, face, trunk,
33 intercostal muscles, diaphragm and respiration stops. Recovery occurs in the reverse sequence:diaphragmatic contractions resume first.Depolarizing agents produce fascilations, lasting fewsecond before inducing flaccid paralysis, but fascila-tions are not prominent in well anaesthezed patients.The action of SCh develops very rapidly. Apnoeaoccurs within 45–90 sec, but lasts only 2–5 min andrecovery is rapid.Autonomic ganglia. Competitive blockers can producesome degree of ganglionic blockade. SCh as an ago-nist of N-receptors may cause ganglionic stimulation.Histamine release with hypotension and broncho-spasm can cause tubocurarine from the mast cells.This does not involve immune system.
34 Pharmacokinetics CVS. Tubocurarine produce significant fall in BP and sometimes – tachycardia (due to vagalganglionic blockade. SCh initially produces bradycar-dia due to activation of vagal ganglia, followed by ta-chycardia and rise in BP, due to stimulation ofsympathetic ganglia.GIT. The ganglion blocking action of competitive agentsmay enhance postoperative paralytic ileus after abdo-minal operations.PharmacokineticsAll neuromuscular blockers are quaternary compounds.They are not absorbed in GIT, not cross placental andBBB. The unchanged drug is excreted in urine and bile.
35 Indications SCh is rapidly hydrolyzed by plasma pseudocholin- esterase to succinylmonocholine and then to succinicacid and choline (action lasts 3-5 min). Some patients(1:3000) have genetically determined abnormality(low affinity for SCh) or deficiency of pseudocholin-esterase. In these patients SCh causes dominantphase II blockade, resulting in muscle paralysis andapnoea, lasting hours. In this case the intubationof patient must be continuous to him full recovery.IndicationsThe most important use of neuromuscular blockers isas adjuvant drugs to general anaesthesia. Surgicalprocedures are performed more safely and rapidly.
36 The competitive neuromuscular blockers are parti- cularly helpful in abdominal and thoracic surgery,intubation and endoscopies, orthopedic procedures.SCh is employed for brief procedures, e.g. endo-tracheal intubation, laryngoscopy, bronchoscopy, eso-phagoscopy, reduction of fractures and dislocations.SCh is most used for avoiding of convulsions andtrauma from electroconvulsive therapy.In sever cases of tetanus and status epilepticus,which are not control by diazepam or other anticon-vulsive drugs, are used competitive neuromuscularblockers.
37 Main drug interactions There is in vitro incompatibility between SChand thiopental (thiopentone).General anaestetics, aminosides (gentamicin etc.) andhypokalemic diuretics potenitate competitive blockers.Anti-ChEs (galantamine, neostigmine) and amino-pyridine (Pymadine®) reverse the action ofcompetitive neuromuscular blockers.SCh potentiates malignant hyperthermia, producedby halothane. SCh has not any antagonists.Calcium channel blockers potentiate both depolarizingand nondepolarizing neuromuscular blockers.Sympathomimetics (adrenaine etc.) reduce competitiveblock by increasing ACh release.