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Cholinomimetic drugs (part one) Cholinomimetic drugs are 1 T direct-acting 1 T indirect—acting 1 T inhibitors of acetylcholinesterase 1 F activators of acetylcholinesterase 1 T stimulators of muscarinic (M) and /or nicotinic (N) receptors Direct or indirect-acting (inhibitors of acetylcholinesterase), stimulators of muscarinic and /or nicotinic receptors. Acetylcholine is 1 T an endogenous compound 1 T hydrolyzed by acetylcholinesterase 1 F hydrolyzed to cholin and lactic acid 1 T a neurotransmitter 1 T poorly absorbed from the site of administration An endogenous compound, the neuromediator, which is hydrolyzed by acetylcholinesterase to cholin and acetic acid. It is poorly absorbed from the site of administration. Acetycholine is a neurotransmitter: 1 T at all autonomic ganglia where it is antagonised by ganglio-blocking drugs (hexamethonium) 1 F at postganglionic sympathetic nerves where it is antagonised by alphalytics 1 T the skeletal neuromuscular junctions where it is antagonised by tubocurarine 1 T the CNS 1 F the post-ganglionic parasympathetic nerves where it is antagonised by muscarine Tubocurarine blocks nicotinic receptors in skeletal muscle. Hexamethonium is very selective for ganglia. Muscarine is an agonist at muscarinic receptors in smooth muscle, glands etc. The direct-acting cholinomimetic alkaloid is: 1 T pilocarpine 1 F bethanechol 1 T muscarine 1 T nicotine 1 T lobeline Pilocarpine, muscarine, nicotine, lobeline. Tertiary amines-cholinomimetic alkaloids are as follow: 1 F muscarine 1 T nicotine 1 T lobeline 1 T pilocarpine 1 F atropine Nicotine, lobeline, pilocarpine. The tertiary amines-cholinomimetic alkaloids are 1 T well absorbed from most sites of administration 1 F are not absorbed from the GIT 1 T absorbed even across the skin (nicotine) 1 F are not distributed in CNS 1 T toxic if ingested in larger doses Are well absorbed from most sites after administration including the GIT. Nicotine is sufficiently lipid-soluble to be absorbed across the skin. All are distributed in the CNS. Are toxic if ingested in larger doses. Muscarine is 1 T an alkaloid from Amanita muscaria 1 F an alkaloid from Amanita phalloides 1 T the quaternary amine 1 T less completely absorbed (if compared with nicotine) 1 F not contained in mushrooms An alkaloid from Amanita muscaria (a mushroom). Is a quaternary amine less completely absorbed. Nevertheless, if ingested with the mushroom muscarine can induce poisoning. Poisoning due to Amanita muscaria (muscarine) is treated with 1 F pilocarpine 1 F physostigmine 1 T atropine 1 F vitamin C 1 F nicotine Atropine. Which has the susceptibility to be hydrolyzed by acetylcholineterase? 1 T acetylcholine is very rapidly hydrolyzed by cholinesterase 1 F methacholine is not hydrolyzed by this enzymes 1 F carbachol is hydrolyzed as rapidly as acetylcholine 1 T carbachol and bethanechol are extremely resistant to hydrolysis 1 T hydrolysis of acetylcholine takes 150 microseconds Methacholine is at least three times more resistant to hydrolysis (in comparison to ACH). Is it true? A.To produce systemic effects ... B. Duration of effects of... 2 T A...acetylcholine has to be administered IV in large doses 2 F A...acetylcholine has to be administered parenterally in large doses 2 T A...methacholine can be administered IV and s.c. 1 T B...acetylcholine is extremely short 2 T B.... of bethanechol and carbachol is prolonged A. If administered parenterally (except IV route) acetylcholine induces only local effects. The effects of carbachol and bethanechol have longer duration which corresponds with high resistance to hydrolysis by cholinesterase. Presence of beta-methyl group (methacholine, bethanechol) 2 F reduces the potency at M receptors 2 F increases the potency at N receptors 2 T reduces potency at N receptors 2 F increases the potency at both M and N receptors 2 F reduces the potency at both M and N receptors Reduces the potency of these drugs at the nicotinic receptors. M receptors exist in high amount in: 1 F parasympathetic ganglia 1 F sympathetic ganglia 1 F neuromuscular junctions 1 T the CNS 1 T postganglionic parasympathetic junctions M receptors exist predominantly in the CNS and in postganglionic parasympathetic junctions. Muscarinic effects in the eye are: 1 T miosis 1 T block of accomodation reflex with resulting focusing to near vision 1 F increase in intraoccular pressure 1 F mydriasis 1 T facilitation of the outflow of aqueous humor into the canal of Schlemm Muscarinic agonists instilled into the conjunctival sac cause contraction of the smooth muscle of the iris sphincter (resulting in miosis) and the ciliary muscle (thus casing block of accommodation reflex with resultant focusing to near vision). As a result, the iris is pulled away from the angle of the anterior chamber and trabecular meshwork at the base of the ciliary muscle is opened up. Both effects facilitate the outflow of aqueous humor into the canal of Schlemm which drains the anterior chamber. In this way intraoccular pressure is reduced. Other muscarinic effects are: 1 T decrease in heart rate, contractile strength and conduction 1 T dilation of arteries, decrease in blood pressure 1 F bronchodilation, reduced secretion of bronchial glands 1 F decrease in GIT motility, constipation 1 F reduced secretion of glands (sweat, salivary, lacrimal. nasopharyngeal) Bronchoconstriction, stimulation of bronchial glands. Increase in GIT motility, secretion and relaxation of sphincters- e.g. diarrhea. Stimulation of glandular secretion (sweat, salivary, nasopharyngeal). Muscarinic effects and asthma. Asthma is 1 F treated with cholinomimetics 1 F not influenced 1 T worsened 1 T asthmatic syndrome can be induced 1 T cholinomimetics can be used to provoke asthma (for diagnosis) Asthma can be worsened (or provoked) by muscarinic effects B - Cholinomimetic drugs (part two) Organophosphates are: 1 T parathion, malathion 1 T echothiophate 1 T soman, sarine, tabun 1 T used as insecticides 1 T many of them are quite lipid-soluble and rapidly absorbed by all routes (except echothiophate) All answers are true. Echothiophate is highly polar and more stable than other organophosphates. What is characteristic for organophosphates-cholinesterase interaction? 2 T the 1st step when the drug undergoes initial binding and hydrolysis by the enzyme 2 T the 2nd step resulting in a phosphorylated active site 2 T the covalent phosphorus-enzyme bond is extremely stable 2 T the covalent phosphorus-enzyme bond is hydrolysed at a very slow rate (hundreds of hours) 2 F the phophorylated enzyme complex does not undergo aging Organophosphates undergo 2 step-hydrolysis sequence. The result is a phosphorylated active site of acetylcholinesterase. The phosphorylated enzyme complex does undergo the process called "aging". Aging in action of organophosphates involves: 2 T the breaking of one of the oxygen-phosphorus bonds of the inhibitor 2 F the breaking of the phosphorus-enzyme bond 2 T the strengthening of the phosphorus-enzyme bond 2 T processes which can be reversed by cholinesterase regenerators 2 T process whose rate varies with the particular organophosphate compounds Aging involves breaking of the oxygen-phosphorus bond which results in the strengthening of the phosphorus-enzyme bond. This process varies with the particular organophosphate compounds and cannot be reversed by cholinesterase regenerators. Its rate varies with the particular organophosphate compounds. Acute intoxication by organophosphates is characterised by: 1 T salivation, sweating, 1 T bronchial constriction, hypersecretion 1 T vomiting, diarrhea 1 T tremor, convulsions 1 T disorientation, hallucinations Acute intoxication by organophosphates is characterised by initial signs of muscarinic excess (miosis, salivation, sweating, bronchial constriction, vomiting, diarrhea). Irritation of the CNS usually follows (tremor, convulsions, disorientation) accompanied by peripheral nicotinic effects. Therapy of poisoning with organophosphates involves: 1 T maintenance of vital signs 1 T decontamination to prevent further absorption 1 T atropine parenterally in large doses 1 T administration of pralidoxime especially before aging 1 F administration of physostigmine and/or edrophonium Maintenance of vital signs. Respiration in particular may be impaired. Decontamination may require removal of all clothing and washing of the skin in cases of exposure to dusts or sprays. Atropine is given as often as required to control signs of muscarinic excess. Cholinomimetic drugs (physostigmine, edrophonium) are contraindicated. Toxic effects of nicotine: 1 T are induced by ingestion of nicotine insecticides and of tobacco 1 F are induced very often by smoking (2 cigarettes/day) 1 T involve central stimulant actions 1 T skeletal muscle endplate depolarization 1 F hypotension and bradycardia The fatal dose of nicotine is approximately 40 mg (in two regular cigarettes). This amount may be ingested with insecticides and/or tobacco especially by children. Most of the nicotine in cigarettes is destroyed by burning or escapes via the side-stream smoke. The most dangerous effects are: central nervous stimulant actions which cause convulsions and may progress to coma and respiratory arrest. Skeletal muscle depolarization may lead to depolarization blockade and respiratory paralysis. Hypertension and cardiac arrhythmias can be induced. Parathion and malathion 1 T are prodrugs 1 T are inactive as such 1 T have to be activated in the body 1 F are not converted to phosphate derivatives in animals and plants 1 T are used as insecticides Parathion and malathion are prodrugs which are inactive as such. They must be converted (activated) in the body; activation occurs in animals and plants. Both are used as insecticides. What is characteristic for ACh-acetylcholinesterase interaction? 2 T ACh undergoes a two-step hydrolysis sequence 2 T the 1st step (binding and hydrolysis by the enzyme) 2 T in the 1st step the acetylated enzyme + free choline as formed 2 T in the 2nd step the covalent acetylenzyme bond is split 2 F the acetylenzyme bond is split with addition of ascorbic acid The acetylenzyme bond is split with addition of water. ACh binds to both acetylcholinesterase (present in cholinergic synapsis) and pseudocholinesterase (present in blood). What is characteristic for physostigmine-cholinesterase interaction? 2 T the drug binds to the enzyme 2 T the drug undergoes a two-step hydrolysis sequence 2 T in the 1st step initial binding and hydrolysis by the enzyme occur 2 T in the 2nd step (hydration) the enzyme is regenerated 2 F the 2nd step is very short (150 microsec) This agent (a carbamate) undergoes a two-step hydrolysis sequence analogous to that for ACh. The 1st step results in carbamoylated enzyme (CaE). The covalent bond of CaE is considerably more resistant to the recent (hydration) process and then the 2nd step is correspondingly prolonged (30 min- 6 h). B - Antimuscarinic drugs The group of antimuscarinic drugs comprises: 1 T Atropine, scolopamine 1 T semisynthetic tertiary ammonium analogues 1 T quaternary ammonium agents 1 F adrenaline, noradrenaline 1 F mecamylamine, hexamethonium Adrenaline and noradrenaline are sympathomimetic agents. Atropine and scopolamine are alkaloids, esters of tropic acid. Semisynthetic tertiary ammonium analogues can be produced by esterifying a natural base tropin with different acids. Quaternary ammonium agents are synthetic. In therapeutic doses atropine A.is... B. has... 1 T A.... an antagonist on M receptors 1 F A.... an antagonist on N receptors 1 F A.... a partial agonist on M receptors 1 T B.... the potency to M receptors 1 T B.... no efficacy on M receptors Atropine is an antagonist on M receptors. This compound has the potency to M receptors and no efficacy. Atropine 1 F causes miosis which may last for days 1 F increases secretion of lacrimal and salivary glands 1 T inhibits accommodation- vision to near 1 T is alkaloid from Datura stramonium and Atropa belladonna 1 T causes constipation which involves contraction of sphincters Atropine causes reversible block of muscarinic receptors whenever they are found. Circular muscle of the iris provides major control and is cholinergically innervated. Mydriasis occurs for hours (24-48 h). Because of sphincter contraction atropine is not recommended in cholelitiasis or urinary retention. Secretion of glands is blocked. Scopolamine 1 T is an alkaloid 1 F produces less marked central effects (if compared to atropine) 1 T causes drowsiness and amnesia 1 F does not prevent vestibular disturbances 1 T can be used in patches for transdermal administration Scopolamine occurs in Hyosciamus niger. This drug has more marked central effects producing drowsiness and amnesia in sensitive individuals. Scopolamine prevents or reverses vestibular disturbances (motion sickness). Scopolamine is particularly rapidly and fully distributed in the CNS. The tissues most sensitive to atropine are: 1 T the salivary and sweat glands 1 T the bronchial glands 1 F secretion of acid by the gastric parietal cells 1 F smooth muscle autonomic effectors 1 F the heart The tissues most sensitive to atropine are the salivary, bronchial and sweat glands. Secretion of acid by the gastric parietal cells is much less sensitive. Smooth muscle autonomic effectors and the heart are intermediate in responsiveness. The effects of atropine on the CNS are: 1 T at the first phase mild stimulant 1 T stimulation of the parasympathetic nervous centers 1 T at the second phase long-lasting sedative effects 1 T (in high doses) excitement, hallucinations, coma 1 F not measured in healthy adults At the first phase there is a mild stimulation of the CNS including the parasympathetic medullary centers resulting in bradycardia as the drug´s antimuscarinic effects at the sinoatrial node become manifest. Later long-lasting sedative effects occur. The SA node is sensitive predominantly to 1 T muscarinic receptor blockade 1 F nicotinic receptor blockade 1 T atropine administered IV 1 F oxyphenonium administered orally 1 F propantheline administered orally The atria of the heart are heavily innervated by parasympathetic nerve fibres. Therefore they are sensitive to muscarinic receptor blockade. Cardiac effects after nicotinic receptor blockade include only a moderate tachycardia. Quaternary ammonium agents (oxyphenonium and propantheline) are poorly absorbed so less active. After atropine or ipratropium administration (by inhalation) 1 F bronchoconstriction occurs 1 T bronchodilatation is induced 1 T reduction of bronchial secretion occurs 1 F increase in bronchial secretion is elicited 1 T beneficial effects for asthma treatment are seen Both smooth muscles and secretory glands of the airway receive vagal innervation and contain muscarinic receptors. Especially in patients with airway disease bronchodilatation and reduction of secretion can be measured. Antimuscarinic agents induce effects as follow: 1 F the walls of viscera are contracted 1 T the tone and propulsive movements are diminished 1 F the rate of gastric emptying is increased 1 T intestinal transit is prolonged 1 T intestinal paralysis which is temporary The walls of viscera are relaxed; the tone and propulsive movements are diminished; gastric emptying and intestinal transit are prolonged; intestinal "paralysis" is temporary. Individuals poisoned by atropine manifest: 1 T dry mouth 1 F miosis 1 T tachycardia 1 T hot and flushed skin 1 T agitation and delirium All symptoms are true except miosis. Mydriasis occurs. Body temperature is frequently elevated. Who is extremely sensitive to atropine administration? 1 T patients with glaucoma 1 T patients with urinary retention 1 T children and infants (especially) 1 F teenagers 1 T elderly men In patients with glaucoma, especially with angle-closure glaucoma, antimuscarinic drugs are contraindicated (an acute glaucoma can be induced). These drugs are contraindicated also in patients suffering from urinary retention. Children and infants are very sensitive to the hyperthermic effects of atropine. Deaths have followed doses as small as 2 mg. Glycopyrrolate and oxyphenonium 1 T are quaternary ammonium analogues 1 F have strong effects on the CNS 1 T have ganglion blocking action 1 F are completely absorbed from the GIT 1 T are spasmolytics of smooth muscles of the GIT These drugs produce more peripheral effects, are muscarinic and nicotinic blocking agents. They are poorly absorbed if given orally or locally. Only 10-30% of a dose is absorbed after oral administration, reflecting the decreased lipid solubility of the charged molecule. They are not absorbed from the GIT (because of quaternary ammonium group in their molecules), do not penetrate into the CNS. These drugs inhibit also the nicotinic receptors in the ganglia- this is a reason that not only smooth muscles of the gut walls but also sphincters relax. Complete spasmolysis occurs. In the eye autonomic impulses 1 F contract the radial muscle of the iris through muscarinic receptors 1 F relax the radial muscle through beta receptors 1 T contract the ciliary muscles through cholinoreceptors 1 F cause miosis by a beta receptor mediated contraction of the iris sphincter 1 F cause mydriasis through relaxation of the ciliary muscles Miosis (pupillary constriction) may be caused by contraction of the iris sphincter muscle by muscarinic agonists. Mydriasis (dilatation) may be caused by contraction of the radial dilator muscle by alpha agonists. Ciliary muscle (musarinic) does not affect pupil size but contraction makes the lens spherical to the focus for near vision. In the eye the belladonna alkaloids: 1 T inhibit responses of the ciliary muscle 1 F cause miosis 1 T prevent accommodation 1 F fix the focus for near vision 1 T may cause photophobia These atropinic agents block muscarinic receptors on the ciliary muscle (thus preventing accommodation) and on the iris muscle (thus causing pupillary dilatation- which may lead to photophobia as light can no longer cause reflex constriction of the pupil). Antimuscarinic agents in ophthalmology 1 T can be used for fundus examination 1 F are not used to prevent the formation of synechia in uveitis and iritis 1 T are used as longer lasting preparation 1 T are contraindicated in glaucoma and urinary retention 1 T are used topically as eye drops or in ointment form Antimuscarinic agents are used for fundus examination and prevention of synechia formation in uveitis and iritis. These drugs can be used as longer lasting preparations, topically as eye drops or in ointment form. They are contraindicated in glaucoma and urinary retention. For therapy of iritis and uveitis ( prevention of synechia formation) we can use: 2 F acetylcholine 2 T scopolamine 2 T phenylephrine 2 F tropicamide 2 T atropine Atropine, scopolamine and phenylephrine. Tropicamide is short-term acting. Mydriasis is also potentially hazardous since acute glaucoma may be precipitated in patients with a narrow anterior chamber angle. ACh is not convenient because of extremely short-term miosis. For diagnosis (fundus examination) it is possible to use: 1 F atropine 1 T phenylephrine 1 T tropicamide 1 F scopolamine 1 F pilocarpine We need antimuscarinic or sympathomimetic drugs with short-term action: tropicamide, phenylephrine. Miosis is induced by local administration of: 1 T pilocarpine 1 T carbachol 1 T physostigmine 1 T muscarine 1 T neostigmine All answers are true. Which are ocular effects of antimuscarinic drugs: 1 T mydriasis 1 T paralysis of the ciliary muscle (cycloplegia) 1 T reduction of lacrimal secretion 1 F increase in drainage out of the globe 1 F keeping the balance between fluid input and drainage out of the globe They are mydriasis- dilated pupils, paralysis of the ciliary muscle resulting in loss of the ability to accomodate and reduction of lacrimal secretion. Glaucoma A.is... B. is recognized as 1 T A.... a major cause of blindness in the aging population 1 F A.... not of great pharmacological interest 1 T A.... is characterized by increased intraocular pressure 1 T B.... open-angle 1 T B.... closed-angle (narrow angle) Glaucoma is of great pharmacological interest because its chronic form often responds to drug therapy. Glaucoma is characterized by increased intraocular pressure which is easily measured as a part of routine ophthalmologic examinations. Glaucoma can be deteriorated by many concurrent drugs (antimuscarininc agents, antidepressive drugs and so on). The closed-angle form is A. associated with...B. must be C. treated with... 1 T A...a shallow anterior chamber 1 T A...the dilated iris which can occlude the outflow drainage pathway 1 T A...an acute and painful increase in intraocular pressure 1 T B...controlled on an emergency basis 1 T C...cholinomimetics, osmotic agents and iridectomy All answers are true. Open-angle glaucoma is treated by: 1 T cholinomimetics 1 T alpha agonists 1 T beta blockers 1 T diuretics 1 T anticholinesterases These drugs induce either reduction of aqueous humor secretion or enhance aqueous outflow. Beta blockers are by far the most popular. Their popularity results from convenience (one- or two- daily doses) and relative lack of adverse effects (except in patients with asthma or cardiac pacemaker or conduction pathway disease).
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