*Cholinergic agonists(Cholinomimetics)Study Unit 3.2Compiled by Prof Daan Venter / Adatpted by Dr M Viljoen

*Study sections 3.2 3.3irreversible inhibitorsreversible inhibitorsdirectly acting muscarinic agonistsAntimuscarinic drugs Competitive antagonists on muscarinic receptorsGanglionblockers Competitive antagonists on nicotinic receptors in the ganglia cholinergic agonistsindirectly acting drugs (Cholinesterase inhibitors)direct acting nicotine agonists

*Parasympathetic Nervous Systemsecond messengers and G-proteins

Receptor

Mega-nism

Effector

2nd mes-senger

Result

M1, M3,

Gq-coupled

PLC (

IP3 (DAG (

Ca2+(

M2,

Gi-coupled

AC (

cAMP (

Cardiac K-channels open:( heart rate (,Ca2+-influx (Enzyme activity (

NNNM

Ion-channel

-

-

DepolariseEvoke action potential

*Smooth muscle cellM3GsGiATPsAMPM3AChGqDAGIP3Ca2+ContractionGqPLC-2NAGsGs(+)ACATPcAMP(-)(-)M2GiGiFacilitate contractionFacilitate relaxationInhibit relaxationAChM3M22PIP2PDE5-AMPG: G-protein; PLC: phospholipase C;PIP2: fosfatidielinositol-bifosfaat; DAG: diacylglycerol;AC: adenylyl cyclase; cAMP: cyclic 3,5-adenosine monophosphate;PDE: phosphodiesterase; 5-AMP: inactive AMP

*Blood vesselM3NONOrelaxationAChM3M3NO: nitrogen oxide = direct vasodilator

*Gastro-intestinal sphincterganglionNM1AchrelaxationINNM1

*Drugs that mimic or increase cholinergic actionAChAChAChChAChacetateSenu-eindeMmitochondriaNikMusNAChERAChEMEffector cellnicotinic agonistMuscarinic agonistAcetylcholine esterase blockerNNNNMMMMDrugs that influence electric properties of presynaptic nerve terminals: 4-aminopyridine4-Aminopyridinenicotinic agonists: nicotine, lobeline (Competitive synergism)muscarinic agonists: muscarine, bethanechol (Competitive synergism)Asetylcholine esterase blockers: physostigmine, edrophonium (reversible)Ca2+Ca2+++

*Directly Acting Cholinergic Agonists

*Cholinergic AgonistsAcetic acid- and carbamic acid esters of choline

Nicotine / Varenicline = Nicotine agonists

*directly acting muscarinic agoniststhe effects of all these agonists are exclusively muskarinic the adverse effects of the muscarinic drugs are directly coupled to their Interaction with muscarinic receptors (DUMB2ELS). * Low affinity for AChE

*Effects of Muscarinic AgonistsBradycardia and endothelium dependant vasodilatation (reduced blood pressure due to NO)contraction of visceral smooth muscles (intestine, bladder, trachea, etc.)Constriction of pupil (miosis) and contraction of ciliary muscles (reduce intra-ocular pressure)

*Poisoning by ToadstoolCholinergic agonist - Muscarinic effectseye: miosis (constriction of pupil)cardiovascular: reduction in heart rate and contractionRespiratory system: brongoconstriction and increased secretionsGastrointestinal tract: increased motility, relaxation of the sphinctersUrinary tract: sphincters relax and bladder contactsGlands: increased secretions

Treatment??Nicotine poisoning??

*Clinical Indications M / N Agonists:Betanechol: Rx Urin retention, Atony Post operative (ileus/stomach) Pilocarpine : Rx Glaucoma

Cevimeline : Rx Sjgren Syndrome ?

Nicotine / Varenicline: Rx Smoking cessation

*Cholinergic AgonistsAChE BuChEDegradation by cholinesterase (hydrolysis)Not degradedAChE, BuChE:: mainly responsible for degradationAChE, BuChE: To a lesser degree responsible for degradationAChE BuChE

*Cholinesterase Inhibitors(indirectly acting mimetics)reversible- and irreversible enzyme inhibitors

*Cholinesterase InhibitorsREVERSIBLEedrophonium* Kneostigmine* M pyridostigmine* M physostigmine** M IRREVERSIBLE***Dyflos Ecotiofate parathion malathion

K: short acting; M: medium acting; L: long acting* Quaternary amine (hydrophilic)** tertiary amine (lipophilic)*** highly lipophilic

*Clinical uses: Reversible Cholinesterase InhibitorsNarcosis reversing of non-depolarizing neuromuscular blockers (tubocurarine) after a surgical procedure operationneostigmine: intra-venous, no influence on CNSMyasthenia gravis (Not direct acting M-agonist)edrophonium: diagnoseneostigmine: time of action, 2-4 h pyridostigmine: time of action, 3-6 hPoisoning with muscarinic antagonist (atropine)physostigmine: increases acetylcholine concentration - muscarinic antagonism is surmountable

*Glaucoma reduce intra-ocular pressurephysostigmineUrine retentionneostigmineSupraventricular arrhythmiaedrophoniumAlzheimers diseaseTacrineStrabismus : CholinomimeticsTCA overdosePhysostigmine

Clinical uses Reversible Cholinesterase Inhibitors (cont.)Myasthenia gravis vs Cholinergic crisis???

*Biotransformation of parathion OrganophosphateparathionCytochrome P450Insects, birds mammals

*Trp: tryptophan Glu: glutamate Ser: serinepralidoximePhosphorylation AChEInteraction of Organophosphate with AChEpralidoxime only works if it is administered shortly after poisoning

*Symptoms of Organophosphate PoisoningInteraction with M-receptorsall muscarinic effects (DUMB2ELS)Interaction with N-receptorseffects of NM- and NN-receptors NM-CNS (Lipophilic)Hallucinations, Respiratory suppression

*Treatment of Organophosphate poisoningRespirationAssist breathingRemove contaminated clothingHalts further poisoningReduce action of acetylcholineatropineReactivation of ACh-esterasePralidoxime / obidoxime

*Glaucoma

*GlaucomaAngle-closure glaucoma AcuteAccompanied by pain and sudden increase in pressureNotable hazinessOpen-angle glaucomaChronicPressure increases steadily without accompanying painLoss of eyesight almost unnoticeable

*Longitudinal ciliary smooth muscle is contracted and stretch the trabecular meshworkCiliary sphincter muscle is contracted, relaxing the zonolesZonules relaxedLens more convex (near vision)Sphincter contracted, cause miosisAfter treatment of angle-closure glaucoma with cholinomimetics

*Glaucoma treatment (autonomic)Pilocarpine (muscarinic agonist)Generally employed as eye dropsEcotiophate (anticholinesterase) / PhysiotigmineEye drops.Timolol (-adrenoceptorantagonist)Eye drops.Acetazolamide (carbonic acid anhydrase inhibitor)DiureticApraclonidine (2-adrenoceptoragonist) / Brimonidine Eye dropsAdrenalien/Dipivefrin

5 Betablockers???

*Clinical problemsCholinomimeticsEffects:Marked PSN activity: reduction of blood pressure, brongoconstriction, salivation, miosis, sweat, gastrointestinal discomfort (DUMB2ELS)Contraindicated for patients with:asthmachronic obstructive pulmonary diseasepeptic ulcersobstruction of the urinary tract or gastrointestinal tractWHY ???

*Cholinergic Antagonists (Anticholinergic drugs)Study section 3.3

*Drugs Inhibiting Cholinergic ActionMuscarinic antagonistsGanglion blockersNeuromuscular blockersOther drugs that reduce of inhibit acetylcholine

*Drugs that inhibit cholinergic actionAChAChChAcCoAChATChAChAChAChmitochondriaPir AcCoAPDH+inhibitors of pyrovate dehydrogenize: bromo pyruvateinhibitors of vesikular uptake: vesamicolInhibitors of Acetylcholine release: botulinus toxineGanglionblocker: hexamethonium, trimethaphan (Competitive antagonists)GBMuscarinic antagonists (antimuscarinic drugs: atropine, dicyclomine, scopolamine (competitive antagonists)AMInhibitors of high affinity choline transport: hemicholineBromo pyruvateAntimuscarineGanglionblockerVesamicolNerve endingNMMMNNEffector cellHemicholinebotulinus toxineCa2+Ca2++

*Muscarinic Antagonists

*Main effects of muscarine antagonistsReduce secretions (dry mouth)TachycardiaPupil dilatation and reduced accommodationRelaxation of smooth muscles (intestine, bladder, trachea, etc.)Reduce secretion of gastric juiceCentral nervous system (CNS) effects; anti-emetics, anti-parkinson

*Clinical usesMuscarinic antagonistsCardiovascularatropine: treatment of sinus-bradycardia after myocardial infarctOphtalmicatropine, scopolamine, tropicamide: eye examination, dilate pupilNeurologicalscopolamine: prevent motion sicknessbenztropine, trihexyphenidyl: Parkinsons disease Respiratoryipratropium: no thickening of mucusUrinary tractokxybutynin, flavoxate: nocturia (urinary incontinence), spasm of urinary tract

*Clinical uses (cont.)Muscarinic antagonistsPre-medication for operations not generally in useatropine, scopolamine: to dry up secretionsGastrointestinal tract - relaxation of GI smooth muscles (antispasmodic) and diminishing gastric juice secretionScopolamine buthylbromide: facilitate endoscope and GI radiologydicyclomine: irritable bowl syndromedicyclomine, oxybutynin, methylatropine: antispasmodicPirenzipine (M1-selective) mainly replaced by H2-antagonists and proton pump inhibitors: peptic ulcersPoisoning with toadstool or organophosphateAtropineHyperhydrosis: Glycopyrrolate; Botox ONLY under arms, AlCl2

*Clinical problemsMuscarinic AntagonistsEffects:urine retention, constipation, tachycardia, dry mouth, mydriasis, reduce sweettoxic psychosisContraindicated by patients with:with atony (relaxation) of the intestineurinary retentionprostate hypertrophyelderly personspatients with angle-closure (glaucoma)

*Atropine (Atropa Belladona) Poisoning NB!NB! children NB!NB!Simptome:urine retention, constipation, tachycardia, dry mouth, mydriasis, reduce sweetCNS: psychosis/ irritability / convulsionsRespiratory suppression Treatment:Symptomatic RxPhysostigmine (lipophilic) small doses/slow IV (Dangerous)Physostigmine for TCA overdose can potentiate cardiotoxicityNeostigmine for peripheral effects

*Ganglion Blocking Agents

*Ganglion blockershexamethoniumtrimethaphanMecamylamineblock NN-receptors on ion channels

*Hypertensive crisistrimethaphan: reduces blood pressure in an emergencyDissecting aorta aneurysm

Because of adverse effects these drugs, with exception of trimethaphan, are not in use anymore

Clinical usesGanglion blocking agents

*Drugs reducing action of acetylcholine on N-receptors

*Drugs that reduce the action of AchReduction of Ach release these drugs cause simultaneously muscle relaxation and ganglion-blockadebotulinus toxin: continuous muscle spasms/wrinkles/hyperhydrosis under arms / cerebral palsy

Continual Depolarization in these cases the ganglia is blocked after initial receptor stimulationnicotine: no clinical use as ganglion blockerAcetylcholine (continual inhibition of Ach esterase)

Inhibition is caused by various mechanisms

*Drugs acting on Neuromuscular junctions (Muscle relaxants)Study section 3.4

*Study section 3.4Katzung Chapter 27

*Non-depolarizingMuscle RelaxantsNm Competitive Antagonists

*Non-depolarizing Muscle Relaxantsd-Tubocurarinehypotension (ganglion block plus histamine release vasodilatation)Brongo constiction (histamine release)Alcuroniumeffects as for tubocurarine releases less histaminenshorter acting than tubocurarine

Gallaminetachycardia (potent muscarinic antagonist)does not release histaminePancuroniumAlmost no tachycardia, no hypotension (weak muscarinic antagonist)does not release histamineRokuronium/ VecuroniumAtracurium / Mivacurium

Al these drugs possess a bi-quaternary structure: hydrophilicSkeletal relaxation is reversed with: neostigmine + ??atropine??

*AChAChAChAChTubTubTubTubInteraction of non-depolarizers with NM-receptorsInside of membraneMembraneTubTub

*Drugs with additive actionon the blocking effect of muscle relaxantsAminoglycoside-antibioticsLocal anesthetics QuinidineInhalation anesthetics

*Clinical problemsnon-depolarizing agentsOlder productsBlood pressure and change in heart rateRelease of histamineGanglionic effectsMuscarinic effectsControlled reversion is difficult (some drugs)Newer productsMinimal or no cardiac effectsMinimal or no release of histamineeffect easily reversed

*DepolarizingMuscle RelaxantsNm Agonist

*Depolarizing Muscle RelaxantAch

*Depolarizing Muscle RelaxantsBradycardia direct muskarine actionIncrease intra-ocular pressure - muscarinic effectMaligne hyperthermia - very rare / inheritable / intense muscle cramps / increased temp Treated with Dantrolene)Dexamethonium not used clinically, No esther groups and thus not easily degradedLong acting

Succinylcholine Clinical useduration: 6-8 minScoline-apnee increase in duration to 2-3 hoursGenetic defect on pseudo-cholinesterase / exposure to organophosphate poisoning / neonates or patients with liver diseases. Treatment artificial ventilation

*Skeletal Muscle Neuromuscular junctionNormal conditions: Nerve impulse release adequate ACh to revoke depolarization / action potential in a muscleACh is quickly degraded (200 s)Longer recovery process on end template / refractory periodIf ACh degradation by ChE-inhibitors is reduced then more ACh will bind to different receptorsIt leads to initial contraction then relaxation due to cont. stimulationThis will result in unsynchronized movements and eventually to muscle relaxation / apnea

*Interaction of depolarizers withNM-receptorsSukSukSukSukIntracellularMembraanDepolarization

*Clinical problemsSuccinylcholineHyperkalemia (severe burns)Increased intra-ocular and intragastric pressureAdditional vagal stimulation: salivation; hypotension; bradicardiaMalignant hyperthermia Post operative myalgiaAtropine administered for repeated succinylcholine doses to vagus effects

*Centrally actingmuscle relaxants (Spasmolytics)Diazepam: benzodiazepineBaclofen : GABA agonist: As effective as diazepam causes less sedationTizanidine: 2-agonist like clonidine, much less hypotensive effects. Rx Spastic conditions + Chronic migraine

*Dantrolene hidantoen derivative (like phenytoin) with central acting effects but muscle relaxation is peripheral actionCauses direct blockade of muscle contractions via interference on Ca2+ release in SR Rx malignant hyperthermia due to general anesthetics; succinylcholineBotulinum Toxin - Ach release also in skeletal muscles. Rx Cerebral palsy

Other centrally actingmuscle relaxants (Spasmolytics)

Alfa1= Gq METABOTROPIC = Alfa; beta ; M Physiologist will say it is indirect action as the receptor stim inducesAlfa2/D2=Gi certain conformational changes in receptor via G-coupled protein and 2nd messengersB/D1=Gs INOTROPIC= ligand-gated ion channels. More direct and very quick action to open / close channels

M2 = HART M1/M3 = GIT/Smooth muscle / Sfincters*N+ = quartenary amine (Water soluble)N = tertiary amine (Lipid soluble)Vareniklien (Champix)= partial agonist on N-receptors*Nicotine = InsecticideCevimelien = partial agonist

*Neostigmine = Reversible AchE inhibitor BUT it also has agonistic activity on Nm receptors, that is why it works well for MG Rx

*Drugs that can aggrevate MG / muscle paralysis= Aminoglycosides; Fluoroquinolones; Macrolides; Mg containing products

Pyridostigmien / Physostigmine/ Edrophonium = not available in SA

*Strabismus occurs when the eyes are not aligned properly. One or both of your childs eyes may turn inward (esotropia), outward (exotropia), upward (hypertropia) or downward (hypotropia) . Early diagnosis is essential in preventing vision loss that occurs as a result of amblyopia, also called Lazy eye". Amblyopia from strabismus occurs when vision does not develop normally during childhood because the eyes are not aligned. Treatment of strabismus may include eyeglasses, patching or eye muscle surgery http://www.childrenshospital.org/health-topics/conditions/strabismus-and-amblyopia*How does mushroom poisoning differ from Organophosphate poisoning?

*Acetazolamide (Diuretic) Dorzolamide Oral / drops

Prostaglandins = Latanoprost/Travoprost Drops*OPPOSITE TO DUMBELS

Cycloplegia = paralysis of accommodation of the eye*Safer in adults than in children. Red as beet (flushed skin); Hot as hare (hyperthermia); Dry as bone (no secretions); Mad as a Hatter (CNS hallucinations, delirium) Blind as a Bat ( blurred vision, cycloplegia)

Antichol Drugs = TCA; Antihistamines; Antipsychotics (Phenothiazine)

*