2ContentsPart 2: Cholinergics & anticholinesterases12. Cholinergic Antagonists (Muscarinic receptor) (2 slides)12.1. Atropine12.2. Hyoscine (scopolamine)12.3. Comparison of atropine with acetylcholine12.4. Analogues of atropine12.5. Simplified Analogues (2 slides)12.6. SAR for Antagonists (3 slides)12.7. Binding Site for Antagonists (2 slides)13. Cholinergic Antagonists (Nicotinic receptor)13.1. Curare (2 slides)13.2. Binding13.3. Analogues of tubocurarine (5 slides)[22 slides]
312. Cholinergic Antagonists (Muscarinic receptor) Drugs which bind to cholinergic receptor but do not activate itPrevent acetylcholine from bindingOpposite clinical effect to agonists - lower activity ofacetylcholinePostsynapticnerveAchAchPostsynapticnerveAntagonist
412. Cholinergic Antagonists (Muscarinic receptor) Clinical EffectsDecrease of saliva and gastric secretionsRelaxation of smooth muscleDecrease in motility of GIT and urinary tractDilation of pupilsUsesShutting down digestion for surgeryOphthalmic examinationsRelief of peptic ulcersTreatment of Parkinson’s DiseaseAnticholinesterase poisoningMotion sickness
6Cycloplegia mydriasis Cycloplegia is the paralysis of the ciliary muscle, resulting in a loss of accommodation.Cycloplegic drugs, including atropine, cyclopentolate, succinylcholine, homatropine, scopolamine and tropicamide, are indicated for use in cycloplegic refractions and the treatment of uveitis. Other cycloplegic drugs include Neostigmine, Phentolamine and PilocarpinemydriasisMydriasisClassifications and external resourcesAn abnormally dilated pupil.Mydriasis is an excessive dilation of the pupil due to disease or drugs. Although the pupil will normally dilate in the dark, it is usually quite constricted in the light. A mydriatic pupil will remain excessively large, even in a bright environment.Constriction of the pupil is called miosis
712. Cholinergic Antagonists (Muscarinic receptor) 12.1 Atropineeasily racemisedRacemic form of hyoscyamineSource - roots of belladonna (1831) (deadly nightshade)Used as a poisonUsed as a medicine decreases GIT motility antidote for anticholinesterase poisoning dilation of eye pupilsCNS side effects - hallucinations
812. Cholinergic Antagonists (Muscarinic receptor) 12.2 Hyoscine (scopolamine)Source - thorn appleMedical use - treatment of motion sicknessUsed as a truth drug (CNS effects)
912. Cholinergic Antagonists (Muscarinic receptor) 12.3 Comparison of atropine with acetylcholineRelative positions of ester and nitrogen similar in both moleculesNitrogen in atropine is ionisedAmine and ester are important binding groups (ionic + H-bonds)Aromatic ring of atropine is an extra binding group (vdW)Atropine binds with a different induced fit - no activationAtropine binds more strongly than acetylcholine
1012. Cholinergic Antagonists (Muscarinic receptor) 12.4 Analogues of atropineIpratropium(bronchodilator & anti-asthmatic)Atropine methonitrate(lowers GIT motility)Analogues are fully ionisedAnalogues unable to cross the blood brain barrierNo CNS side effects
11The combination preparation ipratropium/salbutamol is a formulation containing ipratropium bromide and salbutamol sulfate (albuterol sulfate) used in the management of chronic obstructive pulmonary disease (COPD) and asthma. It is marketed by Boehringer Ingelheim as metered dose inhaler (MDI) and nebuliser preparations under the trade name Combivent.Medications commonly used in asthma and COPD (primarily R03) editAnticholinergics: Ipratropium, TiotropiumShort acting β2-agonists: Salbutamol, TerbutalineLong acting β2-agonists (LABA): Bambuterol, Clenbuterol, Fenoterol, Formoterol, SalmeterolCorticosteroids: Beclometasone, Budesonide, Ciclesonide, FluticasoneLeukotriene antagonists: Montelukast, Pranlukast, ZafirlukastXanthines: Aminophylline, Theobromine, TheophyllineMast cell stabilizers: Cromoglicate, NedocromilCombination products: Budesonide/formoterol, Fluticasone/salmeterol, Ipratropium/salbutamolDiphenoxylate is an opioid agonist used for the treatment of diarrhea that acts by slowing intestinal contractions. It was discovered at Janssen Pharmaceutica in It is a congener to the narcotic Meperidine of which the common brand name is Demerol. This being the case, this medication is potentially habit-forming, particularly in high doses or when long-time usage is involved. Because of this, diphenoxylate is manufactured and marketed as a combination drug with atropine (Lomotil®).This pharmaceutical strategy is designed to discourage abuse, because the anticholinergic effect of atropine will produce severe weakness and nausea if standard dosage is exceeded.This medication is classified as a Schedule V under the Controlled Substances Act by the Food and Drug Administration (FDA) and the DEA in the United States when used in preparations. When diphenoxylate is used alone, it is classified as a Schedule II.
1412. Cholinergic Antagonists (Muscarinic receptor) 12.6 SAR for AntagonistsR' = Aromatic orHeteroaromaticImportant featuresTertiary amine (ionised) or a quaternary nitrogenAromatic ringEsterN-Alkyl groups (R) can be larger than methyl (unlike agonists)Large branched acyl groupR’ = aromatic or heteroaromatic ringBranching of aromatic/heteroaromatic rings is important
1512. Cholinergic Antagonists (Muscarinic receptor) 12.6 SAR for AntagonistsInactiveActive
1612. Cholinergic Antagonists (Muscarinic receptor) 12.6 SAR for Antagonists vs. AgonistsSAR for AntagonistsSAR for AgonistsQuaternary nitrogenAromatic ringEsterN-Alkyl groups = methylR’ = HTertiary amine (ionised)or quaternary nitrogenAromatic ringEsterN-Alkyl groups (R) can belarger than methylR’ = aromatic or heteroaromaticBranching of Ar rings important
1712. Cholinergic Antagonists (Muscarinic receptor) 12.7 Binding Site for AntagonistsRECEPTOR SURFACEAcetylcholinebinding sitevan der Waalsbinding regionsfor antagonists
1812. Cholinergic Antagonists (Muscarinic receptor) 12.7 Binding Site for Antagonists
1913. Cholinergic Antagonists (Nicotinic receptor) 13.1 CurareExtract from ourari plantUsed for poison arrowsCauses paralysis (blocks acetylcholine signals to muscles)Active principle = tubocurarineTubocurarine
20Tubocurarine chloride is a competitive antagonist of nicotinic neuromuscular acetylcholine receptors, used to paralyse patients undergoing anaesthesia. It is one of the chemicals that can be obtained from curare, itself an extract of Chondodendron tomentosum, a plant found in South American jungles which is used as a source of arrow poison. Native indians hunting animals with this poison were able to eat the animal's contaminated flesh without being affected by the toxin because tubocurarine cannot easily cross mucous membranes and is thus inactive orally.The correct chemical structure was only elucidated circa 1970, even though the plant had been known since the Spanish Conquest.The word curare comes from the South American Indian name for the arrow poison: "ourare". Presumably the initial syllable was pronounced with a heavy glottal stroke. Tubocurarine is so called because the plant samples containing it were first shipped to Europe in tubes.Today, tubocurarine has fallen into disuse in western medicine, as safer synthetic alternatives such as atracurium are available. However, tubocurarine is still used in the United States and elsewhere as part of the lethal injection procedure.
2113. Cholinergic Antagonists (Nicotinic receptor) PharmacophoreTwo quaternary centres at specific separation (1.15nm)Different mechanism of action from atropine based antagonistsDifferent binding interactionsClinical usesNeuromuscular blocker for surgical operationsPermits lower and safer levels of general anaestheticTubocurarine used as neuromuscular blocker but side effects
2213. Cholinergic Antagonists (Nicotinic receptor) 13.2 BindingSb) Interaction with tubocurarineprotein complex(5 subunits)diameter=8nm8nma) Receptor dimer9-10nmTubocurarineAcetylcholine binding site
2313. Cholinergic Antagonists (Nicotinic receptor) 13.3 Analogues of tubocurarineSuxamethoniumDecamethoniumLong lastingLong recovery timesSide effects on heartEsters incorporatedShorter lifetime (5 min)Fast onset and short durationSide effects at autonomic ganglia
24Suxamethonium chloride From Wikipedia, the free encyclopedia(Redirected from Succinylcholine)Routes IntravenousSuxamethonium chloride (also known as succinylcholine, scoline, or SUX) is a white crystalline substance, it is odourless and highly soluble in water. The compound consists of two acetylcholine molecules that are linked by their acetyl groups. Suxamethonium is sold under several trademark names such as Anectine®, and may be referred to as "sux" for short.Suxamethonium acts as a depolarizing muscle relaxant. It imitates the action of acetylcholine at the neuromuscular junction, but it is not degraded by acetylcholinesterase but by pseudocholinesterase, a plasma cholinesterase. This hydrolysis by pseudocholinesterase is much slower than that of acetylcholine by acetylcholinesterase.lcholinesterase.There are two phases to the blocking effect of suxamethonium. The first is due to the prolonged stimulation of the acetylcholine receptor results first in disorganized muscle contractions (fasciculations, considered to be a side effect as mentioned below), as the acetylcholine receptors are stimulated. On stimulation, the acetylcholine receptor becomes a general ion channel, so there is a high flux of potassium out of the cell, and of sodium into the cell, resulting in an endplate potential less than the action potential. So, after the initial firing, the cell remains refractory.i
25Suxamethonium chloride On continued stimulation, the acetylcholine receptors become desensitised and close. This means that new acetylcholine signals do not cause an action potential; and the continued binding of suxamethonium is ignored. This is the principal anaesthetic effect of suxamethonium, and wears off as the suxamethonium is degraded, and the acetylcholine receptors return to their normal configuration. The side effect of hyperkalaemia is because the acetylcholine receptor is propped open, allowing continued flow of potassium ions into the extracellular fluid. A typical increase of potassium ion serum concentration on administration of suxamethonium is 0.5 mmol per litre, whereas the normal range of potassium is 3.5 to 5 mmol per litre: a significant increase which results in the other side-effects of ventricular fibrillation due to reduced to action potential initiation in the heart.Its medical uses are limited to short-term muscle relaxation in anesthesia and intensive care, usually for facilitation of endotracheal intubation. Despite its many undesired effects on the circulatory system and skeletal muscles (including malignant hyperthermia, a rare but life-threatening disease), it is perennially popular in emergency medicine because it arguably has the fastest onset and shortest duration of action of all muscle relaxants. Both are major points of consideration in the context of trauma care, where paralysis must be induced very quickly and the use of a longer-acting agent might mask the presence of a neurological deficit.A single intravenous dose of 1.0 to 1.5 milligrams per kilogram of body weight for adults or 2.0 milligrams per kilogram for pediatrics will cause flaccid paralysis within a minute of injection. For intramuscular injection higher doses are used and the effects last somewhat longer. Suxamethonium is quickly degraded by plasma cholinesterase and the duration of effect is usually in the range of a few minutes. When plasma levels of cholinesterase are greatly diminished or an atypical form of cholinesterase is present (an otherwise harmless inherited disorder), paralysis may last much longer.
2613. Cholinergic Antagonists (Nicotinic receptor) 13.3 Analogues of tubocurarinePancuronium (R=Me)Vecuronium (R=H)Steroid acts as a spacer for the quaternary centres (1.09nm)Acyl groups are added to introduce the Ach skeletonFaster onset then tubocurarine but slower than suxamethoniumLonger duration of action than suxamethonium (45 min)No effect on blood pressure and fewer side effects
2713. Cholinergic Antagonists (Nicotinic receptor) 13.3 Analogues of tubocurarineAtracuriumDesign based on tubocurarine and suxamethoniumLacks cardiac side effectsRapidly broken down in blood both chemically and metabolicallyAvoids patient variation in metabolic enzymesLifetime is 30 minutesAdministered as an i.v. dripSelf destruct system limits lifetime
28Atracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarising neuromuscular blocking agents, used adjunctively in anaesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.Side effects owing to histamine liberation are rash, reflex increase in heart rate, low blood pressure and bronchospasm.It is a bisbenzyltetrahydroisoquinolinium mixture of 10 Stereoisomers. Atracurium was first synthesized, in 1974 by George H. Dewar, in John B. Stenlake's medicinal chemistry research group at Strathclyde University, Scotland. It is the first non-depolarising non-steroidal skeletal muscle relaxant rationally designed to undergo chemodegradation in vivo. Atracurium was licensed to Burroughs Wellcome Co., which developed atracurium and eventually marketed it (as a mixture of all ten stereoisomers)under the name Tracrium. Atracurium's rate of degradation in vivo is influenced by pH and temperature.Atracurium was succeeded by cisatracurium, which is the R-cis R-cis isomer constituent of atracurium. The pharamcodynamic and adverse effect profile of cisatracurium proved to be superior to that of atracurium. Cisatracurium was made available worldwide as Nimbex, with its clinical development solely undertaken by Burroughs Wellcome Co.Atracurium is classified as an intermediate-acting neuromuscular blocking agent.
29Atracurium Pharmacokinetic data Bioavailability 100% (IV) Protein binding 82%Metabolism Hoffman elimination (retro-Michael addition) and ester hydrolysisHalf life minutesExcretion ?Routes IVAtracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarising neuromuscular blocking agents, used adjunctively in anaesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.Side effects owing to histamine liberation are rash, reflex increase in heart rate, low blood pressure and bronchospasm.It is a bisbenzyltetrahydroisoquinolinium mixture of 10 Stereoisomers. Atracurium was first synthesized, in 1974 by George H. Dewar, in John B. Stenlake's medicinal chemistry research group at Strathclyde University, Scotland. It is the first non-depolarising non-steroidal skeletal muscle relaxant rationally designed to undergo chemodegradation in vivo. Atracurium was licensed to Burroughs Wellcome Co., which developed atracurium and eventually marketed it (as a mixture of all ten stereoisomers)under the name Tracrium. Atracurium's rate of degradation in vivo is influenced by pH and temperature.Atracurium was succeeded by cisatracurium, which is the R-cis R-cis isomer constituent of atracurium. The pharamcodynamic and adverse effect profile of cisatracurium proved to be superior to that of atracurium. Cisatracurium was made available worldwide as Nimbex, with its clinical development solely undertaken by Burroughs Wellcome Co.Atracurium is classified as an intermediate-acting neuromuscular blocking age
3013. Cholinergic Antagonists (Nicotinic receptor) 13.3 Analogues of tubocurarineINACTIVEACTIVEAtracurium stable at acid pHHofmann elimination at blood pH (7.4)