Patrick Ch19 p2

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Patrick Patrick An Introduction to Medicinal An Introduction to Medicinal

ChemistryChemistry 3/e 3/e

Chapter 19Chapter 19

CHOLINERGICS, CHOLINERGICS, ANTICHOLINERGICSANTICHOLINERGICS

& ANTICHOLINESTERASES& ANTICHOLINESTERASES

Part 2: Cholinergics & anticholinesterasesPart 2: Cholinergics & anticholinesterases

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ContentsContents

Part 2: Cholinergics & anticholinesterases

12. 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]

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12. Cholinergic Antagonists (Muscarinic receptor)12. Cholinergic Antagonists (Muscarinic receptor)

• Drugs which bind to cholinergic receptor but do not activate itDrugs which bind to cholinergic receptor but do not activate it• Prevent acetylcholine from bindingPrevent acetylcholine from binding• Opposite clinical effect to agonists - lower activity of Opposite clinical effect to agonists - lower activity of

acetylcholineacetylcholine

Postsynapticnerve

Ach

Antagonist

Ach

Postsynapticnerve

Ach

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Clinical EffectsClinical Effects• Decrease of saliva and gastric secretionsDecrease of saliva and gastric secretions• Relaxation of smooth muscle Relaxation of smooth muscle • Decrease in motility of GIT and urinary tractDecrease in motility of GIT and urinary tract• Dilation of pupilsDilation of pupils

UsesUses• Shutting down digestion for surgeryShutting down digestion for surgery• Ophthalmic examinationsOphthalmic examinations• Relief of peptic ulcersRelief of peptic ulcers• Treatment of Parkinson’s DiseaseTreatment of Parkinson’s Disease• Anticholinesterase poisoningAnticholinesterase poisoning• Motion sicknessMotion sickness

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http://www.fairview.org/healthlibrary/content/ma_atrosulf_ma.htm

http://www.medicinenet.com/atropine-oral/article.htm

http://healthresources.caremark.com/topic/parkinsondrugs

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CycloplegiaCycloplegia 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 Pilocarpine

mydriasisMydriasisClassifications and external resources

An 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

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12.1 Atropine12.1 Atropine

• Racemic form of hyoscyamine Racemic form of hyoscyamine • Source - roots of belladonna (1831) (deadly Source - roots of belladonna (1831) (deadly

nightshade)nightshade)• Used as a poisonUsed as a poison• Used as a medicine Used as a medicine

decreases GIT motility decreases GIT motility antidote for antidote for

anticholinesterase poisoninganticholinesterase poisoningdilation of eye pupilsdilation of eye pupils

• CNS side effects - hallucinationsCNS side effects - hallucinations

*

N

H

OC

O

Me

CH

CH2OH

easily racemised


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12.2 Hyoscine (scopolamine)12.2 Hyoscine (scopolamine)

• Source - thorn appleSource - thorn apple• Medical use - Medical use - treatment of motion sicknesstreatment of motion sickness• Used as a truth drug (CNS effects)Used as a truth drug (CNS effects)

*

N

H

OC

O

Me

CH

CH2OHO

H

H


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12.3 Comparison of atropine with acetylcholine12.3 Comparison of atropine with acetylcholine

• Relative positions of ester and nitrogen similar in both moleculesRelative positions of ester and nitrogen similar in both molecules• Nitrogen in atropine is ionisedNitrogen in atropine is ionised• Amine and ester are important binding groups (ionic + H-bonds)Amine and ester are important binding groups (ionic + H-bonds)• Aromatic ring of atropine is an extra binding group (vdW) Aromatic ring of atropine is an extra binding group (vdW) • Atropine binds with a different induced fit - no activationAtropine binds with a different induced fit - no activation• Atropine binds more strongly than acetylcholineAtropine binds more strongly than acetylcholine

N

OC

O

Me

H

CH

CH2OH

C

O

O CH3

NMe3

CH2CH2


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12.4 Analogues of atropine12.4 Analogues of atropine

• Analogues are fully ionised Analogues are fully ionised • Analogues unable to cross the blood brain barrierAnalogues unable to cross the blood brain barrier• No CNS side effectsNo CNS side effects

Atropine methonitrate(lowers GIT motility)

N

H

OC

O

CH3

CH

CH2OH

H3CNO3

Ipratropium(bronchodilator & anti-asthmatic)

N

H

OC

O

CH(CH3)2

CH

CH2OH

H3C

Br


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The 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/salbutamol

Diphenoxylate is an opioid agonist used for the treatment of diarrhea that acts by slowing intestinal contractions. It was discovered at Janssen Pharmaceutica in 1956. 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.

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12.5 Simplified Analogues12.5 Simplified Analogues

Pharmacophore = ester + basic amine + aromatic ringPharmacophore = ester + basic amine + aromatic ring

Amprotropine

NCH2

CH2

CH2

OC

O

Et

CH

CH2OH

Et

Tridihexethyl bromide

HO C CH2CH2N(Et)3 Br

Propantheline chloride

Cl

O C

O

O CH2CH2 N

CH

Me

CH

Me Me

Me

Me


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12.5 Simplified Analogues12.5 Simplified Analogues

Tropicamide(opthalmics)

Cyclopentolate(opthalmics)

Benztropine(Parkinsons disease)

Benzhexol(Parkinsons disease)

Pirenzepine(anti-ulcer)

CH

CH2OH

O

N

CH2CH3

N

N

H

OCH

Me

N

CH

N N

CHN

C O

CH2

N

N

O

Me


CH

O

O

OH

Me2N

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12.6 SAR for Antagonists12.6 SAR for Antagonists

Important featuresImportant features• Tertiary amine (ionised) or a quaternary nitrogenTertiary amine (ionised) or a quaternary nitrogen• Aromatic ringAromatic ring• EsterEster• NN-Alkyl groups (R) can be larger than methyl (unlike agonists)-Alkyl groups (R) can be larger than methyl (unlike agonists)• Large branched acyl groupLarge branched acyl group• R’ = aromatic or heteroaromatic ringR’ = aromatic or heteroaromatic ring• Branching of aromatic/heteroaromatic rings is importantBranching of aromatic/heteroaromatic rings is important

R2N

CH2

CH2

O

C

O

CH

R'

R'R' = Aromatic or Heteroaromatic


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InactiveInactiveActiveActive

Cl

O C

O

O CH2CH2 N

CH

Me

CH

Me Me

Me

Me CH2

C

O

O CH2CH2NR2

12.6 SAR for Antagonists12.6 SAR for Antagonists


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Tertiary amine (ionised) Tertiary amine (ionised) or quaternary nitrogenor quaternary nitrogen

Aromatic ringAromatic ringEsterEsterNN-Alkyl groups (R) can be -Alkyl groups (R) can be larger than methyllarger than methylR’ = aromatic or heteroaromaticR’ = aromatic or heteroaromaticBranching of Ar rings importantBranching of Ar rings important

Quaternary nitrogenQuaternary nitrogen

Aromatic ringAromatic ringEsterEsterNN-Alkyl groups = methyl-Alkyl groups = methyl

R’ = HR’ = H

SAR for AntagonistsSAR for Antagonists SAR for AgonistsSAR for Agonists

12.6 SAR for Antagonists vs. Agonists12.6 SAR for Antagonists vs. Agonists


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RECEPTOR SURFACE

Acetylcholinebinding site

12.7 Binding Site for Antagonists12.7 Binding Site for Antagonists

van der Waalsbinding regionsfor antagonists


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12.7 Binding Site for Antagonists12.7 Binding Site for Antagonists

CH

Me

MeCH

MeMe

N

Me

CH2CH2OC

O

O

Cl

H2N Asn

CO2

CH2

CH2

O

O

C

NMeR2

O


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13. Cholinergic Antagonists (Nicotinic receptor)13. Cholinergic Antagonists (Nicotinic receptor)

13.1 Curare13.1 Curare• Extract from ourari plantExtract from ourari plant• Used for poison arrowsUsed for poison arrows• Causes paralysis (blocks acetylcholine signals to muscles)Causes paralysis (blocks acetylcholine signals to muscles)• Active principle = tubocurarineActive principle = tubocurarine

TubocurarineTubocurarine

NHO

MeO

O

CH2

OMe

N

Me

Me

H

O

MeCH2

OH

H

H

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Tubocurarine 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.

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PharmacophorePharmacophore • Two quaternary centres at specific separation (1.15nm)Two quaternary centres at specific separation (1.15nm)• Different mechanism of action from atropine based antagonistsDifferent mechanism of action from atropine based antagonists• Different binding interactionsDifferent binding interactions

Clinical usesClinical uses • Neuromuscular blocker for surgical operationsNeuromuscular blocker for surgical operations• Permits lower and safer levels of general anaestheticPermits lower and safer levels of general anaesthetic• Tubocurarine used as neuromuscular blocker but side effectsTubocurarine used as neuromuscular blocker but side effects

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13.2 Binding13.2 Binding

a) Receptor dimer

S

b) Interaction with tubocurarine

protein complex(5 subunits)diameter=8nm

8nm

9-10nm

N N

N N Tubocurarine

Acetylcholine binding site


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13.3 Analogues of tubocurarine13.3 Analogues of tubocurarine

• Long lastingLong lasting• Long recovery timesLong recovery times• Side effects on heartSide effects on heart

• Esters incorporatedEsters incorporated• Shorter lifetime (5 min)Shorter lifetime (5 min)• Fast onset and short durationFast onset and short duration• Side effects at autonomic gangliaSide effects at autonomic ganglia

DecamethoniumDecamethonium

Me3N(CH2)10NMe3

SuxamethoniumSuxamethonium

Me3NCH2CH2 OC

O

CH2

C

O

O CH2CH2NMe3CH2


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Suxamethonium chlorideFrom 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

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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.

Suxamethonium chloride

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• Steroid acts as a spacer for the quaternary centres (1.09nm)Steroid acts as a spacer for the quaternary centres (1.09nm)• Acyl groups are added to introduce the Ach skeletonAcyl groups are added to introduce the Ach skeleton• Faster onset then tubocurarine but slower than suxamethoniumFaster onset then tubocurarine but slower than suxamethonium• Longer duration of action than suxamethonium (45 min)Longer duration of action than suxamethonium (45 min)• No effect on blood pressure and fewer side effectsNo effect on blood pressure and fewer side effects


Pancuronium (R=Me)Pancuronium (R=Me)

Vecuronium (R=H)Vecuronium (R=H)

MeO

NMeN

O

Me

Me

Me

O

O

H

H H

H

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• Design based on tubocurarine and suxamethoniumDesign based on tubocurarine and suxamethonium• Lacks cardiac side effectsLacks cardiac side effects• Rapidly broken down in blood both chemically and metabolicallyRapidly broken down in blood both chemically and metabolically• Avoids patient variation in metabolic enzymesAvoids patient variation in metabolic enzymes• Lifetime is 30 minutesLifetime is 30 minutes• Administered as an i.v. dripAdministered as an i.v. drip• Self destruct system limits lifetimeSelf destruct system limits lifetime

AtracuriumAtracurium

NCH2 CH2

C

O

O

MeO

OMe

HN

(CH2)5MeO OC

OMe

O

CH2 CH2

Me

MeO

OMe

OMe

OMe


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Atracurium 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.

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Atracurium

Pharmacokinetic dataBioavailability 100% (IV)Protein binding 82%Metabolism Hoffman elimination (retro-Michael addition) and ester hydrolysisHalf life 17-21 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

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Atracurium stable at acid pHAtracurium stable at acid pHHofmann elimination at blood pH (7.4)Hofmann elimination at blood pH (7.4)

NMe

CH2

Ph

CH C

H O

R

ACTIVE

-HCHH2C C

OPh

RN

Me

INACTIVE


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MivacuriumMivacurium

• Faster onset (2 min)Faster onset (2 min)• Shorter duration (15 min)Shorter duration (15 min)


N

MeO

OMe

H3C

NMeO

OMe

Me

MeO

OMe

OMe

OMe

OO

O

O

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Patrick Ch19 p2