1. CHOLINERGICS, ANTICHOLINERGICS & ANTICHOLINESTERASES
Patrick
An Introduction to Medicinal Chemistry 3/e
Chapter 19
CHOLINERGICS, ANTICHOLINERGICS
& ANTICHOLINESTERASES

2. Contents
Part 2: Cholinergics & anticholinesterases
12. Cholinergic Antagonists (Muscarinic receptor) (2 slides)
12.1. Atropine
12.2. Hyoscine (scopolamine)
12.3. Comparison of atropine with acetylcholine
12.4. Analogues of atropine
12.5. 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. Binding
13.3. Analogues of tubocurarine (5 slides)
[22 slides]

3. 12. Cholinergic Antagonists (Muscarinic receptor)
Drugs which bind to cholinergic receptor but do not activate it
Prevent acetylcholine from binding
Opposite clinical effect to agonists - lower activity of
acetylcholine
Postsynaptic
nerve
Ach
Ach
Postsynaptic
nerve
Antagonist

4. 12. Cholinergic Antagonists (Muscarinic receptor)
Clinical Effects
Decrease of saliva and gastric secretions
Relaxation of smooth muscle
Decrease in motility of GIT and urinary tract
Dilation of pupils
Uses
Shutting down digestion for surgery
Ophthalmic examinations
Relief of peptic ulcers
Treatment of Parkinson’s Disease
Anticholinesterase poisoning
Motion sickness

6. Cycloplegia
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 Pilocarpine
mydriasis
Mydriasis
Classifications 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

7. 12. Cholinergic Antagonists (Muscarinic receptor)
12.1 Atropine
easily racemised
Racemic form of hyoscyamine
Source - roots of belladonna (1831) (deadly nightshade)
Used as a poison
Used as a medicine decreases GIT motility antidote for anticholinesterase poisoning dilation of eye pupils
CNS side effects - hallucinations

8. 12. Cholinergic Antagonists (Muscarinic receptor)
12.2 Hyoscine (scopolamine)
Source - thorn apple
Medical use - treatment of motion sickness
Used as a truth drug (CNS effects)

9. 12. Cholinergic Antagonists (Muscarinic receptor)
12.3 Comparison of atropine with acetylcholine
Relative positions of ester and nitrogen similar in both molecules
Nitrogen in atropine is ionised
Amine 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 activation
Atropine binds more strongly than acetylcholine

10. 12. Cholinergic Antagonists (Muscarinic receptor)
12.4 Analogues of atropine
Ipratropium
(bronchodilator & anti-asthmatic)
Atropine methonitrate
(lowers GIT motility)
Analogues are fully ionised
Analogues unable to cross the blood brain barrier
No CNS side effects

11. 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) edit
Anticholinergics: Ipratropium, Tiotropium
Short acting β2-agonists: Salbutamol, Terbutaline
Long acting β2-agonists (LABA): Bambuterol, Clenbuterol, Fenoterol, Formoterol, Salmeterol
Corticosteroids: Beclometasone, Budesonide, Ciclesonide, Fluticasone
Leukotriene antagonists: Montelukast, Pranlukast, Zafirlukast
Xanthines: Aminophylline, Theobromine, Theophylline
Mast cell stabilizers: Cromoglicate, Nedocromil
Combination products: Budesonide/formoterol, Fluticasone/salmeterol, Ipratropium/salbutamol

12. Diphenoxylate 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.

13. 12. Cholinergic Antagonists (Muscarinic receptor)
12.5 Simplified Analogues
Pharmacophore = ester + basic amine + aromatic ring
Tridihexethyl bromide
Amprotropine
Propantheline chloride

14. 12. Cholinergic Antagonists (Muscarinic receptor)
12.5 Simplified Analogues
Benztropine
(Parkinsons disease)
Tropicamide
(opthalmics)
Cyclopentolate
(opthalmics)
Pirenzepine
(anti-ulcer)
Benzhexol
(Parkinsons disease)

15. 12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists
R' = Aromatic or
Heteroaromatic
Important features
Tertiary amine (ionised) or a quaternary nitrogen
Aromatic ring
Ester
N-Alkyl groups (R) can be larger than methyl (unlike agonists)
Large branched acyl group
R’ = aromatic or heteroaromatic ring
Branching of aromatic/heteroaromatic rings is important

16. 12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists
Inactive
Active

17. 12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists vs. Agonists
SAR for Antagonists
SAR for Agonists
Quaternary nitrogen
Aromatic ring
Ester
N-Alkyl groups = methyl
R’ = H
Tertiary amine (ionised)
or quaternary nitrogen
Aromatic ring
Ester
N-Alkyl groups (R) can be
larger than methyl
R’ = aromatic or heteroaromatic
Branching of Ar rings important

18. 12. Cholinergic Antagonists (Muscarinic receptor)
12.7 Binding Site for Antagonists
RECEPTOR SURFACE
Acetylcholine
binding site
van der Waals
binding regions
for antagonists

19. 12. Cholinergic Antagonists (Muscarinic receptor)
12.7 Binding Site for Antagonists

20. 13. Cholinergic Antagonists (Nicotinic receptor)
13.1 Curare
Extract from ourari plant
Used for poison arrows
Causes paralysis (blocks acetylcholine signals to muscles)
Active principle = tubocurarine
Tubocurarine

21. 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.

22. 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.

23. 13. Cholinergic Antagonists (Nicotinic receptor)
Pharmacophore
Two quaternary centres at specific separation (1.15nm)
Different mechanism of action from atropine based antagonists
Different binding interactions
Clinical uses
Neuromuscular blocker for surgical operations
Permits lower and safer levels of general anaesthetic
Tubocurarine used as neuromuscular blocker but side effects

24. 13. Cholinergic Antagonists (Nicotinic receptor)
13.2 Binding S
b) Interaction with tubocurarine
protein complex
(5 subunits)
diameter=8nm
8nm
a) Receptor dimer
9-10nm
Tubocurarine
Acetylcholine binding site

25. 13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Suxamethonium
Decamethonium
Long lasting
Long recovery times
Side effects on heart
Esters incorporated
Shorter lifetime (5 min)
Fast onset and short duration
Side effects at autonomic ganglia

26. Suxamethonium chloride
From Wikipedia, the free encyclopedia
(Redirected from Succinylcholine)
Routes Intravenous
Suxamethonium 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.

27. There are two phases to the blocking effect of suxamethonium
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.

28. Suxamethonium 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.

29. 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.

30. 13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Pancuronium (R=Me)
Vecuronium (R=H)
Steroid acts as a spacer for the quaternary centres (1.09nm)
Acyl groups are added to introduce the Ach skeleton
Faster onset then tubocurarine but slower than suxamethonium
Longer duration of action than suxamethonium (45 min)
No effect on blood pressure and fewer side effects

31. 13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Atracurium
Design based on tubocurarine and suxamethonium
Lacks cardiac side effects
Rapidly broken down in blood both chemically and metabolically
Avoids patient variation in metabolic enzymes
Lifetime is 30 minutes
Administered as an i.v. drip
Self destruct system limits lifetime

32. 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.

33. 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.

34. Atracurium
Pharmacokinetic data
Bioavailability 100% (IV)
Protein binding 82%
Metabolism Hoffman elimination (retro-Michael addition) and ester hydrolysis
Half life minutes
Excretion ?
Routes IV
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.

35. 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

36. 13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
INACTIVE
ACTIVE
Atracurium stable at acid pH
Hofmann elimination at blood pH (7.4)

37. 13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Mivacurium
Faster onset (2 min)
Shorter duration (15 min)

38. THE END- Thank You