Patrick

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Patrick An Introduction to Medicinal Chemistry
3/e Chapter 19 CHOLINERGICS, ANTICHOLINERGICS
ANTICHOLINESTERASES Part 2 Cholinergics
anticholinesterases
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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. Bindin
g 13.3. Analogues of tubocurarine (5
slides) 22 slides
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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

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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 Parkinsons Disease
• Anticholinesterase poisoning
• Motion sickness

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http//www.fairview.org/healthlibrary/content/ma_a
trosulf_ma.htm
http//www.medicinenet.com/atropine-oral/article.h
tm
http//healthresources.caremark.com/topic/parkinso
ndrugs
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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
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12. Cholinergic Antagonists (Muscarinic receptor)
12.1 Atropine

• 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

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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)

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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

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12. Cholinergic Antagonists (Muscarinic receptor)
12.4 Analogues of atropine

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

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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)
edit Anticholinergics Ipratropium,
Tiotropium Short acting ß2-agonists Salbutamol,
Terbutaline Long acting ß2-agonists
(LABA) Bambuterol, Clenbuterol, Fenoterol,
Formoterol, Salmeterol Corticosteroids Beclometas
one, Budesonide, Ciclesonide, Fluticasone Leukotri
ene antagonists Montelukast, Pranlukast,
Zafirlukast Xanthines Aminophylline,
Theobromine, Theophylline Mast cell
stabilizers Cromoglicate, Nedocromil Combination
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. Cholinergic Antagonists (Muscarinic receptor)
12.5 Simplified Analogues
Pharmacophore ester basic amine aromatic
ring
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12. Cholinergic Antagonists (Muscarinic receptor)
12.5 Simplified Analogues
Benztropine (Parkinsons disease)
Tropicamide (opthalmics)
Cyclopentolate (opthalmics)
Pirenzepine (anti-ulcer)
Benzhexol (Parkinsons disease)
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12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists

• 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

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12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists
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12. Cholinergic Antagonists (Muscarinic receptor)
12.6 SAR for Antagonists vs. 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
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12. Cholinergic Antagonists (Muscarinic receptor)
12.7 Binding Site for Antagonists
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12. Cholinergic Antagonists (Muscarinic receptor)
12.7 Binding Site for Antagonists
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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

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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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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

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13. Cholinergic Antagonists (Nicotinic receptor)
13.2 Binding
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13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine

• 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

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Suxamethonium chloride From Wikipedia, the free
encyclopedia (Redirected from Succinylcholine) R
outes 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.
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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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.
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.
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13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine

• 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

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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

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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. Atracur
ium 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 data Bioavailability 1
00 (IV) Protein binding 82 Metabolism Hoffman
elimination (retro-Michael addition) and ester
hydrolysis Half life 17-21 minutes Excretion
? Routes IV Atracurium is a neuromuscular-blockin
g 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 bisbenzyltetrahydroisoquino
linium 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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13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
ACTIVE
Atracurium stable at acid pH Hofmann elimination
at blood pH (7.4)
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13. Cholinergic Antagonists (Nicotinic receptor)
13.3 Analogues of tubocurarine
Mivacurium

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