PowerPoint PNS: outside the brain and spinal cord
Afferent neurons convey information from the
receptors to the CNS.
3
PNS
Somatic nervous system : innervating skeletal muscle (conscious & under voluntary control – not always true, reflex arcs!)
Autonomic nervous system: innervating cardiac and smooth muscle and gland (not conscious and outside of voluntary control – not always true either)
Sympathetic division: 'fight or flight' response, heightened somatic activity
Parasympathetic division: enhanced visceral activity
Enteric nervous system: at intestinal wall, respond to local effects for the control of GIT functions; NTs include serotonin, neuropeptides, ATP, NO.
4
PNS contains 43 pairs of nerves: 31 spinal and 12 cranial.
5
parasympathetic systems
Sympathetic: Activated in emergency, costs energy, prepares to fight or flight.
Sympathetic tone: maintaining the optimal functions during vigilance motivated behaviors.
Parasympathetic Activated during states of rest and repair (e.g. sleep, digestion).
Some afferent signals conscious (hunger or stomach distention), some do not become conscious (b.p. change, plasma osmolarity)
6
PNS
PNS
7
8
Neurochemistry
Parasympathetic preganglionic fibers – Acetylcholine
Parasympathetic postganglionic fibers – Acetylcholine
O +
10
11
Acetylcholine mimetics –
Muscarinic agonists
MethacholineCl
CarbacholCl
BethanecholCl
Drugs covered in this chapter (II)
AchEIs for the treatment of Alzheimer’s disease Tacrine HCl (Cognex)
Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Razadyne)
Acetylcholine
Succinylcholine Cl
Alkaloids: pilocarpine
Nicotinic agonists
Carbamates: physostigmine, neostigmine, pyridostigmine, edrophonium
Irreversible inhibitors of AchE
17
Treatment of glaucoma
Treatment of certain heart defects by decreasing
heart muscle activity and heart rate
Treatment of Alzheimer’s disease (AD), e.g. -----
Nicotinic agonists: e.g. a methacholine isomer
Treatment of myasthenia gravis
Dilatation of eye pupils
Shutting down the GIT and urinary tract during surgery
Ophthalmic examination
Treatment of cholinergic poison
Treatment of motion sickness
20
21

pupil dilates when radially
iris contract.
innervated by the sympathetic
Step 2: Choline + Ac2O Ach
25
symporter
antiporter
cosmetic treatment
pantothenic acid (vit B5!), used as a source of
CoA
N +
O
O
N +
OH
HO
.2Cl-
similar to muscarine, from a poisonous mushroom)
Located at smooth and cardiac muscles and glands.
Nicotinic receptors: (agonist actions similar to nicotine)
Located at skeletal muscle & nerve synapses.
Chemical structures of muscarine and nicotine:
O NMe
The “Muscarinic Actions” -- reproduced by injection of muscarine,
from Amanita muscaria.
Muscarinic receptors (mAChR)
Muscarinic receptors
coupled properties
31
M1: cognitive, seizure activity ; DA release
M4: inh NT release; analgesia, facilitate DA release
M5: dilate cerebral arteries; augment drug seeking
behavior & rewarding
M3: visceral smooth muscles and glands ; NO syn
32
Go: Ca2+ currents
Central metabolic role of β-cell M3 mAChRs
Food intake triggers the stimulation of glucoreceptors in the gut, liver and
brain, resulting in an increase in central parasympathetic outflow.
The resulting stimulation of β-cell M3 mAChRs potentiates glucose-induced
insulin release, primarily by triggering an increase in [Ca+2]i levels
M3 mAchER can be target for DD for T2DM
33
34
H-bonding interaction: Asn-617--- MeCO2 - gp
Dipole interaction: hydrophobic pockets of 3 aromatic amino acids --- -+NMe3 gp
35
The “Nicotinic Actions” -- similar to those induced by nicotine
Similar receptors: GABAA, 5-HT3, glycine receptors
37
NM skeletal mucl incr Na+, K+ Ach/Nicotine d-Tubocurarine
permeability succinylcholine
permeability mecamylamine
neuro junction permeability
Key points (I)
Two types of cholinergic receptors: muscarinic receptors are present at - --, and nicotinic receptors are present at ---.
The secondary messengers of M1-M5 receptors when activated:
The distribution of muscarinic receptors, M1- M5:
G protein- coupled receptor(98-1)
A nicotinic receptor
B 5-HT1A receptor
C muscarinic receptor
D AT1 receptor
Most stable by X-ray and NMR observation
(intramolecular electronic interaction between
--- but might not be the conformation preferred
by the receptor
R4N +--- :O=C-R
to its receptor
44
45
O
Acetyl α-methylcholine nicotinic receptors , . *(nicotinic receptor & AchE).
(ethylene bridge)Me.
Instability of Ach
• Neighbouring group effect
muscarinic effect, but not clinically used.
51
Methacholine: methyl group protecting the C=O
Electronic effects: Carbachol: amine group acts as a bioisostere
Shows very little selectivity between the muscarinic and nicotinic receptors, this good for local use for glaucoma
Combining steric & electronic effects Bethanechol: use for “after surgery”
Shows selectivity and used to stimulating the GIT and urinary bladder after surgery
52
53
Glaucoma
One of the leading cause of blindness (other two: cataract, age-related macular degeneration, ARMD) due to damage of optical nerves by intraocular pressure (IOP) Hypertension glaucoma (HTG)
Normal tension glaucoma (NTG) : most Japanese patients
Type of glaucoma Primary
Open-angle (chronic simple)
Narrow-angle (acute congestive): may be due to the blocking the release of aqueous humor by iris drug only for acute attack, long-range management needs
surgery
Mitotic agents (parasympathomimetics): pilocarpine (q.i.d. not quite used), carbachol
Contraction of the cilliary muscle, tightening the trabecular meshwork and allowing increased outflow of the aqueous humor.
Decrease aqueous humor outflow production b-Blockers: timolol (2nd most common use), levobunolol (Betagan), and betaxolol
(bid or qd)
Carbonic anhydrase inhibitors: dorzolamide (Trusopt), brinzolamide (Azopt), acetazolamide (Diamox)
Lower secretion of aqueous humor by inhibiting carbonic anhydrase in the ciliary body
a2-agonists: Apraclonidine (lopidine), brimonidine (Alphagan, 3rd common use)
Dual mechanism: decreasing aqueous production and increasing trabecular outflow.
Latanoprost
Best-selling glaucoma medication
pigmentation
the indication to lengthen eyelashes was approved in 2008 as
tradename, Latisse.
Travoprost (Travatan) by Alcon
an ester prodrug of the free acid, which acts as an agonist at the
PG F receptor, increasing outflow of aqueous fluid from the eye.
Aqueous outflow
Aqueous humor flows out of the eye using two pathways: 80-90% of
aqueous outflow is through the one that is sensitive to eye pressure (the
trabecular meshwork pathway) and other is through the one that operates
independently of eye pressure (the uveoscleral pathway)
The cellular matrix of the trabecular meshwork facilitates aqueous outflow
via metabolic phagocytosis
58
A. Timolol
A. Anticlinal
B. Antiperiplanar
C. Synclinal
D. Synperiplanar
D.gel refrigerator
60
61
M1 (in CNS) and affinity for M3 (lacrimal and
salivary glands)
sulfoxide, N-oxide, & glucuronide.

O
S
N
disease, e.g. donepezilHCl, rivastigmine tartrate
Arecoline, oxotremorine & xanomeline
64
Anionic binding region (Asp-CO2 - ----)
Ester binding region (Tyr-OH ---- )
65
Referring the processing chart in text:
Histidine residue acts as an acid-base catalyst thru
the mechanism
66
67
O
O
N
N
H
General acid-general base hydrolysis
Physostigmine
dimethylcarbamic acid esters
Reason: stability of phenoxide >> alkoxide
Carbachol, bethanechol
Regeneration of AchE:
acetylated enzyme
Equation:
70
CNS effect
N
N
OH3CHN
O
CH3
CH3
H3C
H2O
N
N
HO
CH3
CH3
H3C
Its salicylate salt used as antidote for atropine
and TCA poisoning (cross BBB)
Once was used for AD treatment
Side effects limited its medical use
Hydrolytic products: eseroline, further photolysis
to become rubreserine
A. Acid
B. Base
C. Light
D. Air
A Acetylation
B Phosphorylation
C Carbamylation
D Methylation
physostigime,physostigmine (Why?)
N
a neuromuscular disease leading to fluctuating muscle weakness and fatiguability. It is an autoimmune disorder, in which weakness is caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine.
Myasthenia is treated medically with cholinesterase inhibitors or immunosuppressants, and, in selected cases, thymectomy.
76
Pyridostigmine
duration than neostigmine
and myasthenia gravis in clinic
Used as chemical cocktails by allied troops in Iraq during
Desert Shield to protect against possible exposure to
organophosphate nerve gas
to be given prior to exposure to the nerve agent Soman in order
to increase survival (AchE, nerve gas!)
77
cholinomimetic effects at skeletal muscle.
Used i.v. for diagnosis of myasthenia gravis
Used i.m. for the reverse of the effects of nondepolarizing
NM blocking agents, e.g. d-tubocurarine and gallamine;
no effects on depolarizing blockers, e.g. succinylcholine
or decamethonium OH N
A physostigmine
B echothiophate
C edrophonium
D atropine
A acetylcholine
B methacholine
C carbachol
D bethanechol
Alzheimer’s disease
)
prevent the time to nursing home
O
N
OH
MeO
disease
81
Rivastigmine tartrate (Exelon® , Novartis)
Inh both AChE & BuChE; it inhibits AChE for up to 10 hr due to slow
hydrolysis of carbamylated enzyme reffered as pseudo-
irreversible AChEIs
Rapid hydrolyzed by CNS ChE with minimal involved in liver CYP
enz low potential hepatoxicity & drug-drug interaction!
82
inh BuChE
daffodil & snowflake
anesthesia
right)
83
A.Ethacrynic acid
used as ocular drops in the treatment of chronic glaucoma
Vapor is highly toxic
Sarin
Actions: inhibit AchE by irreversibly phosphorylating the serine residue at the active site permanent contraction of skeletal muscle!, leading to death
Aging process of phosphorylated AChE
Antidote: Atropine sulfate + Magnesium sulfate, Why?
88
Irreversible inhibitors of AchE
MOA similar to carbamate inhibitors but providing more stable, irreversible AchE-phosphate (phosphorylated AChE), which means long duration and irreverible inhibition with difficulty to recover active AchE
89
The only irreversible AchEI for glaucoma (applied topically!):
intraocular pressure decreasing
case)
Slowly hydrolysis from the enzyme over a matter of days,
safer than DFP.
Insecticidal AchEIs
Parathion, malathion Relatively non-toxic compared to nerve gas to (P=S
bond prevents self molecule from inhibiting AchE)
No metabolic pathways in mammals to convert P=S to P=O), but exist in insects!
Homework: Draw the metabolism of insecticides in mammals and insects.
Irreversible AChEIs used as insecticides
Phosphoesters
Thiophosphoesters
Organophosphate insecticides
Highly lipophilic and skin penetration, avoid to absorb by breath or skin contact.
Sulfur-containing AchEI insecticides:
prodrugs, low toxic effects, when getting in insects body, it can be activated by microsomal oxidation and converted to active oxygenated metabolite, ex: Parathion paraoxon.
human carboxyesterase deactivates parathion by ester hydrolysis to give acid derivative with less leaving group. This action is more rapid than enzymatic oxidation.
X
P
93
Irreversible
acetylcholinesterase
A. 6
B. 7
C. 8
D. 9
active AChE
phosphate ester only at toxic concentration!
Praoxime (2-PAM): deri from reaction of droxylamine with
aldehyde; pyridine ring is common in biological system (e.g.
NAD+ & NADP+)
No work on any enzymes being inhibited in CNS
Pro-2-PAM: a prodrug of 2-PAM and a tertiary amine, can
enter the CNS
Use of 2-PAM
Given within a short period of time after enz phosphorylation, due to
the ageing process of phosphorylated enz
Little reactivation if given 36 hr after exposure
Figure shows the mechanism of reactivation of AChE with 2-PAM
95
96
N +
H
AchE.
Pralidoxime chloride (2-PAM): Can you draw the reaction how 2-PAM hydrolyzes the
phosphate ester?
2-PAM(aging)
A Pralidoxime
B Neostigmine
C Atracurium
D Atropine
Donepezil (Aricept, 1997)
Rivastigmine (Exelon, 2000)
Galantamine (Razadyne, 2001)
(A) Donepezil
(B) Carbachol
(C) Tacrine
(D) Rivastigmine
A indane
B tetrahydroacridine
C naphthane
D indoline
A
B
C
D
A. Physostigmine
B. Pyridostigmine
C. Neostigmine
D. Edrophonium
An AchE inhibitor
105
Key points (II)
AchEIs inhibit AchE and have the same clinic effects as cholinergic agonists.
The active site of AchE is similar to the binding site for the cholinergic receptor, but also includes the His and Ser residues.
The carbamate inhibitors are derived from physostigmine. They react with AchE to produce a carbamoyl-bound intermediate which is stable and slow to hydrolyze.
Organophosphates were used as nerve gases, medicine, insecticides. They irreversibly phosphorylate serine in the active site.
AchEIs were used as smart drugs in the treatment of AD.
106
Patients with myasthenia gravis have a deficiency of nicotinic Ach receptors. Why would administration of an anti-acetylcholinesterase drug, such as neostigmine, improve their muscle function?
(skeletal muscle)(voluntary muscle) (acetylcholine)(nicotinic acetylcholine receptor)
(75%)( )(15%) 10% 85% (ocular myasthenia gravis )(generalized myasthenia gravis)
107
Botox
Botox is a vanity drug that eliminates wrinkles under your eyes. It is a weak solution of Botulinum toxin that is subcutaneously injected under the eye. The effect lasts for months. Given your knowledge of muscle contraction, what are the possible actions of this drug in eliminating wrinkles?
Botox prevents exocytosis of synaptic vesicles in presynaptic membrane of neuromuscular junction, thus blocking release of acetylcholine into synaptic cleft. This blocks muscle contractions, which underlie wrinkles around the eyes.
Case study (scenario)
N
related Macular Degeneration
Glaucoma
Cataract
Aged-related macular degeneration (ARMD)
112
Glaucoma
Optical nerve damage
Any eye pressure that can damage optical nerve is
too high
Retina
Lens
114
Most of the aqueous humor, produced by the ciliary body, exits the eye at
the angle formed by the junction of the iris and cornea. It exits primarily via
the trabecular meshwork and Schlemm's canal.
115
Two ways conversation for signal pathways as
active conversation
of brain) LGN Visual cortex
116

Blood pressure
Immune system
Oxidative stress
Preserve quality of life
Timely diagnosis and treatment through regular,
complete eye exams
patient to carry on as normal a life as possible
and to control the effects of glaucoma
120
Painless
Who is at risk?
121
Learn the risk factors of glaucoma
High eye pressure, nearsightedness, family history,
African decent, Asian descent, high blood pressure
If you have a risk factor, go and see your doctor
Get complete eye exams including eye pressure
test and optical nerve exam
122
early diagnosis and appropriate treatment
Why Do You Need Regular Eye Exams?
Glaucoma has no early symptoms
People may have glaucoma and not know it
Over half of all glaucoma cases are undiagnosed
Glaucoma damage and vision loss is not reversible
Glaucoma may lead to blindness if untreated or if
inadequately treated
Summary
Distressing
blindness
Disabling
125
diagnosis and appropriate treatment
Cataract
A cataract is a progressive, painless clouding of the lens of the eye.
Cataracts occur when protein builds up on the lenses and blocks
some of the light from passing through, making it difficult to see
clearly
126
Cataract
127
In cataract surgery, the cloudy lens is removed and
replaced with an artificial lens. The surgery, which is
done on an outpatient basis, is safe and extremely
effective at improving vision. If cataracts are present in
both eyes, surgery will be done on one eye at a time
Tips to prevent cataracts
Keep diabetes well controlled.
retina (called the peripheral retina). The
macula is what allows you to thread a
needle, read small print, and read street
signs.
Ranibizumab (Lucentis)

Larger MW, 6 wk/dose
cell lung cancer (NSCLC), etc
129
Pegaptanib sodium injection (Macugen)
nucleic acid that binds specifically to VEGF 165, a
protein that plays a critical role in angiogenesis and
increased permeability
0.3 mg dose once every 6 wk by intravitreal injection ( )
130
131
132
133