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Acetylcholine Antagonists
Ming-Kuan Hu
Pharmacy, NDMC
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Anticholinergic agents
Muscarinic antagonists (esp for antispasmodic
actions)
high affinity with reversibly antagonistic actions to
muscarinic receptors without intrinsic activity
Actions: smooth muscles relaxation of GI and urinary
tract, pupil dilation, decreased release of saliva and
GI fluid.
Nicotinic antagonists
Neuromuscular-blocking agents
in clinic as an anesthetic adjunctive during operation.
Ganglionic-blocking agents
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Clinical use of muscarinic antagonists
Shutting down the GIT and urinary tract during surgery
Ophthalmic examination (dilate eye pupil)
Relief of peptic ulcer (reduction of GI motility)
Treatment of Parkinson’s disease
Treatment of cholinergic poison
Treatment of motion sickness
Picture (right) showed the adverse effects on CNS of muscarinic antagonists
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Anticholinergic agents
Natural alkaloids
(-)-Hyoscyamine
Extracted from Atropa belladonna (deadly nightshade, Solanaceae),
阿托平(Atropine) is (±)-Hyoscyamine (racemized at tropic acid moiety), a lead to currently anticholinergic agents.
Scopolamine: (-)-hyoscine.
N
O
OH
H
H3CH
O
*
(-)-Hyoscyamine
(+-)-Hyoscyamine = Atropine
*
N
O
OH
H
O
H3CHO
Scopolamine
((-)-Hyoscine)
____________________________________________________________
Me3N+
O
CH3
O
Same:
Ester of amino alcohol
Different:
Size of acyl groups
Atropine
Cholinergic antagonists
(Muscarinic receptor)
Comparison of
Atropine with Ach
N
OC
O
Me
H
CH
CH2OH
C
O
O CH3
NMe3
CH2CH2
Postsynaptic
nerve
Ach
Antagonist
Ach
Postsynaptic
nerve
Ach
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N
OH
H3CH
OH
H
O
HO*
Tropine Tropic Acid
N
CH3
O
O
OHN
CH3
O
O
OH
N+
CH3
O
O
OH
CH3CH3
N+
O
O
OH
Ipratropium.Br
Br-
HomatropineAtropine
Trospium.Cl
Cl-
Structures of anticholinergic amino alcohol
esters
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Amino Alcohol Esters of General Structure, RCOOR'________________________________________ R R' Generic Name-------------------------------------------------------------------
OH
N+(CH3)2 Br
- Glycopyrrolate
O
N+
CH3Br-
Propantheline
OHN
+H3C
HIpratropiumbromideBr-
-----------------------------------------------------------------------
Clinic use of anticholinergic amino alcohol
esters
Antispasmodics for GI upset or ulcers
4。-ammonium salt
Glycopyrrolate
Propantheline
HomatropineMeBr: weaker than atropine
Pirenzepine & telenzepine: Selectively anti-M1 R
Foye’s, Table 12.19
Clinic use of anticholinergic amino alcohol
esters
Ipratropium bromide
Short-acting bronchodilating for asthma
Tiotropium bromide
Long-acting anticholinergic for chronic obstructive pulmonary disease (COPD)
When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma (N. Engl. J. Med. 2010; 363:1715-1726)
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Overactive bladder (OAB) drugs
inhibiting bladder muscle contraction anti-M3 receptor
drugs!) (M3 most responsible for detrusor muscle
contraction!)
Solifenacin ; Darifenacin ; Teltoridine; Oxybutynine
Flavoxate is used to treat urinary bladder spasms
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Flavoxate
//upload.wikimedia.org/wikipedia/commons/0/09/Flavoxate.svg
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OAB drugs and muscarinic receptors
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Anticholinergic amino alcohols
Procyclidine: for Parkinson’s symptom; (腦炎障礙與動脈硬化症產生的) muscle rigidity.
Trihexphenidyl hydrochloride (Artane): half-fold activity of
atropine, used for treating extrapyramidal disorders caused by
antipsychotic medications; also be combined with other drugs to
treat Parkinson's disease, fewer side effects, same use as
procyclidine.
Trihexphenidyl hydrochloride
Anticholinergic amino ethers
Benztropine: for Parkinson’s symptom, also use as
antihistamine (with sedative effects)
Orphenadrine (Norflex): for Parkinson’s symptom
Tolterodine tartrate: used to treat overactive bladder (frequency
and urgency).
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13
SAR
Bigger R1, R2: carbocyclic or heterocyclic rings.
R3: 為 –OH or –CH2OH --- more potency (∵ H-bonds).
X : ester (more potency) or ether forms.
Amino alcohol esters且呈銨鹽: 不易被吸收,多用作antispasmodics (in ulcers) or mydriatics.
Amino alcohol ethers: 易通過BBB, 多用作antiparkinsonian drugs.
N-取代基: 四級銨鹽或三級氨, N上 alkyl ≧ Me, Et or propyl, isopropyl.
Two methylene units in the bridge.
R1
R3
R2 X (CH2)n N
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Amino amides & miscellaneous
Isopropamide iodide (Darbid)
antispasmotic and antisecretory effects for ulcer and
G-I hypermotility and hyperacidity.
Tropicamide
For eye examination
Actions: relaxing sphincter muscle of iris
Diphemanil methylsulfate
Lack of atropine-like effects at recommended doses.
Relieve gastric hypermotility, hyperhidrosis (多汗症).
EthopropazineHCl
use for PD symptoms e.g. tremor, rigidity, sialorrhea.
Parkinson’s disease (PD)
The pathological hallmark of
Parkinson’s disease is a
loss of dopamine-containing
neurons in the substantia
nigra pars compacta that
provide dopaminergic
innervation to the striatum
(caudate/putamen)
A proper balance between
striatal muscarinic
cholinergic and
dopaminergic
neurotransmission is
required for coordinated
locomotor control
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50.下列anticholinergic藥物中,何者之結構屬於aminoether?(102-2)
A.Atropine
B.Benztropine
C.Oxybutynin
D.Ipratropium bromide
21.下列何種antimuscarinic drug可用於暈動病(motion sickness)?(102-2)
A.Ipratropium
B.Scopolamine
C.Oxybutynin
D.Propantheline
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20.下列何者是antimuscarinic drug之治療用途? (102-2)
A.廣角型青光眼
B.重症肌無力
C.原發性高血壓
D.帕金森氏症
1.下列有關受體通過之離子的敘述,何者錯誤?(102-2)
A.NMDA受體是鈣離子和鈉離子
B.Nicotinic
acetylcholine受體是鈉離子
C.AMPA受體是鈉離子
D.GABAB受體是氯離子
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下列何種anticholinergic agent含有quaternary ammonium結構,可用來治療消化性潰瘍?(103-2)
A.Darifenacin
B.Flavoxate
C.Propantheline
bromide
D.Solifenacin
下列何種antimuscarinic drug可用於緩解泌尿外科手術引起之膀胱痙攣?(103-1藥理)
A.Oxybutynin
B.Propantheline
C.Homatropine
D.Cyclopentolate
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Nicotinic antagonists
Skeletal neuromuscular blocking agents
主要為來自箭毒(arrow poisons)的成份, e.g. d-tubocurarine, 具有一個四級銨鹽與一個三級胺,由結構特性可了解到nicotinic receptors上可能具有兩個anionic sites.此類的藥物常用於手術前肌肉鬆弛與研究分離與純化nicotinic receptors用.
Ganglionic blocking agents:
幾乎已不在臨床上使用,原因?
e.g. Hexamethonium
;
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Structures of d-tubocurarine, metocurine
N
N+
O
O
OMe
MeO
O R
CH3
CH3
CH3
R
ORH
H
d-Tubercurarine chloride (R = H, X = Cl)Metocurine iodide (R = CH3, X = I)
+X-
X-
o
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The Neuromuscular junctions
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Synthetic bis-quaternary ammonium salts (I)
Depolarizing neuromuscular blocking agents:
DecamethoniumCl & HexamethoniumCl
Pharmcol actions: continuous stimulation of N-M junctions resulted
in muscular tachyphylaxis (快速減敏) or desensitization to Ach response
Structure: methylene linker (6 or 10 carbons) bridging on two
quaternary ammonium moieties
Succinylcholine chloride:
Structure looks like linking of two molecules of Ach
Easy hydrolysis in body fluid and loss of effects short actions.
N+
(CH2)nN
+
Decamethonium Chloride, n= 10Hexamethonium Chloride, n= 6
Cl-Cl-
N+
O
O
O
O
N+
2Cl-
Succinylcholine chloride
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Synthetic bis-quaternary ammonium salts (II)
Non-depolarizing (Competitive) N-M blocking agents:
此類藥物的作用方式是: 與Ach競爭接受器,阻止去極化(depolarization),而麻痺N-M transmission. 此為較理想的神經肌肉阻斷劑,作用時間較succinylcholine 長.
d-Tubocurarine, gallamine
Metocurine iodide:由d-tubocurarine與methyl iodide 反應而得到(結構上變成具有兩四級銨鹽基), 作用比 d-tubocurarine強四倍.
其它藥物:
Pancuronuim bromide :作用時間較 d-tubocurarine稍短但較強, 其由腎排除而作用終止(vecuronium bromide與atracurium besylate亦同).
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Steroid-based N-M blockers
These agents derived from (+)-malouetine (an aminosteroid
arrow poison found in the rain forest of south Africa)
O
R2R1
R3O
O
H
H H
H
N+
O
N+
N
O
N+
N+
O
N+
N O
Pancuronium R1=R2 =
bromide R3 =
2Br-
Vecuronium R1 =
bromide R2 =
R3 = Br-
Pipecuronium R1=R2 =
bromide R3 =
2Br-
Rocuronium R1 =
bromide R2 =
R3 = H Br-
Tetrahydroisoquinoline-based N-M
blocking agents
Atracurium besylate: nondepolarizing NM blocker
a complex molecule containing four sites at which different
stereochemical configurations can occur. Me-group attached to the
4-N projects on the opposite side to the adjacent substituted-
benzyl moiety predominate by approximately 3:1.
Mivacurium chloride: a mixture of three stereoisomers with trans-trans
& cis-trans diesters are equal potency
Doxacurium chloride: a mixture of three trans-trans stereoisomers
Not metab by plasma ChEase or hepatic enz
Not undergo Hofmann elimination
25 Atracurium besylate
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Atracurium besylate (Tracrium)
Allowed to use in patients with hepatic and renal disease
Neither Metabolized by liver nor kidney!
Decomposed by hydrolysis or undergoing Hofmann elimination
N+
OMeMeO
MeO
MeO O
O
N+
OMeOMe
OMe
OMeO
O
N
OMeMeO
MeO
MeO O
O
N+
OMeOMe
OMe
OMeO
O
O
O
O
O
N+
OMeOMe
OMe
OMeOH
O
N+
OMeMeO
MeO
MeO O
O
OH
OH OH
X- X-
Laudanosine Hofmann elimination
Hofmann elimination
+ Laudanosine
Ester hydrolysis
X-
X- Ester hydrolysis
IV-ammonium carboxylic acid
IV-ammonium carboxylic acid +
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併用atropine 易導致benzocaine 產生毒性,主要是因為atropine 產生下列何種作用所致?(95-2)
A. 抑制esterases
B. 抑制benzocaine 的排除
C. 促進benzocaine 的吸收
D. 抑制amidases
Atropine 俗稱為: (96-2)
A ( ± )-Hyoscyamine
B (+)-Hyoscyamine
C ( ± )-Hyoscine
D (+)-Hyoscine
下列神經肌肉阻斷劑中,具有5α-androstane 化學結構者為: (96-2)
A. Atracurium besylate
B. Gallamine
triethoiodide
C. Metocurine iodide
D. Pancuronium
bromide
48.下列有關神經肌肉阻斷劑之敘述,何者正確?(102-1)
A.Decamethonium之分子中含有十四個碳原子
B.Succinylcholine屬於非去極化(nondepolarizing)神經肌肉阻斷劑
C.Decamethonium之半衰期比succinylcholine短
D.Succinylcholine屬於diquaternary ammonium
ester
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下列何種吸入型氣喘治療藥物是屬於atropine 的合成類似物?(98-1)
A albuterol
B terbutaline
C ipratropium
D cromoglycate sodium
下列藥物中,何者為非去極化性神經肌肉阻斷劑(nondepolarizing neuromuscular blocking
agent)之解毒劑?(98-1)
A neostigmine
B diazepam
C succinylcholine
D dantrolene
下列何種藥物具有競爭性阻斷蕈毒鹼受體(muscarinic receptor)而加速房室結的傳導?(106-1理)
A. Nifedipine
B. Disopyramide
C. Lidocaine
D. Nitroglycerin
Laudanosine為下列何種藥物經Hofmann elimination所產生的?(106-1)
A. atracurium
B. doxacurium
C. mivacurium
D. pancuronium
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Disopyramide: an Na channel blocker and therefore
classified as a Class 1A anti-arrhythmic
agent; anticholinergic effect on the heart
which accounts for many adverse side
effects.
Overdose of N-M blocking agents
Neostigmine, pyridostigmine, edrophonium preserve
endogenous Ach & act directly on the N-M
Treatment for overdose of competitive blocking agents
On completion of surgery, neostigmine or edrophonium were used
to reverse and decrease the duration of competitive N-M blockade
Malignant hyperthermia
A life-threatening event mostly triggered by the co-admin of
anesthetic and depolarizing N-M blocking agent
Mechanism: uncontrolled release of Ca+2 from SR of skeletal
muscle is the initiating event
Treatment : iv of dantrolene (inhibiting Ca+2 release from SR)
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http://upload.wikimedia.org/wikipedia/commons/f/fb/Dantrolene_Tanaka_et_al.svg
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Papaverine
Isolated from opium (1% contents)
Antispasmodics
Inhibiting phosphodiesterase (PDE), raising [cAMP]i
Use for coronary or pulmonary arterial occlusions.
N
R
R
R
R
Papaverine, R= OCH3
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Botulinum toxin (BTX) 肉毒桿菌毒素
Prevent release of Ach (at nicotinic N-M
junction)
Irreversibly blocking postsynaptic
depolarization (2~3 mon duration)
Contamination of improperly prepared food
Clinical use:
facial muscle spasms, strabismus (斜視), blepharoplasm (眼臉痙巒), 肌張力不全(dystonia), wrinkles.
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BTX type A preparations
Dysport® : used in UK
Botox® : used in US, Taiwan, and others.
Botox ~ 3-fold potency of Dysport
1 unit: LD50 of Swiss-Weber rat (18-20 gm )
Botulinum toxin acts to prevent exocytosis, specifically the
release of acetylcholine at the neuromuscular junction.
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SNARE proteins (SNAP (Soluble NSF Attachment Protein) REceptor")
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Botulinum toxin molecule
7 serum types:
Types A-G
Can cleave SNARE
proteins to block the
release of Ach from
synaptic vesicle
SNARE proteins: (SNAP (Soluble NSF Attachment Protein) REceptor")
NSF: N-ethylmaleimide sensitive fusion proteins
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Normal neurotransmitter release
JAMA 2001, 285, 1059-1071.
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JAMA 2001, 285, 1059-1071.
MOA of botulinum toxin