Acetylcholine Antagonistslms.ndmctsgh.edu.tw/sysdata/4/7004/doc/3bb6c7d367c99f76/...Neuromuscular-blocking agents in clinic as an anesthetic adjunctive during operation. Ganglionic-blocking

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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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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