Bài giảng Thuốc tác dụng trên hệ cholinergic

Effects of nicotine in bodySensitization ofreceptors for pressure,temperature andpain sensationAttentivenessVigilanceAbility to concentrateAvoidance of withdrawalsymptoms:Irritability, i

THUỐC TÁC DỤNG TRÊN

HỆ CHOLINERGIC

Nguyễn Thùy Dương

1

Thuốc tác dụng trên hệ cholinergic

1 Phân tích được tác dụng, chỉ định, tác dụng không mong muốn và thận trọng/chống chỉ đinh của các thuốc nhóm:

- Chủ vận M và N, chủ vận muscarinic, phong bế cholinesterase;

- Ức chế muscarinic, giãn cơ vân

2 So sánh được về cơ chế, tác dụng, chỉ định, tác dụng

không mong muốn giữa:

- Các thuốc kích thích hệ cholinergic (thuốc chủ vận M và N với chủ

vận M, phong bế cholinesterase);

- Mềm cơ cura loại chống khử cực với cura loại khử cực lâu bền

Mục %êu học tập

2

THUỐC TÁC DỤNG TRÊN HỆ CHOLINERGIC

3

Lippincott's Illustrated Reviews: Pharmacology 6 th Edn

THUỐC KÍCH THÍCH CHOLINERGIC

5

98 SECTION II Autonomic Drugs

nerves as well as on some tissues that are not innervated by these nerves, eg, endothelial cells ( Table 7–1 ), and on those tissues

innervated by postganglionic sympathetic cholinergic nerves

Nicotinic receptors are part of a transmembrane polypeptide whose subunits form cation-selective ion channels (see Figure 2–9 )

These receptors are located on plasma membranes of onic cells in all autonomic ganglia, of muscles innervated by

postgangli-somatic motor fibers, and of some central nervous system neurons (see Figure 6–1 )

Nonselective cholinoceptor stimulants in sufficient dosage can produce very diffuse and marked alterations in organ system function because acetylcholine has multiple sites of action where it initiates

both excitatory and inhibitory effects Fortunately, drugs are available that have a degree of selectivity, so that desired effects can often be achieved while avoiding or minimizing adverse effects

Selectivity of action is based on several factors Some drugs stimulate either muscarinic receptors or nicotinic receptors selec- tively Some agents stimulate nicotinic receptors at neuromuscular junctions preferentially and have less effect on nicotinic receptors

in ganglia Organ selectivity can also be achieved by using priate routes of administration (“pharmacokinetic selectivity”)

appro-For example, muscarinic stimulants can be administered topically

to the surface of the eye to modify ocular function while ing systemic effects

Neuromuscular end plate, skeletal muscle

Reversible

Irreversible

muscle Seven transmembrane segments, Gi/o protein-linked Inhibition of cAMP pro- duction, activation of

K+ channels

endothelium Seven transmembrane segments, Gq/11 protein-linked IP3, DAG cascade

receptor Skeletal muscle neuromus- cular junction Pentamer

1 [(α1)2β1δγ)] Na+, K+ depolarizing ion

channel

receptor CNS, postganglionic cell body, dendrites Pentamer

1 with α and β subunits only, eg, ( α4)2( β2)3 (CNS) or

α3α5(β2)3 (ganglia)

Na+, K+ depolarizing ion channel

sub-scripts, eg, [(α1) 2 β1 δ γ] In adult muscle, the γ subunit is replaced by an ε subunit There are twelve neuronal nicotinic receptors with nine α (α2-α10) subunits and three (β2-β4) subunits The subunit composition varies among different mammalian tissues

DAG, diacylglycerol; IP3, inositol trisphosphate

Data from Millar NS: Assembly and subunit diversity of nicotinic acetylcholine receptors Biochem Soc Trans 2003;31:869

Basic and Clinical Pharmacology 12 th Edn

THUỐC KÍCH THÍCH TRỰC TIẾP M & N

Cơ chế

M

M 1: Co cơ trơn (hô hấp,

tiêu hóa, tiết niệu)

tim, cơ trơn

Tăng nhãn áp Liệt ruột (hậu phẫu)

Bí tiểu, trướng bụng (hậu phẫu)

THUỐC KÍCH THÍCH TRỰC TIẾP M & N

Cơ chế

M

tiêu hóa, tiết niệu)

tim, cơ trơn

THUỐC KÍCH THÍCH TRỰC TIẾP M

Cơ chế/ td

M

Co cơ vòng mống mắt Giảm hoạt động của tim

Co cơ trơn (hô hấp,

tiêu hóa, tiết niệu)

Tăng tuyến ngoại tiết

TDKMM Chống chỉ định

Chỉ định

9

THUỐC KÍCH THÍCH TRỰC TIẾP M & N

10

CHAPTER 7 Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs 99

MODE OF ACTION OF CHOLINOMIMETIC DRUGS

Direct-acting cholinomimetic agents bind to and activate inic or nicotinic receptors ( Figure 7–1 ) Indirect-acting agents

muscar-produce their primary effects by inhibiting acetylcholinesterase, which hydrolyzes acetylcholine to choline and acetic acid (see Figure 6–3 ) By inhibiting acetylcholinesterase, the indirect-acting drugs increase the endogenous acetylcholine concentration in syn-

aptic clefts and neuroeffector junctions The excess acetylcholine,

in turn, stimulates cholinoceptors to evoke increased responses

These drugs act primarily where acetylcholine is physiologically

released and are thus amplifiers of endogenous acetylcholine

Some cholinesterase inhibitors also inhibit butyrylcholinesterase (pseudocholinesterase) However, inhibition of butyrylcholinest-

erase plays little role in the action of indirect-acting cholinomimetic drugs because this enzyme is not important in the physiologic ter-

mination of synaptic acetylcholine action Some quaternary esterase inhibitors also have a modest direct action as well, eg,

cholin-neostigmine, which activates neuromuscular nicotinic tors directly in addition to blocking cholinesterase

■ BASIC PHARMACOLOGY OF THE DIRECTACTING

selective for receptor subtypes in either class

Chemistry & Pharmacokinetics

A Structure

Four important choline esters that have been studied extensively are shown in Figure 7–2 Their permanently charged quaternary ammonium group renders them relatively insoluble in lipids

Many naturally occurring and synthetic cholinomimetic drugs that are not choline esters have been identified; a few of these are shown in Figure 7–3 The muscarinic receptor is strongly stereo-

selective: (S) -bethanechol is almost 1000 times more potent than (R) -bethanechol

B Absorption, Distribution, and Metabolism

Choline esters are poorly absorbed and poorly distributed into the central nervous system because they are hydrophilic Although all are hydrolyzed in the gastrointestinal tract (and less active by the oral route), they differ markedly in their susceptibility to hydrolysis

by cholinesterase Acetylcholine is very rapidly hydrolyzed (see Chapter 6 ); large amounts must be infused intravenously to achieve concentrations sufficient to produce detectable effects A

large intravenous bolus injection has a brief effect, typically 5–20 seconds, whereas intramuscular and subcutaneous injections pro-duce only local effects Methacholine is more resistant to hydroly-sis, and the carbamic acid esters carbachol and bethanechol are still more resistant to hydrolysis by cholinesterase and have corre-spondingly longer durations of action The β-methyl group (methacholine, bethanechol) reduces the potency of these drugs at nicotinic receptors ( Table 7–2 )

The tertiary natural cholinomimetic alkaloids (pilocarpine, nicotine, lobeline; Figure 7–3 ) are well absorbed from most sites

of administration Nicotine, a liquid, is sufficiently lipid-soluble

to be absorbed across the skin Muscarine, a quaternary amine, is less completely absorbed from the gastrointestinal tract than the tertiary amines but is nevertheless toxic when ingested—eg, in certain mushrooms—and it even enters the brain Lobeline is a plant derivative similar to nicotine These amines are excreted chiefly by the kidneys Acidification of the urine accelerates clear-ance of the tertiary amines (see Chapter 1 )

Bethanechol (carbamoyl- β-methylcholine)

FIGURE 7–2 Molecular structures of four choline esters

Acetylcholine and methacholine are acetic acid esters of choline and β-methylcholine, respectively Carbachol and bethanechol are

carbamic acid esters of the same alcohols

agonists and antagonists that are directed against specific tor subtypes M1 receptor agonists are being investigated for the treatment of Alzheimer’s disease and M3 receptor antagonists for the treatment of chronic obstructive pulmonary disease [Note: At present, no clinically important agents interact solely with the M4and M5 receptors.]

recep-B Nicotinic receptors

These receptors, in addition to binding ACh, also recognize tine but show only a weak affinity for muscarine (Figure 4.4B) The nicotinic receptor is composed of five subunits, and it functions as

nico-a lignico-and-gnico-ated ion chnico-annel Binding of two ACh molecules elicits nico-a conformational change that allows the entry of sodium ions, resulting

in the depolarization of the effector cell Nicotine at low concentration stimulates the receptor, whereas nicotine at high concentration blocks the receptor Nicotinic receptors are located in the CNS, the adrenal medulla, autonomic ganglia, and the neuromuscular junction (NMJ)

in skeletal muscles Those at the NMJ are sometimes designated NM, and the others, NN The nicotinic receptors of autonomic ganglia differ from those of the NMJ For example, ganglionic receptors are selec-

tively blocked by mecamylamine, whereas NMJ receptors are cally blocked by atracurium.

specifi-IV DIRECT-ACTING CHOLINERGIC AGONISTS

Cholinergic agonists mimic the effects of ACh by binding directly to linoceptors (muscarinic or nicotinic) These agents may be broadly clas- sified into two groups: 1) endogenous choline esters, which include ACh

cho-and synthetic esters of choline, such as carbachol cho-and bethanechol, and 2) naturally occurring alkaloids, such as nicotine and pilocarpine

(Figure 4.5) All of the direct-acting cholinergic drugs have a l onger duration of action than ACh The more therapeutically useful drugs

( pilocarpine and bethanechol) preferentially bind to muscarinic receptors

and are sometimes referred to as muscarinic agents [Note: Muscarinic receptors are located primarily, but not exclusively, at the neuroeffector junction of the parasympathetic nervous system.] However, as a group, the direct-acting agonists show little specificity in their actions, which limits their clinical usefulness.

A Acetylcholine

Acetylcholine [ah-see-teel-KOE-leen] is a quaternary ammonium compound that cannot penetrate membranes Although it is the neurotransmitter of parasympathetic and somatic nerves as well as autonomic ganglia, it lacks therapeutic importance because of its multiplicity of actions (leading to diffuse effects) and its rapid inactiva- tion by the cholinesterases ACh has both muscarinic and nicotinic activity Its actions include the following:

1 Decrease in heart rate and cardiac output: The actions of ACh

on the heart mimic the effects of vagal stimulation For example,

if injected intravenously, ACh produces a brief decrease in diac rate (negative chronotropy) and stroke volume as a result

O

CH3

CH3CH

CH3

H2N

Bethanechol (derivative of acetylcholine)

H2N

Carbachol (derivative of acetylcholine)

N C

CH3

CH2 CH2O

CH3O

2 3

CH3

2

Bethanechol (derivative of acetylcholine)

Ester of carbamic acid;

resists hydrolysis by acetylcholinesterase

Muscarine

Muscarine Acetylcholine Nicotine

High affinity affinityLow

Muscarinic receptors

Nicotinic receptors

Low affinity affinityHigh

A

B

Figure 4.4

Types of cholinergic receptors.

pseudocholinesterase, is found in the plasma, but does not play

a significant role in the termination of the effect of ACh in the synapse.]

6 Recycling of choline: Choline may be recaptured by a

sodium-coupled, high-affinity uptake system that transports the molecule back into the neuron There, it is acetylated into ACh that is stored until released by a subsequent action potential.

III CHOLINERGIC RECEPTORS (CHOLINOCEPTORS)

Two families of cholinoceptors, designated muscarinic and nicotinic receptors, can be distinguished from each other on the basis of their dif- ferent affinities for agents that mimic the action of ACh (cholinomimetic agents).

A Muscarinic receptors

Muscarinic receptors belong to the class of G protein–coupled tors (metabotropic receptors) These receptors, in addition to binding ACh, also recognize muscarine, an alkaloid that is present in certain poisonous mushrooms In contrast, the muscarinic receptors show only a weak affinity for nicotine (Figure 4.4A) There are five sub- classes of muscarinic receptors However, only M1, M2, and M3 recep- tors have been functionally characterized.

recep-1 Locations of muscarinic receptors: These receptors are found on

ganglia of the peripheral nervous system and on the autonomic tor organs, such as the heart, smooth muscle, brain, and exocrine glands Although all five subtypes are found on neurons, M1 recep- tors are also found on gastric parietal cells, M2 receptors on cardiac cells and smooth muscle, and M3 receptors on the bladder, exocrine glands, and smooth muscle [Note: Drugs with muscarinic actions pref- erentially stimulate muscarinic receptors on these tissues, but at high concentration, they may show some activity at nicotinic receptors.]

effec-2 Mechanisms of acetylcholine signal transduction: A number

of different molecular mechanisms transmit the signal generated

receptors are activated, the receptor undergoes a conformational change and interacts with a G protein, designated Gq, that in turn activates phospholipase C This ultimately leads to the production

of the second messengers inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) IP3 causes an increase in intracellular Ca 2+ Calcium can then interact to stimulate or inhibit enzymes or to cause hyperpolarization, secretion, or contraction Diacylglycerol activates protein kinase C, an enzyme that phosphorylates numer- ous proteins within the cell In contrast, activation of the M2 subtype

on the cardiac muscle stimulates a G protein, designated Gi, that inhibits adenylyl cyclase and increases K + conductance The heart responds with a decrease in rate and force of contraction.

3 Muscarinic agonists: Pilocarpine is an example of a nonselective

muscarinic agonist used in clinical practice to treat xerostomia and glaucoma Attempts are currently underway to develop muscarinic

Lippincott's Illustrated Reviews: Pharmacology 5 th Edn

Tóm tắt đặc điểm các thuốc kích thích trực tiếp cholinergic

11

Miscellaneous Effects. The influence of ACh and parasympathetic innervation on various organs and tissues is discussed in detail in Chapter 6 ACh and its analogs stimulate secretion by all glands that receive parasympathetic innervation, including the lacrimal, trache- obronchial, salivary, and digestive glands The effects on the respi- ratory system, in addition to increased tracheobronchial secretion, include bronchoconstriction and stimulation of the chemoreceptors

of the carotid and aortic bodies When instilled into the eye,

musca-rinic agonists produce miosis (see Chapter 63).

Synergisms and Antagonisms. The muscarinic actions

of ACh and all the drugs of this class are blocked by pine, primarily through competitive occupation of musca-rinic receptor sites on the autonomic effector cells andsecondarily on autonomic ganglion cells The nicotinicactions of ACh and its derivatives at autonomic ganglia

atro-are blocked by hexamethonium and trimethaphan;

nico-tinic actions at the neuromuscular junction of skeletal

muscle are antagonized by d-tubocurarine and other petitive blocking agents (see Chapter 9).

com-CHOLINOMIMETIC CHOLINE ESTERS AND NATURAL ALKALOIDS

Muscarinic cholinergic receptor agonists can be dividedinto two groups: (1) ACh and several synthetic cholineesters, and (2) the naturally occurring cholinomimetic alka-

loids (particularly pilocarpine, muscarine, and arecoline)

and their synthetic congeners

Methacholine (acetyl-β-methylcholine) differs fromACh chiefly in its greater duration and selectivity ofaction Its action is more prolonged because the addedmethyl group increases its resistance to hydrolysis bycholinesterases Its selectivity is manifested by slightnicotinic and a predominance of muscarinic actions, the

latter being manifest in the cardiovascular system(Table 7–1)

Carbachol and bethanechol, which are unsubstitutedcarbamoyl esters, are completely resistant to hydrolysis

by cholinesterases; their half-lives are thus sufficientlylong that they become distributed to areas of low bloodflow Bethanechol has mainly muscarinic actions, show-ing some selectivity on gastrointestinal tract and urinarybladder motility Carbachol retains substantial nicotinicactivity, particularly on autonomic ganglia It is likely thatboth its peripheral and its ganglionic actions are due, atleast in part, to the release of endogenous ACh from theterminals of cholinergic fibers

The three major natural alkaloids in this carpine, muscarine, and arecoline—have the same princi-pal sites of action as the choline esters discussed above

group—pilo-Muscarine acts almost exclusively at muscarinic receptorsites, and the classification of the receptors as such isderived from this fact Arecoline also acts at nicotinicreceptors Pilocarpine has a dominant muscarinic action,but it causes anomalous cardiovascular responses; thesweat glands are particularly sensitive to the drug

Although these naturally occurring alkaloids are of greatvalue as pharmacological tools, present clinical use isrestricted largely to the employment of pilocarpine as a

sialagogue and miotic agent (see Chapter 63).

History and Sources. Of the several hundred synthetic choline atives investigated, only methacholine, carbachol, and bethanechol have had clinical applications The structures of these compounds are shown in Figure 7–1 Methacholine, the β -methyl analog of ACh, was studied by Hunt and Taveau as early as 1911 Carbachol and bethanechol, its β -methyl analog, were synthesized and investigated

deriv-in the 1930s Pilocarpderiv-ine is the chief alkaloid obtaderiv-ined from the

leaf-lets of South American shrubs of the genus Pilocarpus Although it was long known by the natives that the chewing of leaves of Pilocar-

pus plants caused salivation, the first experiments were apparently

Table 7–1

Some Pharmacological Properties of Choline Esters and Natural Alkaloids

MUSCARINIC AGONIST

SUSCEPTIBILITY TO CHOLINESTERASES

MUSCARINIC ACTIVITY

NICOTINIC ACTIVITY

vascular

Cardio- intestinal

Gastro-Urinary Bladder

Eye (Topical)

3 Adverse effects: Bethanechol causes the effects of generalized

cho-linergic stimulation (Figure 4.6) These include sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diar-

rhea, and bronchospasm Atropine sulfate may be administered to overcome severe cardiovascular or bronchoconstrictor responses to

sub-but at a much slower rate

1 Actions: Carbachol has profound effects on both the cardiovascular

and GI systems because of its ganglion-stimulating activity, and it may first stimulate and then depress these systems It can cause re-

lease of epinephrine from the adrenal medulla by its nicotinic action

Locally instilled into the eye, it mimics the effects of ACh, causing miosis and a spasm of accommodation in which the ciliary muscle

of the eye remains in a constant state of contraction

2 Therapeutic uses: Because of its high potency, receptor

nonselec-tivity, and relatively long duration of action, carbachol is rarely used therapeutically except in the eye as a miotic agent to treat glaucoma

by causing pupillary contraction and a decrease in intraocular sure Onset of action for miosis is 10 to 20 minutes Intraocular pres-

pres-sure is reduced for 4 to 8 hours.

3 Adverse effects: At doses used ophthalmologically, little or no

side effects occur due to lack of systemic penetration (quaternary amine)

D Pilocarpine

The alkaloid pilocarpine [pye-loe-KAR-peen] is a tertiary amine and is stable to hydrolysis by AChE (see Figure 4.5) Compared with ACh and its derivatives, it is far less potent but is uncharged and will penetrate the CNS at therapeutic doses Pilocarpine exhibits muscarinic activity

and is used primarily in ophthalmology.

1 Actions: Applied topically to the cornea, pilocarpine produces rapid

miosis and contraction of the ciliary muscle When the eye goes this miosis, it experiences a spasm of accommodation The vi- sion becomes fixed at some particular distance, making it impos- sible to focus (Figure 4.7) [Note the opposing effects of atropine, a

under-muscarinic blocker, on the eye (see p 59).] Pilocarpine is one of the most potent stimulators of secretions (secretagogue) such as sweat, tears, and saliva, but its use for producing these effects has been limited due to its lack of selectivity The drug is beneficial in promot-

ing salivation in patients with xerostomia resulting from irradiation

of the head and neck Sjögren’s syndrome, which is characterized by dry mouth and lack of tears, is treated with oral pilocarpine tablets and cevimeline, a cholinergic drug that also has the drawback of be-

ing nonspecific.

Untreated eye

Mydriasis

(dilation of the pupil)

Miosis

(contraction of the pupil)

Figure 4.7

Actions of pilocarpine and atropine on the iris and ciliary muscle of the eye.

Eye treated with atropine

Eye treated with pilocarpine

3 Adverse effects: Bethanechol causes the effects of generalized

cho-linergic stimulation (Figure 4.6) These include sweating, salivation, flushing, decreased blood pressure, nausea, abdominal pain, diar-

rhea, and bronchospasm Atropine sulfate may be administered to overcome severe cardiovascular or bronchoconstrictor responses to

sub-but at a much slower rate

1 Actions: Carbachol has profound effects on both the cardiovascular

and GI systems because of its ganglion-stimulating activity, and it may first stimulate and then depress these systems It can cause re-

lease of epinephrine from the adrenal medulla by its nicotinic action

Locally instilled into the eye, it mimics the effects of ACh, causing miosis and a spasm of accommodation in which the ciliary muscle

of the eye remains in a constant state of contraction

2 Therapeutic uses: Because of its high potency, receptor

nonselec-tivity, and relatively long duration of action, carbachol is rarely used therapeutically except in the eye as a miotic agent to treat glaucoma

by causing pupillary contraction and a decrease in intraocular sure Onset of action for miosis is 10 to 20 minutes Intraocular pres-

pres-sure is reduced for 4 to 8 hours.

3 Adverse effects: At doses used ophthalmologically, little or no

side effects occur due to lack of systemic penetration (quaternary amine)

D Pilocarpine

The alkaloid pilocarpine [pye-loe-KAR-peen] is a tertiary amine and is stable to hydrolysis by AChE (see Figure 4.5) Compared with ACh and its derivatives, it is far less potent but is uncharged and will penetrate the CNS at therapeutic doses Pilocarpine exhibits muscarinic activity

and is used primarily in ophthalmology.

1 Actions: Applied topically to the cornea, pilocarpine produces rapid

miosis and contraction of the ciliary muscle When the eye goes this miosis, it experiences a spasm of accommodation The vi- sion becomes fixed at some particular distance, making it impos- sible to focus (Figure 4.7) [Note the opposing effects of atropine, a

under-muscarinic blocker, on the eye (see p 59).] Pilocarpine is one of the most potent stimulators of secretions (secretagogue) such as sweat, tears, and saliva, but its use for producing these effects has been limited due to its lack of selectivity The drug is beneficial in promot-

ing salivation in patients with xerostomia resulting from irradiation

of the head and neck Sjögren’s syndrome, which is characterized by dry mouth and lack of tears, is treated with oral pilocarpine tablets and cevimeline, a cholinergic drug that also has the drawback of be-

ing nonspecific.

Untreated eye

Mydriasis

(dilation of the pupil)

Miosis

(contraction of the pupil)

Figure 4.7

Actions of pilocarpine and atropine on the iris and ciliary muscle of the eye.

Eye treated with atropine

Eye treated with pilocarpine

Liệt cơ trơn tiết niệu, tiêu hóa Bethanechol

THUỐC KHÁNG CHOLINESTERASE

12

12 Directly and Indirectly Acting Cholinomimetics 129

sion, including that in the adrenal medulla, can produce

complicated effects on the cardiovascular system,

in-cluding vasoconstrictor responses The activation of

flexes can also complicate the total cardiovascular

re-sponse to cholinesterase inhibitors

Clinical Uses

Myasthenia Gravis

Myasthenia gravis is an autoimmune disease in which

antibodies recognize nicotinic cholinoreceptors on

skeletal muscle.This decreases the number of functional

receptors and consequently decreases the sensitivity of

the muscle to ACh Muscle weakness and rapid fatigue

of muscles during use are characteristics of the disease

Anticholinesterase agents help to alleviate the

weak-ness by elevating and prolonging the concentration of

ACh in the synaptic cleft, producing a greater activation

of the remaining nicotinic receptors By contrast,thymectomy, plasmapheresis, and corticosteroid admin-istration are treatments directed at decreasing the au-toimmune response

Anticholinesterase agents play a key role in the agnosis and therapy of myasthenia gravis, because theyincrease muscle strength During diagnosis, the patient’smuscle strength is examined before and immediately af-ter the intravenous injection of edrophonium chloride

di-In myasthenics, an increase in muscle strength is tained for a few minutes

ob-The pronounced weakness that may result from adequate therapy of myasthenia gravis (myasthenic crisis) can be distinguished from that due to anti-cholinesterase overdose (cholinergic crisis) by the use

in-of edrophonium In cholinergic crisis, edrophonium will briefly cause a further weakening of muscles,whereas improvement in muscle strength is seen in the

A No Drug

ACh

ACh ACh

ACh

ACh

AChE ACh

Action of AChE at a cholinergic neuroeffector function and effects of AChE inhibition A Key

features of cholinergic neurotransmission in the absence of drugs After release from a

cholinergic nerve terminal or varicosity, ACh can (1) bind reversibly to cholinergic receptors in the

postsynaptic membrane and elicit a response or (2) bind to AChE and undergo hydrolysis to

choline and acetic acid (inactive metabolites) The survival time of released ACh is quite brief

because of the abundance and effectiveness of AChE B The consequences of inhibiting AChE.

Since ACh no longer has access to the active site of AChE, the concentration of ACh in the

synaptic cleft increases This can result in enhanced transmission due to (3) repeated activation

of receptors and (4) activation of additional cholinergic receptors.

Cholin và acid acetat

• Cơ chế

Modern Pharmacology and Clincal Application 6th edn

O C NN

N

H3C

PO

H3

N

O CON

betel chewing

AChE

Direct mimetics

parasympatho-AChE

Inhibitors ofacetylcholinesterase(AChE)

Indirect parasympathomimetics

E 605

Choline

AChE

ms

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved Usage subject to terms and conditions of license

Parasympathomimetics 107

H3C O

O C

O C N N

N

H3C

P O

OC 2 H 5

OC2H5

N CH3C

O CO

H3

CH CH 3

N

O C O N

betel chewing

AChE

Direct mimetics

parasympatho-AChE

Inhibitors of acetylcholinesterase (AChE)

Indirect parasympathomimetics

Acetyl

Deacetylation

Acetylcholine +

Nitrostigmine = Parathion =

E 605

Choline

AChE

ms

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved Usage subject to terms and conditions of license

Ức chế cholinesterase thuận nghịch và không thuận nghịch

14

CHAPTER 7 Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs 105

blockade persists even when the membrane has repolarized

(dis-cussed further in Chapters 8 and 27) This latter phase of block

is manifested as flaccid paralysis in the case of skeletal muscle

■ BASIC PHARMACOLOGY OF

THE INDIRECTACTING

CHOLINOMIMETICS

The actions of acetylcholine released from autonomic and somatic

motor nerves are terminated by enzymatic hydrolysis of the

mol-ecule Hydrolysis is accomplished by the action of

acetylcholinest-erase, which is present in high concentrations in cholinergic

synapses The indirect-acting cholinomimetics have their primary

effect at the active site of this enzyme, although some also have

direct actions at nicotinic receptors The chief differences between

members of the group are chemical and pharmacokinetic—their

pharmacodynamic properties are almost identical

Chemistry & Pharmacokinetics

A Structure

There are three chemical groups of cholinesterase inhibitors:

(1) simple alcohols bearing a quaternary ammonium group, eg,

edrophonium; (2) carbamic acid esters of alcohols having

quater-nary or tertiary ammonium groups (carbamates, eg, neostigmine);

and (3) organic derivatives of phosphoric acid (organophosphates,

eg, echothiophate) Examples of the first two groups are shown in

Figure 7–6 Edrophonium, neostigmine, and pyridostigmine are

synthetic quaternary ammonium agents used in medicine

Physostigmine (eserine) is a naturally occurring tertiary amine of

greater lipid solubility that is also used in therapeutics Carbaryl (carbaril) is typical of a large group of carbamate insecticides designed for very high lipid solubility, so that absorption into the insect and distribution to its central nervous system are very rapid

A few of the estimated 50,000 organophosphates are shown in Figure 7–7 Many of the organophosphates (echothiophate is an exception) are highly lipid-soluble liquids Echothiophate, a thio- choline derivative, is of clinical value because it retains the very long duration of action of other organophosphates but is more stable in aqueous solution Soman is an extremely potent “nerve gas.” Parathion and malathion are thiophosphate (sulfur-containing phosphate) prodrugs that are inactive as such; they are converted

to the phosphate derivatives in animals and plants and are used as insecticides

B Absorption, Distribution, and Metabolism

Absorption of the quaternary carbamates from the conjunctiva, skin, gut and lungs is predictably poor, since their permanent charge ren- ders them relatively insoluble in lipids Thus, much larger doses are required for oral administration than for parenteral injection

Distribution into the central nervous system is negligible

Physostigmine, in contrast, is well absorbed from all sites and can be used topically in the eye ( Table 7–4 ) It is distributed into the central nervous system and is more toxic than the more polar quaternary carbamates The carbamates are relatively stable in aqueous solution but can be metabolized by nonspecific esterases in the body as well

as by cholinesterase However, the duration of their effect is mined chiefly by the stability of the inhibitor-enzyme complex (see Mechanism of Action, below), not by metabolism or excretion

The organophosphate cholinesterase inhibitors (except for echothiophate) are well absorbed from the skin, lung, gut, and

FIGURE 7–6 Cholinesterase inhibitors Neostigmine exemplifies the typical ester composed of carbamic acid ([1]) and a phenol bearing a

quaternary ammonium group ([2]) Physostigmine, a naturally occurring carbamate, is a tertiary amine Edrophonium is not an ester but binds

to the active site of the enzyme Carbaryl is used as an insecticide

106 SECTION II Autonomic Drugs

conjunctiva—thereby making them dangerous to humans and highly effective as insecticides They are relatively less stable than the carbamates when dissolved in water and thus have a limited half-life

in the environment (compared with another major class of cides, the halogenated hydrocarbons, eg, DDT) Echothiophate is highly polar and more stable than most other organophosphates

insecti-When prepared in aqueous solution for ophthalmic use, it retains activity for weeks

The thiophosphate insecticides (parathion, malathion, and related compounds) are quite lipid-soluble and are rapidly absorbed by all routes They must be activated in the body by conversion to the oxygen analogs ( Figure 7–7 ), a process that occurs rapidly in both insects and vertebrates Malathion and a few other organophosphate insecticides are also rapidly metabo- lized by other pathways to inactive products in birds and mam- mals but not in insects; these agents are therefore considered safe enough for sale to the general public Unfortunately, fish cannot detoxify malathion, and significant numbers of fish have died from the heavy use of this agent on and near waterways Parathion

is not detoxified effectively in vertebrates; thus, it is considerably more dangerous than malathion to humans and livestock and is not available for general public use in the USA

All the organophosphates except echothiophate are distributed

to all parts of the body, including the central nervous system

Therefore, central nervous system toxicity is an important nent of poisoning with these agents

All the cholinesterase inhibitors increase the concentration of endogenous acetylcholine at cholinoceptors by inhibiting acetyl- cholinesterase However, the molecular details of their interaction with the enzyme vary according to the three chemical subgroups mentioned above

O P O O

S

NO2

Parathion

O P O O O

Paraoxon

S P O

C

CH2 O C2H5O

S P O

Malathion Malaoxon

S P O

Edrophonium Myasthenia gravis,

ileus, arrhythmias 5–15 minutes

Carbamates and related agents

Neostigmine Myasthenia gravis,

ileus 0.5–2 hours Pyridostigmine Myasthenia gravis 3–6 hours Physostigmine Glaucoma 0.5–2 hours Ambenonium Myasthenia gravis 4–8 hours Demecarium Glaucoma 4–6 hours

Organophosphates

Echothiophate Glaucoma 100 hours

Các chất phosphat hữu cơ:

- ⋮ tạo liên kết bền vững với enzym

- Parathion và malathion là thiophosphate (tiền chất) à d.chất phosphat trong cơ thể ĐV và TV à thuốc trừ sâu

- Neostigmine: ester của carbamic acid [1], có nhóm amin bậc 4 ở nhân phenol [2]

Ức chế cholinesterase thuận nghịch và không thuận nghịch

15 (2-PAM)

t.dụng của thuốc kéo dài

Enzym bị phosphoryl hóa

Ức chế cholinesterase thuận nghịch và không thuận nghịch

16

Figure 13.9 Reactivation of plasma cholinesterase (ChE) in a volunteer subject by intravenous injection of pralidoxime (Redrawn

from Sim V M 1965 JAMA 192: 404.)

The neuromuscular junction is a robust structure that very rarely fails, myasthenia gravis

being one of the very few disorders that specifically affects it (see Lindstrom, 2000) This

disease affects about 1 in 2000 individuals, who show muscle weakness and increased

fatiguability resulting from a failure of neuromuscular transmission The tendency for

transmission to fail during repetitive activity can be seen in Figure 13.10 Functionally, it

results in the inability of muscles to produce sustained contractions, of which the

characteristic drooping eyelids of myasthenic patients are a sign The effectiveness of

anticholinesterase drugs in improving muscle strength in myasthenia was discovered in

1931, long before the cause of the disease was known.

• Phục hồi hoạt động enzym

- Cần giải độc sớm

- Hiệu quả trong vài giờ đầu

anticholinesterases as possible remedies for the loss of cognitive

function Tacrine [TAK-reen] was the first to become available, but it

has been replaced by others because of its hepatotoxicity Despite

the ability of donepezil [doe-NEP-e-zil], rivastigmine meen], and galantamine [ga-LAN-ta-meen] to delay the progression

[ri-va-STIG-of Alzheimer’s disease, none can stop its progression GI distress is their primary adverse effect (see Chapter 8).

VI INDIRECT-ACTING CHOLINERGIC AGONISTS:

ANTICHOLINESTERASE AGENTS (IRREVERSIBLE)

A number of synthetic organophosphate compounds have the capacity

to bind covalently to AChE The result is a long-lasting increase in ACh at all sites where it is released Many of these drugs are extremely toxic and were developed by the military as nerve agents Related compounds,

such as parathion and malathion, are used as insecticides.

A Echothiophate

1 Mechanism of action: Echothiophate [ek-oe-THI-oh-fate] is an

organophosphate that covalently binds via its phosphate group at the active site of AChE (Figure 4.10) Once this occurs, the enzyme

is permanently inactivated, and restoration of AChE activity requires the synthesis of new enzyme molecules Following covalent modi- fication of AChE, the phosphorylated enzyme slowly releases one

of its ethyl groups The loss of an alkyl group, which is called aging,

makes it impossible for chemical reactivators, such as pralidoxime, to

break the bond between the remaining drug and the enzyme.

2 Actions: Actions include generalized cholinergic stimulation,

paralysis of motor function (causing breathing difficulties), and

convulsions Echothiophate produces intense miosis and, thus,

has found therapeutic use Intraocular pressure falls from the

facili-tation of outflow of aqueous humor Atropine in high dosages can

reverse many of the peripheral and some of the central muscarinic

effects of echothiophate.

3 Therapeutic uses: A topical ophthalmic solution of the drug is

available for the treatment of open-angle glaucoma However,

echothiophate is rarely used due to its side effect profile, which

includes the risk of causing cataracts Figure 4.11 summarizes the actions of some of the cholinergic agonists.

VII TOXICOLOGY OF ANTICHOLINESTERASE AGENTS

Irreversible AChE inhibitors (mostly organophosphate compounds) are commonly used as agricultural insecticides in the United States, which has led to numerous cases of accidental poisoning with these agents In addition, they are frequently used for suicidal and homicidal purposes

Organophosphate nerve gases such as sarin are used as agents of warfare and chemical terrorism Toxicity with these agents is manifested as nicotinic and muscarinic signs and symptoms (cholinergic crisis) Depending on the agent, the effects can be peripheral or can affect the whole body.

Figure 4.10

Covalent modification of acetylcholinesterase by

echothiophate Also shown is the

reactivation of the enzyme with

C2H5–O–P–O–C2H5O

S–R

C2H5–O–P–O–C2H5O

C2H5–O–P–OH O

C2H5–O–P–O–C2H5O

C2H5–O–P–O–C2H5O S–R Echothiophate

Aging (loss of alkyl group)

PHOSPHORYLATION

OF ENZYME

Enzyme inactivated Pralidoxime (2-PAM) can remove the inhibitor

Acetylcholinesterase (inactive)

Acetylcholinesterase (irreversibly inactive)

Acetylcholinesterase (active)

H O2

C2H5–OH

0002115106.INDD 60 6/21/2014 6:40:21 PM

THUỐC KHÁNG CHOLINESTERASE

Cơ chế

M

tiêu hóa, tiết niệu)

- Nhược cơ

- Giải độc thuốc mềm cơ loại chống khử cực

17

THUỐC KHÁNG CHOLINESTERASE

Cơ chế

M

tiêu hóa, tiết niệu)

- Tăng tiết dịch

- ↓ nhịp, ↓ HA

- Kích thích TKTƯ, co giật

- Co cơ vân

18

THUỐC KHÁNG CHOLINESTERASE

• Ứng dụng và thời gian tác dụng của các chất ức chế ChE

19

106 SECTION II Autonomic Drugs

conjunctiva—thereby making them dangerous to humans and highly effective as insecticides They are relatively less stable than the carbamates when dissolved in water and thus have a limited half-life

in the environment (compared with another major class of cides, the halogenated hydrocarbons, eg, DDT) Echothiophate is

insecti-highly polar and more stable than most other organophosphates

When prepared in aqueous solution for ophthalmic use, it retains activity for weeks

The thiophosphate insecticides (parathion, malathion, and related compounds) are quite lipid-soluble and are rapidly absorbed by all routes They must be activated in the body by conversion to the oxygen analogs ( Figure 7–7 ), a process that occurs rapidly in both insects and vertebrates Malathion and a few other organophosphate insecticides are also rapidly metabo-

lized by other pathways to inactive products in birds and mals but not in insects; these agents are therefore considered safe

mam-enough for sale to the general public Unfortunately, fish cannot detoxify malathion, and significant numbers of fish have died from the heavy use of this agent on and near waterways Parathion

is not detoxified effectively in vertebrates; thus, it is considerably more dangerous than malathion to humans and livestock and is

not available for general public use in the USA

All the organophosphates except echothiophate are distributed

to all parts of the body, including the central nervous system

Therefore, central nervous system toxicity is an important nent of poisoning with these agents

All the cholinesterase inhibitors increase the concentration of endogenous acetylcholine at cholinoceptors by inhibiting acetyl- cholinesterase However, the molecular details of their interaction with the enzyme vary according to the three chemical subgroups mentioned above

O P

O O

S

NO2

Parathion

O P

O O O

Paraoxon

S P

O

S P

O CH

Edrophonium Myasthenia gravis,

ileus, arrhythmias 5–15 minutes

Carbamates and related agents

Neostigmine Myasthenia gravis,

Pyridostigmine Myasthenia gravis 3–6 hours

Ambenonium Myasthenia gravis 4–8 hours

Rivastigmine Chọn lọc trên CNS T/d cholinergic giảm dần khi tiếp tục điều trị

Galantamine Tác dụng trên cả AChE và BuChE T/d cholinergic nhẹ

(BuChE, butyryl cholinesterase)

Figure 39.4 Simplified diagram of the organisation of the extrapyramidal motor system and the defects that occur in Parkinson's

disease (PD) and Huntington's disease Normally, activity in nigrostriatal dopamine neurons causes excitation of striatonigral neurons and

inhibition of striatal neurons that project to the globus pallidus In either case, because of the different pathways involved, the activity of GABAergic neurons in the substantia nigra is suppressed, releasing the restraint on the thalamus and cortex, causing motor stimulation In

PD, the dopaminergic pathway from the substantia nigra (pars compacta) to the striatum is impaired In Huntington's disease, the GABAergic

striatopallidal pathway is impaired, producing effects opposite to the changes in PD.

page 485 page 486

Cholinergic interneurons of the corpus striatum (not shown in Fig 39.4) are also involved in

PD and Huntington's disease Acetylcholine release from the striatum is strongly inhibited by dopamine, and it is suggested that hyperactivity of these cholinergic neurons contributes to the symptoms of PD The opposite happens in Huntington's disease, and in both conditions therapies aimed at redressing the balance between the dopaminergic and cholinergic

neurons are, up to a point, beneficial.

PATHOGENESIS OF PARKINSON'S DISEASE