Cholinoceptor blocking drugs

Jiang Junlin 江俊麟

Department of Pharmacology,

School of Pharmaceutical Science, Central South University

Cholinoceptor antagonists are divided into M and N subgroups based on their specific receptor affinities.

The N receptor antagonists consist of ganglion-blockers (N1,NN) and neuromuscular junction blockers (N2,NM).

M Receptor-blocking Drugs

are called parasympatholytic because they block the effects of parasympathetic

autonomic discharge.

Naturally occurring compounds with anti-M receptor effects have

been used for millennia as medicines, poisons, and cosmetics.

Atropine is their prototype. Many similar plant alkaloids are known.

Hundred of synthetic anti-M receptor compounds have been

prepared.

daturaAtropena belladonna

Deadly nightshade (Atropena belladonna) is

the natural source of the alkaloid atropine.

The term atropena is derived from Atropos

because of its high toxicity.

Atropine was a popular choice of poison

among professional poisoners during the

Middle Ages because of the slowness of

their effects which allowed the perpetrator

to escape before suspicions. According to

the Scottish legend, the soldiers of

Macbeth slipped atropine into the drinks

of the invading Danes then slaughter them

in their slumber.

In Roman time, ladies in the Court used the

juice from the berry to dilate their pupils

to make them look more sexsual and

attractive and hence the name belladonna

(beautiful lady). Atropena belladonna can

be translated as femme fatale.

Atropine

PharmacokineticsMost of antimuscarinic drugs being tertiary agents

reaches the CNS

Scopolamine is rapidly and fully distributed into the CNS

well absorbed from the gut and widely distributed in the body

where it has greater effects than most others

The quaternary derivatives are poorly taken up by the brain.

They are relatively less effect of CNS

Atropine

Pharmacokinetics

Atropine disappears rapidly from the blood, t ½ of 2-4 h.

The effect declines rapidly in all organs except the eye . Effects on the eye persist for ≥ 3 days.

About 50% of the dose is excreted unchanged in the urine.

The rest appears as hydrolysis and conjugation products.

A. Mechanism of Action:

blocks M receptor competitively

The effectiveness varies with tissues.

The most sensitive tissues to

atropine are the salivary, sweat

glands, the smooth muscle of

digestive tract, bladder, bronchial,

and uterus.

The least sensitive is the gastric

parietal cells secreting acid.

Pharmacodynamics: block M-R at therapeutic dose

block NN-R at large dose

The smooth muscles of the iris

The sphincter muscle is innervated by cholinergic fibers to M receptors. Its contraction under the influence of an agonist results in miosis

The radial muscle is innervated by adrenergic fibers to an alpha-1 receptor. Its contraction by an agonist results in mydriasis and its blockade results in miosis

1. Eye— Mydriasis

Atropine and other anti-M drugs block M receptor and results in dilatation of iris and mydriasis.

B. Organ System Effects

1. Eye—

Mydriasis

intraocular pressure↑

Atropine block M receptor, contract the iris, and reduce the angle space of anterior chamber so as to prevent outflow of aqueous humor, increasing the the intraocular pressure.

Atropineblocks M receptor,inhibits the contraction of the iris, and narrow the angle space of anterior chamber

so as to prevent outflow of aqueous humor, increasing the intraocular pressure.

1. Eye—

Mydriasis 扩瞳

intraocular pressure↑ 升眼压

cycloplegia 调节麻痹

Anti-M drugs block M receptor, inhibit the contraction of the ciliary muscle, result in cycloplegia.

Accommodation and pupillary reflexs may not fully recover for 7 to 12 days. Muscarinic antagonist with short duration of actions are preferred as mydriatics in ophthalmological practice.

1. Eye— Mydriasis 扩瞳 intraocular pressure↑ 升眼压 cycloplegia 调节麻痹

Dry eyes

Antimuscarinic drugs reduce lacrimal secretion.

2. Cardioavascular system

Cardiomuscle is controlled by lesser degree of M receptor. Atropine has no clinical significant effect on it.

Sinoatrial nodeis controlled by M receptor.Atropine blocks M receptor and causes tachycardia to next. Lower doses (0.4-0.6 mg) results in initial bradycardia due to block presynaptic M receptor which limit ACh release.

Atropine blocks M receptor on atrioventricular node, increase the conduction, and the PR interval of ECG.

In toxic doses, atropine blocks intraventricular conduction

Dose- response curve for the effects of atropine on heart rate

Atropine dose (μg/kg) to back

2 4 6 8 10

60

70

80

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Almost all vessels contain endothelial M receptors that mediate vasodilation. there is little effect on blood pressure alone.

At toxic doses, and in some individuals at normal doses, atropine cause cutaneous vasodilation. (it is may be a compensatory reaction permitting the radiation of heat to offset the atropin-induced rise in temperature that can accompany inhibition of sweating)

Blood Vessels

3. Respiratory System

Both smooth muscle and secretory glands of the airway receive vagal innervation and contain muscarinic receptors.

Atropine dilates bronchi and inhibits secretion of gland. The effect is more significant in patients with airway disease although the antimuscarinic drugs are not as useful as the β-adrenoceptor stimulants in the treatment of asthma.

4. Gastrointestinal Tract

Prolonged inhibitory effects on the motor activity of the stomach, duodenum, ileum and colon

Reduction in tone and in amplitude and frequency of peristaltic contraction.

Antimuscurinic drugs have marked effect on salivary secretion; Dry mouth occurs frequently.

Atropine inhibits gastric secretion less effectively, reduces the volume and amount of acid, pepsin, and basal secretion in large doses.

5. Genitourinary Tract—Atropine and its analogs relax smooth

muscle of the ureters and bladder wall and slows voiding.

This action is useful in the treatment of spasm induced by inflammation, surgery, and certain neurologic conditions, but it can cause urinary retention in elderly men with prostatic hyperplasia.

The antimucarinic drugs have no significant effect on the uterus.

6. Sweat Glands—Sympathetic cholinergic fibers innervate

sweat glands.

Atropine suppresses thermoregulatory

sweating.

In adults, body temperature is elevated by

large dose.

In infants and children even ordinary dose

may cause “atropine fever.”

High fever, body temperature is 39-42 , called " atropine fever ℃".

Scopolamine has marked central effects,

producing drowsiness and amnesia.

In toxic doses can cause excitement, agitation, hallucinations, and coma. (larger doses than toxic doses, stimulation is followed by depression, leading to circulatory collapse and respiratory failure

after a period of paralysis and coma)

7. Central Nerve System Atropine has minimal effects on the CNS.

Parkinson's disease occurs when neurons degenerate (lose the ability to function normally) in a part of the brain called the substantia nigra. Many of these neurons that degenerate contain the neurotransmitter called dopamine. As these neurons degenerate, dopamine levels fall, and the balance between dopamine and other neurotransmitters, such as acetylcholine, is thrown off. This neurotransmitter imbalance affects the way muscles work and leads to movement problems.

Therapeutic ApplicationsA. Central Nervous System Disorders

1.Parkinson’s Disease---

It is due to degeneration of dopamine neuron

and relative hyperactive cholinergic

functions.

Centrally acting antimuscarinic preparations

can block M receptor and decrease the

activity of M receptor to remain useful as

adjunctive therapy in some patients.

Accurate measurement of refractive error requires ciliary paralysis

(iridocyclytis and choroditis).

Examining the retina is facilitated by mydriasis. Antimuscarinic agents, administered locally

are extremely helpful in doing the examination.For adults, the shorter acting drugs are

preferred. For children, the greater efficacy

of atropine is necessary, but the possibility of

poisoning is correspondingly increased.

Accommodation and pupillary reflexs may

not fully recover for 7 to 12 days.

Therapeutic Applications- Ophthalmologic Disorders

Respiratory Disorders

Pre-anesthetic administration Irritant anesthetics such as ether markedly increased airway secretion

Atropine or scopolamine could prevent these effects. Scopolamine also block short-term memory (amnesia).

Cardiovascular Disorders

Patients with hyperactive carotid sinus reflexes experience

faintness or syncope as a result of vagal discharge in

response to pressure on the neck, a tight collar.

Antimuscarinic agents may benefit to the disease.

Excessive vagal discharge may

result in depression of sinoatrial or

atrioventricular node.

Atropine or similar antimuscarinic

drugs are appropriate therapy in this

situation.

Gastrointestinal Disorders Anti-M agents can relieve traveler’s

diarrhea and hypermotility. They are

often combined with an opioid

antidiarrhead drug, diphenoxylate.

In this combination, the very low dosage

of the anti-M drugs can decrease

opioid abuse.

Anti M agents are now rarely used for peptic ulcer disease

in the world.

Urinary Disorders

Atropine and other antimuscarinic drugs can relieve the urinary urgency caused by inflammation bladder disorder.

Oxybutynin is often used to relieve bladder

spasm after urologic surgery.

Imipramine, a antidepressant drug with strong antimuscarinic action, has long been used to reduce incontinence in institutionalized elderly patients.

Cholinergic PoisoningAntimusarinic Therapy

Poisoning of cholinesterase inhibitors

can increase the concentration of ACh

in synaptic space and show both the N

and the M effects. Atropine can reverse

the M effects in the CNS as well as the periphery.

Large doses of atropine may be needed to overcome

the M effects of extremely potent agent like

parathion (1605) and warfare nerve gases

Muscarinic stimulantsNausea, vomiting, diarrhea, abdominal pain, salivation, sweating, cutaneous vasodilation, and bronchial constriction.

They are all due to excitement of M receptors. The effects can be blocked by atropine.

Certain mushrooms contain muscarinic alkaloids which can cause typical signs of muscarine.

Adverse Effects Treatment with atropine at one organ almost always induce undesirable effects in other organ systems.

dry mouth, mydriasis, cycloplegia, tachycardia, hot and flushed skin, agitation, delirium, high temperature.

Atropine intoxication is potentially lethal in children (more

sensitive to its effects, particularly to rapid increase in body temperature).

Atropine intoxication is too risky in older individuals (an attack of

glaucoma due to an increase in intraocular pressure).

The poisoning can be treated with cholinesterase inhibitor such as neostigmine.

Scopolamine( 东莨菪碱 )

Characteristics

1.CNS actions: depression (strong)

2.peripheral actions: glands: strong

others: weak

Uses:

1.preanaesthesia medication

2. prevention motion sickness

3. parkinson disease

4. traditional medicine anaesthesia

Motion Sickness -prophylactic Scopolamine is one of the oldest remedies for seasickness.

Parkinson's disease occurs when neurons degenerate (lose the ability to function normally) in a part of the brain called the substantia nigra. Many of these neurons that degenerate contain the neurotransmitter called dopamine. As these neurons degenerate, dopamine levels fall, and the balance between dopamine and other neurotransmitters, such as acetylcholine, is thrown off. This neurotransmitter imbalance affects the way muscles work and leads to movement problems.

Parkinson’s Disease---

It is due to degeneration of dopamine neuron

and relative hyperactive cholinergic

functions.

Centrally acting antimuscarinic preparations

can block M receptor and decrease the

activity of M receptor to remain useful as

adjunctive therapy in some patients.

Anisodamine山莨菪碱Characteristic of actions

1.high selectivity (smooth muscle and vessels)

2.little side effects (not pass through BBB)

Uses visceral colic-antispasmodic agent

Synthetic atropine substitutes

Synthetic Mydriatics:

Homatropine( 后马托品 ), Tropicamide( 托吡卡胺 ), Cyclopentolate( 环喷托酯 ), Eucatropine( 尤卡托品 )

Selective M1 Antagonists-pirenzepine

Synthetic Antispasmatics

Ganglion-Blocking Drugs

These agents block the action of ACh and similar agonists at

the N receptors of autonomic ganglia.

They lack selectivity and have broad side effects so that they

have been rarely used in clinic.

The ganglionblocking drugs are useful in pharmacologic

research because of their

ability to block all

autonomic outflow.

Clinical Applications ＆ Toxicity

Because of the availability of more selective autonomic

blocking agents, the applications of the ganglion

blockers have almost disappeared.

For most patients, the toxicity of the ganglion blocking

drugs are intolerable except for acute use.

Mecamylamine may reduce nicotine craving.

Trimethaphan is occasionally used in hypertensive

emergencies.

Skeletal muscle relaxants act peripherally at neuromuscular junction. According to their action, they are divided into:

•Nondepolarizing (competitive) agents •Depolarizing (hyperdepolarazing) agents

Neuromuscular Blocking Agents

Competitive(curare-like) blockingagents

N+ (14 Å) N+

GI resorptionBBB

Curare is plant extract from

Chondrodendron tomentosum,Strychnos toxifera etc. It isused by South America tribalsas arrow poison for game hunting. The animals got pa-ralyzed even if not killed bythe arrow. Muscle paralyzingactive principles of curareare alkaloids tubocurarine,toxiferine etc.

Strychnos toxiferaChondrodendrontomentosum

The South Americam lianas

The competitive blockers have affinity for NM receptor at the muscle end-plate, but no intrinsic activity.

The NM-receptor is a macroprotein with5 subunits, which arearranged like a rosettesurrounding the Na+

channel. The two alphasubunits carry two AChbinding sites with nega-tively charged groupswhich combine with thecationic group of AChand open Na+ channel.

Depolarizing agents

Action of succinylcholine(suxamethonium)

Depolarizing agents produce dual mechanism neuro-muscular blockade :Phase I block---persistent depolarization of muscular end-plate which produces transient twitching of the musclePhase II block---membrane repolarize, desensitation of the NM-receptor to Ach which result in paralysis

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