1 chapter 8 cholinoceptor blocking drugs american origin, contains atropine cao yongxiao 曹永孝...

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Chapter 8 Cholinoceptor blocking drugs

American origin, contains Atropine

Cao Yongxiao 曹永孝Department of Pharmacology yxy

@xjtu.edu.cn;029-82655140 http://pharmacology.xjtu.edu.cn

Cholinergic fibers include:

• preganglionic fibers • parasympathetic fibers

• a few sympathetic

postganglionic fibers

• nervous fibers

controlling adrenal

medulla.

• somatic motor fibers

西安交大医学院药理学系曹永孝 [email protected]; 029-82655140


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).

Basic Pharmacology of the 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.西安交大医学院药理学系曹永孝 [email protected]; 029-82655140

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

limit the dose tolerated

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


Pharmacokinetics

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

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

About 60% of the dose is excreted unchanged in the urine.

The rest appears as hydrolysis and conjugation products.


A. Mechanism of Action:

blocks M receptor reversiblely

The effectiveness varies with tissues. Th

e most sensitive tissues to atropine a

re the salivary, sweat glands, digesti

ve tract, bladder, bronchial, and uter

us.

The least sensitive is the gastric parie

tal cells secreting acid.

Antimuscarinic agents block exogenous

M receptor agonists more effectivel

y than endogenous ACh.西安交大医学院药理学系曹永孝 [email protected]; 029-82655140

Pharmacodynamics

B. Organ System Effects

Scopolamine has marked central effects,

producing drowsiness and amnesia.

In toxic doses can cause excitement, agitation, hallucinations, and coma.

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


2. Eye— Block M receptor Mydriasis 扩瞳


The pupillary constrictor muscle, iris depends on M receptor. Atropine and other anti-M drugs block M receptor and results in dilatation of iris and mydriasis.

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, and its blockade by atropine results in mydriasis.

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

2. Eye— Mydriasis 扩瞳


2. Eye— Block M receptor Mydriasis 扩瞳

intraocular pressure↑ 升眼压


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.

2. 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.

Diagram of eye depicting major pathway for outflow of aqueous humor (heavy arrow) which drains at Schlemm's canal. If the angle between the iris and the cornea is narrow, a physical impediment may exist to drainage and the intraocular pressure is increases. This is exacerbated during mydriasis because the iris contracts toward that angle (narrow angle glaucoma) to further impede outflow.

The ciliary muscle is a sphincter. When contracting, it relaxes the su

spensory ligaments on the lens.

The lens rounds of its own elasticity to accomodate to near vision. U

nder the influence of excess ACh, however, the muscle goes into cili

ospasm, and cannot reaccomodate for far vision.

This occurs in anticholinesterase poisoning.

2. 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.

Antimuscarinic drugs reduce lacrimal secretion.


3. Cardioavascular system

Cardiomuscle is controlled by lesser degree of M recep

tor. Atropine has no clinical significant effect on it. 西安交大医学院药理学系曹永孝

Sinoatrial nodeis controlled by M receptor.Atropine blocks M receptor and causes tachycardia. Lower doses 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

The skeletal muscle vascular bed contains M receptor. Almost all vessels contain endothelial M receptors that mediate vasodilation.

The receptors are readily blocked by antimuscarinic drugs. At toxic doses, and in some individuals at normal doses, atropine cause cutaneous vasodilation. But there is little effect on blood pressure.


Blood Vessels

4. 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.


5. Gastrointestinal Tract

Pancreatic and intestinal secretion are little affected by atropine;

They are primarily under hormone.

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.

Atropine inhibits gastrointestinal movement by blocking M receptor.西安交大医学院药理学系曹永孝 [email protected]; 029-82655140

6. 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.


7. 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.”


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 M neuron.

Centrally acting antimuscarinic preparations can block M receptor and decrease the activity of M receptor to remain useful as adjunctive therapy in some patients.


Swedenish Arvid Carlsson The Nobel Prize in 2000

The chemical transmitter dopamine is formed from the precursors tyrosine and L-dopa and is stored in vesicles. In the treatment of Parkinson's disease, L-dopa is given, and is converted to dopamine. This compensates for the patient's lack of dopamine.

Dopamine nerve pathways in the brain. Arvid Carlsson showed that there were high levels of the chemical transmitter dopamine in basal ganglia, which control muscle movements. In Parkinson's disease nerve cells those produce dopamine, and whose nerve fibers project to the basal ganglia die. This causes symptoms such as tremor, muscle rigidity and unability to move.

During movement, signals pass from the cortex, via reticular formation and spinal cord (pathway A), to muscles, which contract.

Other signals pass, by pathway

B, to the basal ganglia; these damp the signals in pathway A, reducing muscle tone so that movement is not jerky.

Dopamine, a nerve transmitter made in the basal ganglia, is needed for this damping effect.

Another transmitter, acetylcholine, inhibits the damping effect.

Parkinson’s Disease-

Degeneration of parts of the basal ganglia causes a lack of dopamine. The basal ganglia are thus prevented from modifying the nerve pathways that control muscle contraction. As a result, the muscles are overly tense, causing tremor, joint rigidity, and slow movement.

Most drug treatments increase the level of dopamine in the brain or oppose the action of ACh.

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


Accurate measurement of refractive error requires ciliary paralysis.

Examining the retina is facilitated by mydriasis. Antimuscarinic agents, administered topically are extremely helpful in doing the examination.


Ophthalmologic Disorders

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.

In the past, anti M drugs have been selected from the tertiary amine to ensure good penetration. Now, Glycopyrrolate, a quaternary agent, is as rapid in onset and as long–lasting as atropine.

Diagram of eye depicting major pathway for outflow of aqueous humor (heavy arrow) which drains at Schlemm's canal. If the angle between the iris and the cornea is narrow, a physical impediment may exist to drainage and the intraocular pressure is increases. This is exacerbated during mydriasis because the iris contracts toward that angle (narrow angle glaucoma) to further impede outflow.

The ciliary muscle is a sphincter. When contracting, it relaxes the te

nsion of the suspensory ligaments on the lens.

The lens rounds of its own elasticity to accomodate to near vision. U

nder the influence of excess ACh, however, the muscle goes into cili

ospasm, and cannot reaccomodate for far vision.

This occurs in anticholinesterase poisoning.

To prevent synechia formation in iritis.

The longer lasting preparation, especially homatropine, are valuable for this indication.


C. Respiratory Disorders

Pre-anesthetic administration Irritant anesthetics such as ether

markedly increased airway secretion

and were associated with frequent

episodes of laryngospasm.

Atropine or scopolamine could prevent these hazardous effects.

Scopolamine also produces significant amnesia.


D. 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.西安交大医学院药理学系曹永孝 [email protected]; 029-82655140

Excessive vagal discharge may resu

lt in depression of sinoatrial or atrio

ventricular node.

Atropine or similar antimuscarinic

drugs are appropriate therapy in this

situation.

E. Gastrointestinal Disorders Anti-M agents can relieve traveler’s diarr

hea and hypermotility. They are often co

mbined 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 USA.


F. Urinary DisordersAtropine and other antimuscarinic drugs can relieve the urinary urgency caused by inflammation bladder disorder.

Oxy-butynin 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.

G. 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 combat

the M effects of extremely potent agent like

parathion (1605) and warfare nerve gases

H. Other Applications Hyperhidrosis is sometimes reduced by anti-M agents


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

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

Atropine is dangerous in children.

Poisoning caused by quaternary anti-M drugs is associated with all of the peripheral signs of parasympathetic blockade.

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


ContraindicationsThe contraindications are relative.

Obvious muscarinic excess, especially that caused by ChE inhibitors, can always be treated with atropine.

Glaucoma, especially angle-closure glaucoma, is a contraindication. Atropine may precipitate angle closure in patients. In elderly men with prostatic hyperplasia, antimuscarinic drugs should be avoided.

Nonselective antimuscarinic agents should never be used to acid-peptic disease. Because they slow gastric emptying and increase symptoms with gastric ulcer.


III. Ganglion-Blocking DrugsThese agents block the action of ACh and similar agoni

sts at the N receptors of autonomic ganglia.

They lack selectivity and have broad side effects so that

they have been abandoned for clinical use.

The ganglionblocking drugs are still important and usef

ul in pharmacologic

research because of their

ability to block all

autonomic outflow.


A. Mechanism of ActionNicotine, carbamoylcholine, succinylcholine and ACh can depolarize the postsynaptic membrane for long time, leading to a reduction in receptor sensitivity manifested by flaccid paralysis. It produces depolarizing ganglion blockade.

Nondepolarizing competitive antagonists Trimethaphan blocks the N receptor.Hexamethonium occupy sites on the ion channel controlled by ACh receptor. The blockade can be overcome by agonist, ACh.


Organ system Effects

1. Central Nervous System—

The quaternary amine agents lack central effects beca

use they do not cross the blood-brain barrier.

Mecamylamine readily enters the CNS.

Sedation, tremor, choreiform movement, and mental a

berrations have all been reported as effects.


2. Eye

Because the ciliary muscle receive primarily the parasympathetic nervous innervation, the ganglion-blocking drug cause a predictable cycloplegia with loss of accommodation.

The iris receives both sympathetic and parasympa-thetic innervation. Because parasympathetic tone is usually dominant in this tissue, ganglionic blockade causes moderate dilation of the pupil.


Cardiovascular System The blood vessels receive chiefly vasoconstrictor fibers from the sympathetic nervous system;

Ganglionic blockade cause an obvious decrease of arteriolar and venomotor tone, and decrease of the blood pressure, because both peripheral vascular resistance and venous return are decreased.

Hypotension is especially marked in the upright position, because postural reflexes are blocked.

Cardiac effects include diminished contractility and, because the sinoatrial node is usually dominated by the parasympathetic nervous system, a moderate tachycardia.


4. Gastrointestinal Tract

Secretion is reduced, although not enough to treat peptic disease.

Motility is profoundly inhibited, and constipation may be marked.


5 Other System Genitourinary smooth muscle is partially dependent on autonomic innervation. Ganglionic blockade therefore causes hesitancy in urination and may precipitate urinary retention in men with prostatic hyperplasia.

6. Response to Autonomic Drugs—

Because the effects of cell receptors are not blocked,

patients receiving ganglion-blocking drugs are fully

responsive to autonomic drugs acting on these receptors,


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 ganglionblocking drugs are intolerable except for acute use.

Mecamylamine may reduce nicotine craving.

Trimethaphan is occasionally used in hypertensive emergencies.


Deadly nightshade (Atropena belladonna) is the natural source of the alkaloid atropine. The term atropena is derived from Atropos because of its high toxicity. Atropos is the Greek goddess of Fate and is responsible for the final part of a mortal life, the unturning inevitability of death. Atropine was a popular choice of poison amongst professional poisoners during the Middle Ages because of the slowness of their effects which allowed the perpetrator to escape before suspicions were aroused. 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 sensual and attractive and hence the name belladonna (beautiful lady). Atropena belladonna can be translated as femme fatale. In ophthalmology, it is used in cycloplegic refraction, post-operative dilatation as following trabeculectomy and in the treatment of anterior uveitis to prevent posterior synechiae. Atropine also dumbs nerve endings and lessen pain when applied locally.

atropine

1 chapter 8 cholinoceptor blocking drugs american origin, contains atropine cao yongxiao 曹永孝...

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