CHOLINERGIC RECEPTOR ANTAGONISTS

They are also called, muscarinic receptor antagonists, anticholinergic, atropinics, parasympatholytics.Those that block effects of ACH at nicotinic receptors are called: nicotinic receptor antagonists .The nicotinic receptor antagonists are either ganglion blockers or neuromuscular blockers.

CLASSIFICATION OF ANTICHOLINERGICS

1)Natural alkaloids e.g. atropine,hyoscine (scopolamine)

2)Atropine derivatives:a)Semi-synthetic derivatives e.g. homatropine,

atropine methonitrate, hyoscine N-butyl bromide(buscopanR) ipratropium bromide and tiotropium bromide

b) Synthetic compoundsi) Mydriatics:e.g. cyclopentolate, tropicamide.ii)Antisecretory-antispamodicsa) Quaternary compounds e.g. propantheline,

oxyphenonium, clidinium, pipenzolate, methyl bromide, isopropamide, glycopyrolate.

CLASSIFICATION OF ANTICHOLINERGICS Cont..

b) Tertiary amines e.g. dicyclomine, valethamate, pirenzepin

c) Vasico selective or urinary antispasmodic e.g. oxybutynin, flavoxate (urispasR), tolterodine

d) Antiparkinsonian e.g. trihexyphenidyl, procyclidine, biperidin.

Other classes of drugs with anticholinergic activity: tricyclic antidepressants, phenothiazines, antihistamines, disopramide,

SOURCE OF NATURAL ALKALOIDS

• They are obtained from plants of Solanaceae family.

• The deadly night shade, Atropa belladonna, contains mainly atropine whereas the thorn apple (Daturastramonium) contains mainly hyoscine.

• They exist in levo and dextro forms with the levo forms being more active

• Atropine is racemic(dl-hyoscyamine) and scopolamine is l-hyoscine

MUSCARINIC RECEPTOR ANTAGONISTS

• These are drugs that block effects of acetyl choline at muscarinic receptors (M1-M5) at parasympathetic neuro effector junctions.

• They inhibit the effects of parasympathetic nerve stimulation .(i.e. they are parasympatholytics)

• Blockade at muscanic receptors is competitive i.e. It can be reversed when high doses of ACH are administered.

Pharmacokinetics of atropine, scopolamine

– Lipid soluble and well absorbed from the GIT,mucous surfaces and intact skin.

– Widely distributed in the body i.e. it crossesBBB, placental barriers and is secreted in milk and saliva.

– Bound to plasma proteins and partly metabolized in the liver as glucoronide.

Pharmacokinetics of atropine, scopolamine Cont..

–Half-life of atropine is 4hrs,50% is excreted unchanged ,the rest is excreted as metabolites in urine.

–Effects of atropine decline rapidly except on the eye which takes 7-12 days after local application as eyedrops.The pigments of the iris bind atropine, which is then release it over many days.

–Hyoscine crosses the BBB better than atropine. It is also more completely metabolized than atropine.

PHARMACOLOGICAL EFFECTS OF ATROPINE AND SCOPOLOMINE

(PROTOTYPES)

• Central Nervous System:• A low dose of atropine has no effect on CNS

since there is restricted entry into the brain.• Hyoscine crosses the BBB even at low doses,

causing a central depressant effect (sedation).• At therapeutic doses, atropine stimulates many

medullary centers-vagal, respiratory, vasomotor.

Central Nervous System Cont..

• It depresses vestibular excitation at therapeutic doses-used in motion sickness.

• It reduces cholinergic over activity in the basal ganglia at therapeutic doses, thereby suppressing tremors and rigidity in Parkinsonism.

• At higher toxic doses atropine crosses the BBB and causes: cortical excitation, restlessness, dis orientation, hallucination, delirium, respiratory depression and coma.

• Most of CNS effects are due to blockade of muscarinic receptors in the brain, but some actions may have a different mechanism.

Cardio-Vascular System Cont..

1)Heart :• Small doses of atropine given

intravenously cause a paradoxical bradycardia due to transient stimulation of the vagal centre.

• At full therapeutic doses, atropine causes tachycardia-by blocking M2 receptors on SAN through which vagal tone decreases heart rate.

2)Blood Vessels:• Cholinergic neurons are not involved in

maintenance of vascular tone, and atropine produces no consistent or marked effect on BP

• Tachycardia and vasomotor stimulation tend to raise BP , while histamine release and direct vasodilator action of atropine tend to lower BP

• Very large doses of atropine tend to cause cutaneous vasodilation in face and neck (atropine flush) due to direct action not related to cholinergic innervation.

SMOOTH MUSCLES

1)Gastro-intestinal tract:

• Tone and motility of g.i.t is decreased leading to prolongation of gastric emptying time, closure of sphincters and decrease in tone, amplitude and frequency of peristaltic movements.

• The antispasmodic effects may be variable and to some extent depend on other mediators apart from ACH e.g. 5HT, enkephalins and others.

Bronchioles.

• Atropine causes bronchodilation and reduces airway resistance in COPD and asthma patients.

• Atropine only reduces bronchospasm as a result of excessive cholinergic activity. It may not be very useful in asthma because otherspasmogense.g. histamine, prostaglandins and kinins, may be involved. These mediators have a direct action on bronchial muscles and glands, they also increase vagal activity.

Ureter And Urinary Bladder.

• Atropine relaxes ureter and urinary bladder. This can cause urinary retention in older males with prostatic hypertrophy.

• In neurogenic bladder/enuresis the relaxant effect of atropine controls detrusor hyperreflexia and increase bladder capacity.

• In the biliary tract, there is slight relaxation of the bile duct,

• In the uterus .there is minimal effect.

GLANDS

• Sweat Glands• These are supplied by sympathetic cholinergic

neurons and are blocked by atropine. The skin becomes hot and dry.

• Toxic doses produce hyper pyrexia, as there is no heat loss due to lack of sweating. Children are more sensitive to this effect.

• Tracheobronchial, lachrymal secretions are also reduced due to blockade of M3 receptors. Talking and swallowing may become difficult.

Gastrointestinal Secretions.• Secretion of HCL, pepsin and mucus is

reduced. However, the secretion of bicarbonate is also reduced which tend to raise the PH and counteracts the acid reducing property of atropine.

• Atropine is therefore less efficacious than H2 blockers in reducing acid production. Very high doses of atropine are required.

• Pancreatic secretions are not significantly affected and so is bile production which is not under cholinergic control.

Eye• Atropine blocks the muscarinic receptors of

circular muscles of the iris leading to un opposed sympathetic activity on the radial muscles causing mydriasis(pupillary dilation)

• The ciliary muscles are also paralyzed leading to loss of accommodation (cycloplegia) i.e. the lens is focused for distant vision (near vision is impaired), light reflex is impaired and there may be photophobia.

• Atropine causes a rise in intraocular tension. This may not be important in normal individuals, but may be dangerous in glaucoma, or in the elderly who are prone to glaucoma.

Effect Of Atropine On Body Temperature

• High doses cause an increase in body temperature by:

• a) Decreasing secretions from the sweat glands

• b) Stimulation of temperature regulating centre in the hypothalamus.

• Children are more susceptible to atropine fever.

Local Anaesthetic Effect• Atropine has a mild anaesthetic action on

the cornea by blocking sensory nerves.

ATROPINE DERIVATIVES• Naturally occurring belladonna alkaloids are

used clinically but they have the following short comings:

a)Non selectivityb) Long duration of action.c) Individual intolerance.d) Toxicity.Semi synthetic and synthetic derivatives have

been developed with the following properties:a) Relatively selective in their activity:i) Drugs for peripheral conditions are mainly

quaternary compounds which cannot cross BBB and hence devoid of central effects.

ATROPINE DERIVATIVES Cont..

ii) Drugs for central effects as in Parkinsonism are able to cross BBB rapidly and they have minimal peripheral effects.

iii) They are structurally dissimilar, hence can be used as substitutes in atropine intolerance.

iv) At higher doses, they can block autonomic ganglia and neuro muscular junction

v) They have a shorter or longer duration of action.

THERAPEUTIC USES OF ANTICHOLINERGICS (ATROPINE AND ITS DERIVATIVES)

1)THERAPEUTIC USES IN CNS

a)Parkinsonism

• Results from excessive cholinergic activity at the basal ganglia. Synthetic muscarinics e.g. benzhexol, procyclidine and biperidin are used.

• The drugs improve siallorhea and tremors more than rigidity and akinesia

b).Motion sickness

• Hyoscine N butyl bromide is preferred to atropine because of its central effects

• It blocks cholinergic impulses from the vestibular apparatus to the vomiting centre.

• It is used orally or as transdermal patches.

c) Twilight sleep• Hyoscine is used together with a narcotic

analgesic, meperidine to produce amnesia, analgesia and a relaxed state during labour.

d) Maniacal state• This occurs during withdrawal of alcohol in

chronic alcoholics, and hyoscine can be used due to its central sedating effects.

THERAPEUTIC USES IN EYE CONDITIONS

a)Ophalmoscopicexaminations• Atropine eye drops is used as a potent mydriatic

and cycloplegic agent for examination of the retina and measurement of refractive error (error in focusing of light by the eye and a frequent reason for reduced visual acuity.

• The draw back with atropine is that cycloplegia takes one week during which the subject is visually impaired.Synthetic analogues tend to overcome these difficulties.

Ophalmoscopic examinations Cont..

• Homatropine eye drops is ten times less potent than atropine but cycloplegia takes only 1-2 days.It however, produces unsatisfactory cycloplegia in children who have high ciliary muscle tone.

• Cyclopentolate eye drops produce rapid cycloplegia in 30-60 minutes with duration of 1 day

Ophalmoscopic examinations Cont..

• Cyclopentolate may produce transient abnormal behavior in children(dis orientation, incoherent speech, visual disturbance) when the drug is absorbed from the eye.

• Tropicamide eye drops have the quickest onset of action of 20-40 minutes, with duration of 3-6 hours. It is however un reliable as cycloplegic, but is satisfactory for refractory testing and a short acting mydriatic in eye exams.

THERAPEUTIC USES IN GASTRO INTESTINAL CONDITIONS.

1)Peptic ulcer.

• Antimuscarinics may be used in peptic ulcer because they reduce gastric acid secretions and motility of the stomach. Pirenzepine and telenzepine are used with telenzepine being more potent.

• H2 receptor blockers have largely replaced these muscarinic receptor antagonists but they can still be used in combination.

2)Antispasmodics.• In the g.i.t, atropine,hyoscine and synthetic atropine

hyper motility conditions e.g. intestinal colic,ulcerative and biliary colics .

• Atropine derivatives are more useful in the followinginconditions:

• Nervous and drug induced diarrhea, but not in infective diarrhea.

• Irritable bowel syndrome and functional diarrhea.• To relieve increased urinary frequency in old age

and enuresis in children .Oxybutynin, tolterodine, and flaxovate are used. Dry mouth and anti-cholinergic effects are dose limiting.

• Dysmenorrhea- the drugs are not very effective.

Bronchial Asthma

• Ipratropium bromide inhalation gives complete protection against bronchospasm induced by cholinergic agents and irritant gases without interfering with mucociliary movement. It is also effective in chronic obstructive pulmonary disease.

Cardiac Indications

• Increased vagal tone may cause symptomatic sinus bradycardia, as happens immediately after myocardial infarction. Atropine can be used to counteract this...Atropine can also be used to increase the atrioventricular conduction velocity in patients with atrio ventricular block.

Cholinergic Poisoning• Treatment of mushroom poisoning (Amanita

mascara) which contains muscarine, a cholinergic agent. It is also used in organophosphate poisoning (1-2 mg i.v every 5-15 minutes till reversal of cholinergic activity occurs.

Myaesthenia Gravis (MG)• When anticholinesterase neostigmine is used in

MG, it may produce excessive muscarinic effects .Atropine or its substitutes may be used to block these effects without interfering with the effects of neostigmine on Nm receptors.

Pre-Anaesthetic Medication

• Irritant general anaesthetics e.g. ether cause increased salivary, trachea and bronchial secretions. Atropine, hyoscine and glycopyrrolate are used to counteract this .However with increasing use of non irritatinganaesthetics e.g. halothane the requirement has decreased.

• Atropine is still being used for the following reasons ;

Pre-Anaesthetic Medication

Cont..• Halothane sensitizes the heart to the

actions of catechol amines, leading to arrhythmias .Small doses of atropine are used because of bradycardia it causes.

• Atropinic drugs also prevent laryngospasm by reducing respiratory secretions that reflexly predispose to laryngospasm.

• Halothane also causes bradycardia and hypotension which are blocked by atropine.

PRECAUTIONS WITH ANTICHOLINERGICS

• Elderly patients- may precipitate glaucoma. • Elderly with enlarged prostate –may cause

retention of urine due to complete closure of sphincter.

• Very high doses of atropine cause tachycardia –not good in myocardial infarction and angina.

• When used alone in peptic ulcers, they may delay gastric emptying and expose the mucosa to acid for a long time causing further damage. Therefore they should be used with antacids or H2 receptor antagonists.

ADVERSE REACTIONS/TOXICITY WITH ANTICHOLINERGICS

• They are of plant origin, therefore accidental or homicidal poisoning may occur. Acute poisoning may also occur during therapeutic use as in nocturnal enuresis in children.

• Atropine has a relatively wide margin of safety in adults but infants and children are more susceptible.

• Acute poisoning produce central and peripheral effects by blocking muscarinic receptors.

• Semi synthetic substitutes have no central effects since they do not cross the BBB,

ADVERSE REACTIONS/TOXICITY WITH ANTICHOLINERGICS Cont..

Peripheral anti muscarinic effects include:• Dryness of mouth, intense thirst, dysphagia,

constipation, dysuria and retention of urine.• Dilatation of pupils dimness of vision, loss of

accommodation, photophobia.• Tachycardia,• Dry, hot flushed skin, hyper pyrexia, drug rush and

atropine flush over neck and upper part of the trunk.• Central effects include:

• Restlessness, rapid breathing confusion ,hallucinations , delirium

• Convulsions followed by coma .Death is due to respiratory depression and vasomotor collapse.

MANAGEMENT OF TOXICITY OF ANTICHOLINERGICS

Control of hper pyrexia:Ice bag, coldsponges,artificial respiration

oxygen by face mask.Removal Of Un absorbed poison• Gastric lavage with potassium

permanganate, or universal antidote which contains charcoal.

Control of ExcitementDiazepam 10 mg i.v

Specific Treatment• Physostigmine 1-4 mg by slow i.v in adults

and, 1-2 mg hourly in children until satisfactory control of anti muscarinic effects. .5-1mg in children

• In case of poisoning with quaternary anti muscarinic compounds which do not cross the BBB, neostigmine can be used instead of physostigmine to counteract peripheral anti muscarinic, ganglion blocking and neuro muscular blocking action of these drugs.

DRUG INTERACTIONS INVOLVING ANTI CHOLINERGICS

• Absorption of most drugs ( those that are absorbed in the small intestine) are delayed because atropine delays gastric emptying i.e. slows absorption of L-dopa .

• Antacids reduce absorption of anticholinergics.

DRUG INTERACTIONS INVOLVING ANTI

CHOLINERGICS Cont..

• Anti histamines, TCAs phenothiazines, disopyramide, pethidine have anti cholinergic properties ,and additive side effects occur with atropinics.

• MAOI interferes with metabolism of anticholinergic and anti parkinsonian drugs and may cause delirium.

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