DR BADAR UDDIN UMARMBBS, MPhil

Senior Lecturer, Pharmacology

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Classify parasympathetic blockers with suitable examples

Classify antimuscarinic drugs based on their uses with suitable examples

List and describe the pharmacological actions of atropine

Discuss the rationale for using drugs blocking the muscarinic actions of ACh

Discuss the clinical features and drug treatment of atropine poisoning

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Cholinergic receptors can be divided into two types – • muscarinic and

• nicotinic

Muscarinic receptors originally were distinguished from nicotinic receptors by the selectivity of the agonists muscarine and nicotine respectively

In tissues innervated by postganglionic parasympathetic neurons

In presynaptic noradrenergic and cholinergic nerve terminals

In non-innervated sites in vascular endothelium

In the central nervous system

There are 5 subtypes of muscarinic

receptors M1, M2, M3, M4, and M5

They mediate their effects through - G proteins coupled to -

Phospholipase C (M1,3,5),

Potassium channels (M2,4)

Muscarinic Acetylcholine ReceptorsMuscarinic Acetylcholine Receptors

MM11 MM22 MM33 MM44 MM55

DistributionDistribution Cortex, Cortex, hippocampus hippocampus

Heart Heart Exocrine Exocrine glands, GI glands, GI tract tract

Neostriatum Neostriatum Substantia Substantia nigra nigra

AntagonistsAntagonists Atropine Atropine DicycloverineDicycloverineTolterodineTolterodineOxybutyninOxybutyninIpratropiumIpratropiumPirenzepinePirenzepineMamba toxin Mamba toxin MT7MT7

Atropine Atropine DicycloverineDicycloverineTolterodineTolterodineOxybutyninOxybutyninIpratropiumIpratropiumGallamineGallamine

Atropine Atropine DicycloverineDicycloverineTolterodineTolterodineOxybutyninOxybutyninIpratropiumIpratropiumDarifenacinDarifenacin

AtropineAtropineDicycloverineDicycloverineTolterodineTolterodineOxybutyninOxybutyninIpratropiumIpratropiumMamba toxin Mamba toxin MT3 MT3

AtropineAtropineDicycloverineDicycloverineTolterodineTolterodineOxybutynin Oxybutynin

Agonists Agonists AcetylcholineAcetylcholineXanomeline, Xanomeline, CDD-0097 CDD-0097

AcetylcholineAcetylcholine AcetylcholineAcetylcholine AcetylcholineAcetylcholine AcetylcholineAcetylcholine

G protein G protein GGααq/11 q/11 GGααi/o i/o GGααq/11 q/11 GGααi/o i/o GGααq/11q/11

Intracellular Intracellular response response

Phospholipase Phospholipase CCββ

Adenylyl Adenylyl cyclase cyclase inhibition inhibition

Phospholipase Phospholipase CCββ

Adenylyl Adenylyl cyclase cyclase inhibition inhibition

Phospholipase Phospholipase CCββ

In sympathetic and parasympathetic ganglia

In the adrenal medulla In the neuromuscular junction of the

skeletal muscle In the central nervous system

There are two subtypes of nicotinic receptors NM and NN

The NM nicotinic receptor mediates skeletal muscle stimulation

The NN nicotinic receptor mediates stimulation of the autonomic ganglia [agonists and antagonists at this site are sometimes called ganglionic agonists and ganglionic blockers]

Nicotinic receptors are ligand - gated ion channels

Their activation results in a rapid increase in cellular permeability to sodium and calcium

nAChRs are directly coupled to cation channels

They mediate fast excitatory synaptic transmission at the neuromuscular junction, autonomic ganglia, and various sites in the central nervous system (CNS)

Muscle and neuronal nAChRs differ in their molecular structure and pharmacology

They are pentameric arrays of one to four distinct but homologous subunits, surrounding an internal channel

The α subunit has binding sites for ACh.

Agonist binding induce a conformational change that opens the channel

Antagonist may bind to these sites but do not elicit the conformational change

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Parasympatholytics

Natural Belladonna Alkaloids

Semisynthetic and Synthetic Products of Belladonna alkaloids

AtropineHyoscine

l-hyoscyamineTertiary amines Quaternary amines

•Dicyclomine hydrochloride•Oxyphencyclimine hydrochloride•Homatropine hydrobromide•Cyclopentolate hydrochloride•Tropicamide

•Atropine methobromide•Atropine methonitrate•Hyoscine butyl bromide•Methantheline bromide•Porpantheline bromide•Mepenzolate bromide•Ipratropium bromide•Oxyphenonium bromide

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Therapeutic uses Name of drugs Clinical Applications

Motion sickness drugs Scopolamine • Prevention of motion sickness Postoperative nausea and vomiting

Gastrointestinal disorders DicyclomineGlycopyrrolateMethanthelinePropanthelineClidiniumOxyphenonium

• Irritable bowel syndrome• Minor diarrhea

Mydriatic and cycloplegic AtropineScopolamineHomatropineCyclopentolateTropicamide

• Retinal examination• Prevention of synechiae after

surgery

Respiratory (asthma, COPD)

IpratropiumTiotropium

• Prevention and relief of acute episodes of bronchospasm

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Therapeutic uses Name of drugs Clinical Applications

Urinary OxybutyninDarifenacinSolifenacin and Tolterodine (Tertiary amines with somewhat greater selectivity for M3 receptors )Trospium (Quaternary amine with less CNS effect)

• Urge incontinence• Postoperative spasms

Cholinergic poisoning

Atropine • Mandatory antidote for severe cholinesterase inhibitor poisoning

Pralidoxime • Usual antidote for early-stage (48 h) cholinesterase inhibitor poisoning

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Muscarinic antagonists (parasympatholytic drugs) are competitive antagonists of ACh at muscarinic receptors

Their chemical structures usually contain ester and basic groups in the same relationship as ACh, but

They have a bulky aromatic group in place of the acetyl group

Muscarinic antagonists are sometimes called parasympatholytic because they block the effects of parasympathetic autonomic discharge

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Atropine:

Atropine is the prototype drug of this group

It is an alkaloid, found in the deadly nightshade (Atropa belladonna)

Tertiary amine

Ester of tropic acid

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The deadly nightshade (Atropa belladonna) contains mainly atropine

The thorn apple (Datura stramonium) contains mainly scopolamine

The Hyoscyamus niger contains Scopolamine (Hyoscine)

These are tertiary ammonium compounds that are sufficiently lipid-soluble to be readily absorbed from the gut or conjunctival sac

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They also penetrate the blood-brain barrier

The quaternary derivative of atropine, atropine methonitrate, has peripheral actions like atropine but, lacks central actions [can not cross BBB]

Ipratropium [a quaternary ammonium compound] is used by inhalation as a bronchodilator

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Cyclopentolate and tropicamide are tertiary amines developed for ophthalmic use and administered as eye drops

Pirenzepine is a relatively selective M1 receptor antagonist

Oxybutynin, tolterodine and darifenacin (M3-selective) are new drugs that act on the bladder to inhibit micturition, and are used for treating urinary incontinence

They produce unwanted effects typical of muscarinic antagonists, such as dry mouth, constipation and blurred vision

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ATROPINE

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Used as a homicidal poison

Atropa: Atropos: Goddess in Greek Mythology

Atropos, Clothos & Lachesis….. 3 sisters Atropos cuts with shears the web of the life span

and woven by her sisters Clothos & Lachesis

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Bella donna:

Italian meaning: Beautiful Lady

Once fashionable female practice of using the extract of the plant to dilate the pupils…. Process of making herself attractive

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Atropine is an antagonist drug-

It blocks all the muscarinic receptors of Ach in the body & antagonizes the effects of Ach

Antagonism is reversible

So, the effects are opposite to Muscarinic effects of Ach

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Inhibition of secretions:

Very low doses of atropine inhibits salivary, lacrimal, bronchial and sweat gland secretions producing dry mouth and skin

Gastric secretion is only slightly reduced

Mucociliary clearance in the bronchi is inhibited, so that residual secretions tend to accumulate in the lungs

Ipratropium lacks this effect

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DOSE (mg) EFFECTS

0.5 Slight cardiac slowing; some dryness of mouth; inhibition of sweating

1 Definite dryness of mouth; thirst; acceleration of heart, sometimes preceded by slowing; mild dilation of pupils

2 Rapid heart rate; palpitation; marked dryness of mouth; dilated pupils; some blurring of near vision

5 Above symptoms marked; difficulty in speaking and swallowing; restlessness and fatigue; headache; dry, hot skin; difficulty in

micturition; reduced intestinal peristalsis

10 Above symptoms more marked; pulse rapid and weak; iris practically obliterated; vision very blurred; skin flushed, hot, dry, and scarlet;

ataxia, restlessness, and excitement; hallucinations and delirium; coma

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Effects on heart:

Biphasic action

Atropine causes transient initial bradycardia due to stimulation of dorsal nucleus of vagus ( with very low doses; due to a central action)

Larger doses cause progressively increasing tachycardia by blocking cardiac mAChRs (up to 80-90 beats/min) in humans

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This is because there is no effect on the sympathetic system, but only inhibition of the existing parasympathetic tone

This is most pronounced in young people (often absent in the elderly)

The response of the heart to exercise is unaffected

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Arterial blood pressure is unaffected, because most resistance vessels have no cholinergic innervation

Large doses cause vasodilatation of the skin blood vessels specially in the blush area -‘atropine blush’

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Effects on the eye:

It dilates the pupil (mydriasis)

Light reflex is lost

Relaxation of the ciliary muscle causes paralysis of accommodation (cycloplegia), so that near vision is impaired

Intraocular pressure may rise (unimportant in normal individuals but can be dangerous in patients suffering from narrow-angle glaucoma)

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Pupil Normal Dilated

Effects on the gastrointestinal tract:

Gastrointestinal motility is inhibited by atropine

Atropine is used in pathological conditions in which there is increased gastrointestinal motility (M3 selective agents may be preferable)

Pirenzepine, owing to its selectivity for M1 receptors, inhibits gastric acid secretion

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Bronchial, biliary and urinary tract smooth muscle are all relaxed by atropine

Reflex bronchoconstriction (during anaesthesia) is prevented, whereas bronchoconstriction caused by histamine and leukotrienes is unaffected

Biliary and urinary tract smooth muscle are only slightly affected

Precipitate urinary retention in elderly men with prostatic enlargement

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Atropine stimulates CNS followed by depression Medulla and higher cerebral centers are stimulated With therapeutic doses there is mild vagal excitation Large doses produce marked central stimulation

leading to:• Restlessness

• Irritability

• Disorientation

• Hallucinations

• Delirium

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Later; depression occurs leading to coma and death due to medullary paralysis

Atropine has anti tremor activity in Parkinson’s disease

It prevents motion sickness either by acting centrally or peripherally

It counteracts central excitatory actions of physostigmine and OPCs and

Reduces electrical activity of brain

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Adjunct for anaesthesia (reduced secretions, bronchodilatation)

Anticholinesterase (OPC) poisoning Bradycardia As antispasmodic in Gastrointestinal hypermotility In ophthalmology used topically

• as a mydriatic (to examine the retina, optic disk)

• Treatment of acute iritis, iridocyclitis, keratitis etc.

• Used alternately with a miotic to break or prevent adhesions between iris and lens

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Nocturnal enuresis

Hyperactive bladder

Motion sickness

Parkinson’s disease

Hyperhidrosis

Mushroom poisoning

Antidiarrheal

Pulmonary obstructive disease42

Ipratropium and Tiotropium are used in the treatment of chronic obstructive pulmonary disease

They are less effective in most asthmatic patients These are often used with inhaled long-acting β2 agonists

• Ipratropium is administered four times daily via a metered-dose inhaler or nebulizer

• Tiotropium is administered once daily via a dry powder inhaler Ipratropium is used in nasal inhalers in rhinorrhea

associated with the common cold or with allergic or non-allergic perennial rhinitis

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Once widely used for the management of peptic ulcer

Can reduce gastric motility and the secretion of gastric acid

But antisecretory doses produce pronounced side effects like- • such as xerostomia, loss of visual accommodation, photophobia,

and difficulty in urination

Patient compliance in the long-term is poor Pirenzepine, Telenzepine

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Diarrhea associated with irritation of the lower bowel [mild dysenteries and diverticulitis]

Dicyclomine hydrochloride [weak muscarinic receptor antagonist] also has nonspecific direct spasmolytic effects on smooth muscle of the GI tract

It is occasionally used in the treatment of diarrhea-predominant irritable bowel syndrome

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Effects on the eye are obtained by topical administration

They cause mydriasis and cycloplegia Mydriasis is necessary for thorough

examination of the retina and optic disc and in the therapy of iridocyclitis and keratitis

The mydriatics may be alternated with miotics for breaking or preventing the development of adhesions between the iris and the lens

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Complete cycloplegia may be necessary in the treatment of iridocyclitis and choroiditis and for accurate measurement of refractive errors

Homatropine hydrobromide a semisynthetic derivative of atropine, Cyclopentolate hydrochloride and Tropicamide are used in ophthalmological practice

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Overactive urinary bladder Lower intravesicular pressure Increase capacity, and Reduce the frequency of contractions by

antagonizing parasympathetic control of the bladder

They also may alter bladder sensation during filling

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Enuresis in children, particularly when a progressive increase in bladder capacity is the objective

To reduce urinary frequency and increase bladder capacity in spastic paraplegia

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Oxybutynin (DITROPAN)

Tolterodine (DETROL)

Trospium chloride (SANCTURA)

Darifenacin (ENABLEX)

Solifenacin (VESICARE) and

Fesoterodine (TOVIAZ);

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Limited clinical utility Used only in coronary care units for short-term

interventions or in surgical settings Initial treatment of patients with acute

myocardial infarction in whom excessive vagal tone causes sinus bradycardia or AV nodal block

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Sinus bradycardia is the most common arrhythmia seen during acute myocardial infarction

Atropine may prevent further clinical deterioration in cases of high vagal tone or AV block by restoring heart rate to a level sufficient to maintain adequate hemodynamic status and to eliminate AV nodal block

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Dry mouth

Blurred vision

Tachycardia

Constipation

Urinary hesitancy and retention

Atropine poisoning

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Occur through accidental or deliberate ingestion of berries or seeds of belladonna or from over treatment with high doses

Characterized by: • Dryness of mouth,

dysarthria, dysphagia• Blurred vision and

photophobia• Hot, dry and flushed skin

• Hyperpyrexia

• Tachycardia (weak and rapid pulse)

• Palpitation

• Urinary difficulty

• Restlessness, excitement, hallucinations, delirium followed by

• Depression and death from respiratory failure

• Convulsions may occur

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Gastric lavage

Physostigmine as antidote – slow i.v. injection 1- 4 mg (0.5 mg in children)

Diazepam for sedation and control convulsions

Artificial respiration

Ice bags and alcohol sponge to reduce fever

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Glaucoma

Elderly males with enlarged prostate

Paralytic ileus

Ulcerative colitis

Gastroesophageal reflux

Tachycardia

Cardiac insufficiency

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Property Subgroup

M1 M2 M3

Primary locations

Nerves Heart, nerves, sm. muscle

Glands, sm. muscle, endothelium

Antagonists AtropinePirenzapineTelenzepineDicyclomineTrihexyphenidyl

AtropineGallamineMethoctramine

Atropine4-DAMPDarifenacinSolifenacinOxybutyninTolterodine

Atropine does not distinguish among the 3 subtypes of Muscarinic receptors

Other antagonists are moderately selective for one or another subtypes of receptors 58

Classify main classes of parasympathetic blockers

Classify antimuscarinic drugs based on their clinical uses with suitable examples

Describe the pharmacological actions of atropine based on the distribution of muscarinic receptors

Discuss the contextual rationale for using drugs blocking ACh

Discuss the clinical features and drug treatment of belladonna (atropine) poisoning

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