Seminar on parasympathomimetic and parasympatholytic converted

SEMINAR ON
PARASYMPATHOMIMETIC AND
PARASYMPATHOLYTIC
1
Department of Pharmacology BVVS COP BGK

❖ OVEREVIW
➢Introduction
➢Definition
➢Cholinergic system
➢Classification
➢Parasympathomimetic drugs
➢Parasympatholytic drugs
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❖ INTRODUCTION
➢ The discovery of the pharmacological action of Acetylcholine (Ach) came, paradoxically,
from work on adrenal glands. Extracts of which were known to produce rise in blood
pressure owing to their content of adrenaline.
➢ In 1900, Reid Hunt found that after adrenaline had been removed from such extracts, they
produce a fall in blood pressure instead of a rise.
➢ He attributed the fall to the presence of choline, but later concluded that a more potent
derivative of choline must be responsible.
➢ He tested a number of choline derivatives and discovered that Ach was some 10,000 times
more active than choline in lowering the rabbits blood pressure.
➢ Early studies of the parasympathetic nervous system showed that the alkaloid muscarinic
mimic the effects of parasympathetic nerve discharge; that is, the effect were
parasympathomimetic.
➢ The effects of Ach itself and other cholinomimetic drugs at autonomic neuro-effector
junctions are called are parasympathomimetic.
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TYPES OF CHOLINERGIC RECEPTOR
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TYPES OF CHOLINERGIC RECEPTOR
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Definition & Classification of Parasympathomimetic
➢ Drugs that partially or completely mimic the actions of cholinergic nerves is
sympathomimetic or cholinomimetic.
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PARASYMPATHOMIMETIC DRUGS
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SYNTHESIS OF Ach
Acetyl CoA+choline
Choline acetyl transferase
Acetylcholine + CoA
Destruction
Acetylcholine(Ach)
cholinesterase
Choline+Acetate
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SYNTHESIS OF Ach
➢ Choline is taken up into nerve terminals by special choline
transport system mediated by a carrier that co-transport sodium.
➢ The choline transport appears to be the rate limiting step.
➢ It can be inhibited by hemicholinium.
➢ The choline acetylated by enzyme choline acetyl transferase.
➢ The acetyl group source of acetyl-COA.
10

STORAGE AND RELEASE OF Ach
➢The Ach is packaged into vesicles by an active transport process coupled
with the efflux of protons.
➢The mature vesicles also contain ATP and proteoglycan.
➢When an action potential propagated voltage sensitive calcium channels
in the presynaptic membrane opens causes an intracellular increase of
calcium.
➢Elevated calcium levels promotes the fusion of synaptic vesicles with the
cell membrane and release of their contents into the into the synaptic
cleft.
➢The release can be blocked by botulium toxin.
➢Ach is degraded by acetylcholinesterase and forms choline and acetate in
the synaptic clef.
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MECHANISM OF ACTION Ach
➢M1, M3 and M5 Receptors activate Gs protein that responsible for the
stimulation of phospholipase C activity. This leads to the hydrolysis of
phosphatidylinositol polyphosphate(PIP) to form inositol 1-4-5
triphosphate and diacylglycerol. The former causes release of
intracellular calcium from endoplasmic reticulum while the latter
activates protein kinase.
➢The M2 and M4 receptors interact with G protein (Gi) with resultant
inhibition of adenylcylase and activation of K+ channels particularly in
the heart and modulation of the activity of calcium channels in certain
cell types.
➢Nicotinic receptors are ligand gated ion channels and their activation
causes a rapid increase in the cell permeability to Na+ and K+ ions with
resultant depolarisation and excitation.
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MUSCARINIC ACTION
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NICOTINIC ACTION
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PHARMACOLOGICAL ACTION OF Ach
Action on heart:-
❖ In mammals, the effect of Ach on the heart is similar to that obtained by
stimulation of the vagus which is a cholinergic nerve, thus it will produce
hyperpolarisation.
1) Decrease in the impulse generation acting on SA node it causes bradycardia
(negative chronotropic action).
2) Decrease the contractility (negative ionotropic action).
❖Direct cardiac action of muscarinic stimulant.
✓ Increase in a potassium current in the sinoatrial & atrio-ventricular nodes.
✓ Decrease the slow influx calcium current in heart cells.
✓ A reduction in the hyperpolarisation activated current that leads to diastolic
depolarisation. 15

❖ Blood vessels
❖ Dilate the blood vessel
I. Stimulation of receptor causes release of nitric oxide (NO) which causes vascular
relaxation.
❖ Smooth muscles
I. Increase the tone and rhythamic activity of smooth muscle of the GI tract & enhance the
peristalsis.
II. Contract the smooth muscle of gall bladder .
III. Constrict the bronchial smooth muscle & causes bronchospasms.
❖ Glands
✓ Increase the cholinergic stimulation, gastric, intestinal, pancreatic secretions.
✓ The bronchial, salivary, lachrymal & nasopharyngeal secretions are also augmented.
❖ Eye
✓ Constriction of the pupil (meiosis) resulting in reduction in intraocular tension.
✓ Contraction of ciliary muscles. 16

❖Genitourinary tract:- Stimulate the detrusor muscle and relax the trigone &
sphincter muscles of the bladder.
❖Central nervous system
Activation of nicotinic receptors occurs at presynaptic & postsynaptic.
To regulate the release of several release of neurotransmitters (glutamate,
GABA, dopamine, adrenaline)
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❖ Carbachol :- (Carbamylcholine) has both muscarinic and nicotinic actions.
➢ Like bethanecholine, carbachol is an ester of carbamic acid & poor substrate
for acetylcholinesterase.
➢ Action:- It has profound effect on both the cardiovascular system & the
gastrointestinal system because of its ganglion stimulating activity & it may
first stimulate & then depress these action.
➢ It can cause release of epinephrine from the adrenal medulla by its nicotinic
action.
❖Bethanechol
• It increases the tone of the detrusar urine muscle produce an increase in the
intravesical pressure.
• It also stimulates gastric and intestinal motility and increases lower
oesophageal sphincter pressure.
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❖Methacholine
✓ It is a contraindicated in patients with react heart attack or stroke, uncontrolled
hypertension and sever airway disease.
❖Muscarine
✓ It is an alkaloid obtained from poisonous mushrooms amantia muscaria. It is not
use thearapeutically but is of toxicological importance.
❖Pilocarpine
✓ It is a tertiary amine alkaloid from leaves of ‘pilocarpus microphyllus’ and
other species ‘pilocarpus jabarandi’.
✓ It readily absorbed from the conjunctiva and causes meiosis.
✓ Spasm of ciliary muscle and reduction of intraocular pressure.
✓ Pilocarpine is one of the most potent stimulators of secretions such as sweat,
tears, & saliva, but its use for producing these effects has been limited due to its
lack of selectivity.
✓ The drug is beneficial in promoting salivation in patients with xerpstomia
(dryness of mouth).
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❖Indirect acting cholinergic drugs
✓ The physiological effects of Ach are terminated by hydrolysis of ester linkage
of the molecule by AchE compounds have been developed which compete
with Ach for the active site of AchE, and inhibit the by forming more stable
complexes, there by increasing the Ach concentration & effectiveness at the
cholinergic site, there indirectly acting Parasympathomimetic are called
Anti-cholinesterase.
❖ Reversible Anti-cholinesterase
✓ They bear structural resemblances to Ach hence if are capable of interacting
with anionic & esteratic of cholinesterase enzyme & receptors, they have
effinity of active sites but no interinsic activity. It produces the tempory
inhibition of the enzyme.
20

❖ Physostigmine:- It is naturally occuring alkaloid isolated from ‘calabarbean’
the dried seeds of Physostigma venenosum.
✓ It can inhibit the AchE enzyme when present in the concentration as low as
10^-6 mol
✓ If administerd in large doses, it can cross BBB & reaches CNS where it first
stimulates and then depress the CNS.
❖ Neostigmine:- It is synthetic quaternary ammonium compound, its action on
nicotinic receptor stronger than muscarinic receptors and it also direct
stimulant action.
✓ It giving combination with atropine to abolish the unwanted muscarinic side
effects.
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❖ Irreversible cholinesterase
❖ Oraganophosphorous compound
✓ These are powerfull inhibitors of chE, it causes accumulation of Ach in the
tissues. Because of prolonged action and high toxicity.
Mechanism of toxicity
✓Ach inhibitors that form a stable irreversible covalent bond to the enzyme.
Occurs at cholinergic junctions of the nervous system including postganglionic
parasympathetic junctions (sites of muscarinic activity), autonomic ganglia and
the neuromuscular junctions (sites of nicotinic activity) and certain synapses in
the CNS.
Acetylcholine is the neurohumoral mediator at the cholinergic junctions. Since
acetylcholinesterase is the enzyme that degrades acetylcholine following
stimulation of a nerve, by inhibiting acetylcholinesterase, organophosphates
allows acetylcholine to accumulate and result in initial excessive stimulation
followed by depression. 22

❖ Uses
✓ Myasthenia gravies:- It is initial treatment for most patients is anticholinesterase
medication, usually pyridostigmine. neostigmine is also available but not commonly
used.
✓ Dementia: Used in mild to moderate Alzheimer disease.
These medication have off label use dementia from Parkinson disease & Lewy body
dementia.
✓ Ophthalmology:- Used in glaucoma to reduce the intraocular pressure by causing
contraction of ciliary body so as to facilitate outflow of aqueous humor & perhaps also
by diminishing the rate of its secretion.
✓ Post operative urinary retention
✓ Post operative decurination
✓ Acute clonic pseudo-obstraction
✓ Anticholinergic overdose:- Physostigmine is specific antidote for poisoning with
belladonna.
✓ Xerostomia:- Use of muscarinic agonist in patients with an in adequate response to
artificial saliva & mechanical stimulation of sjogren syndrome or patients post-radiation
treatment associated with head & neck cancer.
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✓Cobra bite:- Cobra venom has a curare like neurotoxin. Specific
anti-venom serum is the primary treatment, neostigmine + atropine
prevent respiratory paralysis.
❖Adverse effects:
✓Meiosis
✓Salivation
✓Sweating
✓Bronchial constriction
✓Vomiting & diarrhoea
✓Myasthenia gravis
✓Neuromuscular blockade
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PARASYMPATHOLYTIC DRUGS
Definition Parasympatholytics:- Drugs which inhibit the actions of
acetylcholine on structures innervated by postganglionic cholinergic
nerves and smooth muscle cells that respond to acetylcholine but
lack of cholinergic innervation.
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CASSIFICATION OF PARASYMPATHOLYTICS
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➢ Ipratropium is used by inhalation as a bronchodilator.
➢ 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.
➢ Atropine is the prototype drug of this class, is highly selective for
muscarinic receptors.
➢The two naturally occurring compounds, atropine and scopolamine are
alkaloids found in solanaceous plants.
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ATROPINE
Mechanism of action:-
➢Atropine causes reversible blockade of cholinomimetic actions at muscarinic
receptor.
➢When atropine binds to the muscarinic receptor it prevents actions such as
I. The release of inositol trisphosphate (IP3) and the inhibition of adenylyl
cyclase that are caused by muscarinic agonists.
II. Atropine is highly selective for muscarinic receptors. Its potency at nicotinic
receptors is much lower.
III. Atropine does not distinguish between the M1, M2, and M3 subgroups of
muscarinic receptors.
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❖Eye:-
✓Dilation of pupil (mydriasis) this is due to its action on circular muscles of iris
and ciliary muscle.
✓Antagonises miotic effect of Parasympathomimetic drugs.
✓It also stimulates sympathetic nerve dilates the pupil.
✓Cycloplegia or loss of accomodation .
❖Respiratorysystem:-
✓Atropine inhibits secretion of nose, mouth, pharynx and bronchi. The smooth
muscles of bronchioles are dilated. (M3 blockade)
✓More potent than Hyoscine or scopalamine in producing these effects, because
of these effects these drugs are used as pre-anaesthetic agents and patients
with bronchial asthama.
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❖cardiovascular
✓ It produce divergent effect on the CVS depending on dose .
✓ At low dose, the three dominant slight decreasing in HR. This effect results from
blockade of the M1 receptors on the inhibitory pre-junctional neurons. Thus
permitting increasedAch release.
✓ At higher dose, progressive increase in HR by blocking the M2 receptors on the
synoarterial node.
✓ It produce tachycardia.
✓ It blocked of M2 receptors on SA node through which vagal tone decrease heart rate.
❖Action on CNS
✓ Stimulate many medullar centres vagal, Respiratory, Vasomotor.
✓ Depress the vestibular excitation & has anti-motion sickness.
✓ By blocking the relative cholinergic over activity in basal ganglia it suppresses
tremor & rigidity of parkinsonism.
✓ High doses cause cortical excitation, restlessness, disorientation, hallucination.
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❖ GIT:-
✓Decreases tone, motility and peristalsis. All secretions of the GIT are reduced.
But gastric emptying time is increased.
❖Othersmoothmuscles:-
✓Atropine relaxes muscles of ureters, urinary bladder, gall bladder, etc.
✓In general all types of smooth muscles are relaxed.
✓Hence parasympatholytics are also called as spasmolytics.
❖Glands
✓ Markedly decrease sweat, salivary, tracheobronchail & lachrymal secretion (m3
blockade)
✓ Decrease secretion of acid, pepsin & mucus in the stomach.
❖Body temperature
✓ Rise in body temperature occurs at higher dose it inhibition of sweating as well
as stimulation of body temperature regulating centre in the hypothalamus.
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❖Local anesthetic:- Mild anesthetic action on cornea.
❖Miscellaneous effects:- Atropine reduces ADH secretion from the pituitary
gland and thereby decreases diuresis. Sweat secretion is also decreased
and so there is an increase in body temperature.
❖Therapeutic uses
✓ Ophthalmic
✓Antispasmodic
✓Bradycardia
✓Antisecretory
✓Antidote for cholinergic agonist
❖ Adverse effects:- Dryness of mouth, blurred vision, ‘sandy eyes’,
tachycardia, urinary retention, constipation, restlessness, confusion,
hallucination, delirium, Also induced troublesome urinary retention.
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❖Quaternary compounds
✓ Incomplete oral absorption.
✓ Do not penetrate brain & eye, central & ocular effect are not seen after
parenteral/oral administration.
✓ Elimination is slower & most are longer acting than atropine.
✓ Have a higher nicotinic blocking property
✓ At high dose some times neuromuscular blockade may also occur.
❖Scopolamine
✓ Is one of the most effective anti-motion sickness drug.
✓ It also has the unusual effect of blocking short-term memory.
✓ In contrast to atropine, it produce sedation. At high doses it can produce
excitement.
❖ Uses
✓ Motion sickness
✓ Post operative nausea & vomiting.
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❖ Ipratropium & Tiotropium
➢ These agents are approved as bronchodilators for maintenace treatment of branchospasm
associated with COPD.
➢ Ipratropium uses as acute management of bronchospasm in asthma.
➢ Both agents are delivered via inhalation. because of there positive charges these drugs
donot enter CNS, isolating their effects to the pulmonary system.
✓ Ipratropium appears to block all subtypes of muscarinic receptors and thus blocks
presynaptic muscarinic inhibition of ACh release, whereas tiotropium shows some
selectivity for M1 and M3 receptors.
✓ Tiotropium has a lower affinity for M2 receptors, minimizing its presynaptic effect on ACh
release.
✓ Ipratropium produces bronchodilator, tachycardia, and inhibition of secretion similar to
that of atropine when it is administered parentrally.
✓ The Principal clinical use of Ipratropium and Tiotropium is in the treatment of chronic
obstructive pulmonary disease; they are less effective in most asthmatic patients.
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References:
1) Rang H.P., Dale M.M., Ritter J.M., Flower. R.J.Rang and Dale’s
Pharmacology. 6th ed Churchill Livingstone Elsevier 2007:718-719.
2) Goodman and Gilman’s. The pharmacological basis of THERAPEUTICS.
11th ed 2006: 429- 453.
3) Bertram G. Katzung; Basic and clinical pharmacology;10th edition
4) K.D Tripathi (5th edition)
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THANK YOU
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Seminar on parasympathomimetic and parasympatholytic converted

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