This document discusses parasympathomimetic drugs, which mimic the effects of the parasympathetic nervous system. It describes how these drugs activate parasympathetic receptors, especially muscarinic and nicotinic acetylcholine receptors. It provides details on the mechanisms of different parasympathomimetic drugs, including how they stimulate receptors to produce various effects in the body. Specific drugs discussed include acetylcholine, carbachol, and their therapeutic uses and side effects.

1. BANGABANDHU SHEIKH MUJIBUR RAHMAN SCIENCE & TECHNOLOGY
UNIVERSITY.GOPALGANJ-8100.
A Presentation
On
Parasympathomimetic drugs
Presented By: MD. SAJJAD HOSSAIN SIAM
1

2. Drugs that mimic the effects of parasympathetic nervous system
activity specially cholinergic receptors.
Parasympathomimetic drugs activate the parasympathetic nervous
system (PSNS).
As the neurotransmitter of the PSNS is acetylcholine,
parasympathomimetics are also called cholinomimetic agents or
cholinoceptor activating drugs.
These chemicals are also called cholinergic drugs because
acetylcholine (ACh) is the neurotransmitter used by the PSNS.
Parasympathomimetic drugs

3. Parasympathomimetic
drug
Direct acting
Choline ester
1. Acetylcholine
2. Methacholine
3. Carbachol
Alkaloid
1. Pilocarpine
Indirect acting
Reversible ChE
inhibitors
1. Physostigmine
2. Neostigmine
3. Edrophonium
Irreversible ChE
inhibitors
1. Ecothiophate

4. Neurotransmission at cholinergic neurons
Neurotransmission at cholinergic neurons involves 6 sequential steps
1.Synthesis of ACh
2.Storage ACh in vesicles
3.Release of ACh
4.Binding of ACh to a receptor
5.Degradation of the ACh in the synaptic cleft
6.Recycling of choline and acetate

5. 1. Synthesis of ACh
 Choline is transported from the extracellular fluid into the
cytoplasm of the cholinergic neuron by an energy dependent
carrier system that that cotransports sodium.
 Here, choline has a quaternary nitrogen and carries a
permanent positive charge and thus cannot diffuse through
the membrane.
 The uptake of choline is the rate-limiting step in the Ach
release.
 Choline acetyltransferase catalyzes the reaction of choline
with acetyl coenzyme A (Co A) to form of ACh (an ester) in the
cytosol. Acetyl Co A + choline = Ach
 Co A arises from glucose metabolism.
 Synthesis is depedent on choline.

7. 2. Storage of Acetylcholine in vesicles
 ACh is packaged and stored into presynaptic vesicles by an active transport process coupled to the efflux of
protons.
 Ach is transported from the cytoplasm into individual vesicles by means of a carrier protein on the vesicle
membrane called vesicular Ach transport (VACHT).
 VACHT is an antiporter that couples an influx of Ach with an efflux of proton.
 Once packaged in the vesicles, acetylcholine is stored at the nerve ending until an action potential arrives and
allows for its release into the synaptic cleft.
 The mature vesicle contains not only ACh but also adenosine triphosphate proteoglycan.
 Cotransmission from autonomic neurons is the rule rather than the exception. This means that the most synaptic
vesicles contain the primary neurotransmitter (here, ACh) as well as cotransmitter that increase or decrease the
effect of primary neurotransmitter.

9. 3. Release of acetylcholine
When an action potential propagated by voltage sensitive sodium channels arrives at a nerve ending,
voltage sensitive calcium channels on the presynaptic membrane open, causing an increase in the conc. of
intracellular calcium.
Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and the release of
their contents into the synaptic space.
This release can be stopped by botulinum toxin.
 in contrast, the toxin in black widow spider venom causes all the Ach stored in synaptic vesicles to empty
into the synaptic gap.

10. 4. Binding to the receptor
 Ach released from the synaptic vesicles diffuses across the synaptic space and binds to post synaptic
receptors on the target cell, to presynaptic receptors on the membrane of the neuron that release the Ach,
or to other targeted presynaptic receptors.
 The post synaptic cholinergic receptors on the surface of the effector organs are divided into two classes:
i. Muscarinic receptors
ii. Nicotinic receptors
 Binding to a receptor leads to a biological response within the cell.

12. 5. Degradation of acetylcholine
 The enzyme acetylcholinesterase converts Ach into inactive metabolites choline and acetate.
 Ach-esterase is abundant in the synaptic cleft.
 Both the products are reuptake by the presynaptic terminal.

13. 6. Recycling of choline
 Choline may be recaptured by a
sodium-coupled, high affinity
uptake system that transports the
molecule back into the neuron.
There, it is acetylated into Ach that
is stored until released by a
subsequent action potential.

14. Receptors for cholinergic drugs
On the basis of different affinity ,
they are classified into two groups-
A. Muscarinic receptors
B. Nicotinic receptors
Cholinergic receptors (Cholinoceptors)

15. Muscarinic receptors
 Muscarinic receptors belong to the class of G-protein coupled receptors (metabotropic receptors).
 Muscarinic responses are slower, may produce excitation or inhibition.
 They involve second messenger systems, rather than the direct opening of an ion channel.
 Muscarinic is the prototypical muscarinic agonist and derives from the fly agaric mushroom Amanita muscaria.
 Muscarinic receptors are found in the parasympathetic nervous system.
 Muscarinic receptors in smooth muscle regulate cardiac contractions, gut motility and bronchial constriction.
 Muscarinic receptors in exocrine glands stimulate gastric acid secretion, salivation and lacrimation.
 There are five sub-classes of muscarinic receptors.
 However, only M1, M2 and M3 receptors have been functionally characterized.

16. Receptor
name
Typical location Result of ligand binding Effect
Muscarinic M1
(Neural)
 CNS neurons
 Sympathetic postaganglionic
neurons
 Some presynaptic sites
 Gastric parietal cell
 Formation of IP3 and DAG
 Increased intracellular calcium
 CNS excitation
 Gastric secretion
Muscarinic M2
(Cardiac)
 Myocardium
 Smooth muscle
 Some presynaptic sites
 Opening of K channels
 Inhibition of adenylyl cyclase
 Cardiac inhibition
 Neural inhibition
 Central effect: Tremor,
hypothermia
Muscarinic M3
(Glandular)
 Exocrine gland
 Vessels (smooth muscle and
endothelium)
 Formation of IP3 and DAG
 Increased intracellular calcium
 Increased gastric, salivary
secretion
 GIT muscle contraction
 Vasodilation
Muscarinic M4  CNS neurons possibly vagal nerve
ending
 Neural inhibition
Muscarinic M5  Vascular endothelium, especially
cerebral vessels
 CNS neurons
 Neural inhibition

17. Nicotinic receptors
 Nicotinic responses are of fast onset, short duration and excitatory in nature.
 Nicotinic receptors are found in a variety of tissues, including the autonomic nervous system, the neuromuscular
junction and the brain in vertebrates.
 They also are found in high quantities in the electric organs of various electric eels and rays.
 The high quantities of receptors in these tissues and the use of neurotoxins from snake venom (e.g., cobra venom)
that bind specifically to the nicotinic receptor aided the purification of the receptor protein.
 Nicotinic receptors at ganglia are different subtypes from those localized to voluntary skeletal muscle.

18. Receptor name Typical location Result of ligand binding Effect
Nicotinic NN  Postaganglionic neuron
 Some presynaptic
cholinergic terminals
 Opening of Na and K
channels
 depolarization
 Excitation
Nicotinic NM  Skeletal muscle
neuromuscular end
plates
 Opening of Na and K
channels
 depolarization
 Skeletal muscle
contraction

19. Basic pharmacology of the direct acting
cholinoceptor stimulants

20. Structure
 They have permanently charged quaternary ammonia group.
 They are insoluble in lipid .
methacholine
carbachol

21. Production of 2nd messengers ( IP3 and DAG)
Activate the phospholipase C
The receptors undergo a conformational change and interacts with a G-protein , designated Gq
activation of muscarinic receptors ( M1 or M2)
Mechanism of action with muscarinic receptors

22. IP3
IP3 causes an increase in
intracellular Ca
Calcium can then interact
to stimulate or inhibit
enzymes or to cause
hyperpolarization ,
secretion or contraction
DAG
DAG activates protein
kinase C,
Protein kinase C is an
enzyme that
phosphorylates numerous
proteins within the cell.

23. Activation of M2 subtype on the cardiac muscle
Stimulates a G-protein, designated Gi
Inhibition of adenylyl cyclase
Increase potassium ion conductance
Decreasing heart rate and force of conduction

24. Mechanism of action with nicotinic receptors
About nicotinic receptors
 Nicotinic receptors are located in the CNS, the adrenal medulla, autonomic ganglia, and the
neuromascular junction (NMJ) in skeletal muscles.
 Those at the NMJ are sometimes designated NM and the others NN
 The nicotinic receptors of autonomic ganglia differ from those of the NMJ.
 The nicotinic receptors are composed of five subunits, and it functions as ligand gated ion channel.

25. Mechanism as a ligand gated
ion channel
Binding of two Ach molecules elicits a
conformational change
Allows the entry of sodium (Na) ions
Resulting of the depolarization of the effector cell
Nicotinic at low conc. Stimulates the receptor
But nicotinic at high conc. Block the receptor

26. Acetylcholine
 Acetylcholine is a quaternary ammonium compound that cannot penetrate membranes.
 Although it is the neurotransmitter of parasympathetic and somatic nerves as well as autonomic ganglia.
 It lacks therapeutic importance because of its multiplicity of actions and its rapid inactivation by the cholinesterases.
 Ach has both muscarinic and nicotinic activity.

27. Pharmacological effect of Ach
Effector organs Effect Receptors
1. Eye  Constriction of pupil
 Contraction of cilliary muscle for near vision
M3 receptors
2. Heart  Decrease heart rate
 Decrease force of contraction
 Decrease conductivity of velocity
 RESULT: Decrease cardiac output and therefore decrease blood pressure
M2 receptors
3. Blood vessels  Vasodilation
4. Lungs  Bronchoconstriction: contraction of bronchial muscle
 Increased bronchial secretion
 RESULT: aggravation of bronchial asthma.
M3 receptors
Effects due to muscarinic receptor activation

28. Effector organs Effect Receptors
5. GIT  Contraction of GIT smooth muscle
 Relaxation of sphincter
 Increased secretion of HCl and
digestive enzyme
M3 receptors
6. Genitor urinary system  Contraction of detrusor muscle of
urinary bladder
 Relaxation of trigone
 Relaxation of sphincter
 RESULT: Promote voiding of urine
M3 receptors
7. Glands  Increase secretion of all exocrine
glands
M3 receptors
8. Uterus, pregnant  Contraction M3 receptors

29. Effects due to nicotinic receptor activation
Receptors Effect
1. NN Receptor activation at post ganglionic neuron
(adrenal medulla)
 Ach stimulates adrenal medulla and causes release of
adrenaline, which produces sympathetic effects.
2. NM Receptor activation  Immediate depolarization causes contraction of skeletal
muscle followed by flaccid paralysis.

30. Common (ocular) side effects of Acetylcholine
include
Corneal swelling
Corneal clouding
Corneal decompensation
allergic reaction
Change in eyesight, eye pain
Rare (systemic) side effects of Acetylcholine
include
Slow heart rate
Flushing
low blood pressure (hypotension)
breathing difficulty
Sweating
Side effect of Ach

31.  Carbachol a slowly hydrolyzed cholinergic agonist that acts at both muscarinic and nicotinic receptors.
 Carbachol is a synthetic choline ester and a positively charged quaternary ammonium compound.
 Or, Like bethanechol, carbachol is an ester of carbamic acid and a poor substrate for acetylcholinesterase .
 Carbachol is a parasympathomimetic that mimics the effect of acetylcholine on both the muscarinic and nicotinic
receptors.
 It is biotransformed by other esterases, but at a much slower rate.
 A single administration can last as long as 1 hour.
 Carbachol is a potent cholinergic (parasympathomimetic) agent which produces constriction of the iris and ciliary body
resulting in reduction in intraocular pressure.
 The exact mechanism by which carbachol lowers intraocular pressure is not precisely known.
 In the cat and rat, carbachol is well-known for its ability to induce rapid eye movement (REM) sleep when microinjected
into the pontine reticular formation.
 This drug is administered ocularly to induce miosis to reduce intraocular pressure in the treatment of glaucoma.
 Carbachol is also used to stimulate micturition by contraction of detrusor muscle. This drug may cause hypotension,
bradycardia, nausea, vomiting, bronchospasm, and abdominal cramps.
Carbachol

32. Actions of Carbachol
Carbachol has profound effects on both the cardiovascular and GI systems
because of its ganglion-stimulating activity and it may first stimulate and
then depress these system.
It can cause release of epinephrine from the adrenal medulla by its
nicotinic action.
Locally instilled into the eye, it mimics the effect of Ach, causing miosis
and a spasm of accommodation in which the ciliary muscle of the eye
remains in a constant stat of contraction.
High potency.
Long duration of action.
Receptor non-selectivity.

33. Therapeutic uses
Carbachol is primarily used in the treatment of
glaucoma. Carbachol eyedrops are used to decrease the
pressure in the eye for people with glaucoma.
But it is also used during ophthalmic surgery.
It is sometimes used to constrict the pupils during
cataract surgery.

34. Adverse effect of carbachol
 At doses used ophthalmologically, little or no
side effects occur due to lack of systemic
penetration.
Carbachol