Parasympathomimetics

Dr. Syed Saqib Khalid

Lecturer
Department of Pharmacology
Liaquat National Hospital & Medical College
 Synthesis and Release
of Acetylcholine
 What is cholinergic ?
Choline in cholinergic refers to acetylcholine , which is the neurotransmitter
of cholinergic neuron present in the parasympathetic nervous system.
Acetylcholine is also the neurotransmitter for postganglionic nerves in the
SNS (sweat glands, blood vessel & adrenal medulla)
What is Cholinergic drugs
• Acetylcholine is a neurotransmitter in the parasympathetic system. Drugs that combine
with acetylcholine receptors and produce similar responses in the end organ are called
Para sympathomimetic drugs. They are also called cholinergic or cholinomimetic
drugs.
• These are examples of para sympathomimetic agent :
1) Choline ester (acetylcholine , methacholine, carbachol, bethanechol)
2) Naturally occurring cholinomimetic alkaloids (pilocarpine, muscarine, arecoline)
3) Synthetic alkaloids (areclidine and oxotremorine)
4) Anticholinesterase agent:(i) reversible a) natural (physostigmine)
b) Synthetic (neo stigmine , edrophonium, demecarium, ambenonium,
benzoquinonium)
(ii)Irreversible (a number of organophosphorus compounds used
mainly as insecticides
Cholinergic receptors

• Muscarinic receptor
• Nicotinic receptor
 Muscarinic receptors
• These receptors are selectively stimulated by muscarine and blocked by atropine.
• They are located primarily on autonomic effector cells in heart, blood vessels, eye
smooth muscles, sweat gland, gland in gastrointestinal, respiratory tract and in the
CNS.
• G- protein coupled receptors.
• Divided into M1, M2, M3, M4 and M5.
• The first 3 are major subtypes that are present on effector cells as well as on
prejunctional nerve endings and both are expressed in peripheral organs as well as in
the CNS.
• M4 and M5 are present in certain area of brain and regulate the release of other
neurotransmitters.
• M1: The M1 is primarily a neuronal receptor located on ganglion cell and
central neurones, especially in cortex, hippocampus and corpus striatum.
• It play major role in mediating gastric secretion, relaxation of lower esophageal
sphincter(LES) on vagal stimulation and in learning, memory, motor functions.
• M2: cardiac muscarinic receptors are predominantly M2 and mediate vagal
bradycardia.
• Auto receptors on cholinergic nerve endings are also M2 subtype. Smooth
muscles express some M2 receptors as well as which, like M3 mediate
contraction.
• M3: Visceral smooth muscle contraction and glandular secretions are elicited
through M3 receptors, which mediate vasodilatation through EDRF release.
Together the M2 and M3 receptors mediate muscarinic action including
contraction of LES.
 Nicotinic receptors
• Named after agonist nicotine.
• These receptor selectively activated by nicotine and blocked by tubocurarine or
hexamethonium. Their activation causes opening of the channel and rapid flow of
cations resulting in depolarization and action potential.
• Ligand gated ion channels.
• Divided into N1and N2
• N1: these are present at skeletal muscle endplate: are selectively
stimulated by phenyl trimethylammonium and blocked by
tubocurarine. They mediate skeletal muscle contraction.
• N2: these are present on ganglionic cells( sympathetic as well as
parasympathetic), adrenal medullary cell and in spinal cord and
certain area of brain.
• They are selectively stimulated by dimethyl phenyl pipierazinium
(DMPP), blocked by hexamethonium, and constitute the primary
pathway of transmission in ganglia
 Cholinergic drugs

• These are drugs which produce action similar to the ACh, either by directly
interacting with cholinergic receptors or by increasing of availability of ACh.
• Some cholinergic agonist are acetylcholine, methacholine, carbachol, muscarine and
arecoline.
 CHOLINERGIC RECEPTORS AND
MECHANISMS

Organ Area Receptor Type Effect

Eye Sphincter M3 Gq Contraction—miosis
Ciliary muscle M3 Gq Contraction—accommodation for near vision

Heart SA Node M2 Gi ↓ Heart rate (HR)—negative chronotropy

AV Node M2 Gi ↓ Conduction velocity—negative dromotropy No effects on

ventricles, Purkinje system

Lungs Bronchioles M3 Gq Contraction—bronchospasm

Glands M3 Gq Secretion
GI Tract Stomach M3 Gq ↑ Motility—cramps
Glands M3 Gq Secretion
Intestine M3 Gq Contraction—diarrhea, involuntary defecation
 CHOLINERGIC
RECEPTORS AND
MECHANISMS
Organ Area Receptor Type Effect
Bladder M3 Gq Contraction (detrusor), relaxation (trigone/sphincter),
urinary incontinence
Sphincter M3 Gq Relaxation, except lower esophageal, which contracts
Glands M3 Gq Secretion—sweat (thermoregulatory), salivation, and
lacrimation
Blood Vessels M3 Gq Dilation (via NO/endothelium-derived relaxing factor)
Endothelium
Actions
• Depending on the type of receptor through which it is mediated, the peripheral actions of ACh
are classified as muscarinic or nicotinic.
A. Muscarinic
• Heart : ACh hyperpolarize the SA nodal cells and decrease the rate of diastolic depolarisation.
As
a result, rate of impulse generation is reduced – bradycardia or even cardiac arrest may occur.
• At the A-V node and His- Purkinje fibre refractory period(RP) is increased and conduction is
slowed: P-R interval increases and partial to complete A-V block may be produced. The force of
atrial contraction is markedly reduced
• The cardiac muscarinic receptors are of the M2 subtype.
• Blood vessels: all blood vessels are dilated.
• Muscarinic (M3) receptors are present on vascular endothelial cells: vasodilatation is mediated
through the release of an endothelium dependent relaxing factor(EDRF)which is nitric oxide.
• Stimulation of cholinergic nerves to the penis causes erection by releasing NO and dilating
cavernosal vessels through M3 receptors.
• Smooth muscle : Smooth muscle in most organs is contracted (mainly
through M3). Tone and peristalsis in the gastrointestinal tract is
increased and sphincters relax → abdominal cramps and evacuation
of bowel.
• Peristalsis in ureter is increased. The detrusor muscle contracts while
the bladder trigone and sphincter relaxes→ voiding of bladder.
• Bronchial muscles constrict, asthmatics are highly sensitive →
dyspnoea, precipitation of an attack of bronchial asthma.
• Glands : Secretion from all parasympathetically innervated glands is
increased via M3 and M2 receptors: sweating, salivation, lacrimation,
tracheobronchial and gastric secretion.
• Secretion of milk and bile is not affected.
• Eye : contraction of circular muscle of iris → meiosis.
• Contraction of ciliary muscle → spasm of accommodation, increased
outflow facility, reduction in intraocular tension (especially in
glaucomatous patients).
B. Nicotinic
• Autonomic ganglia: Both sympathetic ganglia and parasympathetic are
stimulated. This effect is manifested at higher doses. High dose of ACh
given after atropine causes tachycardia and rise in BP due to stimulation of
sympathetic ganglia and release of catecholamine.
• Skeletal muscles : Iontophoretic application of ACh to muscle endplate
causes contraction of the fibre. Intra-arterial injection of high dose can
cause twitching and fasciculations
Interactions
• Anticholinesterases potentiate ACh, methacholine to less extent and
have only additive action with carbachol or bethanechol
• Adrenaline is a physiological antagonist.
Uses
• Bethanechol has been used in postoperative/postpartum non
obstructive urinary retention, neurogenic bladder, congenital
megacolon and gastroesophageal reflux.
Cholinomimetic alkaloids
• Pilocarpine : it is obtained from the leaves of pilocarpus microphyllus and
other species. It has muscarinic actions and also stimulates ganglia- mainly
through ganglionic muscarinic receptors.
• It causes sweating, salivation and increases other secretions as well.
• Small doses generally cause fall in BP, but higher doses elicit rise in BP and
tachycardia which is probably due to ganglionic stimulation (through
ganglionic muscarinic receptors).
• In the eyes, it penetrates cornea and causes miosis, ciliary muscle
contraction and fall in intraocular tension lasting 4-8 hours.
• Pilocarpine is used only in the eye as 0.5-1% drops.
• Muscarine : it occurs in poisonous mushrooms Amanita muscaria and
Inocybe species and has only muscarinic actions it is not used
therapeutically but is of toxicological importance.
• Muscarine is non selective agonist of the muscarinic acetylcholine
 Specific examples of cholinergic
drugs
o Direct – acting
• Bethanechol (urecholine) – raise the tone &motility of the bladder &Gl tract (should cause
urination with in 60 minutes in a pt. with urinary retention)
• Pilocarpine (pilocar) – used to constrict pupil, which lower intraocular pressure (glaucoma)
o Indirect – acting
• Neostigmine (prostigmin) – given for the diagnosis & treatment of myasthenia gravis – it
causes skeletal muscle contractions
• Donepezil (Aricept ) – used to treat mild – moderate Alzheimer’s disease- it raise ACh in the
brain &helps raise or maintain memory or learning capabilities (manages the symptoms , it
is not a cure)
Anticholinesterases
• Anticholinesterase are agent which inhibit ChE, protect ACh from
hydrolysis – produce cholinergic effects
• Classification :
A) Cholinesterase inhibitors or reversible anticholinesterase :
• carbamates
1. Natural :Physostigmine
2. Synthetic : Neostigmine, Pyridostigmine, Edrophonium, Rivastigmine,
Donepezil, Galantamine
3. Acridine: tacrine
B) Irreversible anticholinesterases :
1. Organophosphorus compound – diisopropyl
fluorophosphates(DFP), Echothiophate, parathion, malathion,
diazinon
2. Tabun, sarin, soman( nerve gases for chemical warfare)
3. Carbamate esters : carbaryl (sevin), propoxur( baygon)
Pharmacological actions
• Ganglia : anti- ChEs stimulate ganglia primarily through muscarinic receptors
present there
• High doses cause persistent depolarisation of the ganglionic nicotinic receptors
and blockage of transmission.
• CVS: cardiovascular effect are complex. Where as muscarinic action would
produce bradycardia and hypertension, ganglionic stimulation would tend to
increase heart rate and BP.
• action on medullary centres (stimulation followed by depression)
• The overall effect are often unpredictable and on the agent and its doses.
• Skeletal muscle: Activates prejunctional fibres→ repetitive firing →
twitching and fasciculations.
• Increases force of contraction in muscle
• Higher doses cause persistent depolarization of endplate resulting in blockade of
neuromuscular transmission→ weakness and paralysis.
Pharmacokinetics
• Physostigmine: It is rapidly absorbed from g.i.t. and parenteral sites.
Applied to the eye , it penetrates cornea freely. It crosses blood brain
barrier and is disposed after hydrolysis by Che.
• Neostigmine : poorly absorbed orally.
• don’t effectively penetrate cornea or cross blood brain barrier. They
are partially hydrolysed and partially excreted unchanged.
• Organophosphates : these are absorbed from all sites including intact
skin and lungs. They are hydrolysed as well as oxidized in the body.
Uses
• Physostigmine
1. Used as miotic drops to decrease IOP in Glaucoma.
2. To antagonize mydriatic effect of atropine
3. In Belladonna poisoning
4. Alzheimer’s disease
5. Atropine is antidote in physostigimine poisoning.
• Neostigmine
1. Used in treatment of Myasthenia Gravis to increase muscle strength
2. Post – operative reversal of neuromuscular blockade
3. In gastric atony paralytic ileus, urinary bladder atony
• Myasthenia gravis : Myasthenia gravis is an autoimmune disorder affecting 1 in
10000 population – reduction in number of N1 receptor
• Structural damage to the neuromuscular junction – weakness and easy
fatigability on repeated activity, with recovery after rest.
• Neostigmine improve muscle contraction by allowing ACh released from
prejunctional endings to accumulate and act on receptors over a larger area
and by directly depolarizing the endplate.
• Treatment is usually started with neostigmine -15 to 30 mg orally every 6
hourly. Adjusted according to the response.
• Myasthenic crisis : acute weakness of respiratory muscles
Anticholinesterase poisoning
• AChEs are easily available and extensively used as agricultural and
household insecticide and homicidal poisoning
• Complex effect – Muscarinic , nicotinic and CNS actions.
• Sign and symptoms:
1. Irritation in eye, lacrimation, salivation, tracheo-bronchial secretion,
blurring of vision, defecation and urination.
2. Fall in BP, tachy or bradycardia and CVS collapse
3. Muscular fasciculations, weakness and respiratory paralysis
4. Irritability, disorientation, ataxia, convulsions and coma.
 Treatment
• Termination of exposure to the poison – fresh air wash the skin and gastric lavage according to
need.
• Maintain patent airway, positive pressure respiration if it is failing.
• Supportive measures – maintain BP, control of convulsions with judicious use of diazepam.
• Specific antidote- Atropine – 2mg i.v. every 10 minutes till dryness of mouth or atropinisation( up
to 200mg/kg)
• Cholinesterase reactivators – oximes:
• Pralidoxime (2-PAM) and Obidoxime Diacetyl monoxime (DAM)
• Dose : 1-2 gm i.v. slowly maximum 12 gms/24 hrs and 20-30 hrs mg/kg/hrs continuous i.v.
infusion.