Download Cholinergic Drugs

AUTONOMIC NERVOUS SYSTEM
 The autonomic nervous system (ANS) functions largely
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below the level of consciousness and controls visceral
functions.
Like the somatic nervous system, the ANS consists of afferents
and efferents.
Autonomic efferents The motor limb of the ANS is
anatomically divided into sympathetic and parasympathetic.
Many organs receive both innervation and the two
subdivisions are functionally antagonistic in majority of these.
Most blood vessels, spleen, sweat glands and hair follicles
receive only sympathetic.
Ciliary muscle, bronchial smooth muscle, gastric and
pancreatic glands receive only parasympathetic innervation.
NEUROHUMORAL TRANSMISSION
 Neurohumoral transmission implies that nerves
transmit their message across synapses and
neuroeffector junctions by the release of humoral
(chemical) messengers.
 Steps in neurohumoral transmission:
- Impulse conduction
- Transmitter release
- Transmitter action on postjunctional membrane
- Postjunctional activity
- Termination of transmitter action
Acetylcholine (ACh)
 Acetylcholine (ACh) is a major neurohumoral
transmitter at autonomic, somatic as well as central
sites.
 Cholinesterase - types of enzymes which hydrolyze
Ach:
- A specific (Acetylcholinesterase— AChE or true
cholinesterase)
- and a nonspecific (or pseudocholinesterase)
CHOLINERGIC
TRANSMISSION
 Two toxins interfere with
cholinergic transmission by
affecting release: botulinum
toxin inhibits release of ACh,
while black widow spider
toxin induces massive release
and depletion.
 Botulinum toxin
 Localized injection of
botulinum toxin A (BOTOX
or DYSPORT) can be used in
the treatment of spastic and
other neurological conditions
(blepharospasm, spastic
cerebral palsy, strabismus,,
hemifacial spasm, post stroke
spasticity, spasmodic
dysphonia)
Cholinoreceptors
 Two classes of receptors for ACh are recognised —
muscarinic and nicotinic
 Muscarinic receptors –
selectively stimulated by muscarine
 Nicotinic receptors – selectively
activated by nicotine
Muscarinic receptors
 They are located primarily on autonomic effector cells
in heart, blood vessels, eye, smooth muscles and
glands of gastrointestinal, respiratory and urinary
tracts, sweat glands, etc. and in the CNS.
Subtypes of muscarinic receptor
 By pharmacological muscarinic receptors have been
divided into 5 subtypes M1, M2, M3, M4 and M5. The
first 3 are the major subtypes.
M1/M2/M3
 The M1 is primarily a neuronal receptor located in CNS
and it plays a major role in mediating gastric secretion.
 M2: Cardiac muscarinic receptors and mediate
bradycardia.
 M3: Visceral smooth
muscle contraction
and glandular secretions
Nicotinic receptors
 On the basis of location two subtypes Nm and Nn are
recognized.
 Nm: is located in the neuromuscular junction. They
mediate skeletal muscle contraction.
 Nn: These are present on ganglionic cells (sympathetic
as well as parasympathetic) - postganglionic impulse,
adrenal medullary cells - catecholamine release
Cholinomimetic
 These are drugs which produce actions similar to that
of ACh, either by :
 directly interacting with cholinergic receptors
(cholinergic agonists)
 or by increasing availability of ACh at these sites
(anticholinesterases).
Muscarinic actions
Eye
 Contraction of circular muscle of iris
miosis.
 spasm of accommodation,
 reduction in intraocular tension
Glands
 Secretion from all parasympathetically innervated
glands is increased : sweating, salivation, lacrimation,
increased tracheobronchial and gastric secretion.
Muscarinic actions
Heart
 bradycardia or even cardiac arrest may occur.
 AV conduction is slowed.
 Force of atrial contraction is reduced
Blood vessels
 All blood vessels are dilated. Vasodilatation is primarily
mediated through the release of an endothelium
dependent relaxing factor (EDRF) which is nitric oxide
(NO).
 Fall in BP
Muscarinic actions
Smooth muscle
 Smooth muscle in most organs is contracted.
 Tone and peristalsis in the GI tract is increased and
sphincters relax → abdominal cramps and evacuation
of bowel.
 Peristalsis in ureter is increased. The detrusor muscle
contracts while the bladder sphincter relaxes
→voiding of bladder.
 Bronchial muscles constrict →bronchospasm,
dyspnoea, precipitation of an attack of bronchial
asthma
Nicotinic actions
Autonomic ganglia
 Both sympathetic and parasympathetic ganglia are
stimulated.
Skeletal muscles
 causes contraction of the fibre, twitching and
fasciculations
CNS
CHOLINOMIMETICS
 MN –Acetylcholine, Carbachol (treatment of
glaucoma)
 M –Pilocarpine (It is used to treat dry mouth
(xerostomia), particularly in Sjögren's syndrome. It has
also been used in the treatment of glaucoma for over
100 years).
 N- Nicotine,
Cytisine,
Treatment of
Lobeline,
tobacco dependence
Varenicline (Champix)
Pilocarpine
 Cause miosis, ciliary muscle contraction and fall in
intraocular tension lasting 4–8 hours.
 Pilocarpine is used only in the eye as 0.5– 4% drops. It
is a third-line drug in open angle glaucoma.
 ADR: bradycardia, hypotension, hypersecretion,
bronchoconstriction, GI tract hypermotility, and
decrease intraocular pressure.
 An initial stinging sensation in the eye and painful
spasm of accommodation are frequent side effects.
ANTICHOLINESTERASES
 Anticholinesterases (anti-ChEs) are agents which
inhibit ChE, protect ACh from hydrolysis → produce
cholinergic effects
Acetylcholinesterase inhibitors
1) Reversible
2) Irreversible - used as weapons in the form of nerve
agents (Sarin, Soman, VX)
Victims of nerve gases for chemical
warfare commonly die of suffocation
as they cannot relax their diaphragm
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- used as Organophosphate Insecticides
(Malathion, Parathion, Azinphos, Chlorpyrifos)
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- used medicinally (Echothiophate –
to treat chronic glaucoma)
Reversible Anti-ChEs
 1)Tertiary ammonium compounds(Lipid-soluble
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nonpolar):
Physostigmine
Donepezil
penetrate into brain; treat symptoms of
Galantamine
Alzheimer's disease
Rivastigmine
2)Quaternary ammonium compounds (Lipidinsoluble polar):
Neostigmine
Pyridostigmine
do not penetrate CNS and
Edrophonium
do not have central effects
Anti-ChEs PHARMACOLOGICAL ACTIONS
 Ganglia
Anti-ChEs stimulate ganglia
 CVS
Cardiovascular effects are complex. Whereas muscarinic action
would produce bradycardia and hypotension, ganglionic
stimulation would tend to increase heart rate and BP. Thus, the
overall effects are often unpredictable and depend on the agent
and its dose.
 Skeletal muscles
Force of contraction in myasthenic muscles is increased.
 CNS
Only lipophilic anti-ChEs penetrate into brain and improve
cognitive functions (used in Alzheimer’s disease).
 Other effects
Stimulation of smooth muscles and glands of the GI, respiratory,
urinary tracts and in the eye
Anti-ChEs Indications
 As miotic - in glaucoma
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-to reverse the effect of mydriatics
Alzheimer's disease
Myasthenia gravis. The autoimmune disorder caused by
development of antibodies that damage the
neuromuscular junction. This results in weakness and
easy fatigability on repeated activity, with recovery after
rest. In myasthenia gravis, Anti-ChEs are used to increase
neuromuscular transmission.
Postoperative paralytic ileus/bladder atony
Antidote to anticholinergic poisoning (Cobra bite, drugs)
To reverse the effect of muscle relaxants
Xerostomia
Myasthenia Gravis
Anti-ChEs ADR/overdose
Bradycardia
Hypotension
SLUD - syndrome
 Salivation
 Lacrimation
 Urination (involuntary)
 Diarrhea
Vomiting
Sweating
Muscle spasm: stimulation of skeletal muscle
Death is generally due to respiratory failure.
Overdose treatment
Specific antidotes :
 Anticholinergics - Atropine
 Cholinesterase reactivators (Oximes)
restore neuromuscular transmission/reactivation of ChE
Pralidoxime
ANTICHOLINERGIC DRUGS
Anticholinergic drugs = Muscarinic receptor antagonists
= Atropinic drugs = Cholinolytics
CLASSIFICATION
 1. Natural alkaloids
Atropine
Hyoscine (Scopolamine)
Hyoscine butylbromide(BUSCOPAN)
 2. Semisynthetic derivatives
Homatropine
Ipratropium bromide (Atrovent)
Tiotropium bromide
 3. Synthetic compounds
Tropicamide (mydriatics)
Pirenzepine (antisecretory – M1-blocker)
Trihexyphenidyl (Benzhexol)
Procyclidine
Antiparkinsonian
Biperiden
PHARMACOLOGICAL ACTIONS
CNS
Atropine has an overall CNS stimulant action (excitation).
Hyoscine produces depressant central effects.
Eye
 Mydriasis → blurring of near vision
 Rise of the intraocular tension
 Paralysis of accommodation
Glands
 Decreasing sweat, salivary, tracheobronchial and
lacrimal secretion.
 Reducing acid secretion.
PHARMACOLOGICAL ACTIONS
Heart
 Tachycardia
 Facilitation of A-V conduction
 Force of atrial contraction is rised
BP
 Since cholinergic impulses are not involved in the
maintenance of vascular tone → no effect on BP.
Smooth muscles – relaxation
 Peristalsis is suppressed → constipation
 Spasm-relieve
 Bronchodilatation
 Relaxant action on ureter and urinary bladder
Indications
1)Antisecretory- sweating or salivation in parkinsonism
-peptic ulcer (Pirenzepine)
2) Antispasmodic- Intestinal and renal colic (Buscopan)
-abdominal cramps
3) Bronchial asthma -Ipratropium bromide (Atrovent)
-Tiotropium bromide
4) Mydriatic –Tropicamide
Homatropine
5) Cardiac vagolytic (useful in sinus bradycardia and heart
block)- Atropine
6) Parkinsonism (Central anticholinergics – Trihexyphenidyl,
Procyclidine, Biperiden)
7) Motion sickness (Scopolamine)
8)To antagonise muscarinic effects (antidote for anti-ChE and
mushroom poisoning)
ADR
 Tachycardia
 Dizziness, loss of balance
 Flushed, hot skin (especially over face and neck), fever
 Blurred vision, dilated pupils, photophobia
 Dry mouth, constipation
 Confusion, dissociative hallucinations and excitation
Ganglionic blockers
 Hexamethonium
 were introduced in the 1950s
 Pentolinium
as the first effective
antihypertensive drugs
 They are still used in some
emergency situations- to
produce controlled
hypotension and in
hypertensive emergency.
 Mecamylamine
 Trimetaphan
 Benzohexonium
 Pentamine
ADR
 Orthostatic(postural) hypotension!
 Tachycardia
 GIT: GIT atony(distension, constipation), digestive
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problems
Urine retention
Sexual Dysfunction: Failure of erection and ejaculation
Mydriasis (photophobia), Cycloplegia (blurring of near
vision)
Inhibition of salivation (dryness of mouth, difficulty in
swallowing and talking)
Orthostatic hypotension
Skeletal muscle relaxants
(Neuromuscular blockers)
A. Nondepolarizing blockers
 1. Long acting: Tubocurarine
Pancuronium
Pipecuronium
 2. Intermediate acting: Vecuronium
Atracurium
Cisatracurium
 3. Short acting: Mivacurium
B. Depolarizing blockers
 Suxamethonium (Dithylin, Lysthenon, Anectine,Quelicin)
NEUROMUSCULAR BLOCKING
AGENTS
 Curare /kjuːˈrɑːriː/ is an Indian word, meaning "poison."
 It is the generic name for certain plant extracts
used by south American tribes as arrow poison
for hunting. The animals were paralysed
(weakness of the skeletal muscles) even if not
killed by the arrow.
 Death by asphyxiation due to paralysis of the
diaphragm.
 Tubocurarine was first clinically used in 1930s to
provide muscle relaxation during medical
procedure.
 Act peripherally and not centrally
Nondepolarizing block
 The nondepolarizing blockers have affinity for the
NM-cholinergic receptors at the muscle end-plate, but
have no intrinsic activity.
 ACh released from motor nerve endings is not able to
combine with receptor to generate potential
muscle
fails to contract in response to nerve impulse
Actions on skeletal muscles
 Small, rapidly contracting muscles of the face and eye
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are most susceptible and are paralyzed first, followed
by the fingers.
Thereafter, the limbs, neck, and trunk muscles are
paralyzed.
Then the intercostal muscles are affected.
The diaphragm muscles are paralyzed lastly.
Recovery of function occurs in the reverse order, with
the diaphragm recovering first.
 Death is due to paralysis of the muscles of respiration.
 With non-depolarizing muscle blockers, there is a fade
phenomenon where twitch amplitude decreases from the
first stimulation (each twitch is weaker than the last)
Depolarizing Neuromuscular Blockers
 Affinity as well as submaximal intrinsic activity at the
NM cholinoceptors.
 They depolarize muscle end-plates just as ACh does
and initially produce twitching and fasciculations,
followed by flaccid paralysis. This is referred to
as phase 1 blockade.
 If the duration of blockade is prolonged or if the
concentration of the blocker is excessive, then phase 2
blockade occurs in which the pharmacological
characteristic is that of a competitive inhibition.
 These drugs are hydrolysed by AChE.
Indications
A. Mainly as adjuvants to surgical anesthesia to
cause muscle relaxation.
B. In orthopedics to facilitate correction of dislocations
and alignment of fractures.
C. To facilitate endotracheal intubation
D. To prevent trauma in electroconvulsive shock therapy
E. In treatment of severe cases of tetanus
ADR
 Respiratory paralysis and prolonged apnoea
 Fall in BP and cardiovascular collapse
 Cardiac arrhythmias and even arrest
 Dangerous hyperkalemia
 Postoperative muscle soreness and myalgia
 Malignant hyperthermia
Depolarizing
Blockers