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Introduction to ANS, Irreversible anticholinesterases:, Actions of…
Introduction to ANS
Autonomic nervous system is involuntary in nature and the activities of this system are maintained autonomically.
In contrast to somatic system, organ systems
supplied by ANS donot atrophy even after the
section of an autonomic nerve rather denervation supersensitivity of receptors occur.
Irreversible anticholinesterases:
these group includes organophosphates(malathion, parathion, ecothiophate, chlorpyrifos, nerve gases like tabun, sarin and soman etc. and diflos) and carbamates(carbaryl and propoxur).
Atropine is an antidote of choice for both organophosphate and carbamate poisoning.
Except ecothiophate these are not used therapeutically. Ecothiophate is useful in glaucoma.
Other drugs are used as insecticides and are important due to their potential to cause poisoning.
Actions of sympathetic and parasympathetic system
Most of the actions of sympathetic and parasympathetic systems are opposite.
To remember major actions, we can assume that sympathy is related to heart, so sympathetic system stimulates it i.e. tachycardia, positive inotropic action etc
On the other hand, parasympathetic system has opposite action, so depress heart.
At most other parts action is reverse i.e. sympathetic system inhibits and parasympathetic system stimulates.
Cholinergic drugs:
Indirectly acting AchE inhibitors:
reversible:
Lipid soluble:
Physostigmine
Tacrine
Rivastigmine
Donepezil
Gallantamine.
Water soluble:
Neostigmine
Pyridostigmine
edrophonium
Indirectly acting - Irreverisble drugs:
Irreversible drugs:
Organophosphates:
Parathion
Malathion
DFP
Chlorpyrifos
Ecothiophate
Nerve gases: tabun, sarin and soman.
Carbmates: carbaryl, propoxur and aldicarb
Directly acting:
Ach
Pilocarpine
Bethanechol
Methacholine
Carbachol.
Symptoms of anti-choline esterase poisoning:
are simply due to the extension of the pharmacological actions of Ach and are manifested as
pin point pupil, salivation, lacrimation, sweating, bronchoconstriction, diarrhea, urination, bradycardia, hypotension and coma.
Blood pressure and heart rate may increase rarely due to stimulation of nicotinic receptors.
Atropine is an antidote of choice for both organophosphate and carbamate poisoning.
Enzyme reactivators
Enzyme reactivators like pralidoxime, obidoxime and diacetylmonoxime can be used to regenerate AchE in the organophosphate poisoning but are contraindicated in the carbamate poisoning.
Principal indications of oximes are muscle weakness and respiratory depression.
The site on which oximes bind and reactivate the enzyme(anionic site) is occupied by carbamates
whereas it is free in the organophosphate poisoning.
Organophosphates bind to esteric site only
whereas carbamates binds to both esteric site as well as anionic sites.
Further oximes themselves possess weak AChE inhibitory action.
Due to these two reasons, oximes should not be given in carbamate poisoning.
ANS is divided into three main divisions:
Sympathetic
Parasympathetic
Enteric nervous system.
Division of ANS into sympathetic and parasympathetic system is anatomical in origin.
pre and post ganglionic fibres
All autonomic nerve fibres form a synapse in the ganglion before supplying the organ and thus can be divided into pre and post ganglionic fibres.
In sympathetic system, postganglionic fibers are equal to or longer than preganglionic fibres
whereas in parasympathetic system preganglionic fibres are much longer than postganglionic fibres(ganglia are closer to the organs)
NT released at postganglionic fibres
In parasympathetic system, NT released at postganglionic fibres is also Ach.
But in sympathetic system at most of the postganglionic fibres, NT secreted is noradrenaline.
But it can be dopamine in renal and mesenteric vasculature, Ach in sweat glands; sympathetic cholinergic or adrenaline in adrenal medulla.
How impulse is conducted?
Impulse is conducted along the axon till it reaches the cell body forming the synapse.
Cell body releases the NT that acts on the receptors present on the post-synaptic membrane(post synaptic receptors) as well as on the pre-synaptic membrane(pre-synaptic receptors)
Parasympathetic nervous system:
in parasympathetic system, acetylcholine is the principal neurotransmitter secreted by preganglionic as well as postganglionic fibres.
Therefore it is also known as cholinergic nervous system.
Synthesis of acetylcholine
Ach is synthesized from acetyl Co-A and choline and stored within the cholinergic neurons.
Uptake of choline by the neurons is the rate limiting step in the biosynthesis of this NT.
After its synthesis Ach is stored in the vesicles. It is released in the synaptic cleft by exocytosis when nerve impulse stimulates the neuron.
Here it stimulates post ganglionic as well as pre-ganglionic cholinergic receptors and produce the response.
Cholinergic receptors:
Nicotinic:
NN – ganglia and adrenal medulla
NM – neuro-muscular junction
Muscarinic:
M1 – gastric ganglia and CNS
M2 – heart and CNS
M3 – eye, GIT, bladder, bronchus, glands and CNS
M4 – CNS
M5 - CNS
Heart:
parasympathetic system has inhibitory effect of the
heart M2 and is responsible for the negative
chronotropic effects decreased heart rate and
dromotropic decreased conduction effects.
Anticholinergic drugs stimulate the heart by decreasing the inhibitory effect of Ach on heart.
Blood vessels:
no direct cholinergic supply is present in blood vessels but cholinergic receptors M3 are present on endothelium of blood vessels.
Stimulation of these receptors causes release of NO from endothelium resulting in vasodilation.
Additional mechanism of vasodilation is inhibitory action of Ach on noradrenaline release from tonically active vasoconstrictor nerve endings.
However if endothelium is damaged, Ach can stimulate the M3 receptors in the vascular smooth muscle leading to vasoconstriction.
Indirectly acting drugs
These drugs act by inhibiting the enzyme acetylcholinesterase, thus increasing the availability and prolonging the action of Ach.
These drugs are also known as anticholinesterases. Cholinesterase inhibitors may be reversible or irreversible
Reversible anticholinesterases:
Physostigmine, neostigmine, pyridostigmine, edrophonium, tacrine, donepezil, galantamine and rivastigmine
are the important drugs in this group. These drugs inhibit the enzyme AchE reversibly and prolong the duration of action of Ach.
Physostigmine is naturally occurring tertiary amine and is lipid soluble.
Tacrine, donepezil, rivastigmine and galantamine are also lipid soluble drugs.
All other reversible anticholinesterases are synthetic quarternary compounds and are lipid insoluble.
Physostigmine
Due to high lipid solubility, physostigmine can be administered orally and it can cross blood brain barrier and corneal membrane.
Lipid insoluble compounds are ineffective orally and donot enter CNS or eye.
Physostigmine is used in glaucoma as a miotic drug and in belladonna(atropine) poisoning as a specific antidote.
Neostigmine
Neostigmine is preferred for the treatment of myasthenia gravis.
It doesn’t produce adverse effects in the CNS doesn’t cross BBB.
And it also has direct Nm receptor agonistic action.
It can also be used for the treatment of cobra bite
(cobra venom contain compounds that cause skeletal muscle paralysis),
post operative paralytic ileus,
atony of urinary bladder
and the reversal of competitive skeletal muscle relaxants.
Cholinergics used in Alzheimers disease
Tacrine was the drug of choice for Alzheimers disease but due to several limitations(frequent dosing requirement, hepatotoxicity and diarrhea),
other drugs like donepezil, rivastigmine and galantamine are now the preferred agent.
Rivastigmine has been approved for the treatment of dementia in alzheimers as well as parkinsons disease.
Origin of Sympathetic system
Fibres of sympathetic system originates from thoracic and lumbar spinal cord(thoracolumbar outflow)
Origin of Parasympathetic system
whereas parasympathetic system originates from cranial nerves 9, 10, 7 and 3 and sacral S2, S3 and S4(craniosacral outflow)
Acetylcholine(Ach)
Acetylcholine(Ach) is the principal neurotransmitter(NT) at neuromuscular junction as well at all preganglionic fibers.
Pre-synaptic receptors, autoreceptors, heteroreceptors
Pre-synaptic receptors increase nicotinic and B or decrease muscarinic and alpha 2.
the release of neurotransmitters from their own neuron(autoreceptors) or from adjoining neurons(heteroreceptors).
Action on various organs
Heart: SS- stimulates/ PS – depresses
Bronchus: SS- relax(bronchodilation)/PS stimulates(bronchoconstriction)
GIT: SS – relax – decreased movements and parasympathetic stimulates increased movements
Bladder: SS – relax – decreased urine flow and PS stimulates increased urine flow.
Pupil: SS- relax(mydriasis) and PS- stimulates(miosis)
Glands: depress secretions except sweating and PS stimulates increased secretions.
Hemicholinium, Vesamicol, Botulinum toxin
Uptake of choline inhibited by hemicholinium. Vesicular uptake inhibited by vesamicol. Ach release inhibited by botulinum toxin.
Functions of cholinergic system:
sympathetic and parasympathetic systems have opposite actions on most of the organs.
At most all organs except heart, cholinergic system has excitatory activity and adrenergic system has relaxing properties.
Eye:
cholinergic system stimulates sphincter pupillae(circular muscle of eye) and thus results in miosis M3.
Ach also causes contraction of ciliary muscle of the eye and thus accomadation is possible.
Anticholinergic drugs result in mydriasis and loss of accomadation(blurred vision).
Glands:
cholinergic system stimulates the secretion of glands and results in the increased salivation, lacrimation as well as sweating.
On the other hand anticholinergic drugs will result in dry mouth, dry eyes and difficulty in swallowing due to decreased saliva.
Urinary bladder:
cholinergic drugs stimulate detrusor and relax the trigone(sphincter) of urinary bladder resulting in increased micturiction(M3).
Anticholinergic drugs may result in urinary retention.
Gastrointestinal tract:
hydrochloric acid secretion in the stomach M1 and M3 is stimulated by parasympathetic system and thus increases the risk of peptic ulcer disease.
Peristalsis of GIT is increased and sphincters are relaxed by the cholinergic drugs.
Anticholinergic drugs can be used as spasmolytic agents for the intestinal colic.
Bronchus:
cholinergic system causes bronchoconstriction M3 and anticholinergic drugs may lead to bronchodilation.
Male sex organs:
due to vasodilation, cholinergic system is responsible for the erection of the male organ.
Autonomic ganglia:
both sympathetic and parasympathetic ganglia are stimulated by Ach through the stimulation of NN receptors.
Neuromuscular junction:
Ach stimulates skeletal muscle contraction by its action on neuromuscular junction NM receptors.
Parasympathomimetic drugs
These drugs may directly activate the muscarinic receptors(directly acting)
or may act by increasing the availability of Ach at the synaptic cleft(indirectly acting).
Directly acting drugs
These are the esters of choline and may be natural alkaloids(Ach, muscarine, nicotine, pilocarpine and arecoline) or synthetic derivatives(methacholine, carbachol and bethanecol).
Why acetylcholine is not used clinically?
Acetylcholine is not used clinically because it is metabolized very quickly by cholinesterases in the plasma and is not effective by IV route.
Methacholine
Methacholine has maximum action on myocardium.
It can be given inhalationally for the diagnosis of bronchial hyperactivity in patients who donot have clinically apparent asthma
called methacholine challenge test.
Bethanecol
Bethanecol is mainly used for its action on urinary bladder and has no nicotinic activity.
Pilocarpine
Pilocarpine is used in glaucoma due to its pupillary constrictor miotic action.
However because of its very short duration of action, intraocular tension may increase even if one or two doses are missed.
Carbachol
Carbachol has common activity on nicotinic and muscarinic receptors.
Pilocarpine and cevimeline
Pilocarpine and cevimeline are used to treat dry mouth associated with Sjogren syndrome and that caused by radiation damage of salivary glands.
Pyridostigmine
Pyridostigmine is the longer acting than neostigmine and can be used for all these indications.
Atropine is added to neostigmine therapy when action is required on Nm receptors to avoid adverse effects due to muscarinic receptor stimulation
as in case of myasthenia gravis and cobra bite.
Use of neostigmine/pyridostigmine:
Muscarinic without atropine: Post operative paralytic ileus and post operative urinary retention.
Nicotinic with atropine: myasthenia gravis, cobra bite and reversal of non-depolarizing muscle relaxants.
Edrophonium
Edrophonium is the short acting synthetic anticholinesterase and is useful in diagnosis of myasthenia gravis.
1-2mg IV dose of edrophonium improves skeletal muscle activity if the weakness is due to myasthenia
whereas it will worsen the condition if it is due to cholinergic crisis (tensilon test).
Diacetylmonoxime
Diacetylmonoxime can cross BBB and regenerate AChE in the brain whereas pralidoxime and obidoxime cannot cross BBB.
delayed neuropathy
Chronic exposure to certain organophosphates e.g. triorthocresyl phosphate(additive in lubricating oils) may cause:
delayed neuropathy(appear 1-2 weeks after exposure) associated with demyelination of axons.
Not caused by cholinesterase inhibition but rather by NTE(neuropathy target esterase) inhibition.
Intermediate syndrome
Intermediate syndrome occurs after 1-4 days caused by cholinesterase inhibition.
Muscarinic actions:
Nicotinic actions
Directly acting drugs
OPC poisoning