Classification of cholinergic drugs Autonomic Nervous System
Classification of cholinergic drugs
Cholinergic Drug is classified into 2 main types which are Cholinergic Agonists and Anti cholinesterases which is further divided into following types;
Cholinergic Drugs is also called as Cholinomimetic or Parasympathomimetic.
1. CHOLINERGIC AGONISTS
Choline esters: Acetylcholine, Methacholine, Carbachol, Bethanechol
Alkaloids: Muscarine, Pilocarpine, Arecoline
a. Carbamates: Physostigmine (Eserine), Neostigmine, Pyridostigmine, Edrophonium, Rivastigmine, Donepezil, Galantamine
b. Acridine: Tacrine
a. Organophosphates: Dyflos (DFP), Echothiophate, Malathione, Diazinon, Tabun, Sarin, Soman
b. Carbamates: Carbaryl, Propoxur,
Cerebroselective; used for Alzheimer’s disease Insecticides Nerve gases for chemical warfare
Preparations of cholinergic drugs
1. Bethanechol: 10 to 40 mg by oral route, and 2.5 to 5 mg by s.c.
UROTONIN 25 mg tab.
2. Pilocarpine: 0.5–4% topically in eye.
PILOCAR 1%, 2%, 4% eye drops; CARPINE 0.5% eye drops;
PILODROPS 2% eye drops.
3. Physostigmine: 0.5 to 1.0 mg by oral or intra-muscular (I.M), 0.25 to 0.5% topically in eyes.
BI-MIOTIC add 0.25% eye drops along with 2% pilocarpine nitrate.
4. Neostigmine: 15–30 mg oral, 0.5–2.5 mg s.c./i.m.
PROSTIGMIN, MYOSTIGMIN, TILSTIGMIN Take 15 milligram tablet, 0.5 mg/ml in 1 millilitre and 5 ml injection.
5. Pyridostigmine: 60–180 mg oral.
DISTINON, MYESTIN 60 mg tab.
6. Rivastigmine: Initially 1.5 mg BD, increase every 2 weeks by 1.5 mg/day upto 6 mg/day.
EXELON, RIVAMER 1.5 or 3 or 4.5 or 6.0 mg caps.
7. Donepezil: 5 mg at night bed time once daily (maximum 10 mg/day).
DONECEPT, DOPEZIL 5 or 10 mg tabs.
8. Galantamine: 4 mg BD (maximum 12 mg BD).
GALAMER 4, 8, 12 mg tabs.
Cholinergic drugs Mechanism Of Action
Acetylcholine (ACh) is a leading neurohumoral transmitter at autonomic, somatic and also at central sites.
These sites are listed Synthesis, storage and destruction of ACh The cholinergic neuronal mechanisms are summarized.
Acetylcholine is synthesized locally in the cholinergic nerve endings by the following pathway;
Choline is actively taken up by the axonal membrane by a Sodium channel (Na+), choline co-transporter and acetylated with the help/aid of Adenosine triphosphate (ATP) and coenzyme A by the enzyme choline acetyl transferase existing in the axoplasm.
Hemicholinium (HC3) blocks choline uptake (the rate limiting step in ACh synthesis) and depletes ACh.
Almost of the Acetylcholine (Ach) is stored in ionic solution inside small synaptic vesicles, but some free Acetylcholine (ACh) is also present in the cytoplasm of cholinergic terminals ends.
Active transport of Acetylcholine (ACh) into synaptic vesicles is effected by another carrier which is obstructed by vesamicol.
Release of Acetylcholine (ACh) from nerve terminals end occurs in small quanta amount contained in each respective vesicles is extruded by exocytosis.
In response to a nerve AP (axonal proteins) synchronous release of multiple quanta also triggers post junctional events.
Two toxins interfere with cholinergic transmission by affecting release: botulinum toxin inhibits release, while black widow spider toxin induces massive release and depletion.
Botulinum toxin A and B are highly potent exotoxins produced by Clostridium botulinum that are responsible for ‘botulism’ (a type of food poisoning).
These neurotoxic proteins cause durable loss of cholinergic transmission by interacting with axonal proteins (AP) involved in exocytotic release of Acetylcholine (Ach).
Localized injection of minute quantity of botulinum toxin A (BOTOX) or its haemagglutinin complex (DYSPORT) can be used in the treatment of a number of spastic and other neurological conditions due to overactivity of cholinergic nerves, like blepharospasm, spastic cerebral palsy, strabismus, spasmodic torticollis, nystagmus, hemifacial spasm, post stroke spasticity, spasmodic dysphonia, axillary hyperhydrosis, etc.
It is increasing being engaged as beauty treatment by removal of age related to facial wrinkles.
However, its incorrect injection or overdose can be dangerous; ptosis, diplopia, facial swelling, dry mouth, dysphagia, dysarthria, muscular weakness and even respiratory paralysis has occurred.
Cholinesterase Instantly after release, (Ach)Acetylcholine is hydrolyzed by the help of enzyme cholinesterase and choline is reused/recycled.
A specific (Acetylcholinesterase-AChE or true cholinesterase) and a nonspecific (Butyrylcholinesterase-BuChE or pseudocholinesterase) type of enzyme occurs in the body; important differences between these two types of the enzyme are given.
While AChE is strategically located at all cholinergic sites and serves to inactivate Ach instantaneously, BuChE present in plasma and elsewhere probably serves to metabolize ingested esters.
Two classes of receptors for Acetylcholine (ACh) are recognized which are muscarinic and other is nicotinic; the muscarinic is a G protein coupled receptor, while the nicotinic is a ligand gated cation (+) channel.
Muscarinic receptors are generally stimulated by muscarinic and is blocked by atropine.
Muscarinic receptors are located mainly on autonomic effector cells in blood vessels, heart, eye, glands and smooth muscles of gastrointestinal, urinary tracts, respiratory and sweat glands, etc.
Auxiliary muscarinic receptors are also present in autonomic ganglia where they seems to play a modulatory role by producing a long lasting late excitatory postsynaptic potential (EPSP).
Muscarinic auto receptors are present on postganglionic cholinergic nerve endings pre junctionally, Activation of these receptors causes inhibition of further release of acetylcholine.
Related ones have been signified on adrenergic terminals and their stimulation or activation inhibits sodium (NA) release which may impart to vasodilator action of injected Acetylcholine (ACh).
All blood vessels have muscarinic receptors (though most of them lack cholinergic innervation) located on endothelial cells whose activation releases EDRF (nitric oxide) which diffuses to the smooth muscle to cause relaxation.
Subtypes of muscarinic receptor By molecular as well as pharmacological cloning techniques, muscarinic receptors have been bifurcated into 5 subtypes M1, M2, M3, M4 and M5.
The first 3 are the major subtypes that are present on effector cells as well as on pre junctional nerve endings, and are expressed both in peripheral organs as well as in the CNS.
The M4 and M5 receptors are presentor found primarily on nerve endings in definite areas of the brain and regulate or modulate the release of other neurotransmitters.
Functionally, M1, M3 and M5 fall in one class while M2 and M4 fall in another class.
Muscarinic agonists have shown little subtype selectivity, but some relatively selective antagonists have been produced (pirenzepine for M1, tripitramine for M2 and darifenacin for M3).
Almost organs have more than one subtype, but normally one subtype predominates in a specific given tissue.
M1: The M1 is principally a neuronal receptor located on ganglion cells and central neurones, particularly in cortex, hippocampus and corpus striatum.
It plays a major role in mediating gastric secretion, relaxation of lower esophageal sphincter (LES)
caused by vagal stimulation, and in learning, memory, motor functions, etc.
M2: Cardiac muscarinic receptors are predominantly M2 and mediate vagal bradycardia.
Auto receptors which is present on cholinergic nerve endings are also of muscarinic 2 (M2) subtype. Smooth muscles also sometimes express some M2 receptors besides which, like M3, mediate contraction.
M3: Visceral smooth muscle contraction and glandular secretions are elicited through M3 receptors, which also has mediated vasodilatation through endothelium derived relaxing factor (EDRF) release.
Together the M2 and M3 receptors mediated most of the well-acknowledged muscarinic actions including contraction of lower esophageal sphincter (LES).
The muscarinic receptors are G-protein coupled receptors having the distinctive seven (7) membrane with traversing amino acid sequences
The M1 and M3 (also M5) subtypes of muscarinic function through Gq type protein coupled receptor and activate membrane bound phospholipase C (Plc) yielding inositol trisphosphate (IP3) and diacylglycerol (DAG) which in turn release Ca2+ intracellularly cause depolarization, glandular secretion, raise smooth muscle tone and release NO (from endothelium).
They also activate phospholipase A2 resulting in increased synthesis and release of prostaglandins and leukotrienes in certain tissues.
The M2 and M4 receptor opens potassium K+ channels (through withsubunits of regulatory protein Gi) and inhibits adenyl cyclase (through subunit of Gi) resulting in hyper-polarization, reduced pacemaker activity, slowing of conduction and decreased force of contraction in the heart.
The M4 receptor has been involved in assistance/inhibition of transmitter release in definite areas of the brain, while M5 has been found to facilitate dopamine release and mediate reward behaviour.
Nicotinic receptors are particularly activated by nicotine receptors and are blocked by tubocurarine or hexamethonium.\
They are pentameric structures (rosette-like) which encloses a ligand gated cation (+) channel their stimulation causes opening of the channel and fast flow of cations resulting in depolarization which causes an action potential
On the base of location and selective agonists and antagonists 2 subtypes NM and NN (formerly labelled as N1 and N2) are acknowledged.
NM: NM are present at skeletal muscle end plate and are selectively activated by phenyl trimethyl ammonium (PTMA) and blocked by tubocurarine. They also mediated skeletal muscle contraction.
NN: NN are present or found on sympathetic as well as parasympathetic i.e. ganglionic cells, adrenal medullary cells which is embryologically derived from the same site as ganglionic cells and also in spinal cord and definite areas of brain.
They are by selection stimulated by dimethyl phenyl piperazinium (DMPP), and is blocked by hexamethonium, and represent the primary pathway of transmission in ganglia.
CHOLINERGIC DRUGS (Cholinomimetic or Parasympathomimetic)
These are drugs which produce or which has actions related to that of acetylcholine (ACh), either by interacting directly with cholinergic receptors (cholinergic agonists) or Acetylcholine availability is increased at these sites (anticholinesterases).
Choline esters: Acetylcholine Methacholine, Bethanechol, Carbachol.
Alkaloids: Muscarine,Arecoline, Pilocarpine.
ACTIONS (of ACh as prototype)
Depending on the type of receptor through which it is mediated, on the basis of peripheral actions of Acetylcholine (ACh) are categorized as muscarinic or nicotinic.
A. Muscarinic actions
ACh hyper-polarizes the SA nodal cells and decreases their rate of diastolic depolarization.
As a result, pace of impulse generation is decreased bradycardia or even cardiac arrest may happen.
At the A-V node and His-Purkinje fibres 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 and RP of atrial fibres is abbreviated.
Due to non-uniform vagal innervation, the intensity of effect on RP and conduction of different atrial fibres varies inducing inhomogeneity and predisposing to atrial fibrillation or flutter
Ventricular contractility is also decreased but the effect is not marked. The cardiac muscarinic receptors are of the M2 subtype.
All blood vessels are dilated, though only few (skin of face, neck, salivary glands) receive cholinergic innervation.
Fall in blood pressure and flushing, particularly in the blush area occurs. Muscarinic receptors (M3) are existing on vascular endothelial cell’s vasodilatation is principally mediated through the release of an endothelium dependent relaxing factor (EDRF) which is nitric oxide (NO).
The Plc-IP3/DAG pathway activates endothelial NO synthase through the Ca+-Calmodulin mechanism.
When the endothelium is damaged by disease, ACh can diffuse to the vascular smooth muscle and cause vasoconstriction via M3 receptors located on their plasma membrane.
Stimulus of cholinergic nerves to the penis causes erection by releasing Nitric oxide and dilating cavernosal vessels through with M3 receptors.
Yet, this response is minimum with injected cholinomimetic drugs
Smooth muscle in almost all organs is contracted (primarily through M3 receptors). 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 gets trigone and simultaneously sphincter relaxes which causes evacuation of bladder.
Bronchial muscles constrict, asthmatics are highly sensitive bronchospasm, dyspnoea, precipitation of an attack of bronchial asthma.
Glands Secretion from all para sympathetically innervated glands is increased via M3 and some M2 receptors: sweating, salivation, lacrimation, increased tracheobronchial and gastric secretion. The effect on pancreatic and intestinal glands is not marked. Production of milk along with bile is not affected.
Eye circular muscle Contraction (iris miosis).
Contraction of ciliary muscle spasm of accommodation, increased outflow facility, reduction in intraocular tension (especially in glaucomatous patients).
B. Nicotinic actions
Autonomic ganglia Both sympathetic and parasympathetic ganglia are stimulated.
This effect is manifested at higher doses.
High dose of acetylcholine (Ach) given after atropine causes tachycardia and rise in blood pressure due to stimulant of sympathetic ganglia and release of catecholamines.
Skeletal muscles Iontophoretic application of ACh to muscle end-plate causes contraction of the fibre. Intra-arterial injection of high dose can cause twitch and fasciculations, but i.v. injection is mostly with none result (due to rapid reaction of Ach).
C. CNS Actions
ACh injected i.v. doesn’t penetrate blood-brain barrier and no central effects ar seen. However, direct injection into the brain produces arousal response followed by depression. Cholinergic DRUGS engaged on ANS drugs that enter brain turn out complicated behavioural and medical speciality effects. The vital options of alternative B-complex vitamin esters are summarized.
Interactions Anticholinesterase raise Ach markedly, medication to less extent and have only additive action with carbachol or bethanechol, relying upon the role of ChE within the termination of action of the actual B-complex vitamin organic compound.
Atropine and its congeners competitively antagonize muscarinic actions. Adrenaline may be a physiological antagonist.
B-complex vitamin esters are seldom, if ever, clinically used.
ACh isn’t used as a result of impermanent and non-selective action.
medication was sometimes accustomed terminate attack supra ventricular tachycardia however is obsolete currently.
Bethanechol has been employed in postoperative/post-partum non obstructive retention, neurogenic bladder to market excretion.
It can afford symptomatic relief in genetic disease and oesophageal reflux, however is never used for these. facet effects are prominent: belching, colic, involuntary urination/defecation, flushing, sweating, fall in BP, spasm.
Dose: 10–40 mg oral, 2.5–5 mg s.c.; UROTONIN, BETHACOL twenty five mg tab.
Pilocarpine it’s obtained from the leaves of Pilocarpus microphyllus and alternative species.
It has prominent muscarinic actions and conjointly stimulates ganglia mainly through ganglionic muscarinic receptors.
Pilocarpine causes marked sweating, secernment and increase in alternative secretions.
The vas effects ar complicated. tiny doses usually cause fall in BP (muscarinic), however higher doses elicit rise in BP and arrhythmia that is perhaps due to ganglionic stimulation (through ganglionic muscarinic receptors).
Applied to the attention, it penetrates tissue layer and promptly causes miosis, ciliary shortening and fall in intraocular tension lasting 4–8 hours.
Pilocarpine is employed solely within the eye as zero.5-4% drops. It’s a third-line drug in open angle glaucoma.
Associate initial stinging sensation within the eye and painful spasm of accommodation ar frequent side effects. Alternative uses as an inborn reflex are to counteract mydriatics when they need been used for testing refraction and to prevent/break adhesions of iris with lens or tissue layer by alternating it with mydriatics.
Though it will be used as a sialogogue, no oral preparation is accessible.
PILOCAR 1%, 2%, four-dimensional eye drops, CARPINE 0.5% eyedrops, PILODROPS a pair of eyedrops.
Muscarine It happens in toxic mushrooms genus Amanita, muscaria and Inocybe species and has solely muscarinic actions.
It is not used therapeutically however is of pharmacology importance.
Mushroom poisoning reckoning on the poisonous principle present within the specific species, a minimum of three sorts of mushroom poisoning is understood.
Muscarine type/kind (Early mushroom poisoning) because of Inocybe and connected species. Symptoms characteristic of muscarinic actions seem at intervals associate hour of ingestion the mushroom, and are promptly reversed by mydriatic.
Hallucinogenic type/kind it’s because of muscimol and alternative isoxazole compounds that are gift.
Muscaria and connected mushrooms in abundant larger quantities than is muscarine.
These compounds activate amino-alkanoic acid receptors, and block muscarinic receptors within the brain; have psychoactive property.
Manifestations of poisoning are primarily central. There’s no specific treatment and mydriatic is contraindicated.
Another psychoactive mushroom is Psilocybe mexicana whose active principle psilocybine may be a tryptaminergic (5-HT related) compound.
Phalloidin type (Late mushroom poisoning): It is due to peptide toxins found in A.phalloides, Galerina and related species.
These inhibit RNA and protein synthesis.
The symptoms start after some hours and are because of damage to the gastrointestinal mucosa, kidney and liver.
Treatment consists of auxiliary measures. Thioctic acid may have many antidote effect.
Arecoline: Arecoline is found in betel nut Areca catechu and it also has muscarinic as well as nicotinic actions, which involves those on skeletal muscle end plate.
It also has spectacular CNS effect, It has been tried in dementia as an enhancer of psychological functions, but it is not found useful and has no therapeutical use.
PHARMACOLOGICAL ACTIONS OF CHOLINERGIC DRUGS
The actions of Anti-ChEs are because of amplification of endogenous ACh. in and of itself they’re qualitatively similar to those of directly acting cholinoceptor stimulants. However, relative intensity of action on muscarinic, ganglionic, musculus and CNS sites varies among the various agents.
Lipid-soluble agents (physostigmine and organophosphates) have additional marked muscarinic and
CNS effects; stimulate ganglia however action on skeletal muscles is a smaller amount distinguished.
Lipid-insoluble agents (neostigmine and different quaternary ammonium ion compounds) turn out additional marked impact on the skeletal muscles (direct action on muscle end-plate cholinoceptors as well), stimulate ganglia, however muscarinic effects are less prominent. they are doing not penetrate CNS and have no central effects.
Ganglia native reaction of ACh is a smaller amount important in ganglia: inactivation happens partially by diffusion and reaction in plasma.
Anti-ChEs stimulate ganglia primarily through muscarinic receptors gift there. High drug doses cause repetitive depolarisation of the ganglionic nicotinic receptors and also obstruction of transmission.
CVS vessel effects are complicated. Whereas muscarinic action would turn out arrhythmia and cardiovascular disease, ganglionic stimulation would tend to increase vital sign and BP.
Action on medullary centres (stimulation followed by depression) more complicates the image, therefore will ganglionic blockade with high doses. Thus, the general effects are typically unpredictable and rely on the agent and its dose.
Skeletal muscles once treatment with antiChEs, the ACh discharged by one electrical discharge is not like a shot destroyed-rebinds to identical receptor, diffuses to act on neighbour receptors and activates prejunctional fibres repetitive firing cramp and fasciculations. Force of contraction in partly curarized and myasthenic muscles is redoubled.
Higher doses cause persistent depolarization of endplates leading to blockade of contractile organ transmission weakness and paralysis.
Objection of anticholinesterase and its congeners at the muscle endplates ends up in augmentation of those options.
CNS lipotropic anti-ChEs that penetrate into brain turn out a generalized alerting response. Cognitive operate is also improved in Alzheimer’s disease.
However, higher doses turn out excitement, disarray, disorientation, tremors and convulsions followed by coma.
Other effects These result from stimulation of swish muscles and glands of the epithelial duct, metastasis, urinary tracts and within the eye as delineate for Ach.
Pharmacokinetics of Cholinergic Drugs
Physostigmine it’s chop-chop absorbed from g.i.t. and canal sites.
Applied to the attention, it penetrates membrane freely.
It crosses blood-brain barrier and is disposed once reaction by ChE.
Neostigmine and congeners these are poorly absorbed orally; oral dose is 20–30 times higher than canal dose. they are doing not effectively penetrate membrane or cross barrier.
They are partly hydrolysed and partly excreted unchanged in excretion.
Organophosphates These are absorbed from all sites including intact skin and lungs. They are hydrolyzed as well as oxidized in the body and little is excreted unchanged.
USES of Cholinergic Drugs
Postoperative paralytic ileus/urinary retention
Other drug overdosages
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