Acetyicholine is a physiological neurotransmitter which acts on both muscarinic and nicotinic receptors. It is not useful as a drug being non-specific and having short duration of action. So such compounds have been developed which are more selective and have longer duration of action than acetylcholine. Drugs, which combine with acetylcholine receptors and mimic the effects of parasympathetic stimulation, are called parasympathomimetics or Cholinergic Agonists or cholinomimetic drugs. On the basis of their mode of action, they can be classified as under:
I. Directly acting
1. Cholinergic Agonists:
2. Cholinoinimetic alkaloids:
II. Indirectly acting (anti-Cholinergic Agonists)
1. Reversible anti-Cholinergic Agonists (carbamates)
Tertiary amine: Physostigmine (eserine)
Quaternary animonium compounds:
- Neostigmine (prostigmine)
- Demecarium (humorosol)
2. Irreversible anti-Cholinergic Agonists (organophosphorus compounds):
- DFP (dyflos)
Besides these Cholinergic Agonists agents, ganglionic stimulants also have parasympathomimetic action.
Directly Acting Drugs(Cholinergic Agonists)
Acetyicholine: It is an ester of choline and acetic acid. It is synthesized with the help of an enzyme cholineacetylase. It is stored in vesicles within the nerve and is released on nerve stimulation by exocytosis. It is rapidly hydrolyzed in the body by acetyicholinesterase and pseudocholinesterase enzymes. Acetyicholinesterase is present in all the sites of action of acetyicholine and has high specificity for acetyicholine. Pseudocholinesterase is found in plasma and liver and it is non-specific because it can break number of drugs with ester linkage.
The actions of acetyicholine are divided into two groups depending on its action on muscarinic or nicotinic receptors.
1. Muscarinic actions of acetyicholine are:
- Stimulation of exocrine
- Stimulation of smooth muscle in bronchi, gastrointestinal tract, bile duct, urinary bladder and ureters
- Stimulation of circular muscle of the iris and the muscles of accommodation so that the pupil is constricted and the lens is fixed for near vision
- Relaxation of the smooth muscles of the blood vessels
- Slowing of the heart (bradycardia)
2. Nicotinic actions of acetylcholine are:
- Stimulation of sympathetic and parasympathetic ganglia
- Stimulation of adrenal medulla to discharge epinephrine and norepinephrine
- Contraction of skeletal muscle.
Acetylcholine is not effective by oral route. The nicotine effects are not seen in ordinary doses. On intravenous administration, it causes transient fall in blood pressure, bradycardia, flushing, sweating, salivation, lacrimation and increased mucous secretions. It is only employed in experimental pharmacology as a tool to study Cholinergic Agonists effects.
Methacholine is a synthetic drug. It has similar muscarinic effects as that of acetylcholine. However, it has no nicotinic action. It has longer duration of action than acetylcholine as three times more resistant to cholinesterases. It is poorly absorbed from gastrointestinal tract and is usually administered by subcutaneous route. It is rarely used now.
Carbachol is also synthetic drug. It has more potent muscarinic actions than acetylcholine on the gastrointestinal tract, urinary bladder and the iris. However, it has less pronounced effects on heart than acetylcholine. It is not hydrolyzed by cholinesterase enzymes. It has potent nicotinic actions also. It is employed to lower intraocular pressure in glaucoma (0.75— 3% solution). It is less commonly used for the treatment of urinary retention.
Bethanechol is a synthetic drug. Its muscarinic effects are similar as that of carbachol. However, it is devoid of nicotinic activity. It has more selective action on gastrointestinal tract and the urinary bladder, but has slight effect on cardiovascular system. It is not hydrolyzed by cholinesterases. It is used orally in a dose of 2.5 to 5 mg to treat postoperative or neurogenic urinary retention.
Pilocarpine is an alkaloid. It is obtained from the leaves of Pilocarpus jaborandi. Like acetylcholine, it has muscarinic effects. However, it has prominent effect on the sweat glands and salivary glands. It also enhances gastric secretion but has less marked effects on cardiovascular system. Pilocarpine hydrochloride or nitrate (0.5 to 4% solution) is used for the treatment of glaucoma every 4—6 hours. It has also employed to produce meiosis for counteracting the mydriatic and cycloplegic actions of atropine.
Important uses of directly acting Cholinergic Agonists
- Methacholine: May be used for the diagnosis of bronchial hyperactivity and asthmatic conditions.
- Carbachol: To lower intraocular pressure in glaucoma.
- Bethanechol: Urinary retention; postoperative abdominal distension; gastric atony and retention or gastroparesis.
- Pilocarpme: Glaucoma; xerostomia, folloving head and neck radiation or associated with Sjogren’s syndrome in women; to counteract the mydriatic and L cycloplegic actions of atropine
Contraindications in the use of choline esters
- Bronchial asthma: Precipitation of bronchospasm
- Hyperthyroidism: Precipitation of cardiac arrhythmias
- Myocardial infarction: Precipitation of hypotension and conduction block
- Peptic ulcer: Increase gastric acid secretion glands such as sweat, salivary, mucous, and lacrimal glands
Muscarine is an alkaloid that is obtained from the mushroom Amanita muscaria. It has 100 times more marked muscarinic effects than acetyicholine and has a prolonged effect because not destroyed by cholinesterases. Muscarinic poisoning is effectively treated by atropine.
Oxotremorine: It is an extremely potent synthetic compound. It stimulates central muscarinic receptors more than peripheral muscarinic receptors and produces tremors and extrapyramidal symptoms. It is used as an experimental tool.
Metoclopramide: It is a synthetic drug, that has cholinomimetic and anti-dopaminergic (D2 receptor blocking) actions. It blocks D2 receptors on chemoreceptor trigger zone and has antiemetic effect. Metoclopramide increases gastro-oesophageal sphincter pressure and prevents gastro-oesophageal reflux. It enhances gastric emptying and intestinal peristalsis. Atropine blocks its action on gastrointestinal tract being cholinomimetic in nature. However, this effect is not blocked by chiorpromazine like anti-dopaminergic drugs. It is well absorbed orally, and metabolized in liver; it crosses blood—brain barrier. Its uses are:
- As an antiemetic
- Reflux oesophagitis
- Prior to radiological investigations of gastrointestinal tract
Dose: 10 mg 3 three times a day.
Indirectly Acting Drugs(Cholinergic Agonists)
Reversible Anticholinestercises (Carbamates)
Physostigmine (eserine): It is an alkaloid, obtained from the dried ripe seeds of Physostignia venenosum. It crosses the blood brain barrier and is well absorbed from gastrointestinal tract and conjunctiva. It is mainly used as a miotic and to treat glaucoma either alone (physostigmine sulphate—O.25— 0.5%) or in combination with pilocarpine hydrochloride (2—4%). Physostigrnine is used in the treatment of atropine, tricyclic antidepressant (imipramine), and antipsychotic (chlorpromazine) poisoning in doses of 0.5—2 mg i.v. bolus, repeated at 5—10 minute interval till the clinical signs of poisoning disappear. Physostigmine is used because it can antagonize both central and peripheral effects of these drugs.
Neostigmine (prostigmine): It is a synthetic quaternary ammonium compound with a quick onset of action. Although it has similar anticholinesterase activity to physostigmine but differs from it in that it is poorly absorbed orally, does not cross the blood-brain barrier and has direct skeletal muscle stimulant action. So it is particularly effective as an anticurare agent (0.5—2 mg i.m. or s.c.) and in the treatment of myasthenia gravis (15—30 mg orally 3 to 4 times daily).
Pyridostigmine: It closely resembles neostigmine. Its onset of action is slow but duration of action is longer. It is used in myasthenia gravis in doses of 60—240 mg per day orally or 1—5 mg intramuscularly or subcutaneously.
Edrophonium: It has a very short duration of action. So it is mainly used as a diagnostic agent to differentiate between cholinergic crisis and myasthenia crisis (10 mg i.v.).
Ambenonium: It is more potent and has a more sustained effect than neostigmine. It may be used for myasthenia gravis in a dose of 10— 25 mg orally.
Demecarium: It is more potent and has a very prolonged effect. It is used in glaucoma in a dose of (0.25% solution) 2 drops twice weekly. Miosis occurs within 20 minutes and persists for a week.
Irreversible Anti-Cholinergic Agonists
Organophosphorus compounds cause irreversible inhibition of cholinesterase enzyme. Most of the insecticides and war gasses (nerve gasses) like tabun, sarin and soman belong to this category and are more of toxicological importance. DFP (di-isopropyl fluorophosphate) is used clinically as topical application (0.1% solution in arechis oil) for glaucoma (one drop instilled once or twice daily).
Ecothiophate has longer duration of action and is used in concentration of 0.06 to 0.25% solutions.
Treatment of organophosphorus poisoning:
Since organophosphorus compounds are widely used as house hold and agricultural insecticides, acute and chronic poisoning with them are quite common. The acute intoxication is manifested by muscarinic and nicotinic signs and symptoms. The cause of death is central as well as peripheral respiratory paralysis followed by cardiovascular collapse. To save life, patient should be immediately given artificial respiration and treatment of shock should be started. The autonomic effects such as excessive salivation, bronchial secretion and bronchoconstriction are controlled by atropine (2—4 mg i.m. or i.v.). Administer pralidoxime (2PAM) i.v. in a dose of 1 to 2 gm to regenerate cholinesterase enzyme. The dose may be repeated if necessary. Administer suitable antibiotic to prevent secondary infection. Patient should be kept under vigilance for 72 hours to prevent relapse.
Myasthenia gravis: It is a chronic disease. It is characterized by abnormal skeletal muscle weakness and fatigue. It is now generally believed that myasthenia gravis is an autoimmune disease (antibody mediated). It occurs due to blockade of the acetylcholine receptors on the motor end plate of skeletal muscle. It is diagnosed by intravenous injection of the short acting anticholinesterase agent edrophonium that produces a brief increase in the muscle strength of the extremities. After proper diagnosis, treatment is started with oral administration of neostigmine, pyridostigmine or ambinonium.
Glaucoma: It is a major cause of blindness in persons over 40 years of age. There are two main types, i.e. open angle (wide angle) and narrow angle glaucoma. Open angle glaucoma is more common. In these patients, the aqueous humor fails to drain and continues to accumulate leading to increase intraocular pressure that in turn causes compression of the retina and optic nerve. Due to this, there occurs visual loss and blindness. Drugs are used to contract the ciliary muscles and constrict the pupil in order to enhance the drainage of aqueous humor (cholinergic and adrenergic drugs).
Some drugs also reduce the formation of aqueous humor.
Points for Dental Students
1. Many drugs produce side effects related to cholinergic system. These may be due to stimulation of muscarinic or nicotinic receptors. Hence the knowledge of basic principles of this system will be useful to understand them and minimize them.
2. Pilocarpine (5—10 mg TDS) or cervimeline (30 mg TDS) is used to treat xerostomia to avoid development of dental caries and oral candidiasis.
- Acetyicholine is not useful as a drug being non-specific and having short duration of actionbecauseitisrapidlyhydrolyzed fri the body by acetyicholinesterase and pseudocholinesterase enzymes.
- Methacholine is a synthetic Cholinergic Agonists, which is rarely used now.
- Carbechol is also a synthetic Cholinergic Agonists, which is less commonly used for the treatment of urinary retention.
- Bethanochol is a synthetic drug which is used orally in a dose of 2.5 to 5 mg to treat postoperative or neurogenic urinary retention.
- Pilocarpine is an alkaloid which is used in glaucoma and as miotic to counteract the mydriatic and cycloplegic actions of atropine.
- Muscarine is an alkaloid. Its poisoning is effectively treated by atropine.
- Oxotremorine is an extremely potent, synthetic compound which is used as an experimental tool.
- Metoclopramide (synthetic drug) has cholinomimetic and antidopaminergic actions. It is used as an antiemetic, in reflux oesophagitis and prior to radiological investigations of gastrointestinal tract.
- Physostigmine (eserine) is an alkaloid which is mainly used as a miotic in glaucoma and to treat atropine poisoning.
- Neostigmine (prostigmine) is a synthetic quaternary ammonium compound which is particularly effective as an anti curare agent and in the treatment of myasthenia gravis.
- Pyridostigmine is used in myasthenia gravis.
- Edrophonium has short duration of action. So it is used to differentiate between Cholinergic Agonists and rnyasthenia crisis.
- Ambenonium may be used for myasthenia gravis.
- Demecarium is used in glaucoma.
- Acute or chronic organophosphorus poisoning is quite common because these compounds are widely used as house hold and agricultural insecticides. Treatment consists of: (a) artificial respiration, (b) treatment of shock and (c) administration of atropine and pralidoxime.
- Myasthenia gravis is a chronic disease which is treated by neostigmine or pyridostigmine or ambinonium.