Anticholinergic Drugs selectively reduce or abolish the muscarinic receptor mediated effects of acetyicholine and parasympathetic stimulation. So Anticholinergic Drugs are also called antimuscarinic or parasympatholytic agents. Anticholinergic Drugs drugs inhibit the actions of endogenous acetylcholine and muscarinic agonists at muscarinic receptor sites in peripheral tissues and in the central nervous system.
The actions of acetylcholine at the nicotinic sites (neuromuscular junction, autonomic ganglia and adrenal medulla) are, however, not blocked by Anticholinergic Drugs. The nicotinic actions of acetylcholine are blocked by neuromuscular blocking (d-tubocurarine) and ganglionic blocking (mecamylamine) agents.
Belladona Alkaloids Anticholinergic Drugs
Clinically two natural alkaloids Anticholinergic Drugs, atropine (from Atropa belladona, Datura stramonium and Atropa accuminata) and hyoscine (from Hyoscyamus niger and Scopala carniolica) are used. The pharmacological effects of atropine Anticholinergic Drugs are described below as a prototype of cholinergic antagonists.
1. Exocrine glands: Atropine inhibits salivary, lacrimal and bronchial glands. So it causes dryness of mucous membranes. It also reduces total acidity and volume of basal (fasting) gastric secretion, pepsin and mucous secretions. Sweating is diminished by atropine leading to an increase in body temperature.
2. Gastrointestinal system: Atropine effectively reduces the tone and motility of the gut. It, therefore, causes prolongation of gastric emptying time, closure of the sphincters and decrease in tone, amplitude and frequency of peristaltic movements. Atropine has little effect on biliary tract.
3. Respiratory tract: The smooth muscles of bronchioles are relaxed. However, it is not useful in bronchial asthma because of the involvement of other spasmogens.
4. Urinary tract: Atropine reduces tone of the ureter and relaxes detrusor muscle of the urinary bladder with increased tone of trigonal sphincter.
• Atropine causes passive dilatation of the pupil by blocking the muscarinic receptors of circular muscle of the iris.
• It causes cycloplegia (loss of accommodation) by paralysing the ciliary muscle.
6. Cardiovascular system:
- In small doses, there may be a brief bradycardia due to transient stimulation of vagal centre and blockade of presynaptic M1 receptors on the postganglionic parasympathetic nerve supplying SA node. This is followed by tachycardia due to the blockade of vagus nerve on the heart.
- In large dose, there may be rise in blood pressure due to stimulation of vasomotor centre.
- In very large doses, there may be cutaneous vasodilatation in face and neck (atropine flush) due to direct effect unrelated to cholinergic innervation.
7.Central nervous system:
• In therapeutic dose (0.5 —1mg), atropine causes mild stimulation of respiratory centre, vagal centre and inhibition of tremorpnd rigidity of skeletal muscle in parkinsonism by reducing cholinergic over activity in basal ganglia.
• However, larger doses produce marked central nervous system stimulation which may cause restlessness, irritability, excitement, agitation, disorientation, delirium and hallucination.
• Death occurs due to respiratory failure and coma.
Pharmacokinetics: Being lipid soluble atropine is readily absorbed from the gut, mucous surfaces and from the intact skin. It can cross the blood—brain barrier, placental barrier and is secreted in milk and saliva. It is considerably bound to plasma proteins and partly metabolized in liver as glucuronide. About 50% is excreted unchanged and the rest as metabolltes in the urine.
Side effects: The common side effects of atropine and other antimuscarinic drugs are dry mouth, visual disturbances (photophobia, and blurred vision), constipation, urinary retention, tachycardia and central nervous system effects.
In toxic doses, there also occurs difficulty in swallowing, hot and dry skin, rash on the face, neck and upper part of the trunk, weak and very rapid pulse, urinary urgency and difficulty in micturition.
Treatment of atropine poisoning consists of
- Gastric lavage
- Physostigmine—0.5—2 mg i.v. bolous dose, repeated at 5—10 minutes till the clinical signs of poisoning disappear. It is preferred on neostigmine due to its central and peripheral effects.
- c. Artificial respiration
- d. Alcohol sponging to reduce fever.
Anticholinergic Drugs are contraindicated in gluacoma, and should be given with care to elderly patients.
Semisynthetic and Synthetic Cholinergic Antagonists
According to their therapeutic uses, Anticholinergic Drugs have been classified into following groups:
1. Mydriatic and cycloplegic drugs: These drugs are used topically. They can be used in cases of intolerance to atropine. As against the atropine and hyoscine, these drugs have shorter duration of action and are devoid of systemic effects when instilled locally.
Drugs: Homatropine, eucatropine, cyclopentolate, tropicamide.
2. Antispasmodic drugs: The common features of these Anticholinergic Drugs are:
- Most of them are either quarternary compounds or tertiary amines.
- Oral absorption is poor and unpredictable.
- Duration of action is longer than atropine.
- Do not cross blood—brain barrier and conjunctival barrier.
- Their fate and excretion from the body are little known.
- Mainly used to reduce secretions and spasm of gastrointestinal and genitourinary system
- There occurs ganglion blockade in higher dose.
- In still higher doses, neuromuscular blocked and respiratory paralysis may occur.
A. Quarternary compounds:
i. Semisynthetic: Atropine methonitrate, homatropine methylbromide, and hyoscine methylbromide, hyoscine butylbromide, amprotropine, anisotropine.
ii. Synthetic: Propantheline, isopropamide, oxyphenonium, ipratropium bromide, clidinium, glycopyrrolate, mepenzolate, penthienate, pipenzolate. Although this group includes’a large number of drugs, there is no much advantage of one compound over the other.
B. Tertiary amines: Synthetic: Dicyclomine, pirenzepine, telenzepine.
3, Antiparkinsonian Anticholinergic Drugs: These synthetic atropine substitutes cross blood—brain barrier. Acting on basal ganglia, they restore the balance between the neurotransmitters acetylcholine (excitatory) and dopamine (inhibitory) which is disturbed in parkinsonism.
- Benzhexol hydrochloride
- Biperidine hydrochloride
- Orphenadrine hydrochloride
- Procyclidine hydrochloride
- Promethazine hydrochloride
Therapeutic Uses of Anticholinergic Drugs
1. Central nervous system conditions:
- Parkinsonism: Anticholinergic Drugs are less effective than levodopa. These are used in mild cases, in drug induced extrapyramidal syndrome and as helping drug to levodopa. Synthetic antimuscarinic drugs are more selective for this purpose.
- Motion sickness: Hyoscine hydrobromide is preferred due to its more sedative and central effects.
- Twilight sleep: Hyoscine plus meperidine are used during labour to produce amnesia, analgesia and a relaxed state.
- Maniacal state during withdrawal of alcohol in chronic alcoholics. Hyoscine is used because of its sedative effect.
2. Eye conditions:
- Atropine and its congeners (preferred due to shorter duration and minimal side effects) are used as an eyedrop or ointment to produce mydriasis and cycloplegia for examination of retina and measurement of reftective error.
- Atropine sulphate can be used alternating with a miotic to break the adhesions between the iris and lens in uveitis and iritis.
- Since atropine has long lasting mydriatic-cycloplegic and local anodyne action on cornea, it is very effective in the treatment of iritis, iridocyclitis, choroiditis, keratitis, corneal ulcer.
3. Gastrointestinal conditions:
a. Synthetic atropine substitutes can be used as antispasmodics in:
- Intestinal colic
- Ulcerative colitis
- Biliary colic
- Traveler’s diarrhoea
b. Peptic ulcer: They are employed as adjuncts to antacids or H2 receptor blockers.
c. Irritable colon
d. Gastritis, gastric hypermotility, nervous dyspepsia, pylorospasm.
4. Atropine and antimuscarinics are used as preanaesthetic medication:
- To reduce bronchial and salivary secretions caused by irritant volatile and gasseous anaesthetics.
- To prevent excessive vagal slowing of the heart.
5. Atropine is sometimes used to treat irregularities of the heart caused by partial block of the conducting tissue and also to treat bradycardia in myocardial infarction.
6. Atropine is used as an antidote in poisoning due to cholinesterase inhibitors.
7. Inhaled ipratropium bromide is useful in the management of asthmatic bronchitis and chronic obstructive pulmonary disease.
Points for Dental Students
1. Atropine is kept as one of the emergency drugs in dental clinic.
2. Adverse effects of many drugs are due to their anticholinergic actions. So the knowledge of basic principles of this system is important for dental students to understand such side effects and minimize those taking precautions.
3. Some Anticholinergic Drugs such as scopolamine, glycopyrrolate and propantheline are used in dental procedures to control excessive salivation. Anticholinergic Drugs are used to provide dry oral cavity; during surgery. Out of the two, glycopyrrolate is preferred because it is a selective antisialagogue and has low incidence of tachycardia in therapeutic doses.
1. Anticholinergic Drugs selectively reduce or abolish the muscarinic receptor mediated effects of acetyicholine and parasympathetic stimulation, Nicotinic actions of acetyicholine are blocked by neuromuscular blocking (d-tubocurarine) and ganglionic blocking (mecamylamine) agents.
2. Synthetic antimuscarinic drugs (ben zhexol benztropne, biperidine. orphenadrine, procydlidine and promethazine) are more selective for the treatment of parkinsonism.
3. Hyoscine is preferred in motion sickness due to its more sedative and central effects.
4. Hyoscine plus meperidine are used during labour to produce amnesia. analgesia and a relaxed state (twilight sleep).
5. Hyoscine is used to treat maniacal state during withdrawal of alcohol in chronic alcoholics due to its sedative effect.
6. To examine retina and measure refrective error, atropine congeners are preferred due to short duration and minimal side effects.
7. To break the adhesions between the iris and lens in uveitis and iritis, atropine sulphate can be used alternating with a miotic.
8. Atropine is used: (a) as an antidote in poisoning due to cholinesterase inhibitors, (b) to treat irregularities of the heart and (c) as preanaesthetic medication.
9. Synthetic atropine substitutes can be used as antispasmodics in intestinal colic, ulcerative colitis, biiary colic and traveller’s diarrhoea.