DRUGS ACTING ON THE PARASYMPATHETIC NERVOUS SYSTEM (CHOLINERGIC DRUGS)
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The neurotransmitter of parasympathetic nerves is acetylcholine. It has two types of receptors – nicotinic and muscarinic. The nicotinic receptors are found at the neuromuscular junction, autonomic ganglia and in the CNS. The muscarinic receptors are found mostly on autonomic effector cells innervated by postganglionic parasympathetic nerves.
A. MUSCARINIC RECEPTOR AGONISTS
Two types – acetylcholine and other choline esters - methacholine, carbachol, bethanechol
Endogenous and synthetic cholinomimetic alkaloids – pilocarpine, muscarine, arecoline (found in betel nuts)
1. Acetylcholine has diffuse effects and is rapidly broken down and so is not often used`` in clinical situations. The synthetic compounds are longer acting and more selective.
a. Cardiovascular system – vasodilatation and hypotension, negative chronotropic effects (decreased pulse), negative inotropic effects (decrease in force of contraction) and decrease in the rate of conduction in the sinoatrial and atrioventricular nodes; the hypotension is usually followed by a reflex tachycardia. Only acetylcholine and methacholine have significant effects on the heart.
b. GIT – increased muscle tone and peristalsis, increased secretions – expressed as nausea, belching, vomiting, abdominal cramps and bowel movements
c. Urinary tract – decrease bladder capacity and increase peristalsis
d. Glands – salivary, lacrimal, sweat, tracheobronchial – increased secretions
e. Other – bronchoconstriction, pupil constriction
3. Routes of administration – oral, subcutaneous, topical to the eye (intravenous or intramuscular administration is less selective with more toxic effects)
a. GIT – bethanechol is used for postoperative gastric atony and gastroparesis, and in some cases of Hirschprung’s disease and gastroesophageal reflux.`
b. Bladder – bethanechol is used in neurogenic bladder and in urinary retention after surgery or childbirth
c. Eyes – for miosis and in glaucoma
d. Methacholine is used to diagnose asthma by bronchial challenge
5. Side effects
a. Flushing, sweating, headache, salivation, problems with visual accommodation, belching and abdominal cramps
b. Large amounts can cause complete heart block.
6. Contraindications – hyperthyroidism, asthma, peptic ulcer disease, coronary artery disease
a. Cardiovascular system – hypotension and bradycardia
b. Eye – miosis with initial increase in intraocular pressure and then a sustained (up to 24 hours) decrease, spasm of accommodation (which lasts about 2 hours)
c. Exocrine glands – excess sweating, salivation, respiratory tract secretions, etc.
d. Increased tone of smooth muscles of GIT and urinary tract
2. Routes of administration – oral and topical to the eye
3. Uses of pilocarpine
a. Dryness of mucus membranes – as in Sjogren’s syndrome or after head/neck irradiation
4. Side effects - nausea, hiccups, vomiting, weakness
5. Toxic effects
a. Excess salivation, sweating and tearing, nausea, vomiting, diarrhea, abdominal pain, bronchospasm, headache, bradycardia, hypotension and shock
b. Treatment is atropine.
B. INHIBITION OF MUSCARINIC RECEPTORS
Mode of action
Prevent acetylcholine from binding to the muscarinic receptor by competing with it for receptors; much less effect on nicotinic receptors
General uses of muscarinic antagonists
1. GIT – irritable bowel syndrome to decrease motility, reduction of excess salivation
2. Ophthalmology for mydriasis (pupil dilatation) and cycloplegia (inhibition of accommodation)
3. Respiratory tract – reduce secretions and cause bronchodilatation
4. Cardiovascular – limited uses in conditions where there is increased vagal tone (myocardial infarction, AV blocks)
5. CNS – to treat Parkinsonism and the extrapyramidal effects of neuroleptic drugs; as antiemetic in cases of motion sickness
6. Used in general anesthesia to decrease respiratory secretions and vagal effects
7. To treat organophosphate poisoning (chemical warfare or pesticides)
1. Examples are atropine (most well-known) and scopolamine
2. Atropine effects receptors in a dose-dependent fashion.
a. First hit are sweating, salivation and respiratory secretions.
b. With increased dose, pupil dilates, heart rate increases and accommodation is inhibited.
c. Last affected are the bladder and GIT.
a. CNS - atropine has no real effect on the CNS; scopolamine passes the blood-brain barrier and has CNS effects such as sleepiness, loss of memory, fatigue, decreased REM sleep and euphoria.
(1) is transient bradycardia, but the main effect is tachycardia
(2) Atropine counteracts vagal effects caused by carotid stimulation, pressure on the eyeballs, peritoneal stimulation, etc.
(3) Used to treat second degree AV block
c. Respiratory tract – inhibit respiratory secretions and bronchoconstriction, reduce laryngospasm
d. GIT – decrease gastric motility and secretions (especially saliva)
e. Other effects include decreased sweating, decreased tone of urinary system
f. Although atropine crosses the placenta, it does not seem to have any adverse effects on the fetus.
4. Administration can be oral, parenteral or topical to the eye or mucus membranes.
a. Antidote to excess muscarinic cholinergic stimulation
b. To relieve extrapyramidal symptoms of neuroleptic treatment and Parkinsonism
c. Scopolamine in a transdermal patch is useful in treating motion sickness.
6. Toxic effects - tachycardia, dry mouth, mydriasis; at higher doses, see headache, palpitations, blurred vision, ataxia, hallucinations, psychoses, convulsions, delirium and coma
7. Absolute contraindication is atropine with closed angle glaucoma. (“atropine with glaucoma – no diploma”)
Quaternary ammonium compounds
1. Most well-known is ipatroprium bromide; other examples are methantheline, methscopolamine and propantheline
2. Not effective orally, in the eye or in the CNS; in general longer acting than the belladonna alkaloids
3. Ipatroprium is administered in inhalation solutions and systemic effects are minimal.
4. Also cause inhibition of ganglionic (nicotinic) receptors and so have nicotinic side effects as well (such as orthostatic hypotension and impotence).
5. Ipatroprium is used in the chronic (not acute) treatment of asthma and COPD; unlike other anticholinergics it does not decrease the activity of the cilia of the respiratory tract
6. Toxic effects – respiratory muscle paralysis
Tertiary amine compounds
a. Ophthalmological use; less long acting than atropine or scopolamine - examples are homatropine hydrobromide, cyclopentolate hydrochloride and tropicamide.
b. To counteract extrapyramidal effects and Parkinsonism , cross the blood-brain barrier – benztropine mesylate and trihexyphenidyl hydrochloride
c. As antispasmodics in the urinary bladder – oxyphencyclimine hydrochloride, flavoxate hydrochloride
C. ANTICHOLINESTERASE AGENTS
1. Cause prolonged action of acetylcholine (after its release from nerve endings) by inhibiting the enzyme that breaks it down (acetylcholinesterase)
2. Examples used in therapeutic medicine are physostigmine, neostigmine, pyridostigmine.
3. Effects – as in muscarinic agonists
4. Can be given orally, subcutaneously, topically and parenterally
b. To increase bladder and GIT motility – best is neostigmine
c. Myasthenia gravis – for treatment (usually pyridostigmine or neostigmine) and diagnosis (edrophonium)
d. Alzheimer’s disease – tacrine helps with symptoms, but does not stop or slow down the process of deterioration
e. As pesticides (parathion, malathion) and chemical warfare (sarin, soman, tabun)
f. Pyridostigmine can be used as prophylaxis against chemical warfare.
4. Toxic effects – iatrogenic, inadvertent or intentional
a. Muscarinic effects - pinpoint pupils, congestion of conjunctiva, pain of eyes and forehead, runny nose, bronchoconstriction, diarrhea, nausea, vomiting, abdominal pain, excess salivation and sweating, bradycardia and hypotension
b. Nicotinic effects – muscle weakness and fasciculations, paralysis
c. CNS effects – confusion, ataxia, areflexia, convulsions, coma
d. Treatment – atropine plus pralidoxime (acts at the neuromuscular junction; atropine does not), along with supportive measures
e. Tacrine causes reversible elevations of liver enzymes.
D. NICOTINIC RECEPTOR AGONISTS – AUTONOMIC GANGLIA
1. Stimulates the receptors at first; the persistent depolarization causes desensitization and inhibition afterward, which is the longer lasting effect.
2. Acts on both sympathetic and parasympathetic receptors – thus its effects can be variable.
3. Causes dependence in users (i.e. in cigarette smokers), and so smoking is very difficult to stop.
a. CNS – stimulation causes tremors and even convulsions; the subsequent depression can be fatal. Also causes vomiting, centrally via the emesis zone of the brain and peripherally from vagal stimulation
b. Cardiovascular – tachycardia, hypertension and vasoconstriction (sympathetic)
c. GIT – increased motility and secretions (parasympathetic)
5. Routes of administration – oral, transdermal, in cigarettes and pipes
6. Uses – nicotine transdermal patch or gums are used to help smokers quit smoking. They are less potent than cigarettes and doses can gradually be decreased.
7. Toxic effects – nausea, vomiting, abdominal pain, excess salivation, diarrhea, mental confusion, disturbances of vision and hearing, headache, dizziness and respiratory failure. Treatment is to induce vomiting and give activated charcoal, together with supportive measures.
8. Nicotine withdrawal symptoms – irritability, restlessness, anxiety, depression, impaired concentration, bradycardia, increased appetite
E. NICOTINE RECEPTOR ANTAGONISTS – AUTONOMIC GANGLIA
1. Trimethaphan competes with acetylcholine for the receptor; hexamethonium blocks the open channel.
2. Effects may be on sympathetic or parasympathetic manifestations, according to which receptor is predominant.
a. Sympathetic blockade of blood vessels causes vasodilatation and hypotension.
b. Cholinergic blockade at the heart, eyes, GIT, salivary glands, sweat glands and bladder causes tachycardia, mydriasis and cycloplegia, reduced GIT motility, dry mouth, lack of sweating and urinary retention.
a. Pentolinium is used in general anesthesia to keep blood pressure down.
b. Trimethaphan is used to control hypertension in patients with acute dissection of aortic aneurysm before surgery and to control hypertension during other major surgery.
4. Toxic effects – cycloplegia, urinary retention, impotence, constipation, syncope, paralytic ileus and orthostatic hypotension
Mechanism of action/Effect:Ganglionic blocking agent ; prevents stimulation of postsynaptic receptors by competing with acetylcholine for these receptor sites; additional effects may include direct peripheral vasodilation and release of histamine. Trimethaphan's hypotensive effect is due to reduction in sympathetic tone and vasodilation, and is primarily postural. Cardiac output may increase in patients with cardiac failure or decrease in patients with normal cardiac function.
F. NICOTINE RECEPTOR ANTAGONISTS – NEUROMUSCULAR JUNCTION
Two types – depolarizing agents (succinylcholine) and stabilizing (competitive) agents (curare, atracurium, pancuronium, tubocurarine)
a. Paralysis of skeletal muscles; succinylcholine also causes fasciculations
b. No CNS effects – can’t pass blood-brain barrier
c. Various effects on autonomic ganglia – tubocurarine causes hypotension and tachycardia, other stabilizing agents less so; succinylcholine usually has no significant effects.
d. Tubocurarine releases histamine with the effects of wheals, bronchospasm, hypotension and increased saliva and bronchial secretions.
2. Oral absorption is very poor. Agents are used intramuscularly or intravenously.
a. Main use is muscle relaxation in surgery, enabling lower doses of inhalational anesthetics.
b. Also used to achieve muscle relaxation in electroconvulsive therapy in psychiatry
4. Toxic effects
a. Succinylcholine causes hyperkalemia – especially in patients with electrolyte imbalances, congestive heart failure or who are taking digitalis or diuretics
b. Persistent apnea – i.e. failure to wake up promptly after anesthesia
c. Malignant hyperthermia – hyperthermia, metabolic acidosis, muscle contractures and tachycardia
5. Contraindications to use of succinylcholine – trauma, burns, non-traumatic rhabdomyolysis, paraplegia or quadriplegia, muscular dystrophy
a. General anesthetics – synergism with competitive agents
b. Antibiotics – aminoglycosides, clindamycin, polymyxin B and tetracycline also produce neuromuscular blockades
c. Calcium channel blockers – enhance neuromuscular blockade by both types of agent
d. Anticholinesterases – reverse the effects of tubocurarine
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