Pharmacology - An Illustrated Review

5. Cholinergic Agents

5.1 Cholinergic Agonists

Cholinergic agonist drugs are termed parasympathomimetics (or cholinomimetics), as they mimic the effects of the neurotransmitter acetylcholine (Fig. 5.1) in the parasympathetic nervous system. They can be either director indirect-acting.

– Direct-acting parasympathomimetics bind directly to cholinergic receptors.

– Indirect-acting parasympathomimetics inhibit the enzyme acetylcholinesterase, thereby increasing the concentration of acetylcholine in the synaptic cleft. They are further subdivided into reversible and irreversible agents.

Fig. 5.1 image Direct and indirect parasympathomimetics.

Direct parasympathomimetics (e.g., carbachol and arecoline) mimic the effects of acetylcholine (ACh) at effector organs but are not hydrolyzed by acetylcholinesterase (AChE), allowing for their therapeutic use. Indirect parasympathomimetics (e.g., neostigmine, and physostigmine) inhibit AChE, thus raising the concentration of ACh at all cholinergic receptors.

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Table 5.1 summarizes the effects of acetylcholine activation in the parasympathetic system and therefore the effects of parasympathomimetic drugs.

  Table 5.1 image Effects of Acetylcholine Activation in the Parasympathetic System and the Effects of Parasympathomimetic Drugs

System/Parameter

Effects

Cardiovascular system

↓ heart rate and velocity of conduction

↓ blood pressure

Vasodilation of arterioles

Respiratory system

↑ bronchoconstriction

Gastrointestinal tract

↑ gastrointestinal motility and peristalsis

Urinary tract

↑ contraction of ureter and bladder smooth muscle

Relaxation of the sphincter

Eye

↑ contraction of ciliary muscle and iris

Secretions

↑ salivation

↑ lacrimation

↑ gastrointestinal secretions

↑ bronchial secretions

↑ sweating

Direct-acting Parasympathomimetics

Direct-acting parasympathomimetics are chemical analogues of acetylcholine; therefore, they have actions similar to acetylcholine. They differ in their degree of selectivity for nicotinic versus muscarinic receptors. Some direct-acting parasympathomimetic agents are illustrated in Fig. 5.1. These agents are less susceptible to degradation by acetylcholinesterases and serum esterases than acetylcholine.

Side effects. General side effects of direct-acting parasympathomimetics include salivation, lacrimation, urination, diarrhea, vomiting, bronchorrhea, bronchospasm, and bradycardia.

Contraindications

– Peptic ulcers (due to increased gastric acid production)

– Asthma (due to bronchoconstriction)

– Cardiac disease (due to decreased heart rate and velocity of conduction)

– Parkinson disease (worsens tremors)

Methacholine

Mechanism of action. Strong muscarinic (little nicotinic) action

Pharmacokinetics. Partially susceptible to ester hydrolysis

Uses

– Diagnosis of asthma (by inducing bronchial hypersensitivity)

Side effects

– Light-headedness, itching, headache

Carbachol

Mechanism of action. Strong nicotinic (little muscarinic) action

Pharmacokinetics. Not susceptible to ester hydrolysis by serum esterases or acetylcholinesterase

Uses

– Used as a miotic to treat glaucoma if pilocarpine is ineffective

Side effects

– Few side effects at ophthalmologic doses

Bethanechol

Mechanism of action. Strong muscarinic (little nicotinic) action

Pharmacokinetics

– Not susceptible to ester hydrolysis by serum esterases or acetylcholinesterase

Uses

– Treatment for urinary retention (stimulates the smooth muscle of the bladder)

– Used to increase GI motility postoperatively and for gastric atony following bilateral vagotomy (stimulates the smooth muscle of the GI tract)

Note: Bethanechol should not be used for urinary retention or to increase GI motility if there is a mechanical obstruction.

Side effects. General side effects of cholinergic stimulation include decreased blood pressure, bronchospasm, nausea, abdominal pain, diarrhea, sweating, and flushing

Pilocarpine

Mechanism of action. Strong muscarinic action

Pharmacokinetics

– Crosses the blood–brain barrier

– Not susceptible to ester hydrolysis by serum esterases or acetylcholinesterase

Uses

– Glaucoma

– Sjögren syndrome (to increase the secretion of saliva)

Side effects

– Same as for bethanechol

Primary open-angle glaucoma

Glaucoma refers to a group of eye diseases that cause damage to the optic nerve. Primary open-angle glaucoma is the most common form of glaucoma. In this case, drainage of the aqueous humor is prevented due to blockage of the drainage channels between the cornea and the iris. The resultant buildup of aqueous humor raises intraocular pressure, causing damage to the optic nerve. The symptoms include the gradual loss of peripheral vision, which progresses to tunnel vision. Drug treatment is aimed at reducing intraocular pressure by decreasing the production of aqueous humor (e.g., β-blockers [timolol], α-agonists [apraclonidine]), and/or increasing the drainage of the aqueous humor (e.g., lantanoprost, pilocarpine).

 

Sjögren syndrome

Sjögren syndrome is an autoimmune disease causing keratoconjuctivitis sicca (diminished tear production) and xerostomia (dry mouth). It is also associated with rheumatoid arthritis (in 50% of cases) and lupus. Lymphocytes and plasma cells infiltrate secretory glands and cause injury. Diminished tear production causes dry, itchy, gritty eyes, while diminished saliva production makes swallowing difficult and increases the likelihood of development of dental caries. Rheumatoid arthritis causes joint pain, swelling, and stiffness. Treatment for dry eyes involves the use of artificial tears. Dry mouth may be relieved by artificial saliva, taking frequent sips of water, and chewing gum to stimulate saliva flow. If this is insufficient, pilocarpine may be used to stimulate saliva production. Nonsteroidal antiinflammatory drugs (NSAIDs) are used for rheumatoid arthritis. Other drugs that may be useful include hydroxychloroquine (an antimalarial drug) and immunosuppressants (e.g., methotrexate and cyclosporine).

 

Indirect-acting Parasympathomimetics (Anticholinesterases)

Indirect-acting parasympathomimetics inhibit acetylcholinesterase (AChE), thereby increasing concentrations of acetylcholine and enhancing cholinergic function (Fig. 5.1). The effects are the same as those seen following activation of nicotinic and muscarinic receptors.

Side effects. All of the side effects seen with direct-acting parasympathomimetics (salivation, lacrimation, urination, diarrhea, vomiting, bronchorrhea, bronchospasm, and bradycardia) plus muscle weakness, cramps, convulsions, coma, and cardiovascular and respiratory failure, caused by the increased nicotinic component.

Physostigmine

Mechanism of action. Physostigmine is a reversible blocker of AChE.

Pharmacokinetics

– Can enter the central nervous system (CNS)

– Slowly hydrolyzed by AChE

– Effects last 4 to 6 hours

Uses

– Atropine poisoning

– Glaucoma

– Myasthenia gravis (rarely)

Neostigmine

Mechanism of action. Neostigmine is a reversible blocker of AChE.

Pharmacokinetics

– Excluded from the CNS because it is polar

– Slowly hydrolyzed by AChE

– Effects last 4 to 6 hours

Uses

– Myasthenia gravis

– Reverses the effects of nondepolarizing (competitive) muscle relaxants

Pyridostigmine and Ambenonium

Mechanism of action. These agents are reversible blockers of AChE.

Pharmacokinetics

– Slowly hydrolyzed by AChE

– Effects last 4 to 8 hours

Uses

– Treatment of myasthenia gravis, especially in patients who have become tolerant to neostigmine

Edrophonium

Mechanism of action. Edrophonium is a reversible blocker of AChE.

Pharmacokinetics

– Rapidly reversible binding to AChE

– Short-acting (10 to 20 minutes)

Uses

– Useful in diagnosis of myasthenia gravis and “cholinergic crisis”

Parathion and Isoflurophate

Mechanism of action. These agents are irreversible blockers of AChE.

Pharmacokinetics

– Covalently binds to ester site on acetylcholinesterase

– Very slowly released from AChE by hydrolysis (hence “irreversible”)

– Removed from AChE by oxime reactivators, such as pralidoxime (2-PAM), along with atropine (to prevent muscarinic effects)

Uses

– Primarily used as an insecticide

– Sometimes used topically to treat glaucoma

– Component of nerve gas for biological warfare

Myasthenia gravis

Myasthenia gravis is an autoimmune disease in which there are too few functioning acetylcholine receptors at the neuromuscular junction. Patients with this condition often present in young adulthood with muscle fatigue that may progress to permanent muscle weakness. Often the eye muscles are the first to be affected causing ptosis (drooping of the eyelids) and diplopia (double vision). It is treated with neostigmine or similar agents to improve muscle contraction and muscle strength. Corticosteroids, e.g., hydrocortisone, or immunosuppressant drugs, e.g., azathioprine or cyclosporine, may also be given to inhibit the immune system.

 

5.2 Cholinergic Antagonists

Drugs are available to block neuronal and muscle nicotinic receptors, as well as muscarinic receptors. Drugs that block peripheral neuronal nicotinic receptors are termed ganglionic blocking agents and are infrequently used. Agents that block nicotinic receptors on skeletal muscle can be depolarizing or nondepolarizing. Depolarizing blockers persistently activate the receptors, leading to receptor desensitization and thereby blocking the effects of acetylcholine. Nondepolarizing blockers are antagonists at muscle nicotinic receptors and thus block the effects of acetylcholine without depolarization. Muscarinic receptor antagonists differ mainly in their relative activities in the CNS and PNS.

Nicotinic Receptor Antagonists: Ganglionic Blocking Agents

Hexamethonium and Trimethaphan

Mechanism of action. These agents block the nicotinic receptors of both sympathetic and parasympathetic ganglia, but they are not effective at the nicotinic receptor of skeletal muscle.

Pharmacokinetics. Trimethaphan is only effective intravenously and has a short half-life.

Uses

– Hexamethonium is an experimental agent.

– Trimethaphan is used clinically in surgery or in emergencies to reduce blood pressure.

Side effects. These depend on the relative balance of sympathetic and parasympathetic influences and are unpredictable.

Nicotinic Receptor Antagonists: Depolarizing Neuromuscular Blockers of Acetylcholine

Succinylcholine

Mechanism of action. Succinylcholine persistently activates nicotinic receptors, leading to initial target stimulation followed by persistent desensitization (Fig. 5.2).

Pharmacokinetics. Neuromuscular blockage appears within 1 minute of injection and lasts up to 30 minutes.

Uses. Succinylcholine is used to produce skeletal muscle relaxation during surgery.

Side effects

– Muscle pain

– Increased intraocular pressure

– Hyperkalemia (high plasma K+)

Nicotinic Receptor Antagonists: Nondepolarizing Neuromuscular Blockers of Acetylcholine

Curare and Vecuronium (and All Other “Curoniums”)

Mechanism of action. These agents act as competitive antagonists at nicotinic receptors, thus blocking the effects of acetylcholine without depolarization.

Pharmacokinetics

– Given intravenously

– These drugs vary in duration of action by 1 to 3 hours.

Uses. Curare, vecuronium, and related drugs are used to produce skeletal muscle relaxation during surgery.

Side effects

– Respiratory paralysis at toxic doses

Muscarinic Receptor Antagonists

– Muscarinic receptor antagonists are active at all muscarinic receptors throughout the body and as such have low organ specificity (Fig. 5.3).

Atropine

Mechanism of action. Atropine is a competitive antagonist at muscarinic receptors.

Pharmacokinetics

– Orally absorbed

– Readily enters the CNS and therefore has both PNS and CNS actions

Uses. Preanesthetic agent (when reductions of bronchial secretions are necessary)

Fig. 5.2 image Action of the depolarizing neuromuscular blocking agent succinylcholine.

Succinylcholine is structurally like a double acetylcholine (ACh) molecule, and as such it can act as an agonist at motor end plate nicotinic receptors. It is unlike ACh, however, in that it is not hydrolyzed by acetylcholinesterase, but rather is degraded more slowly by plasma cholinesterase. This allows it to accumulate in the synaptic cleft and cause persistent depolarization of the motor end plate, which is accompanied by the persistent contraction of skeletal muscle fibers.

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Fig. 5.3 image Muscarinic receptor antagonists.

These agents act on all muscarinic receptors and have low organ selectivity. The mode of administration is therefore important for targeted treatment, as it determines distribution (as indicated by the shading) and organ concentration (indicated in red). (ED, effective dose.).

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Side effects

– Typical anticholinergic effects are dry mouth, mydriasis (excessive dilation of the pupil), cycloplegia (paralysis of the ciliary muscle of the eye), constipation, difficulty in urination, and decreased sweating. There is little direct effect on blood pressure. Larger doses will increase the heart rate and speed conduction of impulses through the atrioventricular node.

– Very toxic in children

Contraindications

– Glaucoma

Scopolamine

Mechanism of action. Scopolamine is a competitive antagonist at muscarinic receptors.

Uses

– Motion sickness

Side effects

– Same anticholinergic side effects as atropine but may cause more sedation

Homatropine, Cyclopentolate, and Ipratropium

Mechanism of action. These agents are synthetic atropine analogues that act as competitive antagonists at muscarinic receptors.

Pharmacokinetics

– Fewer CNS effects than atropine

Uses

– Dry eyes substitutes (homatropine and cyclopentolate)

– Bronchodilation in asthma (ipratropium)

Side effects

– Mydriasis (excessive dilation of the pupil) and cycloplegia (paralysis of the ciliary muscle of the eye)

Benztropine

Mechanism of action. Benztropine is a competitive antagonist at muscarinic receptors.

Pharmacokinetics

– Stronger CNS effects than atropine but less peripheral action

Uses

– Parkinson disease

Side effects

– Same anticholinergic side effects as atropine

Glycopyrrolate

Mechanism of action. Glycopyrrolate is a competitive antagonist at muscarinic receptors. It has fewer CNS effects than atropine (as it cannot cross the blood–brain barrier) but similar actions in the PNS, resulting in blockage of vagal inputs to the heart and decreased secretions.

Pharmacokinetics. Glycopyrrolate is a quaternary ammonium compound that does not cross the blood–brain barrier.

Uses

– Adjunctive agent in anesthesia (to reduce bronchial secretions)

Side effects

– Same anticholinergic side effects as atropine

Table 5.2 summarizes the cholinergic antagonists and their mechanism of action.

  Table 5.2 image Summary of Cholinergic Antagonists

Drug(s)

Mechanism

Nicotinic antagonists

Ganglionic blocking agents: Hexamethonium and trimethaphan

These agents block the following receptors:

—Nicotinic receptors of pre- and postganglionic parasympathetic ganglia

—Nicotinic receptors of preganglionic sympathetic ganglia

Note. Not effective at the NMJ

Depolarizing neuromuscular blocker: Succinylcholine

Desensitization of nicotinic receptors at the NMJ

Nondepolarizing neuromuscular blockers: Curare and vecuronium (and all other “curoniums”)

Competitive antagonists of ACh at nicotinic receptors of the NMJ

Muscarinic antagonists

Atropine,
scopolamine,
homatropine, cyclopentolate,
ipratropium,
benztropine, and glycopyrrolate

Competitive antagonists of ACh at muscarinic receptors

Abbreviations: ACh, acetylcholine; NMJ, neuromuscular junction.

Botulinus toxin

Botulinus toxin is a neurotoxin produced by Clostridium botulinum. It is highly potent and can be lethal in very small amounts. It works by preventing the release of acetylcholine at the neuromuscular junction, thereby causing paralysis of muscles. In its purified form (Botox), this paralysis of muscles is temporary (3 to 4 months) and is used cosmetically to soften the appearance of wrinkles. It is also used therapeutically in the treatment of cervical dystonia (a neuromuscular disorder of the head and neck), severe hyperhydriasis (excessive sweating), achalasia (failure of the lower esophageal sphincter to relax), migraine, and other conditions.