Cholinergic Antagonist

Joseph De Soto MD, PhD, FAIC

Overview Cholinergic antagonists bind to muscarinic and/or nicotinic

receptors and block the actions of acetylcholine. There are three classes of cholinergic antagonists: 1) antimuscarinic (parasympathoplegic), 2) antiganglionic (para and sympathoplegic) and 3) neuromuscular blocking.

Antimuscarinic Agents These medications block muscarinic receptors and do not

block NN or NM receptors and hence, have little effect on autonomic ganglia and skeletal muscle.

Many of our tricyclic antidepressants, and antihistamines have antimuscarinic activity.

Common side effects of antimuscarinic anatgonists include 1) blurred vision, 2) confusion 3) mydriasis 4) constipation and 5) urinary retention.

Atropine Atropine (belladonna) as we learned earlier is an antidote for

overdose of both direct cholinergic drugs and anticholinesterases. The ability of atropine to enter the central nervous system is of critical importance.

Topical atropine may be used by optometrists and ophthalmologists to evaluate the retina and is both mydriatic and cycloplegic. Tropicamide and cyclopentolate are often used to induce mydriasis and cycloplegic in place of atropine due to their shorter duration of action.

Atropine can also be used to treat abdominal cramping, mushroom poisoning (anticholinesterase) and bradycardia.

> 10 mg of atropine may be fatal. 2-3 mg therapeutic.

Scopolamine Scopolamine is a competitive antagonist at muscarinic

receptors. This medication shows some specificity for the M1 receptor as opposed to the M2 and M3 receptors.

Scopolamine may be given as a transdermal patch behind the ear to treat motion sickness. It is also used to treat sea sickness, renal & biliary spasms, and to limit post-operative vomiting.

Half-life 4.5 hours. Side effects: pruritis, urticaria, dyshidrosis and dry mouth.

Physostigmine the acetylcholinesterase inhibitor may be used as an antidote to treat CNS depression symptoms caused scopolamine overdose.

Urticaria

Ipratropium & Tiotropium Ipratropium blocks the M1. M2 and M3 receptors. In the

bronchioles it promotes the degradation of cyclic guanosine monophosphate (cGMP), resulting in a decreased intracellular concentration of cGMP. This inhibits bronchoconstriction and mucus secretion. Hence its use in mild to moderate asthma and others types of chronic obstructive pulmonary disease (COPD). Ipratropium should NOT be used in place of albuterol as a rescue medication. Half – Life 2 hours.

Tiotropium is a long-acting, 24-hour, anticholinergic bronchodilator used in the treatment of COPD. Half-Life 5-6 Days.

The side effects of both medications include mild sedation and dry mouth.

Neither should be used in the presence of closed angle glaucoma.

Ganglionic Blockers Ganglionic blockers (Hexamethonium, Mecamylamine)

act on both the parasympathetic and sympathetic ganglia. They are not selective and will block ganglia of both systems. These drugs are not effective blocking the Nm nicotinic receptor at the skeletal muscle plate.

These tend to be noncompetitive inhibitors.

There are two ways in which a ganglion blocker can exert its effect by either causing a block of the NN channel.

There is the special case of Nicotine which can cause a depolarizing blockade of both NN and NM.

Hexamethonium, Mecamylamine and Nicotine

Mecamylamine is an orally active NN noncompetitive inhibitor that can enter the CNS. Historically, it was used as an antihypertensive drug. Today it is rarely used. This drug can also be used to treat nicotine addiction.

Hexamethonium is an NN noncompetitive inhibitor that cannot enter the CNS. It can be taken through inhalation. It was used as a hypertensive but discontinued.

At low doses nicotine causes stimulatory effects on BOTH NN, and NM however, higher doses it can lead to depolarizing neuromuscular blockade.

Systemic Effects of Ganglion Blockers Central Nervous System: sedation, tremor, choreiform

movements for those ganglionic blockers that enter the CNS

Eye: cycloplegia causing loss of accommodation, occurs as the ANS predominates.

Cardiovascular: Hypotension and moderate tachycardia.

Gastrointestinal: Constipation and decreased secretion

Reproductive organs: Loss of ability for orgasm and erection.

Other: Inability to sweat and urinary retention.

Neuromuscular Blocking Agents Neuromuscular blocking drugs are used during surgical

procedures and in the intensive care unit. These drugs are frequently used to facilitate intubation.

All of the neuromuscular drugs are highly polar and inactive orally. There are two categories of neuromuscular blocking agents nondepolarizing drugs: vecuronium, rocuronium, pancuronium and atracurium and the depolarizing drug succinylcholine.

Mechanism of Action of Nondepolarizing Agents

Small doses of nondepolarizing drugs act as competitive inhibitors of acetylcholine at the NM receptor. In larger doses the drugs can enter the pore of the acetychloline receptor and act as noncompetitive inhibitors.

When noncompetitive inhibition occurs this interferes with the ability of acetylcholine inhibitors such as edrophonium and neostigmine to overcome the nondepolarizing effect of these medications.

As an interesting side note the least potent of nondepolarizing drugs have the fastest onset of action and shortest duration of action. (Shortest half-life)

Nondepolarizing Neuromuscular Agents

Vecuronium: This paralyzing agent is used for surgery and it is part of a drug cocktail that prisons in the United States use to carry out the death penalty. Use cautiously in those with renal failure.

Rocuronium: This drug has minor histamine release hence a risk for asthmatics and minor rebound tachycardia. Also used for executions

Pancuronium: This durg is also used in addition to surgery for executions. Pancuronium raises blood pressure, heart rate and salivation modestly

Atracurium: The breakdown of this medication increases greatly with temperature and elimination increases significantly with a pH increase. Hypotension, bronchospasms and reflex tachycardia

Adverse Effects of Neuromuscular Blockers

Muscle pain greatest in those who are active

Skeletal Muscle Paralysis larger muscles are the last paralyzed and the first to recover. The diaphragm is last to be paralyzed.

Histamine release resulting in hypotension and bronchospasm with tubocararine and atracurium. Subsequen Reflex tachycardia.

Hyperkalemia in patients with burns, nerve damage, and neuromuscular disease extra-junctional acetylcholine may develop. When the muscle is stimulated by a medication like succinylcholine potassium is release by the muscle. This can cause cardiac arrest.

Intraocular pressure a rapid increase in intraocular pressure that last 7-9 minutes.

.

Mechanism of Depolarizing Agents Depolarizing drugs react with the NM to open the channel

and cause depolarization of the motor end plate causing contraction of the muscle. These medications are not metabolized quickly and hence the membranes remain depolarized and unresponsive to subsequent impulses. A flaccid paralysis occurs as repolarization does not occur.

Adding a acetylcholinesterase inhibitor at this point will worsen the paralysis.

In the case of prolonged exposure the end plate depolarization begins to decrease and repolarization can occur. Yet, the membrane cannot be easily depolarized as the membrane has become desensitized Tachyphylaxis).

Succinylcholine Succinylcholine also known as Suxamethonium acts on NM

receptors resulting in persistent depolarization of the motor end plate.

It is degraded by butyrylcholinesterase, a plasma cholinesterase and NOT acetylcholinesterase, hence it has a much longer half life.

Malignant hyperthermia is a rare life-threatening condition that may be triggered by exposure to specifically the volatile anesthetic agents and the neuromuscular blocking agent succinylcholine combined with anesthetics.

Susceptible patients have a mutated ryanodine receptor. The ryanodine receptor when activates releases intracellular calcium from the sarcoplasmic reticulum.

Drug Interactions Neuromuscular blocking agents may interact with

aminogylcoside drugs which are used to treat gram negative infections.

Aminoglycosides limit the release of prejunctional acetylcholine. Neuromuscular blockers will thereby synergetic in effect with these medications.

Among the aminoglycosides are: streptomycin, kanamycin, tobramycin, gentamicin, and neomycin