Cholinergic Antagonists and Antimuscarinic Agents

Cholinergic Antagonists

• Agents that bind to cholinoceptors (muscarinic or nicotinic) and prevent the effects of acetylcholine (ACh) and other cholinergic agonists.
• Most clinically useful agents are selective blockers of muscarinic receptors.
• Commonly known as anticholinergic or antimuscarinic agents, or parasympatholytics.
• Ganglionic blockers show a preference for nicotinic receptors of the sympathetic and parasympathetic ganglia, but are clinically less important.
• Neuromuscular-blocking agents interfere with transmission of efferent impulses to skeletal muscles
• They act as skeletal muscle relaxants in surgical anesthesia and facilitate intubation in critical care.

Antimuscarinic Agents

• Block muscarinic receptors, inhibiting muscarinic functions.
• Block exceptional sympathetic neurons that are cholinergic, such as those innervating salivary and sweat glands.
• Have little to no action at skeletal neuromuscular junctions (NMJs) or autonomic ganglia.
• Atropine and scopolamine are examples of antimuscarinic agents.
• Beneficial in various clinical situations.

Atropine

• Tertiary amine belladonna alkaloid with high affinity for muscarinic receptors.
• Competitively binds and prevents ACh binding
• Acts both centrally and peripherally.
• General actions last about 4 hours, longer when applied topically to the eye.
• Greatest inhibitory effects on bronchial tissue, secretions, and the heart.

Atropine Actions

• Blocks muscarinic activity, causing mydriasis (pupil dilation), unresponsiveness to light, and cycloplegia (inability to focus).
• Can dangerously raise intraocular pressure in patients with angle-closure glaucoma.
• Can be used as an antispasmodic to reduce GI tract activity.
• GI: It is not effective for peptic ulcer treatment because although gastric motility is reduced, hydrochloric acid production is not significantly affected.
• Reduces saliva secretion, ocular accommodation, and urination at doses that reduce spasms.
• Cardiovascular effects vary by dose: low doses cause a slight decrease in heart rate, while higher doses progressively increase heart rate.
• Blocks muscarinic receptors in salivary glands (xerostomia); salivary glands are highly sensitive. Also affects sweat and lacrimal glands.
• Pharmacokinetics: It is readily absorbed, partially metabolized by the liver, and primarily eliminated in urine; half-life is about 4 hours.

Therapeutic Uses of Atropine

• Ophthalmic: Topical application induces mydriatic and cycloplegic effects, enabling refractive error measurement.
• Antispasmodic: Used to relax the GI tract.
• Cardiovascular: Used to treat bradycardia.
• Antisecretory: Used to block secretions in the upper and lower respiratory tracts before surgery.
• Antidote: Used to treat poisoning by organophosphates (insecticides, nerve gases), anticholinesterase overdose, and some mushroom poisoning.
• CNS penetration is crucial for treating toxic effects of anticholinesterases.

Adverse Effects of Atropine

• Dose-dependent: may cause dry mouth, blurred vision, tachycardia, urinary retention, and constipation.
• CNS: restlessness, confusion, hallucinations, delirium progressing potentially to depression, circulatory and respiratory collapse, and death.
• Low doses of cholinesterase inhibitors counter atropine toxicity.
• May induce troublesome urinary retention.
• Dangerous in children due to their sensitivity, especially to rapid body temperature increases.

Scopolamine

• Tertiary amine plant alkaloid producing similar peripheral effects to atropine.
• Has greater action on the CNS compared to atropine, with CNS occurring at therapeutic doses
• It has a longer duration of action.

Actions of Scopolamine

• Effective anti-motion sickness drug and blocks short-term memory.
• Produces sedation, but can cause excitement at higher doses.
• It may produce euphoria and is susceptible to abuse.

Therapeutic Uses of Scopolamine

• Primarily used to prevent motion sickness and postoperative nausea/vomiting.
• Available as a topical patch that lasts up to 3 days.
• Pharmacokinetics and adverse effects are similar to atropine, but scopolamine has a longer half-life.

Aclidinium, Glycopyrrolate, Ipratropium and Tiotropium

• Ipratropium and tiotropium are quaternary derivatives of atropine.
• Glycopyrrolate and aclidinium are synthetic quaternary compounds.
• Ipratropium is a short-acting muscarinic antagonist (SAMA).
• Glycopyrrolate, tiotropium, and aclidinium are long-acting muscarinic antagonists (LAMAs).
• Agents are approved as bronchodilators for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).
• Delivered via inhalation; their positive charge prevents entry into systemic circulation or CNS, restricting effects to the pulmonary system.

Tropicamide and Cyclopentolate

• Used as ophthalmic solutions for mydriasis and cycloplegia.
• Shorter duration of action compared to atropine.
• Tropicamide produces mydriasis for 6 hours.
• Cyclopentolate lasts for 24 hours.

Benztropine and Trihexyphenidy

• Used as adjuncts with other antiparkinsonian agents to treat Parkinson's disease and other parkinsonian syndromes, including antipsychotic-induced extrapyramidal symptoms.

Oxybutynin and other Antimuscarinic Agents for Overactive Bladder

• Oxybutynin, darifenacin, fesoterodine, solifenacin, tolterodine, and trospium are synthetic atropine-like drugs with antimuscarinic actions.
• By blocking muscarinic (M3) receptors in the bladder, decrease intravesical pressure, increase bladder capacity, and reduce bladder contraction frequency.
• Antimuscarinic actions cause adverse effects in the GI tract, salivary glands, CNS, and eye.
• Darifenacin and solifenacin are more selective M3 muscarinic receptor antagonists.
• Other drugs are mainly nonselective and bind to other muscarinic receptor subtypes, contributing to adverse effects.

Therapeutic Use of Oxybutynin

• Used for overactive bladder and urinary incontinence management, and in patients with neurogenic bladder.
• Most agents have a long half-life and allow once-daily administration.
• Immediate-release oxybutynin and tolterodine are dosed two or more times daily.
• Oxybutynin forms: extended-release formulations(daily), transdermal patch, and topical gel.
• Metabolized by the cytochrome P450 system (primarily CYP 3A4 and 2D6), except trospium, which undergoes ester hydrolysis.

Adverse Effects of Oxybutynin

• Adverse effects include dry mouth, constipation, and blurred vision, which limits tolerability.
• Extended-release formulations and the transdermal patch have a lower incidence of adverse effects and may be better tolerated as a result.
• Trospium is a quaternary compound that minimally crosses the blood-brain barrier.
• Trospium has fewer CNS effects than others, making it a preferred choice for treating overactive bladder in patients with dementia.

Ganglionic Blockers

• Act specifically on nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia.
• Some also block the ion channels of the autonomic ganglia.
• Display no selectivity and are ineffective as neuromuscular antagonists.
• Block the entire output of the autonomic nervous system at the nicotinic receptor.
• Responses are complex and mostly unpredictable.
• Rarely used therapeutically, but serve as a tool in experimental pharmacology.

Nicotine as a Poison

• Nicotine is a poison that delivers numerous undesirable and deleterious effects when it is delivered via cigarette smoke.
• Depending on dose, nicotine depolarizes autonomic ganglia, resulting in stimulation then paralysis.
• The release of neurotransmitters is increased, resulting in complex stimulatory effects, resulting in impact to the sympathetic and parasympathetic ganglia.
• A physiologic systems repsonse is a sum of the stimulatory and inhibitory effects of nicotine
• Increased blood pressure and cardiac rate and peristalsis and secretions result.
• At higher doses, blood pressure decreases from ganglionic blockade, and the GI tract and bladder musculature ceases.

Neuromuscular-Blocking Agents

• Block cholinergic transmission between motor nerve endings and nicotinic receptors on skeletal muscle.
• Act either as antagonists (nondepolarizing) or as agonists (depolarizing) at the receptors on the endplate of the NMJ.
• Clinically useful for rapid intubation for respiratory failure.
• Used to facilitate endotracheal intubation and provide complete muscle relaxation at lower anesthetic doses during surgery.
• They offer increased patient safety by allowing recovery quickly and completely.
• NMBs shouldn't replace anesthsia, and they are used in the ICU as adjuvant therapy to facilitate intubation and ventilator for critically ill patients.

Nondepolarizing (Competitive) Blocker

• The first NMB discovered was curare, used by Amazon hunters to paralyze prey.
• Now superseded by drugs with better adverse affect profiles such as cisatracurium, mivacurium, pancuronium, rocuronium, and vecuronium.

Mechanism of Action (Low Dose)

• Nondepolarizing agents competitively block ACh at the nicotinic receptors.
• They compete with ACh without stimulating the receptors, thus preventing the depolarization of the muscle cell membrane and muscular contraction.

Competitive Action

• Can be overcome using cholinesterase inhibitors, such as neostigmine and edrophonium.
• These increase ACh concentration in the neuromuscular junction.
• Anesthesiologists may use this strategy to shorten the duration of the neuromuscular blockade.
• At low doses, muscle is responsive to electrical stimulation which allows the monitoring of the extent of the neuromuscular blockade.

At High Doses

• Nondepolarizing agents may block ion channels of the motor endplate.
• This leads to a weakening of neuromuscular transmission.
• Cholinesterase inhibitors have reduced ability to reverse the action
• Muscles don't respond to electrical stimulation

Sensitivity

• Muscles vary in sensitivity to blockade.
• Face and eye muscle are most sensitive to paralysis, and are paralyzed first, followed by fingers, limbs, neck, and trunk muscles.
• Intercostal muscles affected next, with the diaphragm last. Recovery happens in the opposite process.
• Sugammadex is a selective relaxant binding agent to terminate the action of rocuronium and vecuronium.

Pharmacokinetics of NMBs

• All NMBs given intravenously or intramuscularly, typically.
• Have two quaternary amides within bulky ring which prevents gut absorption
• Poor penetration, cant enter cells or cross blood brain
• Drug action terminated in variety of ways.
• Pancuronium is excreted unchanged in urine.
• Cisatracurium's metabolism is organ independent Hofmann elimination to laudanosine, which is further metabolized, and renally excreted
• Amino steroid drugs vecuronium and rocuronium are deacetylated in the liver and excreted unchanged in bile.
• Mivacurium is eliminated using plasm cholinesterase
• Choice is dependent on desited muscle relaxation and route of elimination

Drug Interactions

• Action of NDMRs can be overcome by cholinesterase inhibitors neostigmine, physostigmine, pyridostigmine and edrophonium
• Increase dose can result in depolarizing block from ACh elevation
• Less effective in ion channels
• Volatile aesthetics such as desflurane enhance NMB by stabilzing at NJM- sensitizing the neuromuscular blocker effect
• AG antibiotics like gentamicin and tobramycin block ACh release by competing for calcium ions, enhancing NMB

Depolarizing Agents

• Depolarizing blocking agents work by depolarizing plasma membrane in muscle fibre- similar to ACh action
• More resistant to acetylcholinesterase degradation - more persistent depolarization
• Succinylcholine is only muscle relaxant in use

Succinylcholine mechanism of action

• Attaches and acts like ACh on the nicotinic receptor to depolarize the junction
• Unlike ACh, it isn't destroyed by acetylcholinesterase instantly
• Persists at high concentrations remaining attached to receptors for constant stimulatiom

Depolarizing Process

• Depolarizing agent causes sodium channel for nicotinic receptor to open
• Leads to receptor depolarization (Phase 1), a transient twitching of muscle (fasciculations)
• Continuous binding makes receptor incapable of signalling
• Depolarization gives way to gradual repolarization as sodium channels are closed, leads to resistance to depolarization (Phase II) and flaccid paralysis

Muscle Actions

• The respiratory muscles are paralysed last, as with competitive blockers
• Succinylcholine gives brief muscle fasciculations that produce muscle soreness
• Can avoid this by administering a small dose of NDMR

Short Action

• Succ duration due to rapid hydrolysis by pseudocholinesterase
• Doesn't metabolise at NJM- allowing agent to bind to nicotinic receeptors
• Plasma redistribution needed for mechanism - limited
• Helpful in rapid endo treacheal intubation during anesthesia induction
• Also during electroculsive shock treatment

Succinylcholine Characteristics

• Action is achieved from redistribution
• Action achieved from rapid hydrolysis
• Is briefly given by continuous infusion to maintain effects
• Rapid drug disappearance
• Hyperthermia potentially in suspectible
• Potential to induce malignant hyperthermia
• Administration can lead to prolonged apnea
• Defeciency in plasma cholinesterase
• High release of pottasium

Hyperkalemia

• Succ can increase pottasium release from intracellular stores
• Massive risk in burn patients
• Massive risk in pottasium loss
• Massive risk in renal patients