(3) 27-28: Anticholinergic Drugs

Categories of cholinergic antagonists

1. Antimuscarinic drugs (M)

2. Ganglionic blockers (Nn)

3. Neuromuscular junction blockers (Nm)

4. Neurotoxins (presynaptic)

Antimuscarinic

topic overview

1. Mechanism

2. Effects on body organs/Shared antimuscarinic side effects

3.  Drug classification

Antimuscarinic

MOA:

• Competitive antagonists at muscarinic receptors.

• Drug blocks M receptor → ACh cannot activate it → parasympathetic effects decrease.

Antimuscarinic

Effects on body organs (+ Shared antimuscarinic side effects)

Organ	Receptor blocked	Effect
Glands	M3	↓ Saliva (dry mouth), tears, sweating (overheating)
Heart	M2	↑ Heart rate → tachycardia
Eyes	M3	Mydriasis + cycloplegia → blurred vision
Lungs	M3	Bronchodilation
Bladder	M3	Relaxation → urinary retention
GI	M3	↓ Motility → constipation

• Confusion, delirium

• CNS effects are especially relevant to drugs with central action and at toxic doses. Inhaled drugs generally have less systemic exposure.

Antimuscarinic

Effects on body organs:

Mydriasis =

Cycloplegia =

Mydriasis = pupil dilation.

Cycloplegia = loss of accommodation (difficulty focusing).

Antimuscarinic

Drug classification

Classification	Drugs
Nonselective M1–M5	Atropine, scopolamine
Some M1 selectivity	Benztropine, trihexyphenidyl
Some M3 selectivity	Darifenacin
SAMA — short acting M3 Blockage in Lungs	Ipratropium
LAMA — long acting M3 Blockage in Lungs	Tiotropium

• Tropicamide

🟡 Recognize: These drugs can also be classified by source (natural, semisynthetic, synthetic).

Atropine

topics

1. MOA

2. Uses

3. Fun Facts

Atropine

MOA

Competitive, nonselective muscarinic antagonist (M1–M5).

Atropine

uses

• Acute symptomatic bradycardia

• Poisoning

  • Organophosphate

  • Muscarinic mushroom

• Ophthalmic dilation/cycloplegia

• GI antispasmodic applications

Atropine

Side effects

Dose	What to remember
Low	Transient bradycardia + dry mouth
High	Tachycardia + CNS excitation, hallucinations, delirium, possible coma

Tiotropium vs. ipratropium

topics

• MOA

• CHART

  • Class

  • Main Use

  • Additional Use

  • Side Effects

Tiotropium vs. ipratropium

MOA

• Both block M3 in the respiratory tract → bronchodilation.

Tiotropium vs. ipratropium

CHART

	Tiotropium (Spiriva)	Ipratropium (Atrovent)
Class	LAMA	SAMA
Main use	COPD maintenance	COPD
Additional uses	Reduce COPD exacerbations	Severe asthma adjunct with SABA nasal rhinorrhea
Side effects	Dry mouth cough/headache	Dry mouth nausea/dizziness tachycardia

Scopolamine

topics

1. MOA

2. Side Effects

3. Uses

Scopolamine

MOA

• Muscarinic antagonist

• crosses BBB and has prominent CNS effects.

  • Blocks vestibular cholinergic signaling → reduces motion-related nausea/vomiting.

Scopolamine

side effects

• Drowsiness/sedation

• Impaired short-term memory/Confusion

• Toxic doses → agitation, hallucinations, delirium, coma

Scopolamine

uses

• Prevents nausea/vomiting

  • Motion sickness

  • After surgery (postoperative)

• Anesthesia adjunct for sedation/amnesia.

Tropicamide

topics

1. MOA

2. Use

3. Side Effects

Tropicamide

MOA

• Competitive muscarinic blockade, mainly M3 in the eyes

• Blocks iris sphincter contraction → mydriasis.

Tropicamide

Use

Short-term pupil dilation for eye exams.

Tropicamide

side effects:

• Photophobia

• Temporary blurred vision

• Reduced visual acuity

Darifenacin

topics

• MOA

• Use

• Side Effects

Darifenacin

MOA

• Competitive antagonist with some M3 selectivity.

• Block M3 in bladder → detrusor relaxes → fewer contractions → reduced urgency/frequency.

Darifenacin

Use

Overactive bladder / urge incontinence

Darifenacin

side effects

• Distinctive additional side effects: Hypertension, headache, nausea.

• Common class effects especially relevant: Dry mouth and constipation.

Benztropine and trihexyphenidyl

topics

1. MOA

2. Uses

3. Side Effects

Benztropine and trihexyphenidyl

MOA

• Muscarinic antagonists with some M1 selectivity.

Benztropine and trihexyphenidyl

Uses:

• Parkinsonian symptoms

• Certain antipsychotic-induced movement problems.

Benztropine and trihexyphenidyl

Side effects:

• Shared antimuscarinic effects, including possible confusion/CNS effects.

Ganglionic blockers (Nn)

drug

mecamylamine

Ganglionic blockers (Nn)

mecamylamine - topics covered

1. MOA

2. Effects

3. Uses

Mecamylamine

MOA

Blocks Nn receptors in autonomic ganglia → reduces both sympathetic and parasympathetic transmission.

Mecamylamine

Effects:

Parasympathetic blockage: NO REST & DIGEST

Think: DRY, WIDE, FAST, CAN'T GO!

• 💧 Dry mouth

• 👁 Wide pupils

• ❤ Fast heart rate

• 💩 Can't poop (constipation)

• 🚽 Can't pee (urinary retention)

Sympathetic blockage: NO FIGHT OR FLIGHT

Think: “Blood vessels RELAX, BP DROPS!”

• Vasodilation

• Hypotension

Mecamylamine

Uses

• Rare hypertensive emergency use

• Tourette syndrome also discussed.

NEUROMUSCULAR JUNCTION BLOCKERS

topic overview

• Normal NMJ transmission

• Depolarizing vs. nondepolarizing blockers

• Shared NMJ blocker effects

• Drug Catogires

  • Depolarizing NMJ blocker

    • Succinylcholine

  • Nondepolarizing blockers and muscle paralysis order

    • Rocuronium

  • Reversal of nondepolarizing NMJ blockade

    • Sugammadex (reversal)

NEUROMUSCULAR JUNCTION BLOCKERS

Normal NMJ transmission

• Motor neuron releases ACh → ACh binds Nm receptor → End-plate potential (EPP) occurs = end-plate depolarization → muscle action potential → contraction.

• End-plate potential (EPP) = electrical response in the muscle membrane when ACh activates Nm.

NEUROMUSCULAR JUNCTION BLOCKERS

Drug Categories

• Depolarizing NMJ blocker

• Nondepolarizing blockers

  • Reversal of nondepolarizing NMJ blockade

NEUROMUSCULAR JUNCTION BLOCKERS

Depolarizing vs. nondepolarizing blockers

Depolarizing	Nondepolarizing
Succinylcholine	Rocuronium
Nm agonist	Competitive Nm antagonist
Activates receptor persistently	Blocks receptor activation
Persistent depolarization	Prevents depolarization
Initial fasciculations → paralysis	Paralysis without initial fasciculations

• Both ultimately cause skeletal muscle paralysis.

• Fasciculations = involuntary muscle twitches

NEUROMUSCULAR JUNCTION BLOCKERS

Shared NMJ blocker effects

Succinylcholine and rocuronium can both cause:

• Skeletal muscle relaxation/paralysis

• Respiratory muscle paralysis

• Respiratory complications if blockade is excessive or prolonged

• Cardiac effects, including arrhythmias

Important: Their mechanisms and distinctive adverse effects are different.

NEUROMUSCULAR JUNCTION BLOCKERS

Succinylcholine - topic overview

• Key distinction

• Phases

• Pharmacokinetics

• Uses

• Distinctive side effects

• Drug interactions listed on slides

Succinylcholine

Key distinction

Ultra-short acting.

Succinylcholine

Phases

Phase I	Phase II
Persistent depolarization	Nondepolarizing-like blockade after prolonged exposure
Initial fasciculations	No new fasciculations
Followed by flaccid paralysis	Continued flaccid paralysis

Succinylcholine

Pharmacokinetics

• Administration: Parenteral

• Onset: Approximately 1–1.5 minutes

• Duration: Approximately 5–10 minutes

• Metabolism: Plasma butyrylcholinesterase

Succinylcholine

Uses

• Rapid tracheal intubation

• Short-duration muscle relaxation during anesthesia

Succinylcholine

Distinctive side effects

• Fasciculations → muscle soreness

• Increased intraocular pressure

• Malignant hyperthermia

• Bradycardia

Succinylcholine

Drug interactions listed on slides

• Potentiated by oxytocin, beta-blockers, and lidocaine.

• The slide lists antagonism by anticholinergic drugs.

NEUROMUSCULAR JUNCTION BLOCKERS

Nondepolarizing blockers - topics overview

• Drugs

• Dose-Dependent Blockage

• Pharmacological Actions

Nondepolarizing blockers

Drugs

Drug	Duration
Rocuronium	Intermediate
Vecuronium	Intermediate
Atracurium	Intermediate
Pancuronium	Long acting

Nondepolarizing blockers

Dose-dependent blockade

1. LOW dose → Neostigmine can reverse ✅

• Drug competitively blocks Nm receptors.

• Neostigmine ↑ ACh.

• More ACh competes with the blocker → muscle function returns.

2. HIGH dose → Neostigmine can't reverse effectively ❌

• Additional ion-channel blockade occurs (as described in your lecture).

• Increasing ACh isn't enough to overcome the blockade.

Nondepolarizing blockers

Pharmacological Actions

Muscle paralysis order

Face/eyes → fingers, limbs, neck, trunk → intercostal muscles → diaphragm

• First: Face/eye muscles

• Last: Diaphragm

• Recovery: Reverse order

Nondepolarizing blockers

Rocuronium - topic overview

• Pharmacokinetics

• Uses

• Distinctive side effects

• Drug interactions

Rocuronium

Pharmacokinetics

• Administration: Parenteral

• Onset: Approximately 1–2 minutes

• Duration: Approximately 20–35 minutes

• Elimination: Mainly hepatic/biliary; some renal elimination

Rocuronium

Uses

• Tracheal intubation

• Muscle relaxation during surgery

• Facilitate mechanical ventilation

Rocuronium

Distinctive side effects

• Residual paralysis/muscle weakness

• Blood pressure changes

• Bronchospasm

• Severe allergic reactions

Rocuronium

Drug interactions

Enhanced blockade with:

• Volatile anesthetics, such as isoflurane

• Aminoglycosides, such as gentamicin

Reversal of nondepolarizing NMJ blockade

topics discussed

• Drug

• MOA

• Use

• Admin

• Side Effects

• Sugammadex vs. neostigmine

Reversal of nondepolarizing NMJ blockade

Drug

Sugammadex

Sugammadex

MOA

• Selectively binds rocuronium and vecuronium.

• Sugammadex binds free blocker → less blocker available at Nm → neuromuscular blockade reverses.

Sugammadex

Use

Reversal of rocuronium/vecuronium-induced blockade after surgery.

Sugammadex

Administration

Parenteral.

Sugammadex

Side effects:

• Nausea/vomiting

• Hypotension

• Bradycardia

Sugammadex vs. neostigmine

Sugammadex	Neostigmine
Binds rocuronium/vecuronium	Inhibits AChE
Decreases free NMJ blocker	Increases ACh
Reverses blockade by binding the drug	Reverses blockade through ACh competition

Memory: Sugammadex binds the blocker. Neostigmine raises ACh.

Neurotoxins

topic overview

• drug

• MOA

• Pharmacokinetics

• Uses

• Local side effects

• BOXED WARNING

Neurotoxins

drug

Botox — OnabotulinumtoxinA

Neurotoxins

MOA

• Acts presynaptically.

• Botox enters nerve terminal → cleaves SNAP-25 → ACh vesicles cannot fuse with membrane → ↓ ACh release → muscle relaxation/paralysis.

  • SNAP-25 = protein required for vesicle fusion.

Neurotoxins

Pharmacokinetics

• Local injection

• Duration: Approximately 3–6 months

• Recovery occurs as functional fusion proteins are restored.

Neurotoxins

Uses

• Muscle spasticity

• Blepharospasm

• Migraine

• Bladder dysfunction

• Primary axillary hyperhidrosis

• Selected speech/voice-related muscle disorders

Neurotoxins

Local side effects

• Injection-site pain/Bruising

• Local muscle weakness

• Possible immune response at higher doses

Neurotoxins

BOXED WARNING

Toxin effects can spread away from the injection site.

• Generalized muscle weakness

• Difficulty speaking

• Difficulty swallowing

• Difficulty breathing

• Severe cases: respiratory arrest/death

The lecture notes symptoms may appear 3–7 days after injection.