Lecture 20: Muscarinic Blockers, Antimuscarinic and Overactive Bladder

What do muscarinic blockers do?

Prevent ACh from activating muscarinic receptors; most are competitive antagonists.

What are other names for muscarinic blockers?

Parasympatholytics, cholinergic antagonists, cholinolytics, anticholinergics, antimuscarinics, and antispasmodics.

What is the most accurate name for muscarinic blockers?

Antimuscarinics, because they specifically block muscarinic receptors.

What non-antimuscarinic drug classes may have anticholinergic effects?

Some antipsychotics, antihistamines, antidepressants, and opioids.

What receptors do ACh and direct cholinergic agonists activate?

Muscarinic and nicotinic receptors.

How do indirect cholinergic agents increase ACh effects?

They inhibit AChE, preventing ACh breakdown and prolonging its effects.

Describe neurotransmission in the sympathetic ANS.

Preganglionic neuron releases ACh onto nicotinic receptors; postganglionic neuron usually releases norepinephrine/epinephrine onto α₁, β₁, or β₂ receptors.

Describe neurotransmission in the parasympathetic ANS.

Preganglionic neuron releases ACh onto nicotinic receptors; postganglionic neuron releases ACh onto muscarinic receptors.

What is the main sympathetic vs. parasympathetic response?

Sympathetic = fight or flight (“gas pedal”); parasympathetic = rest and digest (“brake”).

What is the mydriatic effect of antimuscarinics?

Pupil dilation.

What is the antisecretory effect of antimuscarinics?

Decreased salivation and sweating.

What are the anti-ulcer and antispasmodic effects of antimuscarinics?

Decreased gastric secretion and decreased GI motility.

What are the respiratory and cardiac effects of antimuscarinics?

Bronchodilation and possible increased heart rate.

How do antimuscarinics help in overactive bladder and Parkinsonism?

They reduce bladder contractions; some reduce rigidity and tremor in Parkinsonism.

What is Atropa belladonna also called, and why is it historically important?

Nightshade/belladonna; it is a source of old tropane anticholinergics and was historically used to dilate pupils cosmetically.

Name plants in the Solanaceae family that contain tropane alkaloids.

Henbane (Hyoscyamus niger), jimsonweed (Datura stramonium), mandrake (Mandragora officinarum), and Brugmansia species

What is piperidine?

A six-membered ring containing one nitrogen.

What is pyrrolidine?

A five-membered ring containing one nitrogen.

What is tropane?

A bridged bicyclic ring system related to piperidine and pyrrolidine.

What is tropine?

Tropane containing an –OH group.

What is hyoscyamine?

A tropine–tropic acid ester that competitively blocks muscarinic receptors.

How does scopolamine differ structurally from hyoscyamine, and what is it used for?

It has an extra oxygen bridge/epoxide ring; used for motion sickness and postoperative nausea.

How is atropine formed from hyoscyamine?

Base-catalyzed epimerization produces a 50:50 mixture of stereoisomers called atropine.

What form of a tertiary amine antimuscarinic binds the receptor?

Its cationic/protonated form.

What are key properties of quaternary antimuscarinics?

Generally more potent but cross membranes poorly and have poor, variable GI absorption.

How do tertiary amines compare with quaternary amines in absorption and distribution?

Tertiary amines are usually better absorbed and distributed.

What is the usual X group in potent antimuscarinic drugs?

Often an ester, but it may also be an ether or carbon group.

What nitrogen-to-X-group spacing gives best antimuscarinic activity?

Two or three carbons; acceptable spacing is usually 2–4 carbons.

What ring pattern often gives maximum antimuscarinic activity?

One aromatic ring and one saturated ring.

How can hydroxyl or hydroxymethyl substitution at R3 improve activity?

It may improve receptor binding through hydrogen bonding.

What are common general uses of muscarinic antagonists?

Preoperative anesthesia, anticholinesterase poisoning, COPD, GI disorders, pancreatitis, rhinitis, bradycardia, OAB, eye dilation, and Parkinsonism.

What is atropine used for in severe muscarinic toxicity?

Temporary blockade of severe or life-threatening muscarinic effects.

Which routes can atropine be administered by?

IV, IM, SC, intraosseous, or endotracheal.

How is atropine used for nerve-agent or insecticide poisoning?

An IM pen injector may be used; sufficient parenteral doses must cross the BBB for certain plant/anticholinesterase poisonings.

What are atropine’s ophthalmic uses?

Mydriasis, cycloplegia, and penalization of the healthy eye in amblyopia.

How can atropine be used for acute nonspecific diarrhea?

In combination with difenoxin or diphenoxylate.

What are the main uses of scopolamine?

Motion-sickness prevention, antiemetic use, vertigo, intestinal cramping, and mydriasis; the patch is placed behind the ear.

What is Donnatal, and what is an important safety concern?

Atropine/scopolamine/phenobarbital combination for GI spasms; may cause drowsiness, dependence, or misuse.

What are key facts about homatropine?

Topical pupil dilator for uveal-tract inflammation; weaker and less toxic than atropine; with hydrocodone, it is used as an antitussive.

What is methscopolamine used for?

Adjunctive treatment of peptic ulcer disease; may reduce recurrence and complications.

What is butylscopolamine used for?

Abdominal/menstrual cramps, GI spasms, and prevention of bladder spasms; in the U.S., it is FDA-approved for certain horse colic.

What is ipratropium?

A SAMA inhaled for COPD bronchospasm; it has local effects with limited systemic absorption.

What is tiotropium, and why should it not be used for acute COPD episodes?

A once-daily LAMA for COPD with slow onset; it is not a rescue medication.

Which receptors does tiotropium bind, and from which does it dissociate fastest?

It binds M1, M2, and M3; it dissociates fastest from M2.

What is aclidinium?

A LAMA for COPD with affinity for all five muscarinic subtypes; respiratory benefit mainly comes from M3 blockade.

What is umeclidinium used for?

Maintenance treatment of COPD; it blocks M3 receptors on airway smooth muscle, causing bronchodilation.

Why is benztropine useful in Parkinsonism?

It is a tertiary amine that crosses the BBB and reduces muscle spasms through central effects

What is benztropine’s main non-muscarinic action?

Selective inhibition of dopamine transporters.

What symptoms define overactive bladder (OAB)?

Urinary frequency, urgency, and urinary incontinence.

Compare M2 and M3 receptors in bladder smooth muscle.

M2 receptors predominate, but M3 receptors mediate detrusor contraction.

How do antimuscarinics treat OAB?

They reduce unwanted detrusor smooth-muscle contractions.

Where are M3 receptors found?

Bladder, smooth muscle, salivary glands, eyes, and brain.

What is oxybutynin used for?

An M3-selective antagonist for urinary urgency, frequency, and incontinence; it is also available as a patch.

What is a key advantage of trospium?

t blocks M1, M2, and M3 but is not metabolized by CYP enzymes, lowering drug-interaction risk.

What is important about solifenacin?

It is more selective for the bladder than salivary glands; CYP3A4 inhibitors such as ketoconazole limit dosing to 5 mg daily.

How are tolterodine and fesoterodine related?

Tolterodine uses active 5-hydroxymethyl tolterodine (5-HMT); fesoterodine is a prodrug that also produces 5-HMT.

Compare darifenacin and mirabegron.

Darifenacin is a highly M3-selective antimuscarinic metabolized by CYP2D6/CYP3A4; mirabegron is a β3 agonist that relaxes detrusor muscle during filling.