Mattingly - Cholinergic Pharmacology III Flashcards
GI Tract:
Muscarinic Agonist:
Smooth muscles of sphincters:
Sphincters of the lower esophagus:
Increase tone and motility of GI tract: from lower esophagus to rectum
Smooth muscles of sphincters relax (due to activation of enteric nervous system and release of dilatory peptides; isolated muscles WILL contract if only exogenous ACh applied)
Sphincters of the lower esophagus contract (do NOT relax like other sphincters) in reponse to cholinergic agonists
Note: these drugs were once used to treat acid reflux
GI Tract:
Muscarinic Agonist:
Mechanism of increased tone and motility:
Mechanism of increased tone and motility:
ACh binds M3 receptor –> Activates Gq (tranduces signals) –> Decreased resting membrane potential and increased frequency of APs
Other actions of muscarinic agonists on the GI tract: (3)
Increased secretory activity from mucous cells lining intestinal tract
Increased secretion of digestive enzymes from pancreas
Increased release of HCl and pepsinogen from stomach wall
Muscarinic agonists on the GI
Toxicity: (4)
o Toxicity: Epigastric distress Cramping Vomiting Involuntary defecation
Bethanechol:
Structure:
Action:
Use:
Contraindications:
o Bethanechol:
Structure: synthetic quaternary amine
Action: primarily on GI tract and urinary bladder when administered orally or subQ
- Mostly muscarinic activity
- Long duration
- Resistant to hydrolysis by pseudo and acetylcholinesterases
Use:
- Stasis conditions of GI tract and urinary bladder (ie. post-partum or after general anesthesia)
Contraindications:
- Cases involving mechanical obstruction of the GI tract or urinary bladder (increased pressure may cause perforation)
For pooping after giving birth
Muscarinic Antagonists:
Antagonizes:
Antagonizes most cholinergic drugs and depresses GI motility
Delay movement of food through the GI tract (constipation)
GI Tract
Atropine:
Dosing:
What can be depressed by atropine in the stomach?
Contraindications:
How can it be used to treat GI hypermotility?
Muscarinic antagonist
Atropine:
Formerly used to treat peptic ulcer disease (due to decrease in HCl secretion)
Required high doses with minimal efficacy and lots of side effects
Only HCl secretion mediated by vagus can be depressed by atropine (not secretion related to digestion products that release gastrin and histamine)
Currently contraindicated in cases of gastric ulcers because it delays emptying of the stomach
May still be used in combination with an opioid to treat GI hypermotility
- Quaternary amine agents (propantheline) are better than atropine for this use
Propantheline:
Structure
Action
Use
Structure: quaternary amine
Action: spasmolytic (surpresses muscle spasms) for the GI tract
- May also possess some ganglionic blocking actions when distributed systemically, possibly increasing their effectiveness on visceral smooth muscle organs
Use: Treats GI hypermotility
Lower Urinary Tract:
Agonist Activity: stimulates
Increased tone leads to:
Examples
Agonist Activity: stimulates mAChR receptors (mostly on the detrusor muscle) causing INCREASED bladder wall tone and motility
Increased tone –> Increased intravesical pressure –> Micturition occurs at lower bladder volumes
Most Selective Agonists for Detrusor Stimulation: although they both will also possess prominent GI activity
- Bethanecol: direct acting
- Neostigmine: indirect acting (AChE inhibitor)
Lower Urinary Tract:
Atropine Activity:
Blocks/Doesn’t block
Theory of second transmitter substance
Side effect
Blocks action of muscarinic agonists on pelvic visceral smooth muscle (bladder, uterus, penis);
However, does NOT block PS nerve mediated responses (S2-S4)
Theory of second transmitter substance (ATP, NO, or peptide NT) that is co-released from sacral autonomic nerves along with ACh and act at NON-CHOLINORECEPTOR sites
However, some acute urinary bladder retention may be seen as a side effect
- Especially if pre-existing obstructive lesion is present in bladder neck or urethra (ie. elderly men with benign prostatic hyperplasia)
Muscarinic antagonists for the treatment of urinary urgency:
Oxybutunin Tolterodine Solifenacin Trospium Darifenacin
Oxybutunin: Structure MOA Use Administration Metabolism
Oxybutunin:
Structure: tertiary amine
MOA: weak muscarinic antagonist, possibly with some direct anti-spasmodic effect on smooth muscle (increases utility)
Use:
- Relief of post-operative bladder spasm (ie. post-prostatectomy)
- Urinary urgency
Administration:
-Transdermal patch available for urinary urgency indication (may have less side effects)
Metabolism: liver (CYP3A4)
Tolterodine: Structure Administration Action Use Metabolism
Structure: tertiary amine Administration: oral Action: some selectivity towards muscarinic receptors in the bladder Use: urinary urgency Metabolism: liver (CYP2D6)
Solifenacin: Use
Trospium: Structure, use
Darifenacin: Action, use
Solifenacin:
o Use: overactive bladder
Trospium:
o Structure: quaternary amine (may have fewer side effects)
o Use: overactive bladder
Darifenacin
o Action: some selectivity for M3 agonist activity
o Use: overactive bladder
Lungs:
Muscarinic Agonists
Cause:
Mechanism:
Asthma Patients:
Muscarinic Agonists: causes contraction of bronchiolar smooth muscle via activation of M3 receptors
Mechanism: mediated by Gq and IP3
Asthma Patients: highly susceptible to these effects and cholinergic stimulation may cause severe bronchiolar constriction (made worse by increased secretions) –> dyspnea and acute asthmatic episode
Methacholine:
Action
Use
Metabolism
Structure: synthetic quaternary amine
Action: some preference for the heart; used to be used to suppress atrial tachycardias (have since been replaced by more selective agents)
Use: now available in aerosol form to diagnose bronchial airway hyper-reactivity in patients without clinically-apparent asthma
o Only used when proper equipment and medication to treat acute respiratory distress are available
Metabolism: slowly metabolized by AChE (not pseudocholinesterases); longer duration of action than ACh
Muscarinic Antagonists:
Drugs for COPD (ie. emphysema and chronic bronchitis):
Ipratropium
Tiotropium
Ipratropium:
Structure
Administration
Action
Structure: quaternary amine analog of atropine
Administration: aerosol (acts locally on bronchial tissue)
- Some will be swallowed, but largely eliminated in the feces with little systemic distribution
Action: may not reduce mucociliary clearance (unlike other muscarinic antagonists)
Tiotropium
Structure
Action
Tiotropium:
Structure: quaternary amine analog of atropine
Action:
- Newer agent with longer half life than ipratropium
- Less agonist activity at M2 receptors than ipratropium (may be beneficial if it led to less block of feedback inhibition of ACh release)
- Like ipratropium, may not reduce mucociliary clearance
Secretory Glands:
- Muscarinic Agonists:
Pilocarpine
Cevimeline
Pilocarpine for Secretory Glands:
Structure:
Administration:
Action:
Use:
Structure: tertiary amine
Administration: orally administered and well absorbed from SI to act systemically
Action: distributes to all body compartments but has most prominent effects on salivation (increases) and sweating (increases- diaphoresis)
Use: alleviate xerostomia (dry mouth)
- In patients receiving radiotherapy for head and neck cancer
- In patients with Sjogren’s Syndrome (autoimmune salivary dysfunction)
Cevimeline:
Structure
Action
Use
Metabolism
Structure: synthetic tertiary amine
Action: direct acting muscarinic agonist with some selectivity for M1 and M3 receptors
Use: recently approved for xerostomia (dry mouth)
Metabolism: liver (CYP2D6 and CYP3A3/4)
Atropine use for secretory glands:
Former use
Side effects
Poisoning
Atropine: can block all increased secretory actions
Former Use: pre-anesthetic medication (eliminate increased secretions associated with irritant actions of early general anesthetics)
Side Effects: decreased secretions result in difficulty chewing and swallowing food
Poisoning: warm, dry, red skin due to reflex cutaneous vasodilation because of reduced sweating (reduced body heat loss)
