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)
Nicotine:
Absorption
Action
Structure: lipid-soluble tertiary amine (alkaloid from a plant)
Absorption: rapidly absorbed from the mouth and respiratory tract and distributed throughout the body, including the CNS
- Crosses placenta and secreted in milk
Action: agonist at all nicotinic receptors in CNS and PNS
- Prolonged action can lead to conversion from activation to depolarizing blockade (esp. during acute toxicity)
- Highly addictive
- Likely that chronic nicotine toxicity contributes to long-term adverse effects of tobacco use
Acute Nicotine Poisoning:
Most common in:
Symptoms: (3)
Most common in children
Symptoms:
- Intense autonomic stimulation through the ganglia
- CNS excitation with convulsions followed by CNS depression
- Eventual skeletal muscle paralysis from excessive stimulation (depolarization blockade)
Nicotine uses:
Pharmacological:
Treat nicotine withdrawal symptoms in those attempting to stop using tobacco (chewing gum, transdermal patch, inhaler, nasal spray)
Some evidence for improved cognition in AD and reduced incidence of Parkinson’s
Other: Domestic insecticide (Black Lead 40)
Varenicline:
Structure Action Use Metabolism Side effects
Structure: tertiary amine
Action: partial nicotinic receptor agonist (first approved)
Use: smoking cessation (reduces pleasurable effects and cravings for tobacco)
Metabolism: minimal (mostly eliminated in the urine)
Side Effects: possible negative neuropsychiatric effects (increased risk of suicide)
Nicotinic Blocking Agents at NMJ:
General:
Use:
Almost all skeletal muscle relaxants are used as adjuncts to general anesthesia to control skeletal muscle relaxation
Suppress endogenous breathing movements
- During mechanical ventilation
- During electroconvulsive therapy
- To facilitate intubation during endoscopy
Two Major Classifications of skeletal muscle blocking drugs
Nicotinic blocking agents at NMJ
Competitive Antagonists: D-tubocurarine* Cistracurium Pancuronium Vecuronium Rocuronium
Depolarizing Blockers (Agonists): Succinylcholine
Competitive Blocking Agents (Non-Depolarizing Blockade):
General Action:
General Action: competitive antagonists of AChRs on the motor endplate
- Reduce the number of available AChRs for physiologically released ACh
- RMP remains near resting levels and is less responsive to nerve released ACh (response dressped in both duration and amplitude as more receptors blocked)
Competitive blocking agents
Reversible and competitive with ACh
Increased ACh:
AChE inhibitors:
Reversible and Competitive with ACh: increasing the amount of ACh in synaptic cleft can reverse block
Administration of AChE inhibitors (neostigmine or edrophonium)
- Often used to reverse action of persistent or prolonged effects of competitive blockers in posteroperative patients (may be preceded with atropine to block unwanted muscarinic effects)
Tetanic stimulation of motor nerves
Competitive blocking agents used: (5)
D-Tubocurarine Cisatracurium Pancuronium Vercuronium Rocuronium
D-Tubocurarine:
Structure Action Metabolism Excretion Use
Structure: naturally occurring alkaloid; quaternary amine (also has a tertiary amine)
Action: effects typically last for hours
Metabolism: some is metabolized (~60%)
Excretion: 40% excreted unchanged by the kidney
Use: not often used anymore (hard to get due to shortage of raw materials)
D-Tubocurarine:
Side effects:
Side Effects:
- Rapid and transient drop in blood pressure (occurring shortly after administration and recovers gradually in ~10 minutes)
- Autonomic ganglionic blockade (reduces SS tone to vascular system)
- Direct stimulation of release of histamine from mast cells (decreases vascular resistance)
- May also cause other side effects (ie. increased salivation or bronchial secretions)
- Can precipitate asthmatic-like action in patients with asthma or allergies
Cisatracurium (Curariform Agent):
Action
Metabolism/Excretion
Laudanosine
- How to reduce production of this breakdown product?
Structure: synthetic quaternary amine (potent isomer of atracurium)
Action: competitive antagonist with only mild hypotensive actions (via histamine release)
Metabolism/Excretion: spontaneously inactivated in the plasma (instability at plasma pH)
- Short half-life (20 minutes) leading to intermediated duration of action
- Safe in hepatic and renal failure because not dependent on either for xcretion
Laudanosine: possibly toxic lipid soluble breakdown product that can cross the BBB and cause seizures (rare)
- Replacement of atracurium with cisatricurium allows for lower doses to be used and therefore less production of this breakdown product
2 other curariform agents:
Other Curariform Agents: no longer produced in the US
Doxcurarium: particularly selective action at NMJ with long duration of action
Mivacrium: had the shortest duration of action of all non-depolarizing agents
Pancuronium
Structure
Action
Use
Elimination
Pancuronium:
Structure: steroid based quaternary amine (2 quaternary amines in molecule)
Action: competitive antagonist with long duration of action
- Also blocks cardiac M2 receptors (produces tachycardia)
Use:
- Skeletal muscle relaxation for surgery
- ICU (prolonged use may lead to persistent weakness)
- In combination for lethal injection
Elimination: kidneys
Vercuronium:
Structure
Action
Elimination
Vercuronium:
Structure: steroid based quaternary amine (2nd quaternary amine replaced with tertiary)
Action:
- Selective for NMJ and therefore has little effect on CV system
- No action at cardiac muscarinic receptors
- No tendency to release histamine
- Intermediate duration of action (~30 minutes)
Elimination: eliminated mostly unchanged
- Mostly by the liver in bile (85%)
- Kidney (remaining 15%)
Rocuronium:
Structure Action Use Elimination Side effects
Rocuronium:
Structure: steroid based quaternary amine
Action: fastest onset of action of all competitive non-depolarizing antagonists
- Minimal CV effects
Use:
- Rapid-sequence intubation (as an alternative to SuCh- but has a longer duration of action)
- Low dose given prior to SuCh to prevent fasciculations (pre-curarization)
Elimination: liver (biliary excretion)
Side Effects: rare allergic reactions
The Competitive Neuromuscular Blocking Agents are Potentiated By: (6)
o Some general anesthetics: dosage levels therefore have to be appropriated reduced when employed in conjunction with them
- Halothane
- Methoxyflurane
- Enflurane
o Aminoglycosides: streptomycin, neomycin, gentamicin, kanamycin
o Electrolyte imbalances: for example, high Mg++
o Polypeptide Abx:
- Polymixins
- Colistin
- Lincomycin
o Advanced Age: reduced hepatic and renal clearance (and other factors)
o Certain pathologies: for example, myasthenia gravis
Pathologies Causing Relative Resistance to Paralysis by Competitive NM Blockers:
Mechanism:
Up-regulation of AChRs at the NMJ
- Severe burns
- Upper motor neuron disease or spinal injuries
Depolarizing blocking agent: succinylcholine
Mechanism
Action
Mechanism: primarily an agonist at the NMJ, but also has some agonist activity at most ACh receptors
Action:
o Very rapid onset (less than 1 minute)
o Short duration (only 5 minutes) due to metabolism in the plasma by pseduocholinesterases (NOT by AChE at motor endplate)
Depolarizing blocking agent: succinylcholine
Effects:
Effects on BP
Effects of release of K into blood:
Contraindicated:
Effects:
Liberates detectable levels of histamine (however, no prominent blood pressure changes due to simultaneous effect of mild ganglionic stimulation)
Ganglionic stimulation (mild bradycardia and increased peripheral resistance)
Significant release of K+ in the blood (from depolarized muscle tissue)
- Can lead to cardiac arrest
- Especially concerning in certain patients:
- Those with burns, trauma, NM disorders
- Those being treated for congestive heart failure with diuretics or digitalis
- Those with renal failure
Generally contraindicated in kids due to reports of cardiac arrest
- Should only be used in emergency situations (when intubation is immediately necessary)
Metabolism by Pseudocholinesterases:
Reaction
Genetic polymorphisms
Reaction: SuCh ==> Succinlymonocholine ==> Succinic acid + choline
Genetic Polymorphisms:
~4% of the population heterozygous for atypical plasma cholinesterases and will degrade SuCh much more slowly
- Smaller percentage homozygous, and will not degrade it at all (renal excretion becomes the only route of termination of drug action)
- Can increased biodegradation by administering plasma containing normal cholinesterases
Phases of depolarizing blockade
Phase I: Onset and Cause
Opens what?
When RMP rises above the threshold:
NM blockade results at:
o Phase I Blockade:
Onset: occurs within seconds following IV administration
Cause: due to gradual depolarization of motor end plate
Opens ion channels for Na+ and K+ (same as ACh), however distribution of SuCh to synapse is slower and RMP is therefore gradually decreased
When RMP has risen above threshold, release of ACh cannot generate enough of a potential change to excite the adjacent sarcolemma
NM blockade results at the level of the depolarized motor end plate
Phases of depolarizing blockade
Phase I: Pharmalogical antagonist
No pharmalogical antagonist: overdose can only be treated by manually supporting breathing (PPV) until the effects have diminished
- Giving AChE inhibitors would further reduce RMP and intensify blockade
- Stimulation of motor nerves results in a further decrease in potential difference, intensifying blockade
Phases of depolarizing blockade
Phase I: Uses
When is SuCh employed?
Initial use is usually followed by:
What is the consequence of only using it once?
Use: SuCh generally employed only once during induction of anesthesia
Immediately after patient has been anesthetized to relax laryngeal muscles and facilitate intubation (allows for facilitation of respiratory support and administration of gaseous general anesthesia)
Initial use is usually followed by a longer-acting competitive agonist like cistatracurium for the duration for the surgical procedure
Therefore, because it is generally only used once, patients typically only experience a Phase I blockade
Phase I Blockade and Fasciculations:
Observed where?
What happens to individual fibers?
When may this result in muscle soreness?
How can it be pretreated?
Most often observed in upper thorax, neck and limbs (muscles receiving rich blood supply most susceptible)
Individual muscle fibers may contract one time as depolarization passes threshold; asynchronous and therefore no contraction occurs
May result in muscle soreness postoperatively
Can be pretreated with a low-dose of a non-depolarizing agent (rocuronium), but this results in the need for higher doses of SuCh
Phase II Blockade:
Onset:
Gradual change of blockade occurs:
What happens to the motor endplate?
What does it resemble?
Mechanism
Associated with:
Onset: only occurs when SuCh administered by continuous IV drip or at frequent intervals for protracted period of time (ie. longer than 20 minutes)
Gradual change of blockade occurs:
Motor endplate eventually repolarizes, but transmission failure still present
Resembles competitive antagonism because tetanic stimulation of motor nerve will result in weak muscular contractions
Mechanism unclear
o May be due to block of channel pore by drug
o May be due to accumulation of succinylmonocholine (metabolite of SuCh) which may act as a competitive antagonist
Associated with a mixed blockade/dual blockade
o Not all endplates reach phase II simultaneously
Phase II Blockade:
Partial reversal
Discontinuation can be associated with:
Can be partially reversed: with used of AChE inhibitors (edrophonium and neostigmine)
Discontinuation during phase II blockade: can be associated with slow/prolonged postoperative recovery of muscle tone and slow restoration of respiratory depth
How is transdermal stimulation of nerves of the hand used?
TOF ratio:
Double Burst:
Post-tetanic potentiation
o Using transdermal stimulation of nerves of the hand and recording of evoked twitches: allows for timing of tracheal intubation and extubation of the patient; each type of block will have different results for the following test
TOF Ratio:
- 4 stimuli applied at 2 Hz
- TOF-R= strength of 4th contraction/strength of 1st reaction
Double Burst:
3 stimuli at 50 Hz, 700ms rest, repeat
Posttetanic Potentiation:
- Several seconds of 50Hz stimulation, several seconds of rest, single slow rate stimulus (0.5 Hz)
- Posttetanic count (PTC)= number of detectable post-tetanic twitches
All skeletal muscle relaxants are:
Must be administered:
Cross BBB?
What are the analgesic effects?
quaternary amines
must be administered parenterally
Don’t cross BBB or placenta
No analgesic effects: must only be used in pts who are well anesthetized
Some degree of selectivity with regards to skeletal muscle groups:
Most sensitive muscles (in order, starting with most sensitive):
Digits Neck and limbs Abdominal muscles Thoracic muscles Diaphragm (most resistant)
Note: in standard paralytic doses, respiratory muscles affected to a small degree and some PPV is required to prevent hypoxia and hypercapnia
d-Tubocurarine
Drug Duration of Action
Elimination
Histamine Release
Other Effects
Long
Kidney (40%)
+++
Weak ganglionic blockade
Cistracurium
Drug Duration of Action
Elimination
Histamine Release
Other Effects
Intermediate
Spontaneous breakdown
+
Laudanosine may excite CNS (seizures)
Pancuronium
Drug Duration of Action
Elimination
Histamine Release
Other Effects
Long
Kidney (70%)
No
Vagolytic –> tachycardia
Rocuronium
Drug Duration of Action
Elimination
Histamine Release
Other Effects
Intermediate (fast onset)
Liver/bile (85%) Kidney (15%)
No
Not significant
Vecuronium
Drug Duration of Action
Elimination
Histamine Release
Other Effects
Intermediate
Liver/bile (80%)
No
Not significant
SuCh
Drug Duration of Action
Elimination
Histamine Release
Other Effects
Very short (fast onset)
PseudoChE
+
Weak agonist at most other AChRs, Hyperkalemia
