Anticholinergics (LJ Chp 8) Flashcards
Why use anticholinergics
- Treat +/- prevent ax/preax bradycardia
- Decrease airway/salivary secretions
- Dilate pupil
- Block vagally-mediated reflexes (viscerovagal, oculocardiac, Branham)
- Block effects of parasympathomimetic drugs
Why historically used as part of standard premed protocol
- Inhalant anesthetics (eg diethyl ether) produced profound parasympathetic effects –> hypersalivation, bradycardia
- Used consistently preop to counter effects
- Modern inhalants have lesser effects on the autonomic NS –> indiscriminate use of anticholinergic drugs less popular
Plants that contain naturally-occurring tropane alkaloids (atropine, hyoscyamine, scopolamine)
Deadly nightshade - Atropa belladonna
Henbane - Hyoscyamus niger
Mandrake - Mandragora officilianis
–> plants contain concentrations that are potentially toxic to most species
–> extracts from these plants have been used since ancient times for their anesthetic, mydriatic, antidiarrheal, analgesic properties
When and from what was atropine isolated?
1830s
Deadly nightshade/Atropa belladonna
When and from what was hyoscine isolated?
1880s
Henbane/Hyoscyamus niger
General pharmacology of Anticholinergics
Competitively antagonize ACh at postganglionic muscarinic cholinergic R in the PNS
–Use of “antimuscarinics” to differentiate drugs that only act as antagonists @ muscarinic R from some naturally occurring compounds that can non-specifically antag both muscarinic and nicotinic ACh R
Muscarinic R
5 subtypes –> M1-M5 (based on order in which cloned)
Mechanism of Muscarinic R
Intracellular signaling by activation of different subtypes occurs via coupling to multiple G proteins
–Single receptor subtypes capable of activating more than 1 GPCR in the same cell
Tissue-specific anatomic distribution/physiological response
M1, M3, M5 R
Couple with Gq/11-type proteins
M2, M4 R
Couple with Gi/o-type proteins
Which muscarinic R couple with Gq/11-type proteins?
M1, M3, M5
Which muscarinic R couple with Gi/o-type proteins?
M2, M4
T/F: atropine and glycolic are relatively unselective in binding to muscarinic R types
True!
Different tissues types have different responses to clinically administered doses of these drugs
T/F: receptors in the salivary, cardiac, and bronchial tissues more sensitive than those in the urinary and GIT
True
Which anticholinergic has greater antisialagogue effects?
Glyco > atropine
Which anticholinergic has greater HR increase?
Atropine > glycolic
Which anticholinergic has greater smooth muscle relaxation?
Atropine = glyco
Which anticholinergic has greater ophthalmic effects/pupil dilation?
Atropine
Glyco doesn’t affect ocular tissue
Location of M1
CNS, Stomach
Location of M2
Lungs, Heart (SA/AV node, atrial myocardium)
Location of M3
CNS, Salivary glands, airway SM; also vascular endothelium
Location of M4
CNS, Heart
Location of M5
CNS
Effect of binding to M1
CNS –> neuron depolarization
Stomach –> H+ secretion
Effect of binding to M2
Lungs –> bronchoconstriction
SA/AV nodes –> bradycardia, AV block
Atrial myocardium –> decreased inotrophy
Effect of binding to M3
CNS –> ?
Salivary glands –> salivation
Airway SM –> BC, increased secretions
Vascular endothelium –> VD
Effect of binding to M4
UNK
Effect of binding to M5
UNK
Other roles of M1, M2, M3 receptors?
Cause actions via non-G protein mechanisms such as protein kinase
What are the two anticholinergics used in veterinary medicine?
- Atropine
- Glycopyrrolate
Relatively unselected in their binding to receptor subtypes
Cellular response at the M1
PLC activated
Increased IP3, DAG. Ca2+, PKC, cAMP
Cellular response at the M2
PLC activated, increased/decreased adenylyl cyclase
Cellular response at the M3
PLC activated
Increased IP3, DAG, Ca2+
Increased NO
Cellular response at the M4
Decreased adenylyl cyclase
Cellular response at the M5
PLC activated
Increased IP3, DAG, Ca2+
Decreased PKA, cAMP
AC
adenylyl cyclase
DAG
Diacylglycerol
IP3
Inositol triphosphate
PKC
Protein kinase C
PKA
Protein kinase A
PLC
Phospholipase C
Anticholinergic effects in the heart
-Mediateed by pre/post synaptic M2 receptors located in the SA, AV nodes; atrial myocardium
Cardiac effects of systemic anticholinergic drug administration
- Increase in sinus rate
- Acceleration of AV nodal conduction
- Increased atrial contractility
Downside of increased HR with anticholinergic administration
Tachycardia/tachydysrhythmias - may be unwanted, particularly if changes result in decreased CO or significantly increased myocardial oxygen consumption,
Contraindications for anticholinergic use
- Hypertrophic CM
- Restrictive CM
Mechanism of a paradoxical bradycardia following atropine administration
- DT more rapid blockade of presynaptic M1 R that inhibits negative feedback mechanism –> transient increase in ACh release, further slowing HR
- Wait few minutes or repeat dose –> induction of blockade of postsynaptic M2 receptors –> increased HR
Anticholinergic administration effects: bronchodilator, reduced airway secretions
- via M2, M3 R antagonism
- Can decrease airway resistance, likelihood of airway obstruction
- Can contribute to hypoventilation –> theoretically decreased arterial oxygen tension as a result of increased anatomic dead space
Effect of anticholinergic administration on reduction of airway secretions
Viscosity of the airway secretions increases as the volume is decreased following an anticholinergic administration –> potentially offsets any benefit with respect to reducing airway secretions
Ophthalmic Effects
- Cholinergic fibers originating from CN III innervate circular m (sphincter papillae) of the iris that control pupil diameter
- Also ciliary m that controls shape of lens, facilitating accommodation
- Topical administration to cornea blocks actions of ACh at both of these sites –> mydriasis, cyclopegia
- Atropine in cats, horses, sheep, goats; glyco in rabbits
Effects on IOP
- Acutely increase caused by drainage angle closure in cats (not in sheep, horses)
- Mixed findings –> ROA avoided in patients with preexisting elevations of IOP or those predisposed to developing angle-closure glaucoma
Ranking ocular effects (when administered systemically)
Scopolamine > atropine > glycopyrrolate
T/F: the potential to induce mydriatic, cyclopegia effects with systemic (ie either IV or IM) administration of anticholinergics is lower than with topical administration
True
Probably also dose and drug dependent
Negative ophthalmic effects of anticholinergic administration
-Decreased tear production –> corneal drying
Effect of systemic anticholinergic administration on patients with glaucoma
-Few data for any species to suggest that systemic administration of atropine or glycopyrrolate at clinically relevant doses for treatment of reflex or drug-induced bradycardia would cause adverse effects in patients with glaucoma
Which anticholinergics that cross BBB?
Atropine
Scopolamine
Effects of anticholinergics that cross the BBB
- Potential to induce sedation, prolong anesthetic recovery when administered systemically via M1 R antagonism
- Atropine: sedative potential when clinically relevant doses administered is negligible
Anticholinergics (M3) as Effective Antisialogogues
- Effective antisialogogues in monogastrics
- Ruminants: salivation is not inhibited completely –> saliva becomes more viscous to the point where thickened, ropy saliva may post a risk of causing airway obstruction
- Routine use not recommended in ruminants except for treating intraoperative bradycardia
Anticholinergics and GI Ileus
- Dose required to decrease GI motility via blockade of M3 R higher than that required to treat bradycardia
- Some risk of GI ileus following administration
- May lead of symptoms of colic in horses –> avoided except in instances of bradycardia
Effects of anticholinergics in monogastrics
-Decrease lower esophageal sphincter function –> increased risk GER +/- associated complications (asp pneumonia, esophagitis, esophageal stricture
Atropine
-Racemic mixture L/D-hyoscyamide
Which isomer of atropine is responsible for its activity?
L-isomer
Atropine Structure
Lipid-soluble tertiary amine structure
Tropic-acid ester linked to organic base
Easily crosses BBB, blood-placental barrier
Atropine Onset: IV
1min
Atropine Onset: IM
5min
How long does atropines increase in HR last?
Increase in HR should last approximately 30min
How long does atropine’s effects on other systems last?
generally affected for one to several hours
Mydriasis after topical administration can last for up to several hours
Atropine Metabolism
- Varies btw species
- Rapidly cleared from the central compartment via hydrolysis to inactive metabolites
- Some excreted unchanged by kidneys in dogs and people
Atropine in Rabbits
- Normally eat leaves of deadly nightshade without issue –> have ability to metabolize atropine-like compounds rapidly via plasma esterase (atropinase)
- May render typical clinical doses ineffective
- Large amt of enzyme not possessed by all rabbits so full MOA yet to be elucidated
Atropine metabolism in cats
Hepatic and renal esterases contribute to clearance from plasma
Atropine Clinical Use
- Prevent/treat bradycardia associated with ax
- IM, IV preferred over SQ to maximize absorption, minimize onset time
Atropine Dose: Dogs, Cats
0.02-0.04mgkg
Atropine Dose: Horses
0.02-0.04mgkg
Atropine Dose: Ruminants
0.04-0.08mgkg
Atropine Dose: Pigs
0.04-0.08mgkg
Glyco Dose: Dogs, Cats
0.005-0.01mgkg
Glyco Dose: Horses
0.0025-0.005
Glyco Dose: Ruminants
0.0025-0.005
Glyco Dose: Pigs
0.0025-0.005
Other Clinical Uses: Atropine
- Reversal from NMB prior to administration of cholinergic drugs (neostigmine, edrophonium)
- CPR - if no IV access, can be administered via ETT @ 2-3x IV doses
Atropine Effects: Dose-Dependent Tachycardia
- Mean dose required to increase HR by 50% in conscious dogs ~0.04mgkg IV
- Greater increases in HR may be observed in patients with high pre-existing vagal tone –> “excess tachycardia”
- Occasionally see VPCs but not necessarily proportional to the magnitude of the tachycardia
- Transient tachycardia generally well-tolerated in most patient populations
Atropine’s Tachycardia: Which subset of patients to use with caution?
-Those which may be adversely impacted by tachycardia ie restrictive/hypertrophic forms of cardiomyopathy
What are the two parasympathomimetic effects that often occur with lower doses of atropine?
- Transient bradycardia
2. Second-degree AV block
MOA of Parasympathomimetic Effects of Atropine Administration
- Initial blockade of of presynaptic peripheral M1 receptors that normally inhibit ACh release
- Causes transient increase in ACh prior to onset of atropine-induced postsynpatic M2 blockade
- Resulting bradycardia +/- AV block typically resolves spontaneously with establishment of postsynaptic blockade or upon administration of a supplemental dose
Glycopyrrolate Structure
- Synthetic quaternary ammonium
- Poorly lipid soluble –> difficult to cross BBB, placental-blood barrier.
- Mandelic acid ester linked to organic base
- 4x potency of atropine
Glycopyrrolate Duration of Action
- Onset of action slightly slower compared to atropine –> usually occurs within several minutes
- In conscious dogs CV effects lasted for approximately 1hr –> longer than those for atropine
Glycopyrrolate Metabolism
- Cleared from plasma relatively rapidly
- Excreted unchanged in the urine
Ocular Effects of Topical Glycopyrrolate
Rabbits: persistant mydriasis, cycloplegia
Systemic administration in dogs of clinically relevant doses reported to have minimal effects on ocular parameters
Why is glycopyrrolate preferred in people over atropine?
- People: improved CV parameters with less risk of tachycardia
- Not the case in dogs: drug effects on CV system similar btw the two anticholinergics
Effect of Glyco on GI Motility
- motility decreased for up to 30min in dogs
- Duration of decreased motility was dose-dependent, lasting for over 6hr following 0.005mgkg IV dose
- Development of postop colic in horses is multifactorial - in one study, only 1/17 horses that received glyco colicked after surgery
Clinical use of glyco
- Tx/prevent bradycardia in perioperative period
- Used to counteract cholinergic effects when reversing NMBA with cholinergic drug
- Not used as emergency drug in CPR DT longer onset times
Are anticholinergics water-soluble or fat-soluble?
Water Soluble
Historical use(s) of anticholinergics
- Premixed premed combos in SA ax –> “BAG” (butor, Acepromazine, glyco), “superBAG” (buprenorphine, ace, glyco)
- Often selected to counteract bradycardia associated with a2 agonists
Use of anticholingerics to treat bradycardia
-Important to determine whether bradycardia is a baroreceptor-response to increased arterial BP secondary to peripheral VC or due to centrally mediated suppression of sympathetic output with accompanying low BP
Consequences of increasing HR in face of increased ABP
Has the potential to decrease CO further while significantly increasing myocardial oxygen consumption
T/F: minimal improvement in CO when dogs sedated with dexmed + atropine vs dexmed alone
True
Use of an anticholinergic following a2
- If ABP is low, admin of anticholinergic may be considered to counter bradycardia and improve BP
- If bradycardia is actually secondary to decreased sympathetic nervous system activity, antagonism of PS influence on the sinus node may not cause improvement in HR
- In those cases, administration of sympathomimetic agent (ie ephedrine) or reversal of alpha 2 may be beneficial
