2013-09-05 Cholinergic Drugs + Glaucoma Flashcards
muscarinic vs. nicotinic overstimulation
Muscarinic DUMBBELSS Diarrhea Urination Miosis Bradycardia Bronchorrhea Emesis Lacrimation Salivation Sweating
Nicotinic: Think nicotine poisoning
—symp and para-symp but symp effect dominate
-tachy
-htn
-cold sweat
-n/v/d salivation and urinary incontinene
-syncope—>collapse—>flaccid paralysis via depolarization desensitization blockade
What are some examples of cholinergic poisons?
organophosphates; nicotine overdose
Describe the classification of direct-acting cholinergic drugs. Give examples of each category.
Non-specific: e.g. ACh and carbachol
Muscarinic: muscarine, methacholine, bethenachol, pilocarpine
Nicotinic: nicotine, varenicline
How are indirect cholinergic agonists classified?
Phosphodiesterase inhibitors:
—Short-acting: edrophonium
—Intermediate-acting: neostygmine, physostigmine
—Long-acting: echothiophate, parathion (insecticide), malathion (insecticide), sarin gas, soman gas,
Pre-synaptic-acting drugs: metoclopramide
Where are muscarinic receptors located? Nicotinic?
muscarinic: in brain, at all parasympathetic terminals, (including visceral organs, cardiac musc, and SMM); in symp system at sweat glands
nicotinic: at all sympathetic and parasymp ganglia; synapse at adrenal medulla and at SKM
Where do cholinergic drugs primarily have their effect?
effector tissues and endothelium; maybe some to NMJ, ganglia; hard for quarternary amines to cross the BBB b/c of their + charge
Where are cholinesterases located?
in plasma: pseudocholinesterase
—we’re not sure why we have this; some folks born w/o are plasma AChE are fine unless challenged by cholinergic drugs
in RBCs: AChE
in at all cholinergic junctions: AChE
How does muscarinic activation cause hypotension?
non-inervated receptors (M3, M5) in the endothelium upregulate eNOS —> more NO —> guanalyate cylase —> incr cGMP —> vSMM relaxation
Why do you get brady w/ muscarinic overstim?
paradoxical brady: relaxation of vSMM leads to hypotension; carotid baroreceptor reflex ineffective b/c of cholinergic (i.e. parasympathetic) stimulation of SA node slowing conduction preventing compensatory increase in HR and CO
Methacholine
methylated ACh therefore less readily absorbed via GI
—methacholine challenge —> stimulate bronchoconstriction; pts who are hypersensitive have a positive test (dx = asthma)
Bethanechol
used to be used for GI dysmotility (e.g. post-surgical ileus)
—now we use metoclopromide
How do nicotinic receptors work?
ligand-gate Na+/K+ channels: when stimulated [more] Na+ flows in and [less] K+ flows out —> depolarizes cells —> generates AP
Mechanism of nicotine addiction?
nictonic receptors in nucelus accumbens and prefrontal cortex trigger mesolimbic dopamine release
—pt generates an addiction to the incr [dopa]; when [dopa] falls you get cravings
Varenicline
- -class
- -PD
- -PK
- -Toxicity
- -Interactions
- -Special considerations
Partial agonist – has stimulatory properties but does not have a full-blown stimulation; lessens massive dopamine swings while blocking nicotine receptors from being activated by
- Drug class: Very selective and potent competative partial agonist of α2-β4 nicotinic receptors, for smoking cessation
- Pharmacodynamics: CNS mesolimbic dopamine, partial α4-β2 stimulation prevents low dopamine and cravings; also prevents nicotine from creating dopamine surges, No chemical reward
- Pharmacokinetics: well absorbed; peak 4 h, t1/2 = 24 h; excreted primarily in urine as unchanged drug
- Toxicity: N/A
- Interactions: No direct interactions identified
- Special considerations: Reports of suicidal thoughts and aggressive and erratic behavior → patients and caregivers should be instructed about the importance of monitoring for neuropsychiatric symptoms, and to communicate immediately with the prescriber the emergence of agitation, depression, unusual changes in behavior, or suicidality. Psychiatric patients – use extreme caution. Contraindicated in pregnancy/lactation. Causes drowsiness, caution operating machinery
- Indications and dose/route: 1 mg PO BID for healthy adults, 0.5 mg PO BID for renal impairment CrCl < 50 ml/min
- Monitor: neuropsychiatric symptoms
Effects of AChE inhibitor poisoning?
true cholinergic crisis (not just muscarinic)
—biggest worry is respiratory compromise
—>nicotinic: depolarization desensitization blockade (diaphragmatic paralysis)
—>muscarinic: incr bronchorrhea and bronchoconstriction
—>CNS: central respiratory arrest
Varenicline
- -class
- -PD
- -PK
- -Toxicity
- -Interactions
- -Special considerations
- -indications
- -What should you monitor?
Partial agonist – has stimulatory properties but does not have a full-blown stimulation; lessens massive dopamine swings while blocking nicotine receptors from being activated by
- Drug class: Very selective and potent competative partial agonist of α2-β4 nicotinic receptors, for smoking cessation
- Pharmacodynamics: CNS mesolimbic dopamine, partial α4-β2 stimulation prevents low dopamine and cravings; also prevents nicotine from creating dopamine surges, No chemical reward
- Pharmacokinetics: well absorbed; peak 4 h, t1/2 = 24 h; excreted primarily in urine as unchanged drug
- Toxicity: N/A
- Interactions: No direct interactions identified
- Special considerations: Reports of suicidal thoughts and aggressive and erratic behavior → patients and caregivers should be instructed about the importance of monitoring for neuropsychiatric symptoms, and to communicate immediately with the prescriber the emergence of agitation, depression, unusual changes in behavior, or suicidality. Psychiatric patients – use extreme caution. Contraindicated in pregnancy/lactation. Causes drowsiness, caution operating machinery
- Indications and dose/route: 1 mg PO BID for healthy adults, 0.5 mg PO BID for renal impairment CrCl < 50 ml/min
- Monitor: neuropsychiatric symptoms
basics of AChE biochemistry
has anionic site the binds the cationic quarternary amine
has site that catalyzes lysis of the ester bond between choline and acetate
pilocarpine
see rang
edrophonium
see rang
Neostygmine (vs. physostigmine)
see rang
Why is tx w/ neostigmine an “exercise in brinksmanship”? How do you dx side effects of incorrect dose?
too litte: MG crisis
too much: cholinergic crisis
use edrophonium to distinguish
How do organophosphates act?
AChE inhibitors, can take hours to be hydrolyzed
echothiophate
see rang
parathion vs. malathion
malathion is “mammal-friendly” as in it could be tx’ed
classification of sarin and soman gas?
long-acting AChE inhibitors
Major effects of organophosphate poisoning?
DUMBELSS/SLUDGE S - salivation L - lacrimation U - urination D - defecation G - GI dysmotility E - emesis
Tx of organophosphate poisoning
atropine: blocks mAChR
pralidoxime (2-PAM): helps to reactivate de-activated AChE’s; contraindicated with carbamate poisoning (e.g. neostigmine) b/c it is also competitive inhibitor of AChE
What are the major differences of the cholinergic receptor subtypes?
Nicotinic: ligand-gated, pentameric Na+/K+ channels
- two main types: Nn (nerve) and Nm (muscle)
- 10 alpha subunits
- 4 beta
- 1 gamma
- 1 sigma
Muscarinic: all GPCR M3 —> most cells M1 —> gastric parietal cells M2 —> heart M4&5 —> CNS (odd ones are [Gq] queer overstim phospholipase C —> incr Ca2+; evens are Gi —> inhib adenyl cylase —> activates K+ channels)
Atropine
see rang
scopolamine
see rang
atropine-related for GI
dicyclomine: M3-selective competitive antagonist for IBS and minor diarrhea
atropine-related for overactive bladder
oxybutynin
atropine-related for midriasis
short-acting for fundoscopic exam: tropicamide
long-acting for post ophthalmic surg: atropine, homatropine
Ipratropium
see rang
depolarizing NMJ blockade drug; side effect to watch for
succinylcholine
used in anesthesia by causing paradoxical flaccid paralysis that is practically irreversible
can cause hyperkalemia
malignant hyperthermia is pts w/ mutation in ryanodine receptor —>excess intracellular Ca2+ —>SKM activation decr pO2 incr pCO2 acidosis
Which is the prototypical non-depolarizing nicotinic blocker?
d-Tubocurarine is a reversible competitive inhibitor with a quartenary amine (vs. tertiary in succinylcholine) therefore no CNS penetration; this means pt is fully awake w/ sensorium in tact while paralyzed
How do you reverse paralysis in depolarizing vs. non-depolarizing nicotinic blockades?
w/ non-depolarizing (e.g. d-tubocurarine derivatives) give neostigmine b/c it incr bioavailablity of ACh which allows it to overcome the competitive inhibition of the curare
w/ de-polarizing (e.g. succinylcholine) you just have to wait it out
What are the subclasses of non-depolarizing nicotinic blockers? By what route are they cleared?
PROTOTYPE: d-tubocurarine
AMINOSTEROIDS: pancuronium [renal], rocuronium [hepatic], vercuronium [hepatic]
BENZYLISOQUINOLONES: cisatracurium [plasma AChE], d-tubocurarine
What’s an example of an N_n blocker? Uses?
Ganglionic (Nn) blocker = trimethaphan; charged so only ganglionic effects (1°ly sympathetic)
only used for HTN crisis or dissecting aortic aneurysm etc.
vercuronium
see Rang Card 1.05
What is the most toxic molecule known? How does it work?
botulinum toxin
blocks the release of ACh by cleaving SNARE proteins required for vesicle fusion with the plasma membrane at the NMJ and causes atropine effects at muscarinic receptors
tx: wrinkles, strabismus, hyperhydrosis
Open-angle vs. closed-angle glaucoma? Tx mechanism for each?
Open angle-glaucoma—> 90% of cases; “silent theft of sight”, due to either overproduction of aqueous humor or inhibited flow through trabecular meshwork; tx w/ pilocarpine which will stimulate M3 receptors on ciliary muscle increasing traction on trabecular meshwork leading to more room for the fluid
Close-angle glaucoma: 10% of cases; more acute presentation; causes by narrowing of angle between pupil/iris and cornea; tx w/ pilocarpine which stimulates M3 receptors in pupil sphincter cells (“thins the iris”)
What are sympathetic activities on the eye? Via what receptor?
Causes dilation (mydriasis) and allows for far vision
alpha1: relaxes iris radial muscle (the outer of the radial and circular muscles)
beta2: relaxes ciliary muscle
What are parasympathetic actions on the eye? Via what receptors?
miosis (pupil constriction) via M3 receptors on:
a) circular iris muscle (inner)
b) ciliary muscle
