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
