Term
| what kind of drug is Ach? |
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Definition
|
|
Term
| what kind of drug is muscarine? |
|
Definition
|
|
Term
| what kind of drug is methacholine? |
|
Definition
|
|
Term
| what kind of drug is carbachol? |
|
Definition
| muscarinic and nicotinic agonist |
|
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Term
| what kind of drug is bethanechol? |
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Definition
|
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Term
| what kind of drug is pilocarpine? |
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Definition
|
|
Term
| what kind of drug is nicotine? |
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Definition
|
|
Term
| what kind of drug is physostigmine? |
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Definition
|
|
Term
| what kind of drug is neostigmine? |
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Definition
|
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Term
| what kind of drug is edrophonium? |
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Definition
|
|
Term
| what kind of drug is isoflurophate? |
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Definition
|
|
Term
| what kind of drug is echothiophate? |
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Definition
|
|
Term
| what kind of drug is sarin? |
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Definition
|
|
Term
| what kind of drug is soman? |
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Definition
|
|
Term
| what kind of drug is malathion? |
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Definition
|
|
Term
| what kind of drug is parathion? |
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Definition
|
|
Term
| what kind of drug is pralidoxime? |
|
Definition
| cholinesterase reactivator |
|
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Term
| what is another name for direct cholinergic agents? |
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Definition
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Term
| what is the response of vascular SM to direct cholinergic agents? |
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Definition
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Term
| endothelial cells have what receptors? |
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Definition
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Term
| how do direct cholingergic agents cause vasodilation? |
|
Definition
| M1 or M3 receptors - increase cytosolic Ca - produce NO - dilate BV |
|
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Term
| what layer of BV are the free nerve endings of the SNS? |
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Definition
|
|
Term
| how does the SNS vasoconstrict? |
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Definition
| nerve ending in the adventitia release NE, NE diffuses through the SM, acts on a1 receptor - cause constriction |
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|
Term
|
Definition
short; 2 min
due to plasma cholinesterases |
|
|
Term
| amount of Ach circulating |
|
Definition
high
can sometimes hit receptors and cause a signal |
|
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Term
| effect of Ach on M1 or M3 receptor? |
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Definition
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|
Term
| effect of Ach on M2 receptor |
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Definition
|
|
Term
| receptor types for Ach on endothelium? |
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Definition
| M1 and M3 - increase Ca - cause endothelium to release NO and prostocyclin (vasodilators and anticoagulation agents) |
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|
Term
| a1 receptor effect on arteries |
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Definition
|
|
Term
| effect of Ach release directly onto vascular SM? |
|
Definition
constriction b/c SM cell has M3 receptor and Ca goes up
normally there is no PSNS innervation on vascular SM (only on endothelial cells) - so this would have to be experimental |
|
|
Term
| how does the PSNS cause vasodilation? |
|
Definition
doesn't directly end on vascular SM
impact BV b/c Ach spills over into the blood and causes vasodilation |
|
|
Term
| serious side effects of direct cholinergic agents? |
|
Definition
hypotension - M3, endothelium
bradycardia - M2, heart
bronchial constriction - M3, SM
exacerbation of peptic ulcer - M3, parietal cells |
|
|
Term
| common side effects of direct cholinergic agents? |
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Definition
SLUDS
salivation, lacrimation, urination, defecation, sweating
all M3 responses |
|
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Term
| direct cholinergic agent, NT |
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Definition
|
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Term
|
Definition
| nicotinic (ligand gated) and muscarinic (GPCR) agonist |
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|
Term
|
Definition
| not orally active, hydrolyzed by gastric acid |
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|
Term
|
Definition
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Term
|
Definition
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Term
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Definition
| Ach that contains a B-methyl substitution on the choline moiety |
|
|
Term
| function of B-methyl group on methacholine? |
|
Definition
gives semi-selectivity of the muscarinic receptor
reduces activity at nicotinic receptors |
|
|
Term
| half life of methacholine |
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Definition
|
|
Term
| side effects of methacholine |
|
Definition
hypotension - NO
nausea and vomiting - due to effects on vestibular apparatus
precipitation of asthma attacks - bronchoconstriction
heart block - decrease conduction velocity
SLUDS |
|
|
Term
|
Definition
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|
Term
|
Definition
| Ach with carbamate substitution in the acetyl moiety |
|
|
Term
|
Definition
| little selectivity between nicotinic and muscarinic receptors |
|
|
Term
|
Definition
longer (2-3 hrs)
not susceptible to plasma cholinesterases |
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|
Term
| indications for carbachol |
|
Definition
| used topcially for management of glaucoma |
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|
Term
| carbachol mechanism of action in glaucoma |
|
Definition
acts on muscarinic cholinergic recptors of the iris circular (constrictor) muscle to produce miosis (constricts the pupil)
opens the canal of Schlemm to facilitate outflow of aqueous humor and decrease intraocular pressure |
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|
Term
|
Definition
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|
Term
|
Definition
Ach that combines featurs of methacholine and carbachol
has both a B-methyl substitution and a carbamate substitution |
|
|
Term
|
Definition
long (2-3 hrs)
because of carbamate substitution, not susceptible to plasma cholinesterases |
|
|
Term
|
Definition
selective for muscarinic receptors
b/c of B-methyl substitution, decrease activity at nicotinic receptors |
|
|
Term
| side effects of bethanechol |
|
Definition
mild CV effects
effects mostly GI and urinary bladder
targets M3 more than M2 - less problem with heart block |
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|
Term
|
Definition
|
|
Term
|
Definition
natural plant alkaloid with primarily muscarinic receptor activity
from South American shrub pilocarpus |
|
|
Term
| why does pilocarpine have a longer half life than other direct cholinergic agents? |
|
Definition
| its not a choline ester so its not a substrate for cholinesterases |
|
|
Term
| how is pilocarpine cleared? |
|
Definition
| at least partially by CYP2A6 |
|
|
Term
|
Definition
topically for management of glaucoma
decreases pressure by increasing flow; constricts circular muscle |
|
|
Term
|
Definition
muscarinic antagonist
selectivity from muscarinic over nicotinic receptors |
|
|
Term
|
Definition
|
|
Term
|
Definition
| natural plant alkaloid obtained from tobacco leaves |
|
|
Term
|
Definition
nicotinic cholinergic agonist
activity at both Ng and Nm receptors |
|
|
Term
|
Definition
not used as a drug
except to aid in smoking cessation |
|
|
Term
|
Definition
mild CNS stimulant - can increase resp and induce vomiting
tolerance occurs readily with use |
|
|
Term
| effect of low doses of nicotine |
|
Definition
| stimulate Ng receptors and promote NE release from sympathetic adrenergic nerve fibers |
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|
Term
| effect of high doses of nicotine |
|
Definition
| block nicotinic receptors by inducing persistent depolarization at Ng receptors - decreases BP at Nm receptors - causes muscle paralysis |
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|
Term
| most reversible cholinesterase inhibitors are |
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Definition
|
|
Term
| how do reversible cholinesterase inhibitors work? |
|
Definition
interact with active site of AchE
ester linkage is hydrolyzed in the usual way
carbamylated esteratic site persists much longer than corresponding acetylated site which occurs after the hydrolysis of Ach
prevents degradation of Ach - increases Ach half life and therefore amount available for endogenous receptors |
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|
Term
|
Definition
indirect cholinergic agent
reversible cholinesterase inhibitor |
|
|
Term
|
Definition
natural plant alkaloid obtained from Calabar or 'ordeal' beans from West Africa
tertiary amine
**can penetrate into CNS |
|
|
Term
| excretion of physostigmine |
|
Definition
hydrolyzed by plama esterases
little role for renal excretion |
|
|
Term
|
Definition
antidote against atropine poisoning (b/c its a muscarinic antagonist)
sometimes used topically for glaucoma |
|
|
Term
|
Definition
indirect cholinergic agent
reversible cholinesterase inhibitor |
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|
Term
|
Definition
| quaternary amine (charged) with structural similarities with physostigmine |
|
|
Term
| does neostigmine cross the BBB? |
|
Definition
|
|
Term
|
Definition
destroyed by plasma esterases
cleared in urine |
|
|
Term
|
Definition
non-obstructive intestinal and urinary bladder atony
management of myasthenia gravis |
|
|
Term
|
Definition
indirect cholinergic agent
reversible cholinesterase inhibitor |
|
|
Term
|
Definition
|
|
Term
| does edrophonium cross the BBB? |
|
Definition
|
|
Term
|
Definition
short
weakly binds AchE through anionic site |
|
|
Term
| elimination of edrophonium |
|
Definition
|
|
Term
|
Definition
indirect cholinergic agent
irreversible cholinesterase inhibitor |
|
|
Term
| irreversible cholinesterase inhibitors are mostly |
|
Definition
| organic phosphate inhibitors |
|
|
Term
|
Definition
1. covalently phosphorylate hydroxyl group of serine in the esteratic site of AchE
2. after interaction in the active site, inhibitors are hydrolyzed - phosphorylated esteratic site is extremely stable and resistant to hydrolysis
3. alkylphosphate group at the esteratic site undergoes further chemical modification termed 'aging' - alkylphosphate loses an alkyl group
4. resulting monoalkylphosphate becomes more tightly bound to the esteratic site
5. inhibit both AchE and plasma cholinesterase |
|
|
Term
| what is organophosphate 'aging'? |
|
Definition
the alkylphosphate group at the esteratic site undergoes a chemical modification where the alkylphosphate loses an alkyl group
the resulting monoalkylphosphate becomes more tightly bound to esteratic site |
|
|
Term
| what do organophophates inhibit? |
|
Definition
| both AchE and plasma cholinesterase |
|
|
Term
| when is organophosphate irreversible? |
|
Definition
|
|
Term
| are organophosphates lipid soluble and why is this important? |
|
Definition
yes
breathed in, can gain access via mucous membranes and cross BBB |
|
|
Term
|
Definition
indirect cholinergic agent
irreversible cholinesterase inhibitor |
|
|
Term
|
Definition
| diisopropylflurophosphate, DFP |
|
|
Term
|
Definition
applied from once daily to once weekly
long half life |
|
|
Term
|
Definition
used topically in the eye for glaucoma
systemic spread is bad |
|
|
Term
|
Definition
indirect cholinergic agent
irreversible cholinesterase inhibitor |
|
|
Term
|
Definition
| used topically for glaucoma |
|
|
Term
|
Definition
indirect cholinergic agent
irreversible cholinesterase inhibitor
organic insecticide |
|
|
Term
| what is responsible for more accidental poisoning that any other organophosphate? |
|
Definition
|
|
Term
| what is required for the activity of parathion? |
|
Definition
| requires metabolism for its activity |
|
|
Term
|
Definition
organic insecticide
phased out in 2005 |
|
|
Term
|
Definition
indirect cholinergic agent
irreversible cholinesterase inhibitor |
|
|
Term
| what is required for malathion activity? |
|
Definition
| requires metabolism for activity |
|
|
Term
| what is the basis for selective toxicity of malathion in insects over humans? |
|
Definition
| mammals detoxify malathion readily - its much less toxic in higher animals than it is to insects |
|
|
Term
| what are the first signs of malathion toxicity? |
|
Definition
at high enough doses - muscarinic effects
first warning signs of an OD is SLUDS |
|
|
Term
|
Definition
organic insecticide
widely used
less of a problem in humans than it is in insects but its still a problem in humans |
|
|
Term
|
Definition
indirect cholinergic agents
irreversible cholinesterase inhibitors |
|
|
Term
|
Definition
prototype military nerve gas
why all military personnel carry atropine in the field - muscarinic antagonist that can reverse the poisoning with these compounds |
|
|
Term
| mechanism of sarin and soman |
|
Definition
| cross the BBB and cause profound inhibition of central and peripheral AchE |
|
|
Term
| can sarin and soman cross the BBB? |
|
Definition
|
|
Term
| effects of sarin and soman? |
|
Definition
| circulatory collapse and resp arrest due to persistent neuromuscular depolarization |
|
|
Term
| clearance of organophosphates |
|
Definition
1. hydrolyzed by liver and plasma esterases
2. excreted as hydrolysis products in urine
3. CYPs contribute to inactivation of some organophosphates |
|
|
Term
| irreversible cholinesterase inhibitor overdose |
|
Definition
|
|
Term
| what are the central manifestations of irreversible cholinesterase inhibitors toxicity? |
|
Definition
| confusion, ataxia, convulsions, coma, resp paralysis |
|
|
Term
| what is the usual cause of death in irreversible cholinesterase OD? |
|
Definition
|
|
Term
| what are the peripheral manifestations of irreversible cholinesterase inhibitors toxicity? |
|
Definition
| bronchial secretion, hypotension, skeletal muscle paralysis |
|
|
Term
| treatment of irreversible cholinesterase inhibitors (organophosphate) intoxication |
|
Definition
first choice - atropine; competitive antagonist at muscarinic receptors
neuromuscular components - can be treated with pralidoxime (cholinesterase reactivator) |
|
|
Term
| how does pralidoxime (and related oxime compounds) work in the treatment of organophosphate toxicity? |
|
Definition
compete for the alkylphosphate group attached to the esteratic site for AchE
if the phosphorylated enzyme has fully 'aged' - pralidoxime is not effective |
|
|
Term
| when is pralidoxime not effective in treatment of organophosphate toxicity? |
|
Definition
| when the phosphorylated enzyme has fully 'aged' |
|
|
Term
| does pralidoxime penetrate the BBB? |
|
Definition
|
|
Term
61 yo man
increased intraocular pressure on routine eye exam; normal visual acuity in both eyes; no evidence of optic nerve damage; visual field testing shows mild loss of peripheral vision
diagnosed with primary open-angle glaucoma
started on what? |
|
Definition
| pilocarpine ophthalmic drop |
|
|
Term
glaucoma - eye disease where the eye pressure is too high; can impinge upon optic nerve function
2 ways to lower eye pressure? |
|
Definition
1. increase rate fluid leaves eye
2. decrease rate at which fluid enters eye |
|
|
Term
| pilocarpine effect in the treatment of glaucoma |
|
Definition
contracts the circular muscles in the eye
acts on M3 - cause increase Ca via Gq - increases rate fluid will leave the eye |
|
|
Term
| what muscles control the pressure in the eye? |
|
Definition
circular muscle
radial muscle - pulls in opposite direction as circular; has a1 receptor |
|
|
Term
| what is the action of pilocarpine on the muscles of the iris and cilia? |
|
Definition
constriction
via the M3 receptor |
|
|
Term
62 yo woman with open-angle glaucoma inadvertently applies excessive pilocarpine to her eyes
this may result in? |
|
Definition
dilation of vessels with drop of BP
compensatory stimulation of HR
higher levels - directly inhibit HR
stimulates muscarinic receptors - results in miosis, SM dilation, and increased GI motility |
|
|
Term
| what are the actions of muscarinic cholinergic agonists? |
|
Definition
| activate inhibitor G proteins (Gi) also - stimulates activity of PLC to increase release of Ca via IP3 and DAG effects |
|
|
Term
| what adverse effect of choline esters like carbachol is mostly to occur? |
|
Definition
salivation; diarrhea and lacrimation may be seen
HR - usually slowed
likely to see SLUDS |
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|
