Cholinesterase Inhibitors and Nicotinic Antagonists-T1 Flashcards
the 11 cholinesterase inhibitors
- ambenonium (mytelase)
- demecarium (humorsol)
- donepezil (aricept)
- echothiophate (phospholine)
- galantamine (reminyl)
- neostigmine (prostigmin)
- physostigmine (generic only)
- pyridostigmine (mestinon)
- rivastigmine (exelon)
- tacrine (cognex)
- edrophonium (tensilon)
cholinesterase regenerator
pralidoxime (protopam, 2-PAM)
cholinesterase inhibitors are generally
carbamate derivatives or organophosphates.
acetylcholinesterase (AchE) is a highly
active enzyme that rapidly metabolizes Ach to inactive products. found in high density in the synaptic cleft and nerve endings.
inhibiting AchE
potentiates the effects of Ach released from cholinergic nerves.
cholinesterase inhibitors have an indirect effect on
muscarinic receptors, parasympathetic mimetic
metabolism of Ach by cholinesterase
- very rapid
- example of base hydrolysis of an ester
- Ach binds to enzyme active site via interactions with specific amino acid residues
- the acetate group is hydrolyzed by the addition of water to regenerate the active enzyme.
- during the intermediate state- the enzyme can’t bind another molecule of Ach
reversible cholinesterase inhibitors (3) and what they do
- physostigmine, neostigmine lead to carbamoylation of cholinesterase which prevents binding and metabolism of Ach
- edrophonium competes with Ach for binding and metabolism of Ach
inhibition of cholinesterase by carbamates
- carbamate derivatives bind to same active site of the cholinesterase as Ach
- cleavage of the carbamate yields amino alcohol and carbamoylated enzymes complex.
- This the active site of the enzyme remains blocked for longer periods of time preventing Ach metabolism
- intermediate remains carbamoylated for longer period of time- NOT hydrolyzed as quickly.
inhibition of AchE by organophosphates
- phosphoester bond- very stable and not easy to break.
- organophosphates bind with high affinity to serine residue resulting in phosphorylated enzyme complex.
- complex can undergo aging where one of the ether bonds is broken and becomes even more resistant to hydrolysis.
- result of inhibition leads to increased Ach and increased stimulation of muscarinic and nicotinic receptors.
- 2-PAM able to regenerate active enzyme complex only if aging has not occurred. works by nucleophilic attack of phosphate group.
different rates of hydrolysis of the ether bond to determine extent of cholinesterase inhibition: Ach, neostigmine, and diisofluorophosphate
Ach: fast hydrolysis, low inhibition
neostigmine: slow hydrolysis; high, reversible inhibition
diisofluorophosphate: very slow hydrolysis; high, irreversible inhibition
pharmacological effects of cholinesterase inhibitors
- cardio: decreased HR, force, small or no change in blood pressure
- GI: increased motility, increased digestive secretions, gas, cramps, defecation
- eyes: miosis, increased accommodation for near vision, increased then decreased intraocular pressure.
- respiratory: increased bronchial tone
- CNS: increased alertness, convulsions, seizures
- neuromuscular junction: increased muscle strength, ataxia, tremors.
using cholinesterase inhibitor to treat glaucoma
physostigmine, echothiophate, DFP enhance cholinergic responses of the iris to increase aqueous flow and decrease intraocular pressure. cholinesterase inhibitors stimulate muscarinic receptors indirectly–> increased Ach, increased MR response –> increased constriction of ciliary muscles –> increased outflow of aqueous humor
cholinesterase inhibitor used to treat GI and urinary motility
neostigmine
cholinesterase inhibitors to treat atropine toxicity
reversed by giving physostigmine. want to increase [Ach] in synaptic space.
also can use echothiophate
cholinesterase inhibitors to improve neuromuscular transmission in myasthenia gravis
diagnostic: edrophonium.
therapeutic: pyridostigmine (mestinon)
- MG destroys receptors at NMJ
- want to build up Ach to get better stimulation of receptor- improve depolarization of motor end plate.
toxicity related to cholinesterase inhibition
-usually due to insecticides
SLUDGE
symptoms of intoxication related to cholinesterase inhibition: S- salivation L- lacrimation U- urination D- defecation G- gas E- emesis
8 nicotinic antagonists
mostly affect receptors in motor endplate:
- atracurium (tacrium)
- doxacurium (nuromax)
- mivacurium (mivacron)
- pancuronium
- rocuronium
- tubocurarine
- succinylcholine
- dantrolene (dantrium)
nicotinic receptors are divided into___ and __
Nn: on nerve cells in ganglia
Nm: on skeletal muscle motor end plates
nicotinic antagonists are divided into __ and __
depolorizing (succinylcholine)
nondepolarizing (pancuronium)
4 non depolarizing nicotinic antagonists
- D-tubocurarine
- pancuronium
- venocuronium
- rocuronium
2 depolarizing blockers of nicotinic antagonists
- succinylcholine
- decamethonium
depolarizing nicotinic antagonists bind to__
the nicotinic receptor of the neuromuscular junction and activate the receptor to cause partial depolarization and contraction of the muscle.
flaccid paralysis occurs when
At released from the motor neuron activates the receptor further
the partially depolarized motor end plates results in nicotinic receptor channels that are in the
inactive state
nondepolarizing neuromuscular blockers compete with
Ach for binding to the nicotinic receptor at the neuromuscular junction
nondepolarizing neuromuscular blockers bind to channel but
does not open channel
activation of the nicotinic receptor requires
the binding of 2 molecules of Ach; binding of 1 molecule of the antagonist to the receptor decreases the activity.
Administration of ___ can reverse paralysis from non depolarizing neuromuscular blocking
cholinesterase inhibitor
adverse effects of nicotinic antagonists
- histamine release
- succinylcholine may release excessive K from muscle–> hyperkalemia
- malignant hyperthermia
nicotinic antagonist drug interactions (4)
- inhaled anesthetics: produce synergistic neuromuscular blockade
- aminoglycosides: decrease Ach release from cholinergic nerves to produce additive neuromuscular blockade
- calcium channel blockers: may decrease availability of Ca ions for contraction and enhance effects of neuromuscular blockers
- opiods, lidocaine, phenytoin
