Cholinesterase Inhibitors and Nicotinic Antagonists-T1

Question 1

the 11 cholinesterase inhibitors

Answer 1

• ambenonium (mytelase)
• demecarium (humorsol)
• donepezil (aricept)
• echothiophate (phospholine)
• galantamine (reminyl)
• neostigmine (prostigmin)
• physostigmine (generic only)
• pyridostigmine (mestinon)
• rivastigmine (exelon)
• tacrine (cognex)
• edrophonium (tensilon)

Question 2

cholinesterase regenerator

Answer 2

pralidoxime (protopam, 2-PAM)

Question 3

cholinesterase inhibitors are generally

Answer 3

carbamate derivatives or organophosphates.

Question 4

acetylcholinesterase (AchE) is a highly

Answer 4

active enzyme that rapidly metabolizes Ach to inactive products. found in high density in the synaptic cleft and nerve endings.

Question 5

inhibiting AchE

Answer 5

potentiates the effects of Ach released from cholinergic nerves.

Question 6

cholinesterase inhibitors have an indirect effect on

Answer 6

muscarinic receptors, parasympathetic mimetic

Question 7

metabolism of Ach by cholinesterase

Answer 7

• 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

Question 8

reversible cholinesterase inhibitors (3) and what they do

Answer 8

• physostigmine, neostigmine lead to carbamoylation of cholinesterase which prevents binding and metabolism of Ach
• edrophonium competes with Ach for binding and metabolism of Ach

Question 9

inhibition of cholinesterase by carbamates

Answer 9

• 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.

Question 10

inhibition of AchE by organophosphates

Answer 10

• 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.

Question 11

different rates of hydrolysis of the ether bond to determine extent of cholinesterase inhibition: Ach, neostigmine, and diisofluorophosphate

Answer 11

Ach: fast hydrolysis, low inhibition

neostigmine: slow hydrolysis; high, reversible inhibition
diisofluorophosphate: very slow hydrolysis; high, irreversible inhibition

Question 12

pharmacological effects of cholinesterase inhibitors

Answer 12

• 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.

Question 13

using cholinesterase inhibitor to treat glaucoma

Answer 13

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

Question 14

cholinesterase inhibitor used to treat GI and urinary motility

Answer 14

neostigmine

Question 15

cholinesterase inhibitors to treat atropine toxicity

Answer 15

reversed by giving physostigmine. want to increase [Ach] in synaptic space.
also can use echothiophate

Question 16

cholinesterase inhibitors to improve neuromuscular transmission in myasthenia gravis

Answer 16

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.

Question 17

toxicity related to cholinesterase inhibition

Answer 17

-usually due to insecticides

Question 18

SLUDGE

Answer 18

symptoms of intoxication related to cholinesterase inhibition:
S- salivation
L- lacrimation
U- urination
D- defecation
G- gas
E- emesis

Question 19

8 nicotinic antagonists

Answer 19

mostly affect receptors in motor endplate:

• atracurium (tacrium)
• doxacurium (nuromax)
• mivacurium (mivacron)
• pancuronium
• rocuronium
• tubocurarine
• succinylcholine
• dantrolene (dantrium)

Question 20

nicotinic receptors are divided into___ and __

Answer 20

Nn: on nerve cells in ganglia
Nm: on skeletal muscle motor end plates

Question 21

nicotinic antagonists are divided into __ and __

Answer 21

depolorizing (succinylcholine)

nondepolarizing (pancuronium)

Question 22

4 non depolarizing nicotinic antagonists

Answer 22

• D-tubocurarine
• pancuronium
• venocuronium
• rocuronium

Question 23

2 depolarizing blockers of nicotinic antagonists

Answer 23

• succinylcholine

- decamethonium

Question 24

depolarizing nicotinic antagonists bind to__

Answer 24

the nicotinic receptor of the neuromuscular junction and activate the receptor to cause partial depolarization and contraction of the muscle.

Question 25

flaccid paralysis occurs when

Answer 25

At released from the motor neuron activates the receptor further

Question 26

the partially depolarized motor end plates results in nicotinic receptor channels that are in the

Answer 26

inactive state

Question 27

nondepolarizing neuromuscular blockers compete with

Answer 27

Ach for binding to the nicotinic receptor at the neuromuscular junction

Question 28

nondepolarizing neuromuscular blockers bind to channel but

Answer 28

does not open channel

Question 29

activation of the nicotinic receptor requires

Answer 29

the binding of 2 molecules of Ach; binding of 1 molecule of the antagonist to the receptor decreases the activity.

Question 30

Administration of ___ can reverse paralysis from non depolarizing neuromuscular blocking

Answer 30

cholinesterase inhibitor

Question 31

adverse effects of nicotinic antagonists

Answer 31

- histamine release - succinylcholine may release excessive K from muscle--> hyperkalemia - malignant hyperthermia

Question 32

nicotinic antagonist drug interactions (4)

Answer 32

1. inhaled anesthetics: produce synergistic neuromuscular blockade 2. aminoglycosides: decrease Ach release from cholinergic nerves to produce additive neuromuscular blockade 3. calcium channel blockers: may decrease availability of Ca ions for contraction and enhance effects of neuromuscular blockers 4. opiods, lidocaine, phenytoin