Cholinoceptor - Activating & Cholinesterase-Inhibiting Drugs -2
Review : Mechanism of action:
1) Increase in concentration of endogenous acetylcholine at cholinocepters .
2) Edrophonium :is a quaternary alcohol, which bind electrostatically and by
hydrogen bonds to the active site ,thus preventing access of acetylcholine
3) The enzyme-inhibitor complex does not involve a covalent bond and and
that is why short-lived ( on the order of 2-10 minutes )
4) Carbamate esters, e.g., neostigmine and physostigmine. undergo a two-
step hydrolysis sequence similar to acetylcholine.
5) The covalent bond of the carbamoylated enzyme is more resistant to the
second (hydration) process, and this step is correspondingly prolonged (30
minutes – 6 hours )
6) The organophosphates. undergo initial binding and hydrolysis by the
enzyme, resulting in a phosphorylated active site.
7) The covalent phosphorus -enzyme bond is extremely stable and hydrolyzes
in water at a very slow rate ( hundreds of hours ).
8) After the initial binding-hydrolysis step, the phosphorylated enzyme
complex may undergo a process called aging”
9) Pralidoxime If given before aging has occurred, is able to break the
phosphorus-enzyme bond and can be used as "cholinesterase regenerator"
drugs for organophosphate insecticide poisoning.
Organ System Effects due to indirectly inhibiting drugs
Central Nervous System
“for drugs that can penetrate BBB like Physostigmine and Organophosphates”
1. In low concentrations, the lipid-soluble cholinesterase inhibitors cause a
subjective alerting response.
2. In higher concentrations, they cause generalized convulsions, which may be
followed by coma and respiratory arrest and death.
-Eye, Respiratory Tract, GIT, Urinary Tract: The effects are qualitatively similar
to the effects of the direct-acting cholinomimetics.
“eye:miosis , RT: Bronchoconstriction + increase bronchial secretion , GIT:
Peristaltic activity is increased +diarrhea, UT :avoiding urine , urinary contrast”
, -Cardiovascular System
Mimic the effects of vagal nerve activation on the heart. So, produce Negative
chronotropic[HR goes down], dromotropic[conduction velocity decreases],
and inotropic[contraction strength decreases] effects and cardiac output falls.
The fall in cardiac output is due to bradycardia, decreased atrial contractility,
and some reduction in ventricular contractility[because ventricle not
innervated by parasympathetic neurons],only the tissues that have cholinergic
nerves innervating them that are affected.
The latter effect occurs as a result of prejunctional inhibition of NE release.
“that we know the NE or the neuron that release the EN has cholinergic heteroreceptor that will
stimulated by Ach can decrease NE release then decrease the contractility of the ventricle a little
bit.”
Minimal effects by direct action on vascular smooth muscle ; because most
vascular beds lack cholinergic innervations.
The net cardiovascular effects of moderate doses of cholinesterase inhibitors
consist of:
1. modest bradycardia 2. a fall in cardiac output
3. an increased vascular resistance: which is due to (sympathetic ganglion
stimulation) that results in a rise in blood pressure.
-Neuromuscular Junction
1. Low concentrations prolong and intensify the actions of Ach. This
increases the strength of contraction, especially in muscles weakened by
curare-like neuromuscular blockers or by myasthenia gravis.
Curare: used in surgery mostly, it’s a heavy relaxant for muscles[ muscles
paralysis]+a neurovascular blocker of a competitive type , which competes
with Ach on nicotinic receptor in the muscles leads to muscles paralysis .
myasthenia gravis: a disease that produces weak muscles contractions.
2. higher concentrations fibrillation of muscle fibers. Antidromic firing
(nerve impulses in a direction opposite to normal) of the motor neuron
may also occur, resulting in fasciculations[ irregular muscles or fibers
contraction] that involve an entire motor unit.
Review : Mechanism of action:
1) Increase in concentration of endogenous acetylcholine at cholinocepters .
2) Edrophonium :is a quaternary alcohol, which bind electrostatically and by
hydrogen bonds to the active site ,thus preventing access of acetylcholine
3) The enzyme-inhibitor complex does not involve a covalent bond and and
that is why short-lived ( on the order of 2-10 minutes )
4) Carbamate esters, e.g., neostigmine and physostigmine. undergo a two-
step hydrolysis sequence similar to acetylcholine.
5) The covalent bond of the carbamoylated enzyme is more resistant to the
second (hydration) process, and this step is correspondingly prolonged (30
minutes – 6 hours )
6) The organophosphates. undergo initial binding and hydrolysis by the
enzyme, resulting in a phosphorylated active site.
7) The covalent phosphorus -enzyme bond is extremely stable and hydrolyzes
in water at a very slow rate ( hundreds of hours ).
8) After the initial binding-hydrolysis step, the phosphorylated enzyme
complex may undergo a process called aging”
9) Pralidoxime If given before aging has occurred, is able to break the
phosphorus-enzyme bond and can be used as "cholinesterase regenerator"
drugs for organophosphate insecticide poisoning.
Organ System Effects due to indirectly inhibiting drugs
Central Nervous System
“for drugs that can penetrate BBB like Physostigmine and Organophosphates”
1. In low concentrations, the lipid-soluble cholinesterase inhibitors cause a
subjective alerting response.
2. In higher concentrations, they cause generalized convulsions, which may be
followed by coma and respiratory arrest and death.
-Eye, Respiratory Tract, GIT, Urinary Tract: The effects are qualitatively similar
to the effects of the direct-acting cholinomimetics.
“eye:miosis , RT: Bronchoconstriction + increase bronchial secretion , GIT:
Peristaltic activity is increased +diarrhea, UT :avoiding urine , urinary contrast”
, -Cardiovascular System
Mimic the effects of vagal nerve activation on the heart. So, produce Negative
chronotropic[HR goes down], dromotropic[conduction velocity decreases],
and inotropic[contraction strength decreases] effects and cardiac output falls.
The fall in cardiac output is due to bradycardia, decreased atrial contractility,
and some reduction in ventricular contractility[because ventricle not
innervated by parasympathetic neurons],only the tissues that have cholinergic
nerves innervating them that are affected.
The latter effect occurs as a result of prejunctional inhibition of NE release.
“that we know the NE or the neuron that release the EN has cholinergic heteroreceptor that will
stimulated by Ach can decrease NE release then decrease the contractility of the ventricle a little
bit.”
Minimal effects by direct action on vascular smooth muscle ; because most
vascular beds lack cholinergic innervations.
The net cardiovascular effects of moderate doses of cholinesterase inhibitors
consist of:
1. modest bradycardia 2. a fall in cardiac output
3. an increased vascular resistance: which is due to (sympathetic ganglion
stimulation) that results in a rise in blood pressure.
-Neuromuscular Junction
1. Low concentrations prolong and intensify the actions of Ach. This
increases the strength of contraction, especially in muscles weakened by
curare-like neuromuscular blockers or by myasthenia gravis.
Curare: used in surgery mostly, it’s a heavy relaxant for muscles[ muscles
paralysis]+a neurovascular blocker of a competitive type , which competes
with Ach on nicotinic receptor in the muscles leads to muscles paralysis .
myasthenia gravis: a disease that produces weak muscles contractions.
2. higher concentrations fibrillation of muscle fibers. Antidromic firing
(nerve impulses in a direction opposite to normal) of the motor neuron
may also occur, resulting in fasciculations[ irregular muscles or fibers
contraction] that involve an entire motor unit.
