Cholinergic

Drugs and
Related Agents
Prepared by: Judy Ann B. Jayona N36-A
 Chapter overview:

•This Chapter supports the role of

Acetylcholine (Ach) in the mechanism of
regulation of human physiology.
•A better understanding of how to treat
diseases such as Alzheimer’s disease,
Parkinson disease and overactive bladder.
Chapter overview:

•To understand the action of

cholinergic nerve and it’s
neurotransmitter.
•When Ach was first demonstrated
bin the frog heart in 1921 by Loewi
as the substance release by vagus
nerve stimulation.
Chapter overview:

•The drugs and chemicals

that act on cholinergic
nerves by mimic or block
the action of Ach.
• Synaptic terminals in the cerebral cortex,
corpus striatum, hippocampus, and several
other regions in the CNS are rich in Ach.
• Ach serves as a neurotransmitter at both
sympathetic and parasympathetic.
• Drugs and chemicals that cause the
parasympathetic division to react are
termed parasympathomimetic.
• Whereas , those blocking the actions
are called parasympatholytic.
• Agents that mimic the sympathetic
division are called sympathomimetic,
and those that block the actions are
sympatholytic.
CHOLINERGIC RECEPTORS:
NICOTINIC RECEPTORS:
•Are coupled directly to ion channels and,
when activated by Ach, mediate very rapid
responses.
•The 1st neurotransmitter
•When the neurotransmitter Ach binds to
nicotinic receptors, cause a change in the
permeability of the membrane.
•Ach receptors are interest of targets for
autoimmune antibodies in myasthenia
gravis and for muscle relaxant.
•Nicotinic receptors in autonomic
ganglia, when block by drugs , can play a
role in the control of hypertension.
NICOTINIC RECEPTOR SUBTYPES:
•Nicotinic receptors (N1)
- Are blocked by succinylcholine, d-tubocurarine,
and decamethonium and stimulated by
phenyltrimethylammonium.
•Nicotinic receptors (N2)
- Are blocked by hexamethonium and trimethapan
but stimulated by tetramethylammonium and
dimethyl-4-phenylpiperazinium (DMPP).
•Muscarinic Receptor
- Plays an essential role in regulating the
functions of organs innervated by the ANS to
maintain homeostasis of the organism.
- Muscarinic receptor subtypes:
M1 Receptors
M2 receptors
M3 receptors
M4 receptors
M5 receptors
•M1 receptors
- Defined to have high affinity for pirenzipene
and low affinity for compounds such as AF-
DX116.
- -have been termed neural
- -located in the exocrine glands and autonomic
ganglia.
-affect arousal attention rapid eye
movement(REM),sleep etc.
•M2 Receptors
- Defined to have high affinity for
methoctramine, a polyamine, and by their low
affinity for pirenzipene.
- -also called cardiac muscarinic receptors.
- Activates K† channels to cause
hyperpolarization of cardiac cells, resulting in
bradycardia.
•M3 receptors
-referred to as glandular muscarinic receptors.
-located in exocrine and smooth muscle.
-contraction of visceral smooth muscle is a result
of M3 receptor.
-when activated in endothelial cells cause the
release of endothelium-derived relaxing
factor(EDRF)and contribute to vasodilation.
•M4 receptors
-just like M2 receptors act through Gi protein to
inhibit adenylate cyclase.
•M5 receptors
- Are found in the substancia nigra
- -regulate dopamine release at terminals within
the striatum.
•BIOCHEMICAL EFFECTS OF MUSCARINIC RECEPTOR
STIMULATION:
- The sequence of events in the second messenger
system begins with activation of the receptors by
an agonist and involves the activation of G proteins
that are bound to a portion of the muscarinic
receptor.
- -g protein interacts with guanine nucleotides and
guanosine diphosphate (GDP).
-g proteins consist of 3 subunits alpha,beta
and gamma.
-a single drug receptor complex can
activate several G protein molecules, and in
turn can remain with a target molecule and
cause the production of many molecules.
-M1, M3 and M5 receptors activate PLC,
causing the release of IP3 and DAG.
- M2 and M4 receptors produce
inhibition of adenylate cyclase.
Phosphoinositol System:
•The phosphoinositol system required the
breakdown of membrane-bound
phosphatidylinositol 4,5-diphosphate (PIP2) by
PLC to IP3 and DAG, which serve as second
messengers in the cell.
Phosphoinositol System:
•The Ca2† activates Ca2† dependent kinases
directly or binds to the Ca2†-binding protein
calmodulin, which activates calmodulin-
dependent kinases.
Adenylate Cyclase
•A membrane enzyme, is another target
of muscarinic receptor activation.
•cAMP is synthesized within the cell
from adenosine triphosphate (ATP) by
the action of adenylate cyclase.
Adenylate Cyclase
•Muscarinic receptor activation causes lower
levels of cAMP ,reducing cAMP protein
dependent kinase activity, and relaxation of
muscle contraction.
•GTP-inhibitory protein (Gi) have been
suggested that reduces the activity of
adenylate cyclase.
Ion Channels:
•In addition to the action of protein kinases
that phosphorylate ion channels and
modify ion inductance, G proteins are
coupled directly to ion channels to
regulate their action.
CHOLINERGIC NEUROCHEMISTRY:
•Cholinergic neurons synthesize, store and
release Ach. The neurons also form
choline acetyltransferase (ChAT) and AChE.
•Several quaternary ammonium bases act
as competitive inhibitors of choline
uptake.
CHOLINERGIC NEUROCHEMISTRY:
•Hemicholinium (HC-3),a bisquaternary
cyclic hemiacetal, and the triethyl analog
of a choline, 2-hydroxyethylammonium,act
as the presynaptic membrane to inhibit
the high affinity uptake of choline into the
neuron.
•The acetyl group used for the synthesis of
ACh is obtained by conversion of glucose to
pyruvate in the cytosol of the neuron and
eventual formation of acetyl CoA.
•Transfer of acetyl group from acetyl CoA to
choline may be by a random of or an
ordered reaction of Theorell-Chance Type.
•Newly formed Ach is released from
the presynaptic membrane when a
nerve action potential invades a pre
synaptic nerve terminal.
•Calcium enters the nerve terminal and
causes release of the contents of several
synaptic vesicles containing Ach into the
synaptic cleft.
•This burst, of Ach causes depolarization of
the post synaptic membrane.
•the no. of quanta of Ach released may be
as high as several hundred at a
neuromuscular junction, with each
quantum containing between 12,000 and
60,000 molecules.
•It is generally accepted that there is
enough AChE at nerve endings to
hydrolyze into choline and acetate any
Ach that has been liberated.