The document discusses the cholinergic system and neuromuscular blocking drugs. It begins by outlining the objectives and intended learning outcomes, which are to understand the locations of acetylcholine receptors, the synthesis and fate of acetylcholine, and the classifications and effects of various cholinergic drugs. It then describes the autonomic nervous system, including its parts, locations of ganglia, innervations of organs, and neurotransmitters. Next, it explains the synthesis, storage, release, binding, termination and recycling of acetylcholine. It also classifies cholinergic receptors and their locations and mechanisms. Finally, it discusses the classifications, actions, uses and effects of cholinergic drugs that directly activate receptors

1. University of kirkuk
College of Medicine- department of Pharmacology
Dr. Mohammed K. Turab
2018-2019

2. Drugs Acting On the Cholinergic System and
the Neuromuscular Blocking Drugs
 Objectives and intended learning outcomes:
 The student should be able to:
 List the locations and types of acetylcholine receptors in the major organ systems.
 Describe the steps in the synthesis, storage, release and fate of acetylcholine.
 Classify Cholinomimetic and describe their actions, uses and adverse Effects.
 Classify different muscarinic antagonists and describe their actions, uses, adverse effects and
contraindications.
 Describe the effects of nicotine and the ganglion-blocking drugs.
 Classify neuromuscular blocking drugs, describe their mechanisms of action, report their
clinical applications, state their adverse effects and interpret their interactions.
 The autonomic nervous system (ANS) has two parts: the sympathetic and the
parasympathetic.

3. Now consider the following about the ANS:
 1-Spinal roots of origin:
 The parasympathetic fibers originate from
the 3rd, 7th, 9th and10th cranial n. and from
S2 to S4 segments of the spinal cord,
 while the sympathetic preganglionic fibers
originate in the thoracic T1-T12 and Lumber
L1-L5.

4. 2-Location of the ganglia:
 In the PANS (parasympathetic ANS) the ganglia
are close to the innervated organ (i.e. the
preganglionic fiber is long and the postganglionic
fiber is short) the opposite is true for SANS
(sympathetic ANS) because most of the
sympathetic ganglia are located in the
paravertebral chains that lie along the spinal
column.

5. 3- Innervations of organs:
 a-the motor efferent portion of the PANS is
one of the motor pathways for transmission of
information from CNS to the effector tissues
(smooth m., cardiac m., exocrine glands).
 b- Uninnervated receptors: some receptors
that respond to autonomic transmitters and
drugs receive no innervation e.g. some
muscarinic receptors on the endothelium of
blood vessels & some presynaptic receptors.

6. 4- Neurotransmitters:
 a. At the preganglionic synapse of the SANS &
PANS the mediator is Ach.
 b. At the postganglionic synapse the
neurotransmitter in the PANS is Ach
while in the SANS it is norepinephrine
(noradrenalin) with exception of the
thermoregulatory sweat gland (Acrine sweat
gland) & some blood vessels to skeletal m.
where the mediator is Ach.

7. Diagram comparing some features of PANS & SANS with
the somatic motor system

8. The synthesis, storage, release and termination of action
of Ach:

9. Synthesis
Ach is synthesized from acetyl co A and
choline by the enzyme choline acetyl
transferase. The rate limiting step is
probably the transport of choline into
the nerve terminal. This step is blocked
by hemicholinium.

10. Storage:
Ach is actively transported
into the vesicles for
storage.
This process is inhibited by
vesamicol

11. Release:
 This occurs when an action potential propagated by the action of the voltage
sensitive Na channels arrives at the nerve ending.
 The release of Ach requires entry of Ca++ ions (through Ca voltage gated
channels which become opened) and triggering interaction between several
proteins associated with the vesicle and nerve ending membrane (synapto
brevin, snap and others)
 The interaction results in the fusion of the vesicular membrane and nerve
ending membrane and release of their contents into the synaptic space.
 Botuloinum toxin blocks the release of Ach.
 While (by contrast) black widow spider venom causes the release of all Ach
stored in the vesicles.

12. Binding to receptor:
 Released Ach diffuses cross the
synaptic space & bind either to
postsynaptic receptor on the
target cells or to presynaptic
receptor in the membrane of
the neuron that released the
Ach.

13. Termination of the action
of Ach:
 It is terminated in the synapse by
metabolism of Ach to acetate &
choline by the enzyme
acetylcholine esterase. Inhibition
of those enzymes is important in
the therapeutic effect of many
drugs.

14. Recycling of choline:
 Choline is captured by Na
coupled uptake system that
transports the molecules back
into the neuron where it is
acetylated and stored until
released by a subsequent action
potential (AP)

15. Cholinergic receptors
(cholinoceptor):
 1- Muscarinic receptors (MRs):
  These receptors are G coupled protein receptors.
  Respond to muscarine as well as Ach.
  The effects of activation of these receptors resemble those of
postganglionic PANS stimulation.
  Muscarinic receptors are located primarily on autonomic effector cells
including: heart, vascular endothelium, smooth m., presynaptic nerve
terminal and exocrine glands.
 Types: M1, M2, M3, M4, M5 but the first three types are the most
important.

16. Nicotinic receptors (NRs):
 These are ion cannel receptors.
 Respond to nicotine (another Ach mimic) but not
to muscarine.
 There are two major subtypes of nicotinic
receptors: (Nn) located in the ganglia and (Nm)
located at the neuromuscular end plate of skeletal
m.
 Nicotinic receptors are also found in the adrenal
medulla and CNS

17. R Location Post R. Mechanism
M1 Nerve ending Increase IP3, DAG cascade
M2 Heart , some nerve endings Decrease CAMP, activate K channels
M3 Effector cells: smooth m.,
glands, endoth.
Increase IP3,DAG cascade
Nn ANS ganglia Na/K depolarizing current (evokes AP)
Nm N-M junction Na/K depolarizing current

18. Mechanisms of Ach signal transduction (post receptor
mechanisms)
Muscarinic mechanism:
 Several mechanisms have been defined for muscarinic receptors:
 1- The mechanism for M1 & M3 receptors:
 When M1 and M3 are activated:
 (1) they undergo conformational change and
 (2) interact with a G protein which in turn to activates phospholipase C (a
membrane bound enzyme) leading to (4) release of second messengers DAG (DiAcyl
Glycerol) and IP3 (inositol 1,4,5,triphosphate).
 DAG modulates the action of protein kinase C, an enzyme important in secretion
while
 IP3 evokes the release of Ca from intracellular storage sites which results in

19. 2- The mechanisms for M2
receptors:
 a- Couples M2 to adenylyl cyclase through an
inhibitory G protein which leads to
decrease cyclic AMP production.
 b- Couples M2 receptor directly to K channel
in the heart and elsewhere, muscarinic
agonists facilitate the opening of these
channels.


20. Nicotinic mechanism:
The receptor is located on the channel
protein that is selective to Na & K. When the
receptor is activated the channel opens and
depolarization of the cell occurs (EPSP) as a
direct result of the influx of Na. Those
receptors are present on the ganglionic cells
(of both SANS and PANS) & the neuromuscular
junction.

21. Cholinergic drugs:
cholinergic drugs are of two
types:
1-Direct acting agonists: acts directly on
cholinoceptors.
2- indirect acting agonists
(Anticholinesterase):acts by inhibiting the
action of cholinesterase  accumulation of
Ach in the synaptic space

22. Direct acting Cholinomimetic
agonists:
 These drugs mimic the action of Ach by binding
directly to cholinoceptors.
Those agents are either:
1- Choline esters e.g. Ach, Methacoline, Carbacol
and Bethanecol.
2- Naturally occurring alkaloids e.g. Muscarine,
pilocarpine and Nicotine.

23. These drugs differ in their spectrum
of action to muscarinic or nicotinic
stimulation, e.g. pilocarpine &
Bethanechol preferentially bind to
M.Rs, however direct acting drugs
(as a group) show little specify in
their action.

24. Effects of direct acting cholinoceptors agonists
Organ Response
CNS complex stimulatory effects e.g. nicotine (elevation of
mood)
Eye
 Sphincter m.
 Ciliary's m.
 miosis (constriction of the pupil)
 contraction (accommodation) to near vision
Heart
 SA node
 AV node
 Atria
  heart rate (-ve chronotropy)
  conduction velocity (-ve chronotropy) , R.P (refractory
period)

25. Vasodilatation and decreased blood pressure is not
evoked by PANS discharge.... why?
Because it is mediated by the action of
Uninnervated muscarinic receptors found in blood
vessels which are stimulated by directly acting
muscarinic (muscarinic agonists),normally theses
receptors have no function because Ach is never
released into the blood in significant quantities ,
stimulation of these receptors leads to the release
of NO (EDRF) which causes the vasodilatation.

26. Decreased blood pressure evokes a baroceptor
reflex resulting in a strong sympathetic discharge
to the heart, thus the result may be tachycardia
rather than bradycardia.
Another effect seen with directly acting drugs but
not with PANS stimulation is thermoregulatory
sweating, this is a sympathetic-cholinergic effect.

27. Blood vessels dilation via EDRF (endothelium derived relaxation factor) (NO)
Bronchi bronchoconsriction
GIT
 Motility
 Sphincters
 
 relaxation via ENS (enteric nervous system)
Urinary bladder
 detrusor
 trigon & sphincter
 contraction
 relaxation
Skeletal m, (1) activation of N-M end plate
(2) contraction of m.
Glands  secretion of thermoregulatory sweat, lacrimal, bronchial, gastric and intestinal
glands