Download CHOLINOCEPTOR-ACTIVATING AND CHOLINESTERASE

CHOLINOMIMETIC AGENTS:
CHOLINOCEPTOR-ACTIVATING &
CHOLINESTERASE-INHIBITING DRUGS
CHOLINOMIMETIC AGENTS:
SPECTRUM OF ACTION OF
CHOLINOMIMETIC DRUGS
Cholinoceptors are either:
1. muscarinic (G protein-linked) or
2. nicotinic (ion channel)
In general, Muscarinic receptors regulate the production of intracellular 2nd
messengers
Muscarinic receptors are located on:
1. plasma membranes of cells in the CNS,
2. in organs innervated by parasympathetic
nerves (e.g. heart, smooth muscles, glands)
3. on some tissues that are not innervated by
these nerves, eg, endothelial cells
4. on those tissues innervated by cholinergic
postganglionic sympathetic nerves, e.g.
sweat glands, blood vessels in skeletal
muscles.
Nicotinic receptors are located on:
1. on plasma membranes of parasympathetic
and sympathetic postganglionic cells in all
autonomic ganglia,
2. on membranes of muscles innervated by
somatic motor fibers,
3. and in the central nervous system
Subtypes and characteristics of cholinoceptors.
Receptor
Type
Other
Names
Location
Nerves
Structural
Features
Postrecepto
r Mechanism
M1
M1a
7 transmembrane
IP3, DAG
segments, G protein- cascade
linked
M2
M2a,
Heart,
cardiac M2 nerves,
smooth m.
↓cAMP,activati
7 transmembrane
segments, G protein- on of K+
linked
channels
M3
M2b,
glandular
M2
Glands,
smooth m.,
endotheliu
m
7 transmembrane
IP3, DAG
segments, G protein- cascade
linked
m4 1
?CNS
7 transmembrane
segments, G proteinlinked
m5 1
?CNS
7 transmembrane
IP3, DAG
segments, G protein- cascade
linked
↓
cAMP
Subtypes and characteristics of cholinoceptors (cont’d)
NM
Muscle
Skeletal muscle
type, end neuromuscular
plate
junction
receptor
Pentamer (α2βδγ)
Na+, K+
depolarizing
ion channel
NN
Neuronal
type,
ganglion
receptor
α and β subunits only
as α2β2 or α3β3
Na+, K+
depolarizing
ion channel
Postganglionic
cell body,
dendrites
Selectivity of drug action:
Selectivity of action based on several factors:
1. muscarinic receptors Vs. nicotinic receptors;
2. Some drugs stimulate nicotinic receptors at
neuromuscular junctions preferentially/ less
effect on nicotinic receptors in ganglia;
3. Pharmacokinetic selectivity: using
appropriate routes of administration
muscarinic stimulants to modulate ocular function)
(e.g topical
MODE OF ACTION OF
CHOLINOMIMETIC DRUGS
Direct-acting agents directly bind to and
activate cholinoceptors.
Indirect-acting agents: inhibit the action
of AChE → the concentration of
endogenous ACh ↑ in the synaptic clefts
(amplifiers)
Neostigmine (1) activates neuromuscular nicotinic
cholinoceptors directly in addition to (2) blocking cholinesterase
BASIC PHARMACOLOGY OF
THE DIRECT-ACTING
CHOLINOCEPTOR
STIMULANTS
Chemistry:
esters of choline are permanently
charged and relatively insoluble in lipids
- contain the quaternary ammonium
group:
1) acetylcholine
2) methacholine
3) carbachol
4) bethanecol
Longer duration of action
Pharmacokinetics
1.The choline esters:
Poorly absorbed & poorly distributed into the
CNS (hydrophilic);
All hydrolyzed in the GIT (and less active by the
oral route);
Differ markedly in susceptibility to hydrolysis by
cholinesteras, Ach: (5-20 sec),
Presence of the β-methyl group  ↓the potency
of these drugs at the nicotinic receptor
Properties of choline esters.
Susceptibility to
Cholinesterase
Muscarinic
Action
Nicotinic
Action
Acetylcholine chloride
++++
+++
+++
Methacholine chloride
+
++++
None
Carbachol chloride
Negligible
++
+++
Bethanechol chloride
Negligible
++
None
Choline Ester
Cholinomimetic alkaloids & synthetic
analogs:
1)
2)
3)
4)
muscarine
nicotine
pilocarpine
lobeline
TOXIC
Tertiary amines:
better absorption
and distribution
Structures of cholinomimetic alkaloids
Mechanism of Action:
Activation of the parasympathetic nervous
system modifies organ function by two major
mechanisms:
1.
2.
ACh released can activate muscarinic
receptors on effector organs;
ACh released can interact with muscarinic
receptors on nerve terminals to inhibit the
release of their neurotransmitter
Result of activation of muscarinic
receptors:
1. activation of the IP3, DAG cascade. DAG →
opening of smooth muscle Ca channels; IP3
→ release of Ca from endoplasmic and
sarcoplasmic reticulum.
2. ↑ cGMP.
3. ↑ K+ flux across cardiac cell membranes and
↓ it in ganglion and smooth muscle cells (by
binding of an activated G protein directly to
the channel).
4. in some tissues (eg, heart, intestine)
↓adenylyl cyclase activity.
The mechanism of nicotinic receptor
activation:
Nicotinic receptors NN and NM are ion channels
binding an agonist → channel opening → Na+ and
K+ ions diffuse rapidly down their concentration
gradients → depolarization of the postsynaptic
membrane.
In case of prolonged agonist occupancy of the
receptor, the effector response is abolished; ie,
the postganglionic neuron stops firing-ganglionic
effect-), and the skeletal muscle cell relaxesneuromuscular endplate effect“depolarizing blockade”
Effects of direct-acting cholinoceptor stimulants. Only the direct
effects are indicated; homeostatic responses to these direct actions
may be important.
Organ
Response
Eye
Sphincter muscle of iris
Contraction (miosis)
Ciliary muscle
Contraction for near vision (accomodation)
Heart
Sinoatrial node
Decrease in rate (negative chronotropy)
Atria
Decrease in contractile strength (negative
inotropy). Decrease in refractory period
Atrioventricular node
Decrease in conduction velocity (negative
dromotropy). Increase in refractory period
Ventricles
Small decrease in contractile strength
Blood vessels
Arteries
Dilation (via EDRF). Constriction (high-dose
direct effect)
Veins
Dilation (via EDRF). Constriction (high-dose
direct effect)
Effects of direct-acting cholinoceptor stimulants (cont’d)
Lung
Bronchial muscle
Contraction (bronchoconstriction)
Bronchial glands
Stimulation
Gastrointestinal tract
Motility
Increase
Sphincters
Relaxation
Secretion
Stimulation
Urinary bladder
Detrusor
Contraction
Trigone and sphincter
Relaxation
Glands
Sweat, salivary, lacrimal,
nasopharyngeal
Secretion
Organ System Effects
1. Eyecontraction of iris sphincter (miosis)
contraction of the ciliary muscle
(accommodation).
the iris is pulled away from the angle of the
anterior chamber→the trabecular meshwork
at the base of the ciliary muscle is opened up
→ ↑outflow of aqueous humor into the canal
of Schlemm (drains the anterior chamber)→ ↓
intraocular pressure (IOP)
The net effect on the heart rate depends on local
concentrations of the agonist in the heart and in the
Organ System Effects (cont’d)
vessels and on the level of reflex responsiveness
2. Cardiovascular system (heart)
Primary effects of muscarinic agonists:
(1) ↓in peripheral vascular resistance & (2)
changes in HR (all mediated by M2)
direct effects on heart rate are modified by
homeostatic reflexes.
- I.V. infusions of of min effective dose of Ach (2050 g/min) → vasodilation → ↓BP → reflex ↑in HR
- Larger doses of ACh → bradycardia and ↓
conduction velocity through the AV node in
addition to ↓BP
Organ System Effects
2. Cardiovascular system (the
vessels)
In the intact organism, muscarinic agonists
produce marked vasodilation (EDRF (largely NO)
 ↑ c-GMP)
Isolated blood vessels Ach contraction
Organ System Effects
Exception: Pilocarpine if given I.V. may
produce hypertension after a brief initial
hypotensive response.
The longer-lasting ↑ BP is due to sympathetic
ganglionic discharge caused by activation of M1
receptors in the postganglionic cell membrane,
which close K+ channels and elicit slow
excitatory (depolarizing) postsynaptic
potentials smooth muscle contraction ↑ BP
This effect can be blocked by atropine
(antimuscarinic agent)
Organ System Effects
5. Genitourinary tract
stimulation of detrusor muscle and relaxation
of trigone and sphincter muscles of the
bladder→↑voiding.
human uterus is not notably sensitive to
muscarinic agonists.
6. Miscellaneous secretory glands:
muscarinic agonists ↑secretion of
thermoregulatory sweat, lacrimal, and
nasopharyngeal glands
Organ System Effects
7. CNS
contains both muscarinic and nicotinic
receptors,
Brain: mainly muscarinic sites
Spinal cord: mainly nicotinic sites.
However, nicotine has an effect on brain
stem and cortex (what is it?)
Nicotine effects on CNS:
The mild alerting action of nicotine absorbed
from inhaled tobacco is best known of
nicotine effects on brainstem and cortex
In higher concentrations → nicotine induces
tremor, emesis, and stimulation of the
respiratory center
At still higher concentrations→ convulsions
and fatal coma
Organ System Effects (cont’d)
8. Peripheral nervous system
The autonomic ganglia are important sites of
nicotinic synaptic action
Nicotinic agonists cause marked activation of
these nicotinic receptors and initiate AP in
postganglionic neurons
Nicotine itself has greater affinity for NN than
for NM
The action is the same on both
parasympathetic and sympathetic ganglia
Organ System Effects (cont’d)
8. Peripheral nervous system
In cardiovascular system, the effects of
nicotine are chiefly sympathomimetic: IV
injection of nicotine →↑BP & sympathetic
tachycardia may alternate with a vagally
mediated bradycardia.
In the GI and urinary tracts, the effects are
largely parasympathomimetic: nausea,
vomiting, diarrhea, voiding of urine
Prolonged exposure: depolarizing blockade of
ganglia
Organ System Effects
9. Neuromuscular
nicotinic agonist applied directly → immediate
depolarization of the neuromuscular endplate
(  permeability Na+ & K+)→ contraction of muscle;
depolarizing nicotinic agents that are not
rapidly hydrolyzed (eg, nicotine): rapid
development of depolarization blockade;
transmission blockade persists even when the
membrane has repolarized (flaccid paralysis)