Download Cholinergic drugs

CHOLINERGIC DRUGS
(Parasympathomimetics,
Cholinomimetics)
Assoc. Prof. I. Lambev
E-mail: [email protected]
The motor (efferent) portion of the nervous system can be divided
into two major subdivisions: autonomic and somatic.
The autonomic nervous system (ANS) is largely independent
in that its activities are not under direct conscious control.
It is concerned primarily with visceral functions such as
cardiac output, blood flow to various organs, and digestion,
which are necessary for life.
The somatic division is largely concerned with consciously
controlled functions such as movement, respiration, and posture.
Nerve impulses elicit responses in smooth, cardiac,
and skeletal muscles, exocrine glands, and
postsynaptic neurons by liberating specific
chemical neurotransmitters.
By using drugs that mimic or block the actions of chemical
transmitters, we can selectively modify many autonomic
functions. These functions involve a variety of effector
tissues, including cardiac muscle, smooth muscle,
vascular endothelium, exocrine glands, and
presynaptic nerve terminals.
Autonomic drugs are useful in many clinical conditions.
The ANS has two major portions:
the sympathetic (thoracolumbar) division and
the parasympathetic (craniosacral) division.
Both divisions originate in nuclei within the CNS
and give rise to preganglionic efferent fibers that
exit from the brain stem or spinal cord and
terminate in motor ganglia.
The sympathetic preganglionic fibers leave the
CNS through the thoracic and lumbar spinal nerves.
The parasympathetic preganglionic fibers leave the
CNS through the cranial nerves (especially the third,
seventh, ninth, and tenth) and the third and fourth
sacral spinal roots.
Parasympathetic nerves regulate processes
connected with energy assimilation (food intake,
digestion, absorption) and storage.
These processes operate when the body
is at rest, allowing increased bronchomotor tone
and decreased cardiac activity. Secretion of saliva
and intestinal fluids promotes the digestion of
foodstuffs; transport of intestinal contents is
speeded up because of enhanced peristaltic activity
and lowered tone of sphincter muscles.
To empty the urinary bladder (micturition),
wall tension is increased by detrusor activation
with a concurrent relaxation of sphincter tonus.
Activation of ocular
parasympathetic
fibers results in narrowing of the pupil
and increased curvature of the lens,
enabling near
objects to be
brought into focus
(accommodation).
ACh serves as mediator at terminals
of all postganglionic parasympathetic
fibers, in addition to fulfilling its transmitter role at ganglionic synapses within both the sympathetic and parasympathetic divisions and the motor endplates on striated muscle. However, different types of receptors are present at
these synaptic junctions.
CHOLINERGIC NERVES
ACh is highly concentrated in
synaptic storage vesicles present in
the axoplasm of the terminal. ACh
is formed from choline and
activated acetate acetylcoenzyme
A, a reaction catalyzed by the
enzyme choline acetyltransferase.
The highly polar choline is actively
transported into the axoplasm. The
specific choline transporter is
localized exclusively to membranes
of cholinergic axons and terminals.
During activation of the nerve
membrane, Ca2+ enters into the
axoplasm through voltage-gated
channels to activate protein kinases. As
a result, vesicles close to the presynaptic
membrane and fuse with this membrane.
During fusion, vesicles discharge their
contents into the synaptic gap. ACh
quickly diffuses through the synaptic gap.
The molecule of ACh is a little longer
than 0.5 nm. The synaptic gap is as
narrow as 30–40 nm.
At the postsynaptic effector cell membrane, ACh
reacts with its receptors. Because these receptors
can also be activated by the alkaloid muscarine,
they are referred to as muscarinic (M-)
cholinoceptors. In contrast, at ganglionic and motor
endplate cholinoceptors, the action of ACh is
mimicked by nicotine and they are,
therefore, said to be nicotinic (N-) cholinoceptors.
Released ACh is rapidly hydrolyzed and
inactivated by a specific acetylcholine esterase,
present on pre- and postjunctional membranes, or
by a less specific serum choline esterase (butyryl
choline esterase), a soluble enzyme present in
serum and interstitial fluid.
M-cholinoceptors can be classified
into subtypes according to their molecular structure, signal transduction, and
ligand affinity in the M1, M2, M3 subtypes, etc.
M1-receptors are present on nerve cells, e.g.,
in ganglia, where they mediate a facilitation of
impulse transmission from preganglionic axon
terminals to ganglion cells.
M2-receptors mediate acetylcholine effects on
the heart. Opening of K+ channels leads to
slowing of diastolic depolarization in sinoatrial
pacemaker cells and a decrease in heart rate.
M3-receptors are found in the glandular
epithelia (which respond with activation of
phospholipase C and increases secretory
activity) and in smooth muscle.
In smooth vessels, the relaxant action
of ACh on muscle tone is indirect,
because it involves stimulation of
M3-cholinoceptors on endothelial cells
that respond by liberating NO.
In the CNS, where all subtypes are present,
cholinoceptors serve diverse
functions, including regulation of cortical
excitability, memory, learning, pain processing,
and brain stem motor control.
Muscarinic receptor (G protein-linked: 7 subunits)
Presynaptic regulation of transmitter release from
noradrenergic and cholinergic nerve terminal
Characteristic of Nicotinic receptors
NM-cholinoceptors
Location: neuromuscular junction
Function: depolarization of muscle end
plate and contraction of skeletal muscle
NN-cholinoceptors
Location: autonomic ganglia
Function: depolarization
postganglonic membrane
(in adrenal medula –
catecholamine release)
The NM-receptor
is a macroprotein with
5 subunits, which are
arranged like a rosette
surrounding the Na+
channel. The two alpha
subunits carry two ACh
binding sites with negatively charged groups
which combine with the
cationic group of ACh
and open Na+ channel.
N-receptor: 5 subunits
Acetylcholine receptor stimulants
and cholinesterase inhibitors
together comprise a large group of drugs
that mimic ACh (cholinomimetic agents)
Cholinoceptor stimulants are classified by their
spectrum of action depending on the type
of receptor – muscarinic or nicotinic, that is activated.
They are also classified by their mechanism of
action because some cholinomimetic drugs bind
directly to (and activate) cholinoceptors, while
others act indirectly by inhibiting the hydrolysis
of endogenous ACh.
I. DIRECT-ACTING CHOLINERGIC DRUGS
(1) Choline ester
(stimulants of M- and N-receptors):
Acetylcholine, Carbachol, etc.
(2) Alkaloids
a) stimulants of M-receptors:
Pilocarpine, Cevimeline (dry mouth),
Bethanechole, Musacarine, Phalloidin
b) stimulants of N-receptors:
Nicotine, Cytisine (Tabex®), Lobeline
4+
N
Ionization!!!
BBB
M- и N-effects of ACh
Blood pressure [mm Hg]
A 1 min
B
C
D
200
150
100
50
M-
M-
effect
effect
ACh
2 mcg i.v.
ACh
50 mcg
Neffect
ACh
Atropine ACh
2 mg i.v. 50 mcg 5 mg
Pilocarpus
jaborandi
•Pilocarpine
- in glaucoma
Pilocarpine Hydrochloride
eye drops (Pilocar®)
- sol. 1%, 2%, 4%
- in open angle glаucoma
Applied to the eye, it
penetrates cornea and
promptly causes
miosis, ciliary muscle contraction, and fall in intraoccular
tension (< 22 mm) lasting 4-8 h.
Side effect: painful spasm of
accommodation for near vision.
Systemic effects:
sweating, salivation
Cardiovascular effects: in small doses – fall in BP, but in high
doses elicits rise in BP and tachycardia, probably due to
ganglionic stimulation (through muscarinic receptors)
Development of
angle closure
glaucoma and
its reversal
by miotics
A. Mydriasis occurs in an eye with narrow iridocorneal angle
and the iris makes contact with the lens blocking passage of
theaqueous from the posterior to the anterior chamber.
B. Possibly builds up behind the iris which bulges forward and
closes the iridocorneal angle thus blocking aqueous outflow.
C. Miotic makes the iris thin and pushes it away from the lens
removing the pupillary block and restoring aqueous drainage.
Autonomic
control
of pupil (A)
and site
of action of
mydriatics (B)
and
miotics (C)
Amanita muscaria (muscarine)
Amanita phalloides (phalloidine)
Cytisine (Tabex® p.o.)
Nicorette (chewing gum)
Nicotinell® TTS
II. INDIRECT-ACTING CHOLINERGIC DRUGS
(anticholinesterase drugs: antiChEs)
(1) Reversible drugs (most are carbamates)
a) With N3+ (cross BBB)
Alkaloids: Galantamine, Physostigmine
Synthetic drugs:
Donepezil, Rivastigmine, Tacrine
b) With N4+ (do not cross BBB)
Demecarium, Edrophonium (Tensilon®)
Neostigmine, Pyridostigmine
(2) Irreversible anticholinesterase agents
(most of them are organophosphates)
a) Thiophosphate insecticides
Parathion
Malathion (Pedilin® – in pediculosis)
b) Nerve paralytic gases
for chemical warfare
Tabun
Sarin
Soman
Representative "reversible" anticholinesterase agents employed clinically
AntiChEs inhibit ChE and protect ACh from
hydrolysis. They produce cholinergic effects
and potentiates ACh both in vivo and in vitro.
Lipid soluble agents (physostigmine and
organophosphates) have more marked
muscarinic and CNS effects, stimulates
ganglia but action on skeletal muscles is less
prominent (NB: the action of Galantamine
on skeletal muscles is much stronger in
comparison with neostigmine).
Lipid insoluble antiChEs (neostigmine and
other quaternary ammonium compounds)
produce more marked effect on the skeletal
muscles (direct action on muscle end-plate
NN-cholinoceptors as well).
Stimulate ganglia but muscarinic effects
are less prominent.
They do not penetrate in CNS and
have no central effects.
Galantamine is antiChEs
with direct N-action used in:
•Myastenia gravis
•Alzheimer’s disease
•Poliomyelitis
•Postoperative paresis of GIT and bladder
•As antagonist of competitive
myorelaxants with less
side effects than neostigmine
Prof. D. Paskov
(1914–1986)
Galantamine
(Nivalin®)
Myasthenia gravis (MG) is a disease affecting skeletal muscle
neuromuscular junctions. An autoimmune process causes
production of antibodies that bind to the a subunits of the
nicotinic receptor. This effect causes accelerated degradation
of the receptor and blockade of ACh binding to receptors on
muscle end plates. Frequent findings are ptosis, diplopia,
difficulty in speaking and swallowing, and extremity weakness.
Severe disease may affect all the muscles, including those
necessary for respiration.
The disease resembles the neuromuscular paralysis produced
by tubocurarine and similar nondepolarizing neuromuscular
blocking drugs. Patients with myasthenia are
sensitive to the action of curariform drugs and other drugs that
interfere with neuromuscular transmission e.g., aminoglycoside
antibiotics. Anti-ChEs are extremely valuable as therapy
for myasthenia. Almost all patients are also treated with
immunosuppressant drugs and some with thymectomy.
Edrophonium is used as a diagnostic test in myasthenia gravis.
Diagrams of (A) normal and (B) myasthenic
neuromuscular junctions. The MG junction
has a normal nerve terminal; a reduced number
of AChRs and a widened synaptic space.
• In the Alzheimer’s disease in the brain
tissue there are amyloid plaques and
neurofibrillarly tangles, as well as loss
of cholinergic neurons.
• Cholinacetyl trasferase activity
in the cortex and hippocampus
is reduced from 30% to 70%.
• Loss of cholinergic neurons contributes
for to much of the learning and memory deficit.
• The number of M-cholinoceptors is not
affected, but the number of N-receptors
is reduced.
Thin brain cortex
Enlargement ventricles
Diminished hypothalamus
Alzheimer's disease
Reversible anti-AChEs used in:
•Glaucoma: pilocarpine, demecarium
•Myasthenia gravis: edrophonium, galantamine,
neostigmine, physostigmine, pyridostigmine
•Alzheimer’ disease: donepezil, galantamine,
aminopyridine (Pymadine®), rivastigmine, tacrine
•Postoperative paralytic ileus or/and urinary
retention: galantamine, neostigmine
•Postoperative decurarization: galantamine,
neostigmine, pymadine (it releases ACh!)
•Belladonna poisoning: physostigmine,
neostigmine, galantamine
•Cobra bite (cobra venom has a curare-like
neurotoxin): galantamine, neostigmine
Reactivators of ChE used for the treatment
of intoxication with organophosphates