1. CHOLINERGIC DRUGS
(Parasympathomimetics,
Cholinomimetics)

2. Nerve impulses elicit responses in smooth, cardiac,
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.

3. 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.

4. 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.

6. 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.

7. Activation of ocular
parasympathetic
fibers results in nar-
rowing of the pupil
and increased curva-
ture of the lens,
enabling near
objects to be
brought into focus
(accommodation).

8. ACh serves as mediator at terminals
of all postganglionic parasympathetic
fibers, in addition to fulfilling its trans-
mitter role at ganglionic synapses with-
in both the sympathetic and parasym-
pathetic divisions and the motor end-
plates on striated muscle. However, dif-
ferent types of receptors are present at these synaptic junctions.

9. CHOLINERGIC NERVES

10. 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.

12. 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.

13. 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.

15. M-cholinoceptors can be classified
into subtypes according to their molec-
ular 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.

16. M3-cholinoceptors on endothelial cells
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.

17. Muscarinic receptor (G protein-linked: 7 subunits)

18. Presynaptic regulation of transmitter release from
noradrenergic and cholinergic nerve terminal

19. 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)

20. and open Na+ channel. 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 nega-
tively charged groups
which combine with the
cationic group of ACh
and open Na+ channel.

21. N-receptor: 5 subunits

22. 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.

23. (1) Choline ester (2) Alkaloids I. DIRECT-ACTING CHOLINERGIC DRUGS
(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

24. N4+
Ionization!!!
BBB

25. M- и N-effects of ACh A B C D M- M- N- 5 mg 1 min 200 150 100 effect
Blood pressure [mm Hg]
100 M-
effect M-
effect N-
effect 50
ACh
2 mcg i.v.
ACh
50 mcg
Atropine
2 mg i.v.
ACh
50 mcg
ACh
5 mg

27. Pilocarpus
jaborandi
Pilocarpine
- in glaucoma

28. 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 contra-
ction, 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)

29. A. Mydriasis occurs in an eye with narrow iridocorneal angle
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.

30. Autonomic
control
of pupil (A)
and site
of action of
mydriatics (B)
and
miotics (C)

31. Amanita muscaria (muscarine)
Amanita phalloides (phalloidine)

32. Cytisine (Tabex® p.o.)
Nicorette (chewing gum)
Nicotinell® TTS

33. 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

34. (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

35. Representative "reversible" anticholinesterase agents employed clinically

36. 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).

37. 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.

38. Prof. D. Paskov Galantamine (Nivalin®) (1914–1986)
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®)

39. 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.

40. Toxicity Direct-Acting Muscarinic Stimulants
Varies markedly depending on their absorption, access to the CNS, and metabolism.
Direct-Acting Muscarinic Stimulants
Pilocarpine and the choline esters over dosage cause: nausea, vomiting, diarrhea, urinary urgency, salivation, sweating, cutaneous vasodilation, and bronchial constriction.
The effects are all blocked competitively by atropine
Certain mushrooms, contain muscarinic
alkaloids. Ingestion of these mushrooms
causes typical signs of muscarinic excess
within 15–30 minutes.
Treatment is with atropine, 1–2 mg parenterally. (Amanita muscaria, the first source of muscarine, contains very low concentrations of the alkaloid.)

41. Direct-Acting Nicotinic Stimulants
Acute Toxicity
The fatal dose of nicotine is 40 mg, or 1 drop of the pure liquid. This is the amount of nicotine in two regular cigarettes. Fortunately, most of the nicotine in cigarettes is destroyed by burning or escapes via the "side stream" smoke.
Ingestion of nicotine insecticides or of tobacco by infants and children is usually followed by vomiting, limiting the amount of the alkaloid absorbed.
Toxic effects of a large dose of nicotine are:
(1) central stimulant actions, which cause convulsions and may progress to coma and respiratory arrest;
(2) skeletal muscle end plate depolarization, which may lead to depolarization blockade and respiratory paralysis.
(3) hypertension and cardiac arrhythmias.
Treatment of acute poisoning is symptom-directed.

42. Muscarinic excess resulting from parasympathetic ganglion stimulation can be controlled with atropine.
Central stimulation is usually treated with parenteral anticonvulsants such as diazepam. Neuromuscular blockade is not responsive to pharmacologic treatment and may require mechanical respiration.
Fortunately, nicotine is metabolized and excreted relatively rapidly. Patients who survive the first 4 hours usually recover completely if hypoxia and brain damage have not occurred.

43. Chronic Nicotine Toxicity
Nicotine contributes to the increased risk of vascular disease and sudden coronary death associated with smoking. Also, the high incidence of ulcer recurrences in smokers. Replacement therapy with nicotine in the form of gum, transdermal patch, nasal spray, or inhaler are used to help patients stop smoking.
Varenicline
Has partial agonist action at central nicotinic receptors. It also has antagonist properties that persist because of its long half-life; this prevents the stimulant effect of nicotine at presynaptic nicotinic receptors that cause release of dopamine.
its use is limited by nausea and insomnia and also by exacerbation of psychiatric illnesses, including anxiety and depression.

44. Cholinesterase Inhibitors
The major source of intoxications is pesticide use in agriculture and in the home.
pesticides can cause slowly or rapidly developing symptoms which persist for days.
chemical warfare agents (soman, sarin, VX) induce effects rapidly because of the large concentrations present.
. Miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea.
CNS involvement (cognitive disturbances, convulsions, and coma) usually follows rapidly, accompanied by peripheral nicotinic effects, especially depolarizing neuromuscular blockade.

45. Therapy always includes:
(1) maintenance of vital signs—respiration in particular may be impaired.
(2) decontamination to prevent further absorption.
(3) atropine parenterally in large doses, given as often as required to control signs of muscarinic excess.
Therapy often also includes treatment with pralidoxime, and benzodiazepines for seizures.
Preventive therapy for cholinesterase inhibitors
Used as chemical warfare agents has been developed to protect soldiers and civilians. Personnel are given autoinjection syringes containing pyridostigmine, and atropine.

46. Chronic exposure to certain organophosphate compounds causes delayed neuropathy associated with demyelination of axons.
The effects are not caused by cholinesterase inhibition but rather by neuropathy target esterase (NTE) inhibition whose symptoms (weakness of upper and lower extremities, unsteady gait) appear 1–2 weeks after exposure.
Another nerve toxicity called intermediate syndrome occurs 1–4 days after exposure to organophosphate insecticides. This syndrome is also characterized by muscle weakness; its origin is not known but it appears to be related to cholinesterase inhibition.

47. 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

48. Reactivators of ChE used for the treatment
of intoxication with organophosphates