CHOLINERGIC DRUGS(Parasympathomimetics,

Cholinomimetics)

Assoc. Prof. I. LambevE-mail: itlambev@mail.bg

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 independentin 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 consciouslycontrolled functions such as movement, respiration, and posture.

Nerve impulses elicit responses in smooth, cardiac, and skeletal muscles, exocrine glands, andpostsynaptic neurons by liberating specificchemical neurotransmitters.

By using drugs that mimic or block the actions of chemicaltransmitters, we can selectively modify many autonomic functions. These functions involve a variety of effectortissues, 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 andthe 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 theCNS through the thoracic and lumbar spinal nerves. The parasympathetic preganglionic fibers leave theCNS through the cranial nerves (especially the third,seventh, ninth, and tenth) and the third and fourthsacral spinal roots.

Parasympathetic nerves regulate processes connected with energy assimilation (food intake,digestion, absorption) and storage.These processes operate when the bodyis at rest, allowing increased bronchomotor toneand decreased cardiac activity. Secretion of salivaand intestinal fluids promotes the digestion of foodstuffs; transport of intestinal contents is speeded up because of enhanced peristaltic activityand lowered tone of sphincter muscles. To empty the urinary bladder (micturition), wall tension is increased by detrusor activationwith a concurrent relaxation of sphincter tonus.

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

ACh serves as mediator at terminalsof all postganglionic parasympatheticfibers, 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.

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 classifiedinto subtypes according to their molec-ular structure, signal transduction, andligand 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 actionof ACh on muscle tone is indirect, because it involves stimulation ofM3-cholinoceptors on endothelial cells

that respond by liberating NO.

In the CNS, where all subtypes are present, cholinoceptors serve diversefunctions, 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 fromnoradrenergic 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 with5 subunits, which arearranged like a rosettesurrounding the Na+

channel. The two alphasubunits carry two AChbinding sites with nega-tively charged groupswhich combine with thecationic group of AChand open Na+ channel.

N-receptor: 5 subunits

Acetylcholine receptor stimulants and cholinesterase inhibitors together comprise a large group of drugsthat mimic ACh (cholinomimetic agents)

Cholinoceptor stimulants are classified by theirspectrum 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 binddirectly to (and activate) cholinoceptors, while others act indirectly by inhibiting the hydrolysisof 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

N4+

Ionization!!!

BBB

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A B C D1 min

M- и N-effects of AChB

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ACh2 mcg i.v.

ACh50 mcg

ACh50 mcg

ACh5 mg

M-effect

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N-effect

Atropine2 mg i.v.

Pilocarpus jaborandi

•Pilocarpine - in glaucoma

Pilocarpine Hydrochlorideeye drops (Pilocar®)- sol. 1%, 2%, 4%- in open angle glаucomaApplied to the eye, it penetrates cornea and promptly causesmiosis, ciliary muscle contra-ction, and fall in intraocculartension (< 22 mm) lasting 4-8 h.Side effect: painful spasm ofaccommodation for near vision.Systemic effects: sweating, salivationCardiovascular effects: in small doses – fall in BP, but in highdoses elicits rise in BP and tachycardia, probably due toganglionic stimulation (through muscarinic receptors)

Development ofangle closure glaucoma and

its reversal by miotics

A. Mydriasis occurs in an eye with narrow iridocorneal angleand the iris makes contact with the lens blocking passage oftheaqueous 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 lensremoving the pupillary block and restoring aqueous drainage.

Autonomiccontrolof pupil (A) and siteof action ofmydriatics (B)andmiotics (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 fromhydrolysis. They produce cholinergic effectsand potentiates ACh both in vivo and in vitro.

Lipid soluble agents (physostigmine andorganophosphates) have more markedmuscarinic and CNS effects, stimulates ganglia but action on skeletal muscles is lessprominent (NB: the action of Galantamineon skeletal muscles is much stronger in comparison with neostigmine).

Lipid insoluble antiChEs (neostigmine andother quaternary ammonium compounds)produce more marked effect on the skeletalmuscles (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.

Prof. D. Paskov (1914–1986)

Galantamine(Nivalin®)

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

Myasthenia gravis (MG) is a disease affecting skeletal muscleneuromuscular junctions. An autoimmune process causesproduction of antibodies that bind to the a subunits of the nicotinic receptor. This effect causes accelerated degradationof the receptor and blockade of ACh binding to receptors onmuscle end plates. Frequent findings are ptosis, diplopia, difficulty in speaking and swallowing, and extremity weakness.Severe disease may affect all the muscles, including thosenecessary for respiration. The disease resembles the neuromuscular paralysis producedby tubocurarine and similar nondepolarizing neuromuscularblocking drugs. Patients with myasthenia aresensitive to the action of curariform drugs and other drugs thatinterfere with neuromuscular transmission e.g., aminoglycosideantibiotics. Anti-ChEs are extremely valuable as therapyfor 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) myasthenicneuromuscular junctions. The MG junction has a normal nerve terminal; a reduced numberof 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.

Enlargement ventricles

Diminished hypothalamus

Thin brain cortex

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 treatmentof intoxication with organophosphates