Cholinomimetic drugs

I.Yu. Vysotsky, R.A. Chramova,

A.A. Kachanova

DRUGS AFFECTING PERIPHERAL NERVOUS SYSTEM

(for foreign students being educated in English)

Sumy

Publishers SumSU

Навчальне видання

I.Yu. Vysotsky

R.A. Chramova

A.A. Kachanova

DRUGS AFFECTING PERIPHERAL NERVOUS SYSTEM

(for foreign students being educated in English)

Редактор Н.А. Гавриленко

Комп`ютерне верстання А.А. Качанової

Підписано до друку 09.07.2009, поз.

Формат 60 х 84/16. Папір офс. Гарнітура Times New Roman Cyr. Друк офс.

Ум. друк. арк. 3,72. Обл.-вид. арк. 3,91.

Наклад 100 пр. Замовлення №

Вид-во СумДУ при Сумському державному університеті

40007, м. Суми, вул. Р.-Корсакова, 2

Свідоцтво про внесення суб`єкта видавничої справи до Державного реєстру ДК № 3062 від 17.12.2007 р.

Надруковано у друкарні СумДУ

40007, м. Суми, вул. Р.-Корсакова, 2

MINISTRY OF PUBLIC HEALTH UKRAINE

MINISTRY OF EDUCATION AND SCIENCE UKRAINE

SUMY STATE UNIVERSITY

I.Yu. Vysotsky,

R.A. Chramova,

A.A. Kachanova

DRUGS AFFECTING PERIPHERAL NERVOUS SYSTEM

(for foreign students being educated in English)

Sumy

Publishers SumSU

CHOLINOMIMETIC DRUGS

The nervous system is divided into two divisions: the central nervous system (brain and spinal cord) and peripheral nervous system. Peripheral nervous system is divided into the afferent (or sensory) part and efferent part. The neurons of afferent part bring information from the periphery to the CNS. The efferent neurons carry information from the CNS to the peripheral tissues. Efferent division includes autonomic system and somatic neurons.

The autonomic nervous system carries impulses from the CNS to the inner organs by way of two types neurons. The first neuron is called a preganglionic neuron. Its cell body is located within the CNS. Preganglionic neurons make a synaptic connection in ganglia. The ganglia function as relay stations between the preganglionic neuron and a second nerve cell or postganglionic neuron. The endings of postganglionic neurons contact with cells of inner organs. The efferent somatic nervous system travels directly to skeletal muscles without the mediation of ganglia. The somatic nervous system is under voluntary control, whereas the autonomic system is an involuntary one.

Autonomic nervous system is divided into the sympathetic and parasympathetic parts. The preganglionic neurons of the sympathetic nervous system have their cell bodies within the thoracic and lumbar regions of the spinal cord – the thoracolumbar division. The preganglionic neurons of the parasympathetic division have their cell bodies in the brainstem and in the sacral region of the spinal cord – the craniosacral division. The cranial part of the parasympathetic nervous system innervates the head, neck, thorax, and abdomen (the stomach, part of intestines and pancreas). The cranial parasympathetic fibers leave the CNS in the oculomotor, facial, glosopharyngeal and vagal cranial nerves. Approximately 75% of the parasympathetic fibers are contained within the vagus nerve. The sacral division of the parasympathetic nervous system innervates the remainder of the intestines and the pelvic viscera.

The sympathetic ganglia consist of two chains of 22 segmentally arranged ganglia, which are located laterally to the vertebral column. Because the sympathetic ganglia are located close to the vertebral column, their preganglionic fibers are generally short. But postganglionic fibers are generally long, since they arise in vertebral ganglia and must travel to the innervated effector cells. In contrast, the parasympathetic ganglia are located very close to (or actually within) the organs innervated by the parasympathetic postganglionic neurons. As a rule, all inner organs have both the sympathetic and parasympathetic innervation. Sympathetic and parasympathetic systems work in opposition one to another.

Communication between nerve cells - and between nerve cells and effector organs - occurs through the release of specific chemical substances from nerve terminals. These substances are called neurotransmitters. The neurotransmitters rapidly diffuse across the synaptic cleft (synapse) between nerve endings and bind with specific receptors on the postsynaptic cell.

In the autonomic nervous system the two main neurotransmitters exist. They are acetylcholine and noradrenaline (norepinephrine).

The neurotransmission in the PNS occurs in three major sites:

1) the synapses of both parasympathetic and sympathetic ganglia;

2) the parasympathetic and sympathetic postganglionic neuroeffector junctions;

3) the end plates on skeletal muscle.

Acetylcholine is released in all of these sites except of the majority of sympathetic neuroeffector junctions. Neurons that release acetylcholine are called cholinergic neurons.

Noradrenaline is released in most of sympathetic postganglionic neuroeffector junctions. Neurons that release this substance are called adrenergic or noradrenergic neurons.

But some sympathetic postganglionic neurons are cholinergic. The sympathetic postganglionic neurons that innervate the sweat glands and some of the blood vessels in skeletal muscle, release acetylcholine rather than noradrenaline. But anatomically they are sympathetic neurons.

Figure 1. - The scheme of efferent innervation

Although most tissues receive dual innervation, some effector organs, such as the adrenal medulla, kidneys, pilomotor muscles, and sweat glands receive innervation only from the sympathetic system. The control of blood pressure is also mainly a sympathetic activity.

Adrenal medulla, like the sympathetic ganglia, receives preganglionic fibers of the sympathetic system. The cells of the adrenal medulla (called as chromaffin cells) are homologous with sympathetic postganglionic neurons. The adrenal medulla may be considered as a modified sympathetic ganglion. The adrenal medulla secretes two hormones. First is noradrenaline, which is also the primary neurotransmitter of sympathetic postganglionic neurons. The other medullary hormone is adrenaline. General activation of the sympathetic system during stress, fear, or anxiety is accompanied by increased secretion of adrenal medullary hormones, which in the human primarily consist of adrenaline. The CNS regulates the secretory activity of the adrenal medulla.

The activity of autonomic nervous system may be changed by means of different medicines. Drugs affecting the autonomic nervous system are divided into two groups according to the type of neuron involved in their mechanism of action. There are cholinergic and adrenergic drags. The cholinergic drugs act on the receptors that are activated by acetylcholine. The adrenergic drugs act on receptors that are stimulated by norepinephrine.

Drugs which influence parasympathetic nervous system are divided into cholinomimetic drugs ( they excite cholinergic receptors) and cholinoblockers (they bind with cholinergic receptors and prevent its excitation).

Cholinergic synapses are located:

- in all vegetative ganglia;

- in the inner organs near the endings of the parasympathetic postganglionic fibers;

- in the medullary substance of the adrenal glands;

- in the skeletal muscles;

- in the carotid glomeruli;

- in the vessels of skeletal muscles;

- in the CNS.

Structure of cholinergic synapse is following. As well as all other synapses, cholinergic synapse consists of pre-synaptic membrane, synaptic cleft, and postsynaptic membrane, within which the cholinergic receptors are located.

Neurotransmission in cholinergic synapse involves six steps.

1. The synthesis of acetylcholine. Acetylcholine is synthesized by the means of choline-acetyltransferase from choline and acetyl CoA in the cytosol of preganglionic neuron’s endings.

2. Storage of acetylcholine. The acetylcholine is packaged into vesicles by an active transport process coupled to the efflux of protons.

3. Release of acetylcholine. When an action potential propagated by the action of voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels in the presynaptic membranes open, causing an increase in the concentration of intracellular calcium. Elevated calcium levels promote the function of synaptic vesicles with the cell membrane and release of acetylcholine into the synapse. (For the information, this process is blocked by botulinum toxin. By contrast, black widow spider venom causes all of the cellular acetylcholine stored in synaptic vesicles to spill into the synaptic gap).

4. Interaction with cholinoceptor. Acetylcholine released from the synaptic vesicles diffuses across the synaptic space and binds to either postsynaptic receptors on the target cell or to presynaptic receptors in the membrane of the neuron that released the acetylcholine. Binding to the receptor leads to a biological response within the cell.

5. Degradation of acetylcholine. After the interaction with cholinoceptors, acetylcholine is destroyed by the enzyme “acetylcholinesterase”. This enzyme cleaves acetylcholine to choline and acetate. A rapid hydrolysis of acetylcholine by the enzyme results in a lowering of the concentration of free transmitter and a rapid dissociation of the transmitter from its receptors.

6. Recycling of choline. Choline undergoes the reverse capture by the nerve ending, where it is acetylated and stored into vesicles.

There are two families of cholinoceptors. They are muscarinic (M-) and nicotinic (N-) ones.

The M-cholinoceptors have a following structure. The seven transmembrane helices of muscarinic receptors have a ringlike organization in the cell membrane that forms a narrow central cleft where ACh binds. At least seven amino acids from four transmembrane helices have been implicated in agonist binding to the muscarinic receptors. Some of these residues, particularly a negatively charged aspartate, interact electrostatically with the positively charged quaternary ammonium moiety of ACh, whereas other residues are required for binding to the ester moiety. The muscarinic receptors have a wide distribution and many functional roles. To understand the actions of cholinomimetic drugs it is important to know that muscarinic receptors have following functions:

1. They mediate the activation of effectors by acetylcholine released from parasympathetic nerve endings;

2. M-cholinoceptors mediate the activation of sweat glands by acetylcholine released from sympathetic fibers;

3. These receptors are found on vascular endothelial cells that receive no cholinergic innervation;

4. M-cholinoceptors are widely distributed in the central nervous system, from basal ganglia to neocortex.

5. They are present on presynaptic nerve terminals, including terminals that release acetylcholine and terminals associated with other neurotransmitter systems, such as the catecholamines.

Five subtypes of M-cholinoceptors now are known. The different subtypes of muscarinic receptors are heterogeneously distributed:

1. M₁-receptors are present in brain, exocrine glands, and autonomic ganglia;

2. M₂-receptors are found in the heart, brain, autonomic ganglia and smooth muscle;

3. M₃-receptors are present in smooth muscle, exocrine glands, brain, and endothelial cells;

4. M₄-receptors are present in brain and autonomic ganglia;

5. M₅-receptors are found in the CNS.

Activation of M₁, M₃ and M₅ receptors produces an inosine triphosphate mediated release of intracellular calcium, the release of diacylglycerol (which can activate protein kinase C), and stimulation of adenylyl cyclase. These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle.

Activation of M₂ and M₄-receptors inhibits adenylyl cyclase, and activation of M₂-receptors opens potassium channels. The opening of potassium channels hyperpolarizes the membrane potential and decreases the excitability of cells in the sinoatrial (SA) and atrioventricular (AV) nodes in the heart. The inhibition of adenylyl cyclase decreases cellular cyclic adenosine monophosphate (cAMP) levels.

As you see, the activation of muscarinic receptors may influence most of the organ systems along with CNS pathways involved in regulating voluntary motor activity, memory, and cognition. Activation of presynaptic muscarinic receptors can inhibit the release of endogenous neurotransmitters, and may account for some paradoxical effects of cholinomimetic stimulation.

Nicotinic receptors, in addition to binding acetylcholine, also are interaction with nicotine. Nicotine initially stimulates and then blocks the receptor. Nicotinic receptors are located in the CNS, adrenal medulla, autonomic ganglia, and the neuromuscular junction. The nicotinic receptors of vegetative ganglia differ from those of the neuromuscular junction. For example, ganglionic receptors are selectively blocked by benzohexonium (hexamethonium), whereas neuromuscular junction receptors are specifically blocked by tubocurarine. Ganglionic receptors called to N_n-cholinoceptors, but the neuromuscular junction receptors called to N_m-cholinoceptors. Transmission through autonomic ganglia is more complex than neurotransmission at the neuromuscular and postganglionic neuroeffector junctions. In addition to the cholinergic receptors on autonomic ganglion cells, there also appear to be adrenergic receptors and receptors for variety substances, including angiotensin, bradykinin, histamine, serotonin and substance P.

The N_m-cholinoceptors there are at the muscle end plate. The N_m-cholinoceptor consists of five subunits surrounding a sodium-conducting channel (two a-, b-, γ- and δ-subunits). Activation of the binding sites on the two a-subunits results in a conformational change. This allows simultaneous inflow of Na⁺ and Ca²⁺ and outflow of K⁺.

Cholinergic drugs are the ones, which affect the impulse transmission in the cholinergic synapses. They are divided into the cholinomimetic (agents which stimulate the cholinoceptors or lead to their excitation) and the cholinolytic ones (agents which block the cholinoceptors). Each of these groups is divided into subgroups depending on the influence upon different types of the cholinoceptors.

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