The Adrenergic Nervous System

The Adrenergic Nervous System

• The adrenergic system is a key component of the peripheral nervous system (PNS).
• It utilizes adrenaline and noradrenaline as chemical messengers.
• Noradrenaline, also known as norepinephrine, is released by sympathetic nerves that innervate smooth and cardiac muscle.
• Adrenaline, or epinephrine, is a hormone released along with noradrenaline from the adrenal medulla.

Peripheral Nervous System

• At various tissues, noradrenaline's action is opposite to that of acetylcholine, meaning tissues are under dual control.
• An example is that if noradrenaline stimulates a tissue, acetylcholine inhibits it.
• Both cholinergic and adrenergic systems maintain a 'background' activity.

Fight or Flight

• The adrenergic system can release adrenaline during times of danger or stress, due to the fight or flight response.
• Adrenaline prepares the body for physical action by activating adrenergic receptors when being carried by the blood supply.
• Organs for physical activity are activated, while non-essential organs are suppres\sed.
• Example: Adrenaline stimulates the heart and dilates blood vessels to muscles for increased blood supply.
• Smooth muscle activity in the gastrointestinal tract is suppressed, as digestion is not a priority.
• Noradrenaline effects are, in general, the same as adrenaline; but noradrenaline constricts blood vessels to skeletal muscle, rather than dilating them.

Central Nervous System

• Adrenergic receptors are present in the central nervous system (CNS).
• Noradrenaline is important in CNS functions like sleep, emotion, temperature regulation, and appetite.
• The focus of the chapter will be on the peripheral role of adrenergic agents.

Adrenergic Receptors

• Cholinergic receptors have subtypes, in the same way that adrenergic receptors have subtypes.
• Alpha (α) and Beta (β)-adrenoceptors are the two main types of adrenergic receptors.
• Both α and β-adrenoceptors are G-protein-coupled receptors.
• They vary according to their coupling to the G-protein (Gq for α-adrenoceptors, Gs for β-adrenoceptors).

Receptor Subtypes

• Each receptor type has subtypes with slightly different structures.
• α-adrenoceptor subtypes are: α₁ and α₂.
• Activation of inositol triphosphate (IP3) and diacylglycerol (DG) occurs with α₁ receptors.
• Cyclic-AMP production is inhibited by α₂-receptors.
• β-adrenoceptor subtypes are: β₁, β₂, and β₃.
• Formation of cyclic-AMP is activated by all of the subtypes.
• Further categorization has resulted in a₁- and α₂-adrenoceptors with subcategories such as (α1A, α1B, α1D A2A, α2B, α2C).

Adrenaline and Noradrenaline

• Adrenaline and noradrenaline 'switch on' all adrenergic receptor types and subtypes.
• The differing structures mean it is possible to design selective agonists that differ between them.
• This is important in developing drugs with minimal side effects.
• Selective antagonists that switch off particular types and subtypes of adrenoreceptors should also be able to be designed.

Distribution of Receptors

• Adrenoceptor types and subtypes vary in their distribution across tissues.
• Some tissues may contain more of one type of adrenoceptor than another.
• The type of adrenoceptor which predominates in various tissues and the effect of activating these receptors, differ.
• Smooth muscle contraction occurs with a-receptor activation (excluding in the gut), while smooth muscle relaxation occurs with β-receptor activation.
• The most common of the β-adrenoceptors is the β₂-receptor.
• Predominately β₁-adrenoceptors, stimulation, and contraction of muscle result.

Selective Effects

• Adrenaline can have different effects in various body parts due to the many different types of adrenoceptor.
• Blood vessels supplying skeletal muscle have mainly β₂-adrenoceptors and are dilated by adrenaline.
• Blood vessels elsewhere have mainly α-adrenoceptors and are constricted by adrenaline.
• Overall, the constricting effect of adrenaline on blood vessels is more dominant than the dilating effect.

Adrenergic Agents: Clinical Aspects

• The main clinical application for adrenergic agonists is in asthma.
• Relaxation of the smooth muscles of the bronchi causes a widening of the airways by activating of β₂-adrenoceptors.
• Vasoconstriction resulting from agonists acting selectively on α₁-adrenoceptors can be used alongside local anesthetics in dentistry.
• This localizes and prolongs the effect of the anesthetic at the injection position.
• They are also used as nasal decongestants.
• Selective α₂-agonists treat glaucoma, hypertension, and pain.
• Angina and hypertension are the main uses for adrenergic antagonists.
• Relaxation of smooth muscle in blood vessels, dilation of the blood vessels, and a drop in blood pressure occurs by Agents which act on the α-receptors of blood vessels.
• Selective α₁-antagonists are now preferred to treat hypertension and are being investigated as potential agents.
• Depression is being treated with selective α₂-antagonists.
• Agents, β-blockers, that block B₁-receptors in the heart slow the heart rate and reduce the force of contractions.
• β-blockers have a range of effects in other parts of the body, which combine to lower blood pressure.

Endogenous Agonists for the Adrenergic Receptors

• Any chemical present naturally in the body is referred to as endogenous.
• The body's endogenous chemical messengers are noradrenaline (neurotransmitter) and adrenaline (hormone).
• Both act as agonists and switch on adrenoceptors
• Catecholamines are called due to an alkylamine chain linked to a catechol ring (the 1,2-benzenediol ring).

Catecholamine Biosynthesis

• The biosynthesis of noradrenaline and adrenaline starts from the amino acid L-tyrosine.
• Tyrosine hydroxylase catalyses the introduction of a second phenol group to form levodopa (L-dopa).
• Aromatic L-aminoacid decarboxylase (dopa decarboxylase) then decarboxylates it to give dopamine - an important neurotransmitter in its own right.
• Dopamine is then hydroxylated to noradrenaline, which is the end product in adrenergic neurons.
• In teh adrenal medulla, noradrenaline is then N-methylated to form adrenaline.
• Catecholamine biosynthesis is controlled by regulating tyrosine hydroxylase first enzyme in the pathway.
• The end product of biosynthesis, noradrenaline, inhibits, thus allowing self-regulation of catecholamine synthesis and control of catecholamine levels

Metabolism of Catecholamines

• Metabolism of peripheral catecholamines takes place within cells and involves two enzymes: monoamine oxidase (MAO) and catechol O-methyltransferase (COMT).
• Catecholamines are converted by MAO to their corresponding aldehydes.
• These compounds are inactive as adrenergic agents and are further metabolized (as shown in Fig. 23.3 for noradrenaline).
• The polar final carboxylic acid is excreted in the urine.
• With the same ultimate product, an alternative metabolic route is possible.
• COMT methylates one of the phenolic groups of the catecholamine.
• MAO then oxidizes the methylated product.
• COMT and MAO are the initial enzymes.

Neurotransmission

• Adrenergic neuron mechanisms of neurotransmission innervate smooth or cardiac muscle, as well as synaptic connections within the CNS.
• Biosynthesis of noradrenaline occurs in a presynaptic neuron, then stored in membrane-bound vesicles.
• A nerve impulse arrives at the terminus of a neuron, it stimulates the opening of calcium ion channels and promotes the fusion of the vesicles with the cell membrane to release noradrenaline.
• The neurotransmitter diffuses to adrenergic receptors on the target cell where it binds and activates the receptor resulting in signalling process.
• Then cellular response, the neurotransmitter activates, leading to the signalling process.
• Following the neurotransmitter, leading to the signalling process, noradrenaline departs the receptor and is taken back into the presynaptic neuron by a transport protein.
• The process is the receptor, noradrenaline departs the receptor and is taken back into the presynaptic neuron by a transport protein, it is then metabolized which is balanced out by noradrenaline biosynthesis.

Co-Transmitters

• Adrenergic neurotransmission is more complex than illustrated by process, e.g. adenosine triphosphate (ATP) and a protein called chromogranin A
• Released released from vesicles along with neurotransmission

Controls and Receptors

• A further feature of neurotransmission process is the the existence of presynaptic receptors having a controlling effect on noradrenaline release
• Variety of receptors that respond to a chemical messenger
• Released noradrenaline interacts with the adrenergic receptor (the α₂-adrenoceptor) leading to inhibitory effect by the negative feedback system
• There are receptors specific for prostaglandins released from a targeted cells
• The target cell has some influence on the adr energy signal coming to it
• Specificity from muscarinic receptors that inhibit release to side branches of cholinergic nervous system of of nonadrenaline
• Meaning when cholinergic side branches act they send signals along it to inhibit to adrenergic transmitter from the adrenergic
• As that cholinergic activity increases, the adr energy decreasing it enhancing overall cholinergic effect

Drug Targets

• The study of nerve communication process is used to identify processes in which potential drug targets will affect
• Biosynthetic enzymes with synaptic Synthesis
• Vesicle carriers that package non arenaline.
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• Adr energy receptors in postsynaptic
• Metabolic enzymes which is responsible
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Adrenergic Binding Site

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Binding Agents

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Analogs

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Selectivity

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Asthma And Analogs

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