【Pharmacology】Adrenergic drug (adrenergic agonists)

Adrenergic agonists 

• a large group of drugs that mimic the actions of norepinephrine and epinephrine.
• Norepinephrine and epinephrine naturally occur in our bodies
• Norepinephrine is also known as noradrenaline 
• Epinephrine is also known as adrenaline
• Sympathomimetics: agents that activate adrenergic receptors
• Sympatholytics: agents that block the activation of adrenergic receptors

Content:

1. Neurotransmission process in adrenergic neuron

2. Adrenergic receptors

    a. Alpha receptors

    b. Beta receptors

3. Adrenergic agonists

    i. direct acting agonists 

    ii. Indirect acting agonists

    iii. Mixed action agonists

4. References

1. Neurotransmission process in adrenergic neuron

Step 1

Amino acid tyrosine is transported into the neuron by the sodium dependent tyrosine transporter. 

Once inside the neuron, tyrosine gets hydroxylated by the enzyme.

Tyrosine hydroxylase to L-3,4-dihydroxyphenylalanine also known as L-dopa or levodopa 

L-dopa is converted to dopamine by the enzyme aromatic amino acid decarboxylase

Step 2

Transport of dopamine into the synaptic vesicle where the enzyme dopamine beta hydroxylase converts dopamine to norepinephrine.

Step 3

Arrival of the action potential triggers opening of calcium channels and thus influx of calcium into the neuron.

The increase in calcium causes the synaptic vesicle to fuse with the membrane and release its contents into the synapse

Step 4

Norepinephrine binds to the postsynaptic receptor on effector organ which triggers intracellular response

Norepinephrine also binds to presynaptic receptor which results in decrease of norepinephrine release through negative feedback.

Step 5

Norepinephrine is removed from synaptic space by diffusing out into the systemic circulation

also by being inactivated by the enzyme catechol o-methyltransferase (COMT).

Most of all norepinephrine gets transported back into the neuron by sodium chloride dependent norepinephrine transporter (NET)

Once inside the neuron, norepinephrine may be either transported back to the synaptic vesicle for future use which basically means it gets recycled. 

Or it can be broken down to inactive metabolites by the enzyme monoamine oxidase (MAO)

2. Adrenergic receptors

• Sympathetic preganglionic neurons release acetylcholine which then binds to 
• nicotinic receptors on postganglionic adrenergic neurons 
• nicotinic receptors on adrenal medulla
• Adrenergic neuron release norepinephrine
• Adrenal gland releases approximately 20% norepinephrine and about 80% epinephrine.
• At the end norepinephrine and epinephrine bind to receptors (alpha and beta) on effector organs

a. Alpha receptors

alpha-1 and alpha-2 (further subdivided into alpha-1a alpha-1b alpha-1c)

i. Alpha-1 receptor

• Gq protein-coupled receptor
• causes stimulatory response mediated by increase in intracellular calcium
• located on vascular smooth muscle throughout the whole body 👉 Vasoconstriction
• located on the dilator muscle of the iris 👉 Mydriasis (dilation of pupil)
• located on urinary sphincters 👉 Contraction and urinary retention
• located in liver 👉 Glycogenolysis (breakdown of glycogen to glucose)
• located in the kidney 👉 Inhibition of renin release

*renin is an enzyme that is secreted by the kidney and is involved in the regulation of blood pressure

ii. Alpha-2 receptors

• Gi protein-coupled receptor
• located on presynaptic nerve endings 👉 decrease in production of intracellular cAMP which in turn leads to inhibition of further release of norepinephrine
• located on the pancreatic islets 👉 decrease in insulin secretion

b. Beta receptors

• beta-1, beta-2 and beta-3
• coupled with Gs protein

i. Beta-1 receptors

• located on the heart 👉
• increase heart rate 
• increased cardiac contractility 
• increase AV node conduction
• located on the juxtaglomerular cells in the kidney 👉 increased renin release which results in increase in blood pressure

ii. Beta-2 receptors

• located in the lungs on the bronchial smooth muscle 👉 bronchodilation
• located on the vascular smooth muscle and the arteries of skeletal muscle 👉 vasodilation (relaxation of blood vessel)
• located on smooth muscle in the GI tract and uterus 👉 smooth muscle relaxation 
• in GI results in decreased motility 
• in the uterus it can cause inhibition of labor
• located in pancreas 👉 increase in insulin secretion

iii. Beta-3 receptors

• located in adipose tissue 👉 increase in lipolysis (breakdown of stored fat)
• located in the urinary bladder 👉 cause relaxation of the bladder and prevention of urination

3. Adrenergic agonists

Two major chemical classes: catecholamines and noncatecholamines

Catecholamine is an organic compound that has a catechol which is basically a benzene ring with two hydroxyl side groups intermediate ethyl chain and terminal amine group

Noncatecholamine have similar backbone structure but without those two hydroxyl groups on adjacent carbons on benzene ring 

Three differences in properties between catecholamines and noncatecholamines

• Oral usability
• Duration of action
• CNS penetration

a. Catecholamine

• Oral usability: ineffective
• quickly metabolized by COMT and MAO enzymes in the gut, liver, CNS and even inside the neurons
• Duration of action: short
• CNS penetration: poor
• hydroxyl groups on the catechol portion make the whole molecule polar

b. Noncatecholamine

• Oral usability: effective
• lack the catechol hydroxyl groups and because of that there are not a good substrate for COMT
• metabolized by MAO very slowly 
• Duration of action: long
• less polar
• CNS penetration: good
• penetrate into the CNS fairly easy

Three types of adrenergic agonists

i. direct acting agonists 

• produce their effects by binding to alpha or beta receptor and mimicking the actions of epinephrine, norepinephrine and dopamine that naturally occur in our bodies.
• epinephrine, norepinephrine and dopamine---non-selective: act on both alpha and beta receptors, catecholamines
• Main route of administration: injection

Epinephrine

• can activate almost all adrenergic receptors
• Usage: 
• anaphylactic shock
• Activation of alpha-1 receptors by Epinephrine 👉 vasoconstriction 👉 decreases mucosal edema 👉 relieving airway obstruction and increases blood pressure 👉 relieving shock
• restore cardiac function in patients experiencing cardiac arrest caused by asystole 
• activation of cardiac beta-1 receptors leads to increase in cardiac output 
• emergency treatment of respiratory conditions
• activation of beta-2 receptors in lungs leads to bronchodilation 

Norepinephrine

• similar to epinephrine, however unlike epinephrine at the therapeutic doses. 
• Mainly stimulates alpha-1 receptors 👉 profound vasoconstriction 👉 ultimately increased blood pressure
• has almost no beta-2 activity
• limited clinical use in comparison to epinephrine
• Usage: Cardiac arrest & Hypotensive shock

Dopamine

• not only stimulates alpha and beta receptors but also a dopamine receptors and it stimulates them in a dose-dependent manner
• at low therapeutic doses: dopamine acts on dopamine receptors only
• dopamine receptor: main target for neuropsychiatric drugs
• dose increases: it also activates cardiac beta-1 receptors 
• at even higher doses: it additionally activates alpha-1 receptors
• cardiac beta-1 alpha-1 and dopamine receptors found on vascular smooth muscle
• Usage: acute severe heart failure and hypotensive shock

Selective adrenergic agonists

Alpha-1 selective

• Oxymetazoline
• Phenylephrine
• Usage: 
• Both: treatment of nasal congestion
• due to alpha-1 receptor stimulation
• Oxymetazoline can also be found in eyedrops used for treatment of eye redness 
• Phenylephrine due to its ability to raise systolic and diastolicblood pressure, is sometimes used in hospitalized patients to treat hypotension

Alpha-2 selective

• Clonidine
• Usage: 
• hypertension
• simulation of alpha-2 receptors leads to decrease in sympathetic tone
• attention deficit hyperactivity disorder (ADHD)
• withdrawal symptoms from alcohol and opioids 

Beta-1 selective agonist

• Dobutamine
• Usage: acute heart failure
• beta-1 receptors are mainly found in cardiac tissue, so Dobutamine increases cardiac rate and cardiac output

Beta-2 selective agonists

• stimulate beta-2 receptors predominant in lungs and lead to bronchodilation
• Short-acting: Albuterol and Terbutaline
• for relief of acute asthma symptoms
• Long-acting: Salmeterol and Formoterol
• for prevent asthma attacks (as it produce prolonged bronchodilation)

Beta-3 selective agonists

• Mirabegron
• Usage: relief of symptoms of over-reactive bladder
• simulates beta-3 receptors on the surface of detrusor muscle

*Beta Agonists side effect: 3T

• Tolerance
• Tachcardia
• Tremor

ii. Indirect acting agonists

do not directly interact with postsynaptic receptors instead they enhance the effects of epinephrine or norepinephrine by either inhibition of their reuptake or inhibition of their degradation

Cocaine & Amphetamine

• work by blocking reuptake of norepinephrine as well as dopamine
• particularly in the region of the brain that controls reward system
• so it is highly addictive
• stimulate alpha-1 and beta-1 receptors which lead to sympathetic response 
• eg, rise in blood pressure and increased heart rate

iii. Mixed action agonists

Ephedrine & Pseudoephedrine

• cause activation of adrenergic receptors by both direct binding as well as release of stored norepinephrine from presynaptic terminals 
• long duration of action
• as they are not catecholamines and thus are poor substrates for COMT and MAO enzymes
• Usage: vasoconstriction and bronchodilation
• However, due to its side effects and availability of better drugs, Ephedrine is rarely used in clinical practice
• Pseudoephedrine mainly activates receptors located in the nasal passages the constriction of blood vessels, allow less fluid to leave 👉 decrease inflammation of nasal passages & decreased mucus production
• for this reason, Sudafed is actually very commonly used as a decongestant

4. References

https://youtu.be/KtmV-yMDYPI

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