Adrenoceptors Agonists & Sympathomimetic Drugs (Autonomic Nervous System) (Pharmacology)

Adrenoceptors Agonists
&
Sympathomimetic Drugs
Presenter: Akash Agnihotri
AIIMS, Rishikesh
Department of Pharmacology

Sympathetic Nervous System
• Adrenergic transmission is restricted to the sympathetic division of
the ANS
• Evident in Blood Pressure regulation
• Nor-adrenaline (NA) is the neurotransmitter at most of the sites
• Sympathetic nervous system is the major source of endogenous
catecholamine production and release (NA)
• in rate and force of cardiac contraction
• Modifying peripheral resistance of arterial system
• Inhibit release of insulin, etc

Fig:
A typical adrenergic
neuroeffector junction
Amino
Acid
TH- Tyrosine Hydroxylase
AAAD- Aromatic L-amino acid
decarboxylase
DβH- Dopamine β Hydroxylase
NPY- Neuropeptide Y
ATP- Adenosine triphosphate

Structures of the
major catecholamines

Drugs acting at adrenergic neurons

Catecholamines
• There are three closely related endogenous catecholamines (CAs)
which act as signal molecules
• A catecholamine- Monoamine neurotransmitter, organic compound
Catechol moiety
(Benzene ring with 2
adjacent hydroxyl groups)
+
Ethylamine Catecholamine

Catecholamines
• Most Important catecholamines are:
1. Noradrenaline (norepinephrine):
• A transmitter released by sympathetic nerve terminals
2. Adrenaline (epinephrine):
• Hormone secreted by chromaffin cells in the adrenal medulla
3. Dopamine:
• Metabolic precursor of noradrenaline and adrenaline, also a
transmitter/neuromodulator in the central nervous system (CNS)
4. Isoprenaline (isoproterenol):
• A synthetic derivative of noradrenaline and pharmacological tool

Structure activity relationship of
sympathomimetic Amines
β-Phenylethylamine
(Parent Compound)
Structure permits substitutions to be made on the aromatic ring, the α- and
β-carbon atoms and terminal amino group to yield a variety of compounds
with sympathomimetic activity

Structure & main clinical use of important sympathomimetic
drugs
α Activity: A, Allergic reactions (includes β action); N, Nasal decongestion; P, Pressor (may include β action); V, Other local
vasoconstriction β Activity: B, Bronchodilator; C, Cardiac; U, Uterus

Structure Activity Relationship:
Aromatic ring and catechol hydroxyl groups:
It all depends where you substitute the extra groups
You need 2 to have the maximum receptor affinity
Amine group:
A methyl group here confers α selectivity
The smaller the group, the more α effect is there
α-Carbon atom:
Any additional groups here half-life by inhibiting MAO
& also allow the drug to act as indirect sympathomimetic
β -Carbon atom:
Any addition group here Greatly α and β receptor
activity
α
β
Amine group
Mimosa Catechu

Structure Activity Relationship: Example: 1
• Presence of one —OH group at C-3 or C-4 of the aromatic rings
enhances vasoconstrictor activity
• e.g., Oxymetazoline hydrochloride, Metraminol bitartrate
+ HCl

• Introduction of two —OH groups at C-3 and C-4 invariably enhance
the tendency to induce vasodilation in the presence of other
preferred molecular substituents
• e.g., Adrenaline, Isoprenaline hydrochloride, etc

• N-substituents favour vasodilation:
• e.g., epinephrine (—CH3) ; isoprenaline [–CH(CH3)2]
Isoprenaline

• -OH substitution on the β -carbon (carbon-1): generally decreases
CNS activity largely because it lowers lipid solubility
• However, such substitution greatly enhances agonist activity at both
α- and β-receptors
• E.g., Ephedrine is less potent than methamphetamine as a central stimulant
Ephedrine

Structure Activity Relationship of adrenergic
phenylethylamine agonists

Adrenergic Receptors:
Adrenergic Receptors
α type β type
α 1 α 2
α 1A
α 1B
α 1D
α 2A
α 2B
α 2C
β 1 β 2 β 3

Nomenclature
• The adrenoreceptors (and the genes that encode them) are also
known by the abbreviation ADR
Adrenoceptor alpha 1A
ADR A 1A
Gene type Gene subtype
Approved symbol

Adrenergic Receptors: α1 receptors
• All belong to the superfamily of G protein - coupled receptors
α1 receptors (Gq family)
Phospholipase C
Inositol trisphosphate (IP3) and Diacylglycerol (DAG)
Activate
Produce
Second Messengers

• IP3 promotes the release of sequestered Ca2+
• which increases cytoplasmic free Ca2+ concentrations that activate
various calcium-dependent protein kinases and other calmodulin-
regulated proteins
• DAG cooperates with Ca2+ in activating protein kinase C (PKC), which
modulates activity of many signaling pathways
• α1 receptors- Stimulate- Tyrosine kinases:
• Mitogen-activated protein kinases (MAP kinases) and polyphosphoinositol-3-
kinase (PI-3-kinase)

α2 receptors(Gi)
Inhibition G protein
• Inhibit adenylyl cyclase (thus decreases cAMP level)
• Inward rectifier K+ channels (causing membrane hyperpolarization)
• Inhibition of neuronal Ca 2+ channels
These effects tend to decrease neurotransmitter release from target
neuron

• α2- found on both presynaptic neurons and
postsynaptic cells
• Presynaptic α2 -receptors function as
autoreceptors to mediate feedback
inhibition of sympathetic transmission
• Also Expressed on-
• Platelets- Platelet aggregation
• Pancreatic β cells- Inhibit Insulin resistance
• α2- In Treatment of hypertension

Adrenergic Receptors: β receptors
• β -Adrenoceptors are divided into three subclasses
• β1, β2, and β3 adrenoceptors
• All three subclasses activate a stimulatory G protein, Gs
• Gs activates adenylyl cyclase to increase intracellular levels of cAMP
• In liver:
• cAMP mediates a cascade of events culminating in the activation of glycogen
phosphorylase
• In heart:
• it increases the influx of calcium across the cell membrane
• Smooth Muscle:
• It promotes relaxation through phosphorylation of myosin light-chain kinase to an
inactive form

Adrenergic Receptors: β1 receptors
• Localized primarily in the kidney and heart:
• In the kidney, β1 -renal juxtaglomerular cells- renin release
• Stimulation β1 cardiac receptors (which represent 70–80% of all
cardiac –adrenergic receptors)
• Increase in inotropy (force of contraction)
• Chronotropy (heart rate)
Cardiac Output
(Heart Rate X Stroke Volume)

• Expressed in smooth muscle (including bronchial smooth muscle),
liver, skeletal muscle, and heart
• In smooth muscle, receptor activation stimulates Gs , adenylyl
cyclase, cAMP, and protein kinase A
• Myosin light chain kinase reduces its affinity for calcium-calmodulin
• Relaxation o the contractile apparatus
Phosphorylates
Leading

• β2 -Adrenoceptor activation may also relax bronchial smooth muscle
by Gs -independent activation of K channels
• Increased K+ efflux leads to bronchial smooth muscle cell
hyperpolarization
• Therefore, opposes the depolarization necessary to elicit contraction
• In hepatocytes- increase in plasma glucose
• Recent studies: β2 -Adrenoceptor activation
• Anti-apoptotic activity
• By activating subunit of Gi – activation of phosphatidylinositide-3 kinase
gamma

• β3 Adrenoceptors are expressed in adipose tissue and GIT
• Increase in lipolysis and thermogenesis in adipocytes and to a
decrease in gastrointestinal tract motility
• These physiologic actions have led to speculation that β3 agonists
may be useful in the treatment of obesity, noninsulin-dependent
diabetes mellitus

Sympathomimetic drugs
• Drugs that mimic the actions of epinephrine or norepinephrine have
traditionally been termed sympathomimetic drugs

Direct Acting- Epinephrine (adrenaline)
• Epinephrine is synthesized from tyrosine in the adrenal medulla and
released, along with small quantities of norepinephrine, into the
bloodstream
• Interacts with both α and β receptors
• At low doses: Has predominantly β1 and β2 effects (Vasodilation)
• At high doses: α1 effects become more pronounced (Vasoconstriction)
• Activation of β2 receptors in skeletal muscle contributes to increased
blood flow during exercise

Norepinephrine (Levarterenol)
• Norepinephrine is an agonist at α1 and α2 and β1 receptors, but has
relatively little effect at β2 receptors
• Systemic administration- increases systolic (β1) & Diastolic blood
pressure
• Norepinephrine use – In treatment of hypotension in patients with
distributive shock, most frequently due to sepsis
• Droxidopa is a synthetic prodrug that is converted by AAAD into NE
• FDA-approved for the treatment of orthostatic dizziness and light-headiness
in adults with symptomatic neurogenic orthostatic hypotension

Norepinephrine- Cardiac actions

Isoproterenol
• Isoproterenol is a direct-acting synthetic catecholamine that
predominantly stimulates both β1- and β2-adrenergic receptors.
• Its non-selectivity is one of its drawbacks and the reason why it is
rarely used therapeutically
• Its action on α receptors is insignificant

Schematic representation of the cardiovascular effects of
intravenous infusions of adrenaline, noradrenaline and isoprenaline
in humans

Dopamine
• Dopamine, the immediate metabolic precursor of norepinephrine,
occurs naturally in the CNS in the basal ganglia
• where it functions as a neurotransmitter, as well as in the adrenal
medulla
• Dopamine can activate α- and β-adrenergic receptors

Dopamine
• Dopamine activates one or more subtypes of catecholamine receptor
in peripheral tissues
• At low doses ( 2 mcg/kg per min)- acts predominantly on D1
dopaminergic receptors in renal, mesenteric, and coronary vascular
beds.
• At higher rates of infusion (2–10 mcg/kg per min)
• Dopamine is a positive inotrope via its activation of β1 -adrenergic receptors
• At still higher rates of infusion ( 10 mcg/kg per min), dopamine acts
on vascular α1 -adrenergic receptors to cause vasoconstriction
• Clinically useful in the treatment of shock

α1-Selective Adrenergic Receptor Agonists
• Phenylephrine
• Metaraminol
• Midodrine- Orally active α1-selective agonist
• The clinical utility of these drugs is limited to the treatment of some
patients with hypotension, including orthostatic hypotension, or
shock
• Phenylephrine- α1-selective agonist
• Mydriatic in various nasal and ophthalmic formulations
• Used as nasal decongestion

• Clonidine, Methyldopa, Guanfacine, Guanabenz, Tizanidine,
Moxonidine
• Decrease blood pressure through actions in the CNS that reduce
sympathetic tone (“sympatholytics”) even though direct application
to a blood vessel may cause vasoconstriction
• Clonidine:
• Activating α2 receptors in the CNS, thereby suppressing sympathetic
outflow from the brain
• Apraclonidine and Brimonidine: (Topical) Reduce intraocular pressure
by decreasing production of aqueous humor

• Clonidine:
• Studies in knockout animals demonstrated the requirement for a
functional α2 receptor for the hypotensive effect of clonidine
• Bind to imidazoline receptors, (I1, I2, and I3)
• Activation of the CNS I1 imidazoline receptor also plays a role in the
hypotensive effects of clonidine

Imidazoline Receptors
• It is accepted that all I1 receptor agonists that are sufficiently
lipophilic to cross the blood–brain barrier reduce arterial pressure
and heart rate in all mammalian species tested, including humans,
effects that are mediated by a central sympatho inhibitory action
• According to Mahmoudi et al. (2018), I1 receptor agonists :
• These drugs allow the control of hypertension, but they also have a set of
potential effects (e.g., anti-inflammatory, antiedematous, anti-inflammatory,
and antiapoptotic effects) that can circumvent post-hemorrhagic
complications

Summary of the pharmacological effects
mediated by imidazoline receptors

HOW ,Imidazoline I2 Receptor agonist-induced
analgesia

Imidazoline Pharmacology
• The antihypertensive Moxonidine is a second-generation I1 receptor–
selective drug, with a 10- to 700-fold greater affinity for I1 receptors
than for alpha-2-adrenergic receptors
• Rilmenidine- developed for the same purposes and is, like
moxonidine, used as an antihypertensive drug with fewer adverse
effects, particularly sedation
• Until recently, moxonidine and rilmenidine were considered representative I1
receptor agonists that modulate blood pressure
• LNP599 demonstrate extraordinary I1 receptor selectivity and exciting
therapeutic efficacy in hypertension and the metabolic syndrome

Clonidine Mechanism in Hypertension:
• Pontine locus coeruleus is one of the centrally located areas of alpha-
2 receptors that clonidine affects
• Chiefly responsible for sympathetic nervous system innervations of the
forebrain
• Decreased sympathetic nervous system outflow from the medulla to
peripheral nerves
• which results in peripheral vasodilatation and a decrease in blood
pressure, heart rate, and cardiac output

• Lofexidine is a new α2 agonist recently approved to decrease opioid
withdrawal symptoms
• Guanfacine and guanabenz are α2 agonists similar to clonidine and
are rarely used now
• Tizanidine is used as a muscle relaxant
• Dexmedetomidine: New highly selective alpha-2 adrenergic receptor
agonist that confers sedative, anxiolytic, analgesic, and sympatholytic
properties
• Use to sedate a person who needs a mechanical ventilator

• Yuriy et.al., demonstrated:
• Mafedine (a novel drug) with α2-Selective Adrenergic Receptor
Agonist activity
• Psychostimulant action with some anxiogenic-like effects
• Using a Zebrafish- Sensitive vertebrate aquatic model

β Adrenergic Receptor Agonists
• Play a major role only in the treatment of bronchoconstriction in
patients with asthma (reversible airway obstruction)
• Minor uses:
• Management of preterm labor
• Treatment of complete heart block in shock
• Short-term treatment of cardiac decompensation after surgery or in patients
with congestive heart failure or myocardial infarction
• β Receptor agonists may be used to stimulate the rate and force of
cardiac contraction

β1-selective agents
• Dobutamine
• Clinical formulations of dobutamine are a racemic mixture of (–) and
(+) isomers
• (+) isomer is a potent β1 agonist and an α1-receptor antagonist
• (–) isomer is a potent α1 agonist , which is capable of causing
significant vasoconstriction when given alone
• Use - For the short-term treatment of cardiac decompensation that
may occur after cardiac surgery or in patients with CHF

β1-selective agents
• Prenalterol is the only non-catecholamine β1 selective agent
• It has been promoted recently for the reversal of β blockade

β2-Selective Adrenergic Receptor Agonists
• β2-Selective agents have been developed to avoid β1 receptors
agonist’s adverse effects
• Up to 40% of β receptors in human heart are β2 receptors
• Useful in the treatment of asthma and COPD

• Short-Acting β2 Adrenergic Agonists:
• Metaproterenol, Albuterol, Levalbuterol, Pirbuterol, Terbutaline, Isoetharine,
Fenoterol, Procaterol
• Long-Acting β2 Adrenergic Agonists (LABAs):
• Salmeterol, Formoterol, Arformoterol
• Very Long-Acting β2 Adrenergic Agonists (VLABAs):
• Indacaterol, Olodaterol, Vilanterol
• Other β2-Selective Agonists:
• Ritodrine

• Albuterol, pirbuterol, and terbutaline: SABA
• Used primarily as bronchodilators and administered by a metered
dose inhaler
• Duration of action: 4-6 hours
• Terbutaline:
• Not a substrate for COMT methylation
• It is effective when taken orally or subcutaneously or by inhalation
• It also is available for parenteral use for the emergency treatment of
status asthmaticus

• Salmeterol: LABA
• Salmeterol is a lipophilic β2-selective agonist
• Prolonged duration of action (>12 h)
• Selectivity for β2 receptors about 50-fold gre
• Salmeterol also may have anti-inflammatory activity after than that of
albuterol
• Salmeterol and formoterol:
• Agents of choice for treating nocturnal asthma in symptomatic patients taking
other asthma medications

• Salmeterol Adverse Effects:
• Potential to increase heart rate and plasma glucose concentration, to
produce tremors
• Salmeterol should not be used more than twice daily
• Should not be used to treat acute asthma symptoms
• For that reason, salmeterol is available in a single formulate
combination with the corticosteroid fluticasone

β3 Adrenergic Receptor Agonists
• Mirabegron:
• A β3 adrenergic receptor agonist approved for use against
incontinence
• Activation of this receptor in the bladder leads to detrusor muscle
relaxation and increased bladder capacity
• It is indicated for treatment of overactive bladder

β3 Adrenergic Receptor Agonists

Indirect-acting sympathomimetics
Amphetamine:
• The marked central stimulatory action of amphetamine is often
mistaken by drug abusers as its only action
• The CNS stimulant effects of amphetamine and its derivatives have
led to their use for treating hyperactivity in children, narcolepsy, and
appetite control
• Its use in pregnancy should be avoided because of adverse effects on
development of the fetus

Drugs in Attention- deficit/hyperactivity
disorder (ADHD)

ADHD Treatment
• Most widely used medications are two psychostimulants:
• Methylphenidate (MPH) and Amphetamines (AMP)
• Second-line medications include
• Atomoxetine (ATX), Guanfacine (GFC), and Clonidine (CLO)
• Other unlicensed medication options
• Bupropion, Modafinil, and Tricyclic antidepressants (TCAs)

New drugs on the ADHD portfolio
• HLD200, Dasotraline, Viloxazine, and Mazindol
• Nearly all of drugs in development for ADHD continue to focus on enhancing
dopamine and norepinephrine
• These drugs are being successfully tested in phase II and III trials and are likely
to enter the market soon
• Other drugs:
• Fasoracetam- Metabotropic glutamate agonist
• Approved for stroke and vascular dementia
• Phase II and III trials have been completed with adolescents, but no results
have been published so far

New drugs on the ADHD portfolio (Cont.)
• Other Drugs:
• Metadoxine: GABA modulator
• Approved for acute alcohol intoxication
• It was being tested for ADHD, but it failed phase III trials and the company
halted its development
• Molindone: Antipsychotic drug
• Antagonizes dopamine receptors
• Is being tested as an add-on treatment for aggressive behavior in children and
adolescents with ADHD
• Vortioxetine: Atypical antidepressant, inhibits reuptake of serotonin
• Being tested in a phase II trial with adults with ADHD

New drugs on the ADHD portfolio
Noradrenergic reuptake inhibitors (NRIs), Serotonin–norepinephrine- -dopamine- reuptake inhibitors
(SNDRIs)

• Methamphetamine- very similar to amphetamine
• Methylphenidate- an amphetamine variant
• Modafinil and armodafinil- psychostimulants that differ from
amphetamine

Tyramine:
• Not a clinically useful drug, but it is important because it is found in
fermented foods
• It is a normal by-product of tyrosine metabolism
• Normally, it is oxidized by MAO in the gastrointestinal tract, but if the
patient is taking MAO inhibitors, it can precipitate serious vasopressor
episodes

Foods reputed to have a high content of tyramine or other
sympathomimetic agents

• Catecholamine Reuptake Inhibitors: Atomoxetine, Reboxetine,
Cocaine
• Atomoxetine, Reboxetine uses:
• To treat attention deficit hyperactivity disorders in children and young adults

Beta-adrenergic blockers as a
potential treatment for COVID-19
patients

Beta-adrenergic blockers as a potential treatment
for COVID-19 patients

References
• Katzung, B. G. (2020). Basic and clinical pharmacology. Mc Graw Hill.
• Ritter, J., Flower, R. J., Henderson, G., Loke, Y. K., MacEwan, D. J., & Rang, H. P.
(2020). Rang and Dale's pharmacology.
• Goodman LS. Goodman and Gilman's the pharmacological basis of therapeutics.
New York: McGraw-Hill; 2018.
• https://derangedphysiology.com/
• Nguyen V, Tiemann D, Park E, Salehi A. Aplha-2 Agonists. Anesthesiol Clin. 2017
jun;35(2):233-245. doi: 10.1016/j.anclin.2017.01.009.
• David E Golan’s “Principles of pharmacology” 4th edition. 2017.
• Syoev et al., Pharmacological screening of new alpha-2 adrenergic receptor
agonist, mefedine, in zebrafish, Neuroscience Letters (2019).
• Ali DC, Naveed M, Gordon A, Majeed F, Saeed M, Ogbuke MI, Atif M, Zubair HM,
Changxing L. β-Adrenergic receptor, an essential target in cardiovascular diseases.
Heart Fail Rev. 2020 Mar;25(2):343-354. doi: 10.1007/s10741-019-09825-x. PMID:
31407140.

References
• Vasanthakumar N. Beta-Adrenergic Blockers as a Potential Treatment for COVID-19
Patients. Bioessays. 2020 Nov;42(11):e2000094. doi: 10.1002/bies.202000094. Epub
2020 Sep 2. PMID: 32815593; PMCID: PMC7460992.
• Beale JM, Block J, Hill R. Organic medicinal and pharmaceutical chemistry. 12th edition
• David AW. Foyes principles of medicinal chemistry. 6th edition
• Caye A, Swanson JM, Coghill D, Rohde LA. Treatment strategies for ADHD: an evidence-
based guide to select optimal treatment. Mol Psychiatry. 2019 Mar;24(3):390-408. doi:
10.1038/s41380-018-0116-3. Epub 2018 Jun 28. PMID: 29955166.
• Pozzi, M., Bertella, S., Gatti, E., Peeters, G., Carnovale, C., Zambrano, S., & Nobile, M.
(2020). Emerging drugs for the treatment of attention-deficit hyperactivity disorder
(ADHD). Expert opinion on emerging drugs, 25(4), 395–407.
https://doi.org/10.1080/14728214.2020.1820481
• Bousquet, P., Hudson, A., García-Sevilla, J. A., & Li, J. X. (2020). Imidazoline Receptor
System: The Past, the Present, and the Future. Pharmacological reviews, 72(1), 50–79.
https://doi.org/10.1124/pr.118.016311

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