Pharmacy

1. PCL 302
AUTONOMIC NERVOUS SYSTEM -
ADRENERGIC RECEPTORS
J. A. Badejo, PhD
Department of Pharmacology & Therapeutics
Faculty of Basic Medical Sciences
College of Medicine
University of Ibadan
Ibadan

2. INTRODUCTION
• Adrenergic receptors or adrenoceptors are G protein
coupled receptors
• They are membrane-bound receptors located throughout
the body on neuronal and non-neuronal tissues
• They mediate a diverse range of responses to the
endogenous catecholamines- noradrenaline and
adrenaline
• Binding of cathecolamines to the receptors elicits the
‘fight or flight’ response

4. α- Adrenoceptors
• α1-Adrenoceptors are coupled via G proteins in the Gq family to
phospholipase C. This leads to the formation of:
• IP3, which mobilizes intracellular Ca2+ stores, increasing cytoplasmic
concentration of free Ca2+ and activation of various calcium-dependent
protein kinases
• DAG which activates protein kinase C. This modulates many signalling
pathways
α1 adrenoceptors are expressed in
• Vascular smooth muscle
• Genitourinary tract smooth muscle
• Intestinal smooth muscle
• Heart
• liver

5. • The agonists of α1 adrenoceptors include: Phenylephrine,
Xylometazoline, Pseudoephedrine and Naphazoline
• The antagonists include: Prazocin, Terazocin, Alfuzocin and Doxazocin

6. • α2-Adrenoceptors activate Gi, an inhibitory G protein.
• Gi has multiple signalling actions
• Inhibition of adenylyl cyclase (thus decreasing cAMP levels)
• Activation of G protein-coupled inward rectifier K+ channels (causing
membrane hyperpolarization)
• Inhibition of neuronal Ca2+
All lead to a decrease in neurotransmitter release from target neurones.
α2 adrenoceptors are present on
• presynaptic neurons
• post synaptic cells – function as autoreceptors to mediate feedback inhibition of
sympathetic transmission
• pancreatic β-cells –mediate inhibition of insulin release
• platelets – inhibit platelet aggregation
α2 receptor agonists act at CNS sites to decrease sympathetic outflow;
decrease NE release and decrease vascular SM contraction

7. • The agonists of α2 adrenoceptors include Clonidine, Methyldopa,
Guanabenz and Guanfacine.
• The antagonists include: Yohimbine, Mirtazapine, Idaoxan and
Atipamezol

8. β-Adrenoceptors
Divided into 3:
• β1, β2, β3
• All stimulate Gs
• Gs activates adenylyl cyclase, leading to an increase in the level of
intracellular cAMP
• β1-Adrenoceptors are localized primarily in the heart and kidney
• Stimulation of cardiac β1-adrenoceptors causes an increase in both
inotropy (force of contraction) and chronotropy (heart rate).
• Stimulation of β1-adrenoceptors in the kidney causes renin release.
• Agonists of β1 adrenoceptors - Denopamine, Dobutamine and
Xamoterol
• Antagonists – Atenolol, Metoprolol, Esmolo, Nebivolo and Bisoprolol

9. • β2-Adrenoceptors are expressed in smooth muscle, liver, and skeletal
muscle
• In SM, receptor activation stimulates Gs, adenylyl cyclase, cAMP, and
protein kinase A (PKA)
• PKA phosphorylates several contractile proteins, especially myosin light
chain kinase (MLCK) which reduces the affinity of MLCK for calcium-
calmodulin, leading to relaxation of the contractile apparatus
• Also, leads to bronchial SM hyperpolarization and relaxation
• In hepatocytes, it causes increase in plasma glucose
• In skeletal muscle, it stimulates glycogenolysis and promotes K+ uptake
• Agonists – Salbutamol, Levosalbutamol and Terbutaline
• Agonist - Butoxamine

10. • β3 -Adrenoceptors
• Are involved in the epinephrine and norepinephrine induced
activation of adenylyl cyclase through the action of the G proteins of
the type Gs
• Are expressed specifically in adipose tissue.
• Stimulation leads to an increase in lipolysis
• Agonists – Mirabegron and Solabegron

11. AGONISTS
• An agonist is any molecule that activates or 'turns on' the activity of a
receptor protein.
• It binds to a receptor and stabilizes the receptor in a particular
conformation (usually, the active conformation).
• An agonist may be a drug or an endogenous ligand

12. • Receptors can be activated by either an endogenous or exogenous
ligand which may lead to a change in the biological response
• Types of Agonists-
a) Full agonist
b) Partial Agonist
c) Inverse agonist

13. • Full agonist- A full agonist is a ligand that upon binding increases the
activity of receptor to produce maximal response. Eg., Morphine
mimics the action of endorphins at opioid receptors
• Partial agonist- A partial agonist is a molecule that binds to a receptor
at its active site but produces only a partial response, even when all
of the receptors are occupied (bound) by the agonist. Eg, Buspirone,
an anxiolytic drug used to treat anxiety disorder

14. • Inverse agonist- An inverse agonist is a ligand that acts by abrogating
the intrinsic (constitutive) activity of the free (unoccupied) receptor.
• Inverse agonists function by binding to and stabilizing the receptor in
the inactive form

16. ANTAGONISM
• An antagonist is a molecule that inhibits the action of an agonist but
has no effect in the absence of the agonist.
• A receptor antagonist binds to either the active site (agonist binding
site) or an allosteric site on the receptor
• Receptor antagonists can be reversible or irreversible, competitive or
noncompetitive.

17. •A competitive antagonist competes for the
same binding site with an agonist, and their
binding is mutually exclusive.
•Increasing the concentration of agonist can
overcome competitive antagonist activity
•The potency of the agonist is reduced, but
not the maximum efficacy.

18. • An insurmountable antagonist can reduce the maximum
effect of the agonist, and this inhibitory effect is not
affected by increasing agonist concentration.
• In irreversible antagonism, there is high-affinity binding
between the antagonist and the receptor which does
not permit the binding of any further agonist molecules.
• An irreversible antagonist is insurmountable
- An example is an antagonist which binds covalently to
the receptor binding site

19. NON-COMPETITIVE ANTAGONISM
• Non-competitive antagonism implies that the antagonist, while still opposing
the action of the agonist, does so without competing with it for the binding site
• A non-competitive antagonist can prevent the action of an agonist without any
effect on the binding of the agonist to the receptor.
• In non-competitive antagonism, once a receptor is bound by such a drug,
agonists cannot surmount the inhibitory effect irrespective of their
concentration
• The agonist and antagonist can be bound to the receptor simultaneously and
antagonist binding reduces or prevents the action of the agonist with or
without any effect on the binding of the agonist

20. • Physiological antagonism is situation where the actions of one
substance appear to act in opposition to another without either of them
interacting with the same receptor population.
• A physiological antagonist is non-competitive, but does not have to
be insurmountable.
• An example is an antagonist which acts indirectly to depress the
physiological parameter which the agonist stimulates
- For example, the effect of a calcium channel blocker on the effect
of adrenaline; the same physiological parameter is affected and the
actions of the inotrope are decreased with no effect on its receptor
binding. By giving enough adrenaline one may overcome the effects
of the antagonist activity.

22. Source: Pharmacology education project
Competitive Antagonism
• A competitive antagonist binds
reversibly to the active site of a
receptor.

24. A signalling cascade is a series of protein-protein interactions that starts with the activation of a receptor and
ends with various changes in cellular activity.

25. ADRENOCEPTORS, AGONISTS & ANTAGONISTS

31. Effector Organ Adrenergic Response Receptor Involved
Gastrointestinal tract Relaxation α2
Eye – Radial muscle, iris Contraction (mydriasis) α1
Eye – circular muscle, iris ciliary
muscle
Relaxation β2
Kidney – urinary bladder Renin secretion β1
Kidney - Detrusor Relaxation β2
Nasal secretion Decrease α1
Ureter Contraction α1

32. Effector Organ Adrenergic Response Receptor Involved
Heart - Rate of contraction. Increase β1
Heart - Force of contraction Increase β1
Blood vessels Arterial (most) Vasoconstriction α1
Skeletal muscle Vasodilation β2
Veins Vasoconstriction α2
Bronchial Tree Bronchodilation β2
Uterus Contraction α1

33. CLINICAL USES OF ADRENOCEPTOR AGONISTS
• Cardiovascular system
- Cardiac arrest: Adrenaline
- Cardiogenic shock: dobutamine (β1 agonist)
- Heart block: β-agonists (eg, isoprenaline) can be used temporarily while electrical
pacing is being arranged
• Anaphylactic shock (acute hypersensitivity)
- adrenaline is first-line treatment with steroids and antihistaminics
• Respiratory system
• Asthma: selective β2-receptor agonists (salbutamol, terbutaline, salmeterol
formoterol)
• Nasal decongestion: drops containing oxymetazoline or ephedrine for short use

39. • Nasal → stuffiness due to blockade of α receptor in nasal
blood vessels .
• Miosis due to loss of tone of radial muscle of iris
• Tone of smooth muscle in bladder trigone, sphincter and
prostrate is reduced by blockade of α1 receptor → urine flow
in patients with benign hypertrophy of prostate (BPH) is
improved
• Inhibition of contractions of vas deference and ejaculatory
duct → failure of ejaculation → impotence
• Intestinal motility is increased due to partial inhibition of
relaxant sympathetic influences → diarrhoea

45. Therapeutic uses
Cardiovascular use
-Hypertension
-congestive heart failure
-Angina pectoris:
C/I Prinzemetal angina

46. Adverse Effects
- Bronchoconstriction
- Cold extremities
- CNS side effects: fatigue, sleep disturbance and depression
- Heart failure
- Hypoglycemia
- Adverse serum lipid profile

47. RESOURCE MATERIALS
• Basic & Clinical Pharmacology – Katzung, B. G., Masters, S. B. and
Trevor A. J.
• Pleuvry, Barbara J. "Receptors, agonists and antagonists." Anaesthesia
& Intensive Care Medicine 5.10 (2004): 350-352.
• Textbook of Pharmacology - Bowman, W. C. and Rand, M. J.
• Wyllie, D. J. A., and P. E. Chen. "Taking the time to study competitive
antagonism." British journal of pharmacology150.5 (2007): 541-551.

48. THANK YOU!