Transcript of "L5: Adrenergic agonists; sympathomimetics"
28 June 2014 1
Pharmacology I/ Lecture 5
Dr. Hiwa K. Saaed, HD, M.Sc, Ph.D
28 June 2014 2
agents that act on pathways mediated by
the endogenous catecholamines (CAO);
NEP & EP are modulate the
Rate and force of contraction of heart.
Resistance (constriction and dilation) of blood
vessels and bronchioles.
Release of insulin,
breakdown of fat (lipolysis).
28 June 2014 3
removal (reuptake) of
They are frontline
asthma, angina & etc.
28 June 2014 4
Tyrosine hydroxylase can be inhibited by methyl-p-
MAO: inhibitors of MAO (e.g., phenelzine,
The mobile pool; many indirect-acting
sympathomimetics (e.g., amphetamine, ephedrine,
tyramine) can displace NE from the mobile pool
Uptake: some indirect-acting sympathomimetics
28 June 2014 5
Prejunctional α-receptors: (e.g., clonidine, alpha
methyldopa) cause inhibition of NE release.
Granular uptake of NE: blocker of granular uptake
of NE (e.g., reserpine) .
NE release from granules: blockers (e.g.,
Postjunctional receptors: postjunctional receptors
can be activated or blocked.
28 June 2014 6
divided into subgroups
on the basis of their
Spectrum of action:
α, β, or dopamine
Mode of action:
direct, indirect or
28 June 2014 7
I. α agonists:
• Non selective,
II. β agonists:
• Non selective,
28 June 2014 8
Indirect acting ↑ CAO in the synapse:
1. Releaser: Amphetamine, tyramine
Potentiate by MAOI, COMT blocker. Why?
2. Reuptake inhibitor: Cocaine, TCA
Mixed: Ephedrine, metaraminol
28 June 2014 9
Removal of NE may:
Diffuse out and enter the general circulation.
Be metabolized by COMT in the synaptic
Be recaptured by an uptake systems into the
28 June 2014 10
Selective for NE & EP.
dopamine can also activate some adrenoceptors at
very high ‘supraphysiologic’ concentrations.
Divided into two main classes:
α & β adrenoceptors
All are members of GPCR superfamily.
28 June 2014 11
28 June 2014 13
based on their affinities for a agonists and blocking
drugs, α-receptors are subdivided into two subgroups
α1 & α2,
e.g., α1 receptors have a higher affinity for
phenylephrine than do α2 receptors.
Conversely, clonidine selectively binds to α2
receptors and has less effect on α1 receptors.
α-adrenoceptors (α1 & α2)
28 June 2014 14
α1 Are present on the postsynaptic membrane
α2 Located primarily on presynaptic nerve endings.
The stimulation of α2 receptors causes feedback
inhibition of the ongoing release of NE;
α2 Located on other cells such as the β-cell of the
pancreas control insulin output.
28 June 2014 16
Subdivided to β1, β2 and β3-receptors
β1-receptors have ~equal affinities for both EP &
β2-receptors have higher affinity for EP than for
thus tissue with a predominance of β2-receptors
(vasculature of skeletal muscle) are particularly
responsive to hormonal effects of circulating EP
released by adrenal medulla.
28 June 2014 17
Mechanism of action:
binding of neurotransmitter at the β1 or β2-receptor→
result in activation of AC→↑cAMP concentrations
within the cell.
28 June 2014 18
Mechanisms of action of adrenergic receptors :
28 June 2014 20
Desensitization of receptors:
Prolonged exposure to the CAO reduces the
responsiveness of the receptors due to:
1. Sequestration of the receptors
2. Downregulation (destruction, or decreased
3. An inability to couple to G-protein
28 June 2014 21
A. Catecholamine properties:
High potency in activating α & β receptors
Rapid inactivation by:
1. COMT postsynaptically, gut wall,
2. MAO intraneuronally, liver or gut
CAO have only a brief duration of action when given
parenterally, and are ineffective when administered
orally because of inactivation.
Poor penetration into the CNS (polar)
28 June 2014 22
B. Non Catecholamine properties :
phenylephrine, ephedrine, amphetamine
Have longer t1/2 because they are not inactivated by
COMT, and they are poor substrate for MAO
Increased lipid solubility permits the greater access to
28 June 2014 23
Major effects mediated by adrenoceptors