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Pharmacology I/ Lecture 5
Dr. Hiwa K. Saaed, HD, M.Sc, Ph.D
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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).
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removal (reuptake) of
They are frontline
asthma, angina & etc.
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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
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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.
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divided into subgroups
on the basis of their
Spectrum of action:
α, β, or dopamine
Mode of action:
direct, indirect or
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I. α agonists:
• Non selective,
II. β agonists:
• Non selective,
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Indirect acting ↑ CAO in the synapse:
1. Releaser: Amphetamine, tyramine
Potentiate by MAOI, COMT blocker. Why?
2. Reuptake inhibitor: Cocaine, TCA
Mixed: Ephedrine, metaraminol
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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
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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.
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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)
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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.
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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.
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Mechanism of action:
binding of neurotransmitter at the β1 or β2-receptor→
result in activation of AC→↑cAMP concentrations
within the cell.
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Mechanisms of action of adrenergic receptors :
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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
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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)
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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
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Major effects mediated by adrenoceptors