This document discusses adrenergic agonists, which are drugs that act on pathways mediated by the endogenous catecholamines norepinephrine and epinephrine. These drugs target various steps in catecholamine synthesis, storage, release, binding, and removal and are used to treat conditions like hypertension, depression, shock, asthma, and angina. Adrenergic agonists are classified as direct-acting if they act directly on receptors, or indirect-acting if they increase catecholamine levels in the synapse. The document also describes the subtypes of alpha and beta adrenergic receptors, their locations, mechanisms of action, and the effects of prolonged receptor stimulation.

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Adrenergic agonists
Sympathomimetics drugs
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);
1. norepinephrine
2. epinephrine.
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).
Adrenergic agonists

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synthesis,
storage,
release,
binding
removal (reuptake) of
the neurotransmitter
They are frontline
therapies for
hypertension,
depression, shock,
asthma, angina & etc.
drugs target:

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 Tyrosine hydroxylase can be inhibited by methyl-p-
tyrosine.
 MAO: inhibitors of MAO (e.g., phenelzine,
tranylcypromine)
 The mobile pool; many indirect-acting
sympathomimetics (e.g., amphetamine, ephedrine,
tyramine) can displace NE from the mobile pool
 Uptake: some indirect-acting sympathomimetics
(cocaine, TCA).
Drug Targets

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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.,
guanethidine).
 Postjunctional receptors: postjunctional receptors
can be activated or blocked.
Drug Targets

6. Classification
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divided into subgroups
on the basis of their
 Spectrum of action:
 α, β, or dopamine
receptor affinity
 Mode of action:
 direct, indirect or
both

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Adrenergic agonists
 Direct acting:
I. α agonists:
• Non selective,
• α1-selective,
• α2-selective
II. β agonists:
• Non selective,
• β1-selective,
• Β2-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
Adrenergic agonists

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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
neuron

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Adrenoceptors
 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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α-receptors:
EP≥NE>>Isoproterenol

12. β-receptors:
Isop>EP>NE
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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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α-receptors:
 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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β-receptors:
 Subdivided to β1, β2 and β3-receptors
 β1-receptors have ~equal affinities for both EP &
NE.,
 β2-receptors have higher affinity for EP than for
NE.
 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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β-receptors
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
synthesis)
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
Thus,
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
the CNS

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Major effects mediated by adrenoceptors

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SITE OF ACTION

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SITE OF ACTION