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Adrenergic agonists

Sympathomimetics drugs

Pharmacology I/ Lecture 5Dr. Hiwa K. Saaed, HD, M.Sc, Ph.D

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agents that act on pathways mediated by the endogenous catecholamines (CAO); 1. norepinephrine2. 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

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

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