l5: adrenergic agonists; sympathomimetics
DESCRIPTION
TRANSCRIPT
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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
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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
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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