Autonomic Pharmacology--Adrenergic Drugs
VII. Drugs that affect (or mimic) adrenergic function (Mechanisms)46:
Drugs that have similar effects at adrenergic receptors as endogenous neurotransmitters:46
Phenylephrine and methoxamine are examples of drugs that selectively activate α1-adrenergic receptors (adrenomimetic). Pharmacological effects include an increase in blood pressure and a cholinergic-system (parasympathetic) mediated reduction in heart rate.
Clonidine activates another type of adrenergic receptor, designated α2. Activation of this receptor type centrally reduces sympathetic outflow, which is the proposed mechanism that accounts for antihypertensive actions noted following clonidine administration.
Whereas the above two example drugs show α-adrenergic receptor selectivity (α1 vs. α2), oxymetazoline activates both α1 and α2 adrenergic receptors. Oxymetazoline is an example of a non-selective α-adrenergic receptor agonist.
Dobutamine is an example of a drug that selectively stimulates the heart via β1 receptors, although dobutamine also has activity at α adrenergic receptors as well.
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VIII. Postsynaptic adrenergic receptor blockade:46
Phentolamine binds reversibly to both α1 and α2 adrenergic receptors; this agent is a non-selective receptor blockers. Reversible blockade suggests that the inhibitor dissociates from the receptor relatively easily. Since all reactions are, by definition, reversible, those reactions in which the inhibitor and receptor complex is so stable that dissociation is unlikely are described as "irreversible."
An example of an "irreversible" non-selective α-receptor blocker is phenoxybenzamine (Dibenzyline).
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The α-adrenergic receptor is described by seven α-helical transmembrane (TM) domains which form a "crevice" for ligand binding.52
There are actually three human α2-adrenoreceptor subtypes and the amino acid sequences between them are highly conserved within the seven hydrophobic TM domains.
Transmembrane domains are reasonably well conserved when comparing α- and β-receptors also; that is, of the 182 amino acids defining the TM domains of the human α2A-adrenergic receptors, about 40% are identical with the human β2-adrenergic receptors.
These conserved regions appear to contain those structural elements needed for recognizing and binding various endogenous hormone/neurotransmitters (e.g. norepinephrine and epinephrine) as well as other ligands.
Phenoxybenzamine (PB) has been used to probe α-adrenergic receptor subtypes.52
Furthermore, structural analysis of particular TM domains suggested locations for phenoxybenzamine covalent interactions.
By analyzing specific amino acid mutations of the α2A- receptor with respect to changes in PB binding, certain sites were identified that may serve as the molecular target for phenoxybenzamine-mediated receptor blockade.
For example, if a particular cysteine residue located in the TM3 domain was changed to valine (by mutation), the receptor becomes resistant to phenoxybenzamine inactivation.
This cysteine (at position 117) appears important in the association of phenoxybenzamine with receptor with PB likely covalently coupled to this amino acid. (see model above)
α1-adrenergic receptors antagonists include:46
prazosin (Minipress)
doxasozin (Cardura)
terazosin (Hytrin)
Yohimbine is classified as a selective α2-adrenergic receptor antagonist.46
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IX Inhibition of neurotransmitter breakdown:46
Non-selective inhibition of monoamine oxidase (MAO):
Pargyline (Eutonyl); Nialamide (Niamid):
These agents increase the pharmacological effects of tyramine but have limited effects of either sympathetic responses or on norephinephrine.
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pargyline (Eutonyl) |
nialamide (Niamid) |
Selective inhibition of MAO-B: selegiline (Anipryl, Eldepryl, Zelapar, Emsam, Carbex). 46
This agent is used in the management of some patients with Parkinson's disease.
Peripheral catechol-O-methyl transferase (COMT) inhibition: entacapone (Comtan). 46
This drug may be used in management of some patients with Parkinson's disease,
Central and peripheral COMT enzyme inhibition, Tolcapone (Tasmar). 46
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