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ADRENERGIC DRUGS (Sympathomimetics, Adrenomimetics)
© Assoc. Prof. Ivan Lambev
The sympathetic preganglionic fibers leave the CNS through the thoracic and lumbar spinal nerves. The sympathetic preganglionic neurons (first neurons) project from the intermediolateral column of the spinal gray matter to the paired paravertebral ganglionic chain lying alongside the vertebral column and to unpaired prevertebral ganglia. These ganglia represent sites of synaptic contact between preganglionic axons (1st neurons) and nerve cells (2nd neurons) that emit postganglionic axons terminating on cells in various end organs. In addition, there are preganglionic neurons that project either to peripheral ganglia in end organs or to the adrenal medulla.
ADRENERGIC AND DOPAMINERGIC NERVES
Activation of the Sympathetic Nervous System can be considered a means by which the body achieves a state of maximal work capacity as required in fight or flight situations.
Whereas ACh serves as the chemical transmitter at ganglionic synapses between first and second neurons Norepinephrine (NE, noradrenaline) is the mediator at synapses of the second neuron. Excitation of the neuron leads to activation of a larger aggregate of effector cells, although the action of released NE may be confined to the region of each junction. Excitation of preganglionic neurons innervating the adrenal medulla causes liberation of ACh. This, in turn, elicits a secretion of epinephrine (adrenaline) into the blood, by which it is distributed to body tissues as a hormone.
Adrenoceptors fall into two major
groups, designated alpha (α1, α2) and beta (β1, β2, β3) within each of which further subtypes can be distinguished pharmacologically. The different adrenoceptors are differentially distributed according to region and tissue. Agonists at adrenoceptors (direct adrenomimetics) mimic the actions of the naturally occurring catecholamines, NA and epinephrine, and are used for various therapeutic effects.
Within the varicosities, NE is stored in small membrane-enclosed vesicles (granules, 0.05 to 0.2 µm in diameter). In the axoplasm, L-tyrosine is converted via two intermediate steps to dopamine (DA), which is taken up into the vesicles and there converted to NE by DA-beta-hydroxylase. When stimulated electrically, the sympathetic nerve discharges the contents of part of its vesicles, including NE, into the extracellular space. Liberated NE reacts with adrenoceptors located postjunctionally on the membrane of effector cells or prejunctionally on the membrane of varicosities. Activation of presynaptic α2-receptors inhibits NE (regulative negative feedback).
Presynaptic receptors in adrenergic synapse and their role in the regulatory negative and positive feedback
Presynaptic regulation of transmitter release from noradrenergic and cholinergic nerve terminal
The effect of released NE wanes quickly, because approximately 90% is actively transported back into the axoplasm, then into storage vesicles (neuronal re-uptake). Small portions of NE are inactivated by the enzyme catechol-O-methyltransferase (COMT, present in the cytoplasm of postjunctional cells, to yield normetanephrine), and monoamine oxidase (MAO, present in the mitochondria of nerve cells and postjunctional cells) to yield 3,4-dihydroxymandelic acid).
The liver is richly endowed with COMT and MAO. It therefore contributes significantly to the degradation of circulating NE and epinephrine. The end product of the combined actions of MAO and COMT is vanillylmandelic acid.
Antiparkinsonian dopaminergic drugs moclobemide and selegiline block MAO.
Action on alpha-adrenoceptors
•Contraction of arterioles and veins: rise in BP (α1) •Contraction of radial muscles of iris: mydriasis and decreased aqueous secretion (α1) •GIT: intestinal relaxation, contraction of sphincters •Bladder trigone: contraction •Uterus: contraction •Splenic capsule: contraction •Neuromuscular transmission: increased ACh release •Insulin secretion: inhibited (α2 dominant) •Mail sex organs: ejaculation •Salivary glands: K+ and water secretion (α1) •Nictitating membrane in cats: contraction (α1)
Noradrenaline (a1) (+)
• PLC (phospholipase C) catalyses the formation of two intracellular messengers - InsP3 and DAG, from membrane phospholipids. • InsP3 (inositol-triphosphate) increases free cytosolic calcium by releasing Ca2+ from the endoplasmic reticulum. • Free calcium initiates contractions, secretion, membrane hyperpolarization • DAG activates protein kinase C.
Action on beta-adrenoceptors
•Dilatation of arterioles and veins (β2): fall in BP •Cardiac stimulation (β1): increased heart rate, force, and conduction velocity •Bronchodilation (β2) •Eye: enhanced aqueous secretion •GIT: intestinal relaxation (β2) •Bladder detrusor: relaxation •Uterus: relaxation (β2) •Neuromuscular transmission: tremor (β2) •Augmented insulin and glucagon secretion (β2) •Liver: glycogenolysis (β2) •Fat – lipolysis (β3), Kidney – renin release (β1) •Posterior pituitary: ADH secretion (β1)
Adr (b1&b2) (+) Gs cAMP PKA Effects AC
b-adrenoceptor •7 subunits
Agents which increase cAMP (adrenaline, salbutamol, and other beta-adrenoceptor agonists) inhibit histamine secretion and produce bronchodilation (antiasthmatic effect).
Autonomic control of pupil (A) and site of action of mydriatics (B) and miotics (C)
Chemical structure of catecholamines and affinity for α- and β-receptors
Norepinephrine (noradrenaline): α1, α2, β1 and β3, but no β2 action Epinephrine (adrenaline): α1, α2, β1 and β2, and weak β3 action Isoproterenol (isoprenaline): β1 and β2, but no α action -------------------------------------------------Clonidine: presynaptic α2 agonist (with antihypertensive action)
α-adrenomimetics (activators of phospholipase C) - antihypotensive drugs: Etilefrinе (Effortil), NE - local nasal decongestants: Naphazoline, Oxymetazoline, Xylometazoline (0.1% nasal drops) - eye drops in glaucoma: Phenylephrine Cardioselective α1-adrenomimetics: Dobutamine DA-ergic adrenomimetics: Dopamine Selective β2-adrenomimetics: Fenoterol, Hexoprenaline, Salbutamol, Salmeterol, Terbutaline Non-selective β-adrenomimetics: Iso- and Orciprenaline α- and β-adrenomimetics: Adrenaline (antiallergic): amp. 0,1% 1 ml s.c.; Anapen (0,3 mg/03 ml i.m.)
Antihypotensive drugs Ephedrine, Mephentermine, Midodrine
Reactive hyperemia due to α-adrenomimetics (naphazoline, oxymetazoline, xylometazoline) e.g., following decongestion of nasal mucosa
Some important catecholamines
NB: isoproterenol (isoprenaline)
BP – blood pressure, HR – heart rate
Effects of intravenous infusion of norepinephrine, epinephrine, or isoproterenol in humans
Isolated aortic strip
Isolated bronchial smooth muscle
Dose-response curves of Adr (adrenaline), NA (noradrenaline) and Iso (isoprenaline) on isolated aortic strip and isolated bronchial smooth muscle illustrating two distinct rank orders of potencies respectively for α- and β-adrenergic receptors.
Effect after 3 to 5 min and duration 4–6 h: •Salbutamol •Fenoterol Effect after 15–20 min and duration 12 h: •Salmeterol
FACTORS THAT EXACERBATE ASTHMA
The primary site of bronchodilation action of inhaled β2-adrenergic agonists is mainly bronchiolar smooth muscle. Atropinic drugs cause bronchodilation by blocking cholinergic constrictor tone, act primarily in large airways.
Selective β2-adrenomimetics with tocolytic effect
•Fenoterol (Partusisten: tab. 5 mg) •Hexoprenaline •Salbutamol (Salbupart) •Terbutaline
- Ephedrine with antihypotensive and antiasthmatic effects AR: tachyphyllaxis
Indirect sympathomimetics with central stimulant activity and abuse potential
Erythroxylon coca L.
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