CATECHOLAMINE SYNTHESIS, ACTION, AND DEGRADATION
The important aspects of the adrenergic neuroeffector junction are summarized in Figure
Adrenergic Neuro-Effector Junction
Tyrosine is actively transported into nerve endings and is converted to dihydroxyphenylalanine
(DOPA) via tyrosine hydroxylase (1). This step is rate limiting in the synthesis of NE. DOPA is
converted to dopamine (DA) via L-aromatic amino acid decarboxylase (DOPA decarboxylase).
DA in turn is metabolized to NE via DA beta hydroxylase and is taken up and stored in gran-
ules (6). Inactivation of NE via monoamine oxidase (MAO) (2) may regulate prejunctional lev-
els of transmitter in the mobile pool (3) but not the NE stored in granules.
Presynaptic membrane depolarization opens voltage-dependent ca2+ channels. Influx of this
ion causes fusion of the synaptic granular membranes, with the presynaptic membrane leading
to WE exocytosis into the neuroeffector junction (7). NE then activates postjunctional receptors
(8), leading to tissue-specific responses depending on the adrenoceptor subtype activated.
Termination of NE actions is mainly due to removal from the neuroeffector junction back into the
sympathetic nerve ending via a NE transporter system (uptake 1) (4). At some sympathetic nerve
endings, the NE released may activate prejunctional alpha adrenoceptors (5) involved in feedback
regulation, which results in decreased release of the neurotransmitter. Diffusion away from the neu-
roeffector junction may also contribute to termination of actions. NE accumulated into target cells
(e.g., via uptake 2) is rapidly inactivated by catechol-0-methyltransferase (COMT).
DRUG "TARGETS"
1. Tyrosine Hydroxylase
Tyrosine hydroxylase can be inhibited by methyl-p-tyrosine and is subject to feedback inhibi-
tion by high levels of NE in the mobile pool.
2. MAO
Inhibitors of MA0 (e.g., phenelzine, tranylcypromine) may increase prejunctional levels of NE.
Note that MA0 type A, the enzyme form that metabolizes NE, also metabolizes tyramine and
serotonin (5HT).
3. The Mobile Pool
Many indirect-acting sympathomimetics (e.g., amphetamine, ephedrine, tyramine) can dis-
place NE from the mobile pool.
4. Uptake 1
Some indirect-acting sympathomimetics (eg, cocaine, tricyclics) inhibit uptake into the nerve
cell, increasing the postjunctional actions of NE.
5. Prejunctional Alpha Receptors
Activators of prejunctional alpha receptors (e.g., clonidine, alpha methyldopa) cause inhibition
of NE release from synaptic vesicles.
6. Granular Uptake of NE
Blockers of granular uptake of NE (e.g., reserpine) decrease prejunctional levels available for
release.
7. NE Release From Granules
Blockers of NE release from granules (e.g., guanethidine) decrease postjunctional actions of NE.
8. Postjunctional Receptors
Postjunctional receptors can be activated by many direct-acting sympathomimetics. These
receptors are also "targets" for many antagonist drugs.
Fig: Effect of Alpha Activators on Heart Rate and Blood Pressure
Drugs
Phenylephrine (al): decongestant-mydriasis without cycloplegia.
Methoxamine (al): use in paroxysmal atrial tachycardia-elicits vagal reflex.
a, Agonists
Stimulate prejunctional receptors in the CNS to decrease vasomotor outflow and decrease mean
BP. Primary use is in mild-to-moderate HTN.
Drugs
Clonidine: initial increase in BP (some al activity) followed by decrease-abrupt discontinua-
tion (DC) causes rebound HTN.
a-Methyldopa: a pro-drug forming a-methyl NE.
Beta-Agonists
Beta1: increase HR, SV, and CO.
Beta2:decrease PVR
Fig: Effect of Beta Activators on Heart Rate and Blood Pressure.
Fig: Effect of Norepinephrine on Heart Rate and Blood Pressure
Norepinephrine (NE) has little effect on p2 receptors. It increases PVR and both diastolic and
systolic BP. Positive inotropic action of NE causes a small to moderate increase in pulse pres-
sure (PP). Compensatory vagal reflexes tend to overcome the direct positive chronotropic
effects of NE (reflex bradycardia may ensue), but the positive inotropic effects are maintained.
Fig: Effect of Epinephrine on Heart Rate and Blood Pressure
Other actions-lungs (bronchodilation), liver (glycogenolysis stimulated-increase serum glucose),
pancreas (J insulin release because a2 predominates), muscle (glycogenolysis and glycolysis),
fat (activates lipase-? free fatty acids [FFAs]).
Clinical uses-anaphylaxis, cardiac arrest, adjunct to local anesthetics, glaucoma.
INDIRECT-ACTING ADRENOCEPTOR AGONISTS
Drugs
Tyramine: Present in certain foods and beverages-rapidly metabolized by MA0 type A in GI
tract and liver. At high levels displaces NE from the mobile pool, thus increasing pressor
response-potential problem when MA0 inhibitors are present, leading to hypertensive crisis.
No CNS entry. Amphetamine. Releases NE from mobile pool in nerve ending, causing increased
NE activity-peripheral effects are those of sympathetic stimulation with reflex bradycardia.
CNS actions include release of both NE and DA. Clinical uses include ADHD, short-term
weight loss, and narcolepsy (see CNS section).
Ephedrine: Releases NE from sympathetic neurons and can cause amphetamine-like CNS effects.
Clinical use: decongestant (note similar use of phenylpropanolamine and pseudoephedrine).
Cocaine: Blocks reuptake of NE into sympathetic nerve endings, causing vasoconstriction (this
plus block of axonal membrane Na+ channels forms the basis for clinical use). CNS effects are
probably via block of reuptake of both NE and DA (see CNS section).
Dopamine: DA is probably not a "natural" transmitter in periphery but can be released from
some sympathetic fibers. When infused, it has dose-dependent actions on DA and adrenocep-
tors. Low dose increases renallmesenteric blood flow via Dl activation + ? RBF and GFR.
Medium dose ? CO (positive inotropy) via P1 activation. Useful in management of shock states.
Very high dose causes vasoconstriction-? systolic and diastolic BP via al activation.
Clinical Uses andlor Characteristics of Beta Blockers
The important aspects of the adrenergic neuroeffector junction are summarized in Figure
Adrenergic Neuro-Effector Junction
Tyrosine is actively transported into nerve endings and is converted to dihydroxyphenylalanine
(DOPA) via tyrosine hydroxylase (1). This step is rate limiting in the synthesis of NE. DOPA is
converted to dopamine (DA) via L-aromatic amino acid decarboxylase (DOPA decarboxylase).
DA in turn is metabolized to NE via DA beta hydroxylase and is taken up and stored in gran-
ules (6). Inactivation of NE via monoamine oxidase (MAO) (2) may regulate prejunctional lev-
els of transmitter in the mobile pool (3) but not the NE stored in granules.
Presynaptic membrane depolarization opens voltage-dependent ca2+ channels. Influx of this
ion causes fusion of the synaptic granular membranes, with the presynaptic membrane leading
to WE exocytosis into the neuroeffector junction (7). NE then activates postjunctional receptors
(8), leading to tissue-specific responses depending on the adrenoceptor subtype activated.
Termination of NE actions is mainly due to removal from the neuroeffector junction back into the
sympathetic nerve ending via a NE transporter system (uptake 1) (4). At some sympathetic nerve
endings, the NE released may activate prejunctional alpha adrenoceptors (5) involved in feedback
regulation, which results in decreased release of the neurotransmitter. Diffusion away from the neu-
roeffector junction may also contribute to termination of actions. NE accumulated into target cells
(e.g., via uptake 2) is rapidly inactivated by catechol-0-methyltransferase (COMT).
DRUG "TARGETS"
1. Tyrosine Hydroxylase
Tyrosine hydroxylase can be inhibited by methyl-p-tyrosine and is subject to feedback inhibi-
tion by high levels of NE in the mobile pool.
2. MAO
Inhibitors of MA0 (e.g., phenelzine, tranylcypromine) may increase prejunctional levels of NE.
Note that MA0 type A, the enzyme form that metabolizes NE, also metabolizes tyramine and
serotonin (5HT).
3. The Mobile Pool
Many indirect-acting sympathomimetics (e.g., amphetamine, ephedrine, tyramine) can dis-
place NE from the mobile pool.
4. Uptake 1
Some indirect-acting sympathomimetics (eg, cocaine, tricyclics) inhibit uptake into the nerve
cell, increasing the postjunctional actions of NE.
5. Prejunctional Alpha Receptors
Activators of prejunctional alpha receptors (e.g., clonidine, alpha methyldopa) cause inhibition
of NE release from synaptic vesicles.
6. Granular Uptake of NE
Blockers of granular uptake of NE (e.g., reserpine) decrease prejunctional levels available for
release.
7. NE Release From Granules
Blockers of NE release from granules (e.g., guanethidine) decrease postjunctional actions of NE.
8. Postjunctional Receptors
Postjunctional receptors can be activated by many direct-acting sympathomimetics. These
receptors are also "targets" for many antagonist drugs.
Fig: Effect of Alpha Activators on Heart Rate and Blood Pressure
Drugs
Phenylephrine (al): decongestant-mydriasis without cycloplegia.
Methoxamine (al): use in paroxysmal atrial tachycardia-elicits vagal reflex.
a, Agonists
Stimulate prejunctional receptors in the CNS to decrease vasomotor outflow and decrease mean
BP. Primary use is in mild-to-moderate HTN.
Drugs
Clonidine: initial increase in BP (some al activity) followed by decrease-abrupt discontinua-
tion (DC) causes rebound HTN.
a-Methyldopa: a pro-drug forming a-methyl NE.
Beta-Agonists
Beta1: increase HR, SV, and CO.
Beta2:decrease PVR
Fig: Effect of Beta Activators on Heart Rate and Blood Pressure.
Fig: Effect of Norepinephrine on Heart Rate and Blood Pressure
Norepinephrine (NE) has little effect on p2 receptors. It increases PVR and both diastolic and
systolic BP. Positive inotropic action of NE causes a small to moderate increase in pulse pres-
sure (PP). Compensatory vagal reflexes tend to overcome the direct positive chronotropic
effects of NE (reflex bradycardia may ensue), but the positive inotropic effects are maintained.
Fig: Effect of Epinephrine on Heart Rate and Blood Pressure
Other actions-lungs (bronchodilation), liver (glycogenolysis stimulated-increase serum glucose),
pancreas (J insulin release because a2 predominates), muscle (glycogenolysis and glycolysis),
fat (activates lipase-? free fatty acids [FFAs]).
Clinical uses-anaphylaxis, cardiac arrest, adjunct to local anesthetics, glaucoma.
INDIRECT-ACTING ADRENOCEPTOR AGONISTS
Drugs
Tyramine: Present in certain foods and beverages-rapidly metabolized by MA0 type A in GI
tract and liver. At high levels displaces NE from the mobile pool, thus increasing pressor
response-potential problem when MA0 inhibitors are present, leading to hypertensive crisis.
No CNS entry. Amphetamine. Releases NE from mobile pool in nerve ending, causing increased
NE activity-peripheral effects are those of sympathetic stimulation with reflex bradycardia.
CNS actions include release of both NE and DA. Clinical uses include ADHD, short-term
weight loss, and narcolepsy (see CNS section).
Ephedrine: Releases NE from sympathetic neurons and can cause amphetamine-like CNS effects.
Clinical use: decongestant (note similar use of phenylpropanolamine and pseudoephedrine).
Cocaine: Blocks reuptake of NE into sympathetic nerve endings, causing vasoconstriction (this
plus block of axonal membrane Na+ channels forms the basis for clinical use). CNS effects are
probably via block of reuptake of both NE and DA (see CNS section).
Dopamine: DA is probably not a "natural" transmitter in periphery but can be released from
some sympathetic fibers. When infused, it has dose-dependent actions on DA and adrenocep-
tors. Low dose increases renallmesenteric blood flow via Dl activation + ? RBF and GFR.
Medium dose ? CO (positive inotropy) via P1 activation. Useful in management of shock states.
Very high dose causes vasoconstriction-? systolic and diastolic BP via al activation.
Clinical Uses andlor Characteristics of Beta Blockers
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