Adrenergic Neuron Blockers

ADRENERGIC NEURON BLOCKING DRUGS act to prevent the release of noradrenaline from nerves in
the sympathetic nervous system, which is involved in controlling involuntary autonomic functions including
blood pressure, heart rate and the activity of muscles of internal organs (e.g. blood vessels, gastrointestinal tract,
urogenital tract). Noradrenaline is the main neurotransmitter of the sympathetic nervous system, so adrenergic
neuron blocker drugs act like other antisympathetic agents to cause an overall fall in blood pressure. their
therapeutic action normally takes some weeks to develop, and their mechanisms of action result in some initial
release of noradrenaline. the main use of such drugs is in antihypertensive therapy, but side-effects limit their
use. Examples include bethanidine, bretylium, debrisoquine and guanethidine.

Drugs may:

1. Interfere with synthesis of noradrenaline (Methyrosine)

2. Interfere with storage of dopamine (Reserpine)
3. Interfere with release of noradrenaline (Guanethidine)

Drugs which prevent release of noradrenaline

 Guanethidine
 Guanadrel
 Bethanidine
 Debrisoquine
 Bretylium

Drugs that inhibit storage of noradrenaline

 Reserpine

Drugs that interfere with synthesis of noradrenaline:

 Metyrosine
Metirosine
Metirosine ( α-Methyltyrosine, Metyrosine) is an antihypertensive drug. It inhibits the enzyme tyrosine
hydroxylase and, therefore, catecholamine synthesis, which, as a consequence, depletes the levels of the
catecholamines dopamine, adrenaline and noradrenaline in the body.

It inhibits tyrosine hydroxylase, which catalyzes the first transformation in catecholamine biosynthesis, i.e., the
conversion of tyrosine to dihydroxyphenylalanine (DOPA). Because the first step is also the rate-limiting step,
blockade of tyrosine hydroxylase activity results in decreased endogenous levels of catecholamines, usually
measured as decreased urinary excretion of catecholamines and their metabolites.

Pharmacokinetics
Half-Life: 3-4 hr
Bioavailability: Well absorbed
Metabolism: liver
Metabolite: Catechol metabolites (inactive)
Excretion: urine 53-88%
Clinical use

Metirosine has been used in the treatment of pheochromocytoma. It is contra-indicated for the treatment of
essential hypertension.

However it is now rarely used in medicine, its primary use being in scientific research to investigate the effects
of catecholamine depletion on behaviour.
Reserpine

Reserpine irreversibly blocks the vesicular monoamine transporter (VMAT. This normally transports free
intracellular norepinephrine, serotonin, and dopamine in the presynaptic nerve terminal into presynaptic vesicles
for subsequent release into the synaptic cleft ("exocytosis"). Unprotected neurotransmitters are metabolized by
MAO (as well as by COMT) in the cytoplasm and consequently never excite the post-synaptic cell. Thus,
reserpine decreases metabolic rate of monoamine neurotransmitters; but also decreases magnitude of monoamine
release.

It may take the body days to weeks to replenish the depleted VMAT, so reserpine's effects are long-lasting.

This depletion of dopamine can lead to drug-induced parkinsonism.

Guanethidine
Guanethidine is transported by uptake 1 into the presynaptic terminal transported by norepinephrine transporter
(NET). (In this it competes with norepinephrine so can potentiate exogenously applied norepinephrine.) It
becomes concentrated in norepinephrine transmitter vesicles, replacing norepinephrine in these vesicles. This
leads to a gradual depletion of norepinephrine stores in the nerve endings. Once inside the terminal it blocks the
release of norepinephrine in response to arrival of an action potential. Spontaneous release is not affected.