Medical Pharmacology: Autonomic nervous System (Adrenergic)

Drugs that affect (or mimic) adrenergic function (Mechanisms)⁴⁶:

I. Interference with transmitter synthesis: α-methyltyrosine, which inhibits tyrosine hydroxylase (tyrosine 3-monooxygenase), leading to depletion of the endogenous neurotransmitter, norepinephrine (NE)
- Tyrosine Hydroxylase⁵⁰
II. Drug is transformed using the same pathway as the endogenous precursors⁴⁶
- Methyldopa (Aldomet) , L-α-methyl-3,4 diphydroxyphenylalanine, is transformed in a reaction catalyzed by dopamine-β-hydroxylase to α-methyl-norepinephrine which acts in the CNS as an α₂-agonist.
  - The result of central α₂-receptor activation is a reduction of sympathetic outflow.
  - Methyldopa (Aldomet)

III. Inhibition of nerve terminal membrane transport

By blockade of this transport system, drugs such as cocaine and tricyclic antidepressant drugs, e.g. imipramine (Tofranil) increase synaptic cleft [NE] which increases the likelihood of adrenergic receptor activation.
Cocaine

Imipramine (Tofranil)

**Neuronal Catecholamine Transporters [NET, norepinephrine; DAT, dopamine)⁴⁶**
Norepinephrine Transporter (NET)	Transporter specificity: dopamine > norepinephrine > epinephrine	Sites of action: Sympathetically-innervated locations: sympathetic nerves Placenta: syncytiotrophoblast cells Hepatic: capillary endothelium Adrenal medulla: chromaffin cells	NET inhibitors: desipramine (tricyclic antidepressant drug); cocaine
Dopamine Transporter (DAT)	Transporter specificity: dopamine >>> norepinephrine > epinephrine	Sites of action: Renal: endothelium Stomach: endothelial and parietal cells Pancreas: ductal cells	DAT inhibitors: cocaine

The norepinephrine transporter (NET) in addition to be inhibited by tricyclic antidepressants and cocaine is also Na⁺-dependent.
The transporter has a higher affinity for norepinephrine compared to epinephrine; whereas, isoproterenol is not transported.
- Other specific neurotransmitter transport systems have been described, including examples for dopamine, serotonin, and amino acids.
- Such transporters exhibit a common transmembrane structure consisting of 12-helices.
Displacement of nerve terminal norepinephrine by ephedrine and tyramine (sympathomimetic agents) also depends on NET.
- When, for example, ephedrine is transported across the neuronal membrane by this transporter and is released into the intracellular cytoplasm, the open transporter carrier sites become available at the inner membrane surface.
  - These open sites then can transport norepinephrine outward in a process described as "facilitated exchange diffusion."
- Ephedrine and tyramine also compete for norepinephrine uptake into vesicles and as a result tend to mobilize these neurotransmitter stores also.
- As noted earlier, extraneuronal transporters are also present.
  - One example is ENT a.k.a. uptake-2 and OCT3.
    - ENT is not Na⁺-dependent and transports organic cations.
  - Other organic cation transporters include OCT1 and OCT2.
    - These transporters not only act on catecholamines but also other organic acids such as serotonin, guanidine, creatinine, and histamine.
- The NET transporter plays an important role in termination of norepinephrine and epinephrine action.
  - Reuptake of these catecholamines by NET is a principal mechanism for limiting extended catecholamine-mediated adrenergic receptor activation.
  - Extraneuronal uptake of catecholamines, following diffusion away from the synaptic cleft, also limits catecholamine duration of action.
  - Metabolic transformation of the catecholamines by MAO (monoamine oxidase) and COMT (catechol-O-methyl transferase) is a third factor in termination of catecholamine actions.

IV. Vesicular transport system inhibition⁴⁶

Blockade of this transport system (VMAT, vesicular monoamine transporter) results in depletion of norepinephrine from adrenergic nerve endings.

Inability of NE to be transported into synaptic vesicles exposes the neurotransmitter to enzymatic breakdown, catalyzed by mitochondrial monoamine oxidase (MAO).

Reserpine is probably the best-known agent exhibiting vesicular transport blockade.

Reserpine
Synaptic Vesicle Preparation: Electron Micrograph

**Site of Reserpine Blockade (cytoplasmic neurotransmitter prevented from entering vesicles)⁵¹**

V. Drugs that displace neurotransmitters from nerve terminals:⁴⁶
- Amphetamine and tyramine are examples of drugs in this category.
  - The result of their action is "adrenomimetic."
- Amphetamine
  
  Tyramine
VI. Bretylium and guanadrel (Hyorel) prevent adrenergic neurotransmitter release.

Bretylium

Guanadrel (Hyorel)

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Cocaine	Imipramine (Tofranil)


Amphetamine	Tyramine



Bretylium	Guanadrel (Hyorel)