Adrenergic transmission and presynaptic modification

Question 1

Epinephrine and NE synthesis

Answer 1

1. Tyrosine → DOPA (dihydroxyphenylalanine) via Tyrosine Hydroxylase. Rate limiting step.
2. DOPA → dopamine (DA)
   DOPA decarboxylase
3. Transported into vesicle via VMAT
4. Dopamine → NE
   Dopamine beta hydroxylase, within vesicle.
5. NE → Epinephrine
   PNMT

Question 2

Presynaptic adrenergic inhibitors

Answer 2

Metyrosine -inhibits TH

Carbidopa and Benserazide - inhibit DOPA decarboxylase

Reserpine - inhibits VMAT and causes presynaptic depletion of monoamines NE, 5HT, DA, effects very long lasting, weeks.

Guanethidine, Debrisoquine, Bretylium - Displace NE from the vesicles causing vesicular NE depletion.

Alpha 2 agonists: 
- Clonidine
- Alpha-methyl-dopa. 
   Converted to alpha-methyl-NE the active drug
- Guanfacine
    For ADHD
- Guanabenz 
    For hypertension
Dexmedetomidine 
    anxiolytic

Imidazoline 1 receptor agonists (are also alpha 2 agonists)

Question 3

All the different Adrenergic reuptake inhibitors, presynaptic potentiators.
(11 drug classes)

Answer 3

1) L-DOPA, increased available precursor.

2) monoamine releasers
Tyramine
Ephedrine
Pseudoephedrine
Amphetamine
Methamphetamine
Methylphenidate (ritalin)

3) Reuptake inhibitors:
Cocaine, Amphetamine, Dextroamphetamine, Methylphenidate

4) Atypical antidepressants.
Buproprion and Trazodone –> inhibit NET
Mirtazepine –> increases presyaptic release

5) nonselective MOA inhibitors,
Tranylcypromine
Phenelezine
Isocarboxazide

6) MOA-B inhibitors.
Selegeline
Rasageline
Safinamide

7) RIMAs
Moclobemide

8) TCAs
Amytryptiline - Nortryptyline
Imipramine - Desipramine
Clomipramine
Trimipramine
Doxepin

9) SNRIs:
Venlafaxine
Desvenlafaxine
Duloxetine
Milnacipram, Levomilnacipram

10) ADHD drugs:
Atomexitine - inhibits NET
Methylphenidate - ritalin, inhibits NET and DAT

11) alpha 2 antagonists
Mirtazapine - atypical antidepressant
Yohimbine - not used clinically

Question 4

Imidazoline 1 receptor agonists

Answer 4

Moxonidine
Rilmenidine

Bind these receptors in the medulla.
Decrease sympathetic tone, for hypertension, also alpha 2 agonists.
BUT only if given orally, if given IV it can have direct peripheral effects and cause hypertension.

Side effects are parasympatholytic/antimuscarinic. Dry eyes, mouth, constipation, sedation.