Adrenergic Synapses And Drugs

Question 1

Describe the structure of adrenergic synapses.

Answer 1

• Involve post-ganglionic sympathetic neurones
• Generally possess highly branching axonal network with numerous varicosities (specialised site for calcium-dependent NA release).

Question 2

How is noradrenaline synthesised?

Answer 2

1. Tyrosine is taken up into varicosity and synthesised to DOPA by tyrosine hydroxylase.
2. DOPA is synthesised to dopamine by DOPA decarboxylase.
3. Dopamine moves into synaptic vesicle and is synthesised to noradrenaline by dopamine beta-hydroxylase.

Question 3

How is adrenergic synthesis different in the adrenal medulla?

Answer 3

NA is converted to adrenaline by the enzymatic addition of a methyl group.

Question 4

Where does NA act in the synaptic cleft?

Answer 4

• Pre-junctional adrenoreceptors: regulate processes within nerve terminal (e.g. NA release)
• Post-junctional adrenoreceptors: mediate effect on target tissue

Question 5

How is NA transmission terminated?

Answer 5

1. Re-uptake into pre-synaptic terminal:
   
   • Uptake 1 (90%) - by high affinity sodium-dependent (symport) transporter
   • Uptake 2 (10%) - lower affinity, non-neuronal mechanism
2. NA then recycled into vesicles.
   Cytoplasmic [NA] is low whilst intravesicular [NA] is high as transporter exploits H+-ATPase-generated H+ gradient to move catecholamines against their concentration gradient.

Question 6

How is NA metabolised/degraded in the pre-synaptic terminal?

Answer 6

Pre-synaptic terminal NA not taken up by vesicles susceptible to metabolism by monoamine oxidase (MAO) or catechol-O-methyltransferase.

Question 7

Give examples of drugs acting on adrenergic nerve terminals. When are these clinically used?

Answer 7

alpha-Methyl-tyrosine

• Competitively inhibits tyrosine hydroxylase - blocks de novo synthesis of NA.
• Only used clinically in pheochromocytoma.

alpha-Methyl-DOPA

• Taken up by adrenergic neurones and converted to alpha-methyl-NA by the sequential action of DOPA decarboxylase and dopamine beta-hydroxylase.
• When released by exocytosis, preferentially activates pre-synaptic alpha2 adrenoreceptors, reducing NA release.
• Used clinically in the treatment of hypertension.

Question 8

Are adrenoreceptor (ant-)agonists selective or not?

Answer 8

• Highly receptor subtype-selective agents

Question 9

Give examples of important adrenoreceptor agonists.

Answer 9

1. Selective beta1-agonists (e.g. dobutamine)
   - Cause positive inotropic and chronotropic effects.
   - May be useful in treating circulatory shock.
   - But all beta1-agonists prone to causing cardiac dysrythmias.
2. Selective beta2-agonists (e.g. Salbutamol, terbutaline)
   - Highly effective in reversing bronchoconstriction in asthmatics.
3. Selective alpha1-agonists (e.g. Phenylephrine, oxymetazoline)
   - Used as nasal decongestants.
   - May be given in conjunction with a local anaesthetic injection to cause local vasoconstriction - retard dissipation of anaesthetic.
4. Selective alpha2-agonists (e.g. Clonidine)
   - Stimulation of inhibitory pre-synaptic receptors - decreases NA release, and centrally mediated action.
   - Used as anti-hypertensive agents.

Question 10

Give examples of important adrenoreceptor antagonists.

Answer 10

1. Non-selective alpha-adrenoreceptor antagonists (e.g. Phentolamine & irreversible blocker phenoxybenzamine)
   - Cause peripheral vasodilation.
   - Used in treatment of peripheral vascular disease.
   - NOT used to treat hypertension as cause postural hypotension and reflex tachycardia.
2. Selective alpha1-antagonists (e.g. Prazosin)
   - Used in treatment of hypertension as an add-on therapy to beta1-antagonists.
   - Postural hypotension and impotence still common side effects.
3. Beta-adrenoreceptor antagonists (e.g. Propanolol) or beta1-antagonists (e.g. Atenolol)
   - Used in treatment of hypertension, cardiac dysrhythmias, angina & myocardial infarction.

Question 11

What are the issues with the use of beta-adrenoreceptor antagonists or beta1-antagonists? How can these issues be dealt with?

Answer 11

• Possible side effects include:
  
  • bronchoconstriction - esp. using non-selective beta-adrenoreceptor antagonists in patients susceptible parasympathetically-mediated bronchospasm
  • bradycardia
  • cold extremities
  • insomnia
  • depression
• Some trials report that the use of partial agonists (e.g. Alprenolol, oxprenolol) cause fewer side effects as they provide a low tonic stimulation of beta-adrenoreceptors whilst still blocking receptor stimulation by NA.

Question 12

How is acetylcholine synthesised?

Answer 12

In the pre-synaptic terminal:

• acetyl CoA (glycolysis byproduct) + choline (diet)
• converted by choline acetyltransferase (CAT)
• to ACh + coenzyme A

Question 13

Why does ACh have a very limited synaptic cleft 1/2 life?

Answer 13

Is converted by (acetyl)cholinesterase (AChE) to acetate + choline.
Most choline is then captured by a choline transporter on the presynaptic membrane and recycled.

Question 14

Describe the effects of cholinesterase inhibitors and possible therapeutic applications.

Answer 14

• Limit rate of ACh breakdown - enhance activity of endogenously-released ACh.
• Used to:
  Acutely reverse effects of non-depolarising