Noradrenergic transmission

Noradrenergic transmission

1. Function

   • Creation
     • Tyrosine
     • DOPA
     • Dopamine
     • NA
   • Release
     • Noradrenaline
       • A or B receptors
     • ATP
       • P2 purinergic
   • Storage
     • VMAT maintains
     • 1:4 NA:ATP
   • Sympathetic nervous system

2. Adrenoreceptors

   • Alpha
     • A1
       • Phospholipase C
       • Ip2 -> Ca2+
       • Smooth muscle
     • A2
       • Adenylace cyclase
       • Inhibit neurotransmitter
       • CAMP -> Ca2+
         • Smooth muscle
   • Beta
     • Adenylate cyclase
     • Heart B1
     • Smooth relaxation B2
     • Glyconeogenesis B2
   • GPCR's
     • Specific second messengers
     • Widespread

3. NA degredation

   • Normal
     • Synapse removal
     • Re-cycling
   • NET
     • 75%
     • Presynaptic
     • Recycle or metabolise
   • EMT
     • 25%
     • Other cells
   • Monoamine ocidase inhibitors
     • Antidepressant
     • Leaves in synapse

4. Site of action

   • Direct action on receptors
   • Break A-2 feedback loop
   • Prevent release (guanethidine)
   • Increase stores - MAOI's
   • Change depolarisation - amphetamines
   • Change uptake
   • Clinical drugs
     • Smooth muscle (B-adrenoreceptors of asthma)
     • Heart (A and B adrenergic)
     • Metabolism
     • Monoamine oxidase inhibitors
     • Non selective
       • Agonists
         • Adrenaline
         • Allergy
         • Heart attack
       • Antagonists
         • Phentolamine
         • Irreversible
         • Theocromocytoma removal
         • Fall in blood presure (alpha)
           • Baroreceptor overrride

5. Effects

   • Smooth muscle
     • Agonists
       • Decrease vascular compiance
       • Increased TPR and BP
       • Nasal decongenstants
     • Antagonists
       • Vasodilation, reduced BP
       • Prazoxin
       • Treats hypotension
       • Loss of BP regulation
   • A2
     • Agonists
       • Reduced sympathetic nerves
       • Decrease BP
       • Overautoinhibition
       • Clondine
     • Antagonists
       • Increased NA
       • Postsynaptic complex
   • Heart
     • B1
       • Agonist
         • Increase CO
         • Ianotrophic state
         • May distrb rythm
         • Dobutamine / adrenalnie for arrest
       • Antagonists
         • Beta blockers
         • Propranolol (B1, B2)
         • Atenolol (B1)
         • Effect reduces sympathetic
         • Minimal effect at rest or when normal
         • Lowers BP in hypertensive patients
         • Complex mechanism, less postural issues
   • Lungs
     • B blockers
       • Construction of smooth muscle
       • No asthmatics
       • Bronchial constriction - no use
     • B2 agonists
       • Salbutamol
       • Asthma + premature labour
       • Adrenaline in allergy
   • Metabolism
     • Agonists
       • Glycogen + fat breakdown
       • B3 agonists for obesity?

6. Drugs acting on NA release

   • Storage
     • Reserpine (alkyloid)
     • Blocks NA import to vesicles
     • NA broken down in cytoplasm
     • Also depletes 5HT + dopamine
     • Psyciatric drugs
       • Causes depression
   • Release
     • Amphetamines
     • NET transport into neuron and VMAT
       • Reduced NA uptake
     • Displaces NA from vesicle
       • Breakdown
       • Diffusion release
   • Effects
     • Bronchodilation
     • Longer lasting
     • Uncrease HR, TPR
     • Inbibition of gut activity / loss of apetite
     • Euphoria and wakefulness

7. Uptake inhibition

   • Block uptake
   • Desipramine - depression
   • Cocaine - local anesthetic
   • Tachycardia and euphoria