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Drug Action > NA release > Flashcards

NA release Flashcards

1
Q

What are the two main sources of NA?

A

sympathetic nerve terminals and the adrenal medulla

NAD is released from the post-ganglionic neurone

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2
Q

Where is adrenaline found?

A

the inner part of the AM

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3
Q

What does the ANS regulate?

A

heart rate and force; SM tone, all exocrine and some endocrine secretions

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4
Q

Nerve terminal variscosities

A

Swellings where neurotransmitter vesicles are stored (looks like beads on a string)

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5
Q

Neurones in the ANS

A
  • Para: LONGER PRE

* Symp: LONGER POST

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6
Q

Synthesis pathway of NA and A

A

TYROSINE (Tyrosine hydroxylase) –> Dihydroxyphenylalanine (DOPA) = RDS, feedback inhibition by NA

DOPA (DOPA decarboxylase) –> Dopamine

Dopamine (Dopamine- B- hydroxylase) –> NA

NA (Phenylethanolamine N-methyl transferase) –> Adrenaline

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7
Q

Inhibitor of tyrosine hydroxylase?

A

a-methyltyrosine (blocks AS)

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8
Q

Inhibitor of DOPA decarboxylase?

A

Carbidopa

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9
Q

Inhibitor of Dopamine B-hydroxylase?

A

nepicastat

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10
Q

Where is PNMT located?

A

In A cells of AM

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11
Q

Parkinson’s

A
  • Treatment by L-dopa
  • People who have Parkinson’s disease don’t produce enough dopamine in the brain.
  • If you give someone DOPA, this enzymatic pathway is still active in the periphery, meaning much of the DOPA will still be broken down
  • DOPA can cross BB barrier, Dopamine cannot
  • Whenever DOPA is given to a patient, given with carbidopa (doesn’t enter the brain) and therefore reduces unwanted peripheral actions of administered L-dopa.
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12
Q

Other drugs affecting NA synthesis?

A

Methyldopa: taken up by sympathetic neurones; converted to a-methylNA; displaces NA from vesicles therefore acts as a ‘false’ transmitter. Uses: hypertension in pregnancy

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13
Q

Storage of NA and A in adrenal glands?

A
  • NAd and Ad are not free in the cytoplasm but are stored in subcellular-membrane limited particles inside chromaffin granules
  • Packed into vesicles
  • VMAT: Takes the catecholamines such as Dopamine into the vesicle. This process needs energy which comes from hydrogen ions (uses pH gradient); low pH in vesicles (ATPase)
  • VNUT: Transporters of ATP into vesicles
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14
Q

Reserpine

A
  • Inhibits VMAT catecholamine run down slowly as amines leak out (5% of normal after 12 hours)
  • Used in the past to treat hypertension (SNS drives HR to increase)
  • Fallen out of chemical use: not specific i.e effects SNS and CNS; effects serotonin: people often developed depression
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15
Q

Exocytosis from sympathetic nerves?

A
  • Ca2+ entry increase in concentration of free Ca2+ activates Ca2+ sensitive proteins that initiate the process of exocytosis

Botulinum toxin effects exocytosis
• Many of the nerve terminals have receptors on them for a whole variety of different substances: Pre-junctional receptors; regulate the release of NA by inhibiting or exciting it.
• Best well known pre-junctional receptors are receptors for NA itself.
• When NA is released can act back on the nerve terminals where there are a2 adrenoreceptors
• A-2 adrenoreceptors act to inhibit further neurotransmitter release (negative feedback)
• A lot of activity= a lot of inhibition.
• A lot of early evidence for this:
• Blocking a-2 receptors with an antagonist, amount of NA released will be increased (can be seen by using radioactive labelled NA.)

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16
Q

Regulation of release: pre-junctional modulation

A
  • Ach: INHIBITS release; via muscarinic receptors; produces lateral inhibition from PS nerves
  • Angiotensin II: facilitates release via AT1 receptor
17
Q

Morphine (opiod)

A
  • Potent analgesic, but with important autonomic SE: constipation, pupillary dilation
  • Autonomic SE are through the prejunctional release of NT release
  • Opiod receptors are present on most autonomic nerve terminals where they inhibit NT release. Inhibit Enteric NS increases activity within gut wall.
18
Q

Termination of A and NA action

A
  • 2 stages: uptake (into sympathetic NT or other cells); degradation via intracellular enzymes
  • 2 distinct uptake systems: Neuronal or non-neuronal (both are AT mechanisms)
19
Q

Neuronal uptake and inhibitors

A

• High affinity for NA; low maximal rate of uptake
• Co-transports Na+ and Cl-
• Inhibited by: Cocaine; tricyclic antidepressants
Inhibitors of NA uptake
• NAT inhibitors ENHANCE the effects of the CNS; NAT is closely related to dopamine and serotonin transporters (DAT and SERT)
• Desipramine: Tricyclic antidepressant; major action on CNS; adverse effects are tachycardia, dysrhythmia
• Cocaine: Euphoria and excitement; tachycardia and increased BP; local anaesthetic

20
Q

Non-neuronal

A

• Non-neuronal (e.g cardiac, SM, endothelium)
• Low affinity for NA; high maximal rate of uptake
• Not particularly selective for NA
Inhibited by: Normetanephrine, steroid hormones

21
Q

Metabolic degradation of CC’s

A
  • 2 main intracellular enzymes, in various tissues: MAO; catechol-O-methyl transferase (COMT)
  • 2 other enzymes involved: aldehyde dehydrogenase (ADH); mainly in periphery; aldehyde reductase (AR); mainly in CNS
22
Q

MAO

A
  • Bound to surface of M; found in many tissues in including NT
  • Converts catecholamines to aldehydes aldehydes then metabolised by AD or AR
  • Inhibited by several drugs which are used therapeutically for their effects on the CNS (treatment of depression)
23
Q

MAOI

A
  • Most block MAO IRREVERSIBLY; used clinically as antidepressants increases levels of NA, dopamine, 5-HT in the brain and peripheral tissues
  • Adverse effects include: restlessness, insomnia, weight gain
  • Examples: Phenelzine
24
Q

Catechol-O-methyl transferase (COMT)

A
  • Found in many tissues, including NT; cytoplasmic
  • Converts CC’s to methyl group derivatives by transferring a methyl group to one of the catechol –OH groups
  • Acts not only on CC’s but also on the products of other degradative reactions (MAO)
25
Q

VMA

A
  • Main final metabolite of A and NA; excreted in urine
  • Urinary VMA used as a diagnostic test for a rare tumour of chromaffin tissue (AM) that secretes high levels of CC’s resulting in elevated BP
26
Q

Noradrenergic neuron blocking drugs

A
  • Inhibit NA release from sympathetic NT (e.g guanethidine)
  • Enter NT and inhibit AP’s via ion channels or exocytotic proteins
  • No longer clinically used: severe adverse effects e.g failure of ejactulation, diarrhoea
27
Q

Indirectly acting sympathetic amines

A
  • Amphetamine, tyramine
  • Struturally related to NA; transported into NT and into vesicles
  • Displace NA, which leaks out via NAT
  • Longer lasting effects mimic those of NA: e.g vasoconstriction
  • Cause the release of NA, activates its receptors and mimicks sympathetic effects.
  • INDIRECTLY ACTING as they themselves don’t activate receptors but cause the release of NA

Drug Action (9 decks)

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