adrenergic agonists - concepts

synthesis of norepi and epi

• tyrosine —> DOPA by tyrosine hydroxylase

• DOPA —> dopamine —> norepinephrine in the vesicles

• norepinephrine —> epinephrine

what is the rate-limiting step of norepi/epi synthesis?

tyrosine hydroxylase

what blocks dopamine —> norepi step?

reserpine blocks the VMAT transporter in the vesicle

where does the transformation of norepi —> epi occur?

chromaffin cells of the adrenal medulla ONLY

what blocks the reuptake of norepi?

cocaine, TCAs, SNRIs, meth/amphetamine

how is norepi metabolized/removed/limited?

• methlyated in synaptic cleft by COMT

• oxidized intraneuronally by MAO

• reuptaken into neuron rapidly

where can norepi bind?

pre and post synaptically

what are adrenergic agonists?

• drugs that act on receptors that are stimulated by NE and EPI (adrenoceptors)

• sympathomimetics activate

• sympatholytics block

sympathomimetics

• activate adrenoceptors

• can be:

  • direct-acting - bind and activate directly

  • indirect-acting - promote NE release or prevent reuptake

  • mixed action - both

sympatholytics

• block adrenceptors

  • a and B blockers

what are catecholamines?

• sympathomimetic amines

  • can be endodgenous (EPI/NE/dopamine) or synthesized (Dobutamine/Isoproternol)

  • highly potent

  • rapidly metabolized (brief duration of action, ineffective orally)

  • do not penetrate CNS easily (polar)

noncatecholamines compared to catecholamines

• longer half-lives

  • not targeted by COMT or MAO

• increased lipid solubility (greater CNS penetration)

adrenoceptor subtypes

a1, a2, B1, B2, B3

a1

• a1

  • postsynaptic effector organs

  • Gq protein

  • causes vasoconstriction, mydriasis

a2

• a2

  • presynaptic nerve endings

  • Gi protein

  • negative feedback autoreceptor (blocks release of more NE)

B1

• predominant heart receptor

• some in kidneys

• equal affinity for norepi/epi

• Gs

• increased contractility and renin release

B2

• bronchi, blood vessels, uterus

• Gs

• bronchodilation and vasodilation

• higher affinity for EPI than norepi

B3

• fat cells, bladder detrusor

• Gs

• lipolysis and bladder relaxation

a1 subtypes

• a1a - predominates urinary tract and prostate

• a1b - predominates blood vessels

importance of a/B subtypes?

• allows for selectivity

  • ex. tamsulosin (a1a antagonist) inhibits vasoconstriction in urinary tract but does not affect blood vessels (a1b)

rank order of potency for alpha adrenoceptors

norepinephrine > epinephrine > isoproterenol

rank order of potency for beta adrenoceptors

isoproterenol > epinephrine > norepinephrine

adreneceptors in skeletal muscle

has both a1 and B2 but B2 predominates - net effect is vasodilation

3 ways desensitization can occur for adrenoceptors

• sequestration

  • receptors pulled away from membrane (temporary)

• downregulation

  • receptors destroyed or not produced

• uncoupling

  • receptor is phosphorylated, cannot couple with G protein