M2ii: Sympathomimetics

Classification

  • Sympathomimetic = a drug that evolves a similar response produced by endogenous activation of the SYMP NS.
    • Natural/synthetic
    • Catecholamine / non-catecholamine
    • Direct/indirect
    • α/β agonists

Catecholamine

  • All sympathomimetics derived from β-phenylethylamine
  • β-phenylethylamine with an -OH at C3 & C4 of the benzene ring designates the drug a catechol.

Non-Catecholamine

  • Have the β-phenylethylamine structure, but lack the OH groups on both C3 & C4 of the benzene ring
Non-Catecholamine

Structure Activity Relationships

The relationship between the structure of a molecule and its biological action

Benzene ring substitutions

  • Catechols have low lipid solubility
  • ∴do not cross BBB in sufficient amounts to cause stimulation
  • Nothing on benzene ring = ↑lipid solubility & ∴cross BBB → stimulate CNS but it would also make it a non-catechol i.e. amphetamine = synthetic non-catecholamine

C3 & C4 hydroxylation

  • = drug is catechol.
  • ∴taken up by neurons
  • Susceptible to COMT metabolism
  • ∴short DoA
  • Maximal α & β adrenergic activity requires OH on C3 & C­4

Lacks OH on C4

↓β activity

∴an α1 selective agonist

C3 & C5 hydroxylation

C3 & C5 hydroxylation

OH on C3 & C5 = β2 selectivity in compounds with long chain substituents

∴Terbutaline = relaxes bronchial smooth m. without any β1 effects

Terminal Amine Substitutions

  • Substituting with large groups at terminal amine = ↑β activity & ↓α activity
  • Also = ↓affinity for uptake e. NA has free amino group & minimal β (cf. adrenaline)
  • Adrenaline = optimal for producing β & α effects
  • e. Isoprel = large substitution at amine = maximal β1 & β2 activity and not taken up by neurons

β-carbon

  • The carbon next to benzene ring
  • Substitution will:
    • ↓lipid solubility = ↓CNS stimulation effects
    • ↑α & β agonist activity

α-carbon

  • Substitution will block MAO
    • ∴Prolong DoA
    • of non-catechols that cannot be metabolised by COMT i.e. ephedrine

Isomerism

  • Levorotary forms are more active

Administration

The relationship between the structure of a molecule and its biological action

Catecholamine

  • Not effective oral → metabolised by GI enzyme & liver
  • Adrenaline → subcut, IV, ETT
  • NA, Dopamine, Dobutamine → CVC

Non-catecholamine

  • Absence of 3-OH & 4-OH or α-carbon substitution makes drug resistant to COMT & MAO absorption
  • ∴↑oral availability
  • Cocaine can be administered intranasally

Distribution

  • 25% of NA is metabolised during a single passage through lungs
  • No change to Adrenaline
  • 20% Dopamine metabolised during one lung passage

Clearance

Catecholamines

  • Cleaved by reuptake or metabolism by COMT & MAO
  • Short t½ = 1 – 2 mins
  • Steady state achieved in 5 – 10 mins of starting infusion

Synthetic non-catecholamines

  • Not affected by COMT
  • α carbon substitution will inhibit MAO
  • ∴prolonged DoA of catecholamines

Sympathomimetic MoA

  • Adrenoreceptors & Dopamine receptors are all G PROTEINS
  • 7 transmembrane structure
  • Adrenoreceptors α1 & α2 / β1, β2, β3
  • Dopamine receptors → D1, D2, D3, D4
  • Sympathomimetics exert their effect by activating or inactivating these receptors → directly or indirectly

Indirect Acting Sympathomimetics

  • Enter postganglionic n. endings by neuronal uptake
  • Displace NA from storage vesicles
  • Evoke release of NA into synaptic cleft to act on adrenoreceptors
  • Because NA is released, most effects are α & β, as NA has minimal β2 activity

Direct Acting Sympathomimetics

  • Bind directly to receptors & activate them
  • α receptors: Adrenaline > NA > Isoprenaline
  • β receptors: Isoprenaline > Adrenaline > NA
  • α agonists:
    • Phenylephrine α1 > α2 >>>> β
    • Clonidine α2 > α1 >>>> β
  • α & β agonists:
    • Adrenaline β2 > β1 > α1 = α2
    • NA α1 = α2 ­> β1 >> β2
  • NB: β1 receptors like NA & Adrenaline the same. Β2 receptors prefer Adrenaline
  • Β agonists:
    • Dobutamine β1 >> β2 >>>> α
    • Isoprenaline β1 = β2 >>>> α
    • Terbutaline β2 >> β1
  • Dopamine agonist
    • Dopamine D1 = D2 >> β >> α

α1

Gq protein

α2

Gi protein

Β

GS

D1

GS

D2

Gi

Drug Interactions

MAO Inhibitors

  • Synthetic catecholamines = not metabolised by COMT
  • Rely on MAO for their metabolism
  • ∴MAOI’s prolong their DOA

Digoxin

  • Na / K / ATPase is required for neuronal uptake of Indirect Agents
  • RECALL: amphetamine is taken up at nerve ending & stimulates NA release
  • ∴Digoxin inhibition of Na / K / ATPase = ↓response to Indirect Agents