Norepinephrine Metabolism and Uptake

Metabolism of Norepinephrine (NE)

• NE diffuses out of the synapse and is metabolized in plasma or liver
• Neuronal uptake (NET/Uptake 1): 80% of released NE is taken up into the neuron, major mechanism of termination of action
  • Partly stored in intracellular vesicles for further release
  • Partly metabolized in neuron by MAO
• Extraneuronal uptake (Uptake 2): metabolized in the synapse by COMT in the postsynaptic cell membrane

Metabolism of Epinephrine and Norepinephrine

• Metabolized by COMT and MAO
• The end product is Vanillylmandelic acid (VMA), which is increased in pheochromocytoma, an adrenomedullary tumor

Metabolism of Dopamine

• Metabolized by MAO and COMT
• The end product is Homovanillic acid

Adrenergic Receptors (Adrenoceptors)

• G protein-coupled receptors
• Classified into alpha and beta receptors based on selective antagonists
• Alpha receptors: α1, α2
• Beta receptors: β1, β2, β3
• Dopamine receptors: DA1, DA2

Receptor Location and Function

• Alpha receptors:
  • α1: smooth muscles, blood vessels, radial muscle of iris, gut, and pilomotor smooth muscle
  • α2: brain, platelets, beta cells of pancreas, ciliary epithelium, and blood vessels
• Beta receptors:
  • β1: heart, juxtaglomerular cells in kidney, and liver
  • β2: smooth muscles, liver, eye, skeletal muscle blood vessels, and adipocytes
  • β3: adipocytes and bladder

Terminology in Cardiovascular Actions

• Vasoconstriction: increase in peripheral resistance (PR) → increase in BP
• Vasodilatation: decrease in peripheral resistance (PR) → decrease in BP
• +ve inotropic effect: increase in force of contraction (FOC) → increase in COP
• +ve chronotropic effect: increase in heart rate (HR) → increase in COP

Classification of Adrenergic Drugs

• Directly acting:
  • Catecholamines (contain dihydroxy benzene group): noradrenaline, adrenaline, dopamine, isoprenaline, and dobutamine
  • Non-catecholamines: clonidine, phenylephrine, methyldopa, and xylometazoline
• Indirectly acting:
  • Amphetamine, tyramine, and cocaine
• Mixed action adrenergic agonists:
  • Ephedrine and pseudoephedrine

Sympathomimetic Amines

• Catecholamines: epinephrine, norepinephrine, dopamine, dobutamine, and isoprenaline
• Non-catecholamines: ephedrine, pseudoephedrine, amphetamine, and phenylephrine
• Non-catecholamines are resistant to metabolism by MAO and COMT, hence they are longer acting and effective orally

Receptor Selectivity of Sympathomimetic Agents

• Adrenaline (epinephrine): α1, α2, β1, β2, and DA
• Noradrenaline: α1, α2, and β1
• Amphetamine: α1, α2, and β1
• Ephedrine and pseudoephedrine: α1, α2, β1, and β2
• Phenylephrine and oxymetazoline: α1
• Clonidine: α2
• Dopamine (DA): DA receptors are more sensitive to dopamine
• Dobutamine: β1

Pharmacological Actions of Adrenaline

• Acts on both α and β receptors
• At low doses, β effects (vasodilatation) predominate at the vascular system
• At high doses, α effects (vasoconstriction) are strongest
• α1 = α2, β1 = β2, and weak β3 action
• Cardiovascular actions:
  • ↑ FOC (positive inotropic effect)
  • Positive chronotropic action (↑ heart rate)
  • ↑ in conduction velocity (positive dromotropic effect)
  • ↑ in automaticity
  • Large doses can cause premature ventricular contractions → ventricular arrhythmias
• Activation of β1 receptors in the kidney → ↑ renin release → angiotensin II, a potent vasoconstrictor
• Renal blood flow is decreased
• Constricts arterioles in the skin, mucous membranes, and viscera (α effects) and dilates vessels in liver and skeletal muscles (β2 effects)

Pharmacological Actions of Adrenaline (continued)

• Biphasic response: a rise followed by a slight fall before returning to normal level
• Alpha receptors are more in number, but beta receptors are more sensitive, and action is persistent
• Initial rise in BP is α action, and fall due to β action
• Dale's Vasomotor reversal phenomenon: addition of α blocker will lead to persistent fall in BP

Adrenaline (continued)

• At lower concentrations of adrenaline, β2 receptors are more sensitive
• At higher concentrations of adrenaline, it acts on all receptors
• Biphasic response: initially, the concentration of adrenaline is high, it acts on α1 and β2, and α1-mediated vasoconstriction predominates, causing a rise in BP
• Within a few seconds, the level of adrenaline decreases due to its rapid metabolism and neuronal re-uptake, and only β2-mediated action occurs, causing a fall in BP
• Vasomotor reversal of Dale: after biphasic response, if we administer a non-selective alpha blocker, it blocks the α1 receptors, and only β2-mediated action occurs, causing a fall in BP

Adrenaline (continued)

• Uses:
  • Anaphylactic shock: 0.3 to 0.5 ml of 1:1000 solution of adrenaline should be administered IM
  • Bronchial asthma: Adrenaline can be used in acute bronchial asthma, but selective β2 stimulants like salbutamol (albuterol) are presently favored
  • Cardiac arrest: intracardiac adrenaline may be injected to restore the cardiac rhythm in patients with cardiac arrest due to any cause
  • Duration of local anesthetic action: Adrenaline can increase the duration of action of local anesthetics by producing vasoconstriction at the site of injection
  • Epistaxis (bleeding from the nose): a very weak solution of epinephrine (1:100,000) can be used topically to vasoconstrict mucous membranes to control oozing of capillary blood

Pharmacological Actions of Adrenaline

• Adrenaline acts on both α and β receptors
• At low doses, β effects (vasodilatation) predominate at the vascular system
• At high doses, α effects (vasoconstriction) are strongest
• α1 = α2, β1 = β2, and weak β3 action

Cardiovascular Actions

• Increases force of contraction (FOC) → increased cardiac work and oxygen consumption (β1 action)
• Positive chronotropic action (increases heart rate)
• Positive dromotropic action (increases conduction velocity)
• Increases automaticity
• Large doses can cause premature ventricular contractions → ventricular arrhythmias
• Activation of β1 receptors in the kidney → increases renin release → angiotensin II, a potent vasoconstrictor
• Renal blood flow is decreased
• Constricts arterioles in the skin, mucous membranes, and viscera (α effects) and dilates vessels in liver and skeletal muscles (β2 effects)

Biphasic Response

• Initial rise in blood pressure due to α1 action (vasoconstriction)
• Fall in blood pressure due to β2 action (vasodilatation)
• Observed response is a rise followed by a slight fall before returning to normal levels

Dale's Vasomotor Reversal

• Administration of non-selective α blocker blocks α1 receptors, resulting in only β2 mediated action (vasodilatation)
• Only fall in blood pressure is seen, rather than a biphasic response

Smooth Muscle Actions

• Bronchi: bronchodilatation and inhibition of mast cell secretion (β2)
• Gut: relaxation (α2 & β2) in isolated preparations of gut and constriction of sphincters (α1)
• Urinary tract: detrusor muscle relaxation (β2) and contraction of trigone and sphincter (α1)
• Uterus: inhibition of uterine tone and contractions (β2 action)

Metabolic Actions

• Causes hyperglycemia due to increased glycogenolysis in liver and skeletal muscle (β2) and decreased insulin release from pancreas (α2)
• Increases free fatty acids due to lipolysis in adipose tissue (β3)
• Calorigenic effects: increases basal metabolic rate (β3) due to stimulation of hormone-sensitive lipase and triglyceride lipase

Eye Actions

• Contraction of radial muscle of iris (α1) → dilatation of pupil (active mydriasis)
• Decreases secretions from ciliary epithelium (α2)
• Decreases intraocular pressure (α1) → increases outflow of aqueous humor

Therapeutic Uses

• Anaphylactic shock: drug of choice due to its ability to rapidly increase blood pressure and improve cardiovascular function

Receptor Location and Function

• α1 receptors: smooth muscles (genitourinary muscles, prostate), blood vessels (vasoconstriction), radial muscle of iris (mydriasis)
• α2 receptors: brain (decreases sympathetic outflow), platelets (aggregation), beta cells of pancreas (decreases insulin secretion), ciliary epithelium (decreases aqueous secretion)
• β1 receptors: heart (increases heart rate and force of contraction), juxtaglomerular cells in kidney (increases renin secretion)
• β2 receptors: smooth muscles (bronchi, bladder wall, blood vessels, pregnant uterus), liver (activation of glycogenolysis), skeletal muscle blood vessels (relaxation), skeletal muscle (promotes potassium uptake)
• β3 receptors: adipocytes (stimulates lipolysis), bladder (relaxes detrusor muscle), thermogenesis