Norepinephrine Metabolism and Uptake
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Questions and Answers

What percentage of released NE is taken up into the neuron?

  • 80% (correct)
  • 90%
  • 50%
  • 95%

    • What enzyme is involved in the metabolism of NE in the postsynaptic cell membrane?

  • NET
  • COMT (correct)
  • Uptake 1
  • MAO

    • What is the end product of the metabolism of Epinephrine and Norepinephrine?

  • Vanillylmandelic acid (correct)
  • Dihydroxymandelic acid
  • Metanephrine
  • 3-Methoxytyramine

    • What is the major mechanism of termination of action of NE?

    <p>Neuronal uptake</p> Signup and view all the answers

    What is the end product of the metabolism of Dopamine?

    <p>Homovanillic acid</p> Signup and view all the answers

    What type of receptors are adrenergic receptors?

    <p>G protein-coupled receptors</p> Signup and view all the answers

    What is the classification of adrenergic receptors based on?

    <p>Selective antagonists</p> Signup and view all the answers

    What happens to some of the released NE?

    <p>It diffuses out of the synapse</p> Signup and view all the answers

    What is the enzyme involved in the metabolism of NE in the neuron?

    <p>MAO</p> Signup and view all the answers

    What is the function of α1 receptors in the radial muscle of the iris?

    <p>Mydriasis</p> Signup and view all the answers

    Which subtype of β receptors is involved in increasing heart rate and force of contraction?

    <p>β1</p> Signup and view all the answers

    What is the initial effect of administering adrenaline intravenously on blood pressure?

    <p>It increases</p> Signup and view all the answers

    What is the effect of vasoconstriction on peripheral resistance?

    <p>Increase</p> Signup and view all the answers

    Why does the blood pressure fall after the initial increase when adrenaline is administered intravenously?

    <p>All of the above</p> Signup and view all the answers

    Which of the following is a non-catecholamine?

    <p>Ephedrine</p> Signup and view all the answers

    What is the function of α2 receptors in the brain?

    <p>Decreases sympathetic outflow</p> Signup and view all the answers

    What is the term for the initial increase and subsequent decrease in blood pressure when adrenaline is administered intravenously?

    <p>Biphasic response</p> Signup and view all the answers

    Which receptor subtype is involved in relaxation of skeletal muscle blood vessels?

    <p>β2</p> Signup and view all the answers

    What happens when a non-selective alpha blocker is administered after the biphasic response?

    <p>It blocks α1 receptors</p> Signup and view all the answers

    What is the effect of administering adrenaline again after a non-selective alpha blocker has been given?

    <p>Only a decrease in blood pressure is seen</p> Signup and view all the answers

    What is the function of β2 receptors in the liver?

    <p>Activation of glycogenolysis</p> Signup and view all the answers

    Which receptor subtype is involved in aggregation of platelets?

    <p>α2</p> Signup and view all the answers

    What is the main difference between the biphasic response and vasomotor reversal of Dale?

    <p>The biphasic response is a result of adrenaline administration, while vasomotor reversal of Dale is a result of alpha blocker administration</p> Signup and view all the answers

    What is the reason for the switch from α1 to β2 receptors in the biphasic response?

    <p>Due to the decrease in adrenaline concentration</p> Signup and view all the answers

    What is the effect of +ve chronotropic action on heart rate?

    <p>Increases</p> Signup and view all the answers

    What is the effect of α1 receptors on blood pressure?

    <p>It increases blood pressure</p> Signup and view all the answers

    What is the effect of β2 receptors on blood pressure?

    <p>It decreases blood pressure</p> Signup and view all the answers

    Which of the following sympathomimetic agents acts on all receptors at a higher concentration?

    <p>Adrenaline</p> Signup and view all the answers

    What is the effect of adrenaline on heart rate?

    <p>Increases heart rate</p> Signup and view all the answers

    What is the effect of activation of β1 receptors in the kidney?

    <p>Increases renin release</p> Signup and view all the answers

    What is the effect of adrenaline on blood flow to the skin?

    <p>Decreases blood flow</p> Signup and view all the answers

    What is the effect of adrenaline on vessels in the liver?

    <p>Dilates vessels</p> Signup and view all the answers

    What is the effect of adding an α blocker to adrenaline?

    <p>Decreases blood pressure</p> Signup and view all the answers

    Which receptor is more sensitive to dopamine?

    <p>DA</p> Signup and view all the answers

    What is the effect of adrenaline on cardiac output?

    <p>Increases cardiac output</p> Signup and view all the answers

    What is the effect of adrenaline on blood pressure at low doses?

    <p>Increases blood pressure</p> Signup and view all the answers

    What is the recommended dose of adrenaline in anaphylactic shock?

    <p>0.3 to 0.5 ml of 1:1000 solution</p> Signup and view all the answers

    What is the advantage of salbutamol over adrenaline in bronchial asthma?

    <p>Less cardiac stimulant action</p> Signup and view all the answers

    What is the role of adrenaline in cardiac arrest?

    <p>To restore cardiac rhythm</p> Signup and view all the answers

    How does adrenaline increase the duration of local anaesthetic action?

    <p>By producing vasoconstriction</p> Signup and view all the answers

    What is the concentration of adrenaline solution used in epistaxis?

    <p>1:100,000</p> Signup and view all the answers

    What is the reason for poor bioavailability of oral adrenaline?

    <p>First pass metabolism in intestine and liver</p> Signup and view all the answers

    What is the preferred route of administration of adrenaline?

    <p>Intramuscular</p> Signup and view all the answers

    What is a common adverse effect of adrenaline?

    <p>Tachycardia</p> Signup and view all the answers

    What is a rare but serious adverse effect of adrenaline?

    <p>All of the above</p> Signup and view all the answers

    What is the effect of adrenaline on the bronchi?

    <p>Relaxation and inhibition of mast cell secretion</p> Signup and view all the answers

    Which subtype of receptors is involved in the relaxation of the gut?

    <p>β2</p> Signup and view all the answers

    What is the effect of adrenaline on the urinary tract?

    <p>Relaxation of detrusor muscle and constriction of trigone and sphincter</p> Signup and view all the answers

    Which receptor subtype is involved in the contraction of radial muscle of the iris?

    <p>α1</p> Signup and view all the answers

    What is the effect of adrenaline on glucose levels?

    <p>Hyperglycaemia</p> Signup and view all the answers

    Which subtype of receptors is involved in the calorigenic effects of adrenaline?

    <p>β3</p> Signup and view all the answers

    What is the therapeutic use of adrenaline in anaphylactic shock?

    <p>Drug of choice</p> Signup and view all the answers

    What is the primary effect of α1 receptors on blood vessels?

    <p>Vasoconstriction</p> Signup and view all the answers

    Which receptor subtype is responsible for the decrease in blood pressure after the initial increase when adrenaline is administered intravenously?

    <p>β2</p> Signup and view all the answers

    What is the effect of α1 receptors on smooth muscle contraction?

    <p>Contraction</p> Signup and view all the answers

    Which subtype of α receptors is responsible for mydriasis?

    <p>α1</p> Signup and view all the answers

    What is the mechanism of vasoconstriction mediated by α1 receptors?

    <p>Increase in smooth muscle contraction</p> Signup and view all the answers

    What is the function of β2 receptors in the smooth muscles of bronchi?

    <p>Relaxation</p> Signup and view all the answers

    What is the effect of administering a non-selective alpha blocker after the biphasic response?

    <p>Decrease in blood pressure</p> Signup and view all the answers

    What is the effect of vasoconstriction on blood pressure?

    <p>Increase</p> Signup and view all the answers

    Which of the following sympathomimetic agents acts on both α and β receptors?

    <p>Adrenaline</p> Signup and view all the answers

    What is the effect of β2 receptors on blood vessels?

    <p>Vasodilation</p> Signup and view all the answers

    What is the difference between the biphasic response and vasomotor reversal of Dale?

    <p>The biphasic response is a result of α1 and β2 receptor activation, while vasomotor reversal of Dale is a result of β2 receptor activation only</p> Signup and view all the answers

    Which receptor subtype is involved in the contraction of radial muscle of the iris?

    <p>α1</p> Signup and view all the answers

    What is the function of β1 receptors in the heart?

    <p>Increase in heart rate and force of contraction</p> Signup and view all the answers

    What is the function of β2 receptors in blood vessels?

    <p>Vasodilatation</p> Signup and view all the answers

    Which receptor subtype is involved in vasoconstriction in the skin?

    <p>α1</p> Signup and view all the answers

    What is the effect of adrenaline on heart rate at low doses?

    <p>Increase</p> Signup and view all the answers

    Which receptor subtype is involved in the relaxation of smooth muscles in the gut?

    <p>α1</p> Signup and view all the answers

    What is the effect of α2 receptors on insulin secretion in the pancreas?

    <p>Decrease</p> Signup and view all the answers

    Which receptor subtype is involved in smooth muscle contraction in the radial muscle of the iris?

    <p>α1</p> Signup and view all the answers

    What is the primary mechanism of vasoconstriction in response to adrenaline?

    <p>α1 receptor activation</p> Signup and view all the answers

    Which receptor subtype is more sensitive to dopamine?

    <p>DA</p> Signup and view all the answers

    What is the classification of adrenergic receptors based on?

    <p>Selective antagonists</p> Signup and view all the answers

    In which type of muscle does beta2 receptor activation cause relaxation?

    <p>Smooth muscle</p> Signup and view all the answers

    What is the effect of alpha1 receptor activation on blood vessels?

    <p>Vasoconstriction</p> Signup and view all the answers

    Which receptor subtype is involved in the contraction of radial muscle of the iris?

    <p>Alpha1</p> Signup and view all the answers

    What is the mechanism of vasoconstriction in smooth muscle?

    <p>Increase in calcium ions</p> Signup and view all the answers

    Which receptor subtype is involved in the aggregation of platelets?

    <p>Alpha2</p> Signup and view all the answers

    What is the effect of beta2 receptor activation on smooth muscle?

    <p>Relaxation</p> Signup and view all the answers

    What is the function of α2 receptors in the brain?

    <p>Inhibit release of NE</p> Signup and view all the answers

    Which receptor subtype is involved in increasing heart rate and force of contraction?

    <p>β1 receptors</p> Signup and view all the answers

    What is the effect of α1 receptors on blood vessels?

    <p>Vasoconstriction</p> Signup and view all the answers

    Which receptor subtype is involved in relaxation of skeletal muscle blood vessels?

    <p>β2 receptors</p> Signup and view all the answers

    What is the mechanism of vasoconstriction by α1 receptors?

    <p>Increase in calcium influx</p> Signup and view all the answers

    Which receptor subtype is involved in smooth muscle contraction?

    <p>α1 receptors</p> Signup and view all the answers

    What is the effect of β2 receptors on smooth muscle?

    <p>Relaxation</p> Signup and view all the answers

    Which receptor subtype is involved in contraction of radial muscle of the iris?

    <p>α1 receptors</p> Signup and view all the answers

    What is the effect of α1 receptors on peripheral resistance?

    <p>Increase</p> Signup and view all the answers

    Which receptor subtype is involved in aggregation of platelets?

    <p>α1 receptors</p> Signup and view all the answers

    Study Notes

    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

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    Description

    This quiz covers the mechanisms of norepinephrine metabolism and uptake, including diffusion, neuronal uptake, and extraneuronal uptake. It also touches on the role of enzymes like MAO and COMT.

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