adrenergic quiz

• Adrenergic Agonists are divided into 2 categories:

  • Direct-acting: directly interact with adrenergic receptors
  • Indirect-acting: can increase release of catecholamines, inhibit neuronal reuptake of released catecholamines, and prevent enzymatic metabolism of norepinephrine by MAO and COMT
• Drugs included in this group:

  • Direct-acting:
  • Selective: Phenylephrine (𝛼1), Clonide (𝛼2), Dobutamine (𝛽1), and Terbutaline (𝛽2)
  • Non-selective: Oxymetazoline (𝛼1, 𝛼2), Isoproterenol (𝛽1, 𝛽2), Epinephrine (𝛼1, 𝛼2, 𝛽1, 𝛽2), and Norepinephrine (𝛼1, 𝛼2, 𝛽1)
  • Indirect-acting:
  • Amphetamine-like: Amphetamine, Metamphetamine, and Tyramine
  • Catecholamine-like: Atomoxetine, Reboxitine, Sibutramine, Duloxetine, Milnaciprain, and Cocaine
  • Mixed-acting: Ephedrine (𝛼1, 𝛼2, 𝛽1, 𝛽2, and releasing agent) and Dopamine (D1, D2, 𝛼, 𝛽, and releasing agent)
• Mechanism of Action:

  • Receptor Types:
  • Alpha receptors:
  • 𝛼1 receptors are coupled with phospholipase C by G-proteins (Gq family), leading to the formation of IP3 and DAG
  • 𝛼2 receptors are coupled to G-proteins (Gi family) which inhibit adenylyl cyclase
• Activation sequence for 𝛼1-receptor:

  1. Agonists activate 𝛼1-receptor

  2. The receptor activates the coupled G-protein

  3. The activated subunit of the G-protein activates the effector (Phospholipase C) to form IP3 and DAG

  4. IP3 stimulates release of intracellular Ca+2

  5. DAG stimulates the activation of protein kinase C
• Activation sequence for 𝛼2-receptor:

  1. Agonists activate 𝛼2-receptor

  2. The receptor activates the coupled G-protein

  3. The activated subunit of the G-protein inhibits adenylyl cyclase

  4. Inhibited adenylyl cyclase leads to decreased cAMP
• Receptor Types:

  • Beta receptors:
  • All subtypes (𝛽1, 𝛽2, and 𝛽3) are coupled to a stimulatory G-protein (Gs family), leading to increased conversion of ATP to cAMP
• Receptor Types:

  • Dopamine receptors:
  • D1 receptor is associated with increased levels of cAMP by stimulating adenylyl cyclase
  • D2 receptor inhibits cAMP activity, opens K-channel, and decreases Ca+2 influx
• Receptor Selectivity:

  • When a drug preferentially binds to one receptor subgroup at concentrations that are too low to interact with another subgroup
  • Selectivity is not absolute and drugs can interact with related class of receptors
• Receptor Regulation:

  • Dynamic adjustment or alteration of the number, sensitivity, and activity of cell surface receptors in response to changes in the extra-/intracellular environment
  • Types of desensitization:
  • Homologous: desensitization of only previously exposed receptors
  • Heterologous: desensitization of both previously exposed and unexposed receptors
• Chemistry of adrenergic agonists affects their receptor interaction and effects

  • Structure-Activity Relationship (SAR):
  • Effect of substitution on the benzene ring, absence of ring -OH, substitution in the amino group, substitution at the 𝛼-carbon, and substitution at the 𝛽-carbon
• Organ/System Effects:

  • Cardiovascular (𝛼1-receptors):
  • Constricts smooth muscle of resistance vessels, leading to increased peripheral resistance and venous return
  • In normotensive patients, increase in BP may invoke a reflex barareceptor vagal discharge
• • Cardiovascular (𝛼2-receptors):
  • Produces vasoconstriction when given orally, rapid IV, or in high doses
  • Systemically decreases BP by activating post-synaptic 𝛼2-receptors
• • Cardiovascular (D-receptors):
  • Vasodilation in various resistance vessels by activation of D1-receptors
  • Low dose 𝛽1-receptor activation leads to decreased PVR, high dose 𝛼1-receptor activation leads to vasoconstriction
• • Cardiovascular (𝛽-receptors):
  • Positive chronotropic activity, positive inotropic effect, positive dromotropic effect, and vasodilation in vascular beds upon 𝛽2-receptor activation
• • Bronchial smooth muscle:
  • 𝛽2-receptor activation leads to bronchodilation
• • Eye:
  • 𝛼1-receptor activation leads to mydriasis
  • Increases outflow of aqueous humor to reduce intraocular pressure
• • Genitourinary:
  • Mediates contraction in various parts, plays a role in normal ejaculation and detumescence of erectile tissue
• • Salivary glands and Apocrine sweat glands:
  • Regulation of amylase and water secretion, increased sweat production
• • Metabolic system:
  • 𝛽3-receptor activation increases lipolysis and fatty acid release, enhances glycogenolysis in the liver
• • Hormones:
  • Insulin and renin secretion is affected by receptor activation, adrenoreceptors regulate various hormones
• • CNS:
  • Range of effects from "nervousness" to adrenaline rush, peripheral effects include tachycardia and tremors
• • Endogenous Catecholamines:
  • Epinephrine (Adrenaline)
• Endogenous Catecholamines:
• Epinephrine (Adrenaline):

  • Agonist at both types of adrenoreceptor
  • Potent cardiac stimulant (𝛽1) and vasoconstrictor (𝛼1)
  • Promotes skeletal muscle vasodilation (𝛽2)
  • Increases blood flow during exercise
  • Generally decreases PVR leading to lower DBP
• Norepinephrine (Levarterenol, Noradrenaline):

  • Agonist at both 𝛼 subtypes and ��1, but little effect on 𝛽2 receptor
  • Increases PVR, DBP, and SBP
  • Compensatory baroreflex overcomes the (+) chronotropic effect
  • Maintains (+) inotropic effect on the heart
• Dopamine:

  • Regulates Na+ excretion and renal function
  • Functions as a neurotransmitter in the CNS
  • Responsible for reward stimulus relevant to addiction
  • Target for antipsychotic drugs
• Direct-acting Sympathomimetics:
• Phenylephrine:

  • Pure 𝛼1-agonist
  • Increases arterial peripheral resistance and decreases venous capacitance leading to increased BP
• Midodrine:

  • Selective 𝛼1-agonist
  • Hydrolyzed into active desglymidodrine
• Xylometazoline and Oxymetazoline:

  • Significant 𝛼2-receptor affinity
  • Promote constriction in the nasal mucosa
• Selective 𝛼2-agonists:

  • Clonidine, Methyldopa, Guanfacine, and Guanabenz work in the 𝛼2-receptors in the CNS to lower BP
  • Classic members may cause sedation
  • Newer agents like Moxonidine and Rilmenidine have fewer CNS effects
  • Dexdemetomidine provides sedation for intubated or mechanically ventilated patients in ICU
  • Tizanidine is a centrally active muscle relaxant for MS patients
• Isoproterenol (Isoprenaline):

  • Very potent 𝛽-receptor agonist with little effect on 𝛼-receptors
  • Leads to (+) chronotropic and inotropic effects
  • Potent vasodilator due to its 𝛽-selective activity
  • Increases CO but decreases DBP with minimal increase in SBP
• Selective 𝛽-agonists:

  • Selective 𝛽1-agonists like Dobutamine and Prenalterol (partial agonist) can increase CO with less reflex tachycardia
  • Dobutamine acts on 𝛼 and 𝛽 receptors
  • Selective 𝛽2-agonists like Terbutaline and Ritodrine promote respiratory, uterine, and vascular muscle relaxation
• Indirect-acting Sympathomimetics:
• Amphetamine-like:

  • Amphetamine is a racemic mixture of phenylisopropylamine with the D-isomer being more active
  • Abused as a CNS stimulant to increase alertness, improve mood, and decrease appetite
  • Methamphetamine is similar to amphetamine but more addictive
  • Modafinil is a psychostimulant different from amphetamine
  • Inhibits NE, DAT, 5-HT, glutamate, and GABA to promote wakefulness
• Tyramine:

  • Normal by-product of tyrosine metabolism
  • Can induce the release of catecholamines from noradrenergic neurons
  • Patients taking MAO Inhibitors can experience an increase in BP when taken with tyramine-rich food (hypertensive crisis)
• Sibutramine:

  • SNRI used as an appetite suppressant but discontinued due to CV ADRs (e.g., stroke)
• Catecholamine Reuptake Inhibitor:

  • Atomoxetine is a selective inhibitor of norepinephrine reuptake transporter
  • Has clonidine-like action that decreases sympathetic outflow in the CNS while potentiating NE effect in the periphery
  • Can cause orthostatic tachycardia
• Clinical Application:
• Condition: Cardiac applications

  • Drugs: Epinephrine, Dobutamine
  • Epinephrine can help during cardiopulmonary resuscitation by redistributing blood to coronaries and the brain
  • Dobutamine provides short-acting symptomatic relief