Adrenergic

• Adrenergic Agonists are divided into 2 categories:

  direct-acting and indirect-acting
• Direct-acting agonist — are those directly interacting with adrenergic receptors.
• Indirect-acting — are those that can:

  1. Increase release of catecholamines by displacing them in nerve endings (e.g., tyramine).

  2. Inhibit neuronal reuptake of released catecholamines (e.g., TCAs and cocaine).

  3. Prevent enzymatic metabolism of norepinephrine by MAO and COMT.
• In indirect-acting agonist, it can increase the release of catecholamines by displacing them in nerve endings (e.g., tyramine).
• Indirect-acting agonist can inhibit neuronal reuptake of released catecholamines (e.g., TCAs and cocaine).
• indirect-acting agonist can prevent enzymatic metabolism of norepinephrine by MAO and COMT.
• Drug included in 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)
• 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)
• Drugs included in indirect acting agonist:

  Amphetamine-like: Amphetamine, Metamphetamine, and Tyramine

  Catecholamine-like: Atomoxetine, Reboxitine, Sibutramine, Duloxetine, Milnaciprain, and cocaine
• Amphetamine-like: Amphetamine, Metamphetamine, and Tyramine
• Catecholamine-like: Atomoxetine, Reboxitine, Sibutramine, Duloxetine, Milnaciprain, and cocaine
• Mixed acting drugs includes:

  Ephedrine (𝛼1, 𝛼2, 𝛽1, 𝛽2, and releasing agent)

  Dopamine (D1, D2, 𝛼, 𝛽, and releasing agent)
• 𝛼1 receptors are coupled with phospholipase C by G-proteins (Gq family). Activation leads to the formation of IP3 and DAG leading to release of intracellular Ca+2 which activates protein kinases.
• 𝛼2 receptors are also couple to G-proteins (Gi family) which adenylyl

  cyclase leading to decreased levels of cAMP.
• Activation sequence:

  1. Agonists activates 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:

  1. Agonists activates 𝛼1-receptor.
• Activation sequence:

  2. The receptor activates the coupled G-protein.
• Activation sequence:

  3. The activated subunit of the G-protein activates

  the effector (Phospholipase C) to form IP3 and DAG.
• Activation sequence:

  4. IP3 stimulates release of intracellular Ca+2.
• Activation sequence:

  5. DAG stimulates the activation of protein kinase C
• Activation sequence:

  1. Agonists activates 𝛼2-receptor.

  2. The receptor activates the coupled G-protein.

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

  4. Inhibited adenyl cyclase leads t decreased cAMP.
• Activation sequence:

  1. Agonists activates 𝛼2-receptor.
• Activation sequence:

  2. The receptor activates the coupled G-protein.
• Activation sequence:

  3. The activated subunit of the G-protein inhibits adenylyl cyclase.
• Activation sequence:

  4. Inhibited adenyl cyclase leads to decreased cAMP.
• Beta receptors

  • All subtypes (𝛽1, 𝛽2, and 𝛽3) coupled to a stimulatory G-protein (Gs family).
• Beta receptors

  • Receptor activation stimulates adenylyl cyclase leading to increased conversion of ATP to cAMP (major secondary messenger for 𝛽-receptor).
• Dopamine receptors

  • D1 receptor is associated to increase levels of cAMP by stimulating

  adenylyl cyclase.
• Dopamine receptors

  • D2 receptor inhibits cAMP activity, opens K-channel, and decrease 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.
• Receptor Selectivity:

  • Selectivity is not absolute.

  • Drugs can interact with related class of receptors.

  • Expression of receptor types in tissues also affect the effects exhibited by a drug.
• Receptor Selectivity is not absolute.
• in receptor selectivity, drugs can interact with related class of receptors.
• In receptor selectivity, the expression of receptor types in tissues also affect the effects exhibited by a drug
• the effect of substitution on the benzene ring is increases bioavailability and prolongs DOA
• Substitution on the benzene ring is increases distribution in the CNS
• the effect of substitution in the amino group is Larger alkyl group increases 𝛽 receptor activity; lowers 𝛼 activity
• Effect of Substitution at the 𝛼-carbon is Prolongs DOA by inhibiting MAO oxidation.
• the effect of Substitution at the 𝛽-carbon is Provides direct-action; important of storage at neural vesicles