Wakade - Adrenergic Pharmacology II

Question 1

Metabolic Degradation of NE and EPI:

By what enzymes?

Answer 1

MAO and COMT

Question 2

MAO:
o Location:
o Action in Nerve Terminals:

Answer 2

MAO:
o Location: nerve terminals (mitochondrial outer membrane), brain, liver, intestinal mucosa and neuronal tissue
o Action in Nerve Terminals: metabolizes free NE to regulate transmitter content in cytosol

Question 3

COMT:

Location

Answer 3

Location: effector cells (smooth muscle, cardiac muscle etc.) and liver (cytosol)

Note: NOT found in brain or neuronal cells

Question 4

Metabolism of NE/EPI:

MAO first
COMT first

Answer 4

o MAO first (nerve terminal) followed by COMT (liver)

o COMT first (effector cell or liver) followed by MAO (liver)- primary pathway*

Question 5

Two Types of Adrenergic Receptors:

Answer 5

Alpha

Beta

Question 6

Alpha Adrenergic Receptors primarily produce:

Exceptions:

Answer 6

Alpha: produce primarily CONTRACTION or EXCITATION

Exceptions: inhibition of intestinal smooth muscle, presynaptic nerve terminals, platelets and brain.

Question 7

Beta Adrenergic Receptors primarily produce:

Exceptions:

Answer 7

Beta: produce primarily RELAXATION or INHIBITION

Exceptions: stimulation of heart and kidney cells

Question 8

Can cell have both alpha and beta R?

Final response depends on what?

Answer 8

Cell/organ may have both alpha and beta R: and they may be activated simultaneously

Final response: depends on two factors

• Dominance of a certain type of receptor
• Type of adrenergic agent use

Question 9

Two subtypes of alpha adrenergic R

Answer 9

Alpha1: post-synaptic smooth muscles of blood vessels, salivary glands, pancreas, internal sex organs etc.

Alpha2: presynaptic SS nerve terminals, blood platelets, CNS

Question 10

Potencies:

Phenylphrine (PE) > Methoxamine

Answer 10

Alpha1 Phenylphrine (PE) > Methoxamine

Question 11

Potencies:

Clonidine > Alpha-Methyl-NE&raquo_space; Oxymetazoline

Answer 11

Alpha2 Clonidine > Alpha-Methyl-NE&raquo_space; Oxymetazoline

Question 12

Potencies:

Naphazoline = EPI = NE

Answer 12

Alpha1=Alpha2 Naphazoline = EPI = NE

Question 13

Mechanism of Signaling (Alpha1):

Answer 13

Agonist binds Alpha1 receptor (coupled to Gq protein)

Gq alpha subunit released and binds GTP

Gq alpha + GTP –> Activates phospholipase C

PIP2 –> DAG and IP3 (by PLC)

DAG activates PKC

IP3 causes release of stored Ca++ and increase in free Ca++ (activates protein kinases)

Question 14

Mechanism of Signaling (Alpha2):

Answer 14

Agonist binds Alpha2 receptor (coupled to Gi protein)

GTP kicks off GDP and binds Gi alpha subunit

Gi alpha + GTP –> Inhibits adenylyl cyclase –> decrease in cAMP

Question 15

Beta-Adrenergic Receptors:
Two Subtypes:
Locations:

Answer 15

Beta1: located in the heart, kidney and adipose cells

Beta2: located in the vascular and bronchial smooth muscles

Question 16

Potency

Beta 1

Answer 16

ISO > EPI > NE&raquo_space;> PE

Question 17

Potency

Beta2

Answer 17

ISO > EPI&raquo_space;> NE&raquo_space;> PE

Question 18

Mechanism of Signaling (beta adrenergic receptors)

Answer 18

Agonist binds Beta receptor (coupled to Gs protein)

GTP kicks off GDP and binds to Gs alpha subunit

Gs alpha + GTP –> Activates adenylyl cyclase (AC) –> Increase in cAMP

Increase in cAMP –> Activation of various proteins and enzymes

Question 19

Dopamine Receptors:
Location of major effects
What type of drugs act on DA receptors?

Answer 19

Major Effects: in CNS

Antipsychotics and neuroleptic drugs act through DA receptors

Question 20

Two subtypes of DA-Rs

Answer 20

D1 and D2

Question 21

D1 Family:

Subtype:
Effect:
Location:
Effects on smooth muscle cells of BVs
What is particularly rich in D1 receptors?

Answer 21

D1 Family (D5 Subtype):

Effect: increases cAMP

Location: Mainly CNS (striatum, hypothalamus, hippocampus)
Also in smooth muscle cells of blood vessels (particularly in renal vasculature)

• Vasodilation
• Natriuresis (loss of Na+)
• Diuresis

Renal vasculature

Question 22

D2 Family:

Subtype:
Effect:
Location: (3)

Stimulation effects: (3)

Answer 22

(D3,D4 Subtypes):

Inhibits cAMP, blocks Ca++ channels and opens K+ channels

Location:
o Sympathetic ganglia
o Sympathetic nerve terminals
o Abundant in CNS (pituitary gland, substantia nigra, frontal cortex, medulla, hypothalamus)

Stimulation Effects:
o Hypotension
o Bradycardia
o Vasodilation

Question 23

Relative Dopamine Potencies:

Answer 23

Dopamine: D1 = D2&raquo_space; beta&raquo_space; alpha

Fenoldopam: D1&raquo_space; D2

Question 24

Production of CV Actions by 3 Mechanisms:

Answer 24

1. Releasing NE from adrenergic neurons (indirectly acting sympathomimetic)
2. Interacting with alpha and beta adrenergic receptors
3. Interacting with specific DA receptors

Question 25

What do high doses of DA produce? Due to:

Answer 25

Cause increased HR, increased contraction and increased CO Due to activation of beta receptors by NE released from SS neurons in the heart

Question 26

Adrenergic responses of organs: | Heart:

Answer 26

Heart: beta1 receptors mediate all actions

Question 27

Adrenergic responses of organs: | Effect on heart rate:

Answer 27

o Rate: INCREASED Activation of beta1 R in pacemaker cells of SA node --> more rapid diastolic depolarization and an increase in the frequency of APs Important point: if the amine causes a rise in BP (ie. NE or PE), reflex activation of the vagus may override the direct action on the heart --> SLOWING of heart rate

Question 28

What causes more rapid diastolic depolarization/increase in frequency of AP?

Answer 28

NE accelerates the process of decreasing K+ permeability during diastolic interval - Results in cell being able to reach threshold faster and fire APs faster

Question 29

Adrenergic responses of heart: Contractile force: Effect of activation of beta1-R on myocardial cells: Affect of Ca influx on the AP:

Answer 29

o Contractile Force: INCREASED Activation of beta1 R of myocardial cells INCREASES Ca++ influx with each AP --> greater force of contraction Increase in Ca++ influx occurs with LITTLE (IF ANY) CHANGE to the AP itself

Question 30

Adrenergic responses of heart: Contractile force: Conduction: INCREASED

Answer 30

Velocity of impulse transfer from SA and AV nodes is increased Refractory period of AV node is decreased

Question 31

Adrenergic responses of heart: Arrhythmias: Can be induced by: More common with NE, EPI, or ISO? What enhances the effects of NE?

Answer 31

o Arrhythmias: Can be induced by activation of beta1 R Concomitant rise in BP will also increase the possibility (ie. due to increased workload on the heart) Therefore, arrhythmias are more common with NE and EPI than with ISO Some general anesthetics (ie. halothane) enhance these effects of NE

Question 32

Adrenergic responses of heart: | Cardiac efficiency:

Answer 32

o Cardiac Efficiency: DECREASED* CE= Work/O2 Used - Work=↑↑ - O2=↑↑↑ Therefore, although both work and O2 increase, the O2 used is increased higher to accommodate the increased work, resulting in an overall decrease in CE