Wakade - Adrenergic Pharmacology II Flashcards
Metabolic Degradation of NE and EPI:
By what enzymes?
MAO and COMT
MAO:
o Location:
o Action in Nerve Terminals:
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
COMT:
Location
Location: effector cells (smooth muscle, cardiac muscle etc.) and liver (cytosol)
Note: NOT found in brain or neuronal cells
Metabolism of NE/EPI:
MAO first
COMT first
o MAO first (nerve terminal) followed by COMT (liver)
o COMT first (effector cell or liver) followed by MAO (liver)- primary pathway*
Two Types of Adrenergic Receptors:
Alpha
Beta
Alpha Adrenergic Receptors primarily produce:
Exceptions:
Alpha: produce primarily CONTRACTION or EXCITATION
Exceptions: inhibition of intestinal smooth muscle, presynaptic nerve terminals, platelets and brain.
Beta Adrenergic Receptors primarily produce:
Exceptions:
Beta: produce primarily RELAXATION or INHIBITION
Exceptions: stimulation of heart and kidney cells
Can cell have both alpha and beta R?
Final response depends on what?
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
Two subtypes of alpha adrenergic R
Alpha1: post-synaptic smooth muscles of blood vessels, salivary glands, pancreas, internal sex organs etc.
Alpha2: presynaptic SS nerve terminals, blood platelets, CNS
Potencies:
Phenylphrine (PE) > Methoxamine
Alpha1 Phenylphrine (PE) > Methoxamine
Potencies:
Clonidine > Alpha-Methyl-NE»_space; Oxymetazoline
Alpha2 Clonidine > Alpha-Methyl-NE»_space; Oxymetazoline
Potencies:
Naphazoline = EPI = NE
Alpha1=Alpha2 Naphazoline = EPI = NE
Mechanism of Signaling (Alpha1):
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)
Mechanism of Signaling (Alpha2):
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
Beta-Adrenergic Receptors:
Two Subtypes:
Locations:
Beta1: located in the heart, kidney and adipose cells
Beta2: located in the vascular and bronchial smooth muscles
Potency
Beta 1
ISO > EPI > NE»_space;> PE
Potency
Beta2
ISO > EPI»_space;> NE»_space;> PE
Mechanism of Signaling (beta adrenergic receptors)
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
Dopamine Receptors:
Location of major effects
What type of drugs act on DA receptors?
Major Effects: in CNS
Antipsychotics and neuroleptic drugs act through DA receptors
Two subtypes of DA-Rs
D1 and D2
D1 Family:
Subtype: Effect: Location: Effects on smooth muscle cells of BVs What is particularly rich in D1 receptors?
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
D2 Family:
Subtype:
Effect:
Location: (3)
Stimulation effects: (3)
(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
Relative Dopamine Potencies:
Dopamine: D1 = D2»_space; beta»_space; alpha
Fenoldopam: D1»_space; D2
Production of CV Actions by 3 Mechanisms:
- Releasing NE from adrenergic neurons (indirectly acting sympathomimetic)
- Interacting with alpha and beta adrenergic receptors
- Interacting with specific DA receptors
What do high doses of DA produce?
Due to:
Cause increased HR, increased contraction and increased CO
Due to activation of beta receptors by NE released from SS neurons in the heart
Adrenergic responses of organs:
Heart:
Heart: beta1 receptors mediate all actions
Adrenergic responses of organs:
Effect on heart rate:
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
What causes more rapid diastolic depolarization/increase in frequency of AP?
NE accelerates the process of decreasing K+ permeability during diastolic interval
- Results in cell being able to reach threshold faster and fire APs faster
Adrenergic responses of heart:
Contractile force:
Effect of activation of beta1-R on myocardial cells:
Affect of Ca influx on the AP:
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
Adrenergic responses of heart:
Contractile force:
Conduction: INCREASED
Velocity of impulse transfer from SA and AV nodes is increased
Refractory period of AV node is decreased
Adrenergic responses of heart:
Arrhythmias:
Can be induced by:
More common with NE, EPI, or ISO?
What enhances the effects of NE?
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
Adrenergic responses of heart:
Cardiac efficiency:
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
