Adrenergic Agonists Flashcards
What are catecholamines?
general term for neurotransmitters/hormones of the sympathetic nervous system
How are catecholamines named?
named for their structure
contain an amine side chain -NH2
What are the 3 major catecholamines?
Dopamine
Norepinephrine
Epinephrine
What are the 4 basic categories of adrenergic receptors?
Alpha1 type (a1A, a1B, a1C)
Alpha2 type (a2A, a2B, a2C)
Beta type (B1, B2, B3)
Dopamine type (D1, D2, D3, D4)
What type of receptor are adrenergic receptors?
All = G-protein coupled cell membrane bound receptors
What increases the complexity of the nervous system signaling?
the various subtypes of receptors
will differ by potency and type of response
Which G protein are alpha1 receptors coupled with? And what is the G protein coupled to?
Alpha1 = coupled to Gq proteins
Gq proteins = coupled to phospholipase C
When alpha1 receptors are activated what happens?
results in activation of protein kinases –> activate other enzymes –> physiologic actions
Which G protein are alpha2 receptors coupled with? And what is the G protein coupled to?
Alpha2 = coupled to G1 proteins
G1 proteins = coupled to adenylyl cyclase
When alpha2 receptors are activated what happens?
results in inhibitory activity –> lowers cAMP
lowered cAMP reduces transduction of activating types of enzymatic messages
**no message is still a message (negative message)
Which G protein are beta receptors coupled with? And what is the G protein coupled to?
Beta = coupled to Gs proteins
Gs proteins = coupled to adenylyl cylase (some can be coupled to Gq proteins)
When beta receptors are activated what happens?
activation of beta receptors increases conversion of ATP –> cAMP
will activate multiple kinases –> activate additional enzymes –> physiologic action
What does activation of Dopamine D1 receptors do?
stimulate adenylyl cyclase –> increase cAMP
What does activation of Dopamine D2 receptors do?
inhibit adenylyl cylase (decrease cAMP)
What are the 4 main factors that can alter the degree to which an adrenergic receptors respond to a stimulus?
Selectivity
Regulation
Polymorphisms (genetic alterations)
Catecholamine metabolism
What does receptor selectivity allow for?
sympathomimetic drugs to bind to one subgroup of receptors w/o binding to others
** Drug X binds to alpha1 but not alpha2 or beta receptors
What is the result of selective binding?
selective actions
What is the degree of selective binding dependent on?
Concentration
Low concentrations = selective binding
High concentrations –> nonselective binding; so much of it around it’ll just start binding to everything
How does the body regulate receptors?
it’ll increase or decrease receptor response over time
Up regulation
Down regulation
What is the effect of receptor regulation?
you will see a change in receptor response to sympathomimetic drugs
What is an example of receptor regulation?
desensitization
Name 3 synonyms for desensitization
Tolerance
Refractoriness
Tachyphylaxis
When does desensitization occur?
after long term exposure to catecholamines or drugs
What is the result of desensitization?
decrease responsiveness of that cell/tissue to additional stimulation
What are the 4 mechanisms of desensitization?
altered transcription/translation of receptor DNA and/or RNA
modification of receptors –> interactions w/ enzymes or other proteins
Long term exposure to an agonist –> the mechanism of action of several drugs
Interactions or messages from other receptors
Is desensitization used for therapeutic benefit or is it purely an unintended consequence?
Can be used for therapeutic benefit
have an initial increase in response followed by desired decrease physiologic reaction
What is the mechanism of using desensitization of therapeutic benefit?
Drug X binds to alpha1 receptor –> exaggeration of expected physiologic response
body doesn’t like exaggerated response and will decrease production of alpha1 receptor to try to maintain homeostasis
ultimately means less neurotransmitter will be able to bind to those alpha1 receptors –> desired therapeutic effect
What is receptor polymorphism?
changes in amino acid sequence of receptors
normal genetic variation between people
What can be the result of receptor polymorphism?
can alter receptor response:
+/- risk to develop some diseases (i.e. HTN)
alter degree of susceptibility to desensitization
alter degree or responsiveness to drugs
What are some therapeutic consequences of receptor polymorphisms?
Some drugs may work in some patients but not others
What are the 4 ways adernergic neurotransmitter actions are terminated?
Norepinephrine transporter (NET) –> binds norepinephrine and brings back to axon terminal
Movement of NE out of synaptic cleft into blood stream
Metabolism by catecholamine-o-methyltransferase (COMT)
Metabolims by monoamine oxidase (MAO)
What is the SITE of action of NET (norepinephrine transporter)?
synaptic cleft
What is the MAJOR method of norepinephrine clean-up?
NET (norepinephrine transporter)
removes 90% of released NE
What is the mechanism of NET action?
acts as pre-synaptic pump to remove NE from synapse and back into axon terminal in neuron
allows NE to be recycled
Can NET be used as a therapeutic target?
Yes
What is the point of binding to NET?
inhibit its action –> prolong presence of NE in synaptic cleft –> increased stimulation of adrenergic receptors
Name the 2 drugs that bind NET
Atomoxetine (ADHD)
Cocaine
Besides direct inhibition what is another mechanism to reverse NET action?
increase the release of NE that has been taken up
What does COMT (catechol-o-methyl transferase) do?
metabolizes ALL catecholamines
assist in terminating actions of norepinephrine, epinephrine and dopime
What is the effect of inhibiting COMT?
prolong the effects of catecholamines
What is an example of a drug that inhibits COMT and what is it used in?
Entacapone –> adjunct for Parkinson’s
What is the mechanism of action of Entacapone?
inhibits metabolism of levodopa (precursor of dopamine)
What does MAO (monoamine oxidase) do?
metabolizes endogenous monoamines:
Norepinephrine
Epinephrine
Seratonin
Dopamine
How many MAO forms are there?
2: A and B
What does inhibition of MAO result in?
increase in NE, epinephrine, seratonin, dopamine levels
What types of problems could you have with MAOIs (MAO inhibitors)?
increase in neurotransmitter levels can be dangers
need proper dosing and need to avoid drug interactions
What are sympathomimetics?
drugs that mimic actions of norepinephrine, epinephrine, and dopamine
What are direct sympathomimetic agonists?
Drugs w/ a structure that allows for binding of adrenergic receptors –> activation
What are indirect sympathomimetic agonists?
Can’t directly bind to adrenergic receptors but will still have same result of sympathomimetic agonists
What are the mechanisms of indirect sympathomimetic agonists?
Multiple mechanisms:
can cause release of stored catecholamines
can inhibit reuptake of catecholamines that have already been released
What have medicinal chemists been able to do with direct sympathomimetics over the years?
Been able to create drugs w/ similar structures to natural catecholamines –> able to bind to adrenergic receptors
What is an example of a direct sympathomimetic of norepinephrine?
phenylephrine
What will modifications of sympathomimetics do?
alter the affinity for alpha or beta receptors –> compounds w/ varying levels of agonist/antagonist activity
what will happen if you add a hydroxyl group (-OH) to C3 AND C4 (opposite to alkyl (carbon side chain)) of a benzene ring?
maximize alpha and beta activity
creates catecholamine compounds –> susceptible to COMT breakdown
What will happen if you add hydroxyl (-OH) group to C3 OR C4 of a benzene ring?
reduce adrenergic potency
increase drug duration of action –> resistance to COMT
What happens if there are no -OH groups on benzene ring?
drug = lipophilic –> enter CNS
What happens when you increase the size of alkyl substitutions on the amino group of the benzene ring?
increase beta activity
lower alpha activity
What happens if you add an isopropyl group to the amino nitrogen (it’ll be the @ the end of the molecule)?
Will further increase beta activity
What will substitutions of the alpha carbon (carbon right next to terminal NH2) do?
block oxidation by MAO –> prolonged duration of action
What happens if you add a methyl group to the alpha carbon (carbon right next to terminal NH2)?
increase ability to act as indirect sympathomimetics –> release stored NE/direct agonists
What happens with a beta carbon substitution (side group added to 2 carbon away from terminal NH2)?
Less significant impact on activity
What happens if you add a hydroxyl (-OH) to beta carbon (carbon 2 away from terminal NH2)?
compound is able to act as direct agonist; but don’t not necessary to have
What is the main pharmacologic target of sympathomimetics?
Cardiovascular System
List the other systems that are effected by sympathomimetics (8)
Pulmonary
Ocular
Genitourinary (GU)
Salivary glands
Apocrine Sweat Glands
Metabolism
Hormone Release
CNS
In the cardiovascular system where are Alpha and Beta receptors found?
Heart
Blood Vessels
Other systems that regulate BP
What is the outcome of sympathomimetics on the cardiovascular system dependent on?
Selectivity –> alpha1/2 or beta1/2
Action @ receptor –> agonist/antagonist
Action of body’s compensatory mechanisms to maintain homeostasis –> desensitization
What are the 4 key sympathomimetic effects in the cardiovascular system?
Changes in:
Heart Rate (HR)
Cardiac output (CO)
Peripheral vascular resistance (BP)
Venous Return
Where do you find alpha1 receptors in the cardiovascular system?
vascular beds