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
What happens when sympathomimetics activate alpha1 receptors?
Arterial/venous vasoconstriction
After alpha agonist binding causes vasoconstriction, what else happens?
increase in BP (increase in peripheral vascular resistance) –> reflux slowing of HR (then decrease cardiac output) BUT venous return increases –> stroke volume and maintains cardiac output
CO = HR x SV
What drug is a alpha1 cardiovascular sympathomimetic, and what would you use it for?
phenylephrine
maintain BP in pt w/ poor organ perfusion –> vascular shock
treat stuffy nose –> constrict vessels in nasal passage ways
Where would you find alpha2 receptors in the cardiovascular system?
vascular beds
CNS
What does activation of peripheral alpha2 receptors by a sympathomimetic do?
causes vasoconstriction BUT only when given locally, as IV push, or in very high oral doses
What would systemic administration of an alpha2 sympathomimetic result in?
activate CENTRAL alpha2 –> inhibit sympathetic vascular tone
decrease sympathetic activity
decrease BP
What can a central alpha2 sympathomimetic be used to treat, what is the name of the drug?
treat hypertension
clonidine
What are the cardiovascular effects of a beta agonist?
vary depending on which beta receptors are activated
drugs vary in beta selectivity –> different observed responses
Where are beta1 receptors found in the cardiovascular system, and what do they do?
in the heart
increase contractility and increase HR –> increase cardiac output
Where are beta2 receptors found in the cardiovascular system, and what do they do?
in the vasculature
decrease peripheral resistance (vasodilation) –> decrease BP
Which dopamine receptors would you find in the cardiovascular system, and where would you find them?
D1 receptors
Renal
Splanchnic (small intestine)
Coronary
Cerebral
What is the effect of the stimulation of D1 receptors in the cardiovascular system?
vasodilation in some areas
Renal
Splanchnic (small intestine)
Coronary
Cerebral
What other receptors can dopamine bind to, and what is the response dependent on?
Bind to alpha and beta receptors
response = dose-dependent
Which receptors (besides D1) will low dose of dopamine bind to, what effect would you see?
acitvate beta2 receptors –> vasodilation –> lower BP
Which receptors (besides D1) will medium dose dopamine bind to, what effect will you see?
activate beta2 receptors –> stimulate heart
Which receptors (besides D1) will high dose dopamine bind to, what effect will you see?
activate alpha1 receptors –> vasoconstriction –> increase BP
Which receptors do sympathomimetics bind to in the lungs, and what is the effect?
beta 2 ONLY
bronchodilation
Which receptors do sympathomimetics bind to in the eye, what are the effects?
alpha receptors in radial muscles
mydriasis (widening of pupil)
increase outflow aqueous humor and reduce IOP in glaucoma
Which receptors do sympathomimetics bind to in the genitourinary (GU), what are the effects?
alpha receptors in bladder, urethral sphincter, prostate, others
promote urinary retention
mediate ejaculation
Which receptors do sympathomimetics bind to in the salivary glands, what are the effects?
beta receptors
increase salivation
Which sweat glands are affected by sympathomimetics and what are the effects?
apocrine sweat glands (palms of hands)
increase sweat production in response to STRESS
Which receptors do sympathomimetics bind to that are involved in metabolism, what are the effects?
Beta receptors in the liver: increase glycogenolysis –> increase serum glucose
Beta receptors increase lipolysis; alpha2 decrease lipolysis
beta2 receptors promote K+ uptake into cells –> hypokalemia
beta2 receptors also increase insulin release from islet cells
What is the sympathomimetic effect on Renin?
increased release by beta1
decreased release by alpha2
Besides insulin and renin, which other hormones are mediated by adrenergic receptors?
Parathyroid hormone
Calcitonin
Thyroxine
Gastrin
What are the effects of sympathomimetics on the CNS dependent on?
ability of the drug to cross the blood brain barrier (BBB)
If a drug is able to cross the BBB what receptors are involved?
complex reactions involving alpha, beta, and dopamine receptors
What are the effects of sympathomimetics that are able to cross the BBB?
Nervousness
Adrenaline rush
Feelings of impending disaster
Altertness/improved attention
Elevation of mood
Euphoria
Anorexia
Psychosis
Name the endogenous catecholamines
Epinephrine
Norepinephrine
Dopamine
What are the classes of direct sympathomimetic agonists?
alpha1 agonist
alpha2 agonist
beta1 agonist
beta2 agonist
What is a synonym for epinephrine?
adrenaline
Which receptors do epinephrine bind to?
agonist to alpha1 and beta1 receptors in the heart
What is the physiologic response to epinephrine?
potent vasoconstrictor and cardiac stimulant
alpha1 = increase systolic BP
beta1 = increase HR and cardiac output
Besides alpha1 and beta1 receptors, which receptors does epinephrine bind to?
Beta2 receptors in some blood vessels –> esp.. in skeletal muscle
causes drop in diastolic BP during exercise
What is a synonym for norepinephrine?
noradrenaline
Which receptors bind to norepinephrine?
agonist of alpha1, alpha2, beta1 (minimal beta2)
What is the physiologic response to norepinephrine?
potent vasoconstrictor and cardiac stimulant
alpha1 receptors = increase systolic/diastolic BP
beta1 receptors = incrase HR and cardiac output
What is the effect of dopamine dependent on?
dose-dependent
What are the effects of dopamine in CNS?
addiction –> reward stimuli (cocaine/crack addiction)
dopamine receptors = targets for antipsychotics
What can a deficiency of dopamine lead to?
Parkinson’s
Name 2 direct alpha1 agonists
Phenylephrine
Midodrine
How does phenylephrine work and what is it used for?
not inactivated by COMT –> prolongs duration of action
used as decongestant and to raise BP
What is midodrine used for?
increase BP
treat orthostatic hypotension
Name some alpha2 agonists, what are they all used for?
Clonidine
Methyldopa
Guanfacine
Guanabenze
act in CNS
reduce BP/ treat HTN
What is dexmedetomidine, and what is it used for?
direct alpha2 agonist
acts in CNS
used for sedation of patients in ICU
Name a drug that is a direct alpha1 AND alpha2 agonist and it’s action for each receptor
Oxymetazoline (afrin)
alpha1 = vasocontriction –> decongestant
alpha2 = similar action to clonidine (decrease BP)
Name a nonselective Beta (beta1 and beta2) agonist and its action for each receptor
Isoproterenol
beta1 = heart –> positive chronotropic/inotropic effects –> increase HR and cardiac output
beta2 = vasculature –> vasodilation –> decrease diastolic BP and mean arterial pressure
Name a beta1 selective agonist
Dobutamine
What is dobutamine used for?
increase cardiac output w/o a reflux increase in HR
What is unique about dobutamine?
racemic mixture of 2 isomers w/ different activity
Name the receptor each isomer of dobutamine binds to and its effect on the receptor it binds to
(+) isomer = beta1 agonist and alpha1 antagonist –> increase cardiac output w/o increase BP
(-) isomer = alpha1 agoinst –> increase BP
What is the effect of the racemic mixture of dobutamine?
positive inotropic action w/ little change in BP
What are the beta2 selective agonist that cause bronchodilation and are used to treat asthma and COPD?
Albuterol
Terbutaline
Metaproterenol
Pirbuterol
Salmeterol
Formoterol
What is the beta2 selective agonist that relaxes uterine smooth muscle during labor?
Ritodrine
What do mixed-acting sympathomimetics do?
provides both alpha and beta effects, potency of action varies from drug to drug:
vasoconstriction
decongestion
bronchodilation
CNS effects –> appetite suppression, stimulation, etc
What are 2 examples of a mixed-acting sympathomimetic?
Ephedrine
Pseudoephedrine
What are the 2 mechanisms of indirect-acting sympathomimetics?
displace stored catecholamines
inhibit reuptake of released neurotransmitters by interfering w/ NET
What are some examples of indirect-acting sympathomimetics?
Amphetamines
Tyramine containing compounds (aged meats, cheeses, fish, others)
Catecholamine reuptake inhibitors (doluxetine)
What does amphetamine do?
causes release of stored norepinephrine and dopamine
CNS stimulant: increase mood/alertness, decrease appetite
How would you make methamphetamine and what is its effect?
made from pseudo ephedrine
similar action to amphetamine
potent CNS actions
What kind of actions does phenmetrazine have?
similar actions to amphetamine
What is methylphenidate (Ritalin), what is its action, and what is it used to treat?
amphetamine derivative
treat ADHD
reduces reuptake of norepinephrine and improves brain function
What does modafinil do and what is it used for?
inhibits norepinephrine and dopamine transporters in the CNS (exact mechanism is poorly understood)
used to increase wakefulness in pts w/ narcolepsy, obstructive sleep apnea, and shift work disorder
What is Armodafinil and what is its action and uses?
R-enantiomer of modafinil
has similar action/uses as modafinil –> inhibits norepinephrine/dopamine transporters; used to increase wakefulness in pts w/ narcolepsey, obstructive sleep apnea, and shift work disorder
What is tyramine a product of and where would you find it naturally?
tyrosine metabolism
found in high concentrations of fermented foods (aged cheeses, meats, wine)
What do tyramines do?
causes release of stored catecholamines
similar actions to norepinephrine (alpha1, alpha2, beta1)
How are tyramines metabolized?
metabolized by MAO
Why would a pt taking an MAOI want to avoid tyramine and tyramine containing foods?
they can have side effects –> intensified sympathomimetic actions b/c tyramine isn’t being broken-down –> increase in release of catecholamines
POTENTIALLY DANGEROUS HYPERTENSION
Catecholamine Reuptake Inhibitors - what do they do and what receptors can they work on?
vary in selectivity of reuptake activity –> imbalance between norepinephrine and dopamine –> different actions
act on other receptors –> serotonin receptors
What are 3 examples of catecholamine reuptake inhibitors?
Atomoxetine
Subutramine
Doluxetine
What is Atomoxetine and what is it used to treat?
selective inhibitor of norepinephrine reuptake
mostly CNS effects (can increase BP)
treats ADHD
What is Subtramine and what is it used for?
Serotonin and norepinephrine reuptake inhibitor
approved as appetite suppressant
What is doluxetine do, and what is it used for?
serotonin and norepinephrine reuptake inhibitor
used as antidepressant
What is an illegal drug that is a catecholamine reuptake inhibitor?
Cocaine
What does cocaine do?
inhibits peripheral reuptake of Norepinephrine by NET
Enters CNS produces INTENSE amphetamine-like actions –> inhibits dopamine reuptake in pleasure centers of brain –> addictive
What systems are sympathomimetics used for therapeutically?
Cardiovascular
Pulmonary
Anaphylaxis
Ophthalmic
Genitourinary
CNS
Sedation
What is the goal of sympathomimetics when being used to treat Hypotension?
increase BP and cardiac output
low BP due to severe blood loss, hypovolemia, arrhythmias, antihypertensive overdose, shock
need to maintain BP (ensure proper perfusion to major organs)
Which type of sympathomimetics would you use to treat hypotension?
alpha1 agonists –> increase vasoconstriction (BP)
norepinephrine/phenylephrine
Which type of sympathomimetics would you use to treat shock syndromes?
inotropic agents –> increase cardiac output
dopamine/dobutamine
What is the goal of sympathomimetics when being used to treat hypertension?
decrease BP
Which type of sympathomimetics would you use to treat hypertension?
central acting alpha2 agonists –> bind to central CNS to decrease BP
clonidine (oral tablets or topical patch)
What is the goal of sympthomimetics when being used to treat orthostatic hypotension?
increase BP
orthostatic hypotension is a drop in BP as pt moves from sitting/lying down to standing –> loss of consciousness and trauma due to fall
Which type of sympathomimetics would you use to treat orthostatic hypotension?
alpha1 agonist
midodrine
What is the goal of sympathomimetics when being used to treat emergency cardiac episodes?
Cardiac resuscitation –> complete heart block or cardiac arrest
Which sympathomimetic would you use in an emergency cardiac situation and why?
Epinephrine
alpha1 and beta1 actions redistributes blood flow from periphery –> brain and heart
used in combo w/ other agents
What are the 2 goals of sympathomimetic uses during surgery?
reduce blood loss @ surgical site
slow diffusion of anesthetics away from site of administration
Which sympathomimetics are used to reduce blood loss @ surgical site?
Epinephrine
Cocaine
Which sympathomimetics are used to slow diffusion of anesthetics?
Epinephrine
Norepinephrine
Phenylephrine
What is the goal of sympathomimetics when being used to treat sinus congestion?
decrease nasal stuffiness associated w/ hay fever or sinus colds
Which sympathomimetics are used to treat hay fever or sinus colds?
alpha1 agonist in nasaal spray form –> vasoconstriction
Phenylephrine
Oxymetazoline
BUT limited to no more than 3 day usage –> repeated use leads to ischemic changes followed by hyperemia with discontinuation (when you stop using you’ll get massive vasodilation –> stuffy nose)
What is the goal of sympathomimetics when being used to treat pulmonary issues?
improve pulmonary air flow –> bronchodilation
Which pulmonary diseases would you use sympathomimetics to treat?
Asthma
COPD
**both cause bronchoconstriction
Which sympathomimetics would you use to treat either Asthma or COPD?
Beta2 selective agents in inhaler or nebulizer form
Albuterol
Metaproterenol
Pirbuterol
Salmeterol
Formoterol
What is the goal of sympathomimetics when being used to treat anaphylaxis?
reverse vascular complications of immune hypersensitivity
allergen –> bronchospasm, mucous membrane congestion, angioedema, severe hypotension
Which type of sympathomimetic would you want to use to treat anaphylaxis?
Epinephrine –> activate alpha1, beta1, beta2 receptors to reverse ALL symptoms
often used in combo w/ steroid or antihistamine
What are the goals of sympathomimetics when used to treat opthalmic disorders?
Mydriasis –> eye exams (alpha1 agonist)
Decongestion to r educe eye redness –> allergies (alpha1 agonist = visine)
Reduce intraocular pressure of glaucoma w/ agonists
Which sympathomimetics are used to treat glaucoma?
Apraclonidine
Brimonidine
What is the goal of sympathomimetics when being used to for a pregnant lady?
delay delivery
Which type of sympathomimetics are used to delay delivery of baby?
beta2 selective agents –> relax uterus during premature labor
Ritodrine
Terbutaline
What are some of the CNS applications of sympathomimetics?
Treat narcolepsy to increase alertness and defer sleep
Appetite suppression
Manage ADHD
Which sympathomimetics are used to treat narcolepsy?
amphetamine
modafinil
Which sympathomimetics are used to treat ADHD?
methylphenidate
Dextroamphetamine/amphetamine
Lisdexamfetamine
Why would sympathomimetics be used in the ICU?
improve patient comfort
pts under severe physiologic stress (mechanical ventilation, post-op) need to be sedated
Which type of sympathomimetics are used in the ICU?
alpha2 agonist in combo w/ opiods, benzodiazepines, propofol
dexmedetomidine
