Adrenergic Agonists Flashcards
Catecholamines
general term for neurotransmitters/hormones in the sympathetic NS
named after their structure
catacholamines:
dopamine, neorepinephrine, epinephrine
4 Categories of Adrenergic Receptors
Alpha 1, Alpha 2, Beta 1, Beta 2, Dopamine
all are G-protein couples cell membrane bound receptors
Alpha 1 Receptors
Coupled with Gq proteins to phospholipase C
When activated, results in activation of protein kinas es
kinases activate other enzymes that result in physiologic actions–>see positive action
Alpha 2 Receptors
Couples with G1 proteins to adenylyl cyclase
when activated, results in inhibitory activity that decreases cAMP
decreased cAMP=reduces transduction of activating types of enzymatic messages
Beta Receptors
coupled with Gs proteins to adenylyl cyclase
increases conversion of ATP to cAMP
activated multiple kinases that activate additional enzymes leading to physiologic actions (stimulate kinase to result in some kind of effect)
Dopamine Receptors
D1=receptors stimulate adenylyl cyclase=increased cAMP
D2=receptors inhibit adenylyl cyclase=decreases cAMP
Variations in Adrenergic Receptor Response
selectivity
regulation
polymorphism
catecholamine metabolism
Adrenergic Receptor Selectivity
Sympathomimetic drugs–>able to bind to one subgroup of receptors without binding to other (a drug can bind to alpha 1 receptors but not alpha 2 or beta)
degree of binding is drug concentration dependent
low concentration= selective
high concentration=nonselective binding
Adrenergic Receptor Regulation
receptors up or down regulate over time which results to changes of the deugs response to sympathomimetic drugs
Desensitization
aka tachyphylaxis
occurs after long term exposure to catecholamines. Results in decrease responsiveness of that cell/tissue to additional stimulation
Mechanisms of Desensitization
altered transcription or translation of DNA/RNA
modification of receptors from interactions with enzymes or other proteins
long term exposure to agonist (tachypholyxis)
interactions or messages from other receptors
Desensitization for Theraputic Benefit
desensitixation of receptor desired
Ex. Drug Z binds to alpha 1 receptors and causes an exaggeration of the expected physiologic response
But the body doesnít like exaggerated drug-induced responses and wants to maintain homeostasis in the target organ, meaning less neurotransmitter will be available to bind to those alpha 1eceptors
This results in the actual desired effect of the drug, which is a decrease in alpha 1 activity in a specific target organ
Variations in Receptor Polymorphism
individuals amino acid differences aloter receptor response–>alter degree of susceptibility to desensitization and alter degree or responsiveness to drugs–>some theraputic drugs work in some pt’s but not others
Termination of NT’s action
- NE transporter (NET)–brings NE back to the presynaptic neuron
- movmenet of NE out of synaptic cleft into bloodstream
- Metabolism by COMT (catecholamine-O-methyltransferase)
Metabolism by monoamine axodase (MAO)
Norepinephrine Transporter (NET)
Removes 90% of released NE (most common way)
presynaptic pump that moves NE out of synapse and back into the neruon (NE will then be recycled or metabolized by MAO)
NET as Theraoutic Target
inhibits NET (atomoxetine and cocaine) leads to increased stimulation of adrenergic receptors
Catechol-O-methyl Transferase (COMT)
metabolizes all catecholamines–>terminates actions of NE, Epi, DA
drugs can inhibit COMT and prolong effect of the catecholamine
ex:Enatacopne (will inhibit COMT=increases DA)
Monoamine Oxidase (MAO)
metabolizes Monoamines (NE, EPi, Serotonin, DA) two forms A&B
Sympathomimetics
Drugs that mimic actions of NE, Epi, DA
2 forms-Direct & indirect agonists
Direct Agonist Sympathomimetics
structure allos for binding to adrenergic receptors resulting in activation
Indirect gonists
not interacting with receptor
cause release of stored catecholamines
inhibits reuptake of catechalomine already released
Structure of Sympathomimetics
similar structure to catecholamines, enough that NE receptors will allow it to bind
Benzene Ring Substitution
dding Hydroxyl groups–>maximizes a and b activity
adding hydroxyl to 1 reduces adrenergic potency
absence of OH will allow it to corss BBB and enter CNS
Amino Group Substitutions
increases Beta activity (decrease Alpha activity)
isopropyl on amino Nitrogen increases beta activity
Alpha Carbon Substitutions
block oxidation by MAO=prolonged duration of action (longer 1/2 life)
adding methyl group at alpha carbon increases ability to act as indirect sympathomimetics
Beta Carbon
less significant impact on activity
adding hydroxyl enables direct agonist activity
Sympathomimetic Effcts on Cardiovascular System
outcome is dependent on:
- selectivity for alpha and beta receptors
- agonist or antagonist
- action of body’s compensatory mechanism to maintain homeostasis
will effect HR, CO, BP, Venous return
Alpha 1 Cardiovascular Effects
Alpha 1 are in vascular beds ina rteries
activation of alpha 1=vasoconstriction=increase BP=the body will try and maintain normal range so it will slow HR and decrease CO (CO stays constant)
ex: Phenylephrine
Alpha 2 Cardiovascular Effects
in vascular beds and in CNS
Localy administration or HIGH dose=activation by alpha 2 agonists=vasoconstriction
Systemic administration=activation of central alpha 2 receptors=decrease in sympathetic activity=decrease in BP
ex:clonidide (to tx HTN)
Beta 1 Cardiovascular Effects
in heart
increase contractility and increase HR=increase in CO
stimulates heart
Beta 2 Cardiovascular Effects
in vasculature
vasodilation=drop in BP
Dopamine Effects on Cardiovascular System
stimulation of D1=vasodilation (renal, splanchnic, coronary, cerebral)
also binds to alpha and beta receptors and response is dose dependent
Low Dose DA on CV
activates Beta 2 receptors=vasodilation=lower Bp
Medium Dose DA on CV
activates Beta 1 receptors=increases CO
High Dose DA on CV
Activates Alpha 1 receptors=causes vasoconstriction=Increases BP
Sympathomimetics Effects on the Lungs
Beta 2 receptors → bronchodilation
Sympathomimetics Effect on the Eye
alpha receptors in radial muscle=mydriasis
can reduce IOP by increase outflow of aqueous humor
Sympathomimetics Effects on the GU System
alpha receptors= promote urine retention and mediate ejaculation
Sympathomimetics Effect on Salivary Glands
Beta receptors=increase salivation
Sympathomimetics Effect on Apocrine sweat Glands
(palms of hands)
increase sweat production
Sympathomimetics Effect on Metabolism
increase glycogenolysis in liver via beta receptors and increase serum glucose
Beta receptors=increase lipolysis
Alpha 2 receptors= decrease lipolysis
Beta 2 receptors=promote K+ reuptake
Beta 2 receptors= increase insulin release from islet cells
Alpha 2 receptors= decrease insulin release from islet cells
Epinephrine
“adrenaline”
agonist at alpha and beta receptors
Effect of Epinephrine
potent vasoconstrictor and cardiac stimulant increases BP (alpha 1) increases Hr and CO (B1 receptors)
in skeletal muscle causes vasodilation (B2) receptors
Norepinephrine
noradrenaline, Lvophed alpha 1,2 and Beta 1 agonist vasoconstrictor and cardiac stimulant increases BP (alpha 1) increases HR and CO (beta 1)
Phenylephrine (Neosynephrine)
Direct Alpha 1 agonist
not inactivated by COMT=prolongs duration of action
decongestant and raises BP
Midodrine (Amantine)
increase BP and tx orthostatic hypotention
Clonidine (catapres)
direct alpha 2 agonist, work in CNS to reduce BP and tx HTN
Methyldopa (Aldomet)
direct alpha 2 agonist, work in CNS to reduce BP and tx HTN
Guanfacine (Tenex)
direct alpha 2 agonist, work in CNS to reduce BP and tx HTN
Guanabenz (Wytensin)
direct alpha 2 agonist, work in CNS to reduce BP and tx HTN
Dexmedetomidine (Precedex)
direct alpha 2 agonist, acts in CNS for sedation
Oxymetazoline (Afrin, Dristan)
alpha 1 action=vasoconstriction and used as decongestant
alpha 2 action has similar action to clonidine to decrease BP
Isoproterenol (Isuprel)
Nonselective Beta agonist (B1 and B2)
B2=vasodilation (decreases diastolic BP)
B1=positive chronotropic and inotropic effects in heart (increase HR and CO)
Dobutamine
Beta 1 selective agonist
increases CO w/o reflexive increase in HR
(+)isomer=B1 action and A1 antagonism=increase in CO and NO increase in BP
(-)isomer= a1 action which=vasoconstriction=increase BP
beta 2 selective Agonists
provide bronchodilation and useful in tx of asthma and COPD Albuterol Terbutaline Metaproterenol Pirbuterol Salmeterol Formoterol Ritodrine-->relaxes uterine smooth muscle during labor
Mixed Acting Sympathomimetics
Provide Alpha and Beta effects=vasoconstriction, decongestion, bronchodilation, CNS-apetite supression
Ephedrine=bronchodilation
Pseudophredrine
indirect Acting Sympathomimetics
displace stored catecholamines inhibit reuptake of NE by NET Ex: amphetamines tyramine containing compounds catecholaine reuptake inhibitors
Amphetamines
causes release of stored NE and DA
CNS stimulation=increase mood and alertness and decreased appetite
Modafinil (provigil)
indirect sympathomimetic
inhibits NE and DA transporters in CNS=increases wakefulness in pt’s with narcolepsy or shift work disorder
Atomoxetine (Staterra)
Catecholamine Reuptake Inhibitor
selective inhibitor of NE reuptake with mostly CNS effect, used to tx ADHD
Subutramine (Meridia)
Catecholamine Reuptake Inhibitor
seratonin and NE reuptake inhibitor
appetitie supressant
Doluxetine (Cymbalta)
Catecholamine Reuptake Inhibitor
serotonina nd NE repuptake inhibitor
used an an antidepressant
Cocaine
inhibits peripheral reuptake of NE by NET
inhibition of DA resuptake in pleasure center of brain=leads to very rapid addiction
Sympathomimetic use to Tx Hypotension
use alpha 1 agonists to raise BP (by causing vasoconstriction)
NE and Phenylephrine
use of inotropic agents in shock syndromes
Dopamine, dobutamine
Sympathomimetics to Tx HYPERtension
central acting alpha 2 agonists
clonidine (catapress)
Sympathomimetics Management of Orthostatic Hypotension
tx with alpha 1 agonist like midodrine
Sympathomimetic use in Emergency Cardiac Measures
Epinephrine –>redirects blood flow from less important areas to bran and heart using Alpha 1 and Beta 1
Sympathomimetics in Surgical Apllication
Alpha 1
epinephrine to reduce blood loss at site of surgery
Epi, NE, Phenylephrine-locally acting alpha 1 agonists to slow diffusion of anesthetics away from site
Sympathomimetics in Sinus Decongestants
use alpha 1 agonists in nasal sprays to cause vasoconstriction (Phenylephrine )neosynephrine) Oxymetazline (afrin)
Sympathomimetics Pulmonary use
Selective beta 2 agents=bronchodilation Albuterol (VentolinÆ, ProventilÆ) Metaproterenol (AlupentÆ) Pirbuterol (MaxairÆ) Salmeterol (SereventÆ) Formoterol (PerforomistÆ)
Sympathomimetics Ophthalmic Applications
Alpha 1 agonist–>mydriasis (pupillary dilation)
reduce eye redness
Alpha 2–>reduce IOP w/glaucoma (apraclonidine, lopidine, bromonidie, alphagan)
Sympathomimetics GU Application
Beta 2 selective–> relax uterus in premature labor (Ritodrine, Terbutaline)
Sympathomimetics CNS Apllications
tx narcolepsy, appetitie supression, manage ADHD
Methylphenidate (RitalinÆ) Dextroamphetamine/amphetamine (AdderallÆ) Lisdexamfetamine (VynaseÆ) (prodrug for amphetamine)
Sympathomimetics Sedation applications
Use Alpha 2 agonists
dexmedetomidine
