Lecture 7: Adrenergic Agonists Flashcards
Receptor a1
-signals via Gq
-found on vascular, GI smooth muscle, and heart, and liver
-mediates vasoconstriction
a1 agonist clinical use
-nasal decongestion
-vascular failure in shock and supraventricular tachycardia
a1 ANTAgonist clinical use
-hypertension
-benign prostatic hyperplasia
-pheochromocytoma
direct a1 AGONIST drugs
-phenylephrine
-oxymetazoline
Phenylephrine (Neosynephrine)
-direct a1 agonist
-substrate for MAO
-high first pass metabolism
Phenylephrine clinical use
-a1 agonist
-nasal decongestant (bad tho)
-mydriasis w/o cycloplegia
-pressor
-vasoconstrictor in regional anesthesia
Phenylephrine administration
-parenteral
-oral
-local
2-aralkylimidazolines
-direct a1 receptor agonist
-basicity of imidazoline ring cause compunds to exist in ionized form at physiological pH
-partial agonists
2-aralkylimidazolines types
-naphazoline
-tetrahydrozoline
-oxymetazoline (visine)
2-aralkylimidazoline clinical use
-admin topically to promote vasoconstriction
-nasal and ophthalmic decongestants
Imidazoline
-basic ring structure
-cation is resonance stable = more basic
Beta receptor signaling
-Gs
-activate adenylyl cyclase
-increase cAMP
-cAMP dependent protein kinase
-phosphorylation of ion channels
B1 receptor location
-heart
-kidney
B1 receptor effect on heart
-increase force of contraction (inotropy)
-increase HR (chronotropy)
-increase conduction velocity in AV node
B1 receptor effect on kidney
-increase renin release
B1 AGONIST clinical use
-shock
-congestive heart failure
B1 ANTAgonist clinical use
-hypertension
-angina
-arrhythmias
-congestive heart failure
B2 receptor location
-smooth muscle
B2 receptor effect
-relax smooth muscle esp bronchial
-vasoDILATION
B2 AGONIST clinical use
-asthma
-premature labor
B2 ANTAgonist clinical use
Glaucoma
B3 receptor location
-bladder
B3 receptor effect
-relaxation
-prevention of urination
B3 AGONIST clinical use
-overactive bladder
Non-selective B agonists
-isoproterenol (isuprel)
B1-selective B AGONISTs
-Dobutamine (Dobutrex)
-Dopamine (intropin) (MOA complex)
B2 selective AGONISTS
-Terbutaline (brethine, bricanyl)
-metaproterenol (metaprel, alupent)
-albuterol (proventil, ventolin)
-salmeterol (serevent)
-ritodrine (yutopar)
B3-selective AGONISTS
-mirabegron (myrbetriq)
Isoproterenol (Isuprel)
-non-selective B AGONIST
-bronchodilation
-increase cardiac output
Isoproterenol (Isuprel) metabolism
-by phase II conjugation reactions
-by COMT
-not sensitive to MAO
Isoproterenol administration
-oral
-parenteral
-local (inhaled)
isoproterenol use
-asthma
-COPD
-cardiostimulant
Isoproterenol Action
-B1 and B2 AGONIST
-increase Cardiac Output
Isoproterenol effect on peripheral vessels
-stimulate B2
-vasoDILATION
-reduce peripheral resistance (may lower BP)
Isoproterenol clinical use
-emergency use to increase HR
-patients with bradycardia or heart block
-patients with SYSTOLIC dysfunction, SLOW HR, high systemic vascular resistance: after cardiac surgery in patients who previously used B-blockers
-astma and COPD
Isoproterenol note
-not routinely used
-epinephrine and dopamine more common
selectivity of adrenergic receptor agonists
SLide 37
Response to decrease in Blood pressure
-activates sympathetic fibers
-activate B1 receptors = increase HR (reflex tachycardia)
-activate a1 receptors = vasoCONSTRICT blood vessels
-INHIBITS vagus (PSNS)
-net result=increase BP
Response to increase in blood pressure
-INHIBITS sympathetic fibers
-activates VAGUS (PSNS) = decrease HR (reflex bradycardia)
-no effect on blood vessels
-net result = decrease BP
BP= peripheral resistance x cardiac output
-resistance influenced by vasoconstriction/dilation
-output influenced by HR and stroke volume
Norepinephrine effects
-decrease HR
-increase BP
-increase resistance
-a1,B1
Epinephrine effects
-INcrease HR
-maintain BP
-slight DErease peripheral resistance
-a1, B1, B2
Isoproterenol effects
-INcrease HR
-slight DEcrease BP
-DEcrease resistance
-B1, B2
Selective B2 AGONists
-resorcinol derivatives
-bronchoDILATION
-cardiac effects only observed at high doses
Selective B2 AGONist metabolism
-NOT by MAO or COMT
-longer duration of action than isoproterenol
selective B2 agonist administration
-oral
-parenteral (only resorcinol derivatives)
-local (inhaled)
selective B2 AGONist uses
-asthma
-COPD
-terbutaline used as tocolytic (prevent premature labor)
STRUCTURES
STRUCTURES
Resorcinol derivatives
-selective B2 AGONists
-metaproterenol
-terbutaline
Meta hydroxymethyl derivatives
-selective B2 AGONISTS
-Albuterol
-Salmeterol
Long acting B2 Agonists
-Salmeterol and Formoterol
-10 min and 5 min onset respectively
-longer duration
-INHALED
-use for long-term astma and COPD
-not acute treatment
Problems with B2 receptor agonists
-minor cardiac stimulation
Dobutamine
-MIXED B1 and a1 AGONIST
-dopamine derivative
-racemic
-racemic exerts stronger inotropic than chronotropic effect
-SHORT (2min) half life
+ Dobutamine enatiomer
-potent B1 AGONIST
- Dobutamine enatiomer
-potent a1 AGONIST
-reduced potency for B by 10x
Dobutamine metabolism
-by COMT and conjugation
-NOT sensitive to MAO
Dobutamine administration
-IV infusion (why?)
Dobutamine use
-acute heart failure
-shock
-lab stresss test
Mirabegron
-B3 AGONIST
-use for overactive bladder
-also M3 ANTAgonist!
Mirabegron problems
-slow onset (8 weeks)
-HTN
a2 receptor signaling
-Gi pathway
-inhibit Ca
-decrease NT release
a2 Agonist clinical use
-HTN
-pain
-glaucoma
a2 receptor AGONISTs
-Clonidine
-Methyldopa
-Guanabenz
-Guanfacine
-Brimodine
-Apraclonidine
-Tizanidine
Clonidine
-(phenylimino)imidazoline
-a2 AGONIST
-also imidazoline receptor
Clonidine structure
-imidazoline ring
-basicity of guanidine froup decreased (pKa 13 to 8) bc attachment to dichlorophenyl ring
Clonidine action
-a2 AGONIST
-in CNS: decrease SNS activity to heart and blood vessels
-presynaptic: decrease cAMP, inhibit Ca (decrease vesicular release), activate certain Ka channels (hyperpolarize
Clonidine administration
-oral
-parenteral
-transdermal
Clonidine clinical use
-HTN
-neuropathic pain
-opiate withdrawal
-ADHD
Clonidine problems
-hypotension
-sedation
-dry mouth
-withdrawal sometimes after prolonged use
a2 AGONIST effect
-reduce SNS
-inhibit NE release
Decreased SNS effect
-DEcrease HR
-DEcrease contractility
-DEcrease renin release
-DEcrease vasoCONSTRICTION
open ring imidazolidine a2 agonists
-Guanabenz
-Guanfacine
Guanabenz and Guanfacine admin
oral
Guanabenz and Guanfacine structure
-open ring imidazolidines
-2 atom bridge to guanidine group decreases pKa so drug is mostly non-ionized at physiological pH
Guanabenz and Guanfacine clinical use
-HTN
-ADHD (guanfacine)
Guanabenz half-life
6 hours
-guanfacine and clonidine half life
-12-16 hours
Methyldopa
-a2 AGONIST
-prodrug metabolized to agonist
-decrease SNS
-oral
Methyldopate
-water soluble ester HCL salt
-used for parenteral solutions
Methyldop(ate) uses
-HTN
-esp during pregnancy
Methyldopa metabolism
slide 52
Brimodine action
-a2 AGONIST
-acts on ciliary body
-inhibits aq humor production (acute)
-stimulate aq humor outflow (chronic)
Brimodine use
-Glaucoma (ophtalmic)
Brimonidine problems
allergic conjunctivitis
Meds for Glaucoma
-brimonidine
-apraclonidine (para NH2 on clonidine)
Tizanidine
-a2 AGONIST
tizanidine use
-muscle spasticity
tizanidine adverse effects
-sedation
-Na+ and water retention
-dry mouth
-withdrawal