Adrenoceptor Agonists (Sympathomimetics) Flashcards
drugs that mimic the actions of epinephrine or norepinephrine have been termed….
sympathomimetic drugs
adrenergic agonists can be direct acting, mixed acting, or indirect acting.
what are epinephrine and norepinephrine? also explain their selectivity**
DIRECT ACTING adrenergic agonists
they are nonselective
epinephrine binds a1,a2,b1,b2
norepinephrine binds a1,a2,b1
name 2 adrenergic agonist that is mixed acting
ephedrine, pseudoephedrine
name 4 types of indirect acting adrenergic agonists
releasing agents
uptake inhibitor
MOA inhibitor
COMT inhibitors
why does a beta blocker used for hypertension have to be selective?
blocking b1 only is the goal.
blocking b1 binding will prevent vasoconstriction and thus lower hypertension
however, if b2 is blocked as well, the lungs cannot relax and they will constrict - preventing breathing
name 3 INDIRECT acting adrenergic agonists
amphetamine
cocaine
tyrosine
albuterol is a ____ acting adrenrgic agonist
direct acting
Name 6 direct acting adrenergic agonists, aside from epinephrine and norepinephrine
albuterol
dobutamine
dopamine
isoproteronol
terbutaline
salmeterol
recap: name the 4 things that can block something in the synthesis of norepineprhine
metyrosine blocks tyrosine hydroxylase and dopamine cannot be formed from tyrosine
reserpine stops the packaging of NE/dopamine into vesicles
cocaine and tricyclic antidepressants prevent the reuptake of NE through NET and it thus stays in the synaptic cleft for longer
bretylium and guanethidine prevent the release of NE by blocking SNAPs and VAMPS
what is a direct acting adrenergic agonist
binds and activates adrenergic receptors.
true agonist
explain the mechanism of Tyramine
indirect acting adrenergic agonist
it displaces the stored catecholamines from the adrenergic nerve ending
what has the same MOA as tyramine?
amphetamine
mechanism of cocaine
what else has this same mechanism?
cocaine + tricyclic antidepressants
prevent the reuptake of catecholamines that have already been released
indirect acting adrenergic agonist
what prevents the enzymatic metabolism of norepineprhine?
MAO inhibitors
monoamine oxidase
COMT inhibitors
catechol-o-methyltransferase
INDIRECT ACTING adrenergic agonists
what enzyme(s) is responsible for catecholamine metabolism in the brain
COMT and MAO
drugs that prevent them from metabolizing NE and E are indirect acting adrenergic agonists
true or false
COMT is a phase 2 biotransformation enzyme
true
** rank the following according to their affinity for the alpha adrenoceptor:
norepinephrine, isoproterenol, and epinephrine
highest affinity or equal: epinephrine
norepinephrine is either equal or less than epinephrine
lowest affinity by far is isoproterenol
rank the following according to their affinity for the beta adrenoceptor
norepineprhine
isoproterenol
epinephrine
isoproterenol has the highest affinity
epinephrine
norepinephrine is less than or equal to epinephrine
name a factor that can contorl the response of an indirect acting adrenergic agonist
the underlying sympathetic activity
true or false
the route of administration of adrenergic agonists does not control the response
false - it does
adrenoreceptors are what kinf of receptors?
GPCRs
the alpha 1 receptor uses what class of g protein?
also explain the mechanism
Gq
agonist binds to a1 receptor, alpha subunit of gq protein dissocitates and binds GTP (instead of GDP) and binds phospholipase c
phospholipase c increases DAG and IP3
DAG activates PKC
IP3 releases stored calcium to become FREE CALCIUM which activates calcium dependent protein kinase and second messengers (IP3,PKC, DAG ETC)
in alpha 1 receptors, what releases the stored calcium?
IP3
in alpha1 receptors, what activates PKC (protein kinase c)
DAG
What g protein does alpha 2 adrenoceptors work through
gi
what g protein do Beta receptors work through
Gs
explain the mechanism of agonist binding to alpha 2 receptors
agonist binds, alpha i(nhibitory) subunit binds GTP and disociates from b and y subunits
alpha subunit bound to GTP does NOT bind adenylyl cyclase and cAMP is not produced
cAMP levels decrease
explain the mechanism of agonist binding to beta receptor
as subunit binds GTP and dissociates from by subunits
as binds Adenylyl cyclase which causes ATP to increase cAMP
name an alpha1 agonist
what will it cause when binds to alpha 1?
phenylephrine
vasoconstriction
alpha 1 antagonist
what will be the effect when binding to alpha1?
prazosin
will block vasoconstriction and cause vasodilation
name an alpha 2 agonist
what will happen upon binding to alpha 2 receptor?
clonidine
will cause vasodilation
name an alpha 2 antagonist
yohimbine - not used clinically anymore
true or false
when an alpha 2 agonist binds to it, IP3 and DAG will increase
FALSE
this is alpha 1 mechanism
alpha 2 will decrease camp levels
true or false
a1 receptor works through Gq
true
name a nonselective beta agonist
what happens upon binding?
isoproterenol
increased cAMP levels - works through Gs
increased heart rate and relaxes bronchial smooth muscle
name a nonselective beta antagonist
what happens upon binding?
propanolol
decreased heart rate and possible bronchoconstriction
general effect of beta receptor binding
works through Gs, so increased cAMP levels
explain what receptor selectivity means
the drug preferentially binds to a certain subgroup of receptors
however, only at low concentrations. selectivity is not absolute because at higher concentrations the drug also interacts with related classes of receptors
the effects of a drug depend on the selectivity for certain subtypes and also….
the expression of these receptor subtypes in a given tissue
where is the B3 receptor
adipose tissue
name 2 alpha agonists that are most selective for alpha 1
phenylephrine and methoxamine
a1>a2»»»»»B
name 2 alpha agonists that are most selective for A2
clonidine and methylnorepinephrine
a2>a1»»»»>B
name 2 mixed alpha and beta agonists
epinephrine and norepinephrine
explain the selectivity of both epinephrine and norepinephrine
both have equal affinity for alpha1 and alpha2
epinephrine has equal affinty B1=B2 also
norepinephrine has more affinity for B1 than B2
B1»B2
isoproterenol selectivity
B1=B2»_space;»»»»»»a
albuterol/terbutaline/metaproterenol/ritodrine selectivity
B2»B1»»»a
dobutamine selectivity
B1>B2»»>A
What happens if a potent drug continually binds to a receptor?
desensitization
what is heterologous desensitization?
how can it happen?
the desensitization of receptors that were NOT exposed to the agonist
2nd messengers like PKC and PKA phosphorylate different receptors and decrease their activity
ex: PKA phosphorylates the b2 receptor and changes its preference from Gs to Gi
what does biased agonists mean?
give an example
a receptor can have many effects
for example, binding to B1 incresed the heart rate and cardiac workload through the GPCR mechanism BUT also has non-GPCR arrestin-mediated efects
biased agonists for heart attack work through non-GPCR pathway
NET reuptakes norepinephrine
breakdown where it takes the NE
reuptakes 90% NE into heart synapses and about 60% into other synapses
there, it enters vesicles and undergoes metabolism by MAO and COMT
explain how amphetamine works
an indirect acting adrenergic agonist
instead of NET reuptaking the NE in the cleft, the transporter is reversed and more NE comes out into the cleft
explain how cocaine works
indirect acting adrenergic agonist
blocks the reuptake of NE by NET so it stays in the synaptic cleft longer
effect of alpha 1 binding on most vascular smooth muscle
contraction
effect of alpha1 binding on the eye
contracts the pupillary dilator muscle (which dilates the eye)
effect of alpha1 binding on pilomotor smooth muscle
hair gets erected
effect of alpha 1 on prostate
contraction
effect of alpha 1 on heart
increased force of contraction
effect of alpha 2 binding on fat cells
inhibitis lipolysis
effect of alpha 2 on platelets
causes them to aggregate
effect of alpha 2 on adrenergic/cholinergic nerve terminals
inhibits the release of neurotransmitter
effect of B1 on the heart and on juxaglomerular cells
increased force and rate of contraction of the heart
increases release of renin (body retains fluid, increased BP)
effect of B2 on smooth muscle
smooth muscle relaxation
true or false
b2 binding causes bronchodilation and vasodilation
true
effect of b3 binding on fat cells
activates lipolysis
true or false
alpha 2 agonists cause lipolysis
FALSE inhibits lipolysis
B3 agonists cause lipolysis
explain how the cardiovascular effects of adrenergic agonists can vary
there is a widespread distribution of alpha and beta receptors in heart/blood vessels/neural/hormonal systems that are all involved in BP regulation
thus, the effects depend on whether the agonist acts on alpha, beta, or both
