Adrenergic Drugs I Flashcards
adrenergic receptors are _
GPCR’s
alpha-1 receptors
Gq phosphorylates alpha subunit –> beta-gamma detach –> Galpha-Pi activates PLC –> PLC cleaves PIP2 into DAG and IP3 (2nd messengers)
alpha-1 receptor functions
vasoconstriction, smooth muscle relaxation, contraction of GI tract, increase heart force, and stimulates glygenolysis/gluconeogenesis
muscle contraction by alpha-1 receptors
increases intracellular [Ca++] via release of intracellular stores –> calmodulin activation –> phosphorylation of MLCs
alpha-2 receptors
activation of Gi
Gi protein
inhibits adenylyl cyclase, reducing cAMP; also activates K+ channels for repolarization
alpha-2 receptor functions
contraction of smooth muscle, decreases insulin secretion, decreases NE release
beta-receptors
activate Gs which activates adenylyl cyclase
beta-1 receptors
in heart, kidneys, and adipocytes; produce positive inotropic and chronotropic effect
beta-2 receptors
in heart, vascular, bronchial and GI smooth muscle, glands, leukocytes, hepatocytes; smooth muscle relaxation
beta-3 receptors
in adipose tissue and GI tract; metabolic effects
beta receptors are found on _
post-synaptic cells
alpha-2 receptors are found on _
pre or post-synaptic cells
alpha-1 receptors are found on _
post-synaptic cells
beta-1 effects
tachycardia, increased renin, increased myocardial contractility
beta-2 effects
vasodilation, decreased peripheral resistance, bronchodilation, increases glucagon, increases glycogenolysis
signal termination steps
desensitization –> sequestration –> recycling/degradation
desensitization
ligand binding promotes phosphorylation of receptor –> beta-arrestin will bind –> now less sensitive to hormones or NTs binding
sequestration
after beta-arrestin binds, clathrin-coated vesicles will form –> pulls receptor away from membrane
catecholamines
dopamine, norepinephrine, epinephrine
high dose epinephrine
increase vasoconstriction, increase inotropy, increase chonotropy, increase HR and BP
low dose epinephrine
vasodilation, increase inotropy and chonotropy so still increases HR and CO (increased to overcome vasodilation)
at low doses epinephrine will bind _
beta receptors which allows vasodilation
at high doses epinephrine binds _
alpha receptors which causes vasoconstriction (lower affinity for alpha than beta)
epinephrine smooth muscle effects
relaxes GI smooth muscle (alpha and beta) and contracts bladder sphincter (alpha only)
epinephrine respiratory effects
relaxes bronchial smooth muscle
epinephrine metabolic effects
elevates blood glucose (decreases insulin secretion) and increases metabolism (increases triglyceride lipase activity and FFA)
epinephrine therapeutic uses
treatment of bronchospasm, relief of hypersensitivity reactions, prolong local anesthetics, topical hemostatic agent
low doses of dopamine
binds dopamine receptors and causes vasodilation and Na+ reabsorption
high doses of dopamine
binds beta-1 receptors causing inotropic effects, induces release of NE
very high doses of epinephrine
binds vascular alpha-1 receptors and causes vasoconstriction
life cycle of NTs
- synthesis
- uptake into storage vesicles
- release
- receptor binding
- removal/reuptake
- metabolism
synthesis of catecholamines
tyrosine –> L-DOPA –> dopamine –> norepinephrine or epinephrine
rate limiting step in catecholamine synthesis
tyrosine hydroxylase hydroxylating tyrosine
uptake into storage vesicles
dopamine enters a vesicle and is converted to NE or E; protected from degradation in vesicle (presynaptic cell)
VMAT1 and VMAT2
transport catecholamines into storage vesicles
VMAT1
peripheral
VMAT2
CNS
reserpine
irreversibly binds VMAT and inhibits them from taking up catecholamines; will deplete the storage vesicles
therapeutic uses of reserpine
antihypertensive; not used because of CNS effects
catecholamine release
influx of calcium (from AP) causes fusion of the vesicles with the cell membrane through exocytosis
catecholamine reuptake
norepinephrine transporter (NET) transports back into neuron
reuptake inhibiters
SNRIs, cocaine, imipramine
imipramine
tricyclic antidepressant; block NET and prolong stimulation of receptors
cocaine
blocks NET and DAT; prolongs stimulation of both central and peripheral receptors; can be used as local anesthetic
catecholamine metabolism
done by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)
MAO-A
noradrenergic neurons
MAO-B
serotonergic and histaminergic neurons
COMT
not found in sympathetic neurons
MAO-A inhibition
responsible for antidepressant effects
MAO-B inhibition
decreases dopamine metabolism in the brain; useful for Parkinson’s
safinamide
MAO-B inhibitor; Parkinson’s disease
isocarboxazid & seleginline
MAO inhibitors
tolcapone & entacapone
COMT inhibitors; Parkinson’s disease (with levodopa)
COMT inhibitors
inhibit levodopa metabolism, leaving more available for conversion to dopamine
