Adrenergic Agents Flashcards
general principles for characterizing receptors and subtypes
block agonist effects by specific competitive agonists
potency (selectivity) sequences of agonists
molecular biology, cloning receptors and demonstrating different structural subtypes
EPI reversal
high doses of EPI with ergotoxin (alpha1 blocker) decreases blood pressure instead of increasing it
effects of alpha1 receptors
contraction of iris, bronchioles, vascular smooth muscle, splenic capsule, uterine smooth muscle, male sexual organs, pilomotor muscle, urinary bladder, gastrointestinal sphincters
effects of beta2 receptors
relaxation of bronchioles, vascular smooth muscle, splenic capsule, uterine smooth muscle, urinary bladder, and intestinal smooth muscle
effects of beta1 receptors
increase cardiac sinus rate, contractile force, and conduction
renin release in kidney
increases aqueous humor secretion
effects of alpha2 receptors
relaxation of intestinal smooth muscle
decrease in cardiac sinus rate
accumulation of fat
decrease in insulin secretion
decrease in aqueous humor secretion
contractile and secretory signal transduction motif
for alpha1 agonists
phospholipase C activation, fast enzymes
G protein stimulation, rapid increase in cytoplasmic Ca concentration
mediates CRAC channels aka store-operated calcium channels (SOCs) to open
amplifies contractile response
protein kinase A/cyclic AMP signal transduction motif
for beta agonists
slower, metabolic processes used by beta receptors
involves G protein-linked synthesis of cAMP and PKA phosphorylation
alpha2 receptor mechanism
G-protein mechanism that opens potassium channels and reduces excitability of cells
blocks calcium channels
inhibits adenylyl cyclase
direct effect on neurotransmitter release through the secretary apparatus
three prototype chatecholamines and their structure-activity releationships
norepinephrine - good stimulant of alpha and beta1, but no beta2
epinephrine - good stimulant of alpha, beta1, and beta2
isoproterenol - good stimulant of beta1 and beta2, but no alphas
non-cardiovascular effects of the prototypes
mydrasis - alpha potency
bronchiolar relaxation - beta2 potency
intestinal relaxation and glycogenolysis - produced by all types, EPI is the best
direct cardiovascular effects of the prototypes
heart rate increased by beta1 receptors, increased rate of diastolic depolarization by stimiulating pacemaker current If and Ca currents
force is augmented by increasing calcium entry from outside the cell and SR
most vascular beds have both alpha and beta2 receptors
three things to consider when looking at vascular bed effect of a catecholamine
selectivity of the drug
ratio of alpha to beta2 receptors
concentration of the drug
describe a cardiac action potential
sodium current
potassium opens at peak
L-type calcium channel maintains depolarization
delayed rectifiers restore the polarization
effect of norepinephrine on heartrate, blood pressure, and TPR
decrease TPR
increase in blood pressure
decreased heart rate
effect of epinephrine on heartrate, blood pressure, and TPR
decreas in TPR
small increase in blood pressure
increased pulse
effect of isoproterenol on heartrate, blood pressure, and TPR
decreased TPR
small decrease in pressure
increased heartrate
What happens when a high dose of EPI is administered to the heart?
increase and rate and force, leading to a great increase in systolic blood pressure
subsequent to this there is an increased diastolic pressure due to alpha vasoconstriction by the high EPI concentration
result is a rapid rise in mean blood pressure
therapeutic uses of prototypes
bronchodilator = beta 2
mydriatic = alpha
increased cardiac contractile force = beta1
vaso constrictor = alpha
contraindications of catecholamines
pressor effects - high bp, hyperthyroid problems
arrhytmias - hyperthyroid patients have more beta receptors
diabetes
narrow angle glaucoma
prostate enlargement
absorption, fate, and excretion of clinical prototypes
EPI - oral absorption satisfactory, but metabolized by MAO in gut and liver, little effect
NE - orally ineffective, poor absoprtion from subcutaneous injection site, usually given by IV infusion, quickly inactivated in the body
iSO - poor substrate for MAO due to N-isopropyl group so longer acting
selective alpha1 receptor agonists
phenylephrine
imidazoline derivatives
midodrine
physiologcially relevant alpha2 sites involved in the control of blood pressure
tonic firing of sympathetic nerves contribute to cardiac output via beta1 receptors and to the tonic constirction of blood vessels via alpha1 receptors
the activation of alpha2 receptors in the hypothalamus or the medulla inhibits this tonic sympathetic firing and relieves the tonic constriction of blood vessels, thus reducing blood pressure
alpha2 receptor agonists
clonidine
guanfacine
guanabenz
alpha-methyl dopa
apraclonidine
brimonidine
clonidine suppression test
used to distinguish essential hypertension from pheochromocytoma
has no effect in pheo because there is such a high amount of NE present
beta1 receptor agonist
dobutamine
“selective” beta2 receptor agonists
all are resistant to COMT action and are metabolized by sulfate conjucation
albuterol
terbutaline
ritodrine
salmeterol
formoterol
indirect sympathomimetic agents
tyramine and amphetamines
tachyphylaxis
depletion of NE with indirect sympathomimetic amines such as tyramine
effect of Uptake 1 inhibitor on tyramine
drastic increase in bp
effect of a MAO inhibitor tyramine
hypertensive crisis
mixed acting sympathomimetic amines
epedrine derivatives such as speudoephedrine
clinical uses of sympathomimetic amines in the periphery
treatment of spasm of bronchiolar smooth muscle associated with asthma
nasal decongestants
cardiac effects
premature labor and other OB uses
treatment of asthma
EPI inhaler for quick action
isoproterenol also available
over-the-counter prophylaxis - primatene tablets with ephedrine
non-selective agents that produce tachycardia such as albuterol, salmeterol, and formoterol
mechanism of nasal congestion
unusual vessles with erectile properties that fill the sinusoids
vessels ahve venous fluid reservoir, so that when they dilate, then more fluid is in the mucosa, and more mucus is secreted and mroe nasal congestion occurs
nasal decongestants
phenylephrine for short term relief
imidazoline derivatives
problem with long-term use is the release of metabolites locally so that the rebound congestion is worse
blood vessels also constrict because of extrajunctional alpha2B effects - reactive hyperemia
cardiac arrest treatments
EPI has been found to be useful here for a great number of years
the beta1 stimulatory effect is obvious but the main benefit may be secondary to vasoconstriction
cardiogenic shock treatments
tremendous fall in cardiac output
fall in areterial systolic pressure
reflex tachcardia
reflex venous constriction
oliguria
treatment with dobutamine to increase CO with minimal increas in heart rate
treatment with dopamine to increase cardiac output with an additional vasodilator effect
treatment for severe hypotension in the ICU
levophed because it is norepinephrine, only clinical use
premature labor and other OB treatments
terbutaline - beta2 agonist, so relaxes uterus
adrenergic blocking agetns
drugs that block adrenergic activity
traditionally termed sympatholytics
prevent the action of NE released from nerve endings by competing with NE at receptor site
alpha2 inhibition effect on heart rate
increases
alpha2 inhibition on GI tract
increases motility
alpha2 inhibition on corpus cavernosum
increases erectile function
alpha2 inhibitors on CNS
stimulant
alpha receptor blockers
phenoxybenzamine
phentolamine
side effects of phenoxybenzamine
orthostatic hypotension
nasal congestion
inhibition of emission
inhibition of mydriasis
increases motility (blocks alpha2 on cholinergic nerve endings)
persistent tachycardia (blocks alpha2 on adrenergic nerve endings)
alpha1 receptor blockers
prazosin - alpha1 selective
tamsulosin - alpha1A selective
alfluzosin - alpha1A selective
silodosin - the most selective alpha 1A antagonist
alpha2 receptor blocker
disinhibition of neurotransmitter release effects may be similar to nerve stimulation
produces persistent tachycardia by disinhibition of NE release
yohimbine - most selective alpha2 antagonist
innervation of the corpus caverosum
non-ad-renergic, non-cholinergic (NANC) innervation has alpha receptors on it and is responsible for the stimulation of arousal - alpha2 leads to inhibition of relaxation through NO and PDE5
sympathetic nerves are responsible for detumescence
sexual dysfunction treatments
drugs of choice are ___denafils or ___afils
prototype is sildenafil (viagra)
selective inhibiotrs of phosphodiesterase type 5 (PDE 5
this causes the breakdown of cGMP
beta receptor blockers
sometimes called “first generation”
effects are predictable based on the functions of beta receptors
propranolol is the prototype
timolol
therapeutic uses of proranolol
anti-arrythmic
anti-anginal
antihypertensive-block of renin
pheochromocytoma
stage fright
contraindications of propranolol
asthmatics need beta2 drive
diabetics, propranolol masks signs of hypoglycemia and decreases glycogenolysis
metabolism for beta blockers
phase I oxidation by CYP2D6
phase II by glucuronidation and sulfation
latanoprost
current therapy for glaucoma
PGF2alpha derivative that increases AH outflow by the uveal-scleral route
major side effect - may produce irreversible darkening of the iris and eyelashes
beta1 receptor blockers
spare bronchioles because it is selective for beta1 receptors at low concentrations
metoprolol
atenolol
betaxolol
esmolol
mixed alpha1 and beta blocker
beta blockers with additional actions that are sometiems called “third generation”
labetalol - current drug of choice to treat hypertension in pregnancy
carvedilol - durg of choice to treat patients with mild heart failure
