final material Flashcards
what causes catecholamines to be released
sympathetic stimulus - usually a fight or flight response
what is a catecholamine
2 OH + amine on a aromatic ring
epinephrine low concentration
best B1 agonist
Beta > alpha
B1, B2
not much B3 bc NE
beta 1
increases heart rate and force of contraction (positive chronotropic and positive inotropic effects, renin release
Beta 2
bronchodilation, relaxes the smooth muscles (uterine and bronchus), increases vasculature, increases renin
Alpha 1
acts on more than sympathetic activity, vasoconstriction, contraction of smooth muscles (ureter, uterus, ciliary body), glycolysis/gluconeogenesis
alpha 2
auto-receptor, negative synaptic loop, decreases synaptic activity, decreases heart rate, vasodilation, inhibits NE, inhibit insulin, stimulates glucagon release
epinephrine response at the heart
inc heart rate, increase SV, increase CO, increase force of contraction, increase blood pressure
epinepherine response at lungs
bronchodilation can enhance epi for asthma, BUT high heart rate
epi response at vasculature
high conc: alpha 1 predominates, vasoconstrict, increases TPR
low conc: B2, decreases TPR, vasodilation
epi therapeutic uses
not as much vasoconstriction as NE
epi in asthma
dilates airways
epi in conjunction with local anesthetic
prolongs action of anesthetic, hangs out longer, vasoconstrictor can be removed from site
MOA of epi-pen
activates the alpha 1 receptors, lessens the vasodilation and lessens the increased vascular permeability that occurs during anaphylaxis - leads to a loss of intravascular fluid volume and hypotension
NE
best at increases BP, synthesized and stored in the terminal of the sympathetic post-ganglionic neuron, targets alpha 1, alpha 2, b1, b2
NE effect on the heart
increases the heart rate and increases the force of contraction and increases the CO
NE on lungs
no effect, no B2
NE on vasculature
vasoconstrict - alpha 1
NE administered for shock
dangerously low blood pressure - admin levophed, dec BP, not enough BV, vasoconstrict because not enough BP, increases peripheral resistance
isoproterenol
B1 and B2 agonist, decreases peripheral resistance, increases pulse rate, decreases blood pressure
dopamine
synthesized and stored in the terminal of the SNS postganglionic neuron, concentration dependent
low concentration dopamine
D1
high conc dopamine
alpha 1, lowest kd affinity
mild conc dopamine
B1
D1
vasodilator, prominent in mediatic vasculature, renal vasculature, helps regulate renal flow, highest affinity
renal dose dopamine
low dose, keeps the renal flow going to preserve kidney function
dopamine at the kidney
increases RPF, increases GFR at low and mild dose, starts going away at higher dose
dopamine at the heart
increases heart rate, force of contraction
dopamine at vasculature
TPR decreases in low conc, TPR increases at high conc
therapeutic uses for dopamine
shock, hypotension, poor tissue perfusion, low cardiac output
sympathommetics
mimic endogenous catecholamines so they are called sympathomemetics
phenylephrine
alpha 1 receptor agonist, opthalmic (dilates), visine (gets red out), constricts vessels
naphazoline
alpha 1 receptor agonist
oxymetazoline
alpha 1 receptor agonist
tetrahydrozoline
alpha 1 receptor agonist
alpha 2 receptor agonist
centrally, decreases SNS, decreases HR, TPR, BP
clonidine
alpha 2 receptor agonist
guanfacine
alpha 2 receptor agonist
methyldopa
alpha 2 receptor agonist
Dexmedetomidine
alpha 2 receptor agonist
upregulation
alpha/b receptors upregulate because not normal stimulation, cause tachycardia because receptors not activated alpha 2 agonist and need more alpha 2 regulation in the frontal cortex
dobutamine
B1 receptor agonist, increases heart rate and force of contraction, IV only, can have down regulation and loose effect over time, opposing alpha 1 effect (R,S) eantiomer
B2 receptor agonist
bronchodialation
(lev)albuterol
SABA - short acting beta agonist, asthmatic episode, not an every day drug
terbutaline
B2 receptor agonist
salmeterol
long acting beta 2 agonist
(Ar)Formoterol
Beta 2 receptor agonist
indacterol
long acting beta 2 agonist
olodaterol
long acting beta 2 agonist, inhalation administration
D1 receptor agonist
selective, fenoldopam
alpha 2 receptor dopamine
possible to increase the symp and decrease the para symp - alpha 2 hetero receptor when symp neuron is activated, activity decreases
beta adrenergic receptor antagonists
used in CV disorders (hypertension), chronic angina, heart failure, anxiety, migraine headaches, glaucoma, hypertension, angina
hypertension and angina - NE
block effect of NE on the heart
decrease HR, decrease FOC, decrease CO
beta blockers therapeutic uses
CV disorders, hypertension, chronic angina, heart failure, anxiety, migraine headaches, glaucoma
hypertension and angina- bblockers
block effects of NE on the heart. decreases the HR, decreases FOC, decreases the CO
bblocker - RAA system
JG cells secrete renin- B1 receptors
B2 very powerful vasoconstrictor through Ang 2, can cause vasodilation through blocking of ang 2!
heart failure - BBlocker
patients have high levels of catecholamines and excess sympathetic activity - leads to acute coronary syndromes and altered contractility - bblockers very effective!`
BBlockers cardioselectivity
B1 over B2, lower kd for B1 over B2
BBlockers are great for
COPD (want to avoid B2), diabetes (glucose/glycogen regulation), decrease insulin secretion, tissue sensitivity to insulin
Intrinisic Sympathomimetic Activity
partial agonist
pindolol
ISA bblocker
acebutolol
ISA bblocker
labetolol
ISA bblocker, has B2 receptors, causes vasodilation- causes TPR to decrease, B1 antagonist, B2 ISA, alpha 1 block
nimidane
normalizes pressure
advantages of B1 with ISA
reduce the degree of brady cardia, limits the effects of lipid profile
carvedilol
blocks alpha, blocks L-type CC, anti-oxidant
elimination of b-blockers
nearly all eliminated in the liver
bblockers excreted in the kidney
nadolol, atenolol - used in patients with liver issues who require a bblocker
nadalol half life
24 hours. most of all bblockers
atenolol half life
12 hours
esmolol half life
10 minutes
most hepatically cleared bblockers half life
4-6 hours
lipids and bblockers
inc LDL and VLDL
dec HDL
CNS and bblocker
drowsiness, fatique, nightmares
sexual dysfunction and bblockers
dec libido, erectile dysfunction
hypoglycemia and bblockers
masks symptoms of hypoglycemia (which are inc heart rate, shakiness, sweating, SNS increased)
bblocker effects on the EKG
dec heart rate, prolonged PR interval, conduction time increase, abrupt discontinuation of bblocker, 2x receptor upregulation (hypertension, tachycardia)
glaucoma and bblocker
aqueous humor production
thyrotoxicosis bblocker
thyroid hormone increases the expression of beta receptors
tremor bblocker
activation of beta 2 receptors cause tremor
migraine bblocker
bblocker effective at preventing migraines
alpha-adrenergic antagonists (alpha blocker) treatment for
BPH (benign prostatic hyperplasia) and hypertension (last resort)
have alpha 1 antagonists demonstrated superiority over other drug classes?
no they have not demonstrated superiority over other drug classes such as ACE inhibitors, B blockers, or thiazide diuretics
doxazosin
alpha 1 agonist - discontinued because its inferiority in reducing coronary events
prazosin
alpha 1 subtype non-selective reversible competitive antagonist
terazosin
alpha 1 subtype non-selective reversible competitive antagonist
doxazosin
alpha 1 subtype non-selective reversible competitive antagonist
alfuzosin
alpha 1 urinary tract reversible competitive antagonist
tamulosin
alpha 1 A reversible competitive antagonist
silodosin
alpha 1 A reversible competitive antagonist
phentolamine
alpha 1 / alpha 2
phenoxybenzamine
irreversible competitive antagonist
zosin
non-selective alpha 1 antagonist
osin
selective
amine
alpha 1/ alpha 2
B2 adrenergic agonists and binding sites
affinity- if you want a highly potent agent (low dose)
activation: full agonist or partial agonist
lipophilicity: does play a role in b2 selectivity,
B2 adrenergic agonist SAR
NE- B1, alpha 1/2
Epi- addition of a methyl B2 > b1, alpha 1
drawbacks to isoproterenol
short duration of action, increases the heart rate and the force of contraction
isoproterenol structure
isopropyl, bulky
metaproterenol structure
phenolic groups not a substitute for COMT, more selective than tertbutyl, like isoproterenonol but OH instead of ortho they are meta
albuterol
B2» B1, active eantiomer of albuterol, short acting b2 agonist, t-butyl group, 3 hydroxy methyl, OH on a methyl makes it more selective
tertbutyl
B2>b1, like metaproterenol but with a t-butyl group instead of an isopropyl group
long acting beta2 agonists
B2»_space;> B1
salmeterol
long acting beta2 agonists, has the 3-hydroxymethyl group that makes it more selective
vilanterol
looks like salmeterol but has 2 Cl- on the ring, partial agonist, binds to exo-site, long chain is like hinges of a door bound to the exo site - long acting beta2 agonists
formoterol
long acting beta2 agonists- formic acid attached, lipophillic side chain that fits inside the receptor
indacaterol
tautomer, looks like 3-hydroxymethyl, full agonist, either tautomer or could bind to the receptor long acting beta2 agonists
olodaterol
bind with the receptor at the active site, has formic acid- long acting beta2 agonists
formoterol, indacaterol, olodacterol
QD daily, effecient agonist, fast onset of action 15-45 seconds
structure- activity relationship: Long acting B2 agonists
- aromatic ring: 4-hydroxy group required unless there is a 3,5 biphenolic substitution, better affinity for the b2 receptor- long acting beta agonist
- 3-hydroxymethyl aromatic substituents
- ethanol-amine side chain absolute requirement- R configuration for the hydroxyl group is required for receptor activation
- 3-formidioo - not substrates for COMT
- basic nitrogen alkyl substitutes-
carostyril
has 4 phenol, 3-formamido, hydroxymethyl like, indacaterol - long acting beta agonist
beta blocker SAR
aromatic ring containing system and not specific variable, either bridge (beta 1 selective), aromatic side chain
non specific beta blockers
ether bridge connectts side chain
nadolol
not aromatic, single aromatic ring, nonspecific bblocker
pindolol
indole, ISA, nonspecific bblocker
metoprolol
H bond acceptor ether b1 selective bblocker
atenolol
H bond acceptor carbonyl - b1 selective bblocker
bisprolol
b1 selective bblocker H bond acceptor ether
esmolol
H bond acceptor ester DOA short, soft drug, fine control of BP
structure activity on bblocker SAR
- bulky substituent on nitrogen beta adrenergic side chain
- ether group between aromatic ring and beta adrenergic side chain (contributes to antagonist properties)
- aromatic ring system- non-selective antagonists have a non-specific aromatic system containing group, beta-1 selective agents have the following: single benzene ring, para substituent (H bond acceptor, 1 to 3 atoms from the benzene ring, meta substitution is out)
alpha 2 agonists structure
ortho attachments with bridge and cl-
structure-activity relationships for alpha 2 agents
- Aromatic ring with 2,6-ortho substituents- all seen with 2,6 Cl- structure
- Bridge- Ch2 or NH
- Basic nitrogen grouping:
- Perpendicular relationship between:
Aromatic ring and basic functional group - not in the same plane
yohimbine
alpha 2 antagonist, increases blood pressure on alpha 2
hydroxylation is decreased or inhibited by
strong electron withdrawing groups: § CN, SO2R, NO2, CF3, Cl, C=OR (ester, amide)
hydroxylation will occur on rings that have ___
electron donating groups attached
steric hinderence - what substitutions are favored
meta electronically not favored, ortho may not happen because it can;t get to the site easily, para is the most favored.
phase 1 dealkylation via CYP 450 enzymes
carvedilol undergoes dalkylation (removal of a methyl ether), drug is initially oxidized to drug- O-Ch2-OH t
side chain oxidation
secondary oxidized over primary - free radical reactions, where oxidation occurs it is governed by the following:
- free radical stability Benzylic > tertiary > secondary > primary
- sterics
