Term
therapeutic management of asthma requires the use of QUICK ACTING DRUGS to relieve an acute attack followed by DRUGS THAT CONTROL THE CONDITION
1) the quick reliever medication in asthma is almost always an inhaled short-acting B-adrenergic agonist
2) controller drugs are inhaled corticosteroids, long-acting B-adrenergic agonists, leukotriene modifiers, cromolyn sodium, methylxanthines |
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Definition
| approaches to the treatment of asthma and COPD |
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Term
chemistry of NE and EPI
[image]
basic side chain amine and "acidic" phenols
>90% protonated at physiological pH
very polar |
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Definition
| chemistry of B-adrenergic agonists: catecholamines |
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Term
[image]
NE is synthesized in the CNS (within adrenergic neurons, near terminus of axon and junction with the effector cell)
TYROSINE HYDROXYLASE step is rate-limiting and carefully controlled
EPI is formed in the chromaffin cells of the adrenal medulla
metyrosine has been widely used to demonstrate the effects of exercise, stress, and various drugs on the turnover of catecholamines
carbidopa can inhibit peripheral AADC during L-Dopa therapy for parkinson's disease.
this allows more of the dose of L-Dopa to penetrate BBB where it is converted to dopamine by the brain by AADC in that compartment. |
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Definition
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Term
[image]
the major end products are interconvertable |
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Definition
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Term
B1 in the heart: agonism increases rate, force, and conduction velocity
B2 in bronchiole smooth muscle: AGONISM CAUSES DILATION
B2 in intestine: agonism causes decreased molitily
B2 in liver: agonism causes increased gluconeogenesis, increased glycogenolysis
B2 in uterus: agonism causes relaxation
most important subtypes for asthma/COPD are B1 and B2 found primarily in the heart and lung, respectively |
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Definition
| actions of beta-adrenergic receptors throughout the body |
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Term
agonists:
E >/= NE >> ISO
phenylephrine
methoxamine
antagonists:
prazosin
corynanthine
G protein:
Gq
signaling:
(+) PLC -> increased IP3 and DAG, Ca2+ |
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Definition
| a1 receptor: agonist, antagonists, G protein, and signalling |
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Term
agonists:
E >/= NE >> ISO
clonidine
antagonists:
yohimbine
G protein:
Gi
signaling:
(-) AC -> decreased cAMP |
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Definition
| a2 receptor: agonists, antagonists, G protein, signaling |
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Term
agonist:
ISO
antagonist:
propranolol
G protein:
Gs
signaling:
(+) AC -> increased cAMP |
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Definition
| B receptor: agonist, antagonist, G protein, signaling |
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Term
agonist:
ISO > E = NE
dobutamine
antagonist:
metoprolol
G protein:
Gs
signaling:
(+) AC -> increased cAMP |
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Definition
| B1 receptor: agonists, antagonist, G protein, signaling |
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Term
agonists:
ISO > E > NE
terbutaline
antagonist:
butoxamine
G protein:
Gs
signaling:
(+) AC -> increased cAMP |
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Definition
| B2: agonists, antagonist, G protein, signaling |
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Term
[image]
7 transmembrane units
[image]
3 IMPORTANT INTERACTIONS:
1) ionic interaction with aspartate and protonated amine
2) hydrogen bonding of serines and catechol
3) hydrogen bonding of OH with valine and asparagine
[image] |
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Definition
| B2 adrenergic receptor binding and coupling to adenylate cyclase |
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Term
direct-acting adrenergic agonists: bind B-adrenergic receptors just like NE/EPI producing a sympathetic reponse
indirect-acting agonsists: work by several other mechanisms (stimulate NE release, inhibit NE reuptake, inhibit NE degradation by MAO) |
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Definition
| MOA of direct vs indirect acting adrenergic agonists |
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Term
[image]
1) the substituents on the amino group (R1) determines a- or B-receptor selectivity
2) the larger the bulk of the N-substituent, the greater the B-selectivity (isoproterenol). N-tert-butyl afford B2 selectivity
3) substituents on a-carbon (R2) slow MAO metabolism and increase duration of action
4) in addition to N bulk need an appropriate catechol surrogate for B-selectivity
[image] |
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Definition
| SAR of B-agonists: direct, indirect, and mixed |
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Term
[image]
MOA:
catechol, B-OH, N-Me give EPI a DIRECT ACTION
strong affinity for all adrenergic receptors
metabolism:
catechol unstable to oxidation (form quinones)
metabolized by COMT and MOA, followed by sulfation or glucuronidation
tricyclics and MAO inhibitors potentiate effects on heart
ADRs:
palpitations, tachycardia, sweating, nausea, vomiting, respiratory difficulty, dizziness, tremor, anxiety |
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Definition
[image]
MOA, metabolism, ADRs |
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Term
[image]
MOA:
isopropyl gives B-selectivity
a-ethyl confers B2-selectivity
catechol, B-OH therefore DIRECT ACTING
metabolism:
COMT, MOA resistant
at high doses get B1-cardiovascular ADRs
lower B2 potency as compared to newer agents |
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Definition
[image]
MOA and metabolism |
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Term
[image]
MOA:
DIRECT ACTING resorcinol analogue of isoproterenol
N-isopropyl is B-directing
resorcinol enhances B2-selectivity
least potent of the B2-selective agonists (isopropyl as poor B2-selectivity)
metabolism:
good oral BA
resistant to COMT and slowly metabolized by MAO |
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Definition
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Term
[image]
MOA:
N-tert-butyl analogue of metaproterenol
3x potency at the B2 receptor
metabolism:
resistant to COMT
slowly metabolized by MAO |
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Definition
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Term
[image]
bitolterol is a prodrug that releases coterol upon esterase activation
MOA:
direct acting, B2 selective
metabolism:
lipophilic diester keeps it in the lung until hydrolyzed
resistant to COMT |
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Definition
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Term
d,l albuterol:
N-t-butyl and salicyl alcohol phenyl ring gives it optimal B2-selectivity
good oral BA (resistant to COMT, slowly metabolized by MAO)
levalbuterol:
active R (-) isomer of albuterol = lower dose
pirbuterol:
pryidine isostere of albuterol
0.5 x as potent at the B2-receptor |
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Definition
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Term
[image]
MOA:
optimal direct acting B2 selectivity and potency
greatest receptor affinity of agonists
metabolism:
resistant to both COMT and MAO
long acting |
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Definition
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Term
[image]
MOA:
B2 selective
metabolism:
resistant to COMT and MAO
long acting |
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Definition
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Term
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Definition
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Term
catalytic apparatus:
[image]
[image] |
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Definition
| mechanism of acetylcholinesterases |
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Term
muscarinic receptors:
G protein coupled receptors
5 subtypes
M1, M3, M5 are coupled to Gq - phospholipase C
M2, M4 are coupled to Gi - adenylate cyclase
[image]
M3 is important in asthma/COPD |
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Definition
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Term
M3 receptors cause bronchiole constriction and counterbalance the bronchiole dilation of the B2-adrenergic receptor activation in lung to maintain bronchiole tone
basis for therapeutic use of inhaled antimuscarinics - BLOCK CHOLINERGIC BRONCHIOLE CONSTRICTION ALLOWING ADRENERGIC BRONCHIOLE DILATION
[image]
2 main interactions:
asp ion interaction with choline + charge
tyrosine and thr H-bond with carboxy |
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Definition
| MOA of M3 muscarinic receptor |
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Term
[image]
[image]
distance between N and carbonyl is the exact same with atropine and ACh |
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Definition
| muscarinic antagonist SAR |
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Term
[image]
MOA:
N-isopropyl analogue of atropine
hydrophilic and poorly absorbed after inhalation
thus bronchodilation is local and site-specific
metabolism:
the little that reaches circulation is partially metabolized to inactive esterase products
ADRs:
common of antimuscarinics - blurred vision, dry mouth, tachycardia, urinary difficulty, HA |
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Definition
[image]
MOA, metabolism, ADRs |
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Term
[image]
MOA:
dithienyl analogue of N-methyl scopolamine
site specific local medication to lung for COPD bronchospasms
longer duration of action than ipratropium (24h vs 4h)
metabolism:
74% excreted unchanged in the urine
some cleavage of ester to alcohol and acid
minor metabolites by CYP3A4 and CYP2D6 followed by glutathione conjugation |
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Definition
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Term
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Definition
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Term
used for bronchodilation effects in asthma
phosphodiesterase-4 (PDE4) inhibitor
narrow therapeutic window requires frequent monitoring of blood
MOA still not fully understood |
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Definition
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Term
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Definition
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Term
selective PDE4 inhibitor
used for COPD exacerbations - flare ups
[image] |
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Definition
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Term
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Definition
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Term
[image]
esters used to modulate lipophilicity, metabolism
C-21 esters MUST be prodrugs (must have the OH to H-bond to Asn-564)
C-17 esters prolong duration of action by slowing metabolism
increased logP provides local action, less systemic absorption
inhaled forms used to treat asthma, COPD
glucocorticoid diesters and ketals:
[image]
diesters and ketals slow metabolism, further enhancement of lipophilicity
increase duration of action (plain ketals are NOT prodrugs)
21 ester has to come off, 17 ester doesn't have to come off
hydrophilic glucocorticoid esters:
[image]
water soluble prodrugs for IV, IM injections in asthmatic emergencies
rapid onset, rapidly hydrolyzed by plasma esterases |
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Definition
| esterification of glucocorticoids |
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Term
cortisol
prednisone
prednisolone
methylprednisolone
beclomethasone dipropionate
budesonide
flunisolide
triamcinolone acetonide
mometasone
fluticasone propionate |
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Definition
| glucocorticoids used to treat asthma |
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Term
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Definition
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Term
prednisolone:
delta1 increases GC activity at the expense of MC activity
4x GC activity of cortisol
0.5x MC activity of cortisol
prednisone:
prodrug of prednisolone
HSDH converts prednisone to the active form, prednisolone which is a liver enzyme so the drug may be inactive in patient with hepatic dysfunction |
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Definition
[image]
activity
why should prednisone not be used in patients with hepatic dysfunction? |
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Term
6a-methyl prednisolone
enhances GC, abolishes MC
5x GC activity of cortisol
no MC activity |
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Definition
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Term
[image]
20% systemic BA upon inhalation
16 B-methyl decreases MC
9a-Cl increases GC and MC
net result is potent GC and little to no salt retention
metabolized to 17a-mono ester which is more active in the lungs
also to 21a-mono in liver |
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Definition
[image]
activity, metabolism |
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Term
[image]
16a, 17a acetal decreases MC activity
some systemically absorbed with high protein binding
metabolism:
16a-hydroxyprednisolone (ketal hydrolysis and HSD)
6B-hydroxybudesonide (CYP3A4) |
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Definition
[image]
activity, metabolism |
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Term
[image]
acetonide decreases MC activity
6a-F increases GC
40% inhaled dose systemically absorbed
metabolism:
6B-hydroxy (CYP3A4)
glucuronides
limits ADRs |
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Definition
[image]
activity, metabolism |
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Term
[image]
acetonide decreases MC
9a-F increases GC and MC
25% inhaled dose systemically absorbed (from swallowing)
metabolism:
6B-OH and 21-carboxy-6B-OH readily excreted in kidney |
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Definition
[image]
activity, metabolism |
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Term
[image]
combo of C21-Cl and furoic ester at C17 results in highest GC activity of any topical
16a-methyl decreases MC
9a-Cl increases MC and GC
local acting, least systemic BA (<1%) of all inhaled GC's
extensively metabolized with 6B-OH and 21-OH present
REMEMBER THE 21 CL!!! |
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Definition
[image]
activity, metabolism |
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Term
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Definition
[image]
activity, metabolism |
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Term
[image]
F mimics O very well
17a is very large, but it fits in the GC-receptor but not in the MC-receptor |
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Definition
| interaction of dexamethasone and fluticasone with the MC/GC receptor |
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Term
rhodopsin family of GPCRs
cysLT2 can be selectively antagonized
treatment for leukotriene related broncho-constriction in asthma
2 overall approaches in asthma:
1) inhibit biosynthesis of leukotrienes
2) identify selective LT1 antagonists |
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Definition
| actions of leukotrienes on cysteinyl leukotriene receptors (cysLT) |
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Term
[image]
INHIBITOR OF LEUKOTRIENE BIOSYNTHESIS
N-hydroxy is essential for activity
racemic mixture - both R and S are active
benzothienyl group contributes to lipophilicity
metabolized in liver, O-glucuronide major
inhibitor of CYP3A4/5/7 and CYP2C9
weak inhibitor of CYP1A2 (theophylline, propanolol)
highly protein bound (warfarin) |
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Definition
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Term
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Definition
| leukotriene receptor antagonists SAR |
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Term
leukotriene receptor antagonist
high affinity selective antagonist of cysLT1
[image] |
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Definition
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Term
metabolized by CYP3A4 and CYP2C9
[image] |
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Definition
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Term
leukotriene receptor antagonist
accolate, indole core
selective antagonist of cysLT1
antagonizes the bronchoconstriction effects of all leukotrienes
well absorbed, decreased a lot by food |
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Definition
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Term
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Definition
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Term
mast cell degranulation inhibitor
contains a fundamental fragment of khellin; middle eastern herb with bronchodilation effects
prevents release of histamine, leukotrienes, prostaglandins from mast cells
exact mechanism still not completely understood but inhibition of the role of calcium in the deganulation process |
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Definition
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