Med Chem - Anti Arrhythmic Drugs Flashcards
arrhythmia is an ____ or ____ heart rhythm
irregular, abnormal
when do heart rhythm problems occur?
when the electrical signals that coordinate the hearts beats dont work properly
faulty signaling of the electrical signals that coordinate the heart cause the heart beat to
too fast - tachy
too slow - brady
erratically - irregular
tachycardia is
greater than 100 bpm
brady cardia is
less than 60 bpm
what kind of arrhythmia is due to issues in the hearts conduction system (SA, AV or His purkinje fibers)
bradyarrhythmiash
how are bradyarrhythmias characterized?
an abnormally slow and irregular heart beats
which arrhythmias begin in the ventricles?
ventricular arrhythmias
which type of arrhythmias begin in the atria
atrial fibrillation
ventricle depolarization is depicted as what on an EKG wave
QRS complex
the p wave represents
atrial depolarization
PR interval covers both ___ and ____
atrial depolarization
and propagation of the stimulus through the AV node
the T wave represents
repolarization of ventricles
which subclass of antiarrhythmic drugs has the greatest strength of Na+ channel blockade
IC > IA > IB
class III drugs are potassium ion channel blocking drugs that have a MOA of
prolonging APD
what drugs are in Class III
sotalol
ibutilide
dofetilide
amiodarone
dronedarone
what are the Class IA drugs
quinidine
procainamide
disopyramide
the action potential of a cardiac muscle consists of how many phases
Phase 4, 0, 1,2, 3
what happens in phase 4 of the action potential
Na+ and Ca++ channels are closed
open K+ rectifier channels that keep TMP stable at -90 mV
what happens in phase 0 of the action potential
rapid Na+ influx through open fast Na+ channels
which class of drugs affect the phase 0 slope of action potential in cardiac muscle
class I Na+ blockers
what happens in Phase 1 of ap of cardiac muscle
transient K+ channels open and K+ efflux returns TMP to 0mV
what happens in phase 2 of the action potential of cardiac muscles
influx of ca++ through l type calcium channels which is electrically balanced by K+ efflux thorugh delayed rectifier K+ channels
what happens in phase 3 of an ap in cardiac muscle
ca++ channels close but delayed rectifier k+ channels remain open and return to TMP to -90 mV
what class of drugs act on phase 3 of an ap and what do they do
class III k channel blockers, delay repolarization
phase 4 is also known as the resting phase which means
there is no net movement of ions across the cell membrane
time between two ap
what drugs are in class IB
lidocaine
mexiletine
tocainide
the predominant Na channel is encoded by the
SCN5A gene
each Na+ channel contains ___ membrane spanning alpha helical segments in each domain
6
how many homologous domains are in a Na+ ion channel
4
S4 of the NA+ domain is rich in which amino acids
arg/lys
what is the significance of the S4 segment of the Na+ ion channel domain
acts a a sensor of the transmembrane voltage
every 3rd aa is positively charged with hydrophobic residues
the s4 helix of the na+ ion channel domain can be called as a
amphipathic helix
mutations in the S4 segment of the na+ ion channel domain leads to
loss of voltage gating
between what two segments does a pore form a p loop
s5 and s6
compared to quninine, qunidine has greater effects on the heart due to
its stereochemistry
the chiral carbon on quinidine is S configuration
torsades de pointests TdP is also known as
twisting in the peaks
TdP is a ventricular arrhythmia that is associated with
marked QT prolongation due to K+ channel blocking activity
how many major alkaloids are found in cinchona officinalis
4, with 4 chiral centerswh
where are the chiral centers on the alkaloids like quinidine
on the quinuclidine ring
The nitrogens on quinidine are acidic or basic?
basic
in what form is the quinidine drug used
water soluble salt forms such as
quinidine sulfate
quinidine gluconate
quinidine polygalacturonate
what is a common impurity that is contained in the quinidine salt formations
dihydroquinidine - reduced 3 vinyl group
why is the dihydroquinidine on quinidine salt formulations clinically significant
it has antiarrhythmic potency
what is a major DDI concern of quinidine
strong inhibitor of CYP2D6
the primary active metabolite of qunidine is
3s hydroxyquinidine
how is quinidine metabolized
CYP3A
what is the half life of quinidine
6-8 hours
what is the half life of 3s hydroxyquinidine, metabolite of quinidine
12 hours
what is the MOA of qunidine
blocks Na + channels in the activated state
slows phase 0 depolarization
reduces the amplitude of the ap without affecting resting potential
blocks certain K+ channels which delays phase 3 rp and can prolong the QT interval
What is the quinidine and digoxin interaction
quinidine inhibits p-gp
leads to the inhibition of tubular secretion of digoxin
enhances the plasma concentration of digoxin
DDI concern
the effects of procainamide are _____ antiarrhythmic effects
short lived
procainamide was dervied from ____ based on significant findings from IV administration
procaine
how is procainamide metabolized
by N acetyltransferase II (NAT II) - phase 2 metabolism
metabolized by NAT II procainamide becomes
NAPA
is NAPA an active or inactive metabolite
active , 25% compared to parent drug
what type of molecular change is procainamide to NAPA
amine to amide
Why would one expect NAPA to accumulate more compared to the parent drug?
NAPA is mainly excreted unchanged by the kidneys
it has a longer half life
NAPA forms due to acetylation which varies between individuals
decrease or impairment of kidney function can cause accumulation
what percent of procainamide becomes NAPA is slow acetylators?
20 %
what percent of procainamide becomes NAPA is fast acetylators?
33 %
NAPA metabolite has class _____ K + channel blocking activity
class III
what does NAPA metabolite cause due to its class III K+ channel blocking activity?
TdP
slow acetylators are predisposed to _______ compared to fast acetylators
Lupus syndrome
which class IA drug is marketed as a racemix mixture in phosphate salt form?
dispyramide
the structure of disopyramide resembles the pharmacophore of
acetylcholine
dispyramide shares similar anticholinergic side effects which are
dry mouth
blurred vision
constipation
urinary retention
how is disopyramide metabolized
hepatic metabolism
CYPP3A4 oxidation
what is the metabolite of dispyramide
mono N des Isopropyl metabolite which has 50% anti-arrhythmic activity and LESS ANTI CHOLINGERGIC EFFECT
dispyramide has ddi concerns with
cyp3a4 inhibitors
what anti-arrhythmic drug is a local anesthetic derived from isogramine pharmacophore ?
lidocaine
lidocaine is a ______ derivative
meta xylene
the kinetics of class IA drugs are
intermediate dissociation
what kind of kinetics does class IB have
fast dissociation
lidocaine’s mechanism of action is that it selectively targets the
open and inactivated states of Na+ channels with low affinity for deactivated state (closed or resting)
lidocaine is also known as a _____
use dependent / frequency dependent blocker
what does it mean that lidocaine is a use dependent blocker
diminished effects at low heart rates
increased effects at high heart rates
lidocaine and other class I drugs can be efficacious in the therapy of ______ because they are use dependent blockers
rapid heart rate conditions including vtach
T or F Lidocaine is just as effective orally as it is IV
F, administered IV
not as effective orally
why is lidocaine not as effective orally
due to first pass hepatic metabolism
T or F Lidocaine is lipophilic
T
Lidocaine is extensively metabolized in the liver by
CYP1A2 and CYP3A4
what is the active metabolite of lidocaine
desethyl lidocaine
which class IB drug was developed specifically to reduce the first pass metabolism to enhance oral activity
tocainide
which is more lipophillic tocainide or lidocaine?
lidocaine
why does tocainide have good oral activity?
due to the alpha methyl substituent , amide hydrolysis is slow
what is the difference structurally between tocainide and mexiletine
mexiletine is an ether isotere of tocainide
the -NH is isosterically replaced with -O and carbonyl replaced with CH2
this avoids amide hydrolysis metabolism issue
what type of kinetics do class IC drugs have
slow dissociation kinetics
What is the mechanism of action of class IC
block the Na+ channel and dissociate slowly thus they prominently depress the upstroke velocity of phase 0
encainide is hepatically metabolized to two active metabolites which are
ODE, MODE
the active metabolites of encainide has a longer or shorter half life than the parent drugs?
longer
what kind of derivative is flecainide
bis trilfluoroethoxybenzamide
flecainide is structurally related to ______ and marketed as a acetate salt
procainamide
flecainide clearance is affected by
urinary pH
if the urinary pH is acidic it ____ the clearance of flecainide
increases
urinary clearance decreases of flecainide if the pH is ______
basic
flecainide is metabolized to meta o dealkylated metabolite (50% active) via
CYP2D6 oxidation
what kind of structure does flecainide become oxidized to in order to become inactive?
lactam metabolite
what kind of pharmacophore does propafenone contain?
aryloxypropanolamine
the aryloxypropanolamine pharmacophore in propafenone is commonly seen in
beta blockers
how many chiral carbons are in propafenone?
one chiral carbon
is there a difference between the R and S enatiomer of propafenone ? what are they?
yes.
Same Na+ channel blocking
S enantiomer produces beta 1 blocking , more potent antiarrhythmic
R enantiomer is eliminated more quickly
propafenone via extensive first pass metabolism is metabolized by CYP2D5 nd CYP3A4 to
two active metabolites
5 hydroxypropafenone
N despropylpropafenone
what is the mechanism of action of propafenone
does not block Na_ channels in the resting state
propafenone enters the pore and blocks the open state - when the inward sodium current approachees its max
all class IA-C anti arrhythmic drugs bind to Na+ ion channels via
strong electrostatic cation pi interaction with aromatic phe1759
K channels are formed by the co assembly of _____ each composed of ___
four identical alpha subunits
each composed of
six transmembrane segments
both Na + channels and K+ channels assemble with a single
transmembrane doman, beta subunit
the residues on the S4 segment of K+ channels are basic or acidic?
basic
sotalol has a ____ pharmacore that is also generally found in beta adrenergic blockers
arylethanolamine
sotalol is marketed as a ____ mixture
racemic
T or F sotalol yields enantiomers with the same activity
F, different for R and S
is sotalol a selective or nonselective beta blocker
non selective
can block beta 2 in lungs - exacerbation of asthma
What is the activity of the R enantiomer of sotalol
beta adrenergic blocker with substantial K+ channel blocking ability
what is the activity of the S enantiomer of sotalol
same K+ blocking activity but is 30-60 times less than beta adrenergic blocker
ibutilide is available as a _____ dosage form
injectable
T or F ibutiide is an analog of sotalol
t
what kind of analog is ibutilide to sotalol
butyl homolog
has little or if any beta adrenergic blocker ability
what is the key structural characteristic of ibutilide that differentiates it from sotalol
addition of an ethylene group between the phenethyl and N groups
how is ibutilide metabolized
extensive metabolism to inactive metabolites via omega and beta oxidation
is ibutilide suitable for oral administration?
no, unstable due to metabolism
dofetilide is a _____ analog
bis methanesulfonamide
dofetilide is a highly selective
delayed rectifier postassium channel blocker
T or F dofetilide causes life threatening ventricular arrhythmias
T
what metabolized dofetilide and to what?
CYP3A4
Ndesmethyl inactive
changing the NHSO2CH3 of dofetilide to NO2 does what to activity
retention of affinity
changing the NHSO2CH3 to NH2 of dofetilide does what to activity
substantial loss of affinity
the center nitrogen group of dofetilide must be ____ for affinity
basic
what is the unique chemical structure of amiodarone
benzofuran and di-iodophenylketone
what is a key characteristic of amiodarone?
contains 40% iodine by weight which may partially be released via deiodination
what moiety of amiodarone resembles thyroid hormones?
di-iodophenoxy
what is the di-iodophenoxy moiety of amiodarone clinically significant?
it leads to hypo or hyperthyroidism
T or F amiodarone is highly lipophillic
T
how long is the half life of amiodarone?
25-60 days
why does amiodarone have a long half life? What is important to note about this?
its highly lipophillic
amiodarone toxicity can occur well after drug withdrawal
what is amiodarone metabolized to ?
DEA via N de ethylation . CYP1A1/3A4
T or F DEA has the same electrophysiological effects as amiodarone, the parent
T
_____ is an autoimmune condition that causes hyperthyroidism
graves disease
what are the intrinsic effects of amiodarone
direct hyroid cytotoxicity
blockage of TH entry into cells
inhibition of type I and II 5-deiodinase (decreases T4 to T3)
decreases T3 binding to its TR (due to DEA metabolit)
what are the iodine induced effects of amiodarone
iodine mediated potentiation of thyroid autoimmunity
inability to escape from wolff chaikoffe ffect
unregulated hormone synthesis - jod basedo effect
increased intrathyroid iodine stores
what are the structural modifications of amiodarone that led to dronedarone
- removal of iodine with aim of eliminating thyroid effects and other organ toxicities
- addition of a methane sulfonamide group to reduce half life and tissue accumulation by decreasing lipophilicity thus reduce toxic effects
is dronedarone less or more lipophillic than amiodarone
less lipophillic
what is the half life of dronedarone
13-19 h
how is dronedarone metabolized
via CYP3A4 to active AND inactive metabolites
what are the anti arrhythmic properties of adenosine
activates adenosine A1 rceptors in the cardiac SA and AV nodes
what are the effects of adenosine when it attaches to its receptor
activates A1 receptors
Gi coupled
activates adenylyl cyclase
decrease cAMP
decreases chronotropy - HR
decrease dromotropy - conduction velocity
gives the heart the opportunity to restart in normal sinus rhythm
how long do the effects of adenosine last when administered via IV
10-15 seconds
atropine is a competitive ______
mAChR antagonist
atropine is available as
sulfate salt
what are the key components of atropine
tropine and tropic acid
atropine is indicated for ___ to increase vagal tone
vagus mediated sinus bradycardia
what are the side effects of atropine
dry mouth, blurred vision, constipation, urinary retention
due to non selective antagonism of mAChR in other tissues
the vagus nerve ___ heart rate
decreases
_____ is released from the vagus nerve which decreases heart rate
Ach
______ opposes the vagus nerve action by increasing heart rate
atropine
atropine acts on ____ cardiac nerves
sympathetic
ach acts through _____ receptors
muscarinic
