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pharm
spear
2/6/98

comments regarding CHF events slide. 

when there is increased afterload/peripheral resistance, there is also 
increased work. that's not indicated on the diagram. increased preload 
and increased afterload both increase workload. the diagram isn't a case 
study; it's just a flow of events. individual patients are usually first 
treated with a diuretic, maybe a sympathomimetic if heart failure isn't 
severe or if it is really really severe, if you don't have time to wait 
for digitalis to kick in to save the patient. or you may give a 
vasodilator to decrease peripheral resistance. it's going to depend on 
the presentation of a particular patient, and why that patient has 
decreased myocardial contractility in the first place.

Digitalis:


history: a very old drug, been around since egyptian times, was in their 
folklore and in 1500 BC it was written about. in early 1700s it was known 
by physicians as a poison. then, William someone studied how it worked. 
he worked out the dose requirements in about 1775-1785, and found that 
digitalis, although it can be toxic, can also be therapeutic - it has a 
narrow therapeutic margin, though. in 1785 he published an account of 
medical uses of foxglove. he found that when people with dropsy were 
given digitalis, they'd make a lot of urine. he assumed it worked on the 
kidney. the people would excrete the water they were retaining because 
kidneys were being reperfused, since heart was pumping better. it wasn't 
really working on the kidney of course. the mechanism of action wasn't 
really figured out til about 1962. they figured out that it inhibits the 
Na+/K+ ATPase pump. 

digoxin is basically a steroid, and there's a 
lactone ring attached to it, and it's the "aglycone" structure that gives 
it the main activity. there is a sugar attached which is responsible for 
solubility, rapidity and duration of action. all these cardiac glycosides 
are derived from plants. 

digoxin came from digitalis purpurea, first 
isolated in pure form in 1869. precursor glycoside is glycoside A, and 
glycoside is digitoxin.

other plants: digitalis lanata, and two other 
plants, make other glycosides.

digitalis is given orally, and absorbed 
mainly in small intestine. then the various tissues in the body go into 
equilibrium w/serum concentrations - including the heart (site of 
interest) and other tissues in teh body like liver and kidneys which are 
responsible for elimination. digitalis is also secreted in the bile, so 
can enter enterohepatic circulation. some can be excreted from intestines 
prior to absorption. it can also be excreted unchanged by the kidneys. 
but the liver is a site for biotransformation of digitalis, and 
metabolites are also excreted by the kidney. digitalis is going to 
inhibit the Na+/K+ ATPase pump in all body tissues, but some tissues are 
more sensitive to its effects. we are looking to have effects in heart, 
but toxicity can occur in other organs including CNS.

digitoxin is 
another cardiac glycoside. digoxin, digitoxin, and digitalis all act the 
same way, but have different pharmcokinetic properties. some have more 
rapid onset of effects, some more toxicity. all have same main structure, 
with different sugars and lactone rings. 

digoxin vs digitoxin:

GI 
absorption: dig 60-85%; digit 90-100%
onset of action: dig 15-30 min; 
digit 25-120 min
peak effect: dig 1.5-5 hr; 4-12 hrs digit
t1/2: dig 36 
hr; digit 4-6 days
elimination: dig renal, some GI; digit hepatic 
breakdown, renal excretion 
protein binding: dig 25%; digit 90%


differences mainly due to fact that digitoxin is so highly protein bound, 
compared to digoxin. because it is absorbed from the gut and excreted by 
the kidney, patients absorbance and excretion times vary, and things like 
diarrhea can change paramaters, and you can get into problems with 
toxicity due to narrow therapeutic margin, and since digitoxin has a long 
duration of activity, you could have a problem. so you might choose 
digoxin since it comes on fast, has brief duration, so you won't have 
problems with toxicity for as long. 

how digitalis works:

inhibits 
Na+/K+ ATPase. increases contractile force without shortening time of 
contraction or increasing HR. Na+ accumulates due to pump inhibition; 
Na+/Ca++ exchange slows due to decreased sodium concentration gradient 
(normally, sodium coming in pushes calcium out, but now there's already a 
lot of sodium in the cell); Ca++ concentration in the cell increases due 
to the slowed exchange, and this leads to increased contractile force. 


cardiac arrhythmias: two kinds - bradycardia and tachycardia
remember HR 
x SV = CO. When HR decreases, CO decreases. When HR increases a LOT, SV 
decreases, and CO decreases. SV = contractility x venous return. when HR 
is very fast, there is poor venous return due to insufficient time for 
filling. you may end up not being able to generate enough pressure to 
open the aortic valve - this is when you might feel a pulse/HR mismatch - 
pulse will be lower since aortic valve isn't always opening.

mechanisms 
of cardiac arrhythmias:
irregularity in impulse generation or disturbance 
in impulse conduction

irregularity in impulse generation:

normal 
automaticity - the heart has pacemaker cells responsible for normal 
rhythm - the sinus node produces normal automaticity. this can be 
responsible for arrhythmia if there is autonomic imbalance, eg high vagal 
tone can produce bradycardia, or abnormally high sympathetic output can 
cause tachycardia. There are situations where the pacemaker is fine but 
conduction to atria is disrupted, also. 
abnormal automaticity - this is 
automaticity that looks like normal pacemaker activity but occurs outside 
of the pacemaker - eg normal myocardium may produce ectopic rhythms. this 
is in depolarized tissue.
triggered activity - there are clinical 
conditions where this can occur. it's due to a genetic defect in sodium 
and K+ channels which generate APs, or due to drug toxicity. two types - 
one, multiple responses arising out of early afterdepolarizations. this 
may reach threshold and produce multiple responses. quinidine can cause 
this. it produces early afterdepolarizations. any drug that prolongs AP 
duration by blocking K+ channels has potential to do this. another type 
of triggered activity is due to delayed afterdepolarization, one that 
occurs after AP has recovered. it may reach threshold and produce 
multiple responses. both of these mechanisms produce tachycardia. delayed 
type is seen with digitalis toxicity, or other situations of 
intracellular calcium overload. this isn't true automaticity - requires 
an AP generated by some other mechanism to trigger it. often 
spontaneously self terminating, but then recur with trigger.

disturbance 
in impulse conduction: slow conduction and block

slow response - occurs 
in very depolarized tissue. depolarization is so severe that you 
basically inactivate all the Na+ channels responsible for the fast 
upstroke, and you're left only with slow inward Ca++ current, which is so 
slow in terms of activation kinetics that it conducts extremely slowly. 
some tissues normally have this response - like the AV node, which 
doesn't have a fast inward Na+ current under normal conditions. 

depressed fast response - occurs in depolarized tissue like myocardium, 
muscle, his-purkinje network, etc. if there is an abnormality producing a 
depolarization, you start to inactivate some Na+ channels as you 
depolarize, and as you do this, you get a slower/depressed upstroke. when 
you decrease rate of rise of an action potential, conduction velocity is 
slowed. look at the upstroke of the AP - you start at resting potential - 
you depolarize the tissue - in fully polarized tissue you get rapid 
upstroke of Na+ current and fast conducting beat. as you depolarize, you 
inactivate the Na+ channels, then they can't open again til they return 
to their resting state. they aren't ready. as you depolarize, fewer and 
fewer of Na+ channels are in active state. at some point, none of the Na+ 
channels are in resting state anymore. this is what happens with the slow 
response. but for depressed fast response, you're not as depolarized - so 
your upstroke, instead of being normal, is depressed. the key is, if 
you're going to use drug therapy to affect upstroke of AP, in this case, 
b/c your sodium current is still causing AP, you'd use something to block 
sodium current. but if your patient has slow response, you'd use calcium 
channel blocker.
electrical uncoupling - cells normally have gap 
junctions through which current can flow. there may be abnormalities 
causing electrical uncoupling as seen with myocardial infarction
abnormal 
cellular excitability and/or refractoriness- if you have prolonged 
refractoriness, you can have barrier to conduction of impulse. changed 
excitability - can be decreased, harder to provoke a response.

in terms 
of therapies, the drugs we discuss are going to have an affect on the 
depressed fast and slow responses, and abnormal 
excitability/refractoriness. 

the most common mechanism of cardiac 
arrhythmia is reentry. Reentry:

minimum requirements for reentry 
circuit: impulse comes down, finds pathway around which it can conduct, 
splits off into two directiosn, conducts in both directions in this 
pathway. possibility exists that impulse may get around continuously 
under certain conditions. if everything is the same in both limbs, 
impulse will come down on both sides, collide, and extinguish itself, so 
there's no reentrance circuit. however, there may be differences b/w the 
limbs. you need, to set up a reentrance circuit, the following things:
1. 
anatomic or functional barrier - scar tissue or something. this is what 
causes impulse to split.
2. unidirectional block - to allow impulse 
coming around to get back w/o colliding with other impulse
3. slow 
conduction or long pathway, so that area of block and tissue beyond has 
time for recovery (longer than refractory period for initial impulse); 
*or*
4. brief refractory period

once impulse gets across block, it 
continues around loop, and every time it goes around it makes an extra 
beat. most common form of tachycardia.

how do you stop this? 

1. remove 
the anatomical or functional barrier, and the impulse won't split in the 
first place. 
2. speed up conduction velocity, so impulse gets back and 
hits refractory barrier of initial impulse
3. eliminate unidirectional 
block, so impulses collide
4. depress conduction in area of 
unidirectional block - that area could be due to depolarized tissue that 
makes conduction marginal - if you further depress it, you can turn it 
into a site of block instead of slow unidirectional conduction
5. prolong 
refractory period

as it turns out, antiarrhythmics we talk about do 
either 4 or 5. they depress conduction or prolong refractoriness. this is 
the main thing that antiarrhythmics effective against reentrance 
tachycardias do. they don't do the other things. removing the anatomic 
barrier is really a surgical problem. there is no magic potion to remove 
unidirectional blocks. 

so, we're going to try to take a depressed area 
and get rid of conduction through that area. say there's an area of 
unidirectional block and slow conduction due to depressed fast response. 
do you use Ca++ or Na+ channel blocker? what if it's got a slow response? 
you figure it out based on teh mechanism of the arrhythmia. paroxysmal 
atrial tachycardias rely on conduction through AV node for reentrance 
circuit. you have to use agent that blocks Ca++ current to fix that.

so 
you have a reentry circuit. the impulse hits a unidirectional block, 
circles around, and continues to circulate. every time it comes around, 
it triggers a new beat. these circuits can make very rapid beats 
depending on size andconduction characteristics. 

some of the circuits 
have "short excitable gap" - impulse comes around, leaving refractory 
tail. if another impulse coming in at that point tries to get into the 
tissue it finds a refractory barrier. the impulse comes around because of 
this gap. a second type of circuit has a "long excitable gap" a wide 
interval b/w head and tail of circuit, due to area of very slow 
conduction. this allows time for a lot of the tissue to recover. the gap 
b/w head and tail is large compared to short excitable gap circuit. 


pharmacologically, how do approaches to treatment differ? if you gave an 
agent to slow conduction (Na+ channel blocker), you would widen the 
excitable gap. that doesn't help. but if you gave an agent to prolong 
refractoriness (class III agent) it will cause short excitable gap 
impulse to run into its tail and extinguish itself. but for a long 
excitable gap situation, it won't run into its tail - you can't prolong 
refractoriness enough to have an effect. but, say the AV node is the area 
of slow conduction - you can give calcium channel blocker, further 
depress conduction, produce block, interrupt the circuit. if it were in 
the ventricle, you'd give a class I agent to block sodium current. 
at 
this point, you should say "what the hell is he talking about??"


classification of antiarrhythmic drugs: note: all act on voltage gated 
ion channels in the membrane or ion pumps in the membrane, or by way of 
second messengers such as those activated by beta receptors.

I: all 
class I drugs block sodium current

Ia: moderate slowing of conduction 
(decreased Vmax)(due to moderate effect on fast inward sodium current), 
also cause prolongation of refractoriness (increased AP duration due to 
K+ blocking). E.g. quinidine, procainamide, disopyramide

Ib: slight 
slowing of conduction (less potent than Ia), no change or slight decrease 
in refractoriness. Eg lidocaine (very rapid effect - comes on in minutes, 
brief duration, used acutely IV), tocainide, mexiletine, phenytoin

Ic: 
marked slowing of conduction (really block fast sodium current a lot), 
slight prolongation of refractoriness (mild potassium blocking effect). 
E.g. encainide, flecainide, propafenone. These drugs are dangerous due to 
marked effects on fast sodium currents. They're only used for atrial 
arrhythmias, not for ventricular arrhythmias anymore. Clinical trials 
showed that patients on these drug died more often than patients on 
placebos.

II: beta adrenoceptor antagonism. E.g. beta blockers like 
propranolol

III: K+ blockers - prolongation of refractoriness, e.g. 
bretylium, amiodarone, sotalol. sotalol is also a beta blocker like 
propranolol. but sotalol has profound K+ blocking activity - the D isomer 
of it has no beta blocking potency and a lot of K+ potency; the racemic 
mixture has both kinds of activity.

IV: calcium channel antagonists - 
block of calcium entry, decrease slope of diastolic depolarization, e.g. 
verapamil, diltiazem. nifedapine acts mainly peripherally on vessels, 
which is why he didn't mention it here.

all these drugs also have other 
effects. class I drugs, some also affect K+ currents and prolong 
depolarization. they're classed based on their main effects. class I 
drugs are also separated by their effects on repolarization.

Effects/Toxicities:

quinidine/procainamide/disopyramide: conduction 
effects: decrease Vmax, prolong ERP (effective refractory period), 
abolish reentry by depressing conduction. automaticity effects: decrease 
normal automaticity

lidocaine/tocainide/etc: decrease Vmax, shorten ERP, 
abolish reentry by depressing conduction

encainide, flecainide, etc: 
marked decrease in Vmax, increase ERP, abolish reentry by depressing 
conduction.

propranolol: little effect on conduction; abolishes any kind 
of rapid automaticity depending on increased catecholamine levels


bretylium: prlong ERP, abolish renentry by producing refractory barriers

verapamil, diltiazaem: abolish reentry by depressing conduction by 
blocking ca++ channels. depresses conduction and prolongs ERP of AV node


class I toxicity: impaired conduction, cause triggered activity type 
ventricular arrhythmias. lidocaine and tocainide and mexiletine and 
phenytoin can cause convulsions and respiratory arrest. the encainide 
type drugs are especially proarrhythmia. 

Bretylium: GI disturbances

amiodarone: skin pigmentation, corneal deposits. this is a class III type 
drug used for ventricular arrhythmias. this is a good drug.

verapamil/diltiazem: can produce impaired AV nodal conduction since Ca++ 
channel blockers. 

this is all in the handout. check that out.
what's 
not on here is another drug which affects membrane pumps as the main 
action of the drug - mainly the Na+/K+ ATPase. antiarrhythmic properties 
aren't due to direct effect but an indirect action - it increases vagal 
tone and decreases sympathetic tone.

digitalis as positive inotropic 
agent increases contractility and systemic arterial pressure. this 
stimulates baroreceptors, and this is facilitated by digitalis which also 
increases baroreceptor sensitivity. enhanced baroreceptor reflex 
increases vagal tone and decreases sympathetic tone. at nontoxic doses, 
also there are CNS effects which increase vagal tone and decrease 
sympathetic tone, but at toxic doses, CNS effects cause increased 
sympathetic tone. 

electrophysiologic effects of digitalis:

check out 
the handout! focus on atrial effects and specifically the AV nodal 
effects, and especially AV nodal effects on refractory period. as it 
turns out the direct effect of digitalis is to prolong av nodal 
refractoriness, and indirect effect is to prolong it alot due to vagal 
tone. increase in vagal activity depresses AV nodal conduction and 
prolongs refractoriness. (he lost me just now)

atrial flutter: common in 
older people. classic kind of reentrance circuit. every time the impulse 
comes around it goes through AV node to ventricle. it's a rapid atrial 
rhythm due to reentry through atrium. older folks get it due to increased 
fibrous tissue in atria providing more pathways. it also happens with 
atrial hypertrophy. this impulse conducts around and we can sort of 
demonstrate what's going on - every time the impulse comes around, an 
atrial response occurs. you may have rates of 300/min, so atrium is 
ticking along at 300/min, but AV node doesn't allow impulses at that rate 
to reach the ventricle - it filtres out rapid rates due to low 
conductance. so with these flutters you often see 2:1 conduction, where 
every other impulse gets down, and ventricular rate is 150 bpm. so lets 
attack this circuit - it's in fast conducting tissue. what agent do you 
use to attack this? quinidine is a good bad example. if you gave 
quinidine to this patient you might drop the HR to 200 bpm. you wouldn't 
get rid of circuit, but you'd slow it to 200 from 300. now, you've slowed 
atrial rate, and now the AV node can conduct every beat instead of every 
other. now your ventricular rate is increased to 200 bpm. this is a worse 
situation. 
but digitalis would act better. with atrial flutter, you have 
a rapid ventricular rate, decreased end diastolic volume, and decreased 
cardiac output. w/digitalis, you prolong the AV nodal refractoriness. you 
also increase the rate of atrial flutter and fibrillation, but with 
prolonged nodal refraactoriness, fewer impulses reach ventricle, you 
improve end diastolic volume and improve cardiac output. this is due to 
enhancement of vagal tone. now that you've protected the ventricle, you 
can use quinidine or other drug to tx the atrial flutter.
what else 
prolongs AV nodal refractoriness? Ca++ blockers, beta blockers. 


digitalis toxicity:
cardiac: ventricular ectopy and tachycardia possibly 
terminating in ventricular fibrillation. this occurs because you're 
blocking Na/K+ ATPase pump, depleting intracellular K+ and building up 
Na+ in cell. membrane depolarization can occur, enhancing automaticity,d 
ue to K+ depletion, also delayed afterdepolarizations. tx - d/c 
digitalis, give IV potassium salts, tx w/lidocaine to control arrhythmia, 
tx of choice is to give digitalis specific Abs. 

it also causes 
atrioventricular block due to direct effect on conduction and indirect 
efect on enhanced vagal tone. can cause atrial arrhythmias due to 
enhanced automaticity and depressed conduction
extracardiac:
vomiting - 
stimulates CTZ
diarrhea
anorexia, weakness, lethargy, fatigue, 
convulsions, coma - due to CNS activity

pharmacologic therapy for common 
arrhythmias:

atrial premature beats: usually no acute tx, quinidine for 
chronic problem, or disopyramide, procainamide.
atrial flutter: acute: 
digitalis (quinidine in horse); verapamil or propranolol are 
alternatives. for chronic problem - digitalis and quinidine, or 
propranolol, flecainide, amiodarone. it's important to protect the 
ventricle before treating the atrial problem
paroxysmal atrial 
tachycardia- verapamil for acute tx
ventricular premature beats - 
lidocaine effective acutely - short acting, rapid onset, given IV. for 
acute tx also can use procainamide, quinidine. for chronic problem, 
quinidine, or procainimide, etc
ventricular tachycardia - potentially 
life threatening - DC cardioversion tx of choice, or alternatively 
lidocaine for acute problem. chronic - procainamide, quinidine, sotalol; 
amiodarone, propafenone (flecainide - kills people)

also see handout for 
that stuff. 

modulated receptor thing - we had this before with someone 
(fluharty?)

ion channels are also receptors. most of them are. all the 
ones we talk about are. that's how these drugs work -t hey bind to some 
site on the channel and alter their kinetics, their ability to allow 
currents to pass. so, ion channels ct as receptors, and what has come out 
in past few years is the concept that receptors modulate the way in which 
antiarrhythmic agents interact with them. generally, we know they go from 
resting state to active state to inactive state. the drug will bind 
preferentially to one of the states. the inward current is generated 
while the channel is in the active state. then the channel becomes 
inactive and remains there during plateau state, then later reverts to 
resting/ready state. some drugs preferentially bind the resting state - 
they have an affinity for that state. some drugs may have affinity for 
active or inactive state. so for effectiveness, if channel is usually 
inactive, a drug thatbinds the inactive state will be more likely to 
bind. etc.the lingo has been - a drug shows "use dependence" - 
effectiveness is dependent on HR, duration of myocardial depolarization, 
or other things related to shifting channel states. also, some drugs take 
longer to bind and unbind. it's a combination of affinity for a state, 
binding/unbinding properties, and the behavior of the heart, that 
determine the therapeutic effect of the drug.

examples: say you have an 
agent that binds active state of a channel.during a ventricular 
tachcardia, there are many rapid depolarizations. channels are more often 
in the active state than not. if your drug binds this state, it will be 
more effective than a drug that doesn't like to bind the active state. 
some agents bind inactive state - membrane is depolarized for a long 
time, so agents that bind inactive state will bind more effectively in 
cases where you spend more time in the depolarized state. agents that 
bind to the resting state don't usually show use dependence. they just 
bind to that state,  so this binding means it's just tonicly blocking the 
channel. it doesn't really show rate dependent action. agents that bind 
to inactive state - 
hmmm. he stopped in the middle of a sentence.

ok. 
if a tissue is depolarized...normally, the heart operates with -80-90 mv 
resting potential. your channels are resting and capable of generating 
inward current. when tissue is depolarized and conducting slowly, not all 
the sodium channels are able to get active - some of them are in inactive 
state b/c of depolarization. abnormally depolarized tissue may have a -70 
resting potential. if you give a drug that binds  the resting state, it 
moves the curve to the left. effect on inward current - normally, a well 
polarized situation, when you give drug you get a certain effect on 
sodium current. if you start out depolarized, you have a more profound 
effect on blocking the channels. it's like a magic bullet, preferentially 
kicking out depolarized tissue.

(??????)

example of use dependent 
channel block - lidocaine has high affinity for inactive state - binds 
during plateau state when tissue is depolarized and fast recovery 
kinetics (comes off quickly); quinidine has high affinity for activated 
state - binds during upstroke of AP; slow recovery kinetics (comes off 
slowly)

when lidocaine is on board, your mean degree of block remains 
constant because binding is over by the timethe next beat starts.
when 
quinidine is on board, it binds, blocks, takes longer to come off, so 
stays in effect while next beat starts - causes larger degree of block 
that increases with heart rate. 

the more sodium channels that open when 
threshold is reached, the greater the sodium current, the faster the 
depolarization. therefore we can use rate of depolarization as index of 
magnitude of sodium current. looking at rate of depolarization of cells 
vs beats per second - normally, rate of depolarization is pretty constant 
until you get to very high rates of beats/sec. with quinidine, at low 
rates, there is no depression of AP upstroke velocity. as you increase 
rate of beating, the rate of depolarization drops a lot. this correlates 
with depression of upstroke of AP. this is quinidine's use dependence.


high affinity for active state - highly rate dependent block: quinidine 
(Ia), flecainide (Ic), verapamil (IV)

high affinity for inactive state - 
APD and steady state potential: amiodarone (III), lidocaine (Ib), 
diltiazem (IV)

high affinity for resting state - not dependent on rate 
or APD: nifedipine (IV)
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