Cv Pharm - Antiarrhytmic Drugs Ve

Front 1

Describe adenosine

Back 1

-Endogenously is a synaptic transmitter in purinergic nerves of the GI tract and CV system
-Produced by myocardium during hypoxia and released into interstitial space
-Exerts effects on adenosine receptor subtype A1
-Similar effects to ACh (increases outward K in the SA and AV nodes and atria, but not in ventricles)
-Has a weak depressant effect on L-type Ca channels

Front 2

What is the primary action of adenosine?

Back 2

-Decrease sinus rate and AV nodal conduction
-Prolong AV nodal refractory period
-Decrease atrial action potential duration and refractory period

Front 3

Describe the effect of adenosine on cardiac arrhythmias

Back 3

-Terminates supraventricular tachycardias that rely on the AV node as part of the reentrant pathway
-These include AV nodal reentrant tachycardia and tachycardia using the AV node as an accessory pathway
-Causes transient block of AV nodal conduction for 1 to 2 beats
-No therapeutic effects on other atrial or ventricular arrhythmias

Front 4

Describe the administration and elimination of adenosine

Back 4

-Rapid IV injection
-Cleared from blood by cellular uptake and enzymatic metabolism
-t1/2 <5s
-Direct effects only through first passage of heart
-Tachycardia can start again if the initiating event reoccurs

Front 5

Describe the adverse effects of adenosine

Back 5

-Decrease in BP due to vasodilation not a problem because it is so short acting
-Facial flushing due to dilation can occur
-A few seconds of sinus bradycardia, sinus arrest or AV block can occur
-Transient atrial fibrillation occasionally occurs related to the shortening of the atrial refractory period

Front 6

Describe atropine

Back 6

-Used to treat sinus bradycardia or AV block caused by enhanced effects of the vagus nerve
-Increased vagal activity commonly occurs with a posterior myocardial infarction or digitalis toxicity and causes sinus bradycardia or AV block
-Atropine used when these bradyarrhythmias cause hypotension

Front 7

Describe Digitalis

Back 7

-Also called Digoxin
-Used to treat certain supraventricular arrhythmias
-Also have effects on the heart (+ inotrope) and circulation (vasodilation) that make it useful for heart failure

Front 8

Describe the effects of digitalis on the electrical properties of the heart at therapeutic concentrations

Back 8

-Modifies activity of the autonomic nervous system
-Increases vagal nerve actiyicy (parasympatheomimetic effects) by stimulating the central vagal nucleus
-Sensitizes the baroreceptors to decrease sympathetic activity and increase vagal activity
-The baroreceptor effect is more important in causing vasodilation in patients with heart failure
-All effects are explainable in terms of the effects of ACh on the cardiac cell membrane to increase K conductance and decrease L-type Ca conductance

Front 9

Describe the effect of digitalis on the SA node, Atrium, AV node, and other places

Back 9

SA node- Maximum diastolic potential increases, slope of phase 4 decreases and sinus rate slows

Atrium - Resting potential may increase (more -), repolarization is accelerated, effective refractory period is abbreviated

AV node - Action potential phase 0 and amplitude is reduced, conduction is slowed or blocked, effective refractory period is prolonged

Minimal effects on electrical activity of structures below the AV node since parasympathetics do not significantly affect electrical activity of ventricle

Front 10

What are the effects of digitalis on the ECG?

Back 10

-Seen in therapeutic doses
-May be exaggerated in toxic doses
-All effects explained by increase in vagal activity

i. Decreased sinus rate
ii. Increased PR interval
iii. Unchanged QRS duration during sinus rhythm

Front 11

What is responsible for antiarrhythmic effects of digitalis?

Back 11

Action on the autonomic nervous system

Front 12

Describe the uses of digitalis to treat cardiac arrhythmias

Back 12

-Terminates ore prevents paroxysmal supraventricular (AV nodal reentrant) tachycardia
-Slows the ventricular rate in atrial fibrillation (rate control of atrial fibrillation)
-Not effective in treating ventricular arrhythmias since parasympathetic activation does not significantly alter ventricular electrical activity.
-Some ventricular arrhythmias may occur in heart failure due to poor coronary perfusion and cardiac function may improve with digitalis due to improved flow

Front 13

Describe how digitalis can terminate or prevent paroxysmal (AV nodal reentrant) tachycardia

Back 13

-Parasympathomimetic effect transiently blocks conduction in the AV node during reentrant AV nodal tachycardia
-Digoxin is not used less frequently for this since the advent of calcium channel blockers, adenosine, and ablation for the treatment of AV nodal reentrant arrhythmias

Front 14

Describe how digitalis can slow the ventricular rate in atrial fibrillation (rate control of atrial fibrillation

Back 14

-Parasympathomimetic effects on the AV node prolong refractoriness and increase the percentage of atrial beats that block in the AV node and thus fail to excite the ventricles
-This slows the ventricular rate
-Digitalis does not usually cause atrial fibrillation to convert to sinus rhythm and therefor is used only for control of ventricular rate

Front 15

Describe the effects of digitalis on cardiac output

Back 15

-Increases contractility and augments the ability of the heart to pump blood (positive inotropic effect)
-Direct effect on heart (not through parasympathomimetic effects)
-Two components lead to positive inotropic effect by increasing stores of Ca in the sarcoplasmic reticulum and the release of an increase amount of Ca with each beat
-This results in a higher concentration of Ca2+ that acts directly on the myofilaments

Front 16

What are the two components that lead to the positive inotropic actions of digitalis

Back 16

i. Effects on the sodium pump and the Na-Ca exchanger
ii. Effects on the Ca current

Front 17

Describe the effects of digitalis on the Na pump and the Na-Ca exchanger

Back 17

-Digitalis binds specifically to the sarcolemmal Na-K-ATPase (the digitalis receptor) to inhibit its enzymatic acticity and impaire the active transport of these two monovalent cations
-There is a gradual but small increase in intracellular Na and a gradual decrease in intracellular K
-These ion changes have little detectable effect on the resting potential and phase 0 of the action potential
-The heart fibers intracellular Ca is exchanged for extracellular Na by a transport system that is driven by conc gradients and transmembrane potential
-When inhibition of the pump by digitalis increases Na in the cell, the exchange of extracellular for Na for intracellular Ca is diminished and [Ca2+]i increases.
-Ca2+ stores in sarcoplasmic reticulum increase and with each action potential a greater amount of Ca2+ is released
-More Ca2+ ions results in a greater force development by the myofilaments

Front 18

Describe the Na-K exchanger in cardiac fibers

Back 18

What are the consequences ydrolysis of ATP by a sarcolemmal Na,K-ATPase provides the energy for the Na pump - the system in the sarcolemma cardiac fibers that actively extrudes Na and transports K into the fibers

Front 19

Describe the effects of digitalis on calcium current

Back 19

-Digitalis increases Ca2+ entry into the cell through L-type Ca channel
-More Ca2+ is delivered during the plateau of each action potential to cause increased Ca release from the SR during each contraction

Front 20

Describe the results of the positive inotropic effect of digitalis

Back 20

-Digitalis acts directly on both normal and "failed" cardiac muscle from all four chambers to increase the strength of contraction (increase rate of force development and increased peak force)
-This effect can shift the curve describing the PV relationship to the left

Front 21

Describe the indirect actions of digitalis in the treatment of heart failure

Back 21

-These indirect effects may augment CO
-They are neurally mediated

Parasympathomimetic effects: Digitalis augments the effects of the vagus on the heart and other vagally innervated structures. Digitalis acts directly on central vagal nucleus and also sensitizes carotid and other baroreceptors in the circulation to augment vagal activity

Sympatholytic effects - Because of increased activity of baroreceptors, digitalis in therapeutic concentrations decreases efferent sympathetic firing to heart and vessels. This decreases sinus rate and diminished systemic vascular resistance. Reduction in afterload from reduced neurohormonal mechanisms is very important for the beneficial effects of digitalis in HF since in HF the baroreceptors are desensitized leading to increase symp activity

Front 22

Describe the effects of digitalis on the circulation in patients with heart failure

Back 22

i. Actions
a) Direct + inotropic effect
b) Sympathetic withdrawal (indirect) (actions on baroreceptors)
c) Arteriolar dilation (indirect) (actions on baroreceptors).
d) Venous dilation (indirect) (actions on baroreceptors)
e) Enhanced vagal actions

ii. Hemodynamic changes
a) CO increased (positive inotropic effect plus decreased afterload)
b) Arterial pressure unchanged or increased
c) Venous return increased
d) HR decreases

Front 23

What factors promote excessive digitalis accumulation?

Back 23

i. High dosage
ii. Decreases excretion
a) Renal disease
b) Old age
c) Hypothyroidism

Front 24

Describe the factors that increase myocardial sensitivity to digitalis toxicity

Back 24

i. Myocardial disease or ischemia
ii. Hypokalemia
and hypomagnesemia (e.g. after diuretic therapy or dialysis)
iii. High serum calcium (e.g., prolonged bed rest, myeloma, parathyroid adenoma)

Front 25

What is the major risk with digitalis toxicity?

Back 25

Cardiac arrhythmias

Front 26

Describe the cardiac arrhythmias associated with digitalis toxicity

Back 26

Severe bradycardia - Results from an excessive increase in parasympathetic nerve activity

AV block - Are also primarily from the result of excessive increase in parasympathetic nerve activity

AV junctional and ventricular arrhythmias - Result from direct effects of digitalis to cause delayed afterdepolarizations (DAD). The DAD results from an excessive increase in intracellular Ca. This causes an oscillatory change in the intracellular Ca concentrations after each action potential due to repetitive release and reuptake of Ca2_ by the sarcotubular system. Oscillatory changes in Ca2+ concentration cause an inward current (transient) that results in the DAD.

Front 27

What does treatment of arrhythmias due to digitalis toxicity depend on?

Back 27

Nature and severity of arrhythmia. Usually you:
a) Admit to intensive care area for monitoring
b) Withhold digitalis

Front 28

Describe treatment of arrhythmias due to digitalis toxicity if withholding digitalis and admitting to an IC area do not work

Back 28

a) Give lidocaine for serious ventricular arrhythmias
b) Measure serum potassium concentration. The intensity of digitalis effect on the Na-K pump is K-dependent
-If serum K+ is low, administer K salts with care. This often will suppress ventricular arrhythmias and improve AV conduction
-If serum K is initially elevated, a further increase may lead to complete AV block, depression of ventricular automaticity and asystole
c) Correct abnormalities of serum Ca or Mg
d) Severe toxicity can be reversed by giving Fab fragments of digoxin-specific Ab through IV
e) If digitalis toxicity is manifest as severe sinus bradycardia, SA block or AV block, atropine can be considered to overcome the vagal contribution

Front 29

Describe the administration of digitalis

Back 29

-Occasionally administered as a large initial dose to establish a therapeutic plasma concentration
-Followed by daily maintenance doses
-Initially dose given IV and then subsequent doses are taken orally

Front 30

Describe the absorption, distribution, and excretion of digitalis

Back 30

Absorption: Oral absorption is moderately rapid for digoxin (onset of action >1.5 hours)

Distribution: Distribution phase takes a very long time (half-time 1-3 hours)

Excretion: Mostly excreted unchanged by kidney so that as renal function becomes impaired, plasma concentration and risk of toxicity increase