Agents used in cardiac arrhythmias pptx.

Cardiac arrhythmias are the most common cause of death in
patients with a myocardial infarction or terminal heart failure.
They increase in prevalence in the elderly and atrial fibrillation
is particularly common in this group. Arrhythmias are also the
most serious manifestation of digitalis toxicity and are often
associated with anesthetic procedures, hyperthyroidism, and
electrolyte disorders. The drugs used for arrhythmias fall into
five major groups or classes, but most have very low therapeutic
indices and when feasible, nondrug therapies (cardioversion,
pacemakers, ablation, implanted defibrillators) are used.

1. Agents used in
cardiac arrhythmias

2. Introduction
Cardiacarrhythmiascommonly occurinthe
presenceofpreexistingheartdiseases
Arethemostcommoncauseofdeathinpatients
withMIorterminalHF
Thearealsothemostseriousmanifestationof
digitalistoxicityandareoftenassociatedwith
anesthesia,hyperthyroidism,andelectrolyte
disorders
Drugsusedforthetreatmentofarrhythmiasfall
intofivemajorgroupsorclasses.Nondrug
therapiesareused

3. Classes of drugs used in arrhythmia

4. Introduction
What is an Arrhythmia???
Normalelectricalcardiacfunction(normalsinus
rhythm,NSR)isdependenton:
generationofanimpulseinthenormalsinoatrial(SA)node
pacemaker
conductionofimpulsethroughtheatrialmuscle,through
theatrioventricular(AV)node,throughthePurkinje
conductionsystem,totheventricularmuscle.
Normalpacemakingandconductionrequirenormal
actionpotentials(dependentonsodium,calcium,
andpotassiumchannelactivity)underappropriate
autonomiccontrol.
Arrhythmias(alsocalleddysrhythmias)are
thereforedefinedbyexclusion,thatis,anyrhythm
thatisnotnormalsinusrhythmisanarrhythmia.

5. Introduction
Arrhythmiasmayrequiretreatmentbecauserhythms
thataretoorapid,tooslow,orasynchronouscanreduce
cardiacoutput
Canprecipitatemoreseriousorevenlethalrhythm
disturbances…..Insuchpatients,antiarrhythmicdrugs
maybelifesaving
Ontheotherhand,becauseantiarrhythmicdrugscan
precipitatelethalarrhythmiasinsomepatients,
treatmentofasymptomaticorminimallysymptomatic
arrhythmiasshouldbeavoidedforthisreason

7. Introduction
Conceptuallysimple—dysfunctionthatcause
abnormalityinthesiteoforiginoftheimpulse,its
rateorconductioninthemyocardium……
dysrhythmia,abnormalsinusrhythm
Clinically,arrhythmiasareclassifiedaccordingtothe
siteoforigin(atrial,ventricular)andwhethertherateis
increased(tachycardia)ordecreased(bradycardia)
Ex.:atrialtachycardiaforarapidarrhythmiaoriginating
intheatria

8. Normal Electrical Activity in the cardiac cells
Theflowofionsacrosscellmembranesgeneratesthe
currentsthatmakeupcardiacactionpotentials
Thetransmembrane potentialofcardiaccellsis
determinedbytheconcentrationsofseveralions—
chieflysodium(Na
+
),potassium(K
+
),calcium(Ca
2+
),
andchloride(Cl
–
)—oneithersideofthemembraneand
thepermeabilityofthemembranetoeachion
Ionsmoveacrosscellmembranes inresponseto
electricalandconcentrationgradients,notthroughthe
lipidbilayerbutthroughspecificionchannelsor
transporters

9. Antiarrhythmic drugs
The antiarrhythmic agents are usually classified
using a system loosely based on the channel or
receptor involved. This system specifies 4 groups
or classes, usually denoted by the numerals 1
through 4, plus a miscellaneous group :
1. Sodium channel blockers
2. Beta-adrenoceptor blockers
3. Potassium channel blockers
4. Calcium channel blockers

10. Drug Group PR Interval QRS DurationQT Interval
Procainamide,
disopyramide,
quinidine
1A ↑ or ↓* ↑↑ ↑↑
Lidocaine,
mexiletine
1B — —* —
Flecainide 1C ↑ (slight)↑ —
Propranolol,
esmolol
2 ↑↑ — —
Amiodarone 3, 1A, 2, 4↑ ↑↑ ↑↑↑↑
Ibutilide,
dofetilide
3 — — ↑↑↑
Sotalol 3, 2 ↑↑ — ↑↑↑
Verapamil 4 ↑↑ — —
Adenosine Misc ↑↑↑ — —

11. Group 1 Antiarrhythmics
(Local Anesthetics)
Prototypes
The group 1 drugs are further subdivided
on the basis of their effects on AP duration:
Group 1A agents (prototype procainamide )
prolong the AP.
Group 1B drugs (prototype lidocaine )
shorten the AP in some cardiac tissues.
Group 1C drugs (prototype flecainide ) have
no effect on AP duration.

12. Group 1 Antiarrhythmics
Mechanism of action
All group 1 drugs slow or block conduction in ischemic and
depolarized cells and slow or abolish abnormal pacemakers
wherever these processes depend on sodium channels.
The most selective agents (those in group 1B) have significant
effects on sodium channels in ischemic tissue, but negligible
effects on channels in normal cells.
Less selective group 1 drugs (groups 1A and 1C) cause some
reduction of I_Na even in normal cells.
Useful sodium channel-blocking drugs bind to their receptors
much more readily when the channel is open or inactivated
than when it is fully repolarized and recovered from its
previous activity.

13. Group 1 Antiarrhythmics
Mechanism of action
Ion channels in arrhythmic, abnormal tissue spend more
time in the open or inactivated states than do channels
in normal tissue.
Therefore, these antiarrhythmic drugs block channels in
abnormal tissue more effectively than channels in
normal tissue.
Use dependent or state dependent in their action:
they selectively depress tissue that is frequently
depolarizing, e.g., during a fast tachycardia; or tissue
that is relatively depolarized during rest, e.g., by
hypoxia.

14. Drugs with Group 1B Actions
Lidocaine, mexiletine, phenytoin
Lidocaine is the prototype 1B drug and is used exclusively
by the IV or IM routes.Mexiletine is an orally active 1B
agent.
Lidocaine selectively affects ischemic or depolarized
Purkinje and ventricular tissue and has little effect on atrial
tissue; the drug reduces AP duration in some cells, but
because it slows recovery of sodium channels from
inactivation it does not shorten (and may even prolong) the
effective refractory period.
Mexiletine has similar effects. Because these agents have
little effect on normal cardiac cells, they have little effect on
the ECG.

15. Drugs with Group 1B Actions:
PK, clinical use, toxicities
Lidocaine is useful in acute ischemic ventricular
arrhythmias, for example, after myocardial infarction.
Atrial arrhythmias are not responsive unless caused by digitalis.
Usually given IV , but IM administration is also possible. It is
never given orally because it has a very high first-pass effect and
its metabolites are potentially cardiotoxic. most common adverse
effects—like those of other local anesthetics—are j: paresthesias,
tremor, nausea of central origin, lightheadedness, hearing
disturbances, slurred speech, and convulsions.
Mexiletine has similar actions and is given orally. Dose-related
adverse effects are seen frequently at therapeutic dosage. These
are predominantly neurologic, including tremor, blurred vision,
and lethargy. Nausea is also a common effect.
Both these drugs may also precipitate arrhythmias, but this is
much less common than with group 1A drugs. Hyperkalemia
increases cardiac toxicity.

16. Group 2 Antiarrhythmic (Beta Blockers)
Prototypes, Mechanisms, and Effects
Propranolol and esmolol are prototypic antiarrhythmic blockers.
Their mechanism in arrhythmias is primarily cardiac-
adrenoceptor blockade and reduction in cAMP, which results in
the reduction of both sodium and calcium currents and the
suppression of abnormal pacemakers. The AV node is
particularly sensitive to blockers and the PR interval is usually
prolonged by group 2 drugs.
Under some conditions, these drugs may have some direct local
anesthetic (sodium channel-blocking) effect in the heart, but
this is probably rare at the concentrations achieved clinically.
Sotalol and amiodarone, generally classified as group 3 drugs,
also have group 2 -blocking effects.

17. Group 2 Antiarrhythmic (Beta Blockers)
PK, Clinical Uses and Toxicities
Esmolol,a very short-acting blocker (IV), used exclusively in
acute arrhythmias.
Propranolol,metoprolol, and timolol are commonly used as
prophylactic drugs in patients who have had a
myocardial infarction.These drugs provide a protective effect
for 2 years or longer after the infarct.
The toxicitiesof blockers are the same in patients with
arrhythmias as in patients with other conditions. While patients
with arrhythmias are often more prone to B-blocker-induced
depression of cardiac output than are patients with normal hearts
Judicious use of these drugs reduces progression of chronic heart
failure and reduces the incidence of potentially fatal arrhythmias
in this condition.

18. Prototypes: Dofetilide and ibutilide. Sotalol is a chiral compound
(i.e., it has 2 optical isomers). One isomer is an effective
blocker, and both isomers contribute to the antiarrhythmic
action. The clinical preparation contains both isomers.
Amiodarone is usually classified as a group 3 drug because it
blocks the same K channels and markedly prolongs AP duration
as well as blocking sodium channels.
Dronedarone is a new drug, similar to amiodarone but less
efficacious and less toxic.
Group 3 Antiarrhythmic (K+ Channel Blockers
Prototypes

19. Group 3 Antiarrhythmic (K+ Channel Blockers)
PK, clinical uses and toxicities
Sotalol is available by the oral. It may precipitate torsade de
pointes arrhythmia as well as signs of excessive blockade
such as sinus bradycardia and asthma.
Ibutilide and dofetilide are recommended for atrial flutter and
fibrillation. Their most important toxicity is induction of
torsade de pointes. The toxicities of group 1A drugs (which
share the I
Kpotassium channel-blocking action of group 3
agents) are discussed with the group IA drugs.
Amiodarone: A Special Case
Amiodarone is useful in most types of arrhythmias and
is considered the most efficacious of all antiarrhythmic drugs.
This may be because it has a broad spectrum: It blocks
sodium, calcium, and potassium channels and adrenoceptors

20. Group 3 Antiarrhythmic (K+ Channel Blockers)
Amiodarone (cont’d)
Because of its toxicities, however, amiodarone is approved for use
mainly in arrhythmias that are resistant to other drugs.
Nevertheless, it is used very extensively, off label, in a wide variety
of arrhythmias because of its superior efficacy.
Amiodarone causes microcrystalline deposits in the cornea and
skin, thyroid dysfunction (hyper-or hypothyroidism), paresthesias,
tremor, and pulmonary fibrosis.
Amiodarone rarely causes new arrhythmias, perhaps because it
blocks calcium channels and receptors as well as sodium and
potassium channels.
Dronedarone , an amiodarone analog that may be less toxic, has
recently been approved. Like amiodarone, it acts on sodium,
potassium, and calcium channels but at present it is approved only
for the treatment of atrial fibrillation or flutter.

21. Group 4 Antiarrhythmic (Ca Channel Blockers)
Prototype
Verapamil is the prototype. Diltiazem is also an effective
antiarrhythmic drug.
Nifedipine and the other dihydropyridines are not useful as
antiarrhythmics, probably because they decrease arterial pressure
enough to evoke a compensatory sympathetic discharge to the
heart. The latter effect facilitates rather than suppresses
arrhythmias.
Mechanism and Effects
Verapamil and diltiazem are effective in arrhythmias that must
traverse calcium-dependent cardiac tissue (e.g., the AV node).
These agents cause a state-and use-dependent selective
depression of calcium current in tissues that require the
participation of L-type calcium channels.
AV conduction velocity is decreased and effective refractory period
increased by these drugs. PR interval is consistently increased.

22. Miscellaneous Antiarrhythmic Drugs
Adenosine
Adenosine is a normal component of the body, but when it is
given in high doses (6–12 mg) as an IV bolus, the drug
markedly slows or completely blocks conduction in the AV
node, probably by hyperpolarizing this tissue (through
increased I
K1) and by reducing calcium current.
Extremely effective in abolishing AV nodal arrhythmias,
and because of its very low toxicity it has become the drug of
choice for this arrhythmia.
Extremely short duration of action (about 15 s).
Toxicity includes flushing and hypotension, but because of
their short duration these effects do not limit the use of the
drug. Transient chest pain and dyspnea (probably due to
bronchoconstriction) may also occur.