Module 4 Pharmacology

Front 1

How do we characterize cardiac dysrhythmias?

Back 1

They are characterized by abnormalities of impulse generation and/or conduction.

Front 2

Characterizing by impulse generation...

Back 2

1. The site of impulse generation
- is automaticity occurring at some site other than the SA node?

2. The rate of impulse generation
- if automoticity is coming from the SA node, does it fire too fast or too slow for normal cardiac fxn

Front 3

Characterizing by impulse conduction...

Back 3

1. Does the abnormal conduction follow an anatomically defined re-entry pathway?
- Wolff-Parkinson-White (WPW)
- "classical" atrial flutter
- AV nodal re-entry tachycardia = paroxysmal supraventricular tachycardia (PVST) = paroxysmal atrial tachycardia (PAT)

2. Does the abnormal conduction occur b/c the signal can travel through two different pathways?

Front 4

Questions before you decide to treat w/ drugs.

Back 4

1. Is the dysrhythmia a physical sign of extracardiac pathology which needs to be corrected?
- atrial fib seen in pts w/ hyperthyroidism

2. Are there predisposing factors which contribute to the genesis of the dysrhythmia?
- hypoK and hypoMg make heart more likely to display abnormal rhythm
- cardiac ischemia
- drugs

3. Abnormalities of the EKG do not always require pharm treatment and may increase mortality

4. Do you really know the nature of the dysrhythmia?

Front 5

What about non-pharm treatment indications?

Back 5

1. Re-entry dysrhythmias w/ anatomically defined pathways can be cured by ablation (physical destruction) of the re-entry pathway w/ a catheter

2. Dual-chamber, rate-adaptive pacemakers are implanted to maintain cardiac rhythm in patients with:
- sinus node dysfxn (sick sinus syndrome, brady/tachycardia syndrome, or carotid sinus hypersensitivity
- AV block (symptomatic or nonsymptomatic Mobitz type II)

3. An automatic implantable cardioverter-defibrillator (AICD or ICD) is used for:
- primary prevention cardiac arrest in pts w/ nonsustained ventricular tachy and decreased LV fxn from CAD
- secondary prevention in pts who have survived cardiac arrest

Front 6

Strategies in treating cardiac dysrhythmias?

Back 6

1. THE BEST ANTIDYSRHYTHMIC DRUG IS AN ANTILIPEMIC DRUG

2. Block Na channels to decrease phase 4 automaticity or increase threshold potential

3. Block K channels to prolong repol in atria or ventricles; slowing rate of repol increases the ERP and thus prevents early and late-after-depols

3. Control ventricular rate in atrial tachy by decreasing the number of impulses that pass through AV node (decrease conduction velocity and increase ERP of AV node)

5. Block conduction in re-entrant pathways to restore normal rhythm

Front 7

Vaughn-Williams Class I antiarrhythmic drugs?

Back 7

BLOCK Na CHANNELS

1A = quinidine
procainamide

1B = lidocaine

Front 8

Vaughn-Williams Class II antiarrhythmic drugs?

Back 8

BETA-ADRENOCEPTOR ANTAGONISTS (beta-blockers)

atenolol
propanolol
esmolol

Front 9

Vaughn-Williams Class III antiarrhythmic drugs?

Back 9

INCREASE EFFECTIVE REFRACTORY PERIOD (partially block the K current)

amiodarone
dofetilide

Front 10

Vaughn-Williams combined Class II and III antiarrhythmic drugs?

Back 10

sotalol

Front 11

Vaughn-Williams class IV antiarrhythmic drugs?

Back 11

verapamil
diltiazem

Front 12

Other drugs for the treatment of dysrhythmic disorders

Back 12

digoxin
adenosine

Front 13

Which drugs have been shown to decrease death during long-term treatment?

Back 13

amiodarone
beta-blockers

Front 14

Quinidine pharmacological action?

Back 14

- blocks Na channels
- blocks K channels
- blocks a-adrenoceptors
- blocks muscarinic receptors

Front 15

Quinidine cardiac effects?

Back 15

BLOCKADE OF Na CHANNELS (partial)
- suppresses phase 4 automaticity in fast fibers
- increases threshold potential for depol
- decreases conduction velocity = QRS widens

BLOCKADE OF K CHANNELS (partial)
- prolongs ADP w/ increased length of the ERP in all cardiac tissue, including the AV node = P-R interval increased
- decreases number of impulses passing through the AV node b/c the ERP of the AV node is increased
- Delayed repol of the ventricles = Q-Tc interval is increased

VAGOLYTIC ACTION = BLOCKADE OF MUSCARINIC RECEPTORS
- tachycardia, but initial tachy is eventually attenuated by direct effect to suppress automaticity
- increased AV conduction, but w/ time AV conduction slows due to direct suppressant effect of quinidine

Front 16

Other CV effects of quinidine?

Back 16

- blockade of a-adrenoceptors dilates arterioles and venules

- baroreflexly-mediated tachycardia

Front 17

Therapeutic uses of quinidine?

Back 17

- control ventricular rate in patients w/ atrial fib or flutter

- suppress PVCs

Front 18

Adverse cardio effects of quinidine?

Back 18

- prolongation of Q-T interval precipitates torsade de pointes in 5% of patients (may occur at therapeutic plasma conc)

- large dose can cause ventric tachy

- muscarinic receptor blockade can cause ventricular tachy in pts w/ atrial fib or flutter

- direct effect can cause AV block

- exerts a direct negative ionotropic effect, but usually does not impair CO in patients w/ HF b/c it decreases afterload via blockade of a-adrenoceptors in arterioles

- blockade of a-adrenoceptors causes hypotension and syncope

Front 19

Other adverse effects of quinidine?

Back 19

- diarrhea in 30-50% of patients; K loss from chronic diarrhea increases likelihood of torsade de pointes

- cinchonism = headache and tinnitus

- numerous drug-drug interactions; blocks CYP2D6 and also clearance of digoxin

Front 20

Procainamide MOA?

Back 20

Blocks Na and K channels, so its cardiac effects are essentially the same as those caused by quinidine

Has much less anticholinergic effect

Front 21

Therapeutic use procainamide?

Back 21

-- given i.v. for acute control of ventricular rate in patients w/ atrial fibrillation or flutter (slows AV conduction to decrease ventricular rate)

-- suppress PVCs

-- seldom used for prolonged outpatient therapy due to toxicity

Front 22

Procainamide pharmacokinetics?

Back 22

-- metabolized by active metabolite N-acetylprocainamide (NAPA) by acetylation in the liver

-- NAPA blocks K channels (class III activity) and contributes to prolongation of QT interval

-- acetylation follows a bimodal distribution w/ slow acetylators at the greatest rist for drug toxicity

Front 23

Procainamide adverse effects?

Back 23

1. hypotension w/ rapid i.v injection

2. torsade de pointes

3. a syndrome resembling SLE which is characterized by arthralgia, arthritis, pericarditis and positive ANA
-- occurs in 23-50% of pts during long-term therapy
**malvar rash (buzz word)

Front 24

Lidocaine MOA

Back 24

ONLY AFFECTS THE VENTRICLES!

- blocks Na channels
- Decreases the ERP and APD of fast fibers

Front 25

Lidocaine cardiac effects?

Back 25

1. suppresses automaticity (spontaneous phase 4 depol) in partially depolarized tissue (ischemia, digoxin toxicity) w/ little effect on conduction in normally polarized tissue
-- suppresses PVCs!!
-- main use

2. abolishes ventricular re-entry dysrhythmias by causing 2-way blockade of conduction in the area that allows retrograde transmission b/c they inhibit a one-way block

3. increases threshold potential to further suppress automaticity

4. NO EFFECT on AV conduction

5. Essentially no effect on the EKG

6. "stuns" the heart and makes it less likely to respond to other drugs

Front 26

Therapeutic uses of lidocaine?

Back 26

-- given by i.v. b/c of extensive first-pass metabolism

1. used selectively to suppress PVCs in pts immediately after MI b/c prophylactic use post-MI increases mortality

2. digoxin induced PVCs

3. ventriculary tachycardia in pts w/ healed MIs

**amiodarone is replacing lidocaine in the ACLS algorithms for ventricular dysrhythmias

Front 27

Lidocaine adverse effects?

Back 27

NEURO - usually after rapid i.v. injection

1. CNS depression - slurred speech, nausea, tremor, paresthesias

2. Seizures - treat w/ diazepam

Front 28

atenolol, esmolol, propanolol MOA?

Back 28

blockade of cardiac beta-adrenoceptors

-- atenolol and esmolol are cardioselective
-- propranolol is non-selective

Front 29

B-blocker cardiac effects?

Back 29

MAJOR EFFECTS
1. suppress catecholamine-induced automaticity
2. reduces conducion velocity and increases the ERP of the AV node

OTHER EFFECTS
1. increases the ERP in fast fibers when the ERO has been shortened by stimulation of beta-adrenoceptors
2. decrese rate of discharge of SA node
3. P-R interval is increased

Front 30

B-blocker therapeutic uses?

Back 30

1. reduces post-MI sudden death by 25-40% by preventing fatal ventricular dysrhythmias, probably ventricular tachy (V Tach)
2. prevents PVCs triggered by physical or emotional stress
3. suppresses the tachycardia caused by hyperthyroidism
4. controls (reduces) ventric rate in pts w/ atrial tachys (fib or flutter)
5. suppresses AV nodal re-entry tachycardia (AVNRT)
6. b/c the blockers don't affect repol, they are the DOC for trtmt of V Tach in pts w. congenitally prolonged Q-T syndrome

B/C of it's short half-life ---- Esmolol is used to control ventricular rate in pts w/ A fib, A flutter, or sinus tachy during cardiac cath

Front 31

Adverse cardio effects of B-blockers?

Back 31

1. negative ionotropic effec

Front 32

d,l-sotalol MOA?

Back 32

**combined Class II (b-block) and Class III (delays repol)

1. L-isomer causes non-selective, competitive blockade of B-adrenoceptors in both slow (SA and AV nodes) and fast fibers

2. Blockade of K channel delays repolarization
-- outward K rectifier current (IKr) is responsible for termination of the plateau portion of the cardiac AP in fast fibers of the atria and ventricles (NB: K out causes repol or hyperpol)
-- Both the D- and L-isomers inhibit the rapid component of this outward K repol current
-- This effect delays repol and thus increases both the APD and ERP in the atria and ventricles

Front 33

Cardiac effect of L-sotalol caused by blockade of B-receptors?

Back 33

1. decreased HR

2. Fewer depol pass through AV node b/c conduction velocity is decreased and the ERP is increased

3. Increases the APD everywhere in the heart, so the ERP is increased everywhere in the heart

4. Decreases catecholamine-induced automaticity everywhere

****See chart on pg 200

Front 34

Additional cardiac effects due to blockade of outward repolarizing K current by both D- and L-sotalol?

Back 34

1. An additional increase in the APD and ERP in fast fibers over and above that caused by B-adrenoceptor blockade

2. An additional increase in the ERP of the AV node

3. Delayed ventricular repol increases the Q-T interval

Front 35

Therapeutic uses for d,l-sotalol?

Back 35

1. Cardioversion of atrial fib/flutter to sinus rhythm

2. Control (reduce) ventricular rate in pts w/ persistent A fib

3. Chronic therapy is used to prevent life-threatening V.tach and V.fib. Sotalol is used before amiodarone b/c sotalol causes less long-term toxicity. (DOC!)

Front 36

Adverse cardiac effects of sotalol?

Back 36

1. Class III action can precipitate torsade de pointes, especially when serum K is low

2. Decreased ventric contractility in heart failure assoc w/ systolic dysfxn via B-adrenoceptor blockade

3. AV block via B-adrenoceptor block

Front 37

Amiodarone MOA?

Back 37

***Class III agent which increases ADP and ERP

1. blocks inward Na and outward K channels

2. Non-competitive a- and B-adrenoceptor blockade

Front 38

Amiodarone cardiac effects?

Back 38

1. Extremely effective in suppressing automaticity via blockade of Na channels!
***FIRST LINE for PVCs

2. Blockade of K channels delays repol and thus prolongs the APD and ERP in the atria and ventricles

3. Prolongs the ERP in the AV node; reduces transmission of depol through the AV node

4. Prolongs the P-R, QRS, and Q-T intervals

5. Reduces the rate of firing of the SA node

Front 39

Therapeutic uses of amiodarone?

Back 39

1. cardioconversion of A.flutter/fib to sinus rhythm

2. Control (reduce) ventricular rate in patients w. persistent A.fib/flutter

3. Can be given i.v. to terminate life-threatening V.tach and V.fib

4. Chronic therapy used to prevent life-threatening V.tach adnd V.fib

5. NOT the first-line drug for recurrent V.tach and V.fib (sotalol is the DOC)

Front 40

Special points on the treatment of V.tach and V.fib...

Back 40

1. Amiodarone is probably more effective than sotalol in preventing reoccurance but is more toxic

2. An automatic implantable cardioconverter-defibrillator (AICD or ICD) is superior to medical tx w/ either of the above drugs, especially when the pt is symptomatic or has a low EF

3. Pts are usually managed w/ "hybrid" therapy consisting of ICD + sotalol. Trtmt w/ sotalol decreases the number of shocks that the patient experiences from the ICD and does not affect the E required to defib

4. Amiodarone is not used w/ an ICD b/c it increases the E req'd for defib by as much as 50%. Increase in E req'd reduces the safety margin btwn defib E and the max E output

Front 41

Amiodarone pharmacokinetics?

Back 41

-- Very large Vd (44 +/- 22L/kg) due to avid binding issues throughout the body -- PURPLE MAN

-- half-life of 53 +/- 24days

Front 42

Adverse cardio effects of amiodarone?

Back 42

1. severe bradycardia and/or AV block

2. Despite prolongation of the Q-T interval it SELDOM CAUSES torsade de pointes

3. Minimal effect to suppress myocardial contractility in HF

Front 43

Other amiodarone adverse effects?

Back 43

1. pneumonitis which may progress to pulmonary fibrosis (5-15%)

2. corneal microdeposits which cause halos in peripheral vision

3. photodermatitis (25%)

4. Some develop slate grey, blue, or purple skin from cutaneous deposits

5. Peripheral neuropathy w/ weakness in proximal muscles

6. Is 37% iodide by weight, and prolonged therapy can result in hypothyroidism (prevents conversion of T4 to T3) or hyperthyroidism (provides iodide for T4 synth)

7. Reducing daily dose, in attempt to decrease adverse S/Es, also decreases efficacy
-- trtmt A.fib is treated w/ 100-200mg/d to reduce toxicity
-- V.tach/fib still requires 400mg dose to be effective

Front 44

Amiodarone drug-drug interactions?

Back 44

decreases hepatic and renal clearance of many other drugs

Front 45

dofetilide MOA?

Back 45

***pure Class III - given p.o.

1. structurally related to sotalol, but has no B-blocking ability

2. delays repolarization
-- blocks outward repol K current
-- delayed repol increases the APD and ERP in fast fibers ONLY

Front 46

dofetilide cardiac effects?

Back 46

1. produces dose-related increase in the Q-T interval

2. No effect of AV conduction

3. No effect on the P-R interval or the width of the QRS

Front 47

Therapeutic uses of dofetilide?

Back 47

1. cardioconversion of A.fib and A.flutter of short duration

2. more effective than amiodarone or sotalol, but also more likely to cause torsade b/c prolonged Q-T

3. No negative effect on mortality after MI or in pts w/ CHF

Front 48

Adverse effects of dofetilide?

Back 48

1. Torsade de pointes
2. No effect on BP or cardiac contractility

**beneficial AND toxic effect derived from the same pharm effect --> blocking K channels

Front 49

verapamil, diltiazem MOA?

Back 49

** Class IV = calcium channel antagonists (CCAs)

-- Blockade of calcium channels in slow fibers, especially the AV node (slow AV conduction to control ventricular rate)

Front 50

Cardiac effects of CCAs?

Back 50

1. Decreased HR

2. Decreased conduction velocity in the AV node = increased P-R interval

3. Decreased ERP in the AV node

4. Decreased contractility (dp/dt)

Front 51

Therapeutic uses CCAs?

Back 51

1. to control (reduce) ventricular rate in pts w/ A.fib or flutter

2. Converts AV nodal re-entry tachy (AVNRT) to sinus rhythm by blocking the re-entry pathway in the AV node.
-- HR in AVNRT is 140-220bpm w/ narrow QRS complexes
-- B-blockers also effective in AVNRT trtmt

Front 52

Adverse effects CCAs?

Back 52

1. hypotension

2. sinus bradycardia

3. heart block

Front 53

Digoxin MOA?

Back 53

**also known as digitalis

1. acts centrally to increase efferent vagal nerve activity

2. acts centrally to decrease sympathetic outflow at serum concentrations w/in the therapeutic window (1-2ng/ml)

3. increases dp/dt via partial inhibition Na-K ATPase

Front 54

Cardiac effects of digoxin?

Back 54

VIA INCREASED VAGAL ACTIVITY
1. decreased HR
2. decreased conduction velocity in the AV node
3. increased ERP in the AV node

VIA PARTIAL INHIBITION ATPase
1. increased SV via increased dp/dt

Front 55

Therapeutic uses of digoxin?

Back 55

1. control (reduce) ventricular rate in pts w. atrial tachy (fib/flutter) in presence of heart failure caused by systolic dysfxn
-- b/c NO negative effect on CO

2. Increase dp/dt in pts w/ HF from systolic dysfxn

Front 56

Adverse effects digoxin?

Back 56

**at serum conc above therapeutic window

1. Inhib Na-K ATPase and increased intracellular Ca can elicit automaticity in fast fibers resulting in PACs and PVCs

2. Sympathetic activity increased

3. ADP and ERP are decreased in persence of excessive intracellular Ca leading to delayed afterdepol triggered by increased symp activity

4. sinus bradycardia

5. AV block (decreased vagal tone + direct depressant effect)

Front 57

Adenosine MOA?

Back 57

1. increases K conductance to hyperpol the AV node

2. inhibits ability of sympth stim to increase Ca conductance in the AV node

3. half-life in circulation is about 10 seconds, so actions are short-lived

Front 58

Cardiac effects adenosine?

Back 58

1. decreased conduction velocity and increased ERP in the AV node

2. AV conduction momentarily ceases! Yes, the heart stops!

Front 59

Therapeutic uses of adenosine?

Back 59

1. diagnosis of AV nodal re-entry tachycardia (PSVT)

2. conversion of AVNRT to normal sinus rhythm (90+% effective)

3. produce coronary vasodilaiton during technetium scan in pts who cannot exercise

Front 60

If tachycardia DOES NOT go away w/ adenosine...

Back 60

Then the tachy is VENTRICULAR and not supraventricular

Front 61

Explain the therapeutic use of adenosine for PVST diag?

Back 61

block AV node so circular path will go away --> cardioconvert to sinus rhythm --> then give verapamil + B blocker to prevent________________

Front 62

adverse effects adenosine?

Back 62

1. transient asystole

2. short-lived, intense burning sensation in the chest

3. flushing

4. dyspnea

Front 63

Which is the most common dysrhythmia and what is a cause?

Back 63

Atrial fib

- HTN
- ischemic heart disease (CAD)
- systolic heart failure
- valvular heart disease

- increased age

All of the above predispose to sustained A.fib

Front 64

Lack of atrial coordination leads to?

Back 64

- blood stasis and formation of thrombi in arterial appendages

Front 65

Patients w/ A.fib are at high risk for?

Back 65

- ischemic stroke

**must be treated daily w/ warfarin and/or antiplatelet drug (aspirin, ticlopidine)

Front 66

Two schools of thought on best way to prevent ischemic strokes in pts w/ A.fib?

Back 66

1. RHYTHM SCHOOL
- conversion AF to sinus rhythm (drugs or DC shock) and continued maintenance of sinus rhythm reduces stroke incidence and need for warfarin therapy

RATE SCHOOL
- don't worry about persistant A.fib as long as drugs are used to control (decrease) ventricular rate and warfarin is given daily

Front 67

Results of AFFIRM study?

Back 67

1. overall mortality and incidence of disabling stroke, ischemic encephalopathy, cardiac arrest, and bleeding was the same in both groups

2. When compared to rate group, rhythm control group spent more time in hospital, exhibited more adverse drug effects, and experienced more episodes of torsade and bradycardic arrest

** use of drugs to convert AF to sinus rhythm and maintain sinus rhythm does not decrease incidence of stroke; rather, it increases the risk of potentially-fatal ventricular dysrhythmias and adverse drug effects

Front 68

Thus if chronic A.fib, control _______ by...?

Back 68

RATE

NO HF
- verapamil
- B-blocker

Has HF
- digoxin (inc vagal tone)
- B-blocker

Front 69

Cardiac dysrhythmias graph

Back 69

See below