Lesson 12.4. Class III Anti-Arrythmitic Drugs

APD prolongation

CLASS III

1. Hallmark effect: _______________________

2. Caused mainly by blockade of ______ (rapidly activating delayed rectifier potassium current) channel, which is responsible for AP repolarization

3. This increases _________________________

4. It also reduces the ability of the heart to respond to ____________

5. Action is observed in the ECG, mainly as an increase in ____________

1 = ?

IKR

CLASS III

1. Hallmark effect: _______________________

2. Caused mainly by blockade of ______ (rapidly activating delayed rectifier potassium current) channel, which is responsible for AP repolarization

3. This increases _________________________

4. It also reduces the ability of the heart to respond to ____________

5. Action is observed in the ECG, mainly as an increase in ____________

2 = ?

ERP (effective refractory period)

CLASS III

1. Hallmark effect: _______________________

2. Caused mainly by blockade of ______ (rapidly activating delayed rectifier potassium current) channel, which is responsible for AP repolarization

3. This increases _________________________

4. It also reduces the ability of the heart to respond to ____________

5. Action is observed in the ECG, mainly as an increase in ____________

3 = ?

rapid tachycardias

CLASS III

1. Hallmark effect: _______________________

2. Caused mainly by blockade of ______ (rapidly activating delayed rectifier potassium current) channel, which is responsible for AP repolarization

3. This increases _________________________

4. It also reduces the ability of the heart to respond to ____________

5. Action is observed in the ECG, mainly as an increase in ____________

4 = ?

QT interval

CLASS III

1. Hallmark effect: _______________________

2. Caused mainly by blockade of ______ (rapidly activating delayed rectifier potassium current) channel, which is responsible for AP repolarization

3. This increases _________________________

4. It also reduces the ability of the heart to respond to ____________

5. Action is observed in the ECG, mainly as an increase in ____________

5 = ?

potassium channels or potassium efflux

CLASS III

1. During that time (prolonged ERP), they block __________________________ so that it is not immediately released or is slowly released from the cell.

2. It takes longer for cardiac cells to ____________.

3. It also takes a long time before we conduct __________________ again.

1 = ?

repolarize

CLASS III

1. During that time (prolonged ERP), they block __________________________ so that it is not immediately released or is slowly released from the cell.

2. It takes longer for cardiac cells to ____________.

3. It also takes a long time before we conduct __________________ again.

2 = ?

cardiac muscle activity

CLASS III

1. During that time (prolonged ERP), they block __________________________ so that it is not immediately released or is slowly released from the cell.

2. It takes longer for cardiac cells to ____________.

3. It also takes a long time before we conduct __________________ again.

3 = ?

APD and QT interval

CLASS III

Amiodarone — Cardiac Effect

1. Significant uniformly prolonged _______________ prolongation by blocking IKR and IKS (chronic use)

2. No __________________ action

3. Has a ________________ of activity

4. Low incidence of _____________

5. It also blocks inactivated ____________________

6. Has a weak ____________________________ blocking action

1 = ?

reverse-use dependent

CLASS III

Amiodarone — Cardiac Effect

1. Significant uniformly prolonged _______________ prolongation by blocking IKR and IKS (chronic use)

2. No __________________ action

3. Has a ________________ of activity

4. Low incidence of _____________

5. It also blocks inactivated ____________________

6. Has a weak ____________________________ blocking action

2 = ?

broad spectrum

CLASS III

Amiodarone — Cardiac Effect

1. Significant uniformly prolonged _______________ prolongation by blocking IKR and IKS (chronic use)

2. No __________________ action

3. Has a ________________ of activity

4. Low incidence of _____________

5. It also blocks inactivated ____________________

6. Has a weak ____________________________ blocking action

3 = ?

Torsades de Pointes

CLASS III

Amiodarone — Cardiac Effect

1. Significant uniformly prolonged _______________ prolongation by blocking IKR and IKS (chronic use)

2. No __________________ action

3. Has a ________________ of activity

4. Low incidence of _____________

5. It also blocks inactivated ____________________

6. Has a weak ____________________________ blocking action

4 = ?

Na-channel

CLASS III

Amiodarone — Cardiac Effect

1. Significant uniformly prolonged _______________ prolongation by blocking IKR and IKS (chronic use)

2. No __________________ action

3. Has a ________________ of activity

4. Low incidence of _____________

5. It also blocks inactivated ____________________

6. Has a weak ____________________________ blocking action

5 = ?

adrenergic and Ca-channel

CLASS III

Amiodarone — Cardiac Effect

1. Significant uniformly prolonged _______________ prolongation by blocking IKR and IKS (chronic use)

2. No __________________ action

3. Has a ________________ of activity

4. Low incidence of _____________

5. It also blocks inactivated ____________________

6. Has a weak ____________________________ blocking action

6 = ?

Peripheral vasodilation

CLASS III

Amiodarone — Extra-Cardiac Effect

• good for patients with hypertension

bradycardia

CLASS III

Amiodarone — Toxicity

1. Symptomatic ____________

2. _____________________________________ in sun-exposed areas (due to accumulation in many tissues)

3. Most important ADRs: ________________________________

4. Abnormal liver function tests / ________________

5. optic neuritis may progress to blindness

6. blocks peripheral conversion of T4 to T3

1 = ?

Photodermatitis / Gray-Blue skin discoloration

CLASS III

Amiodarone — Toxicity

1. Symptomatic ____________

2. _____________________________________ in sun-exposed areas (due to accumulation in many tissues)

3. Most important ADRs: ________________________________

4. Abnormal liver function tests / ________________

5. optic neuritis may progress to blindness

6. blocks peripheral conversion of T4 to T3

2 = ?

dose-dependent pulmonary toxicity (fatal pulmonary fibrosis

CLASS III

Amiodarone — Toxicity

1. Symptomatic ____________

2. _____________________________________ in sun-exposed areas (due to accumulation in many tissues)

3. Most important ADRs: ________________________________

4. Abnormal liver function tests / ________________

5. optic neuritis may progress to blindness

6. blocks peripheral conversion of T4 to T3

3 = ?

hypersensitivity hepatitis

CLASS III

Amiodarone — Toxicity

1. Symptomatic ____________

2. _____________________________________ in sun-exposed areas (due to accumulation in many tissues)

3. Most important ADRs: ________________________________

4. Abnormal liver function tests / ________________

5. optic neuritis may progress to blindness

6. blocks peripheral conversion of T4 to T3

4 = ?

Asymptomatic corneal microdeposits

CLASS III

Amiodarone — Toxicity

1. Symptomatic ____________

2. _____________________________________ in sun-exposed areas (due to accumulation in many tissues)

3. Most important ADRs: ________________________________

4. Abnormal liver function tests / ________________

5. optic neuritis may progress to blindness

6. blocks peripheral conversion of T4 to T3

5 = ?

Hypo/Hyperthyroidism

CLASS III

Amiodarone — Toxicity

1. Symptomatic ____________

2. _____________________________________ in sun-exposed areas (due to accumulation in many tissues)

3. Most important ADRs: ________________________________

4. Abnormal liver function tests / ________________

5. optic neuritis may progress to blindness

6. blocks peripheral conversion of T4 to T3

6 = ?

IV loading

CLASS III

Amiodarone — PK and Dosage

1. __________ is useful to get pharmacologic results

2. Amiodarone metabolism is affected by enzyme inducers/inhibitors. It may inhibit _______________ for other drugs

3. It has an active metabolite: __________________.

4. T1/2 is complex with _________________________.

1 = ?

CYP450

CLASS III

Amiodarone — PK and Dosage

1. __________ is useful to get pharmacologic results

2. Amiodarone metabolism is affected by enzyme inducers/inhibitors. It may inhibit _______________ for other drugs

3. It has an active metabolite: __________________.

4. T1/2 is complex with _________________________.

2 = ?

desethylamiodarone

CLASS III

Amiodarone — PK and Dosage

1. __________ is useful to get pharmacologic results

2. Amiodarone metabolism is affected by enzyme inducers/inhibitors. It may inhibit _______________ for other drugs

3. It has an active metabolite: __________________.

4. T1/2 is complex with _________________________.

3 = ?

rapid and slow components

CLASS III

Amiodarone — PK and Dosage

1. __________ is useful to get pharmacologic results

2. Amiodarone metabolism is affected by enzyme inducers/inhibitors. It may inhibit _______________ for other drugs

3. It has an active metabolite: __________________.

4. T1/2 is complex with _________________________.

4 = ?

recurrent ventricular tachycardia

CLASS III

Amiodarone — Therapeutic Use

1. Prevention of __________________________

2. Adjuvant therapy to decrease uncomfortable _________________________ in ventricular tachycardia

3. Maintenance of ___________ in patients with atrial fibrillation

1 = ?

cardioverter defibrillator discharges

CLASS III

Amiodarone — Therapeutic Use

1. Prevention of __________________________

2. Adjuvant therapy to decrease uncomfortable _________________________ in ventricular tachycardia

3. Maintenance of ___________ in patients with atrial fibrillation

2 = ?

sinus rhythm

CLASS III

Amiodarone — Therapeutic Use

1. Prevention of __________________________

2. Adjuvant therapy to decrease uncomfortable _________________________ in ventricular tachycardia

3. Maintenance of ___________ in patients with atrial fibrillation

3 = ?

Structural analog

CLASS III

Dronedarone

• a.___________________ to Amiodarone where the b.__________ atoms are removed – no c.______________________________.

a = ?

iodine

CLASS III

Dronedarone

• a.___________________ to Amiodarone where the b.__________ atoms are removed – no c.______________________________.

b = ?

thyroid dysfunction or pulmonary toxicity

CLASS III

Dronedarone

• a.___________________ to Amiodarone where the b.__________ atoms are removed – no c.______________________________.

c = ?

multi-channel (IKR, IKS, ICa, INa) and 𝛽-blocking

CLASS III

Dronedarone

• Has ___________________________________________ action

creatine

CLASS III

Dronedarone

• Inhibit tubular secretion of a._________________ (increase levels); affected by co-administration of b._______________ (inhibits drug metabolism

a = ?

CYP3A4 inhibitors

CLASS III

Dronedarone

• Inhibit tubular secretion of a._________________ (increase levels); affected by co-administration of b._______________ (inhibits drug metabolism

b = ?

AF (Atrial Fibrillation)

CLASS III

Dronedarone

1. Restores sinus rhythm in patients with ____________________

2. ________________ for patients with Class IV heart failure

1 = ?

“Black-box” warning

CLASS III

Dronedarone

1. Restores sinus rhythm in patients with ____________________

2. ________________ for patients with Class IV heart failure

2 = ?

Sotalol

CLASS III

• Non-selective 𝛽-blocker with AP prolonging action

life-threatening ventricular arrhythmias

CLASS III

Sotalol Uses

1. For ______________________________

2. maintain ________________ in patients with atrial fibrillation

3. for ______________________________ in pediatric patients

1 = ?

sinus rhythm

CLASS III

Sotalol Uses

1. For ______________________________

2. maintain ________________ in patients with atrial fibrillation

3. for ______________________________ in pediatric patients

2 = ?

supraventricular or ventricular arrhythmias

CLASS III

Sotalol Uses

1. For ______________________________

2. maintain ________________ in patients with atrial fibrillation

3. for ______________________________ in pediatric patients

3 = ?

Torsades de Pointes

CLASS III

Sotalol ADRs

1. Dose-related incidence of _________________

2. In patients with HF: further ___________________________

1 = ?

depression of left ventricular function

CLASS III

Sotalol ADRs

1. Dose-related incidence of _________________

2. In patients with HF: further ___________________________

2 = ?

Dofeltilide

CLASS III

• Can prolong AP by a dose-dependent blockade of IKR which further increase during hypokalemic states

bioavailability

CLASS III

Dofetilide

• 100% a.______________________

• mostly eliminated b._________________

• Verapamil can increase c.______________ → increase d.________________________________

• Increases e.___________ with inhibitors of renal cation secretion

a = ?

unchanged renally

CLASS III

Dofetilide

• 100% a.______________________

• mostly eliminated b._________________

• Verapamil can increase c.______________ → increase d.________________________________

• Increases e.___________ with inhibitors of renal cation secretion

b = ?

plasma concentration

CLASS III

Dofetilide

• 100% a.______________________

• mostly eliminated b._________________

• Verapamil can increase c.______________ → increase d.________________________________

• Increases e.___________ with inhibitors of renal cation secretion

c = ?

QT prolonging effects and risk of ventricular proarrhythmia

CLASS III

Dofetilide

• 100% a.______________________

• mostly eliminated b._________________

• Verapamil can increase c.______________ → increase d.________________________________

• Increases e.___________ with inhibitors of renal cation secretion

d = ?

half-life

CLASS III

Dofetilide

• 100% a.______________________

• mostly eliminated b._________________

• Verapamil can increase c.______________ → increase d.________________________________

• Increases e.___________ with inhibitors of renal cation secretion

e = ?

normal sinus rhythm

CLASS III

Dofetilide

• Used to maintain _________________ in patients with AF

Ibutilide

CLASS III

• Slows cardiac repolarization by blocking IKR and activation of INa → AP prolongation

IV

CLASS III

Ibutilide

• administered as an _____ because it is rapidly cleared by hepatic metabolism and excreted by the kidneys

atrial flutter and atrial fibrillation

CLASS III

Ibutilide

• For the acute conversion of ________________________ to normal sinus rhythm

Torsades de Pointes

CLASS III

Ibutilide — ADRs

• Excessive QT prolongation → __________________