Antiarrhythmic Drugs and CHF Rx Flashcards
Bradycardiac drug
Ivabradine Blocks funny channels ➡️ inhibits SAN ➡️ decreases heart rate ➡️ decreases oxygen demand Uses: 1. Stable angina 2. Chronic CHF
Vaughan Williams classification of antiarrhythmic drugs
Classes: 1. Na+ channel blockers 2. β blockers 3. K+ channel blockers 4. Ca+2 channel blockers 5. Miscellaneous • Adenosine • MgSO4 • Atropine • Digoxin
Prophylaxis of SVT/PVST (Atrial arrhythmia)
AVN blockers used in order of decreasing preference:
- β blockers
- Verapamil: Ca+2 channel blocker
- Digoxin: parasympathomimetic effect
Treatment of acute attack of SVT/PVST
Short acting AVN blocker
DoC is IV adenosine
If not effective then AVN inhibiting agents like IV esmolol.
Edrophonium can also be used as it has parasympathomimetic effect on AVN ➡️ AVN inhibition
Treatment of acute attack of atrial fibrillation/ flutter
ToC: cardioversion
If not:
DoC IV Ibutelide followed by repeat cardioversion
Long term treatment of atrial fibrillation/ flutter
1. Rate control: To maintain ventricular rates <100 Inhibit AVN, DoC is β blockers 2. Rhythm control: Atrial myocytes are made refractory • Na+ channel blockers to block depolarisation • K+ channel blockers to block repolarisation , preferred DoC Amiodarone
Class I of antiarrhythmic drugs and their basic properties
Blocks Na+ channels 1. Ia 1-10 sec In open state Significant K+ channel blocker 2. Ib <1 sec In closed state K+ channel opener 3. Ic >10 sec In open state Negligible K+ channel blocker
Properties of subclass Ia of class-I of antiarrhythmic drugs
- Delay in depolarisation less than Ic
- Maximum delay of repolarisation
- QT prolongation ➡️ risk of Torsades de pointes
- Increase refractoriness of both normal cells and accessory pathway
- Anticholinergic effect ➡️ increases AVN condition instead ➡️ PR shortening
Properties of subclass Ib of class I of antiarrhythmic drugs
- Negligible delay in depolarisation
- Early opening of K+ channels ➡️ early repolarisation
- QT shortening
- No effect on AVN ➡️ no effect on PR interval
Properties of subclass Ic of class I of antiarrhythmic drugs
- Maximal delay in depolarisation
- Negligible effect in repolarisation
- No effect on QT interval
- Increase refractoriness in both normal cells and accessory pathway
- AVN inhibition ➡️ PR prolongation
Examples of Ic subclass of Class I antiarrhythmic drugs
- Flecainide
- Encainide
- Propafenone
- Moracizine
Uses of subclass Ic of Class I antiarrhythmic drugs
Most arrythmogenic. So used in:
- Refractory/ life threatening arrhythmias in SVT/PVST, ventricular tachycardia/ fibrillation
- Flecainide is also used in diagnosis of Brugada syndrome
Flecainide
Preferred Ic subclass antiarrhythmic drugs for general uses
Also used for diagnosis of Brugada syndrome
S/E:
1. Worsen CHF
2. Blurring vision
DoC for WPW syndrome
Propafenone and moracizine
Both are Ic subclass of antiarrhythmic drugs
Propafenone:
Inhibits both Na+ and Ca+2 channels
Weak β blocker
Moracizine: not used because of low efficacy
Uses of Ia subclass of antiarrhythmic drugs
Increase AVN so convert atrial arrhythmias into VT/ VF
So when used in SVT/ PVST, it is given with AVN blockers (β blockers, verapamil, digoxin)
Side effect:WT prolongation
Examples of Ia antiarrhythmic drugs
- Quinidine
- Procainamide
- Disopyramine
- Ajmaline: diagnosis of Brugada syndrome
Quinidine
- Ia subclass of antiarrhythmic
- Anti malarial
- Antipyretic
S/E: - Diarrhoea M/C
- Cinchonism (tinnitus, vertigo)
- α blocker ➡️ hypotension
- QT prolongation at normal doses
- Ventricular tachycardia (high doses)
Procainamide
Ia subclass of antiarrhythmic S/E: 1. Ganglion blocker ➡️ hypotension 2. SLE DoC for atrial fibrillation associated with WPW syndrome
Disopyramide
Ia subclass of antiarrhythmics Maximum anticholinergic effect S/E: 1. Mydriasis 2. Dry mouth 3. Urine retention CI: 1. Glaucoma 2. BPH 3. CHF
Uses of antiarrhythmics based on effects on accessory pathway
Wolff-Parkinson-White syndrome treatment ToC: radiofrequency ablation, if not DoC: oral flecainide Associated atrial fibrillation: DoC IV procainamide
Ib subclass of antiarrhythmics are not useful in atrial arrhythmia because
In atria the Na+ channels are closed (depolarised state) for a shorter time compared to ventricles
Drugs belonging to Ib subclass of antiarrhythmics
- Lidocaine
- Mexiletine
- Phenytoin
- Tocainide- clinically not used
Lidocaine
Ib subclass of antiarrhythmics
High 1st pass metabolism (oral)
For systemic uses- given IV
High volume of distribution ➡️ loading dose required
Uses:
DoC for induced VT/VF associated with MI and digitalis toxicity (Ca+2 accumulation)
Side effects of lidocaine
•Neurological 1. Paresthesia 2. Tremor 3. Nystagmus- earliest sign of toxicity 4. Delirium 5. Seizures (Phenytoin is CI here) Treatment is instead benzodiazepines •Malignant hyperthermia
Mexiletine
Ib subclass of antiarrhythmics Oral derivative of lidocaine Uses: 1. Ventricular tachycardia 2. Neuropathic pain (stopping action potentials) 3. Myotonia
Phenytoin
Ib subclass of antiarrhythmics Used for treatment of digoxin indices VT
Uses of class II anti-arrhythmic drugs
β blockers Inhibit both AVN and SAN DoC for: 1. Idiopathic ventricular tachycardia 2. Ventricular premature beats 3. Congenital long QT syndrome (long term treatment) 4. Rate control: atrial fibrillation/ flutter 5. Catecholamine induced arrhythmia 6. Acute attack of SVT/PVST
DoC for rate control of atrial fibrillation/ flutter
β blockers
For stable patients: metaprolol
For unstable patients: esmolol shortest acting
Causes of catecholamine induced arrhythmia
- Pheochromocytoma
- Exercise
- Emotional
- Anaesthetic agents (halothane, cyclopropane)
QT prolongation is caused by
Delay in repolarisation is seen in
Classes Ia and III of antiarrhythmics
Class III antiarrhythmic drugs
K+ channel blockers Delay in repolarisation Increase QT interval Causes torsades de pointes Maximum: Ibutilide Minimum: Amiodarone QT prolongation is not seen in Vernakant
Examples of Class III antiarrhythmics
S. Sotalol B. Bretylium D. Dofetilide I. Ibutilide V. Vernakant A. Amiodarone
Amiodarone
Widest spectrum antiarrhythmic drugs
Blocks: K, Na, Ca, α and β receptor channels
Least risk of QT prolongation among Class III
High volume of distribution ➡️ loading dose is given
Longest acting drug-53 days
Most toxic side effects due to iodine present in it
Uses of Amiodarone
DoC in:
- VT / VF except those caused by MI or digoxin toxicity (where lidocaine is used
- Rhythm control in Atrial fibrillation/ flutter (rate control-β blockers)
Vernakant
Multi ion channel blocker of K, Na, Ca channel
No QT prolongation since it hardly affects the ventricles
Uses: Rx of atrial fibrillation
S/E: cardiogenic shock
Ibutilide
Shortest acting K+ blocker
Given IV
Use: Rx of acute attack of atrial fibrillation/flutter
Bretylium
K+ channel blocker- class III antiarrhythmic
Use: Rx of ventricular fibrillation
Known as medical defibrillator
S/E: hypotension (DoC: Norepinephrine)
Sotalol
K+ channel blocker Use: Rx of 1. Atrial fibrillation/ flutter 2. Ventricular tachycardia 3. Ventricular fibrillation
Dofetilide
K+ channel blocker
Uses of both Ibutelide and Amiodarone
Oral bioavailability: 100%
Dronedarone
Uses
Amiodarone-iodine = dronedarone Less toxic but less efficacious Do not preferred Uses: 1. Similar to Amiodarone 2. As a substitute to Amiodarone intolerance
Dronedarone properties
Amiodarone-iodine = dronedarone CI: 1. Pregnancy (category X drug) 2. Lactation 3. CHF t1/2: 12 hours Food increases absorption so it is given along with food
Side effects of amiodarone
Potassium. Pulmonary fibrosis Channel. Corneal deposits Blocker. Blue/ grey skin / ceruloderma Makes. Myocarditis Liver. Liver granulomas And. α-1 blockade ➡️ hypotension Skin. Photosensitivity Toxic. To thyroid
Pulmonary fibrosis seen due to amiodarone
Type II pneumocyte damage
DoC: prednisolone
Whorl like pattern of corneal deposits or
Vortex keratopathy or
Cornea vertecellata is seen in
1. Fabry’s disease Drugs like: 2. Amiodarone (M/C) 3. Chloroquine 4. Chlorpromazine 5. Indomethacin (least common)
Amiodarone and thyroid
In most areas (euthyroid):
Hypothyroidism since excess iodine is inhibitory
In iodine deficiency zones:
Hyperthyroidism since iodine is available
Non DHP calcium channel blockers as antiarrhythmics
Cause mild vasodilation ➡️ reflex tachycardia
Delay in recovery of CC from block ➡️ SAN andAVN inhibition ➡️ decreases HR
• Near normal heart rate
• Inhibition of AVN
Uses:
1. SVT / PVST
2. Stable angina as monotherapy
DHP calcium channel blockers as antiarrhythmics
Vasodilation ➡️ significant reflex tachycardia
So never used in arrhythmias
Use: stable angina along with β blockers
Adenosine as an Class V antiarrhythmic drug
Mechanism of action
Adenosine stimulates: 1. A1 receptor: Gi • Inhibits AVN • Bronchoconstriction 2. A2 receptor: Gs Vasodilation
Adenosine as Class V antiarrhythmic
Pharmacokinetics
Adenosine
Rapid IV infusion
Rapidly taken up by cellular adenosine uptake protein ➡️ t1/2: 1-5 sec ➡️ shortest acting antiarrhythmic
Uses of adenosine as a class V antiarrhythmic
Adenosine
- DoC: acute attack of SVT/ PVST
- To control hypotension in surgeries
- Diagnosis of coronary artery disease
Side effects of adenosine
- Flushing (vasodilation)
- Dyspnea (bronchoconstriction)
Above 2 are M/C - Drug interactions with theophylline and dipyridamole
Contraindications of adenosine
- Bronchial asthma
- COPD
In cases of acute attack of SVT/ PVST with asthma/ COPD, DoC is IV verapamil (β blockers also can’t be used) - In patients with transplanted heart ➡️ denervation hypersensitivity
Drug interactions of adenosine
- Theophylline (bronchodilator)
PDE inhibitor and adenosine receptor antagonism ➡️ adenosine failure - Dipyridamole:
Inhibits cellular adenosine uptake protein ➡️ adenosine toxicity ➡️ opening of K+ channels in atrium ➡️ action potential graph shortens ➡️ atrial fibrillation
MgSO4 as class V antiarrhythmic
Blocks Ca2+ channels ➡️ early opening of K+ channels ➡️ shortening of QT
Use: treatment of long QT syndrome for acute attacks ➡️ torsades (both congenital and acquired)
Long term treatment of QT syndrome
1. Congenital: ToC: pacing using ICD (implantable cardioverter defibrillator), if not DoC: β blocker 2. Acquired: Avoid drugs causing QT prolongation
Atropine as class V antiarrhythmic
Stimulates both SAN (increases HR) and AVN (increases conduction)
Uses:
1. Treatment of bradyarrhythmia like:
• sinus arrest
• sinus bradycardia
• inferior wall MI
2. AVN block reversal like digoxin toxicity.
Digoxin as class V antiarrhythmic
Parasympathomimetic effect Blocks AVN Slow onset of action so not used on acute cases Uses: Long term Rx of SVT/ PVST (chronic CHF)
Most common pathophysiology of acute CHF
MI ➡️
acute insult to myocardium ➡️
decreased contraction ➡️
stasis of blood on left ventricle and atrium ➡️
contraction of blood in pulmonary veins ➡️
fluid leaks into interstitial ➡️
pulmonary oedema
Treatment of acute CHF
- Pulmonary oedema of treated 1st:
• DoC: Furosemide
+ morphine (decrease afterload and preload)
• If not responding: IV NTG
• If not responding: BNP analogues - Then for decreased contractions:
+ve inotropes are given
• Dobutamine (except in CHF with oliguria- dopamine)
• If not responding: phosphodiesterase-3 inhibitors
Recent drugs for pulmonary oedema
- Cinaciguat:
Activates guanylate cyclase ➡️ increases cGMP ➡️ vasodilation - Serelaxin:
Relaxin analogue ➡️ vasodilation
Recent drugs for decreased cardiac contraction for acute CHF
- Omecamtiv mecarbil:
Selective myosin stimulator which does not increase O2 demand - Istaroxime:
Mechanism: Na+/K+ ATPase inhibitor and Ca+2 ATPase stimulator
Pathophysiology of decompensated CHF
Chronic CHF
➡️ gradual decrease in cardiac output
➡️ decreased O2 supply
➡️ body activated compensatory mechanism ➡️ fails
➡️ presentation and treatment same as acute CHF
Both of these together of called AHFS Acute Heart Failure Syndrome
Pathophysiology of (compensated) chronic CHF
Compensation succeeds ➡️ increased catecholamines ➡️: 1. Heart: contraction and HR increases 2. Blood vessel: vasoconstriction 3. Liver: stimulates renin: RAAS vasoconstriction, Na+/ H2O retention ➡️ cardiac remodeling (myocardial cells increase in size) ➡️ increased O2 demand (proportional to decrease in O2 supply) ➡️ mortality
Treatment of (compensated) chronic CHF SHIBA
To decrease mortality, block cardiac remodeling by blocking catecholamine actions
1. Heart:
β blockers decrease contraction
Ivabradine decreases HR
2. Blood vessels: isosorbide dinitrate + hydralazine for vasodilation
3. RAAS: ACEi/ARB, spironolactone decreases Na+/H2O retention
If symptomatic, digoxin (does not decrease mortality)
Mechanism of natriuretic peptides
Increase in blood volume ➡️ increase stretch in renal blood vessel, atrium, ventricles ➡️ release of urodilatin, ANP and BNP respectively
Kidney: natriuresis and diuresis
Blood vessel: vasodilation
➡️ Increase blood flow to kidney, heart
Examples of natriuretic peptide analogues
Urodilatin: ularitide
ANP: carperitide
BNP: nesiritide (FDA approved)
Decrease blood flow to kidney, heart ➡️ decreases pulmonary oedema
Nesiritide
BNP analogue OV route Use: acute CHF (decreases pulmonary oedema) S/E: M/C hypotension Metabolised by neutral endopeptidase
Sacubitril
Blocks neutral endopeptidase (metabolises nesiritide) Use: chronic CHF Used along with Valsartan S/E: angioedema CI: with ACEi Within 36 hrs of use of ACEi
PDE-3 inhibitors
Blocks metabolism of cAMP in heart and blood vessels ➡️
Increased cardiac contraction and vasodilation ➡️ inodilators
Eg., inamrinone (not preferred because of thrombocytopenia), milrinone, enoximone, levosimendan
Milrinone, enoximone
PDE-3 inhibitors Use: 1. Resistant left sided heart failure 2. DoC for right heart failure 3. Patient of CHF in β blocker
Levosimendan
Mechanism: 1. PDE-3 inhibitor 2. Opens K+ channel ➡️ vasodilation 3. Sensitises myocardium to calcium ions Uses: In case of ineffectiveness of other drugs to acute CHF
Drug regimen followed in chronic CHF for primary set of drugs
1. ACEi/ARB: • started at low doses • doses increased weekly till max If well tolerated ➡️ 2. Switch to Sacubutril + Valsartan: 3. β blockers: • at midway of ACEi/ARB dose increase • started at low doses • doses increased every 2 weeks till max
Drug regimen when primary set of drugs against chronic CHF is not effective
4. Add spironolactone If not responding 5. Add Ivabradine If not responding 6. Add Isosorbide dinitrate + hydralazine If symptomatic add digoxin
Why ACEi/ ARB and β blockers are started at low doses in chronic CHF
ACEi/ARB are started at low doses to decrease the risk of postural hypotension in patients already having high renin levels
β blockers are started at low doses and increased gradually to prevent decompensation
Digoxin basic features
Sources: Digitalis lanata (white foxglove) • Good oral absorption • High distribution so high loading dose • t1/2 of 36-48 hrs Digitalisation: Steady level of digitalis takes 7-10 days • Renal elimination Mechanism: cellular and organ level
Extracellular mechanisms of digoxin action
Blocks Na+/K+ ATPase pump (reverse depolarisation) ➡️ decrease in:
1. Na+ efflux ➡️ increased intracellular Na+
2. K+ influx ➡️ increased extracellular K+ ➡️ hyperkalemia
Hyperkalemia inhibits digoxin (K+ binds to Na+/K+ ATPase)
Why are patients on diuretics not preferred digoxin
For these patients, there is hypokalemia ➡️
inhibition of digoxin by K+ is reduced ➡️
Digoxin toxicity
Intracellular mechanism of digoxin
Increased intracellular Na+ blocks Na+/Ca2+ exchanger pump ➡️ Ca2+ efflux reduced ➡️ Intracellular Ca increases ➡️ Increased contraction ➡️ extra depolarisation called DAD Delayed After Depolarisation ➡️ Further increase in Ca2+ ➡️ extra systole
