Class Ia Anti-arrhythmics

Prolong action potential duration by modest blockage of sodium channels to slow conduction velocity (prolong phase 0)

Procainamide

Class Ia anti-arrhythmic that has modest Na channel blocking capabilities. Effective in atrial/ventricular arrhythmias and drug of choice for atrial fib, emergency V tach/fib.  Metabolized to N-acetylprocainamide which is a Class III anti-arrhythmic, but can drastically prolong QT interval (esp in fast acetylators)

Can cause hypotension, agranulocytosis, and drug induced lupus (esp in slow acetylators), with AE resolving relatively rapidly after discontinuation.  Cimetidine and TMP both decrease renal clearance and therefore increase circulating levels.  EtOH increases hepatic clearance

Quinidine

Class Ia anti-arrhythmic that also has anti-cholinergic effects that can augment conduction at the AV node (should co-administer with a beta blocker). Can be used in atrial fib and flutter, paroxysmal supraventricular tachycardia

AE are alpha adrenergic blocking activity inducing hypotension.  Metabolized by the liver.  Diarrhea common and there can also be QT elongation (which can induce toursade de pointes).  Leads to increased circulating digoxin levels if co-administered

Disopyramide

Class Ia anti-arrhythmic similar in effects to quinidine, with many fewer of the GI side effects and does not increase circulating levels of digoxin. Administered orally and is excreted via the kidney

AE include very strong anti-cholinergic effects resulting in dry mouth, exacerbation of glaucoma, urinary retention, and must be used with caution in patients with LV systolic dysfunction

Used in A fib/flutter as long as the heart is normal

Class Ib Anti-arrhythmics

Inhibit fast sodium channels but typically shorten the action potential and refractory period due to blockage of sodium channels involved in phase 2. 

Tend to be effective in re-entrant arrhythmias by slowing conduction velocity, but the most common use is in ventricular arrhythmias (INEFFECTIVE IN ATRIAL ARRHYTHMIAS).  No QT prolongation

Lidocaine

Class Ib anti-arrhythmic agent that is useful for treatment of exclusively ventricular arrhythmias.  Do not use for treatment of atrial arrhythmias!! Tends to decrease myocardial refractory period, suppress automaticity and suppress EADs and DADs. Most effective in premature ventricular depolarizations.  Negative inotrope, so it should be avoided in pts with CHF

AE include CNS side effects (slurred speech, dizziness, seizures), but it is rarely pro-arrhythmic.  Propanolol, metoprolol and cimetidine dec metabolism by dec hepatic blood flow. 

Class Ic anti-arrhythmics

Most potent sodium channel blockers with mild prolongation or no effect on action potential duration, but prolongation of refractory period within AV node.  Shown to be effective in treatment of supraventricular, but not ventricular arrhythmias

Can commonly precipitate heart failure in patients with LV dysfunction (including CAD) because they block beta receptors and Ca channels as well.  Common pro-arrhythmic agents

Propafenone

Class Ic anti-arrhythmic that acts as a potent blocker of sodium channels.  It also has negative inotropic effects due to beta and Ca channel blocking, and can therefore blunt heart rate during exercise.  See a widened QRS on ECG.  Used primarily in AVNRT, Atrial Fib and flutter, only in normal hearts.

AE include hypotension, parasthesias, constipation, nausea, and significant risk of pro-arrhythmia in pts with underlying heart disease, though this drug has less risk than other Ic's. 

Flecainide

Class Ic anti-arrhythmic that is well absorbed orally and excreted in the urine. Used only in AVNRT, Atrial fib and flutter, never used for ventricular arrhythmias or with heart defects.

AE common and include worsening of ventricular arrhythmias especially in pts with LV dysfunction.  Negative inotrope, so hypotension with dizziness, confusion very common

Class II Anti-arrhythmics

Beta blockers that exert anti-inotropic effects on the heart by blocking sympathetic activity.  Reduce automaticity and conduction velocity and are commonly used in EADs and DADs.  They also decrease oxygen demand which can relieve ischemia.  Effective in tachyarrhythmias, atrial flutter and fib (protect ventricle), ventricular premature beats, and do not prolong QT interval

Mainstay of treatment for reentry loops and automaticity

Propanalol

Prototypic non-selective beta blocker, highly lipophilic and well absorbed with PO.  No ISA. Undergoes extensive first-pass metabolism so high doses required, and highly protein bound, so drug interactions common

Commonly used in CHF, migraines and stage fright.  Also effective as anti-arrhythmic against atrial arrhythmias, tachyarrhytmias, and any arrhythmias mediated by sympathetic stimulation.  Most common treatment of AVNRT, not used in ventric arrhytmias

Class III Anti-arrhythmics

Function by prolonging action potential duration and the refractory period by blocking potassium channels (delayed repolarization). Uses vary by drug

Can VERY commonly prolong QT interval to induce EAD and toursades de pointes arrhythmias

Amiodarone

Broad spectrum class III anti-arrhythmic effective at maintaining normal sinus rhythm with atrial tachyarrhymias, and effective in AVNRT.  Very effective in long-term preventiion of V-tach and V-fib and most effective anti-arrhythmic in those with CHF

AE include GI upset including severe reflux, and chronic interstitial fibrosis of the lungs, ocular complications including corneal deposits and blindness, hypothyroidism due to decreased conversion of T4 to T3, and photosensitivity with discoloration of skin

Drug interactions of

Amiodarone

Digoxin - Serum concentration increases as much as 100 percent due to decrease in digoxin clearance --> Digoxin toxicity with increased cardiac inotropy and potential for induced arrhythmia

Warfarin - Drug potentiates warfarin anti-coagulant effects by decreasing metabolism and lead to bleeding/hemorrhage

Also increases levels of quinidine, procainamide, phenytoin, flecainide, beta blockers and Ca channel blockers

Sotalol

Can function as both a Class II (weak) and Class III anti-arrhythmic, and acts as a negative inotrope (can be contraindicated in pts with LV dysfunction).  Effective in treatment of ventricular tachycardia and atrial fib (long-term prevention, not in emergency).  Can also prevent recurrences of SVTs. 

AE include bradycardia, bronchoconstriction, prolonged QT interval (with Torsades)

Ibutilide

Class III anti-arrhythmic that is useful in atrial fib or flutter, and functions by blocking K channels with better effects at high heart rates (QT interval elongation not as pronounced). IV version of Sotalol effective for rapid dosing and treatment of A fib and flutter

Very commonly can cause QT prolongation with Torsades development.  Usually occurs soon after dosing

Class IV anti-arrhythmics

(include 2 examples)

L-type calcium channel blockers that primarily affect the SA and AV nodes since these depend on Ca for generation of the action potential.  They effectively elevate the threshold potential and will slow heart rate, slow transmission at AV node, and stop reentrant rhythms traveling through the AV node. Include verapamil, diltiazem

Effective against paroxysmal supraventricular tachycardia, though largely replaced by adenosine now.  Can be commonly used in patients with A Fib or flutter.  Can cause hypotension.  No use in Ventricular arrhythmias

Excessive bradycardia if coadministered with beta blockers, few vasodilating effects

Adenosine

Anti-arrhythmic that is administered IV and is effective by binding to and opening K channels and hyperpolarizing the membrane (suppresses spontaneous depolarization of SA and AV node).  This effectively slows SA firing and AV conduction.  Ventricular myocytes are not affected because the specific K channels are not present. Very effective against supraventricular arrhythmias

Short half life gives it transient side effects of headache, chest pain, flushing.  Effects lengthened by dipyridamole

Digoxin

Enhances central and peripheral vagal tone and function to slow sinus node discharge and prolong AV refractoriness.  Also inhibits sodium-potassium ATPase which leads to a functional increase in intracellular Ca.  This results in positive inotropic effects (inc contractility) and negative chronotropic effects (decreased conduction).  It is therefore very effective in arrhythmias

AE are common because therapeutic index is narrow and include AV block, severe bradycardia, induced arrhythmias, delirium, dizziness, headaches, diarrhea, loss of appetite, gynecomastia

Atropine

Anti-cholinergic used for treatment of sinus bradycardia

Dihydropyridines

Calcium channel blockers that primarily act on Ca channels in the vasculature.  Produce pronounced dilation of arterioles and coronary vessels which results in sympathetic reflex activity and reflex tachycardia and inc FOC. Useful in patients with vasospasm/Prinzmetal angina

AE include excessive vasodilation with hypotension, headache and peripheral edema

Aspirin

Non-selectively inhibits COX 1 and 2, effectively reducing production of TXA2 and decreasing platelet aggregation and vasoconstriction

Very commonly used post-MI, can predispose to ulcer, but extended release can prevent this.

Clopidogrel

Inhibits ADP-mediated activation of platelets and blocks 2b/3a complex activation to effectively prevent platelet activation and aggregation.  Very commonly administered with ASA and is effective at preventing both arterial and venous thrombosis

Takes a few days to have full inhibitory effects

Abciximab

GP IIb/IIIa inhibitor that effectively prevents platelet aggregation, but still allow initial platelet binding, so there is slightly less risk of bleeding.  Very commonly used during an acute, non-ST elevation MI (as adjunct to fibrinolytics) and after stent placement.

AE include intracranial hemorrhage

Heparin (unfractionated)

Binds to and increases the activity of anti-thrombin III which promotes the degradation of thrombin, and factors IXa, Xa, XIa, XIIa and kallikrein.  Also interferes with platelet aggregation.  Must be given IV.  Bleeding is a risk

Overdose can be treated with Protamine

Low Molecular

Weight Heparin

Warfarin

Vitamin K antagonist that inhibits synthesis of the Vitamin K-dependent coagulation factors.  Factors II, VII, IX, and X, as well as proteins C and S.  This inhibits the coagulation cascade, but can lead to venous thrombosis (from protein C inhibition) with "purple toe syndrome"

Highly protein bound, so has many interactions with other protein bound factors including digoxin and amiodarone

tPA

Anti-thrombotic that functions by activating plasminogen (to plasmin), only if it is bound to fibrin already.  This makes it relatively selective to points where clots are already formed, rather than acting to prevent any future clot from forming.  Also tends to act more readily on newer clots which are more rich in fibrin (rather than platelets)

AE include bleeding, but it is very effective in reducing morbidity and mortality post-MI

Streptokinase

Binds to any plasminogen and activates it to plasmin by making it more accessible to cleavage by endogenous tPA.  Because it binds plasminogen without fibrin present, it produces a systemic fibrinolytic state. 

Can produce reperfusion dysrrhythmias, and allergic reactions common.  Bleeding a common complication

Furosemide

Potent loop diuretic that is effective for use in CHF in the presence of pulmonary edema.  Functions by inhibiting NaCl reabsorption in the thick ascending loop of Henle

AE include hypokalemia, which can induce arrhthmyias among other problems.  Hyperuricemia (and gout) are also potential AE

Spironolactone

Competitive agonist at aldosterone receptor, inhibiting fluid retention and functioning as a diuretic.  It prevents formation of a protein important in a Na/K exchanger, and therefore spares K, unlike furosemide.

Very effective in patients with CHF with pulmonary edema (or any edema).  Can cause gynecomastia

Enalapril

ACE inhibitor that functions by blocking inhibiting conversion of Ang I to and Ang II.  Effective against pulmonary edema by preventing Na retention, promotes vasodilation, inhibits sympathetic outflow, prevents LV remodelling

AE include terrible cough, and hypotension

Cholestyramine

Lipid lowering agent that binds bile acids in the gut and prevens their reuptake.  Since a major component of bile acids is cholesterol, this results in increased excretion.  The liver responds by increasing cholesterol synthesis and LDL receptors. Commonly used in combination with a statin or nicotinic acid derivative, generally not a first line drug.

AE include diarrhea, constipation, and interference with absortion of digoxin, warfarin and beta blockers (space dosing).  It also causes a rise in serum triglycerides, which effectively depletes HDL, so it should be avoided in pts with already high circulating TG

Gemfibrozil

Fibric acid derivative that interferes with synthesis of VLDL to lower TGs (-8%) and LDL and raise HDL (8%).  Also increases lipoprotein lipase and LDL receptor activity. Used to treat mixed dyslipidemia

AE include gall stones (prevent with aspirin), myopathies and potentiation of warfarin.  Do not combine with statins as there is increased risk of rhabdomyolysis (breakdown of muscle fibers) and renal failure.  Better than fenofibrate in patients with kidney disease

Fenofibrate

Fibric acid derivative that interferes with synthesis of VLDL to lower TGs (-8%) and LDL and raise HDL (8%).  Also increases lipoprotein lipase and LDL receptor activity. Used to treat mixed dyslipidemia

AE include gall stones (prevent with aspirin), myopathies and potentiation of warfarin.  Do not combine with statins as there is increased risk of rhabdomyolysis (breakdown of muscle fibers) and renal failure.  Contraindicated in patients with any pre-existing kidney dysfunction. 

Nicotinic Acid Derivatives

(Niacin, Niospan)

Lipid lowering agents that function by inhibiting hepatic VLDL production, resulting in decreased VLDL-TGs and LDL (very effective lowering) as well as increased HDL. -cin is fast acting and -span is extended release.  Can be used in combination with cholestyramine

Rarely used because of many side effects, despite effectiveness.  AE include glucose intolerance (diabetics), gout, rash, flushing, itching, arrhythmias, and hepatic toxicity.  Used for short term treatment of severe dyslipidemia

Statins

(Mechanism of Action, Metabolism)

Lipid lowering agents that inhibit HMGCoA Reductase, essential in cholesterol synthesis.  Fesults in an upregulation of hepatic LDL receptors (to inc uptake) enhancing uptake of LDL, VLDL and TGs as well.  This effectively raises HDL.  Can be used in combination with cholestyramine or ezetemibe

Metabolized by Cytochrome P450 3A4 isoenzyme (except fluvastatin (2C9, also inhibits this) and pravastatin (not metabolized by P450)), so their concentrations are affected by drugs that alter P450 metabolism

Effectiveness of Statin Drugs

(6 drugs)

Andy Rautins Sure Loves Playing Forward

1. Atorvastatin

2.Rosuvastatin

3. Simvastatin

4. Lovastatin

5. Pravastatin

6. Fluvastatin

Side Effects of Statins

Most side effects are related to drugs that inhibit 3A4 activity, effectively raising drug concentration.  These include antibiotics, fluoxetine, protease inhibitors and grapefruit juice.  Fluvastatin has similar effects with drugs that affect 2C9 (warfarin, NSAIDs)

AE are relatively rare, making these very effective, but include myopathies and GI distress.  Rosuvastatin is especially associated with proteinuria due to inhibition of HMG CoA Reductase

Ezetemibe

Lipid lowering agent that selectively inhibits intestinal absorption of cholesterol by acting on the brush border.  It has only minor efficacy by itself but is extremely effective in combination with a statin, and does not influence P450. 

It is contraindicated in people with hepatic dysfunction