Antiarrhythmic drugs
-any depolarization which schould not appear is considered as arrhythmia ( dep. on the origin of an impulse and its propagation)
-atrial flutter: fast but regular
-atrial defibrillation: fast and unregular
* re-entry conduction: goes in inproper direction, making circles ( causing permanent excitement)-> atrial fibrillation as an example.
a) supraventricular arrythmias: atrial flutter, atrial fibrillation, tachycardia
b) ventricular arrythmias: ventricular extrasystoles
*AP are dependent mainly on sodium, calcium
#sodium channels: 3 states: active state, inactive state (closed and no possibility od being openeded) , resting state ( closed but opening is possible)
DRUGS SHOW THE HIGHEST AFFINITY TO THE ACTIVE AND INACTIVE CHANNEL STATES. AFFINITY TO RESTING CHANNELS IS VERY SMALL.
-inactive channels are present for ex.in hypoxic tissues ( no ATP produced-> no action of the pump); site where drugs are acting
-active channels are the site of action of drugs for ex. in case of ectopic pacemakers ( drugs inactivate this channels by blockade)
1) Group 1: sodium channel blockers
these drugs are not the first choice!! soemtimes used as second choice in ventricular arrythmias
a) 1a: prolong AP (slowing phase '0')
-porolog Q-T interval: torsade de pointes risk
-antimuscrainic effect: many side effects ( esp. disopyramide)
-metabolite NAPA accumulation (in case of prokainamide)-> torsade risk
*PROCAINAMIDE: use and state dep. block of INa channels, some block of IK channels also!!; used in atrial and ventricular arrythmias( second choice drug in most sustained ventricular arrythmiast associated with MI) , especially after MI; used orally (xr forms available) or parenterally, duration 2-3h; can cause arrythmias, hypotension, lupus-like syndrome; eliminated by hepatic metabolism as N-acetylprocainamide (NAPA)
*QUINIDINE (pol.chinidyna): similar to procainamide but more toxic ( cinchonism: tinitus, headache, GI disturbances, torsades); rarely used in arrythmias
*DISOPYRAMIDE: similar to procainamide but significant antimuscarinic effects; may precipitate HF, not commonly used
b)1b: shorten AP
-less dangerous than 1a group
-most rapid dissociation from the channels
-used in many cases of ventricular arrythmias
*LIDOCAINE: sodium channel (INa) blockade, no effect on IK!! minimal effect in normal tissue; blocks activated and inactivated chennels with fast kinetics; DOES NOT PROLONG AND MAY SHORTEN AP!!, used in ventricular tachycardia and prevents ventricular fibrillation after cardioversion, ONLY IN VENTRICULAR ARRYTHMIAS! ; used IV : first pass hepatic metabolism, reduce dose in patients with HF or liver disease; can cause neurologic symptoms, tremor, seizures, depresios of cardiovascular sys. ; duration 1-2h
-VENTRICULAR ARRYTHMIAS ARE OFTEN CAUSED BY ISCHAEMIA! ( MI)
-USED ALSO AS ANAESTHETIC
*MEXILETINE: orally active congener of lidocaine; used in ventricular arrythmias, chronic pain syndromes; longer duration
-USED ALSO IN NEUROPATHIC PAIN ( ex.in diabetes)
c)1c: no effect on AP
*FLECAINIDE: selective use and state-dep. block of INa (sodium channel blockad), slowing conduction velocity and pacemaker activity with NO CHANGE IN AP DURATION!!; used in refractory arrythmias, supraventricular arrythmias( atrial flutter and fibrillation) in patients with normal, healthy heart; DO NOT USE AFTER MI!!; used orally, hepatic and kindey metabolism, half life ca 20 h; can be proarrhytmic!!
*PROPAFENONE: orally active, weak beta blocking activity!!!, used in supraventricular arrythmias, hepatic metabolism
*MORICIZINE: phenothiazine derrivative, orally active, used in ventricular arrythmias; can cause arrythmias ( proarrhythmic)
2) Group 2: beta blockers
-prolongation of AP duration
-more active in supraventricular arrythmias, less effective in ventricular
*PROPRANOLOL: beta-adrenoreceptor blockade; direct membrane effects (sodium channel block!) and PROLONGATION OF AP DURATION!!; slows SA node automacity and AV nodal conduction velocity; used in atrial arrythmias and prevention od recurrent infarction and sudden death; used orally and parenterally, duration 4-6h; may cause asthma, AV blockade, acute HF. MAY INTERACT WITH OTHER CARDIAC DEPRESSANTS AND HYPOTENSIVE DRUGS!!, AV block
*METOPROLOL: beta1 selective, but similar to propranolol
*ESMOLOL: beta1 selective; very short-acting, IV only, used for intraoperative and other acute arrythmias; degraded very fast by plasma esterase
3) Group 3: potassium channel blockers
-prolongation of AP (PHASE '3')
-prolongation of QT interval
-prolongation of refractory period
-its very similar to group 1a but in the opposite, it is beeing more often used
*AMIODARONE: blocks IKr, INa, ICa-L channels and beta adrenoreceptors; PROLONGS AP DURATION AND QT INTERVAL; slows HR, slows AV nodal conduction, low incidence od torsades de pointes( polymorphic ventricular tachycardia); used in serious ventricular arrythmias and supraventricular arrythmias; used orally and IV; variable absorption and tissue accumulation; hepatic metabolism, elimination complex and slow; may cause bradycardia and heart block in diseased heart, peripheral vasodilation, pulmonary and hepatic toxicity, hyper or hypothyroidism, pulmonary fibrosis. May interact with other drugs ( based on CYP metabolism)
-BROAD SPECTRUM OF ACTION
-VERY EFFECTIVE DRUG IN BOTH SUPRAVENTRICULAR AND VENTRICULAR ARRHYTHMIAS
-BOTH FOR CHRONIC TREATMENT AND ACUTE STATES
-DOES NOT CAUSE TORSADE USUALLY ( SO ITS NICE)
-many extracardiac effects: ADVERSE REACTIONS ARE NUMEROUS!: long duration of action( 2 weeks is the time to wait for proper drug action), shows affinity to other tissues ( lungs cornea, skin, cornea, liver)
-AMIODARONE CONTAINS IODINE!! dysfunction of thyroid: both hyper and hypothyroidism ( blocked conversion of T4 into T3: hypothyroidism more often)
*DRONEDARONE: analog of amiodarone but has no pulmonary effects! no iodine in chemical structure ( no thyroid disturbances), used only in atrial fibrillation; but can cause fatal liver dysfunction
*DOFETILIDE: IKr, PROLONGS AP, effective refractory period; used in maintaining or restoration of sinus rhythm in atrial fibrillation; used orally, renal excretion; may cause torsades de pointes, may be additive with other QT prolonging drugs
*SOTALOL (BETA BLOKER WITH ADDITIONAL POTASSIUM BLOCKING FEATURE): used in ventricular tachyarrhythmias
*IBUTILIDE: used iv, in acute supraventricular arrythmias, maybe also in atrial flutter
*DOFETILIDE: orally, used in chronic r=treatment of supraventricular arrythmias
4) Group 4: calcium channel blockers
-only calcium channel blcokers used because of normalization of SA node activity and no effect on vessels (?)
-CONTROL ONLY THE RATE!!! NO PREVENTION, NO TREATING!
*VERAPAMIL: calcium channel ( I Ca-L type) blockade; slows SA node automacity and AV nodal conduction velocity, decreases cardiac cotractility, reduces BP; used only !!! in supraventricular tachycardias!!! hypertension, angina; used orally and IV, hepatic metabolism, CAUTION IN PATIENTS WITH HEPATIC DYSFUNCTION; may cause cardiac depression, constipation, hypotension, duration 7h
*DILTIAZEM: equivalent to verapamil
5) Other drugs:
*ADENOSINE: increase in diastolic IK of AV node that causes marked hyperpolarization and condution block ( complete AV blockade), reduced ICA; used in acute nodal tachycardia, used in acute paroxisomal SUPRAventricular tachycardia!!! ; IV only! duration 10-15 seconds; may cause flushing, chest tightness, dizziness, minimal interactions
-VERY EFFECTIVE ( IN 90% OF PATIENTS)
*MAGNESIUM: interacts with Na+/K+ ATPase, K+ and Ca+ channels; normalizes or increases plasma Mg2+ but poorly understood; used in digitalis arrythmias and other arrythmias if serum Mg is low, used IV only, may cause muscle weakness in overdose
*POTASSIUM: increases K+ permeability, increase all K currents, decreased automacity, decreased digitalis toxicity; used in digitalis toxicity and other arrythmias of serum K is low; used rally or IV; may cause both hypokalemia and hyperkalemia ( severe hyperkalemia causes cardiac arrest)
PRESCRIPTIONS:
1) FOR PAROXYSOMAL NOCTURNAL ARRYTHMIA
a)- in case of attack
Rp. Propafeone 150 mg
tab.
Lag.orig.No 1
D.S. take two tablets orally
in case of A. F [atrial fibrillation]
b) -"- for chronic treatment
Rp. Sotalol 80 mg
tab.
Lag.orig.No1
D.S. take one tablet
orally twice daily
2) FOR SUPRAVENTRICULAR OR VENTRICULAR ARRYTHMIAS
Rp. Amiodarone 200 mg
tab.
Lag.orig.No1
D.S. Take one tablet
orally once a day
(maintainence dose)