Antiarytmika Lydia Melchior VT-06

Bakgrund Många antiarytmika har använts länge, men majoriteten av de som används idag är ganska nya. Dagens forskning har lett till kunskap om den cellulära bakgrunden till arytmier, men den generella approachen är empirisk. Många antiarytmika ökar mortaliteten.

Bakgrund Alla antiarytmika verkar genom att ändra jonflöde i exciterbar vävnad i myocardet. De tre viktigaste jonerna är Na+, Ca++ och K+. Antiarytmika kan klassificeras genom deras förmåga att blockera flöde av en eller flera av dessa joner över membranen i hjärtmuskelceller. Vid akut arytmi är det vanligare med elektrokonversion än med farmaka.

Singh-Vaughan Williams Klassifikation Baserad på elektrofysiologisk effekt. Många droger passar dock inte in perfekt i systemet.

Singh-Vaughan Williams Klassifikation Ib Ic II III IV V Natriumkanalblockad Förlänger repol. Förkortar repol. Liten effekt på repol. b-adrenerg blockad Förlänger repol. (K+) Calciumkanalblockad Olika effekter Baserat på deras elektrofysiologiska effekter

Aktionspotential i icke-konduktiv vävnad 4: pacemaker potential 0: Snabb depolarisation 1: partiell repolarisation 2: platå 3:repolarisation

Aktionspotential 0: depolarisation 1: partiell repolarisation Snabba Na+-kanaler öppnas när tröskelpotentialen (-70mV) nås. 1: partiell repolarisation Stängning av Na+-kanaler 2: Platåfas Långsamma Ca++-kanaler öppna 3: Repolarisation Ca++-kanaler stängs och K+-kanaler öppnas, vilket leder till massivt utflöde av K+ 4: Vilomembranpotential Phase 4 Phase 4 is the resting membrane potential. This is the period that the cell remains in until it is stimulated by an external electrical stimulus (typically an adjacent cell). This phase of the action potential is associated with diastole of the chamber of the heart. Certain cells of the heart have the ability to undergo spontaneous depolarization, in which an action potential is generated without any influence from nearby cells. This is also known as automaticity. The cells that can undergo spontaneous depolarization the fastest are the primary pacemaker cells of the heart, and set the heart rate. Usually, these are cells in the SA node of the heart. Electrical activity that originates from the SA node is propagated to the rest of the heart. The fastest conduction of the electrical activity is via the electrical conduction system of the heart. In cases of heart block, in which the activity of the primary pacemaker does not propagate to the rest of the heart, a latent pacemaker (also known as an escape pacemaker) will undergo spontaneous depolarization and create an action potential. The mechanism of automaticity is still unclear. Depolarization of SA and AV nodal cells largely depend on a net increase in intracellular positive charge. Mechanisms include a decrease in the net K+ outward flow, and a time-dependent increase in flow of Na+ and Ca2+ ions. [edit] Phase 0 Phase 0 is the rapid depolarization phase. The slope of phase 0 is determined by the maximum rate of depolarization of the cell and is known as Vmax. This phase is due to opening of the fast Na+ channels and the subsequent rapid increase in the membrane conductance to Na+ (gNa) and a rapid influx of ionic current in the form of Na+ ions (INa) into the cell. The ability of the cell to open the fast Na+ channels during phase 0 is related to the membrane potential at the moment of excitation. If the membrane potential is at its baseline (about -85 mV), all the fast Na+ channels are closed, and excitation will open them all, causing a large influx of Na+ ions. If, however, the membrane potential is less negative, some of the fast Na+ channels will be opened earlier, causing a lesser response to excitation of the cell membrane and a lower Vmax. The maximal fast inward Na+ current is generated when the membrane potential is at the normal resting potential (-85 to –95 mV). If the resting membrane potential is reduced to a low enough level, the increase in fast inward Na+ current may be inadequate to produce a response, making the fiber unexcitable. The fast Na+ channel The fast sodium channel is made up of two gates, the m gate and the h gate. It is the interaction of these two gates that allows Na+ to enter the cell through this channel. In the resting state, the m gate is closed and the h gate is open. Upon electrical stimulation of the cell, the m gate opens quickly while simultaneously the h gate closes slowly. For a brief period of time, both gates are open and Na+ can enter the cell across the electrochemical gradient. Phase 1 Phase 1 of the action potential is due to closure of the fast Na+ channels. The transient net outward current is due to the movement of K+ and Cl- ions. Phase 0 and 1 together correspond to the R and S waves of the ECG. Phase 2 Phase 2 of the action potential corresponds to the ST segment of the ECG. This "plateau" phase of the cardiac action potential is sustained by a balance between inward movement of Ca2+ (ICa) through L-type calcium channels and outward movement of K+ through potasium channels. Phase 3 During phase 3 of the action potential, the K+ channel is still open, allowing more K+ to leave the cell and accumulate in the extracellular space. This net loss of positive charge causes the cell to repolarize. The k+ channels close when the membrane potential is restored to about -40 to -45 mV. Phase 3 of the action potential corresponds to the T wave on the ECG.

Aktionspotential i konduktiv vävnad (grön) Slow response type action potentials, found in cardiac conductive tissue such as the sinoatrial (SA) and atrioventricular (AV) nodes and junctional (associated with the AV node) tissue, differ from the fast type in several ways: the resting potential is less negative (-50 to -60mV), thus the magnitude of the action potential is less. there is little, if any, overshoot. these cells require less depolarization to reach threshold. the depolarization phase is slower. shorter action potential duration (approximately 150 vs 250 msec). Depolarization is due to the influx of Ca2+ and some Na+ through slow channels and repolarization is due to the efflux of K+. There are no fast Na+ channels in these cells. Normally the SA node is the pacemaker because it depolarizes spontaneously at a more rapid rate than any other area of the heart (approximately 70 times/min). It dominates other areas that may be depolarizing at a slightly slower rate, resulting in what is known as overdrive suppression. The AV node has an intrinsic rate of about 50-60/min, the His-Purkinje system rate is about 30-40/min and ventricular myocardium rate is about 15-25/min. The latter rate is too slow to permit normal physical acitivity and calls for implantation of an electronic pacemaker. If one should fail, the hierarchy of pacemakers permits another to assume the role.

Förändring i jonkonduktans under aktionspotential The top figure shows the temporal relationship between changes in ionic conductances and the electrical state during the action potential. The initial increase in Na+ conductance and subsequent return to baseline is caused by the sequential opening of m gates and closing of h gates (see bottom figure). Closing of the h gates inactivates the 'fast' Na+ channels. The probability that the m gates are open decreases as the cell begins to repolarize during the plateau phase (phase 2) of the action potential. The h gates begin to reopen during phase 3. The point during phase 4 at which the h gates have returned to their resting level marks the end of the relative refratory period. Phase 1, a small repolarizing voltage change prior to the onset of the plateau, is associated with the efflux of positive charge (probably K+ leaving and Cl- entering the cell), which occurs prior to a decrease in K+ conductance (remember, the inside of the cell is at this time positive with respect to the outside). With the subsequent decrease in K+ conductance, K+ efflux is decreased, and repolarization is delayed. The maintained depolarization or plateau (phase 2) is caused by several events occurring simultaneously: 1. "slow' Na+channels open 2. "slow" Ca2+ channels open (conductance increases) 3. K+ channels close (conductance decreases). These events maintain a relative state of depolarization. After a period of approximately 200 msec, there is a rapid increase in K+ conductance and, since the electrical and chemical gradients now favor K+ efflux, K+ leaves the cell, taking positive charge with it. The conductance of the slow calcium is decreasing at this time. These changes result in repolarization (phase 3).

Refraktärperiod During phases 0, 1, 2, and part of 3, the myocardial cell cannot be depolarized again because the voltage sensitive gates have not completed their cycle of opening and closing. This results in an absolute refractory period (ARP) during which the heart cannot be depolarized and explains the inability to induce a subsequent contraction until the membrane has recovered. As a consequence, tetanic contractions cannot be induced in cardiac muscle. A relative refractory period (RRP) follows the absolute, during which the cell will respond to a stronger-than-normal stimulus. The resting membrane potential (RMP) is then reestablished (phase 4) and maintained until the next suprathreshold stimulus excites the cell. During this period the activity of the Na+/K+ pump is increased, to return the intracellular concentrations of Na+ and K+ to their resting levels. This increase in activity is so small, however, that it has no significant effect on the membrane potential.

Pacemakerpotential Oviktig i ickekonduktiv vävnad. I konduktiv vävnad (SA och AV noderna) depolariseras pacemakerpotentialen gradvis under diastole, tills tröskelpotentialen nås, vilket resulterar i en spike. Konduktiv vävnad fyrar alltid AP med varierande frekvens (de har “intrinsic firing capacity”). SA fyrar snabbast, och får därför rollen som pacemaker. Icke-konduktiv vävnad behöver impuls för att depolarisera (utom vid vissa patologiska tillstånd) I konduktiv vävnad är depolarisationen inte lika beroende av Na+ kanaler, utan av långsamt inflöde av Ca++

Arytmityper

Delayed after depolarisation Normally, non pacemaker cells don’t fire unless they receive a signal from the pacemakers. In this condition, non conducting cells have a slow, rising phase 4, which allows them to fire without a signal from the pacemaker. It is due to an increase in intracellular Ca++ which increases the pacemaker potential. Conditions which can lead to an increased intracellular Ca are: Treatment with Cardiac glycosides Increased sympathetic tone (adrenergic stress) Myocardial ischemia

Re-entry Re-entry occurs when a heart muscle fibre is made to contract immediately after its refractory period, by the same impulse which caused its contraction in the first place. Normally, this does not occur because the muscle fibre is still in the refractory phase. The best example of re-entry is when there are 2 different pathways for an action potential. As the action potential separates to depolarise the 2 different pathways, it meets again. Re entry occurs when there is a blockage of one of these pathways. The action potential which passes through the unblocked pathway can circle back and depolarise part of the blocked pathway, if this is no longer refractory. Drugs which prolong the refractory period (e.g. class III drugs) are effective at preventing re entry.

Abnormal pacemaker activity The pacemaker is the tissue which has the fastest rate of firing. Normally, this is the SA node. Sometimes, other tissues in the heart can assume the role of pacemaker The main predisposing factors are similar to those in delayed after depolarisation: 1. b-adrenoceptor stimulation Causes increase in Ca++ levels 2. Myocardial ischemia There is a reflex increase in sympathetic tone as a result of poor perfusion. This increase in sympathetic tone increases Ca++ levels Also, ischemia affects the Na+ pump which requires ATP to extrude Na out of the cell, against its concentration gradient. If this pump fails to work (due to lack of ATP) Na+ concentrations increase in the cell, resulting in depolarisation.

Heart block Damage to nodal tissue (e.g. during a myocardial infarct), prevents conduction of the signal to other parts of the heart. The areas of the heart which normally rely on this signal start to beat independently, under the action of their own pacemakers. A myocardial infarct damages nodal tissue by: Causing fibrosis Causing ischemia in the area of conduction tissue

Clincally, arrhythmias are classified according to: 1. Their site of origin (atrial or ventricular) 2. Whether they cause bradycardia or tachycardia

Antiarytmika

Singh-Vaughan Williams Klassifikation Ib Ic II III IV V Natriumkanalblockad Förlänger repol. Förkortar repol. Liten effekt på repol. b-adrenerg blockad Förlänger repol. (K+) Calciumkanalblockad Olika effekter Baserat på deras elektrofysiologiska effekter

Klass I Blockerar natriumkanaler Genom att binda a-subenheten Detta inhiberar aktionspotentialens propagering i många exciterbara celler. Effekten är att den maximala depolarisationshastigheten (Vmax) minskas under fas 0. Viktiga vid behandling av arytmier där Na+ kanaler är viktiga (icke-nodal vävnad)

Klass I Centralt begrepp: use-dependent blockad. Detta gör att klass I läkemedel kan blockera högfrekvent excitation utan att hindra normal rytm. Natriumkanaler finns i tre former: Vilande Öppna Refraktära 1997 Clinical pharmacology By Duy Thai · This is called use dependent block · The class I drugs are divided up into subclasses, according to their rate of dissociation from the channel Class Ib drugs · The most used drug is the class Ib drug lignocaine · Lignocaine is also used as a local anaesthetic · Binds preferentially to the refractory channels · Refractory channels occur when the cell is depolarised · Lignocaine is useful for ventricular arryhtmias after a myocardial infarct because + when ischaemia occurs, it causes cells to be partially depolarised, hence the Na channels will be in their refractory state. · Lignocaine dissociates rapidly · It binds to the channel during phase 0 and dissociates before the arrival of the next action potential (assuming normal rhythm) · In abnormal rhythms, a premature beat will be prevented from occurring because lignocaine will not have dissociated yet. · Administered intravenously · Adverse effects: · CNS effects: drowsiness, convulsions · CVS effects: reduced cardiac contractility, bradycardia Class Ic drugs · Flecainide · Not used much anymore since it may cause death by increasing ventricular fibrillation after myocardial ischaemia · Many anti arrhythmics can also be pro arrhythmic under particular circumstances. In the case of flecainide, it becomes proarrythmic under ischaemic conditions. · Slow association and dissociation (10 sec) · Reaches a steady state level of block which does not vary within the cardiac cycle · Causes a general reduction in excitability · Used for severe ventricular tachycardia Class Ia drugs · Disopyramide · Older generation drug · Intermediate rate of dissociation · Used for atrial and ventricular tachycardias

Natriumkanaler byter state från vilande till öppna som svar på depolarisation. Aktivering. Förlängd depolarisation (ex. ischemi) gör att kanalerna långsammare går från öppna till refraktära. Klass I läkemedel binder starkast till öppna eller refraktära kanaler -> use dependence.

Klass Ib Ex. lignocain Associerar och dissocierar snabbt. Binder till öppna kanaler under fas 0 Dissociation sker i god tid innan nästa aktionspotential. Prematura hjärtslag hindras eftersom kanalerna fortfarande är blockerade. Binder också till refraktära kanaler -> spec. för skadad vävnad (ex. ischemi)

Klass Ib

Klass Ic Associerar och dissocierar mycket långsammare. Steady-state blockad som inte varierar under hjärtcykeln. Ej specifika för skadad vävnad (refraktära kanaler) Generell reduktion av retbarhet. Inh. Konduktion i His-Purkinje -> förlänger QRS

Klass Ic

Klass Ia Effekt mitt emellan Ib & Ic. Förlänger dessutom repolarisation.

Klass Ia

Klass II b-adrenoceptor antagonister Ex propranolol Används vid stressinducerad takykardi eller ischemiinducerade arytmier, då det finns ökad sympatisk aktivitet. Class II drugs · These drugs are ß adrenoceptor antagonists · They are useful for stress induced tachycardia or ischaemia induced arryhthmias when there is increased sympathetic activity · ß antagonists are also useful to reduce anxiety associated with increased heart rate (due to a stressful situation -e.g. before an interview) · The two drugs which are commonly used are: · Propranalol + · Propranalol is known to be membrane stabilising (can block Na channels) but at the concentrations used clinically, this effect is not seen · Atenolol · What does adrenaline/noradrenaline do to the heart? A. Increases the rate of depolarisation during phase 4, therefore, increases the automaticity of non conducting heart tissues 2+ B. Increases the slow inward Ca current · After depolarisation · Increases AV conduction velocity

Sympatikuseffekter i hjärtat Vad gör NA med hjärtat? Ökar depol. I fas 4 (ökar alltså automaticiteten i ickekonduktiv vävnad) Ökar den långsamma innåtströmmen av Ca++ Efter depolarisation Ökar AV konduktionshastighet

Klass III - amiodarone Amiodarone Okänd verkningsmekanism Förlänger aktionspotentialen, och ökar därmed refraktärperioden. Är därför användbara för att förebygga ventrikulära och supraventrikulära arytmier. Class III drugs · Amiodaraone · Mechanism of action unknown · They prolong the cardiac action potential, thus increasing the refractory period · As a result, they are useful in preventing ventricular and supraventricular arrhythmias · Limited use due to lots of side effects: · These drugs have a very long half life (10 to 100 days) · The drugs accumulates in tissue causing: · Cornea:Deposits, causing halos in vision. Reversible if stop taking drug · Skin:Photosensitivity, rashes · Thyroid:Hypo or hyperthyroidism (due to high iodine content in the drug) · Lungs:Fibrosis (may be irreversible) · Liver damage · GIT · Sotalol · A class III drug and also a ß antagonist · The L isomer is a ß blocker · Both the D and the L isomer contributes to its class III activity · Less adverse effects than amiodorone · The adverse effects which do occur are the result of its ß blocking effects (e.g. bronchoconstriction, decreased cardiac activity)

Klass III amiodarone Används lite pga många bieffekter: Lång halveringstid (10-100 dagar) Ackumuleras I vävnad -> Cornea: upplagring, synstörningar. Reversibelt Hud: Fotosensitivitet, utslag Thyroidea: hypo- eller hyperthyroidism (pga högt jodinnehåll) Leverskador Class III drugs · Amiodaraone · Mechanism of action unknown · They prolong the cardiac action potential, thus increasing the refractory period · As a result, they are useful in preventing ventricular and supraventricular arrhythmias · Limited use due to lots of side effects: · These drugs have a very long half life (10 to 100 days) · The drugs accumulates in tissue causing: · Cornea:Deposits, causing halos in vision. Reversible if stop taking drug · Skin:Photosensitivity, rashes · Thyroid:Hypo or hyperthyroidism (due to high iodine content in the drug) · Lungs:Fibrosis (may be irreversible) · Liver damage · GIT · Sotalol · A class III drug and also a ß antagonist · The L isomer is a ß blocker · Both the D and the L isomer contributes to its class III activity · Less adverse effects than amiodorone · The adverse effects which do occur are the result of its ß blocking effects (e.g. bronchoconstriction, decreased cardiac activity)

Klass III - Sotalol Ett klass III läkemedel som även är en b–antagonist (klass II). L isomeren är en b–antagonist. Både D och L formerna ger klass III effekter. Bieffekter Färre än för amiodarone. Bieffekterna är resultat av b-blockaden (ex bronkkonstiktion, minskad hjärtaktivitet)

III

IV Verapamil Blockerar spänningskänsliga Ca++ kanaler. Mer selektiva för hjärtvävnad än annan vävnad (ex vaskulär glatt muskulatur). Förkortar fas 2 (platåfas) genom att minska inflödet av Ca++. Detta leder till: Hämning av prematura ektopiska hjärtslag genom att förhindra fas 4 depolarisation. Minskning av hjärtkontraktilitet. Effektiva vid behandling av förmakstakykardier, men ej ventrikeltakykardier. Används ej tillsammans med b–blockerare eftersom de har additiv effekt när det gäller hjärtdepression. Används ej om det finns underliggande störning I hjärtkontraktilitet.

Övriga farmaka Digoxin Adenosin Atropin

Digoxin Hjärtglykosid Positiv inotropi (ökar kontraktionskraften) & förlångsammad AV-överledning. Sensitiserar AV noden för vagalt input -> Förstärker parasympatisk aktivitet I hjärtat Ökat CO (resulat av ökad inotropi) minskar sympatisk aktivitet Reflexsvaret på försämrad kontraktilitet är att öka sympatisk drive på hjärtat Detta kan leda till arytmier Därför minskar risken för arytmier om sympatisk aktivitet reduceras. Används för att minska ventrikelhastighet vid FF Stoppar alltså inte FF, utan förlångsammar AV överledning så att de impulser som når ventriklarna är färre

Adenosin Produceras endogent och är en viktig kemisk mediator (ex i lunga & hjärta). Verkar på A1-receptorer för att förlångsamma AV-överledning Dessa receptorer är kopplade till samma K+-kanal som aktiveras av ACh. Adenosin hyperpolariserar den konduktiva vävnaden. Används akut (intravenöst) för att reversera supraventrikulära takykardier. Kortvarig effekt: 20-30s Bieffekter: Flushing (vasodilatation) Bronkospasm Yrsel Illamående

Atropin Muskarinerg antagonist Blockerar parasympatikus effekter i hjärtat. Används för att behandla sinusbradykardi