Cardiac non table drugs Flashcards
Inotropes vasopressors Summary of cardiac pharm inc. antiarryhthmics
Classify the inotrope agents (5)
Direct sympathomimetics
Indirect sympathomimetics
Phosphodiesterase inhibitors
Clacium sensitisers
Cardiac glycosides
Describe the 2 subclasses of direct sympathomimeitcs and indirect sympathomimeitcs providing MOA
What non sympathomimetic inotropes are there? Describe their mechanisms
Give the properties of an ideal inotrope
- Pharmaceutics 3
Pharmacokinetics 5
Pharmacodynamics 5
Safety
2
Dobutamine vs milronone
- CLass
- Chemistry
- Route of adminsitration
- Solubility and pKa
Dobutamine vs milronone pharmacokinetics
MOA and effect dobutamine vs milronone
What are the 4 reasons arrhythmias occur? Describe the mechanism? What drugs might therefore work
- Abnormal automaticity
◦ where some normal tissue becomes overexcited and decides to become a pacemaker, or existing pacemakers make pace in some disorganised or abnormal manner.
◦ To treat
‣ Of normal pacemakers –> Anything that reduces the slope of phase4 of those cells e.g. calcium and beta blockers
‣ Non pacemaker tissue –> beta blockade by reducing resting potential voltage of the membrane - Early afterdepolarisations
◦ triggered depolarisations which occur during Phase 3, and which are promoted by anything which prolongs the repolarisation - Late afterdepolarisations
◦ triggered depolarisations which occur during Phase 4, and which are promoted by anything that might increase the intracellular calcium
◦ Catecholamines or calcium are the tissue –> therefore beta blockers and calcium channel blockers address this - Reentry
◦ where acton potential re-excites a patch of myocardium shortly after it has already depolarised, either because of some anatomical shortcut or because of an abnormally short refractory period
◦ Abnormally short refractory period –> Prolong by class 1a and class 3 agents
◦ As for abnormal conducting pathways - slowing conduction using class 1c agents
How does abnormal automaticity occur? (2) What can be done to prevent each
- Abnormal automaticity
◦ where some normal tissue becomes overexcited and decides to become a pacemaker, or existing pacemakers make pace in some disorganised or abnormal manner.
◦ To treat
‣ Of normal pacemakers –> Anything that reduces the slope of phase4 of those cells e.g. calcium and beta blockers
‣ Non pacemaker tissue –> beta blockade by reducing resting potential voltage of the membrane
Earyl afterdepolarisations occur because of?
- Early afterdepolarisations
◦ triggered depolarisations which occur during Phase 3, and which are promoted by anything which prolongs the repolarisation
Late afterdepolarisation occur because of? How to prevent it 2
- Late afterdepolarisations
◦ triggered depolarisations which occur during Phase 4, and which are promoted by anything that might increase the intracellular calcium
◦ Catecholamines or calcium are the tissue –> therefore beta blockers and calcium channel blockers address this
What is a re-entry circuit? How might you abort each
- Reentry
◦ where acton potential re-excites a patch of myocardium shortly after it has already depolarised, either because of some anatomical shortcut or because of an abnormally short refractory period
◦ Abnormally short refractory period –> Prolong by class 1a and class 3 agents
◦ As for abnormal conducting pathways - slowing conduction using class 1c agents
Classify Vaughan Williams anti-arrhtyhmics?
- Class I: fast sodium channel blockers i.e. interfere directly with depolarisation
◦ Class Ia: prolong the action potential (eg. quinidine)
◦ Class Ib: shortens the action potential (eg. lignocaine)
◦ Class Ic: no effect on the action potential (eg. flecainide) - Class II: Beta-blockers (eg. metoprolol) - antisympathetic
- Class III: Potassium channel blockers (eg. sotalol and amiodarone) - prolong the duration of the action potential
- Class IV: calcium channel blockers (eg. verapamil and diltiazem)
What effect do the subclasses of Vaughan Williams 1 antiarrhtyhmics have on the action potential
- Class I: fast sodium channel blockers i.e. interfere directly with depolarisation
◦ Class Ia: prolong the action potential (eg. quinidine)
◦ Class Ib: shortens the action potential (eg. lignocaine)
◦ Class Ic: no effect on the action potential (eg. flecainide)
How do you reduce pacemaker automaticity
- Reduction of pacemaker automaticity: agents which decrease the calcium currents in pacemaker cells, i.e. Class II and Class IV agents
How do you reduce abnormal automaticity
- Reduction of abnormal automaticity: agents which decrease the membrane resting potential in ventricular myocytes, i.e. mainly Class II agents
How do you stop or reduce early afterdepolarisations 2
agents which reduce the action potential and repolarisation duration, i.e. Class II and Ib agents
◦ Some agents actually increase early afterdepolarizations by delaying repolarisation
◦ These are the same agents that prolong the QT interval (i.e. Class Ia and Class III agents)
How do you reduce delayed afterdepolrisations 3
◦ Agents which decrease the availability of intracellular calcium (i.e. Class II and IV agents)
◦ Agents which decrease the availability of intracellular sodium (i.e. Class I agents)
What agents slow AVN conduction 4
◦ Agents which slow AV nodal conduction (i.e. adenosine, digoxin, Class II and Class IV agents)
What afents slow velocity of conduction
◦ Agents which slow the velocity of conduction (i.e. Class Ia and Ic agents)
What afgents increase the refractory period
◦ Agents which increase the refractory period (i.e Class III, Ia and Ic agents)
Class 1 agents bind to what? When do they bind to this
Class 1 agents
* All have local anaesthetic effects
* All bind to a site in the pore of the Nav1.5 subunit of the fast voltage-gated sodium channel
* All prefer to bind to open or inactivated sodium channels (though slowly dissociating class 1c drugs remain bound even when the channels return to their resting state)
* Effects are more pronounced in ischaemic tissue
How does a class 1 agent affect each of the aetiologies of arrhthmias
- Automaticity of normal pacemakers
◦ Will remain normal on class 1 agent - phase 4 of normal pacemaker cells does in fact depend on sodium currents (funny current targeted by ivabradine) but distinct from the voltage gated fast ones.
‣ Class 1 agents may somehow affect phase 4 but this is debated - flecainide appears to assist with rhythm control for AF by mechanisms unknown. - Automaticity of non pacemaker tissue
◦ should also remain unchanged but decreases but by uncertain mechanisms as these drugs are used for VT and VF - Early afterdepolarisations - can increase with class 1 gents particularly 1a which prolong repolaristion therefore risk of polymorphic VT
- Late afterdepolarisations - should decrease with sodium channel blockade as decreased intracellular sodium for sodium/calcium exchanger so less intracellular calcium available (and this is what is responsible for this phenomenon). However these agents to do not appear to help with this
- Re-entry - most effective - by decreasing velocity of conduction AP propogation is slowed along abnormal conducting pathways preventing re-entrant tachycardias (class 1c ideal)
Draw an action potential for each class 1 agent
Describe the 3 states of a sodium channel
What i the refractory period of cardiac conduction tissue
250-350msec
How is the refractory period in cardiac conduction tissue caused
Inactivation of sodium channels
What effect do class 1 antiarrhtyhmics have on cardiac conducting tissuerefractory period
- Class 1a agents increase the effective refractory period - action potential is longer
- Class 1c agents have no effect on the effective refractory period of anything except AV node and atrial muscle where it is prolonged.
- Class 1b agents shorten the effective refractory period by shortening the duration of the overall action potential
How do class 1 drgus affect the ECG
Class Ia drugs prolong both the QRS and QT
Class Ib drugs have no effect on the QRS, and slightly shorten the QT.
Class Ic drugs markedly prolong the QRS, and have minimal effect on QT.
What is use dependence and describe how it occurs and what aegnts it effects
- Tendancy for class 1 agents to favour ianctvie sodium channels and to dissociate slowly makes them more effective at faster HR
◦ Observe: each time the channel opens, block develops, and then gradually un-develops during diastole. Ergo, the shorter your diastole, the less block you lose between beats, and the more potent the block which affects the next beat. This is manifested as an increase in QRS duration which occurs with tachycardia.
◦ On the other hand, if the drug dissociates extremely rapidly from the sodium channels, its activity will again be unaffected by heart rate. Even with a preposterously short diastole, most of the drug will be gone from the active site long before the next systole - which means tachycardia will not do anything to change the effectiveness of the block.
◦ Extremely slowly dissociating drugs (Class Ic agents such as flecainide) should be the most affected by use dependence, and their effect should be amplified considerably by a fast heart rate.
◦ Moreover, for drugs with use-dependence, the QRS prolongation effect should increase with the duration of the tachycardia, as more and more drug molecules end up trapped at the effect site because frequent systoles prevent them from dissociating.
Electrochemical actions of class 1 a
- Class Ia: prolong the action potential (eg. quinidine)
◦ Prolongs the duration of the action potential (mainly by their potassium channel blocker effects); prolong the QT interval and QRS complex because of a longer Phase 0
Electrochemical actions of class 1b
- Class Ib: shortens the action potential (eg. lignocaine)
◦ No effect on the duration of Phase 0 (do not prolong the QRS); shorten the QT interval
Class 1 c electrochemical actions
- Class Ic: no effect on the action potential (eg. flecainide)
◦ Prolong Phase 0 more than other subclasses; have little effect on the duration of the action potential and therefore do not prolong the QT interval
Non vaughan williams anti-arrhtyhmics
Non-VW agents:
* Agents which slow AV nodal conduction (i.e. adenosine, digoxin)
* Physiological membrane stabilisers (magnesium)
Class 2 Vaughan willaims drugs
Class II: Beta-blockers (eg. metoprolol)
* Increase IK1 inward rectifier potassium current and reduce other currents;
* Lower resting membrane potential, reduce action potential duration, promote rapid repolarisation in Phase 3, decrease AV node conduction
Class 2 Vaughan willaims drugs electrochmical action
Class II: Beta-blockers (eg. metoprolol)
* Increase IK1 inward rectifier potassium current and reduce other currents;
* Lower resting membrane potential, reduce action potential duration, promote rapid repolarisation in Phase 3, decrease AV node conduction
Class 3 electrochemical actions
Class III: Potassium channel blockers (eg. sotalol and amiodarone)
* Block Ikr, Iks and Ik1 currents which are responsible for Phase 3 of the cardiac action potential
* Increase the duration of the refractory period and of the action potential as a whole
Class 4 electrochemical actions
Class IV: calcium channel blockers (eg. verapamil and diltiazem)
* decrease the rate of Phase 0 rise in pacemaker cells
* shorten repolarisation by decreasing the duration of Phase 2
* decrease AV node conduction
Beta 1 selective beta bloickers
◦ Atenolol
◦ metoprolol
◦ Bisoprolol
◦ Nebivolol
◦ Esmolol
◦ Sotalol (also blocks potassium channels)
AM NEB
Combined beta and alpha beta blocker
labetalol, carbedilol
Non selective beta blocker
propanolol
Class 2 effect on
- Depolarisation rate (phase 0)
- Conduction velocity
- AP duration
- PR duration
- QRS duration
- QTc duration
- Effective refractoyr period
- Automaticity
- Dissocation rate
Beta blocker vs phase 0 of action potential
- an unchanged slope of Phase 0
◦ Fast voltage gated sodium channels largely unaffected except by propanolol which does decrease the slope by 30%
◦ HOWEVER - 2 studies found that the slope of phase 0 is affected by beta inhibition therefore it is possible for the QRS to widen
beta blocker vs conduction velcoity
- decreased conduction velocity through specialised conducting tissue e.g. AV node
◦ Myocyte conduction velocity is unaffected
beta blocker vs effective refractory period
- decreased effective refractory period
◦ The Stoerling table from which the table on the right is derived suggests this is the case however other resources suggest it is increased
Beta blocker vs action potential duration
ncreased action potential duration
◦ reduce calcium entry preventing earlier repolarisation - phase 2 is prolonged and phase 3 begins later
Beta blocker vs action potential duration
increased action potential duration
◦ reduce calcium entry preventing earlier repolarisation - phase 2 is prolonged and phase 3 begins later
Beta blocker vs QTc duration
- Decreased QTc duration - prolong at slow rates and shorten at faster rates, promoting L type calcium channel inactivation (reverse of beta agonists which delay L type calcium channel inactivation prolonging QTc)
beta blocker vs automaticity
- decreased automaticity
◦ of normal pacemakers as catecholamines are one the main stimulants of this phenomenon - they do this by lowering the resting membrane potential during phase 4
◦ Reduce appearance of VEB by lowering resting membrane potential preventing automaticity in non pacemaker tissues
Beta blocker vs early and late afterdepolarisations
- Decreased early afterdoparisations because repolarisation time is reduced counteracting pro-arrhtyhmic effects of class 3 agents
- Late afterdopalarisations are realted to intracellular calciume xcess and improve due to the anti-catecholamine actions of beta blockers
Re-entry vs beta blockers
- Re-entry is unaffected as myocyte conduction velocity is largely unchanged except for AV nodal re-entry
Draw and describe the effect of a beta blocker on an ECG
Corresponding ECG thereofre
* Longer PR interval
* Shorter QT interval
What does a class 3 antiarrhthmics do
◦ Prolongs repolarisation by interfering with inward rectifier and outward delayed rectifier potassium currents increasing refractory period and action potential as a whole
◦ In short, these drugs mainly block Ikr, Iks and Ik1 currents which are responsible for Phase 3 of the cardiac action potential. Class III drugs are not unique in the effect, as there are many other drugs which interfere with this current (notably, macrolide antibiotics and antipsychotic drugs).
What occurs with rapid infusion of amiodarone
‣ Hypotension due to decreased contractility (polysorbate 80)
Acute use amiodarone effects
Class 2 and 4 effects - delayed AVN conduction
Chornic use of amiodarone causes what class of effects
- How does it affect repolarisation
- QTc duraiton
- AP
- re0entry
- Earyl afterdpolarisation
- QRS
◦ With chronic use, Class Ia and Class III effects
‣ Prolonged repolarisation and QTC duration
‣ Prolonged action potential duration
‣ Decreased reentry, as the result of this
‣ Increased risk of early afterdepolarisations
‣ Minimal effect on QRS
Draw a AP for someone on amiodarone
Effect of class 3 agents on autoamticity
◦ Automaticity of normal pacemakers unchanged with pure potassium blockade but as beta blocker effects seen in sotalol and amiodarone rate slowing occurs
◦ Abnormal autoamaticity of non pacemaker tissue - increased early afterdopalarisations due to prolonged repolarisation but counteracted by beta blockade in sotalol/amiodarone
How does digoxin affect the cardiac action potential
Perhaps more correctly
* The whole action potential duration decreases (Ruch et al 2003)
* Phase 0 can be either shortened or lengthened (Hordof et al, 1978); most textbooks seem to think it is lengthened.
* Phase 1 is shortened (Woodbury & Hecht, 1952).
* Phase 2 is shortened the most (Woodbury & Hecht, 1952).
* Phase 3 is lengthened (Woodbury & Hecht, 1952).
* Phase 4 slope is increased in pacemaker tissues (Hordof et al, 1978) and in Purkinje fibres (Rosen et al, 1975), increasing their automaticity.
