0715 - Kinetics and Dynamics of Cardiac Drugs - RM Flashcards
What are the three key ‘tropics’?
Force – INOtropic (tendon-affecting)
Rate – CHRONOtropic (time-affecting)
Velocity – DROMOtropic (running-affecting)
A cardiac drug can have a positive or negative effect on any or all of these.
What are the classes of antiarrythmic drugs? (4+1)
Class I – Voltage sensitive sodium channel blocker – subdivided into Ia, Ib, and Ic.
Class II – Beta-adrenoreceptor antagonists (beta-blockers)
Class III – Prolong cardiac action potential (repolarisation inhibitors)
Class IV – Calcium antagonist
‘Catch-all’ - Several antiarrythmic drugs are not classified by this class system.
What do Class I antiarrhythmics do, and how do they do it?
(Class I – voltage-sensitive Na+ channel blocker)
On the SA node – all decrease automaticity of SA nodal cells by increasing the threshold and decreasing slope of phase 4 depolarisation (funny current).
In ventricles – all inhibit phase 0 upstroke (by Na channel block), thus decreasing conduction velocity.
Ia (e.g. quinidine) – Moderate inhibition of depolarisation (Na channel block) and prolong repolarisation, increasing the length of the AP and the effective refractory period (negative chronotropic). Also decrease AV conduction (negative dromotropic) and contractility (negative inotropic).
Ib (e.g. lidocaine) – Mild inhibition of depolarisation (Na channel block) and shorten repolarisation, shortening the action potential, but increasing effective refractory period.
Ic (e.g. Flecainide) – Strong inhibition of depolarisation (Na channel block) and no change in repolarisation. Slows AV conduction and decreases contractility.
What do Class II antiarrhythmics do, and how do they do it?
Inhibit sympathetic input on heart pacing via antagonising beta-adrenergic receptors (beta-1 preferentially expressed in cardiac tissue).
Decrease the slope of pacemaker cell phase 4 depolarisation (funny current), and prolong repolarisation at AV node. (Slow AV conduction, and lower contractility)
Most commonly prescribed for supraventricular and ventricular arrhythmias caused by SY stimulation. Also used in angina (key) to decrease HR, BP and contractility, thus reducing myocardial O2 requirement.
What are the three generations of Class II antiarrhythmics (beta-blockers)? Give an example of each, their selectivity, and at least one side-effect.
1st (e.g. Propranolol) – Beta1/Beta2 selectivity approximately equal. Can cause bronchospasm, cold extremities and impotence.
2nd (e.g. Bisoprolol, Metoprolol) – Selective for Beta1 over Beta 2. Can cause Heart block and bradycardia (excessive negative inotropic effect)
3rd (eg. Carvedilol) – Selective for Beta1 over Beta2, also cause vasodilation by antagonising alpha-receptors. Can cause insomnia and depression.
What do Class III antiarrhythmics do, and how do they do it? What is an example of one?
Inhibit repolarisation by inhibiting K+ channels – longer plateau (Ph2) and downstroke (Ph3), increasing AP duration and effective refractory period. Also slow AV conduction and sotalol decreases contractility.
E.g. – Ibutilide, amiodarone sotalol.
What do Class IV antiarrhythmics do and how do they do it? What is an example of one?
Slow depolarisation (Ph0), by blocking Ca++ channels. Act preferentially on SA and AV node (pacemaker AP); so significantly slow conduction through AV node. Also lowers contractility.
Nifedipine – more effective on Ca++ channels in vascular smooth muscle.
Verapamil and Diltiazam – more effective on CA++ channels in cardiac tissue, but serious interactions with beta-blockers and digoxin.
What are the three most important cautions when prescribing antiarrhythmics?
Significant drug interactions
Narrow margin between efficacy and toxicity
Can cause dysrhythmias.
What are the two broad categories of drugs used in heart failure? What are their subcategories?
Positive inotropic drugs – Cardiac glycosides, phosphodiesterase inhibitors, and beta-agonists.
Non-cardiac target drugs – diuretics, ACE inhibitors/angiotensin antagonists, and beta blockers.
Briefly describe the pharmacodynamics and pharmacokinetics of Digoxin
Digoxin – increase contractility, slow heart, and slow conduction through AV node.
Dynamics – Inhibits Na+/K+ ATPase, which affects Na+/Ca++ exchanger, increasing intracellular Ca++. This is stored at the SR, increasing contractility when it is released.
Kinetics – very narrow therapeutic window. Oral bioavailability 75% (increases with antibiotics), 90% renal excretion with large VD of 640L(70kg) - (renal failure reduces clearance and VD). Digoxin plasma levels are increased by several drugs (e.g. verapamil, quinidine). Hypokalemia also increases potency (so be careful of diuretics).
Briefly describe the mechanism of action of beta-agonists. Give an example of one.
Increases cAMP, allowing PKA to activate, which increases intracellular calcium (Pi from PKA activates Ca++ channel). Leads to positive inotropic and chronotropic effect, increasing cardiac output. Also enhances rate and extent of relaxation in diastole.
Only used in the short-term to support a failing circulation.
Example – dobutamine.
Briefly describe the mechanism of action of phosphodiesterase inhibitors.
Inhibits Phosphodiesterase degradation of cAMP, allowing more active PKA, which in turn increases intracellular calcium (Pi from PKA activates Ca++ channel).
Like beta-agonists, only used for short-term to support failing circulation – increased mortality associated with long-term use.
Example – Amrinone, Milrinone, Vesnarinone.
What is an ACE inhibitor? Give an example?
Inhibits conversion of angiotensin I to angiotensin II (AT2) by Angiotensin-Converting Enzyme. As AT2 is a vasoconstrictor, vascular growth agent, and salt-retainer, ACE inhibitors act as effective vasodilators, (and prevent hyperplasia/hypertrophy and assist in salt expulsion). Used in hypertension, cardiac failure, following MI, diabetic nephropathy, and progressive renal insufficiency.
Examples – Captopril, Enalapril, Fosinopril.
What are aldosterone and spironolactone?
Aldosterone is a hormone that has an anti-diuretic effect by limiting Na+ excretion and increasing K+ excretion. Spironolactone is its competitive antagonist (thus a K+-sparing diuretic), though with a slow onset of action.
Why are beta-blockers used in heart failure?
They reduce myocardial oxygen demand.
They inhibit the SY compensation in a failing heart, and inhibit renin release. Use is somewhat counterintuitive because of negative inotropic effect.
