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2012-02-14 13:44:55
Igor Systems

Igor Systems
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  1. How can the frequency of pacemaker discharge be varied?
    • 1) rate of phase 4 depolarization,
    • 2) threshold potential, or
    • 3) "resting membrane potential" (Vm).
  2. pacemaker potential is caused by a net influx of positive charge. How does this occur?
    • a) a progressive decrease in K+ efflux during maintained influx of Na+ and/or Ca2+.
    • b) a progressive increase in Na+ and/or Ca2+ influx during steady K+ efflux.
    • c) a combination of (a) and (b).
    • Thus, automaticity may be decreased by drugs acting to increase K+ permeability or decrease Na+ and/or Ca2+ permeability.
  3. How does norepinephrine affect pacemaker firing frequency?
    Release of norepinephrine causes an increase in the slope of the pacemaker potential.
  4. How does vagal activity affect pacemaker firing frequency?
    Increased vagal activity, through the release of acetylcholine, diminishes heart rate by hyperpolarizing Vm and reducing the slope of the pacemaker potential.
  5. Conduction Velocity is dependent upon?
    • a) intracellular resistance
    • b) gNa+ : transmembrane [Na+] gradient, state of Na+ channel "readiness"
    • drugs that block the Na+ current will slow conduction velocity
  6. What does conduction velocity along the syncytium depend on?
    • a) The intracellular resistance to current flow.
    • b) The intensity of the inward Na+ current. This is reflected in the maximal rate of rise (Vmax) of the action potential phase-0. Those cells that have more prominent fast Na+ current component in the action potential have higher conduction velocities. The intensity of the Na+ current is determined by:
    • i. the transmembrane [Na+] gradient.
    • ii. the state of "readiness" or activation of Na+ channels.
  7. Effective refractory period (ERP)
    • - shortest interval at which a premature stimulus results in a propagated response
    • Na channels go through rest, open and inactivated states.
    • The time constant for recovery from inactivation of Na+ channels is normally very short, such that recovery of the ability to generate a propagated action potential is mainly a function of transmembrane voltage as repolarization occurs.
    • This is because the driving force for the Na current is greater as membrane voltage moves away from the reversal potential for Na.
    • The more hyperpolarized the Vm and the longer, the more Na channels are available for activation and the larger the Na current will be.
  8. Implications for conduction velocity of the action potential.
    • -the relationship btw AP conduction velocity & the rate of rise of the upstroke of the AP (the Na+ current) is the upswing of the AP
    • the more hyperpolarized the membrane potential at the time of stimulus, the larger the Na+ current will be
    • the larger the Na+ current, the faster the conduction velocity
    • in the ventricles, or His-Purkinje system, there are large APs that rise very fast- these have the fastest conduction velocity
  9. Altered normal automaticity
    • (abnormal impulse generation)
    • 1. Sick Sinus Syndrome
    • 2. Increased automaticity of the His-Purkinje system
    • 3. Prolonged reduction in Vm
  10. Sick sinus syndrome
    • Intrinsic disease of sinus node pacemaker cells.
    • The precise mechanism of pathogenesis is unknown but may be caused by ischemic or inflammatory damage to the SA node.
    • Severe sinus bradycardia
    • Intermittent replacement of sinus rhythm by ectopic rhythm, with possible atrial fibrillation.
    • Potential cardiac arrest when sinus bradycardia is not replaced by an ectopic pacemaker. It is typical for the ventricular pacemakers also to be depressed.
    • Primarily treated by permanent pacemaker implantation; pharmacotherapy is secondary and supportive
  11. Augmented automaticity in the His-Purkinje system.
    • Common cause of arrhythmias in humans.
    • Increased sympathetic activity increases rate of spontaneous firing.
    • Ionic mechanism is similar to that in sinus tachycardia.
  12. Repetitive discharge due to substantial reductions in Vm
    may occur in Purkinje fibers, atrial cells and ventricular cells.
  13. Irregular triggered activity
  14. (abnormal impulse generation)
    • 1. Early afterdepolarizations
    • 2. Delayed afterdepolarizations
  15. Reentrant arrhythmias
    • Initiation requires an anatomical or functional “unidirectional barrier" to conduction that forms a circuit.
    • Reentry in atria:
    • e.g., paroxysmal supraventricular tachycardia (PSVT) - usually caused by AV nodal reentry.
    • e.g., atrial flutter - caused by a regular, dominant repeating pathway (circus-reentry).
    • e.g., atrial fibrillation - disorganized pattern of conduction.
    • Reentry in His-Purkinje system:
    • e.g., extrasystolies.
    • e.g., ventricular tachycardia.
    • e.g., ventricular fibrillation.
  16. Antiarrhythmics mechanisms of action
    • some drugs have multiple actions and therefore belong to more than one class.
    • Therapy has to be highly individualized and depends on type of arrhythmia, pre-existing conditions, ability to tolerate side effects, etc.
    • Since there are quite a few drugs, you are responsible for the prototype in each group.
    • Again, many of the drugs are used interchangeably for treating hypertension, arrhythmias, angina or congestive heart failure.
    • 1) Na+ channel blockade
    • 2) Beta-adrenergic blockade
    • 3) Prolonged repolarization
    • 4) Ca2+ channel blockers- the main 2 used as antiarrhythmics are listed here
    • 5) miscellaneous- everything else that doesn’t fit in previous categories
    • -the other thing to recognize abt antiarrhythmic drugs: therapy for each drug must be highly individualized, depending on the type of arrhythmias, preexisting conditions, ability of pt to tolerate various side-effects
    • -you are responsible for one prototype for each group- we will go over each in subsequent slides; unless another drug is mentioned a lot in lecture
    • -many of these drugs are used interchangeably to treat other CV diseases (congestive heart failure, angina, HTN), not just arrhythmia
  17. Class IA antiarrhythmics
    • exhibit local anesthetic-like action; mechanism of action is use-dependent block of Na+ channels
    • usually administered 1-2 days prior to DC cardioversion. Patients commonly revert to sinus rhythm before DC.
    • quinidine
    • Use-dependent block of Na+ channels
    • Action on the heart similar to peripheral nerve
    • Affect the heart at lower concentrations
    • prophylaxis & treatment of supraventricular arrhythmias
    • treatment of ventricular arrhythmias
  18. What are the Consequences of Na channel blockade?
    • 1) increased action potential threshold
    • 2) increased refractory period
    • 3) decreased automaticity
    • 4) decreased conduction velocity

  19. Class IA drugs affect A and C.
    • -effect on automaticity: Class I drugs cause A and C effect
    • A- decrease slope of phase 4, thus reducing automaticity (less frequency of APs)
    • B- hyperpolarization of membrane potential
    • C- increase threshold for potential generation, as in Na+ channel blocking
    • D- increasing AP duration
  20. Class IA side effects:
    • Side effects: nausea, vomiting, diarrhea, tinnitus, loss of hearing, blurred vision.
    • Hypotension from alpha block. 1/3 patients discontinue. Increasingly Class III antiarrhythmics are used to treat atrial fibrillation and flutter.
    • All antiarrhythmics can cause arrhythmias.
    • Class IA: AV node block, torsade de pointes.
    • Some of the effects are due to blockade of K-channels.
    • -GI irritation: nausea, vomiting, abdominal pain
    • -slew of side effects that are collectively termed “cinchonism”: inc tinnitus (ringing in the ears), loss of hearing, blurred vision (prim from muscarinic receptor blockade), hypotension (from alpha adrenergic receptor blockade)
    • -this is a main reason why 1/3rd of the pts end up discontinuing use of the drug, bc they can’t tolerate the side effects; result is increased use of Class III antiarrhythmics
    • -these drugs are also capable of causing arrhythmias, bc of their ability to produce Na+ channel and muscarinic receptor blockage
    • all anti-arrhythmics can cause arrhythmias- you can cause them in the same way that you treat them; the most common arrhythmias seen w Class IA antiarrhythmics are AV node block, and ____?
  21. Class IB antiarrhythmics
    • lidocaine
    • decrease slope of phase-4 depolarization
    • - G-I and CNS side effects
  22. Lidocaine
    • Class IB
    • treatment of ventricular arrhythmias caused by myocardial infarction, open-heart surgery and digitalis intoxication. Administered by i.v. or i.m. route only
  23. b-adrenergic antagonists
    • Class II antiarrhythmatic
    • -olol ending
    • propranolol, acebutolol, esmolol
    • inhibit automaticity in the presence of catecholamines.
    • All cause a substantial decrease in conduction at the AV node.
    • The P-R interval is increased without widening of the QRS complex.
    • Propranolol also increases background K+ current in Purkinje fibers similar to lidocaine and phenytoin.
    • Therapeutic uses Management of supraventricular arrhythmias. Also useful in ventricular arrhythmias where catecholamine stimulation is involved.
    • Pharmacokinetics Extensive first-pass metabolism of propranolol. Elimination decreased by decreasing hepatic blood flow (e.g. left ventricular dysfunction).
    • Untoward effects Hypotension; AV block or asystole; sudden withdrawal may produce anginal episodes and myocardial infarction
  24. Class III antiarrhythmics
    • amiodarone, sotalol, bretylium
    • all prolong AP duration and refractoriness
    • used to treat ventricular and
    • supraventricular arrhythmias
    • any AP prolonging drug will produce a large increase in effective refractory period (see right)- the main mechanism by which these drugs decrease automaticity
    • Diverse pharmacological properties, yet share the ability to prolong AP duration and refractoriness in Purkinje and ventricular muscle fibers.
    • All interact significantly with the autonomic nervous system.
    • Therapeutic uses
    • Bretylium - life-threatening ventricular arrhythmias; amiodarone - recurrent ventricular fibrillation, sustained ventricular tachycardia resistant to other drugs as well as atrial fib. and flutter.
    • Pharmacokinetics: Variable, depending on drug. Bretylium is eliminated by renal excretion without metabolism. Amiodarone has an active metabolite.
    • Untoward effects: Hypotension, arrythmias; amiodarone has a large number of diverse effects (esp. with long-term administration) on various organ systems.
  25. Class IV antiarrhythmics
    • Ca2+ channel blockers
    • verapamil, diltiazem
    • treatment of PSVT
    • Paroxysmal supraventricular tachycardia –usually caused by AV node re-entry
    • The clinically important consequences of Ca2+ channel blockade are depression of Ca2+-dependent action potentials and conduction at the AV node. Both drugs prolong the P-R interval and decrease ventricular rate in patients with atrial fibrillation.
    • Therapeutic uses Primarily for treatment of paroxysmal supraventricular tachycardia and atrial flutter or fibrillation. Contraindicated in patients with sick sinus syndrome.
    • Pharmacokinetics First-pass metabolism, peak effects within 15 min of i.v. administration.
    • Untoward effects Hypotension; AV block; constipation; gingival hyperplasia, decreased myocardial contractility.
  26. Miscellaneous antiarrhythmics
    • Adenosine - endogenous purine nucleoside
    • Ca2+ channel blockade
    • Increases gK+
    • decreases SA node & Purkinje fiber automaticity
    • decreases AV node conduction
    • treatment of paroxysmal supraventricular tachycardia
    • Main effects via A1 receptor activation.
    • Used intravenously usually as a bolus to terminate attack.
    • Short duration of action.
    • Side effects: hypotension, bronchoconstriction.
    • Digitalis glycosides will be covered in a separate lecture.
    • -will not see this drug, bc it is used in a hospital setting, to terminate supraventricular tachycardia
  27. Implications for dentistry
    • use of vasoconstrictors
    • stress
    • orthostatic hypotension (most antiarrythmic drugs)
    • salivary inhibition (with quinidine & disopyramide)
    • oral anticoagulants (with phenytoin & quinidine)
    • gingival hyperplasia (with phenytoin & verapamil)