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How can the frequency of pacemaker discharge be varied?
- 1) rate of phase 4 depolarization,
- 2) threshold potential, or
- 3) "resting membrane potential" (Vm).
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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.
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How does norepinephrine affect pacemaker firing frequency?
Release of norepinephrine causes an increase in the slope of the pacemaker potential.
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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.
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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
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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.
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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.
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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
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Altered normal automaticity
- (abnormal impulse generation)
- 1. Sick Sinus Syndrome
- 2. Increased automaticity of the His-Purkinje system
- 3. Prolonged reduction in Vm
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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
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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.
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Repetitive discharge due to substantial reductions in Vm
may occur in Purkinje fibers, atrial cells and ventricular cells.
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Irregular triggered activity
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(abnormal impulse generation)
- 1. Early afterdepolarizations
- 2. Delayed afterdepolarizations
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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.
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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
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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
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What are the Consequences of Na channel blockade?
- 1) increased action potential threshold
- 2) increased refractory period
- 3) decreased automaticity
- 4) decreased conduction velocity
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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
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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 ____?
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Class IB antiarrhythmics
- lidocaine
- decrease slope of phase-4 depolarization
- - G-I and CNS side effects
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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
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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
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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.
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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.
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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
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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)
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