Nodal conductance

After po dosing, verapamil s absorption is rapid and almost complete (>90%). There is extensive first-pass hepatic metabolism and only 10—35% of the po dose is bioavahable. About 90% of the dmg is bound to plasma proteins. Peak plasma concentrations are achieved in 1—2 h, although effects on AV nodal conduction may be apparent in 30 min (1—2 min after iv adrninistration). Therapeutic plasma concentrations are 0.125—0.400 p.g/mL. Verapamil is metabolized in the liver and 12 metabolites have been identified. The principal metabolite, norverapamil, has about 20% of the antiarrhythmic activity of verapamil (3). The plasma half-life after iv infusion is 2—5 h whereas after repeated po doses it is 4.5—12 h. In patients with liver disease the elimination half-life may be increased to 13 h. Approximately 50% of a po dose is excreted as metabolites in the urine in 24 h and 70% within five days. About 16% is excreted in the feces and about 3—4% is excreted as unchanged dmg (1,2). 

Patients having high plasma renin activity (PRA) (>8 ng/(mLh)) respond best to an ACE inhibitor or a -adrenoceptor blocker those having low PRA (<1 ng/(mLh)) usually elderly and black, respond best to a calcium channel blocker or a diuretic (184). -Adrenoceptor blockers should not be used in patients who have diabetes, asthma, bradycardia, or peripheral vascular diseases. The thiazide-type diuretics (qv) should be used with caution in patients having diabetes. Likewise, -adrenoceptor blockers should not be combined with verapamil or diltiazem because these dmgs slow the atrioventricular nodal conduction in the heart. Calcium channel blockers are preferred in patients having coronary insufficiency diseases because of the cardioprotective effects of these dmgs. 

In randomized, controlled, clinical trials, calcium channel blockers were as effective as p-blockers at preventing ischemic symptoms. Calcium channel blockers are recommended as initial treatment in IHD when /3-blockers are contraindicated or not tolerated. In addition, CCBs may be used in combination with /3-blockers when initial treatment is unsuccessful. However, the combination of a (1-blocker with either verapamil or diltiazem should be used with extreme caution since all of these drugs decrease AV nodal conduction, increasing the risk for severe bradycardia or AV block when used together. If combination therapy is warranted, a long-acting dihydropyridine CCB is preferred. (3-Blockers will prevent reflex increases in sympathetic tone and heart rate with the use of calcium channel blockers with potent vasodilatory effects. 

The goals of treatment of AF are (1) ventricular rate control with drugs that inhibit AV nodal conduction (2) restoration... 

Ventricular Rate Control is achieved by inhibiting the proportion of electrical impulses conducted from the atria to the ventricles through the AV node. Therefore, drugs that are effective for ventricular rate control are those that inhibit AV nodal impulse conduction P-blockers, diltiazem, verapamil, and digoxin (Tables 6-5 and 6-6). Amiodarone also inhibits AV nodal conduction, but is not a preferred drug for ventricular rate control in AF due to its unfavorable adverse-effect profile (Table 6-6). 

P-Blockersa Inhibit AV nodal conduction by slowing AV nodal conduction and prolonging AV nodal refractoriness Esmolol 500 mcg/kg IV over 1 minute Propranolol 0.15 mg/kg IV Metoprolol 2.5-5 mg IV x 2-3 doses Esmolol 50-200 mcg/kg/minute continuous infusion Propranolol 80-240 mg/day Metoprolol 50-200 mg/day ... 

Diltiazem Inhibits AV nodal conduction by slowing AV nodal conduction and prolonging AV nodal refractoriness 1.0.25 mg/kg IV load over 2 minutes 2. If necessary, 0.35 mg/kg IV over 2 minutes after first dose Continuous infusion of 5-1 5 mg/hour Oral 120-360 mg/day Inhibits elimination of cyclosporine... 

Digoxin Inhibits AV nodal conduction by 1. Vagal stimulation 2. Directly slowing AV nodal conduction and prolonging AV nodal refractoriness 0.25 mg every 2 hours up to 1.5 mg 0.125-0.25 mg PO once daily Amiodarone, verapamil, quinidine inhibit digoxin elimination... 

Vagal maneuvers Maneuvers that stimulate the activity of the parasympathetic nervous system and thereby inhibit atrioventricular nodal conduction. Examples of vagal maneuvers include cough, carotid sinus massage, and Valsalva maneuver. 

Verapamil decreases heart rate, slows atrioventricular (AV) nodal conduction, and produces a negative inotropic effect that may precipitate heart failure in patients with borderline cardiac reserve. Diltiazem decreases AV conduction and heart rate to a lesser extent than verapamil. 

Pharmacology Therapeutic concentrations of lidocaine attenuate phase 4 diastolic depolarization, decrease automaticity and cause a decrease or no change in excitability and membrane responsiveness. Action potential duration and effective refractory period (ERP) of Purkinje fibers and ventricular muscle are decreased, while the ratio of ERP to action potential duration is increased. Lidocaine raises ventricular fibrillation threshold. AV nodal conduction time is unchanged or shortened. Lidocaine increases the electrical stimulation threshold of the ventricle during diastole. 

Cardiac conduction IV verapamil slows AV nodal conduction and SA nodes it rarely produces second- or third-degree AV block, bradycardia, and in extreme cases, asystole. This is more likely to occur in patients with sick sinus syndrome. 

Amiodarone, like its major metabolite desethylamiodarone, increases A-V nodal conduction time and refractory period. 

There are few absolute contraindications, but several points should be considered. Medications that produce changes in sinus node or AV nodal conduction may potentiate the cardiovascular adverse effects of the a2 agonists. This may be particularly relevant for concomitant administration of beta-blockers, which, similar to the agonists, have been used to treat aggression. 

Verapamil blocks both activated and inactivated L-type calcium channels. Thus, its effect is more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current, such as the sinoatrial and atrioventricular nodes. Atrioventricular nodal conduction time and effective refractory period are invariably prolonged by therapeutic concentrations. Verapamil usually slows the sinoatrial node by its direct action, but its hypotensive action may occasionally result in a small reflex increase of sinoatrial nodal rate. 

Adenosine is a nucleoside that occurs naturally throughout the body. Its half-life in the blood is less than 10 seconds. Its mechanism of action involves activation of an inward rectifier K+ current and inhibition of calcium current. The results of these actions are marked hyperpolarization and suppression of calcium-dependent action potentials. When given as a bolus dose, adenosine directly inhibits atrioventricular nodal conduction and increases the atrioventricular nodal refractory period but has lesser effects on the sinoatrial node. Adenosine is currently the drug of choice for prompt conversion of paroxysmal supraventricular tachycardia to sinus rhythm because of its high efficacy (90-95%) and very short duration of action. It is usually given in a bolus dose of 6 mg followed, if necessary, by a dose of 12 mg. An uncommon variant of ventricular tachycardia is adenosine-sensitive. The drug is less effective in the presence of adenosine receptor blockers such as theophylline or caffeine, and its effects are potentiated by adenosine uptake inhibitors such as dipyridamole. 

Propranolol 13- Adrenoceptor blockade Direct membrane effects (sodium channel block) and prolongation of action potential duration slows SA node automaticity and AV nodal conduction velocity Atrial arrhythmias and prevention of recurrent infarction and sudden death Oral, parenteral duration 4-6 h Toxicity Asthma, AV blockade, acute heart failure Interactions With other cardiac depressants and hypotensive drugs... 

Verapamil Calcium channel (ICa-i type) blockade Slows SA node automaticity and AV nodal conduction velocity decreases cardiac contractility t reduces blood pressure Supraventricular tachycardias Oral, IV hepatic metabolism caution in patients with hepatic dysfunction Toxicity Interactions See Chapter 12... 

The response of older individuals to calcium channel antagonists is a combination of changes in direct drug effects and age-related alterations in reflex responses to drug effect. Hypotensive responses are maintained because direct arterial vasodilatation remains intact/ even though there is the age-related impairment in reflex sympathetic stimulation/ as previously noted (55). For verapamil and diltiazeni/ atrioventricular nodal conduction delay is less in older than... 

Several reviews of the clinical pharmacology, actions, therapeutic uses, and adverse reactions and interactions of adenosine and ATP have appeared (1-4). After intravenous administration adenosine enters cells, disappearing from the blood with a half-life of less than 10 seconds intracellularly it is phosphorylated to cyclic AMP. Its mechanism of action as an antidysrhythmic drug is not known, but it may act by an effect at adenosine receptors on the cell membrane. Its electrophysiological effects are to prolong AV nodal conduction time by prolonging the AH interval, without an effect on the HV interval. The pharmacological and adverse effects of adenosine triphosphate are similar to those of adenosine. 

Although drugs of class Ic, such as propafenone, can slow atrial and atrioventricular nodal conduction in patients with atrial fibrillation or atrial flutter, they do not alter the refractoriness of the atrioventricular node, and this allows 1 1 atrioventricular conduction as the atrial rate slows. This happens despite prolongation of the PR interval. 

Case Conclusion Diuretics and beta-blockers are first-line agents for treating HTN. Because this patient has asthma, beta-blockers should be avoided. Calcium channel blockers are favorable therapeutic options in patients with both angina and HTN. Because her heart rate is low, diltiazem and verapamil are not optimal choices because they can slow down AV nodal conduction. A long-acting dihydrof ridine, amlodipine, was started. 

C Diltiazem. Quinidine can be used to maintain normal sinus rhythm (NSR) after cardioversion of atrial fibrillation. Metoprolol is commonly used to control ventricular rate before conversion to NSR. However, this patient has two contraindications (COPD and diabetes) for beta-blocker use. Unlike diltiazem, amlodipine and nimodipine do not block AV nodal conduction therefore, they would be ineffective at rate control. 

Propranolol and sotalol are non-selective (1-ad renoceptor antagonists that differ in the relative contributions of their (h-blocking (decreased atrioventricular nodal conduction, propranolol) and direct membrane (prolonged... 

Patients may present with a slow ventricular response (in the absence of AV nodal-blocking drugs) and thus do not require therapy with digoxin, verapamil, or esmolol. This type of presentation should alert the clinician to the possibility of preexisting SA or AV nodal conduction disease such as sick sinus syndrome. DCC should not be attempted in these patients without a temporary pacemaker in place (see below). 

Answer D. An increase in AV conduction is characteristic of quinidine, which exerts quite marked blocking actions on muscarinic receptors in the heart. Thus, an atrial rate, formerly transmitted to the ventricles in a 2 1 ratio, may be transmitted in a 1 1 ratio after quinidine. This effect of quinidine can be offset by the prior administration of an antiar-rhythmic drug that decreases AV nodal conduction, such as digoxin or verapamil. All of the drugs listed (except quinidine) slow AV nodal conduction, but adenosine and esmolol (a beta blocker) are very short-acting agents used IV only. 

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