- •Contents
- •1. Pharmacokinetics
- •3. Practice Questions
- •2. Antiarrhythmic Drugs
- •3. Antihypertensive Drugs
- •3. Anticonvulsants
- •5. Opioid Analgesics
- •8. Drugs of Abuse
- •1. Antibacterial Agents
- •4. Antiprotozoal Agents
- •1. Histamine and Antihistamines
- •3. Drugs Acting on Serotonergic Systems
- •1. Drugs Used in Diabetes
- •2. Steroid Hormones
- •6. Endocrine Drug List
- •1. Anticancer Drugs
- •1. Immunopharmacology
- •1. Toxicology
- •2. Toxicology Practice Questions
- •Index
Antiarrhythmic Drugs |
2 |
CLASS I: Na+ CHANNEL BLOCKERS
Class 1A
•Antiarrhythmic: block fast Na+ channels (-i INa)
•Preferentially in the open or activated state-"state-dependent" blockade
•I action potential duration (APD) and effective refractory period (ERP)
•Also blocks K+ channel (prolongs repolarization)
•Drugs:
-Quinidine
0 In addition to the above, causes muscarinic receptor blockade, which can t HR and AV conduction.
0 May also cause vasodilation via alpha block with possible reflex tachycardia.
0 Orally effective, wide clinical use in many arrhythmias; in atrial fibrillation, need initial digitalization to slow AV conduction.
0 Adverse effects: cinchonism (GI, tinnitus, ocular dysfunction, CNS excitation), hypotension, prolongation of QRS and t QT interval associated with syncope (torsades).
0 Drug interactions: hyperkalemia enhances effects and vice versa; dis- places digoxin from tissue binding sites, enhancing toxicity.
Procainamide
0 Less muscarinic receptor block
0 Metabolized via N-acetyltransferase (genotypic variation) to N-acetyl procainamide (NAPA), an active metabolite
0 Adverse effects: systemic lupus erythematosus (SLE)-like syndrome (30% incidence) more likely with slow acetylators; hematotoxicity (thrombocytopenia, agranulocytosis); CV effects (torsades)
Class 18
•Antiarrhythmic: block fast Na+ channels (-iIN)
•Block inactivated channels-preference for tissues partly depolarized (slow conduction in hypoxic and ischemic tissues). This results in an increased threshold for excitation and less excitability of hypoxic heart muscle.
•-i APD-due to block of the slow Na+ "window" currents, but this increases diastole and extends the time for recovery.
Note
For the exam, you should understand which effect is antiarrhythmic (slows heart) and which is proarrhythmic (speeds up heart) .
Note
Quinidine is a weak base, and antacids increase its absorption, th us greatly increasing its toxicity.
MEDICAL 89
Section Ill • Cardiac and Renal Pharmacology
• Drugs and uses:
Lidocaine
0Post-MI
0Open-heart surgery
0Digoxin toxicity
0Side effects: CNS toxicity (seizures); least cardiotoxic of conven- tional anti-arrhythmics
0IV use because of first-pass metabolism
Me:xiletine
0Same uses as lidocaine
0Oral formulations
Class lC
•Block fast Na+ channels (-1.INa), especially His-Purkinje tissue
•No effect on APD
•No ANS effects
•Drug:
-Flecainide
0 Limited use because of proarrhythmogenic effects, leading to i in sudden death post-MI and when used prophylactically in VT
CLASS II: BETA BLOCKERS
•Prevent -receptor activation, which would normally i cAMP
•-1- SA and AV nodal activity
• -1- Slope of phase 4 (diastolic currents) of AP in pacemakers
•Drugs:
-Propranolol (nonselective) and the cardioselective drugs: acebutolol and esmolol
-Uses:
0 Prophylaxis post-MI and in supraventricular tachyarrhythmias
(SVTs)
0 Esmolol (IV) is used in acute SVTs
CLASS Ill: K+ CHANNEL BLOCKERS
• -1- IK (delayed rectifier current) slowing phase 3 (repolarization) ofAP
•i APD and ERP, especially in Purkinje and ventricular fibers
•Drugs:
-Amiodarone
0 Mimics classes I, II, III, and IV
0 Increase APD and ERP in all cardiac tissues
0 Uses: any arrhythmias
0 t112 >80 days
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0Binds extensively to tissues (large Vd and multiple effects)
0Side effects:
Pulmonary fibrosis
Blue pigmentation of the skin ("smurf skin")
Phototoxicity
Corneal deposits
Hepatic necrosis
Thyroid dysfunction
Sotalol:
0..J, IK, slowing phase III
0Non-selective beta blocker: 1 blockade, leading to ..J, HR, ..J, AV
conduction
0Use: life-threatening ventricular arrhythmia
0Side effects: torsades
CLASS IV: Ca2+ CHANNEL BLOCKERS
•Block slow cardiac Ca2+ channels
•..J, phase 0, ..J, phase 4
•..J, SA, ..J, AV nodal activity
•Drugs:
Verapamil and diltiazem
0Prototype Ca2+-channel blockers (see Antihypertensive Drugs and Antianginal Drugs chapters in this section)
0Uses: supraventricular tachycardias
0Side effects: constipation (verapamil), dizziness, flushing, hypoten sion, AV block
0Drug interaction:
Additive AV block with -blockers, digoxin
Verapamil displaces digoxin from tissue-binding sites
UNCLASSIFIED
• Adenosine
Activates adenosine receptors: causes Grcoupled decrease in cAMP
J. SA and AV nodal activity
-Uses: DOC for paroxysmal supraventricular tachycardias and AV nodal arrhythmias
Administered IV: t112 <10 seconds
Side effects: flushing, sedation, dyspnea
Adenosine is antagonized by methylxanthines (theophylline and caffeine)
•Magnesium
Use: torsades
Drugs causing torsades include:
0Potassium-channel blockers (class lA and class III)
0Antipsychotics (thioridazine)
0Tricyclic antidepressants
Chapter 2 • Antiarrhythmic Drugs
Clinical Correlate
Long QTSyndrome
A familial condition associated with increased risk ofventricular arrhythmias may result from mutation in the gene encoding cardiac potassium channels. Class IA and class Ill antiarrhythmic drugs may increase the risk oftorsades in such patients.
Treatment ofTorsades
•Correct hypokalemia.
•Correct hypomagnesemia.
•Discontinue drugs that prolong the QT interval.
•Attempt to shorten
APD with drugs (e.g., isoproterenol) or electrical pacing.
Clinical Correlate
Potassium
Both hyperkalemia and hypokalemia are arrhythmogenic.
MEDICAL 91
Section Ill • Cardiac and Renal Pharmacology
Chapter Summary
•The class I antiarrhythmic drugs block Na+ channels. Class IA drugs are state-dependent blockers of fast Na+ channels, and they increase the action potential duration (APO). Quinidine, in addition, is an M blocker and can increase the heart rate and AV conduction. Procainamide has less M block than quinidine and no alpha block. The uses and contraindications of quinidine and procainamide are provided.
•Class IB drugs are less state-dependent blockers offast Na+ channels, and they decrease the APO. The uses for lidocaine, mexiletine, and tocainide are discussed, as are the metabolism and adverse effects of lidocaine.
•The class IC drug flecainide blocks fast Na+ channels, especially of His
Purkinje cells, and has no effect on the APO and no ANS effects.
•Class II antiarrhythmic drugs are beta-blockers that decrease SA and AV nodal activity, decrease the phase 4 slope, and prevent 1 adrenoceptor activation, thereby circumventing the normal increase in cAMP. Propranolol is nonselective; acebutolol and esmolol are selective. Their antiarrhythmic use is discussed.
•Class Ill antiarrhythmic drugs are K+-channel blockers that increase the APO
and effective refractory period (ERP), especially in Purkinje and ventricular tissues. Amiodarone and sotalol are the examples discussed.
•Class IV antiarrhythmic drugs are Ca2+-channel blockers that decrease the SA and AV nodal activity and the slope of phase 4 ofthe action potential in pacemakers. The uses and adverse effects ofverapamil are indicated.
•Adenosine and magnesium are two unclassified antiarrhythmic drugs. Adenosine decreases SA and AV node activity and increases the AV node refractory period. Magnesium has possible use in torsades. Drugs (other than classes la and Ill antiarrhythmics) associated with torsades include thioridazine and tricyclic antidepressants.
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