Agents used in the treatment of HT, CHF, Arrhythmia and Angina

Drug Class Hyper- CHF Arrhyt Angina Contraindications/Cautions

tension
Antiarrhythmias aa
hmia Notes
Beta-Blockers aaa aaa aaa Caution: CHF (unstable CHF,
a a a bronchospasm, significant
bradycardia); diabetes, asthma (use
1-selective)
Ca++-Blockers aaa aaa aaa CHF, gingival hyperplasia,
Edward JN Ishac, Ph.D. a a a constipation, cardiac depress
ACEI or ARBs aaa aaa Low GFR, renal stenosis, glossitis,
a a tetrogenic, dry cough (ACEI), taste,
Smith Building, Room 742
hyperkalemia
eishac@hsc.vcu.edu Diuretics aaa aaa Low GFR, hypokalemia (CG);
828-2127 a glucose intolerance (diabetes)
Cardiac aaa a Many Rx interactions, [K+]
glycosides a important, low K+toxicity
Department of Pharmacology and Toxicology Vasodilators aaa aa Flushing, dizziness, headache,
reflex tachycardia, combo Rx
Medical College of Virginia
Campus of Virginia Commonwealth University Na+-Channel aaa Effects enhanced in depolarized
blockers a tissue
Richmond, Virginia, USA
Nitrates aa aaa Tolerance, flushing, dizziness,
a headache, reflex tachycard, ED Rx

Heart Physiology

Closed system Pressure driven

Supply nutrients/O2 Remove metabolites

Heart Physiology Heart Physiology

P - atria depolarization
QRS - ventricle depolarization Closed system
PR - conduction A-V Pressure driven
T - ventricle repolarization Supply nutrients/O2
Remove metabolites
QT - duration ventricle of repolarization

P - atria depol.
QRS - ventricle depol.
PR - conduction A-V
T - ventricle repol.
QT - duration
ventricle repolarization

1
 Ion Permeability
Cardiac Action Potentials mM Na+ K+ Ca++
mM Na+ K+ Ca++
Ion Flow Out 140 4 2.5
Out 140 4 2.5
In 10 150 0.1
In 10 150 0.1
1 0 Na+i - open
2
0 Na+i - open
1 Na+ - close
1 Na+ - close 3 K+o - open/close
K+o - open/close O
2 Ca++i - open
2 Ca++i - open
4 4 K+o - leak
K+o - leak
3 Ca++ - close
1 2 3 Ca++ - close
K+o - open
K+o - open
3 4 K+ - close
0
4 4 4 K+ - close

Na+/Ca++ - exchange (3:1)

Na+/Ca++ - exchange (3:1) Na+/K+ - ATPase (3:2)
Na+/K+ - ATPase (3:2)

Characteristics of Arrhythmias Classification of arrhythmia

Definitions: 1. Characteristics:
- normal sinus rhythm (60-90bpm), SA node pacemaker a. flutter very rapid but regular contractions
- arrhythmia; any abnormality of firing rate, regularity or b. tachycardia increased rate
site of origin of cardiac impulse or disturbance of c. bradycardia decreased rate
conduction that alters the normal sequence of activity of
atria and ventricles. d. fibrillation disorganized contractile activity

2. Sites involved:
Occurrence: a. ventricular
- 80% of patients with acute myocardial infarctions b. atrial
- 50% of anaesthetized patients c. sinus
- about 25% of patients on digitalis d. AV node
e. Supraventricular (atrial myocardium or AV node)

Examples of Arrhythmias Mechanisms of arrhythmias

1. Abnormal impulse generation (abnormal automaticity)

a. automaticity of normally automatic cells (SA, AV, His)
b. generation of impulses in normally non-automatic cells
- development of phase 4 depolarization in normally
non-automatic cells
- triggered activity due to afterdepolarizations
- early afterdepolarization
- delayed afterdepolarization

2. Abnormal impulse conduction (more common mechanism)

a. AV block ventricle free to start own pacemaker rhythm
b. Re-entry: re-excitation around a conducting loop, which
produces tachycardia
- unidirectional conduction block
- establishment of new loop of excitation
- conduction time that outlasts refractory period

2
 Heart Physiology Unidirectional Block
Closed system
Pressure driven
Supply nutrients/O2 Damaged tissue is usually depolarized conduction velocity
Remove metabolites

P - atria depol.
QRS - ventricle depol.
PR - conduction A-V
T - ventricle repol.
QT - duration
ventricle repolarization

Strategy of Antidysrhythmic Agents

Classification of Antidysrhythmic Drugs
Suppression of dysrhythmias

A. Alter automaticity Vaughan-Williams classification (1970),

i. decrease slope of Phase 4 1
2
depolarization
ii. increase the threshold potential
subsequently modified by Harrison.
iii. decrease resting (maximum 3
diastolic) potential
O
Helpful, But?
B. Alter conduction velocity 4 4
i. mainly via decrease rate of
rise of Phase 0 upstroke
ii. decrease Phase 4 slope 1. based on electrophysiological actions in normal tissue
iii. decrease membrane resting
potential and responsiveness 2. presumes a mechanism of action of antidysrhythmic
drugs
C. Alter the refractory period 3. consists of four main classes and three subclasses
i. increase Phase 2 plateau
ii. increase Phase 3 repolarization 4. does not include actions of other agents (ie. adenosine)
iii. increase action potential
duration

Vaughan-Williams Classification
mM Na+ K+ Ca++
Subclass Mechanism Prototype Action Potential Ion Flow Out 140 4 2.5
IA. Mod. block Ph.0; slow conduction; APD Quinidine
Procainamide In 10 150 0.1
IB. Min. block Ph.0; slow conduction (less); shorten Lidocaine
Ph.3 repolarization Phenytoin 1
2 0 Na+i - open
IC. Marked block Ph.0; slow conduction; no change Flecainide
APD or repolarization. Increased suppression Encainide
1 Na+ - close
3 K+o - open/close
of Na channels
O
Class II Beta blockers; decrease adrenergic input. No major Propranolol 2 Ca++i - open
effect on APD, suppress Ph.4 depolarization others 4 4 K+o - leak
Class III Prolong repolarization/refractory period other Amiodarone
means than exclusively iNa block (mainly K+ Bretylium 3 Ca++ - close
channel blockade). K+o - open
Class IV Ca channel blockers. Slow conduction and Verapamil
4 K+ - close
effective refractory period in normal tissue (A-V Diltiazem
node) and Ca-dependent slow responses of
depolarized tissue (atria, ventricle, Purkinje) Na+/Ca++ - exchange (3:1)
Others Adenosine, Digoxin, Anticoagulants, ANS agents Na+/K+ - ATPase (3:2)

3
 Electrophysiological Properties Of Specialized Cardiac Fibers
ACC/AHA Classification of Agents
CLASS OF ANTIARRHYTHMIC DRUG

IA IB IC II III IV
Class1: Conditions for which there is evidence and/or
general agreement that a given procedure or treatment is
Sinus node 0, 0 0 ,
useful and effective. Automaticity
Class II: Conditions for which there is conflicting AV node
Effective refractory , 0, 0, , 0,
evidence and/or a divergence of opinion about the period (ERP)
usefulness/efficacy of a procedure or treatment. Purkinje fibers
Class IIa: Weight of evidence/opinion is in favor of Action potential amplitude 0, , 0 0 0
usefulness/efficacy. Phase-0 Vmax 0, , 0, 0, 0
Action potential
Class IIb: Usefulness/efficacy is less well established by duration (APD) , , 0, 0,
evidence/opinion.
Effective refractory
Class III: Conditions for which there is evidence and/or period (ERP) , , 0, 0,
general agreement that the procedure/treatment is not
useful/effective and in some cases may be harmful. ERP/APD 0 0
Membrane responsiveness 0, 0 0
Automaticity , 0 , 0,

Quinidine (Class IA prototype) Actions of Quinidine

Other examples: Procainamide, Disopyrimide
1. General properties:
Cardiac effects
a. D-isomer of quinine
b. As with most of the Class I agents a. automaticity, conduction velocity and excitability of
- moderate block of sodium channels cardiac cells.
- decreases automaticity of pacemaker cells
b. Preferentially blocks open Na channels
- increases effective refractory period/AP duration
c. Recovery from block slow in depolarized tissue; lengthens
refractory period (RP)
d. All effects are potentiated in depolarized tissues
e. Increases action potential duration (APD) and prolongs AP
repolarization via block of K channels; decreases reentry
f. Indirect action: anticholinergic effect (accelerates heart), which
can speed A-V conduction.

Actions & Toxicity of Quinidine Quinidine: Pharmacokinetics/therapeutics

.
a. Oral, rapidly absorbed, 80% bound to membrane proteins
Extracardiac
b. Hydroxylated in liver; T1/2 = 6-8 h
a. Blocks alpha-adrenoreceptors to yield vasodilatation.
b. Other strong antimuscarinic actions c. Drug interaction: displaces digoxin from binding sites; so avoid giving
drugs together
d. Probably are active metabolites of quinidine
Toxicity
- "Quinidine syncope"(fainting)- due to disorganized ventricular e. Effective in treatment of nearly all dysrhythmias, including:
tachycardia 1) Premature atrial contractions
- associated with greatly lengthened Q-T interval; can lead to 2) Paroxysmal atrial fibrillation and flutter
Toursades de Pointes (precursor to ventricular fibrillation) 3) Intra-atrial and A-V nodal reentrant dysrhythmias
- negative inotropic action (decreases contractility) 4) Wolff-Parkinson-White tachycardias (A-V bypass)
- GI - diarrhea, nausea, vomiting
f. Especially useful in treating chronic dysrhythmias requiring outpatient
- CNS effects - headaches, dizziness, tinnitus (quinidine treatment
Cinchonism)

4
 Procainamide (Class 1A) Lidocaine (Class IB prototype)
Cardiac effects Other examples: Mexiletine, Phenytoin, Tocainide
a Similar to quinidine, less muscarinic & alpha-adrenergic blockade
b. Has negative inotropic action also General
a. Commonly used antidysrhythmic agent in emergency care (decreasing use)
Extracardiac effects b. Given i-v and i-m; widely used in ICU-critical care units (old DOC, prior 2001)
a. Ganglionic blocking reduces peripheral vascular resistance c. Low toxicity
d. A local anesthetic, works on nerve at higher doses
Toxicity
a. Cardiac: Similar to quinidine; cardiac depression
b. Noncardiac: Syndrome resembling lupus erythematosus

Pharmacokinetics/therapeutics
a. Administered orally, i-v and intramuscularly
b. Major metabolite in liver is N-acetylprocainamide (NAPA), a weak Na
channel blocker with class III activity. Bimodal distribution in population of
rapid acetylators, who can accumulate high levels of NAPA.
c. T1/2 = 3-4 hours; necessitates frequent dosing; kidney chief elimination
path. NAPA has longer T1/2 and can accumulate
d. Usually used short-term. Commonly used in CCUs for ventricular
dysrhythmias associated with acute myocardial infarctions (MI)

Lidocaine Actions
Phenytoin (Class IB)
Cardiac effects
a. Generally decreases APD, hastens AP repolarization, decreases
automaticity and increases refractory period in depolarized cells.
b. Exclusively acts on Na channels in depolarized tissue by blocking 1. Non-sedative anticonvulsant used in treating epilepsy
open and inactivated Na channels ('Dilantin')
c. Potent suppresser of abnormal activity
d. Most Na channels of normal cells rapidly unblock from lidocaine 2. Limited efficacy as antidysrhythmic (second line
during diastole; few electrophysiological effects in normal tissue antiarrythmic)
Toxicity: - least cardiotoxic, high dose can lead to hypotension 3. Suppresses ectopic activation by blocking Na and Ca
- tremors, nausea, slurred speech, convulsions channels
Pharmacokinetics/therapy 4. Especially effective against digitalis-induced
a. i-v, i-m since extensive first pass hepatic metabolism dysrhythmias
b. T1/2 = 0.5-4 hours
c. Effective in suppressing dysrhythmia associated with depol. tissue 5. T1/2 = 24 hr - metabolized in liver
(ischemia; digitalis toxicity); ineffective against dysrhythmias in
normal tissue (atrial flutter). 6. Gingival hyperplasia (40%)
d. Suppresses ventricular tachycardia; prevents fibrillation after acute
MI; rarely used in supraventricular arrythmias

Flecainide (Class IC prototype)

Gingival Hyperplasia
Other examples: Lorcainide, Propafenone, Indecainide, Moricizine
Depress rate of rise of AP without change in refractoriness or APD in normally
Phenytoin (Dilantin) anticonvulsant (40%) polarized cells
1. Decreases APD, decreases automaticity, conduction in depolarized cells.
Calcium blockers especially nifedipine (<10%) 2. Marked block of open Na channels (decreases Ph. 0); no change repolarization.
3. Used primarily for ventricular dysrhythmias but effective for atrial too
Cyclosporine immunosuppressant (30%) 4. No antimuscarinic action
5. Suppresses premature ventricular contractions
6. Associated with significant mortality; thus, use limited to last resort applications
like treating ventricular tachycardias

5
 Propranolol (Class II, beta adrenoreceptor blockers) mM Na+ K+ Ca++
Cardiac Action Potentials
Other agents: Metoprolol, Esmolol (short acting), Sotalol (also Class III), Acebutolol
Ion Flow Out 140 4 2.5
a. Slow A-V conduction
b. Prolong A-V refractory period In 10 150 0.1
c. Suppress automaticity

Cardiac effects (of propranolol), a non-selective beta blocker 1 0 Na+i - open

2
a. Main mechanism of action is block of beta receptors; Ph 4 slope. which
decreases automaticity under certain conditions 1 Na+ - close
b. Some direct local anesthetic effect by block of Na channels (membrane
stabilization) at higher doses 3 K+o - open/close
c. Increases refractory period in depolarized tissues O
d. Increases A-V nodal refractory period
2 Ca++i - open
4 4 K+o - leak
Non-cardiac: Hypotension
3 Ca++ - close
Therapeutics K+o - open
a. Blocks abnormal pacemakers in cells receiving excess catecholamines
(e.g. pheochromocytoma) or up-regulated beta-receptors (ie. hyperthyroidism)
b. Blocks A-V nodal reentrant tachycardias; inhibits ectopic foci
4 K+ - close
c. Propranolol used to treat supraventricular tachydysrhythmias
d. Contraindicated in ventricular failure; also can lead to A-V block.
Na+/Ca++ - exchange (3:1)
Oral (propranolol) or IV. Extensive metabolism in liver. Na+/K+ - ATPase (3:2)

Beta-Adenoceptor Antagonists Clinical uses: Beta-Blockers

Angina (non-selective or 1-selective)
- Cardiac: O2 demand more than O2 supply
- Exercise tolerance in angina patients

Arrhythmia (1-selective, LA-action)

- catecholamine-induced increases in conductivity and automaticity

Congestive Heart Failure

- caution with use

Glaucoma (non-selective)
- aqueous humor formation (Timolol)

Other
- block of tremor of peripheral origin (2-AR in skeletal muscle)
- migraine prophylaxis (mechanism unknown)
- hyperthyroidism: cardiac manifestation (only propranolol)
- panic attacks, stage fright

Amiodarone (Class III)

-Blockers: Untoward Effects, Contraindications
General
a. New DOC for ventricular dysrhythmias (Lidocaine, old DOC)
Supersensitivity: b. prolongs refractory period by blocking potassium channels
Rebound effect with -blockers, less with - c. also member of Classes IA,II,III,IV since blocks Na, K, Ca channels and
alpha and beta adrenergic receptors
blockers with partial agonist activity (ie. pindolol). d. serious side effects (cardiac depression, pulmonary fibrosis)
Gradual withdrawal e. effective against atrial, A-V and ventricular dysrhythmias
f. very long acting (>25 d)

Asthma:
Blockade of pulmonary 2-receptors increase in
airway resistance (bronchospasm)

Diabetes:
Compensatory hyperglycemic effect of EPI in
insulin-induced hypoglycemia is removed by block
of 2-ARs in liver. 1-selective agents preferred

6
 Bretylium (Class III, K+ channel blockers) Verapamil (Class IV, Ca++ channel blockers)
Others Amiodarone , Ibutilide, (Sotalol, also beta-blocker) Other example: Diltiazem - Increasing use and importance

General: originally used as an antihypertensive agent a. Blocks active and inactivated Ca channels, prevents Ca entry
b. More effective on depolarized tissue, tissue firing frequently or areas
Cardiac effects where activity dependent on Ca channels (SA node; A-V node)
a. Direct antidysrhythmic action c. Increases A-V conduction time and refractory period; directly slows SA
b. Increases ventricular APD and increases refractory period; decreases and A-V node automaticity
automaticity
d. suppresses oscillatory depolarizing after depolarizations due to digitalis
c. Most pronounced action in ischemic cells having short APD
d. Initially stimulates and then blocks neuronal catecholamine release from
adrenergic nerve terminals
e. Blocks cardiac K channels to increase APD

Extracardiac effects: Hypotension (from block of NE release)

Pharmacokinetics/therapeutics
a. iv or intramuscular
b. Excreted mainly by the kidney
c. Usually for emergency use only: ventricular fibrillation when lidocaine and
cardioversion therapy fail. Increases threshold for fibrillation.
d. Decreases tachycardias and early extrasystoles by increasing effective
refractory period

Ca++ Channel Blockers - Actions Dysrhythmics - Others

Extracardiac
a. Peripheral vasodilatation via effect on smooth muscle
1. Adenosine: i.v. (secs), activates P1 purinergic
b. Used as antianginal / antihypertensive
receptors (A1) coupled to K channels, CV, refractory
c. Hypotension may increase HR reflexively period

Toxicity 2. Potassium ions (K+): Depress ectopic pacemakers

a. Cardiac
- Too negative inotropic for damaged heart, depresses contractility
- Can produce full A-V block 3. Digoxin: used to treat atrial flutter and fibrillation
b. Extracardiac - AV node conduction (vagal stimulation)
- Hypotension - myocardium refractory period
- Constipation, nervousness - Purkinje fibers refractory period, conduction
- Gingival hyperplasia

Pharmacokinetics/Therapeutics 4. Autonomic agents: used to treat A-V block

a. T1/2 = 7h, metabolized by liver - -agonists, anticholinergics
b. Oral administration; also available parenterally
c. Great caution for patients with liver disease
d. Blocks reentrant supraventricular tachycardia (A-V nodal reentrant
5. Anticoagulant therapy:
tachycardia), decreases atrial flutter and fibrillation - prevent formation of systemic emboli & stroke
e. Only moderately effective against ventricular arrhythmias

Cardiac Effects of Antiarrhythmic Drugs Pharmacokinetic Properties of Antiarrhythmic Drugs

Drug Class Auto CV RP APD ANS effects Drug Class Plasma Binding % T1/2 Drug Excretion
Quinidine IA vagal, -block (hrs) Unchanged
Quinidine IA 60 6 20-40%
Procainamide IA vagal, -block
Procainamide IA 15 4 60%
Disopyramide IA vagal, -block
Lidocaine IB 0 Disopyramide IA 39-95 5 50-70%
Tocainide IB 0
Lidocaine IB 40 2 <10%
Mexiletine IB 0
Tocainide IB 10 14 40%
Flecainide IC 0
Mexiletine IB 65 12 10%
Propafenone IC 0 Flecainide IC 45 15 40%
Propranolol II -block Propafenone IC 85 5 <1%
Acebutolol II -block
Propranolol II 90 4 <1%
Esmolol II -block
Sotalol II/III -block Acebutolol II 25 3 40%

Amiodarone III -, -block Esmolol II (hydro. esterase) 9 min <1%

Bretylium III 0 Sympatholytic Sotalol II/III 9 80%

Verapamil IV Amiodarone III 95 > 25 days <1%
Digitalis other vagal stimulation Bretylium III 5 9 80%

More important agents Verapamil IV 90 5 2%

7
 Agents used in the treatment of HT, CHF, Arrhythmia and Angina
Dysrhythmia
Drug Class Hyper- CHF Arrhyt Angina Contraindications/Cautions
Treatment tension hmia Notes
Beta-Blockers aaa aa aaa aaa Caution: CHF (unstable CHF,
a a a bronchospasm, significant
bradycardia); diabetes, asthma (use
1-selective)
Treatment Ca++-Blockers aaa aaa aaa CHF, gingival hyperplasia,
Acute vs Chronic a a a constipation, cardiac depress
ACEI or ARBs aaa aaa Low GFR, renal stenosis, glossitis,
a a tetrogenic, dry cough (ACEI), taste,
hyperkalemia
Site Diuretics aaa aaa Low GFR, hypokalemia (CG);
a
Ventricular vs glucose intolerance (diabetes)
Cardiac aaa a Many Rx interactions, [K+]
Supraventricular a
glycosides important, low K+toxicity
Vasodilators aaa aa Flushing, dizziness, headache,
Old DOC reflex tachycardia, combo Rx
New DOC
Na+-Channel aaa Effects enhanced in depolarized
blockers a tissue
Nitrates aa aaa Tolerance, flushing, dizziness,
a headache, reflex tachycard, ED Rx