OS 213 [A]: Circulation and Respiration
LEC 24: Cardiovascular Pharmacology I
October 2, 2013
Dr. Richard P. Tiongco II
TOPIC OUTLINE
PART 1: Anti-angina Drugs
I.
Drugs for Angina Pectoris
A. Causes of Angina Pectoris
B. Types of Angina Pectoris
C. Pathophysiology of Angina Pectoris
D. Principles of therapy for Angina
II.
Pharmacology of Angina Pectors
A. Direct Agents
B. Indirect Agents
III.
Anti-Anginal Agents
A. Natirates and Nitrites
B. Calcium Channel Blockers
C. Beta Blockers
D. Miscellaneous Antianginal Drugs
PART 2: Anti-Arrhythmia
I.
Arrhythmia
II.
Pharmacology
A. Pharmacology therapy
B. Classes of drugs
C. Clinical Uses
MOSTLY FROM DR. TIONGCO’s Lecture and NOTES
BLOCK A’s transfer 
Remember the video about ion channels
HAND Movement regarding Class I anti-arrhythmic drugs
1
C. Pathophysiology of Angina Pectoris

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

Myocardial ischemia is related to myocardial O2 supply and demand
Physical exercise and sympathetic discharge precipitate angina in
patients with obstructive coronary disease
A globular, large heart is a weakening heart
Coronary blood flow is during DIASTOLE!
Table 1.1. Determinants of Myocardial Oxygen Consumption
 Determined by intraventricular systolic
Wall Tension or
pressure, ventricular volume, and wall
Stress
thickness
 Frank Starling principle: a SMALLER heart is
a more efficient pump (and a LARGER heart is
a weak heart)
 HIGHER tension translates to GREATER
oxygen requirements
 FASTER heart beats require GREATER O2
Heart Rate
 INCREASED heart rate SHORTENS diastolic
filling, DECREASING coronary blood flow
Contractility
 STRONGER heartbeats require GREATER O2
PART 1: DRUGS FOR ANGINA PECTORIS
I. ANGINA PECTORIS





Angina – pain; Pectoris – chest
Squeezing/compressing retrosternal chest discomfort / parang
dinadaganan (typical angina)
May radiate to the arm (left arm, ulnar surface), jaw, shoulder, back,
teeth, and to other dermatomal levels
Typically occurs when the coronary blood flow is inadequate to
supply the O2 required by the heart
75% related to atherosclerosis (hardening of the arteries) – primary
due to hypercholesterolemia and dyslipidemia with inflammation
o 50% stenosis is significant, 70% requires action
A. Causes of Angina Pectoris


Primary cause: imbalance between O2 demand of the heart and
O2 supply via its coronary arteries
May be from the following mechanism:
o Coronary artery disease – atheromatous (lipid and inflammatory
disorder causing blocks), classic angina (precipitated by effort,
described as compressing or squeezing, relieved by nitrates)
o Coronary artery spasm – variant or Prinzmetal angina (you can
get a heart attack purely due to spasm)
o Other causes like hypovolemia (as in gunshot bleeds, losing too
much blood) and anemia (iron deficiency, bone marrow failure)
B. Types of Angina Pectoris



Effort Angina or Classic Angina
o Most common
o Fleeting, infrequent (once a month)
o Due to an atheromatous obstruction of the large coronary
vessels, causing myocardial ischemia
o Chest discomfort and associated symptoms precipitated by some
activity with minimal symptoms at rest
Variant or Prinzmetal Angina
o Due to transient spasm of localized portions of the coronary
vessels, causing significant myocardial ischemia and pain
o With or without atherosclerosis and no stenosis
o No ECG changes
Unstable Angina (Discussed)
o Also called acute coronary syndrome
o Episodes of angina at rest (severe)
o Worsening in character, frequency, and duration of chest pain
o Most common cause: rupture of labile, non-occlusive thrombi
at the site of a fissured or ulcerated plaque (from an
atherosclerosis), reducing blood flow and causing myocardial
ischemia
BUBUCA
Figure 1.1. Pathophysiology of Myocardial Ischemia
(from Braunwald’s Heart Disease, 7th ed)
Note: Blue – end effect, Green – modifiable parameters, Orange Determinants
Table 1.2. Determinants of Coronary Perfusion Myocardial Oxygen
Supply (2016)
Determined by the gradient between aortic
Perfusion Pressure
diastolic pressure and LV end diastolic
pressure (AoP-LVED gradient)
Duration of
Important since coronary flow drops to
Diastole
negligible values during systole
Spasms
May reduce coronary artery perfusion
May enhance coronary artery perfusion (We
Presence of
are all born with collaterals that are closed, but
Collaterals
when we have chest pains, these vessels
open up: different from neovascularization
NOTEs:
1. Increase in wall tension increases endocardial tension which
could lead to stretched (and damaged) actin-myosin filaments
and therefore decreased ability to contract.
2. A large heart may be a sign of a failing heart.
3. The systolic pressure can be decreased by decreasing the
afterload (the heart would then work less less O2 demand).
4. If the Volume (End diastolic volume) is increased, the heart
becomes distended and heavier harder time to contract.
Therefore, preload should be decreased.
5. Opening of collaterals are signaled by chronic ischemia.
6. Lower aortic diastolic pressure (severe AR) -> faster diastolic
time -> less coronary perfusion
D. Principles of Therapy for Angina

Modification of Risk Factors – since cause is atherosclerosis,
address smoking, hypertension, dyslipidemia, diabetes, drug use,
obesity, age, sedentary life style. etc. You have to treat the
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LEC 24: Cardiovascular Pharmacology I OS 213
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underlying cause. Aspirin – 40% decrease in mortality; Statin – 2030% decrease in mortality.
Reduction of Myocardial O2 demand – either slows heart rate or
decreases heart size. A lower heart rate gives more time for filling,
and the heart is able to deliver oxygen properly.
Increase in Coronary Blood Flow
Prevention of morbidity and Mortality – treating the MI/CHF using
anti-platelets, lipid-lowering agents, ACE inhibitors, etc.
II. PHARMACOLOGY OF ANGINA PECTORIS


Remember that drugs can be poisons
In theory, correcting may be made by:
o DECREASING O2 demand (MVO2) – again, by either slowing
heart rate or decreasing heart size
o INCREASING delivery by INCREASING coronary flow

Excretion of glucuronide derivatives of denitrated metabolites largely
by way of the kidney
Table 1.3. Pharmacokinetics of Nitrates and Nitrites (2016)
Dinitro derivatives
significant vasodilator; most of the therapeutic
effect of orally administered nitroglycerin
5-mononitrate
metabolite of isosorbide dinitrate; active; clinically
available as isosorbide mononitrate;
100% bioavailable making it the drug of choice for
the maintenance form
Pharmacodynamics
 nitroglycerin denitrated by glutathione S-transferase, releasing free
nitrite ion, resulting in increase in cGMP and smooth muscle
relaxation
A. DIRECT AGENTS
Figure 1.2. Direct acting agents for Angina



AKA Anti-anginals
Work by DECREASING myocardial O2 requirements (HR, ventricular
volume, BP, and contractility)
Nitrates and Ca2+ channel blockers (CCBs) may:
o Cause redistribution of blood flow and increase O2 delivery
o Reverse coronary arterial spasms
B. Indirect Agents (2016)

Work by addressing the coronary artery disease risk factors to
prevent MI and death
o Antiplatelets (aspirin, clopidogrel, triclopidine, dipyridamole)
o Lipid –lowering agents (statins)
o ACE inhibitors and some ARBs
Figure 1.3. Mechanism of Action of Nitrates and Nitrites
(Brawnwall Cardiology)


Nitrates produce nitric oxide (NO) that act in the same way as
endogenous NO produced by NO synthase in the endothelium
o If stenosis is more than 70%, the medicine will only do so much
NO acts on guanylate cylcase to increase conversion of GTP to
cGMP which would have the following effects:
o Decrease in intracellular calcium, causing vasodilation (relax)
o Inhibits vascular and cardiac Ca ion channels
o Inhibits mitochondrial respiration
III. ANTIANGINAL DRUGS
A. Nitrates and Nitrites

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Nitrates mostly, nitrites are in tocino! Nitrates are more popular.
Mainstay of therapy; provide immediate relief from MI, variant
angina, and unstable angina
Simple nitric and nitrous acid esters of polyalcohol
Prototype drug is nitroglycerin used in dynamite, but of course
medical formulations are not explosive
o Nitrogycerins are photoreactive (should be in brown bottles)
All therapeutically active agents in the nitrate group have identical
mechanisms of actions and similar toxicities
Pharmacokinetics
 Pharmacokinetic factors determine choice of agent and mode of
therapy
 Highly metabolized in the liver (first pass effect).
o Traditional nitrates, such as nitroglycerin,
o Have very low oral bioavailability, that oral nitroglycerin is a
waste of money! Less then 10-20%  given 2-3 times a day.
 Sublingual route is preferred (but for short-acting drugs only)
o When absorbed by the venous plexus, which is present
sublingually, it bypasses the liver, thus no first pass effect.
o Hence, it’s fast!
o Must be properly prepared
 Total duration of effect 15-30 minutes, at least for the short- acting
drugs; oral preparation available for a longer duration of action
(particularly true for mononitrate and isosorbide dinitrate)
o Not ideal as maintenance drug
o Mononitrates should not be given in sublingual
 Low volume of distribution
 Nitroglycerin metabolites (two dinitroglycerins and two mononitro
forms)
BUBUCA
Figure 1.4. Effects on NO on Smooth Muscle Contraction (not
discussed) production of prostaglandin E and prostacyclin (PGI2) and
hyperpolarization may also be involved
Tolerance
 MAIN DISADVANTAGE OF NITRATES
 with long-acting preparations (oral, transdermal), or continuous IV
infusion for hours without interruption – repeated use with
insufficient rest -> results to lag of effect
 important consideration in the use of nitrates; partially caused
by decrease in tissue sulfhydryl groups
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LEC 24: Cardiovascular Pharmacology I OS 213
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
solution – nitrate free intervals allow for recovery; can also use long
acting nitrates
o Nicarandyl – nitrate like medicine that practically has no
tolerance
Organ System Effects
 relaxes all types of smooth muscle irrespective of the cause of preexisting muscle tone
 practically no direct effect on cardiac or smooth muscle
o Vascular Smooth Muscle - all segments from large arteries
(higher doses) through large veins (lowest doses) relax
* Primary Direct Effects
 increased venous capacitance and decreased
ventricular preload (nitrates work on veins too, not just
on coronary arteries)
 Thus, decreasing preload to decrease oxygen demand;
relief due to dilation and lower preload)
 venous pooling decreases preload while arterial dilation
induces forward flow
 heart becomes smaller, stronger, and more efficient
 dilation of large arteries (e.g. aorta); temporal artery
pulsations and throbbing headache due to meningeal
artery pulsations
Indirect Effects (2016)
 tachycardia, increased cardiac contractility due to
compensatory responses (baroreceptors and hormonal
mechanisms)
 Na+/ H2O retention
 may redistribute coronary flow from normal to ischemic
tissues
Additional effects (2016):
o Other Smooth Muscle Organs - relaxation of smooth muscle of
the bronchi, gastrointestinal tract, & genitourinary tract (brief
duration)
 6 hours should pass between use of nitrate & sildenafil,
otherwise results in severe hypotension, MI.
o Action on Platelets - decreased platelet aggregation due to
increase in cGMP in platelets as well
o Other Effects - binds to hemoglobin to produce methemoglobin
which has low O2 affinity; may result in hypoxia
Acute Adverse Effects
 direct extensions of therapeutic vasodilation
o orthostatic hypotension
o tachycardia
o throbbing headache – most common, bitemporal, very nagging,
contraindicated in increased intracranial pressure (ex.
hydrocephalus, closed-head trauma); due to swelling of
meningeal arteries
Mechanism of Clinical Effect
 Principal hemodynamic effect:
o Decreased cardiac venous return -> Reduction of intracardiac
volume -> Decreased wall tension or stress -> Decreased MVO2
 REMEMBER! major mechanism for relief of angina: reduction in O2
consumption, not necessary dilation of arteries
 may have different effects on different anginas
slowly absorbed preparations for those with problems with
tolerance
 for transdermal nitroglycerin,
 blood levels for 24 hours but effect does not persist for
more than 6-8 hours
 not recommended for daily use due to erratic absorption
o Chewable or Sublingual ISGN and Other Organic Nitrates similar to those of nitroglycerin
Table 1.5. Nitrate and Nitrite Drugs Used in Angina Treatment
Drug
Dose
Duration of Action
“Short Acting” (nitroglycerin,
0.15-1.2 mg
10-30 min
sublingual)
Isosorbide dinitrate,
2.5-5 mg
10-60 min
sublingual (packs)
Isosorbide dinitrate, oral
10-60 mg q 4-6 h
4-6 hours
Isosorbide mononitrate,
20 mg q 12 h
6-10 hours
oral
Note: Mononitrates are the most efficient oral nitrates with 60-80%
bioavailability.
B. Calcium Channel Blockers (CCBs)
o Ca2+ influx is necessary for the contraction of smooth and cardiac
muscle
o L-type Ca blockers are the ones blocked by CCBs NOT the Ttype!
o Discovery of the calcium channels paved the way for the
development of clinically useful blocking drugs (L-type channel)
Organ System Effects (Pharmacodynamics)
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Decrease Myocardial oxygen requirement
o
↓ myocardial contraclity or contractile force
o
↓ arteriolar tone & systemic vascular resistance (SVR)
o
↓ arterial and intraventricular pressure
o
↓ wall stress
o
↓ HR (seen in nondihydropyridines like verapamil, diltiazem)
Causes relaxation of most muscles in the body
Smooth Muscle
o
causes relaxation of most smooth muscle, though vascular
o
seems to be more sensitive than GI, GU, or
bronchiopulmonary smooth muscle
o
reduced BP as arteries seem to be more sensitive; may cause
orthostatic hypotension
o
useful in treating/preventing focal coronary artery spasm, the
primary cause of variant angina, most effective prophylactic
treatment
Cardiac and Vascular Muscle
o
since the heart is highly dependent in Ca2+influx for normal
function, causes decrease in almost all heart activities
o
thereby decreasing myocardial oxygen requirement
Skeletal Muscle - not affected as they use intracellular pools of Ca2+
Table 1.4. Clinical Effects of Nitrates (2016)
Effect in Variant
relaxing smooth muscle of coronary artery and
Angina
relieving coronary artery spasm
Effect in Unstable
precise mechanism not clear; probably dilatation of
Angina
epicardial coronary arteries simultaneous with
reducing myocardial oxygen demand
Clinical Use of Nitrate
 various preparations are available and are used depending on
urgency of use and problems with tolerance
o Sublingual Nitroglycerin
 most frequently used
 immediate relief and treatment of angina (onset 1-3 min)
 not suitable for maintenance therapy due to its short
duration of action (20-30 min)
 maximum of 3 doses; if angina persists, bring patient to
hospital already right after you give 3rd for IV
o Intravenous Nitroglycerin
 Usually during cases of acute MI
 rapid onset but effects are quickly reversed by stopping
infusion
 for severe, recurrent rest angina, very pronounced
o Buccal, Oral, and Transdermal Nitroglycerin
BUBUCA
Figure 1.5. Mechanism of Action of Calcium Channel Blockers (not
shown in class)
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LEC 24: Cardiovascular Pharmacology I OS 213
Types of CCBs
 Dihydropyridines (DHP) –they rhyme!
o
greater ratio of vascular smooth muscle effects
o
ONLY dilate vessels; DOES NOT decrease heart rate
o
e.g. NIFEDIPINE (prototype, 1st generation),
o
FELODIPINE
 Non-dihydropyridines (non-DHP) - they not rhyme!
o
block tachycardias in Ca2+-dependent cells (e.g. AV node)
o
more selective for heart muscle
o
e.g. VERAPAMIL and DILTIAZEM
Toxicity
 Most toxic effects are direct effects of therapeutic action (not in all
patients)
o
cardiac depression and cardiac arrest
o
bradycardia o AV block
o
heart failure
 has non-specific sympathetic antagonism effect
o
most marked in diltiazem, much less in verapamil
o
nifedipine – none; associated with significant reflex
tachycardia (first generation calcium channel blocker)
o
diltiazem and verapamil – slow down supraventricular
tachycardia
Clinical Uses of CCBs
 Choice depends on specific potential effects and pharmacologic
properties
 For Patients with A-V Conduction Abnormalities
o
give nifedipine since it doesn’t decrease AV conduction
 Caution
in
verapamil/diltiazem
+
B-blockers
(usually
contraindicated)
o
may cause AV block (with severe pain), depression of
ventricular function
 For Patients with History of Atrial Tachycardia, A-flutter, or A-Fib
o
give verapamil and diltiazem due to their antiarrhythmic
effects
 For Patients with Unstable Angina
o
immediate release short- acting CCBs are contraindicated
 Not for Patients with Overt Heart Failure (LVEF <40%  systolic
failure)
o
may be worsened by CCBs (e.g. verapamil, diltiazem)
 Not for Patients with Relatively Low BP
o
DHPs can cause further lowering of blood pressure
(verapamil and diltiazem may be better tolerated)
o
a drastic decrease in BP can be fatal; use titratable drugs
instead of sublingual administration of punctured capsules
unless BP is precariously high (ex. more than 200 mmHg)
o
instead use slower acting drugs like clonidine (Catapres) and
captopril
o
immediate release short acting CCBs are contraindicated.
NOtES:
1.
2.

o
BISOPROLOL (selective beta-1 blocker)
o
CARVEDILOL (nonselective beta-1 and alpha-1 blocker)
note that β1 selectivity is most effective for the heart, since there are
β1 receptors all over the heart.
D. Miscellaneous Drugs for Angina




These are proven therapies more effective than placebo but
SHOULD NOT be the first line of treatment of angina
Ivabradine: lf (funny current) Inhibitor
o
prolongs repolarization time by inhibiting the funny current
(bet systole and diastole)
o
Slows heart rate with effects on BP
Metabolic Agents:
o
Nicorandil – nitrate like activity, stimulate cGMP, decrease
calcium
o
Trimetazidine (Europe)
o
Ranolazine (US)
Metabolic agents act by forcing the cells to go into aerobic
circulation through the krebs cycle (“It’s up to you if you believe it or
not”- Sir Tiongco)
Most common side effect is Headache
[Pharmacokinetics] Most drugs are well absorbed after oral
administration, peaking in concentration 1-3 hours post-ingestion
Table 1.6. Effects of Nitrates Alone and with β-Blockers or Calcium
Channel Blockers in Angina Pectoris
Nitrates
BBs/CCBs
Nitrates
+
BBs/CCBs
HR
Reflex ↑
↓*
↓
Arterial
↓
↓
↓
Pressure
End-diastolic
↓
↑
None or ↓
volume
Contractility
Reflex ↑
↓
None
Ejection time
↓
↑
None
PART 2: DRUGS FOR ARRHYTHMIA
I. ELECTROPHYSIOLOGY OF NORMAL CARDIAC RHYTHM
A. THE CARDIAC ACTION POTENTIAL
 Na+ dependent action potential starts with phase 0
Selectivity to Beta-1 receptors:
Propanolol> Bisoprolol> Mesoprolol> Carvedilol
Atenolol – equally effective, most popular hypertension drug
(pinakabugbog na drug  )
ARBs and ACE-I are technically not for anti-angina but (as med
students) can actually reduce the symptoms
C. Beta-Blockers


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antagonizes
effects
of catecholamines
(adrenaline
and
noradrenaline) at β-adrenoreceptors, although some have partial
agonist effects
benefits are primarily related to their hemodynamic effects that result
in ↓ MVO2
o
↓ HR, BP, contractility
o
↓ MVO2
o
↑ diastolic coronary perfusion time
o
↑ diastolic ventricular filling time
relief of angina and improved exercise tolerance in angina pectoris
associated with effort
may alleviate mitral stenosis because of increase in diastolic filling
time
All are potentially equally effective in the treatment of angina
BFAD and US-FDA* Approved Drugs:
o
PROPANOLOL - prototype, nonselective, also used for
hyperthyroidism (due to decreased T4 to T3 conversion)
o
NADOLOL*
o
ATENOLOL – long-acting, selective partial beta-1 blocker,
may increase lipids, produce hypoglycemia unawareness in
diabetic patients
o
METOPROLOL (selective beta-1 blocker)
BUBUCA
Figure 1. Cardiac Action Potential in the Ventricles.
Table 1. Phases of the Cardiac Action Potential
Phase 0
Rapid

action potential upstroke
Depolarization

opening of Na+ channels
Phase 1
Early

early repolarization
Repolarization

Na+ channels close

repolarizing K+ current
Phase 2
Plateau

Ca influx = K efflux (PLATEAU)
Phase 3
Final

Closure of of Na+ and Ca2+
Repolarization
channels

Continuous K+ permeability
Phase 4
Restoration of

Concentrations of Na+ & Ca2+ at
Resting Ionic
rest are restored
Concentrations
IMPORTANT

Phase 0 is absent in Calcium channels. These channels are
present in the SA node and AV node.
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LEC 24: Cardiovascular Pharmacology I OS 213


REMEMBER!
Sodium

Calcium

Potassium!
Na  Ca  K!
K – Phase 3 and 4. Blocking this prolongs the effective refractory
period, slows down the heart rate
B. DIFFERENT ACTION POTENTIALS IN THE HEART
 Cardiac action potential differs significantly in different portions of the
heart, giving them different electrical characteristics
Table 2. Cardiac Rhythms
Ca2+

upstroke - Ca2+ channels opening
Dependent

SA and AV nodes
Pacemaker

REMEMBER: has NO PHASE 0
Potential
Na
Disorganized electrical impulses
Dependent

Increased heart pumping
Action

Atria, ventricles, Purkinje cells, Bundle of His,
Potential
ALL EXCEPT SA and AV NODES!
II. ARRHYTHMIA
 any disorder in which there is abnormal electrical activity in the heart,
resulting in an abnormal heart rate or rhythm
A. TYPES OF ARRYTHMIA
Table 3. Different types of arrhythmia [Video]
Atrial Fibrillation Electrical impulses are disorganized. Heart
pumps too fast
Supraventricular Impulses go back from the ventricles to the atria
Tachycardia
(Note: that there are illegal connections which
usually comes out during stress)
Ventricular
Abnormality in the lower chambers of the heart
Tachycardia
causing inadequate ventricle filling
(Note: impulse generated at a focal point in the
apex)
Heart Block
Electrical impulses are slowed down or blocked
Ventricular
Impulses fire rapidly and irrgularly at the lower
Fibrillation
chambers of the heart. It is fatal without prompt
treatment
(Note: Impulse are generated from different
points in the heart)

can compromise cardiac output
o
CO = Heart Rate x Stroke Volume

Mechanisms of Arrhythmias - all arrhythmias result from
(1) disturbances in impulse formation
(2) disturbances in impulse conduction
(3) both

can be relatively or seemingly benign, can be very slow (normal
heart rate of sleeping person is 40bpm)

If HR is 20 bpm  seizure, chest pain, or stroke

Can lead to shock and death

Arrest rhythms – deadliest arrhythmias
o Ventricular fibrillation
o Pulseless ventricular tachycardia
o If patient is in arrest (seizing, in Vfib, with PVT), it means he’s
dying  Defibrillate!!!
o Prevention – anti-arrhythmics




Figure 2. Normal Cardiac Electrical Activity.
B. WOLFF-PARKINSON-WHITE SYNDROME
Re-entry is also known as “circus movements” since one pulse
reenters the atrium and excites areas of the heart more than once
Pulses prematurely enter the ventricle through the bundle of Kent
in a delta wave (“sharksfin wave”)
ECG shows short PR interval.
in re-entry, there are 3 important determinants
1. Arrhythmogenic substrate
2. Modulating factors (ex. autonomic tone, exercise)
3. Trigger (ex. extra systole)
C. NORMAL CONDUCTION
 SA node – pacemaker of the heart
 SA Node (conducts from both the right atrium and left Atrium)  AV
node  Bundle of His  left and right classical bundles Hispurkinje system  through the musculature of the heart
o
SA node runs at 60-100 bpm normally,
o
If it’s obliterated or diseased the AV node – new pacemaker40-60 bpm.
Figure 4. Wolf-Parkinson-White Syndrome
Figure 3. Electrical Conduction System of the Heart
 If both SA node and AV node are obliterated/diseased (ex. complete
heart block),
o
New pacemaker - his-purkinje system which has an inherent
unstable heart rate of 20-40 bpm
o
ECG – wide QRS complexes.
BUBUCA
III. PHARMACOLOGY OF ANTI-ARRHYTHMIC DRUGS
A. GOALS OF THERAPY
 Arrhythmias are caused by abnormal pacemaker activity or
abnormal impulse propagation
 The aim of therapy is:
 Reduce ectopic pacemaker activity
 Modify conduction or refractoriness in re-entry circuits to
disable circus movement (like in Parkinsons Disease)
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LEC 24: Cardiovascular Pharmacology I OS 213
 Interfere with cardiac depolarization (such as in Na-channel
blocking)
 How? By altering the following:
1. Diastolic potential in pacemaker cells and/or resting
membrane potential in ventricular cells
2. Phase 4 depolarization
3. Threshold potential – ability to hit phase 0
4. Action potential duration – area under the curve
B. EFFECT ON EFFECTIVE REFRACTORY PERIOD
 Antiarrhythmic drugs alter the effective refractory period, thereby
altering cellular excitability
 Is particularly effective in abolishing re-entry currents that lead to
tachyarrhythmias
 e.g. drugs that block K+ channels like amiodarone delays phase 3
repolarization and increases the ERP
Figure 5. Effect on Antiarrythmics on ERP
Note that
IV. ANTI-ARRHYTHMIC DRUGS
 act on 1 or more of 3 major currents or 2nd messenger systems
 target proarrhythmic regions in the heart; most agents interact
preferentially to particular states of ion channels suppressing specific
triggers/areas of arrhythmia
 most antiarrhythmic drugs act by modulating activity of ion channels
Table 4. The Vaughan-Williams Classification of Anti-Arrhythmic
Drugs
CLASS
TYPE
ACTION
Class I
Na+ Channel
has varied effects APD and kinetics of
Blockers
Na+ channel blockade
Class II
β Blockers
reduces adrenergic activity in the heart
Class III K+ Channel
prolongs APD by blocking the rapid
Blockers
component of the delayed rectifier K+
current (IKr)
Class
Ca2+ Channel
slows conduction in regions where AP
IV
Blockers
upstroke is Ca2+ dependent (SA and AV
nodes)
*summary table = SEE APPENDIX

Figure 6. Effects of Class I Drugs
on Ventricular Action Potential
SUBCLASS IA (QPD- Quiapo Prostitution District  or Quezon City
Police District)
 Quinidine, Procainamide, Disopyramide
 Slows upstroke of action potential, decreases conduction velocity;
prolongs QRS duration
 Prolong APD - K+ channel blockade (non-specific)
 Maintenance of normal sinus rhythm - atrial flutter or fibrillation,
ventricular tachycardia
 Generally, they prolong the repolarization and thus, the action
potential duration.
 Moderate block on Na+ channels and prolongs APD of both SA
nodal cells & ventricular myocytes by the following mechanisms:
o Na+ channel block - slows phase 0 of AP (decrease the slope of
phase 0) = ↓conduction velocity; prolonged QRS
o K+ channel block - prolongs repolarization = inc. ERP and action
potential duration; non-specific
 Toxicity - excessive Na+ blockade and slowed conduction showing
excessive QT interval prolongation and induction of torsades de
pointes,
resulting
in
syncope
(polymorphic ventricular tachycardia)
(Note that this is contraindicated in pateints with problems of prolonged
QT interval)
Torsades De Pointes (TDP)
 (French) “turning of the points”
 A polymorphic ventricular tachycardia in which the mean electrical
axis of the QRS complex within any single electrocardiographic lead
appears to twist around the isoelectric line (rapid undulating QRS
morphology)
 polymorphic VT in the setting of TDP
A. CLASS I: SODIUM CHANNEL BLOCKERS
has varied effects on action potential duration and varied kinetics of
Na+ channel blockade

Table 5. Class I Anti-arrhythmics
Na+ Channel Blocking
Effect on APD
(potency to inhibit Phase O)
Class 1A
moderate
prolong
Class 1B
minimal
shortened
Class 1C
marked
no effect
REMEMBER: Hand gestures taught by Dr. Tiongco!
BUBUCA
Figure 7. Torsade de Pointes
Table 6. QUINIDINE
Other

Cardiac
Effects

Pharmaco
kinetics

Therapeutic

Use
antimuscarinic effects - blocking vagus nerve =
accelerated AV nodal conduction when used
alone
α-adrenergic blockade (Alpha-1 receptors)
Eliminated primarily by hepatic metabolism
Raises digoxin levels – drug reaction
rarely used - cardiac & extracardiac side effects
and other better-tolerated drugs
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LEC 24: Cardiovascular Pharmacology I OS 213
Side Effects


GI - diarrhea, nausea, and vomiting in 1/3 of
patients
Cinchonism - headache, dizziness, and tinnitus
Table 7. PROCAINAMIDE
Extracardiac Effects


Pharmacokinetics




Therapeutic Use

Side Effects



has ganglion-blocking properties
- hypotension with rapid IV use or
severe underlying left ventricular
dysfunction
less antimuscarinic effects than
quinidine
IV or IM, well absorbed orally
major metabolite is Nacetylprocainamide or NAPA,
which has class 3 activity,
accumulation implicated in TDP,
especially in patients with renal
failure
eliminated by hepatic metabolism to
NAPA, then NAPA is eliminated by
renal elimination
dosage must be reduced in patients
with renal failure
effective for most atrial and
ventricular arrhythmias but longterm therapy is avoided
in 1/3 of patients on long-term
therapy, causes reversible lupuslike syndrome (rash, arthralgia,
arthritis)
increased ANA (anti-nuclear
antibodies) In almost all patients
other effects include nausea and
diarrhea
*Don’t use this for renal failure!
SUBCLASS IB (LiTMan HAHAHAHA)
 Lidocaine, Tocainide, Mexiletine
 Has a tendency for shortening repolarization and action potential
 blocks activated and inactivated Na+ channels
o greater effects on cells with long action potentials
(Purkinje/ventricular cells)
 selective depression of conduction in depolarized cells due to
increased inactivation and slower unblocking kinetics
 for ventricular arrhythmias, especially those associated with
myocardial infarction/ischemia
Table 8. LIDOCAINE
Cardiac
 raises electrical stimulation threshold and
Effects
suppresses spontaneous depolarization of
ventricle
Pharmaco fast-onset, easily administered, short half-life
kinetics
 extensive first-pass hepatic metabolism such that
oral intake results in only 3% bioavailability;
 parenteral administration is preferred
 lower infusion rates in patients with CHF, shock,
advanced age, and liver cirrhosis
Therapeutic
 agent of choice for termination of ventricular
Use
tachycardia & prevention of ventricular
fibrillation after cardioversion in acute ischemia
Side Effects
 one of the least cardiotoxic Na+ channel blockers;
effects are dose-related and usually short-lived
 most common are neurologic such as drowsiness,
dizziness, paresthesia, or euphoria
 in large doses = hypotension - depressing myocardial
contractility.
You will kill the patient
 in the eldery, or if given in a too rapid bolus causes
CNS symptoms such as confusion, agitation,
psychosis, tremor, slurred speech, & convulsions
(ICU psychosis)
You can’t drink lidocaine. You have to inject it intravenously due to its
extensive first-pass effect.
Table 9. MEXILETINE
Pharmaco
orally active congener of lidocaine; resistant to
kinetics
first-pass hepatic metabolism
Side Effects

also predominantly neurologic, including tremor,
blurred vision, and lethargy and nausea
BUBUCA
SUBCLASS IC (First Menstrual Period )
 Flecainide, Moricizine, Propafenone
 Marked sodium blocking Na+ effect
o
do not affect K+ current - NO prolong ventricular AP or
increase QT (no effect on repolarization)

quite proarrhythmic, so use as last resort and do not give to
patients with pre-existing heart disease

used for refractory arrhythmias
Table 10. Flecainide
Pharmaco
well absorbed, half-life of 20 hours
kinetics

elimination by hepatic metabolism and kidney
Therapeutic
Use

currently used in patients with otherwise normal
hearts who have supraventricular arrhythmias

very effective - premature ventricular
contractions
Side Effects

severe exacerbation of arrhythmia in pre-existing
ventricular tachyarrhythmia and previous MI and
ventricular ectopy

Cardiac Arrhythmia Suppression Trial (CAST
study), a 2-fold increase in mortality between
conduction depression and chronic & acute
myocardial ischemia
Given to patients with a normal heart, with no heart hailure, but the
patient has a large SVT and WPW-like symptoms.
B. CLASS II: BETA-ADRENOCEPTOR BLOCKERS
Propranolol, Sotalol, Acebutolol, Metoprolol, Esmolol, Lebatolol
 Main targets: SA and AV nodes (calcium dependent, slow response
cells full of Beta-1 receptors)
 Antiarrhythmic by virtue of their β-receptor-blocking action and
direct membrane effects
o role of Beta-blocker-induced tachycardia in precipitating
arrhythmias
o increased sympathetic activity in patients with sustained
ventricular tachycardia and acute MI
o fundamental role of cAMP in causation of ischemia-related
ventricular fibrillation
o Antihypertensive and anti-ischemic
 Anti-arrhythmic activity of β-blockers are reasonably uniform
Effect of β-Blockers on Pacemaker Action Potential
Figure 8. Effects of β-Blockers on Pacemaker Potential
Effect on Myocardial Electrophysiology:
1. Increase slope of Phase 4 spontaneous depolarization
2. Increase in maximal rate of phase 0 depolarization
3. Increase in conduction velocity
Thus conduction velocity in SA and AV node is decreased during
repolarization time = Decrease SA/AV automaticity and conduction =
Prolonged ERP = reduced contractility (ultimate goal) through indirect
impairment of Ca++ release
 Indication of use: Ventricular tachycardia and supraventricular
tachycardia precipitated by sympathetic stimulation
 Contraindication: asthma, COPD
Esmolol—short-acting β-blocker used for intraoperative and other
arrhythmias
Sotalol – non-selective β-blocking drug which prolongs AP (Class III
action); Increases ERP.
Metoprolol, Bisoprolol- B1 selective blockers
Carvedilol and Labetalol (oral and IV) - A1 and B1
Page 7 / 9
LEC 24: Cardiovascular Pharmacology I OS 213
 Use cautiously in patients with heart failure
C. CLASS III: POTASSIUM CHANNEL BLOCKERS
Amiodarone, Bretylium, D,L-Sotalol,
Dofetilide, Ibutilide*
*Ibutilide – has less side effect compared to its precursor, amiodarone
 Increases refractoriness (prolong ERP) by prolonging APD
 blocks K+ channels
 exhibits the undesirable property of “reverse use-dependence”
o AP prolongation is most marked at slow rates, which can contribute
to the risk of TDP
*Among the side effects, Dr. Tiongco only gave emphasis on the one in
bold and underlined
o Amiodarone, unlike digoxin, can knock out ectopic rhythm and make
the predominant pacemaker cell come back to its normal function
o Converts atrial fibrillation to sinus rhythm
o Slows down the heart rate
o Amiodarone is awesome, but also prone to accumulation.
D. CLASS IV: CALCIUM CHANNEL BLOCKERS
Non-dihydropyridine: Verapamil, Diltiazem
Figure 9. Effect of K+ Channel Blockers on Action Potential
 Have very similar mechanism of action with beta blockers (slows
down phase 4)
 Predominantly blocks calcium entry in slow response cells like SA
and AV node
 causes a slow rise in action potential and prolonged repolarization at
the AV node
 no effect in repolarization
An example of this is amiodarone simply because it does many things. It
has a sodium blocking effect, beta blocking effect and potassium
blocking effect.
Table 11. AMIODARONE
Cardiac
 does not have “reverse use-dependent” Action
Effects
o APD is prolonged uniformly over a wide range
of heart rates
 BROAD SPECTRUM of activity
o significantly blocks inactivated Na+ channels
o has weak adrenergic action (slows down heart
rate)
o weak Ca2+ channel blocking actions
 high efficacy and low incidence of TDP despite
significant QT interval prolongation
Pharmaco Bioavailability of 35-65%
kinetics
 large loading doses to achieve effective serum
concentrations
 high volume distribution
 half-life is complex; rapid component of 3-10 days
(50% of drug) and a slower component of several
weeks such that effects are maintained for 1-3
months after discontinuation of use
 has many important drug interactions so all drugs
taken should be reviewed when initiating therapy.
 INTERACTION: Increase plasma concentration of
warfarin (100%), digoxin (70%), quinidine (33%),
procainamide (55%) and NAPA (33%), phenytoin,
flecainide
Therapeutic
 for treatment of ventricular and supraventricular
Use
arrhythmias
 conversion of ventricular fibrillation in CPR (with
lidocaine and procainamide)
 shown in the ALIVE Trial (Amiodarone vs
Lidocaine In Ventricular Emergency Trial), there’s
better rate of survival to hospital admission
Toxicity
 Amiodarone & its major metabolite,
Desethylamiodarone, are highly lipophilic (can be
distributed almost anywhere in the body!)
 accumulates in tissues 10-50x greater than
plasma; concentrated in tears
 can be stored in liver, adipose tissue, lung,
myocardium, kidney, eyes, thyroid, skin, and
skeletal muscle
Side
 corneal microdeposits, clinical hypothyroidism or
Effects*
hyperthyroidism, bluish-gray skin discoloration,
photosensitivity, liver function abnormalities or
hepatitis, neuropathy, myositis, pulmonary
toxicity (fibrosis), arrhythmia, bradycardia, AV
block.
 side effects have been described in virtually every
system, treatment should be reevaluated whenever
new symptoms develop
BUBUCA
Figure 10. Effect of Ca2+ Blockers on Pacemaker Action Potential.
Compare with that on Class II Antiarrythmics (Beta-blockers)
Table 12. VERAPAMIL
Cardiac
 blocks both activated and inactivated L-type
Effects
Ca2+ channels
 effect more marked in SA and AV nodes since
their activation depends exclusively on Ca2+
current
 results in slow rise of phase 0, prolonged AV
nodal conduction time & prolonged ERP
Extracardiac
 causes peripheral vasodilation
Effects
Pharmaco half-life is approximately 7 hours
kinetics
 Hepatic metabolism
o Bioavailability is only 20% in oral prescription
and must be administered with caution in
patients with hepatic dysfunction
Therapeutic
Use
Toxicity
Side Effects
 major arrhythmia indication is supraventricular
tachycardia
 also controls rate in A-fib and A-flutter, but rarely
converts them to sinus rhythm
 dose-related and usually avoidable
 negative inotropic effects limits usefulness in
diseased hearts
 can induce AV block when used in large doses or
in patients with AV nodal disease
 CHF, constipation, lassitude, nervousness, and
peripheral edema
 Peripheral edema = vasodilate end arterioles but
venules are not dilated that is why fluids seep out
the interstitium; capillary leak)
 CONTRAINDICATIONS:
o Pediatric patients due to decreased Ca2+
stores in infants
o patients with systolic heart failure
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LEC 24: Cardiovascular Pharmacology I OS 213
E. MISCELLANEOUS ANTIARRHYTHMIC DRUGS
Digitalis, Adenosine, Magnesium, Potassium (DAMP)
 certain drugs that do not fit the conventional class 1-4 organization
Table 13. Adenosine
Cardiac
 opens K+ and inhibits Ca2+ channels causing
Effects
marked hyperpolarization and suppression of
Ca2+-dependent APs
Pharmaco half-life in blood is <10s, so you can just keep
kinetics
administering without risk of overdose!
 (but eventually may lead to asystole)
Therapeutic
 DRUG OF CHOICE: for prompt conversion of
Use
paroxysmal supraventricular tachycardia to
sinus rhythm due to high efficacy (90-95%) and very
short duration of action
 effects are lessened by adenosine receptor blockers
like theophylline or caffeine; effects are potentiated
by adenosine uptake inhibitors like dipyridamole
Toxicity
 High-grade AV block (short-lived)
 Headache, flushing (20% of patients) and
shortness of breath (over 10%)
 alsohypotension, nausea, & parasthesia
 IMPORTANT TO REMEMBER (Sir kept reiterating this in his lecture):
Drugs that supress SA and AV nodes by inhibiting Ca2+ dependent
AP:
o Adenosine
o Beta-blockers (Class II)
o Non-dihydropyridine Calcium Blocker (Class IV)
Table 14. Magnesium
Cardiac
 influences Na+-K+ ATPase, Na+ & certain K+ channels
Effects
 mechanism of effects not certain; awaits further
investigation
 indicated in patients with digitalis-induced
arrhythmias (if hypomagnesemia is present) and in
Torsades de Pointes (even with normal Mg2+)
 Magnesium is used as hemodynamic agent and not just as a cofactor
– used in preeclampsia wherein Mg (5g) is injected intramuscularly to
bilateral gluteus maximus muscles causing vasodilation and
stabilization of the membranes
Therapeutic
Use
Digoxin
 Na-K ATPase inhibitor
 Supresses entry ot impulses from the atria to the ventricles
o Especially important in preventing conduction of arrhythmic
impulses from atria (e.g. Atrial fibrillation) to the ventricles
(which will eventually result to V Fib which is fatal!)
 When K entry is slowed, the amount of stimulation is slowed
 Ultimately decreases calcium =
V. PRINCIPLES IN CLINICAL USE
 There is a narrow margin between efficacy and toxicity
 Familiarity with indications, contraindications, risks, clinical
pharmacologic characteristics of prescribed drug is very important.
 all anti-arrhythmic drugs are also potentially pro-arrhythmic, so one
should always weigh the risks and benefits before administering any
drug of choice.
The Main Objective of administering Antiarrythmic Drugs:
1. Eliminate the Cause
2. Make a Firm Diagnosis of Arrhythmia
END OF TRANSCRIPTION
Jai: Super lapit na ng sembreak!!!
Juvan the QT interval: Thank you sooo much block A transers! !!!!
Guys, badminton tayo..  Sembreak naaaaa!!!!
Raiser: onga sembreak!
BUBUCA
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