Pharmaceuticals

affecting
cardiovascular
system
 Cardiotonic
and
antiarrhythmic
drugs

Module "Pharmacology"
Lecture number 10
 Cardiotonic agents

drugs
increasing strength
of myocardial contractions
in acute or chronic heart failure
Heart
 HEART FAILURE
reduction of myocardial contractile
function (decompensation)

HF leads to the inability of the circulatory

system to deliver the necessary amount of
blood to organs and tissues.
 EPIDEMIOLOGY

HF affect 10% of older people

(0.5-2% of the total population of ~ 2 million
people in the Russian Federation)

Death ~ 1.7-3.2 years after Ds

The cost of HF - 1-2% of all health care costs

 HF etiology
1. Primary myocardial damage :
(myocarditis etc.) – «remodeling»
2. Secondary myocardial overload :
- “Pressure overload” (AH, stenosis);
-“Blood volume overload” (valve
insufficiency)
By the rate of the disease:
- Acute HF (minutes - days)
- Chronic HF (months - years)
Types of heart failure:
1. Left ventricular
2. Right ventricular
3. Total
Manifestations of HF -
1. Shortness of breath (LV). 2. Edema (RV). 3. Cyanosis.

Normal myocardium and myocardium in heart failure

The severity degrees - I (compensated), IIA, II B, III.
Grade III (decompensation) is an indication for a heart transplant.
Drugs used in heart failure

 contractions of insufficient myocardium

(cardiotonic, anabolic, etc.)

 myocardial overload increased VCB

(diuretics)

 increased blood pressure in hypertension

(antihypertensives)
 Ways to increase myocardial contractility
1.  strength and  heart rate (cardiotonic action). In
chronic forms of total heart failure with a rapid
rhythm
Glycoside inotropic drugs that used do not  oxygen
demand.

2.  strength and  heart rate (cardiac stimulating

effect). Used in acute forms of left ventricular heart
failure with a rare rhythm.

Non-glycoside inotropic agents are used do oxygen demand

Glycoside inotropic drugs (cardiac glycosides, greek. glykys - sweet)
- these are cardiotonic agents of natural origin, the nitrogen-free
molecules of which consist of two parts connected by an ether
linkage:

1. Glycon (sugar part - rhamnose, digitoxosis) - provides the

pharmacokinetics of cardiac glycosides (polarity, solubility in water,
lipids and ability to cumulate)
2. Aglycone (genin, non-sugar part - 5- or 6-membered lactone ring) -
structure, providing pharmacodynamics
Агликон

Гликон

Дигоксин
 Glycoside inotropic drugs

1600 BC - Egypt (chives, sea onion),

In German herbalism, digitalis is mentioned in the 16th century and then

called "digitalis"
in 1785 - William Withering - clinical studies of digitalis

Claude Bernard and Ludwig Traube found that small doses of digitalis
stimulate the activity of the heart, while large doses, on the contrary,
suppress and can even cause paralysis.

In 1824, the French chemist Royer managed to isolate the purple poison
from digitalis leaves, which he called digitalis

In 1896 (45 years after the start of work), the substance Glycoside of nature
was isolated from the leaves of digitalis purpurea, which was called
"digitoxin". The body acts in the same way as the extract from the
leaves, but about 100 times stronger.
 Glycoside inotropic drugs
Sources

Oleandr Yellow oleandr Digitalis Cryptosteygea

Lily of the valley Azalea Periwinkle Saby

Episcia Sharpener Meteoris Hellebore

 Classification
I. - with 5-carbon lactone ring - "cardenolides»:
1. Non-polar (lipophilic - contain 1 hydroxyl group)
Digitoxin

2. Moderately polar (contain 2 hydroxyl groups)

Digoxin (Lanikor) tablets - 0.25 mg., “Semi" - 0.125 mg, "mité" - 0.0625 mg.,
1 ml ampoules. 0.025% sol.
Lanatozid C (Celanid, Izolanid) tablets - 0.25 mg., weaker.

3. Polar (water soluble - 4-5 hydroxyl groups)

Strophanthin K - 1 ml ampoules. 0,025% or 0.05% sol.
Ouabain (Strofantin G),
Korglikon
II. - with a 6-carbon lactone ring - “baph-dienolide”:
Sea onion remedies - Meproscillarine (Clift) – do not reduce HR,
CG of hellebore and toad skin glands secretion (Bufo)
 Effects of CG on decompensated myocardium:
1. Positive inotropic effect – increase of the heart rate strength
2. Negative chronotropic effect - reduction of heart rate and
lengthening of diastole (increased vagus nerve tone).
3. Negative dromotropic effect is a direct inhibitory effect on
conductivity in the atrioventricular node - from the sinus node
(“pacemaker”) to the working myocardium.
4. Positive bathmotropic effect - increase in myocardial
excitability
5. Positive tonotropic effect - an increase in myocardial tone

у 5-50%
больных
 Cardiac effects of cardiac
glycosides

Positive inotropic effect

-Systole becomes stronger, shorter and more economical;
-Increased stroke volume and completeness of the expulsion of
blood;
-Increased MCV, blood circulation efficiency and blood supply
to all organs and tissues;
-Hyposystolia is eliminated in patients with heart failure;
-ECG: shortening of the Q-T interval
 Cardiac effects of cardiac
glycosides

Positive inotropic effect

Cardiotonic action is benign because:

•The expenditure of energy substrates (glycogen) and oxygen
increases to a lesser extent, when converted for one contraction -
decreases;
•Efficiency increases;
•The synthesis of ATP, creatine phosphate, glycogen does not
change;
•Utilization of lactic and pyruvic acid reduces acidosis
 Cardiac effects of cardiac
glycosides
Negative chronotropic effect

Reflex consequence of the systolic effect: increased shock wave leads

to more intense stimulation of the baroreceptors of the aortic arch and carotid
sinus and reflex stimulation of the n.vagi center, which leads to a decrease in
heart rate and Bainbridge reflex
Cardio-cardiac effect: parasympathetic effects increase in the myocardium
as a result of the separation of the ACh and the excitation of AChR
The center n.vagus is directly stimulated
As a result of improving blood circulation, hypoxia and sympathetic nervous
system tone decrease, which leads to a decreased heart rate.
Normalization of the work of ion pumps: complete removal of calcium
from the cytoplasm to the sarcoplasmic reticulum and mitochondria occurs,
incomplete relaxation during diastole (hypodiastolia) and the associated energy
overuse is eliminated.
 Cardiac effects of cardiac
glycosides
The clinical significance of the negative chronotropic effect :

-The increased period for rest and recovery of cardiomyocyte

energy resources;
-Lengthening the time for filling the chambers of the heart, which
increases the efficiency of blood circulation;
-Improvement of the myocardial blood supply, which occurs only
in the diastole stage. This compensates for an increase in
myocardial oxygen consumption;
-Most pronounced for digoxin and digitoxin
 Cardiac effects of cardiac
glycosides
Negative dromotropic effect :
Lengthening the effective refractory period throughout the
conducting system, except for the bunch of His, due to the direct
influence on the myocardial conducting system and n.vagus
Clinical significance :
+ Favorable for tachysystolic form of atrial fibrillation,
reduces the risk of extraordinary contractions of the heart in
the presence of an ectopic focus in the atria, blocking the
conduction of impulses through the atrioventricular node
- May result in complete atrioventricular block.
 Cardiac effects of cardiac
glycosides
Positive bathmotropic effect :
-The appearance of foci of spontaneous depolarization, because as
a result of inhibition of Na / K-ATPase, the difference in ion
concentrations inside and outside the cell decreases, which leads
to a decrease in the action potential and depolarization occurs
more easily.
-To induce a contraction of the heart, an impulse of lesser force is
required, which increases the risk of ventricular arrhythmias,
extrasystoles and fibrillations.

Reduced automaticity :
- Contributes to the appearance of ectopic foci of excitation
and the development of arrhythmias due to the direct action on
the myocardium.
 Extracardiac effects of cardiac
glycosides

- Normalization of blood pressure;

- Decreased venous pressure and venous stasis;
- Increased diuresis;
- Reduction of swelling (edema);
- Reducing stagnation in the portal vein and improving the blood
supply to the gastrointestinal tract;
- Sedative effect (direct and psychosomatic);
- Dyspnea reduction;
- Improving pulmonary gas exchange and reducing the risk of
pulmonary edema;
- Improved coronary blood flow.
 Indications for use of cardiac
glycosides

1. Chronic form of systolic heart failure (digoxin, digitoxin)

2. Acute heart failure (strophanthin, corglikon, digoxin)
3. Prevention of heart failure in patients with compensated
failure (before surgery)
4. Disorders of atrial rhythm
 Features of cardiac glycosides

1. Show their therapeutic effects only in the "sick" heart (in

healthy heart effect is exerted in toxic doses)

2. They have a low therapeutic latitude (~ 60% of toxic).

3. The effect occurs “spasmodically” with administration of the

full effective dose into the body, which determines the
characteristics of dosing
 Individual sensitivity to cardiac
glycosides depends on
- hypo or hypercalcemia;
- hypomagnemia, hypercalcemia;
- Acid-base misbalance;
- myocardial ischemia;
- myocarditis;
- thyroid and respiratory diseases;
- renal failure;
- liver failure (for digitoxin)
- concomitant drug therapy;
 Principles of cardiac glycoside
administration
2 stages:
1.Digitalization Stage – Saturation
saturation rate - fast (1-2 days)
average (3-5 days)
slow (8-12 days)
2. Stage of maintenance therapy (the patient receives a
maintenance dose that is equal to the amount of the drug being
eliminated)
Mechanism: reversible (~ 35%) blockade of the phosphorylated form of Na +, K + -
ATPase (CG lactone ring binds to SH-groups of the -subunit)
Mechanism: reversible (~ 35%) blockade of the phosphorylated form of Na +, K + -
ATPase (CG lactone ring binds to SH-groups of the -subunit)
Mechanism: reversible (~ 35%) blockade of the phosphorylated form of Na +, K + -
ATPase (CG lactone ring binds to SH-groups of the -subunit)
 Cardiac glycosides
Strophanthin K - polar (5 hydroxyl groups) - with a weak ability to
cumulation, with the maximum severity of inotropic effect. The drug is
very poorly absorbed through the gastrointestinal tract into the blood,
so it is injected only intravenously. The onset of action is 2-10 minutes,
the duration of action is 1.5 hours.
 Cardiac glycosides
Digoxin – moderately polar (3 hydroxyl groups), the most widely
used. Bioavailability of 60-85%.
Sther = 1-2 ng / ml. T 1/2 = 32-48 hours.
Extrarenal excretion - 25%

Slow digitalization - 0.5 mg for 7 days, then 1/2 dose

 Cardiac glycosides
Digitoxin – non-polar (1 hydroxyl group), with the longest duration of
action. Well absorbed from the gastrointestinal tract and with the mucous
membrane of the eye, bioavailability - 95-100%.
The onset of action is 1-4 hours, the peak of action is after 8-14 hours.
Can be used as eye drops for eye fatigue. Stimulates the ciliary muscle
(Digophtone).
 Cardiac glycosides
Pharmacokinetics

Characteristics Digitoxin Digoxin Strophanthin

1. Oral absorption Very good Good Virtually poor

erratic
2. Plasma t1/2 5-7 days 36-40hrs 1-2hrs

3. Plasma protein binding 95% 25% negligible

4. Onset of action ½ hours 15-30 minutes 1-5 minutes

5. Duration of action 2-3 weeks 2-6 days 24 hours

6. Potency Least Intermediate Highest

7. Route of administration Oral Oral/I.V I/V

8. Route of elimination Hepatic Unchanged via Renal Excretion

kidney
9. Uses Maintainer Maintainer Emergency
 Cardiac glycosides

Positive inotropic effect

Strofinatin Celanid Digoxin Digitoxin

Negative chronotropic effect

Strofinatin Celanid Digoxin Digitoxin

 Contraindications for appointment
cardiac glycosides

Absolute:
Intoxication with cardiac glycosides

Relative:

Diastolic myocardial dysfunction

Sinus tachycardia due to thyrotoxicosis, anemia, fever,
hypoxia
Aortic valve insufficiency
Isolated mitral stenosis
Diffuse myocarditis
Toxic effect of cardiac
glycosides

Glycoside intoxication
 Toxic effects of cardiac glycosides
- Occur in each 4th patient due to low therapeutic breadth
Transition phase :
- Bradycardia up to 50-60 beats / min
- AV blockade
- Pulse pressure increases
 Toxic effects of cardiac glycosides
Toxic phase : recurrence of heart failure, arrythmia, coronary insufficiency
-The appearance of ectopic foci of excitation, ventricular premature beats
-Tachycardia, reduction of myocardial contractility
-AV blockade
-Coronary blood flow reduction
-Anorexia (accumulation of NA in the food center of the hypothalamus), nausea
and vomiting (excess Dopamine in the trigger point), abdominal pain (increased
tone of n.vagus)
-Eye symptoms (staining of objects yellow and green, halos around light sources,
"flies", reduced visual acuity, macro and micropsia)
-Neurological symptoms: weakness, fatigue, headache, depression, aphasia,
delirium (impaired neurotransmitter circulation)
-Decrease in blood clotting, thrombopenia, genicomastia (rarely)
 Toxic effects of cardiac glycosides
Mechanisms of cardiac symptoms :
-Disturbances of the Na removal from cells and the K flow into cells leads to
low tissue potassium level and hyperpotassemia, decreased polarization and
depolarization and contractility of the myofibrils
-Due to low tissue potassium level, the synthesis of macroergs, glycogen and
protein decreases, acidosis develops in cardiomyocytes
-Increasing the concentration of Na and Ca increases the secretion of NA,
increases the excitability of the cells and causes arrhythmias.
-Disturbances of the Ca removal from cells leads to hypodiastolia, increases
the secretion of lysosomal enzymes, and necrosis occurs
-The expulsion of blood from the ventricles is disturbed, the diastolic pressure
increases, the coronary blood flow worsens, HF develops
-Vasoconstrictor action of CG leads to hemodynamic overload
 Toxic effects of cardiac glycosides
Treatment :
-Drug withdrawal
-Removal of the drug compounds using chelators
-Potassium preparations (elimination of low tissue potassium
level)
-EDTA, sodium citrate (elimination of hypercalcemia)
-Chemical inactivation of CG in the blood (unithiol, antibodies)
-Antiarrhythmic drugs
-Calcium channel blockers
-Beta-blockers (reduction of action NA)
-Antiemetics
 Non-glycoside inotropic agents
2. Not affecting adrenoreceptors
a) Phosphodiesterase III inhibitors (since the 1960s)
Bipyridine Der.- Amrinone, Milrinone
Imidazole Der.- Enoximon, Pyroximon, Phenoximone
b) Calcium drugs - Calcium chloride

в) PDE-III inhibitors + calcium sensitizers (increase the

affinity of troponin to calcium ions, facilitate the interaction of
actin with myosin)
Benzimidazole der.- Pimobendan, Levosimendan

г) Cytokine antagonists (TNF-, IL1, IL-б) -

Vesprinon, Pentoxifylline, Etanercept, Taurine, Glucagon

д) Fatty acid carriers – L-carnitine, Mildronate

MECHANISM OF ACTION
non-glycoside drugs
Non-glycoside inotropic agents

1. Stimulants of β1-adrenergic receptors

Dobutamine (Dobutrex) - 5% - 5 ml,
Dopamine, Midodrin, Adrenaline, Prenalterol, Xamoterol
 Antiarrhythmic drugs

drugs for the prevention and treatment of

cardiac arrhythmias.
 NORMAL HEART RHYTHM
sinus contractions of all parts of the heart with a frequency of 60-80 beats/min
 Heart rhythm disorders (arrhythmias)
any deviations from the normal rhythm of contractions of the whole
heart or its individual parts
 Types of arrhythmias

- tachiforms
- bradyforms
- blockade (conduct disorders of impulses)
- extrasystoles (additional pathways, premature
contractions)

INDICATIONS FOR ANTI-ARITHMIC THERAPY

life-threatening and / or painful arrhythmias
Conduction system of heart
 Causes of arrhythmias

• functional (psychogenic, reflex)

• organic (heart defects, myocardial dystrophy, ischemic heart
disease, etc.)
• toxic (for example, overdose of digitalis)
• hormonal (for example, thyroid hormone imbalance)
• dielectrolyte (for example, changes in the level of potassium in the
blood)
• mechanical (operations, injuries)
• congenital (for example, WPW syndrome)
The most common causes of heart rhythm disorders

CHD (chronic forms)

Myocardial infarction
Unstable angina
Heart failure
Cardiomyopathy
Acquired heart disease
Congenital heart defects
Myocarditis
Mitral valve prolapse, etc.
The most common causes of heart rhythm disorders

Electrolyte disorders :
Hypopotassemia
Hyperpotassemia
Hypomagnesiumemia
Hypercalcemia and others.
Toxic effects :
Alcohol
Smoking
Thyrotoxicosis
 Classification

Class I (Na+ - blockers; membrane stabilizing agents):

Subclass IA - Quinidine, Procainamide (Novocainamide),
Disopyramide (Rhythmylene).
Subclass IB is lidocaine, mexiletin, tokainid, phenytoin (Difenine).
Subclass IC - Moratsizin (Ethmozine), Propafenon (Ritmonorm),
Flekainid, Enkainid, Etacizin.

Class II (β-blockers) - Propranolol.

Class III (K+ - blockers; repolarization inhibitors) - Amiodarone,

Bretiliya tosilate, Sotalol.

Class IV - L-type Ca2+ blockers - Verapamil.

Drugs of different groups - alpha-blockers, M-Ach-blockers
(Nibentan), If-channel blockers (Alinidin), cardiotonic agents,
bradycardic drugs, etc.
PHARMACODYNAMICS - change of transport of
Na+, K+, Ca2+ in 0, II, III and IV phases of the action potential
0-positive action potential + 20--30 mV, I-fast repolarization (Cl ion input), II-
slow repolarization (K output, slow Ca, III input - final repolarization, IV-slow
spontaneous diastolic depolarization of calcium type

If-каналы Р-клеток = фаза 0

(деполяризация желудочков) На ЭКГ -
Р = предсердная деполяризация;
QRS = фаза 0; ST = I,II; T = III.
Phase 0 - rapid depolarization of the cell membrane, which is
associated with a fast incoming flow of sodium ions through
channels selectively permeable for these ions.
Phase 1 is a short initial period of rapid repolarization, caused
mainly by the current of potassium ions emerging from the cell.
Phase 2 is the period of slow repolarization, caused mainly by
the slow movement of calcium ions from the extracellular space
into the cell through calcium channels that are selectively
permeable to these ions.
Phase 3 is the second period of rapid repolarization, during
which potassium ions move out of the cell.
Phase 4 is a state of complete repolarization (slow spontaneous
depolarization, diastolic potential or resting potential). During
this phase, the potassium ions move back inside the cell, and the
sodium and calcium ions move out of the cell, causing a state in
which a new cycle begins.
 I phase II phase

0 Na+1, K+1 Ca2+2

0 phase
III phase
Na 0, K 0
+ +

Ca2+0 K +3

IV phase
Na+4, K+4
Action potential of the
cardiac conduction
system
 II phase
Ca2+2

0 phase
Na+0, K+0 III phase
Ca2+0
K +3

IV phase
Na+4, K+4

Conductivity Automatism
(blockade) (extrasystoles)
 II phase
Ca2+2

0 phase
III phase
Na 0, K 0
+ +

Ca2+0 IA K +3

все - K+0 IV phase

Na+4, K+4

Conductivity Automatism
(blockade) (extrasystoles)
 II phase
Ca2+2
IВ

0 phase
III phase
Na 0, K 0
+ +

Ca2+0 IA K +3

all - K+0 IV phase

Na+4, K+4

Conductivity Automatism
(blockade) (extrasystoles)
 II phase
Ca2+2
IС IВ

0 phase
III phase
Na 0, K 0
+ +

Ca2+0 IA K +3

все - K+0 IV phase

Na+4, K+4

Conductivity Automatism
(blockade) (extrasystoles)
 II phase
Ca2+2
IС IВ

0 phase
III phase
Na 0, K 0
+ +
K +3
Ca2+0 IA
all - K+0 IV phase
Na+4, K+4
II

Conductivity all Automatism

(blockade) (extrasystoles)
 II phase
Ca2+2
IС IВ

0 phase
Na+0, K+0 III phase III
Ca2+0
IA K +3

all - K+0 IV phase

Na+4, K+4
II

Conductivity all Automatism

(blockade) (extrasystoles)
 II phase
Ca2+2
IС IВ
IV
0 phase
III phase III
Na+0, K+0
Ca2+0 IA K +3

all - K+0 IV phase

Na+4, K+4
II

Conductivity all Automatism

(blockade) (extrasystoles)
 Disadvantages of hybrid classification
1. Incomplete

2. Does not provide for the possibility of

antiarrhythmic action when activating channels and
receptors

3. Based on data obtained on healthy myocardial

tissues.

4. Strongly simplifies the problem of arrhythmias,

creating the illusion of omniscience
 «SICILIAN GAMBIT» (1990 г.)
action on the most effective and safe
“VULNERABLE EFFECT PARAMETER OF
ARYTHMY”
(taking into account its development mechanism)
"Targets" (for nerves, hormones and drugs):
channels
pumps
receptors
 Class I: sodium channel blockade

Subclasses:

IA: moderately pronounced inhibition of

initial depolarization and an increase in
the duration of repolarization: quinidine,
procainamide (procainamide),
disopyramide
 Class I: sodium channel blockade

• IВ: poorly pronounced inhibition of

initial depolarization and a
decrease in the duration of
repolarization.
• Local anesthetics: lidocaine,
meksiletine, tokainide, and difenine
 Class I: sodium channel blockade

IC: pronounced inhibition of initial

depolarization and lack of influence
on repolarization.
Flicaine, enkainide,
etmozin (moricizin), propaphenone
 Class I: sodium channel blockade
Sodium channel blockers are united with
several common properties. :

- reduce the rate of initial depolarization

(phase 0 EP) in the tissues with a “quick
response”, which is accompanied by a
significant slowdown in the conduction of an
electrical impulse along the atria and the His-
Purkinje system;
 Class I: sodium channel blockade

- reduce the speed of spontaneous diastolic

depolarization (phase 4 EP), which leads to a
decrease in automatism of ectopic centers II and
III order, as well as CA-nodes;
- reduce the amplitude of EP and increase the
threshold potential, in connection with which the
excitability of the atrial myocardium and ventricles
decreases.
 Class I: sodium channel blockade

SDD - spontaneous diastolic depolarization. The arrows

indicate the main effects of class I antiarrhythmic drugs:
a decrease in the speed of phase 0 EP and SDD, a decrease
in the amplitude of EP and an increase in the threshold
potential
 Class I: sodium channel blockade

- possess properties to inhibit exiting

potassium currents, which is accompanied by
a slowdown in the process of repolarization
(mainly during phase 3 EP) and an increase
in the duration of EP and refractory periods
of atria and ventricles.
 Class I: sodium channel blockade

As a result, there is a significant

slowdown of conduction in tissues
with a “fast” response, i.e. in the
specialized His-Purkinje conduction
system and in the atrial and
ventricular myocardium.
Quinidine

alkaloid contained
in the bark of the
cinchona tree
 Quinidine (Chinidin)

One of the most powerful and universal AAD of the

prolonged action.
It has a membrane stabilizing effect. Reduces the
maximum speed of depolarization in the phase O;
increases ERP to a greater extent than the duration of
ED,
reduces the rate of diastolic depolarization, which
indicates a slowdown in the rate of reactivation of
fast sodium channels. It has an indirect vagolytic
effect on the heart.
 Procainamide (Procainamidi
hydrochloridum)

- Moderately inhibits the incoming fast ionic sodium

current, reduces the maximum depolarization rate in
the O phase (Vmax).
- Reduces conductivity in the atrium, in the fibers of
His-Purkinje, in the ventricles less in the AV-node,
briefly increases the fibrillation threshold in the
ventricular myocardium.
- It has an antiarrhythmic effect in case of
arrhythmias caused by increased automatism.
 Disopyramide
(Disopyramide)
Reduces the maximum rate of depolarization in
the O (Vmax) phase and the slope of the 4-
depolarization phase, and also increases the ED.
A decrease in Vmax and a slowdown in
conductivity are associated with the blockade of
fast potassium channels. It has an anticholinergic
effect, which can lead to urinary retention,
worsening of glaucoma, myasthenia, and
constipation.
 Aymalin (Giluritmal) Aimalin

It has a membrane stabilizing effect. The most

important feature of the action is that the drug is
capable of significantly extending ERP in
additional pathways for WPW syndrome. Weakly
reduces blood pressure and reduces myocardial
contractility, slightly increases coronary beds.
Onset of action 1 hour after ingestion, duration of
action 5-6 hours
WPW syndrome
•Heart palpitations – a sudden
pounding, fluttering or

•Racing feeling in your chest

•Dizziness – feeling lightheaded

or faint

•Shortness of breath (dyspnea)

•Anxiety

•Rarely, cardiac arrest (sudden

death)
 Class I: sodium channel blockade

Most drugs class Ia (with the exception of

disopyramide) have the property to reduce blood
pressure by reducing TPVR. Especially often the
hypotonic reaction is observed when intravenous
administration of these drugs
 Class I: sodium channel blockade

Side effects.
1. Cardiovascular complications :
•arterial hypotension (including the development of
collapse with intravenous administration of drugs);
•decreased ejection fraction (EF) of the LV;
•proarrhythmic action, including the emergence of
polymorphic type “pirouette” VT;
•blockade of bundle branch block;
•AV blockade of the distal type;
•sick sinus syndrome (SSS);
•VF and sudden cardiac death.
 Class I: sodium channel blockade
2. Cerebral complications :
•“light” - headache, dizziness, blurred vision, tremor;
•“severe” - diplopia, narrowing of visual fields, night blindness, hearing
impairment, psychosis.
3. Gastrointestinal complications :
•diarrhea;
•nausea, vomiting;
•abdominal colic and others
4. Other complications :
•violation of urination (with prostate adenoma);
•increased intraocular pressure (with glaucoma);
•development of Raynaud's syndrome, myalgia, myositis, SLE.
 Ib class
Lidocaine, trimecaine, mexiletine (mexitil), diphenine
and others.
-the effect is mainly on the rate of initial depolarization
(phase 0 ED) of the His – Purkinje system cells and
ventricular myocardium, especially against the background
of significant organic changes in the heart muscle (ischemia,
acute MI).
-The rate of depolarization of the atrial myocardium is
almost unchanged
-Not used for the treatment of supraventricular arrhythmias.
 Ib class
• Cells of a “slow” electrical response (CA node,
AV compound) do not respond to therapeutic
concentrations of these drugs. The function of the
SA node and the AV conduction do not change
during treatment.
• They do not affect potassium channels and do not
slow down the process of repolarization. In this
regard, the duration of EP, refractory periods, as
well as the Q – T interval during treatment does
not change or even decreases.
 Ib class

• Used almost exclusively for the treatment of

ventricular arrhythmias.
Previously, lidocaine was used in patients with acute MI for
the prevention of VF and sudden cardiac death.
Recently, for this purpose, lidocaine is used much less
frequently due to the increased risk of ventricular asystole.
Lidocaine (Lidokain)

The only drug that is used to stop

arrhythmias in the acute stage of
myocardial infarction in the form of
a long-term infusion, as well as
arrhythmias that occur during
surgical operations or cardiac
catheterization. Able to prevent
recurrence of ventricular fibrillation
with supraventricular arrhythmias.
 Mexiletine (Mexiletine)

Structural analogue of lidocaine.

Chemical and physiological properties
similar to lidocaine, differs from
lidocaine in that it can be used inside.
 Diphenine (Dipheninum)

Effective in arrhythmias caused by

digitalis intoxication with its blockade in
the region of the AV node, while difenin
improves conductivity in the AV node.
 IC class
Ethmozin, etacizin, propafenone,
allapinin
Cause a pronounced inhibition of phase 0
EP in tissues with a “fast” response, but
do not affect the duration of
repolarization, EP and effective refractory
period.
 IС class

• Cause a significant slowdown in the

conduct of excitation in the His-Purkinje
system, as well as in the atrial and
ventricular myocardium.
• The drugs have no effect on the duration
of the Q – T interval.
 IC class
Highly effective in both supraventricular and
ventricular arrhythmias.

Used to relieve supraventricular and ventricular

extrasystoles in patients with WPW syndrome,
prevention of supraventricular and ventricular
paroxysmal tachycardias.
 Propafenone (Propafenone)

• It is used only for life-threatening ventricular

arrhythmias.
• It combines the properties of a local anesthetic and a
very weak β-blocker and calcium antagonist.
• A relatively safe drug for stopping and preventing both
ventricular and supraventricular arrhythmias, including
those that occur in patients with Wolff-Parkinson-
White syndrome.
 Ethmozine (Aetmozin)

- high efficiency in ventricular heart rhythm

disorders
- high breadth of therapeutic action and good
tolerability,
- weak antiarrhythmic effect.
- can be combined with cardiac glycosides and
β-blockers.
Etacizin (Aethacizinum)

The intensity and duration

of the antiarrhythmic effect
significantly exceeds
ethmozine. In large doses,
it may cause a
deterioration in
conductivity.
 Etacizin (Aethacizinum)

• Side effects develop in 15–20% of patients. The

most common side effects include: CA blockade;
• AV blockade;
• neurological disorders (dizziness, metallic taste in
the mouth, visual impairment, etc.);
• gastrointestinal disorders (anorexia, nausea,
vomiting, constipation, etc.).
 Contraindicated in:
• Disorders of intraventricular
conduction.
• Severe liver disease.
• AV-blockades II and III degree.
• Obstructive pulmonary disease.
 General characteristics of class II drugs
β- blockers
-inhibit excitability and conduction due to blockade
of adrenergic stimulation of heart pacemakers.
-reduce the slope of phase 4 of depolarization and
the spontaneous rate of excitation of the sinus node
and ectopic pacemakers,
-contribute to the reduction of automatism and
inhibition of the mechanism of the re-entree in the
myocardium.
General characteristics of class II drugs

Used in
•myocardial infarction,
•digitalis intoxication,
•hyperthyroidism and
pheochromocytoma.
•In large doses have a membrane
stabilizing effect.
 General characteristics of class II drugs

Most effective for supraventricular and

ventricular arrhythmias associated with
increased SAS activity or provoked by
physical exertion.
Decrease in the rate
of spontaneous
diastolic
depolarization of
pacemaker cells
under the influence
of beta1-blockers
Main electrophysiological effects
of β-blockers
 β-blockers are effective :

• in sinus tachycardia (except in cases of

cardiac glycoside intoxication);
• in paroxysmal supraventricular
tachycardias;
• in paroxysmal atrial fibrillation;
 β-blockers are effective :
• in WPW syndrome;
• in ventricular arrhythmias that have developed in
patients with congenital long Q – T interval
syndrome
• in patients with catecholamine-dependent
arrhythmias and arrhythmias provoked by physical
exertion;
• in patients with CHD, especially those who have
suffered
• MI (decrease in the number of sudden deaths.
Anaprilin (obzidan, inderal)
Nebivolol
Super selective b1 – III generation
adrenergic blocker. The b1-
selectivity index is 293,
bisoprolol - 1:75,
atenolol and betaxolol - 1:35,
metoprolol - 1:20.

The b-blocker cardio-selectivity

decreases or disappears completely
when high doses are prescribed.
 General characteristics of class II drugs
The main errors in administration of β-blockers are:
•the use of small doses of drugs
•their administration is less than necessary
•the abolition of drugs in the event of a heart rate at rest less
than 60 beats per minute

It should also be borne in mind the possibility of

withdrawal syndrome, so b-blockers must be canceled
gradually.
 Class III drugs
Potassium channel blockers
Amiodarone (cordarone), sotalol and bretylium.

The property combining all three drugs is a

significant slowing of repolarization (phases 2 and 3
EP) and lengthening of EP and ERP of specialized
cells of the CA node, AV connection, His – Purkinje
system, additional conduction paths (Kent bunch)
and atrial myocardium and ventricles
 Increasing the duration of EP and ERP
under the action of class III antiarrhythmic
drugs (red curves)
 Class III drugs
• The second property explaining the antiarrhythmic
effect of amiodarone and sotalol is their β-
adrenoblocking effect.

• Amiodarone also has the property to block fast

sodium channels, which leads to a significant
slowdown in the initial depolarization of the
cardiac fiber and an increase in the duration of the
QRS complex.
 Amiodarone (cordarone,
palpitin)

It is one of the most effective

AAD.
When amiodarone was used in
post-infarction patients, it was
found that it reduces overall
mortality by 46% and reduces the
incidence of sudden death by 56%.
 Amiodarone
Application:
• Life-threatening ventricular arrhythmias,
myocarditis, and CHF;
• atrial fibrillation and flutter in combination
with frequent VES or WPW syndrome;
• bouts of AV-reciprocal tachycardia with WPW
syndrome;
• prevention of paroxysmal atrial fibrillation
attacks.
 Amiodarone: Side Effects
• Immunological damage to the lungs - interstitial
pneumonitis, requiring the abolition of amiodarone and
the appointment of glucocorticoids.
• Thyroid dysfunction
• Dermatological toxicity (rash associated with increased
sensitivity to ultraviolet radiation).
• AV blockade.
• Paroxysmal VT of the “pirouette” type (by slowing
down the repolarization and the occurrence of early
post-depolarisations).
 Class IV drugs
slow calcium channel blockers (calcium
antagonists)
• acting on slow incoming calcium channels, inhibit sinoatrial
automatism and slow down depolarization in the AV node.
• slow down sinus rhythm, broaden the PQ interval, reduce the
frequency of ventricular contractions in atrial arrhythmias.
• Can cause blockade of arrhythmias coming from the atrio-
ventricular node.
• In pathology, they can act on Purkinje fibers and affect
ventricular arrhythmias.
• Only verapamil and diltiazem have an antiarrhythmic effect.
The main electrophysiological effects of
slow calcium channel blockers
 Verapamil (isoptin,
phenoptin)

- It has antiarrhythmic action in

supraventricular arrhythmias.
- Reduces the spontaneous activity of the
sinus-atrial node, blocks the circulation of
the pulse during arrhythmias associated
with the return of excitement, slightly
reduces the contractility of muscle fibers.
- Does not affect the rate of
depolarization and repolarization in the
atrium, ventricle and Purkinje fibers.
Arrhythmogenic effect of antiarrhythmic
drugs
Drug The frequency of
arrhythmogenic actions (%)
according to ECG data
within 24 hours.
Quinidine 1 – 16
Novocainamide 9
Disopyramide 1–8
Mexiletin 1–8
Propafenone 6
Propranolol 14 – 16
Metoprolol 6–8
Amiodarone 5
 Other antiarrhythmic drugs
Cardiac glycosides

- K + -Na + –ATP-ase blockade, which is

accompanied by a decrease in the resting potential of
myocardial cells and the cardiac conduction system,
as well as the rate of initial depolarization of the
cardiac fiber (phase 0 AP). - vagotropic effect, which
leads to an increase in the refractoriness of the AV
compound.
Adenosine (ATP)
inhibits the conduction
of the AV-junction and
the automatism of the
CA-node, mainly due
to hyperpolarization of
the cell membrane (an
increase in the negative
values ​of the
transmembrane resting
potential).
 Magnesium preparations - magnesium sulfate,
chloride, aspartate, gluconate

Magnesium is required
- for the transfer, storage and disposal of energy, for the synthesis of
protein and nucleic acids associated with the utilization of energy by the
body.
- for the normal functioning of sodium-potassium ATPase,
-for the functioning of calcium-ATPase and proton pumps.

It is indicated for ventricular arrhythmias caused by digoxin intoxication

for the prevention of ventricular arrhythmias in patients with myocardial
infarction during ventricular fibrillation.
Contraindicated in sinoaortic AV blockade.
Potassium preparations - potassium chloride, panangin,
asparcam
Potassium ions
- participate in the transmission of nerve impulses, in
the contraction of the heart, skeletal and smooth
muscles,
- support normal kidney function.
A deficiency of potassium in the body leads to the
appearance of weakness, fatigue, heart rhythm
disturbance, with the appearance of beats.
 Potassium preparations - potassium chloride,
panangin, asparkam
Indicated for
•arrhythmia due to hypopotassemia,
•acute myocardial infarction in the composition of the
polarizing mixture.
Side effects:
• ulceration and bleeding in the esophagus in the upper and
lower GI tract,
•vomiting,
•diarrhea.
 Atropine

Indicated in
•in sinus bradycardia - most often of a noncardiac
nature, as well as caused by the administration of
morphine
• patients with acute myocardial infarction
•in brady-arrhythmias in cases of AV-blockade.
The main danger of antiarrhythmic drugs
RHYTHM WRONG! What to do ?
With tachyarrhythmias (frequent uneven pulse, heartbeat).
1. CALM (measure pressure, pulse, give a sedative drug).
2. GIVE NITROGLYCERINE.
3. MASSAGE EYE APPLES.
4. CALL EMERGENCY- (damage the rhythm, or defibrillate).
When bradyarrhythmia (loss of consciousness).
1. EVALUATE HR, PUPILS.
2. MECHANICAL DEFIBRILLATION.
3. INDIRECT MASSAGE + ALV.