Treatment of Angina Pectoris Agents Used in Dyslipidemia PhD Oksana Bondar Scientific and Educational Center of Pharmacology of KFU

1. Lecture 9
DRUGS REGULATING FUNCTIONS OF
ORGANS AND SYSTEMS
Сardiotonic agents
Antiarrhythmic drugs
PhD, docent, senior research fellow
Renata Ruvshanovna Kazakova
Kazan, 2024 3

2. 4
Drugs acting to the heart
Cardiotonics Antiarrhythmics Antianginal
myocardial contractility frequency and rhythm blood supply and metabolism

3. 5
Contractility is the main function of working cardiomyocytes.
Heart failure is reduction of the pumping function of the heart.
Symptoms of cardiac insufficiency:
https://en.wikipedia.org/wiki/Heart_failure

4. 6
Cardiomyocytes contraction mechanisms
NCХ (Na+-Ca2+- exchanger) is antiporter
uses the sodium gradient to move calcium
against its concentration gradient from the
cytoplasm to the extracellular space.
SERCA (Sarcoplasmic endoplasmic
reticulum Ca2+ - ATPase) is a calcium
transporter ATPase that pumps calcium
into the sarcoplasmic reticulum.
CalS is calcium bound to calsequestrin, a
high-capacity Ca2+ -binding protein.
RyR (ryanodine RyR2 receptor) is a calcium-
activated calcium channel in the membrane
of the SR that is triggered to release stored
calcium.

5. 7
Cardiotonic agents are used to stimulate contractility
Cardiac glycosides
Cardiotonic agents
Non-glycosides

6. 8
Cardiac glycosides are agents of plant origin with marked
cardiotonic effect
W. Withering (1741-1799)
Digitalis purpurea
Digitóxin
Digitalis lanata
Lanatóside C, Digóxin
Strophanthus Kombe
Strophanthin G (Ouabain)
Convallária majális
Corglycon
β-acetyldigoxin

7. 9
Cardiac glycosides
https://de.wikipedia.org/wiki/Herzglykoside
Aglycone
(genin)
Glycone
(D-digitoxose, D-glucose, D-cimarose, etc)
Steroid
Lactone ring
Pharmacokinetic properties
(accumulation, absorption, excretion)
Pharmacodynamic properties
(cardiotonic effect)

8. 10
Сardiotonic agents’ action mechanisms
NCХ (Na+-Ca2+-exchanger) is antiporter uses the sodium
gradient to move calcium against its concentration gradient
from the cytoplasm to the extracellular space.
SERCA (Sarcoplasmic endoplasmic reticulum Ca2+ -ATPase) is
a calcium transporter ATPase that pumps calcium into the
sarcoplasmic reticulum.
CalS is calcium bound to calsequestrin, a high-capacity Ca2+ -
binding protein.
RyR (ryanodine RyR2 receptor) is a calcium-activated calcium
channel in the membrane of the SR that is triggered to
release stored calcium.
Na+
Na+
Na+
Сa2+
Сa2+
Сa2+
Сa2+
Сa2+

9. 11
Main effects of cardiac glycosides:
• + inotropic action – strengthen the heart contractions
(systole amplification and shortening) – cardiotonic action
• - chronotropic effect – HR (lengthening of the diastola), SAN
(bradicardia)
• - dromotropic effect – conduction velocity in AVN
• ventricular automatism – K+, Ca2+
• + bathmotropic effect – myocardial excitability
(in low doses)
• diuresis due to blocking Na+/K+-ATPase of kidney
The most
economic
regimen
of cardiac work
Cardioinhibitory
center (Vagus)
 GEB,
 cardio-cardiaс
reflex
 baroreceptor pressor-depressor effect
Na reabsorption

10. 12
Cardiotonic agents classification:
Cardiac glycosides
Cardiotonic agents
Non-glycosides
AHF
Strophánthin
Corglycon
AHF/CHF
Lanatoside C
Digóxin
CHF
Digitóxin
AHF – acute heart failure,
CHR – chronic heart failure.

11. 13
Cardiac glycosides
Cardiotonic agents
Non-glycosides
AHF
Corglycon
Strophanthin
AHF/CHF
Lanatoside C
Digoxin
CHF
Digitoxin
AHF – acute heart failure,
CHR – chronic heart failure.
1 Frog’s action units (FAU) corresponds to a minimum dose of a standard agent, which causes systolic
cardiac arrest in the majority of experimental frogs. Also, cat (CAU) and dove (DAU) action units were
used.
Raw medicinal material Individual glycosides
1 g of digitalis leaves contains 50-66 FAU 1 g of digitoxin contains 8000-10000 FAU
1 g of strophanthus seeds contains 2000 FAU 1 g of strophanthin K contains 44000-56000 FAU
Cardiotonic agents classification:

12. 14
Side effects of cardiac-glycosides:
• Nausea, vomiting, diarrhea, abdominal pain (increased tone of the parasympathetic
nervous system)
• Visual disturbance (xanthopsia – Yellow and green are typical colors in digoxin toxicity)
• Atrioventricular block (vagus)
• Ventricular extrasystole ( K+, Сa2+)
• The most common cause of death is ventricular fibrillation
“Sunflowers”
Vincent van Gogh

13. 15
Cardiac glycosides intoxication treatment:
• Drug withdrawal
• Ventricular extrasystole – Phenytoin, Lidocaine block Na+-channels
• Atrioventricular block – Atropine blocks M2-receptros of heart
• Magnesium, potassium agents (panangin) activate Na+/K+-ATPase
• Unithiol is donor of sulfhydryl groups. Reactivate Na+/K+-ATPase
• Potassium agents (KCl) (potassium competes with digoxin on the Na+/K+-ATPase)

14. 16
Cardiotonic agents non-glycoside structure
Cardiac glycosides
Cardiotonic agents
Non-glycosides
AHF
β-adrenomimetics
Corglycon
Strophantin
Lanatoside C
Digoxin
Digitoxin
β1-adrenomimetic
Dobutamine
Dopaminomimetic
Dopamine
(D-receptors)
+ presynaptic β2 ( NE)
α1-adrenoceptors - pressor action
Phosphodiesterase
Inhibitors III
Milrinone
non-selective action:
vasodilation,
TPR,
afterload
Calcium
sensitizers
Levosimendan
Binds with
Troponin C
+ inhibits
phosphodiesterase
TPR - total peripheral resistance

15. 17
Therapeutic uses of sympathomimetic drugs
α1
Adrenergic agonists
β
β1
Presynaptic
Not innervated
α
α2
β2
, HR, AV Albuterol
Fenoterol
Metaproterol
Terbutaline
Pirbuterol
Salbutomol
Salmeterol
Formoterol
Indacaterol
Phenylephrine
BP
Naphazoline
Oximethaxoline
Xylometazoline
https://ru.depositphotos.com/13916393/stock-illustration-cartoon-nasal-spray.html
Methyldopa
Clonidine
Guanfacine
Guanabenz
Dobutamine
CNS
https://fr.123rf.com/photo_76367217_vector-illustration-de-cartoon-tortue-relaxant-
isol%C3%A9-sur-fond-blanc.html
https://www.cartoonstock.com/directory/m/muscle_spasm.asp
Midodrine
IOP
Apraclonidine
Brimonidine
Ritodrine
Terbutaline
30
weeks
Not innervated
IOP
I1
Tizanidine
Isoprenaline

16. 20
I went to the doctor and I think
that he prescribed me a trip to the sea

17. 21
Anti-arrhythmic drugs

18. 22
Cardiac conduction system
The myocardium includes typical (pump function) and atypical cardiomyocytes –
pacemakers, which form the cardiac conduction system
Atypical: automatism
conductivity
Internodal pathways
(70-80 imp/m)
(40-60 imp/m)
Typical: contractility
automatism
conductivity
(20-30 imp/m)

19. 23
Cardiac conduction system
Heart innervation:
Atypical: automatism
conductivity
Internodal pathways
n. vagus
Typical: contractility,
automatism,
conductivity
M2
β1
β1
SNS

20. B.Katzung Basic and clinical pharmacology 14th edition.
Muscarinic transmission to the sinoatrial node in heart
K+
K+ K+
K+
K+
K+
PKA - protein kinase 24

21. 25
Some causes of arrhythmias:
• heart failure
• metabolic disorders (thyrotoxicosis)
• some medications (adrenergics, cardiotonics, antiarrhythmics)
• structural changes of the heart (thrombembolia, abnormality of heart)
• smoking
Atypical: automatism
conductivity

22. 26
Classification of arrhythmias by:
• location:
- sinus
- atrial
- ventricular
• rate:
- bradycardia
- tachycardia
- fibrillation (uncoordinated,
repetitive excitation)
• mechanism of the development:
- heart block
- extrasystole
- reentry (conduction disturbance)
https://serdce.guru/aritmiya/snyat-pristup-v-domashnix-usloviyax/
Normal Fibrillation

23. 27
Mechanism of action potential of Purkinje fiber:
-90
Membrane
potential
(mV)
0
-60
35
Time
Threshold
Effective refractory period
Na+
K+
Ca2+
K+
Na+
out
in
0 – fast depolarization
(conductivity)
1 – early-fast repolarization
2 – plateau
3 – repolarization
4 – spontaneous slow
diastolic depolarization
(automatism)
Phases 4 0 1 2 3 4
K+
-40
Na+
K+
K+
K+
(non-excitability)

24. 28
Mechanism of action potential of SA node:
Ca2+
out
in
Na+
K+
4 – spontaneous depolarization
0 – depolarization
3 – repolaziation
Membrane
potential
(mV)
Phases 4 0 3 4

25. Schematic representation of the heart and normal cardiac electrical activity:
29
Basic and Clinical Pharmacology Ed. B. Katzung. 2012

26. 30
https://www.instagram.com/p/CHnj8M0AmNa/

27. 1918-1921 - K.Wenkebach noticed sinus rhythm restoration in two
patients with atrial fibrillation who received quinine to prevent malaria
31
Karel Frederik Wenckebach
(1864-1940)
Quinine
Cinchona pubescens
Quinidine

28. 32
Vaughan-Williams classification of antiarrhythmic drugs:
Drugs used for extrasystoles and tachyarrhythmias
Class Drug Mechanism of action
Clinical
use
I Fast sodium channel blockers
IA
Quínidine, Procaínamide
Disopýramide
+ blocking potassium channels. AP, RP
Сontractility, automatism, conductivity AVN, SAN, PF
AA, VA
IB Lidocaine, Phenytoin, Mexiletine Automatism, conductivity PF AP VA
IC Propafenone, Flecainide, Moricizine
+ blocking calcium channels
Automatism, conductivity AVN, PF
VA
II
β-adrenoblockers: atenolol,metoprolol,
propranolol, bisoprolol, nebivolol
Automatism, conductivity SAN, AVN. Contractility. AA, VA
III
Potassium channel blockers:
amiodarone, sotalol, bretylium tosylate,
ibutylide, nibentan
Automatism, conductivity SAN, AVN, PF AP, RP AA, VA
IV
(Slow) calcium channel blockers:
verapamil, diltiazem Automatism, conductivity SAN, AVN AA
Adenosin, cardiac glycosides (digoxin) AV-block AA
Magnesium, potassium
Drugs used for bradyarrhythmias and blockades
M-cholinoblockers
β-adrenomimeticks
SAN – sinoatrial node
AVN – atrioventricular node
AA – atrial arrhythmia
VA – ventricular arrhythmia
RP – refractery period
PF – Purkinje fibers
AP – action potential

29. 33
Mechanism of action of IA class drugs: quinidine, procainamide:
Na+
Ca2+
Na+
out
in
0 – fast depolarization conductivity
1 – early-fast repolarization
2 – plateau
3 – repolarization (+ blocking potassium channels)
4 – spontaneous slow diastolic depolarization automatism
Phases 4 0 1 2 3 4
K+
K+
Side effects:
Contractility doesn’t lead to antiarrhythmic action
BP
AV conductivity (M-cholinoblocking)
Ventricular tachyarrhythmias (torsades de pointes)
Anticholinergic ( automatism SA) HR
K+
СYP

30. 34
Drugs used for tachyarrhythmias and extrasystoles
Class Drug Mechanism of action Clinical use
I Fast sodium channel blockers
IA
Quinidine, Procainamide
Disopyramide
+ blocking potassium channels AP, RP.
Сontractility, automatism, conductivity AVN, SAN, PF
AA, VA
IB Lidocaine, Phenytoin, Mexiletine Automatism, Conductivity PF AP, RP MI, VA
IC Propafenone, Flecainide, Moricizine
+ blocking calcium channels
Automatism, conductivity AVN, PF
VA
II
β-adrenoblockers: atenolol,metoprolol,
propranolol, bisoprolol, nebivolol
Automatism, conductivity SAN, AVN AA, VA
III
Potassium channel blockers: amiodarone,
sotalol, bretylium tosylate, ibutylide,
nibentan
Automatism, conductivity SAN, AVN, PF AP, RP AA, VA
IV
(Slow) calcium channel blockers:
verapamil, diltiazem Automatism, conductivity SAN, AVN AA
Adenosin, cardiac glycosides (digoxin) AV-block AA
Magnesium, potassium
Drugs used for bradyarrhythmias and blockades
M-cholinoblockers
β-adrenomimeticks
SAN – sinoatrial node
AVN – atrioventricular node
PF – Purkinje fibers
AP – action potential
AA – atrial arrhythmia
VA – ventricular arrhythmia
RP – refractery period
MI – myocardial infarction
Vaughan-Williams classification of antiarrhythmic drugs:

31. 35
Mechanism of action of IB class drugs: lidocaine, phenytoin, mexiletine
-90
Membrane
potential
(mV)
0
-60
35
Time
Threshold
Na+ K+
K+
Ca2+
K+
Na+
out
in
Phases 4 0 1 2 3 4
0 – fast depolarization conductivity
1 – early-fast repolarization
2 – plateau
3 – repolarization
4 – spontaneous slow diastolic depolarization automatism
Side effects:
BP
AV conductivity
arrhythmogenic
Action potential
Effective refractory period
of action potential

32. 36
Drugs used for tachyarrhythmias and extrasystoles
Class Drug Mechanism of action Clinical use
I Fast sodium channel blockers
IA
Quinidine, Procainamide
Disopyramide
+ blocking K-channels. AP, RP
Сontractility, automatism, conductivity AVN, SAN, PF
AA, VA
IB Lidocaine, Phenytoin, Mexiletine Automatism, conductivity PF AP, RP MI, VA
IC Propafenone, Flecainide, Moricizine
+ blocking Ca-channels
Automatism, conductivity AVN, PF
VA
II
β-adrenoblockers:atenolol, metoprolol,
propranolol, bisoprolol, nebivolol
Automatism, conductivity SAN, AVN. Сontractility AA, VA
III
Potassium channel blockers: amiodarone,
sotalol, bretylium tosylate, ibutylide,
nibentan
Automatism, conductivity SAN, AVN, PF AP, RP AA, VA
IV
(Slow) calcium channel blockers: verapamil,
diltiazem Automatism, conductivity SAN, AVN AA
Adenosin, cardiac glycosides (digoxin) AV-block AA
Magnesium, potassium
Torsades de
pointes
Drugs used for bradyarrhythmias and blockades
M-cholinoblockers
β-adrenomimeticks
AA – atrial arrhythmia
VA – ventricular arrhythmia
RP – refractery period
SAN – sinoatrial node
AVN – atrioventricular node
PF – Purkinje fibers
AP – action potential
Vaughan-Williams classification of antiarrhythmic drugs:

33. 3
9
Adrenergic receptors subtypes
α1
Adrenergic receptors
β
β1
β3
Presynaptic
Not innervated
GI
exocrine glands
uterus
α
α2 β2
NE
, HR, AV
Renin, BP Glycoginolis
Glycogen glucose
https://www.123rf.com/photo_34821793_stock-vector-glycolysis-and-glycogenolysis.html
https://pngtree.com/free-png-vectors/kidney
https://www.shutterstock.com/ru/image-vector/mascot-illustration-lungs-doing-ok-sign-
477953383?src=fBaOpRfXBHB5epV8_oH0EQ-1-8
Lipolysis
http://mediwikis.com/wiki/index.php?title=File:Platelet_cartoon.jpeg
Lipolysis
BP
BP
Not innervated
CNS

34. 40
B.Katzung Basic and clinical pharmacology 12th edition.
Activation and inhibition of adenylyl cyclase by agonists that bind
to catecholamine receptors
C – catalytic subunits
R – regulatory subunit
CREB - cAMP response element binding protein

35. 41
Characteristics of the most important receptors
cAMP - cyclic adenosine monophosphate
DAG – diacylglycerol
IP3 -inositol-1,4,5-trisphosphate

36. 42
Therapeutic uses of adrenoceptor antagonist drugs
α1,α2
Adrenoceptor antagonist
β
β1
α
α1
Phentolamine
β, α1
β1, β2
Prazozin
Doxazosin
Terazosin
α2
Yohimbine
Tolazoline
Labetalol
Carvedilol
Esmolol
Metoprolol
Atenolol
Nebivolol
Alprenolol
Betaxolol
Celiprolol
Propranolol
Nadolol
Timolol
Phenoxybenzamine
Tamsulosin
Dihydroergotamine
https://impotencija.net/prostatit/giperplazija-prostaty/
https://ubisafe.org/explore/chast-clipart-angina/#gal_post_1215_chast-clipart-angina-2.jpg
Pindolol
Bopindolol
Oxprenolol
Carteolol
Penbutolol
Intrinsic
sympathomimetic effect
http://crazynews.in/english/heart-failure-facts/
https://www.frontiersin.org/articles/253130
Acebutol
Bisoprolol
NO
withdrawal syndrome

37. 43
Drugs used for tachyarrhythmias and extrasystoles
Class Drug Mechanism of action Clinical use
I Fast sodium channel blockers
IA
Quinidine, Procainamide
Disopyramide
+ blocking potassium channels. AP, RP
Сontractility, automatism, conductivity AVN, SAN, PF
AA, VA
IB Lidocaine, Phenytoin, Mexiletine Automatism, conductivity PF AP, RP MI, VA
IC Propafenone, Flecainide, Moricizine
+ blocking calcium channels
Automatism, conductivity AVN, PF
VA
II
β-adrenoblockers: atenolol, metoprolol,
propranolol, bisoprolol, nebivolol
Automatism, conductivity SAN, AVN. Сontractility. AA, VA
III
Potassium channel blockers: amiodarone,
sotalol, bretylium tosylate, ibutylide,
nibentan
Automatism, conductivity SAN, AVN, PF AP, RP AA, VA
IV
(Slow) calcium channel blockers: verapamil,
diltiazem Automatism, conductivity SAN, AVN AA
Adenosin, cardiac glycosides (digoxin) AV-block AA
Magnesium, potassium
Torsades de
pointes
Drugs used for bradyarrhythmias and blockades
M-cholinoblockers
β-adrenomimeticks
SAN – sinoatrial node
AVN – atrioventricular node
PF – Purkinje fibers
AA – atrial arrhythmia
VA – ventricular arrhythmia
RP – refractery period
Vaughan-Williams classification of antiarrhythmic drugs:

38. 44
Mechanism of action of Class III potassium channel blockers
-90
Membrane
potential
(mV)
0
-60
35
Time
Threshold
Na+
K+
Ca2+
K+
Na+
out
in
Phases 4 0 1 2 3 4
0 – fast depolarization (conductivity)
1 – early-fast repolarization
2 – plateau
3 – repolarization
4 – spontaneous slow diastolic depolarization (automatism)
Side effects:
negative inotropic
bradicardia
AV conductivity
BP
K+
Amiodaron’s SE:
hypo/hyperthyroidism,
skin deposits,
corneal microdeposits
Amiodaron’s T1/2=10-50 days
Effective refractory period

39. 47
Drugs used for extrasystoles and tachyarrhythmias
Class Drug Mechanism of action Clinical use
I Fast sodium channel blockers
IA
Quinidine, Procainamide
Disopyramide
+ blocking potassium channels. AP, RP
Сontractility, automatism, conductivity AVN, SAN, PF
AA, VA
IB Lidocaine, Phenytoin, Mexiletine Automatism, conductivity PF AP, RP MI, VA
IC Propafenone, Flecainide, Moricizine Automatism, conductivity AVN, PF VA
II
β-adrenoblockers: atenolol,metoprolol,
propranolol, bisoprolol, nebivolol
Automatism, conductivity SAN, AVN. Сontractility. AA, VA
III
Potassium channel blockers: amiodarone,
sotalol, bretylium tosylate, ibutylide, nibentan
Automatism, conductivity SAN, AVN, PF AP, RP AA, VA
IV
(Slow) calcium channel blockers: verapamil,
diltiazem Automatism, conductivity SAN, AVN AA
Adenosin, cardiac glycosides (digoxin) AV-block АА
Magnesium, potassium
Torsades de
pointes
Drugs used for bradyarrhythmias and blockades
M-cholinoblockers
β-adrenomimeticks
SAN – sinoatrial node
AVN – atrioventricular node
AA – atrial arrhythmia
VA – ventricular arrhythmia
RP – refractery period
Vaughan-Williams classification of antiarrhythmic drugs:

40. 48
Mechanism of action of Class IV calcium channel blocker verapamil
Ca2+
out
in
Na+
4 – spontaneous depolarization
0 – depolarization (automotism&conductivity)
3 – repolaziation
Membrane
potential
(mV)
Phases 4 0 3 4
SA node
Side effects:
AV conductivity
Contractility (cardiomyocytes Ca2+-channels blocking)
BP
K+

41. 52
Drugs used for extrasystoles and tachyarrhythmias
Class Drug Mechanism of action Clinical use
I Fast sodium channel blockers
IA
Quinidine, Procainamide
Disopyramide
+ blocking potassium channels. AP, RP
Сontractility, automatism, conductivity AVN, SAN, PF
AA, VA
IB Lidocaine, Phenytoin, Mexiletine Automatism, conductivity PF AP, RP VA
IC Propafenone, Flecainide, Moricizine Automatism, conductivity AVN, PF VA
II
β-adrenoblockers: atenolol,metoprolol,
propranolol, bisoprolol, nebivolol
Automatism, conductivity SAN, AVN. Сontractility. AA, VA
III
Potassium channel blockers: amiodarone,
sotalol, bretylium tosylate, ibutylide, nibentan
Automatism, conductivity SAN, AVN, PF AP, RP AA, VA
IV
(Slow) calcium channel blockers: verapamil,
diltiazem Automatism, conductivity SAN, AVN AA
Adenosin, cardiac glycosides (digoxin) AV-block АА
Magnesium, potassium
Torsades de
pointes
Drugs used for bradyarrhythmias and blockades
M-cholinoblockers
β-adrenomimeticks
SAN – sinoatrial node
AVN – atrioventricular node
PF – Purkinje fibers
AA – atrial arrhythmia
VA – ventricular arrhythmia
RP – refractery period
Vaughan-Williams classification of antiarrhythmic drugs:

42. 59