Introduction. Classification . Drugs used in Anti-Arrhythmias agents Mechanism of action . Structure Synthesis Adverse Drug Reactions . Uses.

1. 3RD UNIT
ANTI-ARRHYTHMIC DRUGS
Prepared by
G. Nikitha, M.Pharmacy
Assistant Professor
Department of Pharmaceutical Chemistry
Sree Dattha Institute Of Pharmacy
Hyderabad
1
Subject: Medicinal Chemistry-II
Year: B.Pharmacy 3rd Year
Semister: 1st Semister

2. CONTENTS
 Introduction.
 Classification .
 Drugs used in Anti-Arrhythmias agents
 Mechanism of action .
 Structure
 Synthesis
 Adverse Drug Reactions .
 Uses.
2

3. INTRODUCTION
 Arrhythmias may occur due to abnormalities in the normal rhythm of
heart causing irregularities in heart rate.
 SA (Sinoatrial node) present in the right atrial well acts as the main
pacemaker which initiates the impulse.
 Any abnormality in the rhythm of heart may hinder the formation as
well as conduction of impulse through the heart.
 The abnormality is termed as arrhythmias.
3

4. 4

5. CAUSES
Arrhythmias may be precipitated due to the following reasons,
1. Underlying heart disease, thyroid disease (hyperthyroidism),
hypertension, heart valve problem etc.
2. Insufficient O2 supply (ischaemia or hypoxia), acidosis, alkalosis,
hypokalaemia, sympathetic and parasympathetic (ANS) influence.
3. They may also be precipitated in patients receiving digitalis therapy.
4. Sometimes it may also occur due to overstretching of myocardial
contractile fibers.
5. They may also be provoked due to the presence of scarred or
diseased tissue (as in myocardial infarction).
6. Some antiarrhythmic drugs may themselves precipitate arrhythmias.
Egs: Amiodarone, lignocaine, procainade, quinidine etc.
7. In some cases, arrhythmias may be iatrogenic, where the underlying
cause is unknown.
5

6. SYMPTOMS
1. Palpitations, fluttering sensations in chest, skipping of heart beat,
difficulty in breathing due to poor O2 supply, chest pain.
2. The patient also experiences dizziness and may faint due to poor
blood supply to the brain.
6

7. CLASSIFICATION
1. Class I/ Sodium Channel blockers.
These have a membrane stabilizing or anesthetic effect on cells
myocardial. Hence Class IA, IB, IC drugs are used.
Class IA:
Class IA blocks the sodium channel and slow phase O depolarization.
eg: Quinidine, Procainamide, Disopyramide. They suppress A-V
conduction and prolonged P-R, QRS, QT and potential duration.
7

8. 8
Quinidine Sulphate Procainamide Hcl
Disopyramide Phosphate

9. Class IB:
These drugs also affect the sodium channels in both activated states but
they shorten phase 0 repolarization.
Eg: Lidnocaine, Mexelitine, Tocainide.
9
Lidocaine Hcl
Mexelitine Hcl

10. 10
Tocainide Hcl Phenytoin Sodium

11. Class IC:
Class IC drugs block the Sodium channel with marked slowing of
Phase 0 depolarization. They markedly delay conduction prolong P-
R broaden QRS complex but have variable effect on action potential
duration.
Eg: Flecainide, Propafenone, Lorcainide.
11
Flecainide

12. 12
Propafenone Lorcainide Hcl

13. 2. Class II- β-blockers:
It include β-adreno receptor blocking drugs decrease myocardial
response to epinephrine, and nor- epinephrine because of their
ability to block β-receptor of heart.
Eg: Propranolol, Esmolol, Acebutolol, Sotolol, and Timolol.
13Propranolol
Esmolol

14. 14
Acebutolol Sotolol
Timolol

15. 3. Class-III- Potassium channel blockers
This class of drugs prolong repolarization prolongs refractory period
and increase the ventricular fibrillation threshold. These drugs are in
general potassium channel blockers.
Eg: Bretylium, Amiodarone
15
Amiodarone
Bretylium

16. 4. Class IV- Calcium Channel blockers:
These act by inhibiting the movement of calcium through the
channels across the myocardial cell membrane and vascular smooth
muscle by reducing the ca+2 flow conduction through SA node and
AV node is slowed and the refractory period is prolonged resulting
in suppression of arrhythmia.
Eg: Verapamil, Diltiazem
16
Verapamil Diltiazem

17. 5. Miscelloneous Drugs:
17
Adenosin Digoxin

18. CLASS I/ SODIUM CHANNEL BLOCKERS.
18

19. 19
Mechanism of Action:
 These agents block the specific channels and decrease the threshold
for excitability.
 It decreases conduction velocity in fast response tissues and
increases QRS duration.
 These drugs also inhibit the triggered activity arising from delayed
after depolarization (DAD) or early after depolarization (EAD) and
shift the voltage dependence of recovery from inactivation to more
negative potentials.

20. Quinidine Sulphate:
It is the Protype drug of class IA antiarrhythmic drugs. It is
chemically an alkaloid which is extracted from the cinchona tree. It
is the d – isomer of quinine (antimalarial drug).
Structure:
IUPAC:5-ethenyl-1-azabicyclooctan-2-yl](6-methoxy quinolin-4-
yl)methanol. Sulphate
Properties:
White or almost white crystalline powder, insoluble in acetone,
slightly soluble in water, soluble in boiling water, alcohol. Quinidine
is an alkaloid isolated from cinchona bark. 20
Molecular formula:C20H24N2O6S

21. Pharmacokinetics:
 Quinidine is available in its salt form i.e, quinidine sulphate or
gluconate hydrochloride.
 This drug is administrated through oral route. Three-fourth of the
drug administrated reaches the systemic circulation.
 The drug is metabolized in the liver through hydroxylation reaction
and about 20% of the drug is excreted unchanged in urine.
 It is a plasma protein bound drug. About 80-90% of the drug binds
to plasma proteins.
21

22. Adverse Drug Reactions:
 Nausea, vomiting, diarrhea
 Thrombocytopenia (decrease in number of platelets in blood)
 Hypokalaemia ( decrease in potassium concentration in blood)
 Hypersensitivity
 Headache, tinnitus, blurred vision.
 Loss of appetite, stomach pain
 Weakness, tremor
Therapeutic Uses:
 Quinidine is useful for the long term treatment of ventricular
premature depolarization or to prevent recurrences of ventricular
tachycardia after cardio version of the arrhythmia.
Dose:
 200 to 400mg t.i.d or q.i.d.
22

23. Procainamide Hcl:
It is an amide derivative of the local anaesthetic, procaine. It shows
similar mechanism of action, pharmacological effects and
therapeutic efficacy as that of quinidine with the following
differences in the pharmacokinetic and pharmacological parameters.
 It is less potent.
 It has minimal antivagal action.
 It decreases the contractility and A-V conduction to lesser extent.
 It does not block α-receptor hence fall in B.P is minimal and is
mainly because of ganglionic blockade.
23

24. Structure:
IUPAC:4-amino-N-[2-(diethylamino)ethyl]benzamide hydrochloride
Properties:
White crystalline powder, odorless, soluble in water, alcohol, slightly
soluble in chloroform, very slightly soluble in ether, more stable in
water. 24
Molecular formula: C13H22ClN3O

25. Pharmacokinetics:
Oral, intramuscular, intravenous route of administration. The drug
undergoes first pass metabolism give rise to the active metabolite N-
acetyl Procainamide (NAPA) which lacks sodium channel blocking
activity but blocks the efflux of K+ ions. 50% of the administered is
excreted unchanged in urine.
Adverse Drug Reactions:
 Nausea, vomiting, bitter taste in mouth
 Thrombocytopenia (decrease in number of platelets in blood)
 Haemolytic anaemia
 Hepatitis, Hypersenitivity
 Rapid I.V administration of Procainamide leads to hypertension,
fever, rash, itching.
 Depression, Hallucination, dizziness
25

26. Therapeutic Uses:
 Used in the treatment of arrhythmias, alcohol withdrawal ventricular
fibrillation. It is also used against premature arterial contractions.
Dose:
 IM Administration
0.5-1 g IM q4-8hr
 IV Administration
Loading dose: 100-200 mg/dose or 15-18 mg/kg; infuse slowly over
25-30 min not to exceed 50 mg/min; may repeat q5min PRN not to
exceed 1 g
 Maintenance: 1-4 mg/min by continuous IV infusion
26

27. Disopyramide Phosphate:
• This drug shows similar cardiac electrophysiological activity as that
of quinidine and Procainamide.
• Hence, it is used as a substitute for the above two drugs (i.e
Procainamide HCl, Quinidine Sulphate) in preventing the recurrence
of ventricular tachyarrhythmia (ventricular tachycardia and
venautricular fibrillation).
27

28. Structure:
IUPAC:4-[bis(propan-2-yl)amino]-2-phenyl-2-(pyridin-2-yl)
butanamide; phosphoric acid
Properties:
White or almost white powder, soluble in water, sparingly soluble
in alcohol, insoluble in methylene chloride.
28
Molecular formula: C21H32N3O5P

29. Synthesis:
 Step-I: Preparation of 2-Phenyl-2-(pyridin-2yl) acetonitrile from
2-phenylacetonitrile
29

30.  Step-II: Preparation of (S)-4-(disopropylamino)-2-phenyl-2-
(pyridine-2-yl)butanenitrile from 2-Phenyl-2-(pyridine-2yl)
acetonitrile.
30

31.  Step-III: Preparation of Disopyramide Phosphate from (S)-4-
(disopropylamino)-2-phenyl-2-(pyridine-2-yl)butanenitrile
31

32. Pharmacokinetics:
Oral, intravenous route of administration. Undergoes the metabolism
in liver through N-dealkylation reaction. About 80% of the drug is
excreted unchanged in urine.
Adverse Drug Reactions:
 Dry mouth, constipation,
 Headache, nausea, vomiting
 Urinary retension, abdominal pain
 Blurred vision, dizziness
 Dry nose, eyes
 Low blood sugar, sweating
 liver problems,
 Stomach pain, shortness of breath
 Heart failure, Sudden weight gain
 Allergic reactions
32

33. Therapeutic Uses:
Used as an antiarrhythmic agents to suppress and treat sustain
ventricular or supraventricular arrhythmias.
Dose:
Daily dose is 400-500 mg; 100-150 mg four times per day.
33

34. Lidocaine Hcl:
Lidocaine is the drug of choice for the treatment of ventricular
arrhythmias. Moreover, it is most commonly employed local
anaesthetic.
Structure:
IUPAC:2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide hydrate
hydrochloride
Properties:
White crystalline powder, soluble in water, freely soluble in alcohol. 34
Molecular formula: C14H25ClN2O

35. Pharmacokinetics:
Lidocaine is not administered through oral route as it is readily and
almost completely metabolized in liver through hydrolysis, de-
ethylation and conjugation reactions. Instead it is given as an
intravenous injection or bolus. The inactive metabolites are excreted
in urine.
Adverse Drug Reactions:
 Low blood pressure (hypotension)
 Swelling (edema), Redness at injection site
 Small red or purple spots on skin, Skin irritation
 Constipation, Nausea, Vomiting
 Confusion, Dizziness, Headache, convulsions
 Numbness and tingling, Drowsiness, Tremor
 Irritation symptoms (topical products); i.e., redness, swelling
 Cardiac arrest, Abnormal heartbeat
 Seizures, Severe allergic reactions (anaphylaxis)
 Blurred vision, Slurred speech
35

36. Therapeutic Uses:
It is used as local anaesthetic agent. It is used in the treatment of
arrhythmias.
Dose:
1-2mk/kg in 30 sec I.v followed by continuous administration of 1-
4mg/min by I.V infusion.
36

37. Mexelitine Hcl:
It is basically a local anaesthetic drug which also possesses active
antiarrhythmic activity. It shows chemical and pharmacological
resemblance to Lidocaine. The only difference is that it does not
undergo first pass metabolism to the extent of lidocaine and hence
unlike the latter, can administered oral route.
Structure:
IUPAC:1-(2,6-dimethylphenoxy)propan-2-amine hydrochloride
37
Molecular formula: C11H18ClNO

38. Properties:
White crystalline powder, bitter taste, soluble in alcohol, water .
Pharmacokinetics:
Oral route of administration. Undergoes the metabolism in liver
through CYP2D6 and CYP1A2 (primarily CYP2D6).
Approximately 10% is excreted unchanged by the kidney.
Adverse Drug Reactions:
 Nausea, vomiting, dry mouth
 Hypotension, Thrombocytopenia.
 Tremors, blurred vision.
 upset stomach, decreased appetite, diarrhea, constipation
 depression, Head ache
 heartburn, dizziness, tiredness, weakness
38

39. Therapeutic Uses:
 It is used in the treatment of arrhythmias.
 It is employed in the patients who are unresponsive to lidocaine. It is
used for treating ventricular tachyarrhymias following myocardial
infarction.
Dose:
 Initial: 200 mg PO q8hr; may load with 400 mg followed by 200
mg PO q8hr if necessary for rapid control of ventricular arrhythmia
 Dose range: 200-300 mg PO q8hr
 May increase to 400 mg q8hr; not to exceed 1200 mg/day
39

40. Tocainide Hcl:
• Tocainide Hydrochloride is the hydrochloride salt form of tocainide,
a primary amine analog of lidocaine exhibiting class 1b
antiarrhythmic property.
• Tocainide hydrochloride stabilizes the neuronal membrane by
reversibly binding to and blocking open and inactivated voltage-
gated sodium channels.
• This inhibits the inward sodium current required for the initiation
and conduction of impulses and reduces the excitability of
myocardial cells.
40

41. Structure:
IUPAC:2-amino-N-(2,6-dimethylphenyl) propanimidic acid
hydrochloride
Properties:
Tocainide hydrochloride is a white crystalline powder with a bitter
taste and is freely soluble in water. 41
Molecular formula: C11H17ClN2O

42. Pharmacokinetics:
Oral route of administration. Undergoes negligible first pass hepatic
degradation. No active metabolites have been found. excreted by the
kidney.
Adverse Drug Reactions:
 dizziness
 spinning sensation (vertigo)
 tiredness
 upset stomach, decreased appetite, diarrhea
 Headache, nausea, vomiting
 blurred vision, confusion
 numbness or tingling
 tremor (shaking)
 sweating
 low blood pressure (hypotension), and fatigue
42

43. Therapeutic Uses:
It is used to treat premature ventricular contractions and ventricular
tachycardia.
Dose:
The recommended initial dosage is 400 mg every 8 hours. The usual
adult dosage is between 1200 and 1800 mg/day in a three dose daily
divided regimen.
43

44. Phenytoin Sodium:
• Phenytoin Sodium is the sodium salt form of phenytoin,
a hydantoin derivate and non-sedative antiepileptic agent with
anticonvulsant activity.
• Phenytoin sodium promotes sodium efflux from neurons located in
the motor cortex, thereby stabilizing the neuron and inhibiting
synaptic transmission.
Structure:
IUPAC: sodium 2-hydroxy-4,4-diphenyl-4H-imidazol-5-olate
44
Molecular formula:C15H11N2NaO2

45. Properties:
White crystalline powder, slightly hygroscopic in nature, insoluble in
methylene chloride, soluble in water, alcohol.
Pharmacokinetics:
Oral, intramuscular, intravenous route of administration. Undergoes
metabolism by liver through cytochrome enzyme (CYP1A2,
CYP2A6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and
CYP3A4). The majority of phenytoin is excreted as inactive
metabolites in the bile. An estimated 1-5% of phenytoin is
eliminated unchanged in the urine.
45

46. Adverse Drug Reactions:
 Headache, nausea, vomiting,
 constipation, dizziness, feeling of spinning, drowsiness,
 Trouble sleeping or nervousness may occur.
 Swelling and bleeding of the gums.
 Confusion, blurred vision
 Rashes, joint pain
 Depression, suicidal thoughts
 Liver problems, stomach pain, Abdominal pain
Therapeutic Uses:
It is used to prevent and control seizures (also called an
anticonvulsant or antiepileptic drug). It works by reducing the
spread of seizure activity in the brain.
46

47. Dose:
 For the treatment of status epilepticus
15 to 20 mg/kg/dose IV administered
 For the treatment of tonic-clonic seizures or partial seizures.
4 to 7 mg/kg/day PO divided into 2 or 3 doses per day.
4 to 7 mg/kg/day IV given divided into 2 or more doses per day.
 For the treatment of serious cardiac arrhythmias
100 mg IV every 5 minutes as needed until desired effect obtained to
control the arrhythmia or adverse events limit tolerance, or up to a
maximum total dose of 1,000 mg IV. Oral therapy may follow use of
IV dosing.
47

48. Lorcainide Hcl:
Lorcainide (Lorcainide hydrochloride) is a Class 1c antiarrhythmic
agent that is used to help restore normal heart rhythm and
conduction in patients with premature ventricular
contraction, ventricular tachycardiac and Wolff-Parkinson-White
syndrome.
Structure:
IUPAC:N-(4-chlorophenyl)-2-phenyl-N-[1-(propan-2-yl) piperidin-4-
yl]acetamide Hydrochloride
48
Molecular formula: C22H28Cl2N2O

49. Properties:
White crystalline powder, soluble in DMSO, water, ethanol .
Pharmacokinetics:
Oral, intravenous route of administration, metabolized in liver, excreted
through kidneys.
Adverse Drug Reactions:
 Head ache, dizziness
 Sleep disturbances, CNS effects are seen when the drug is orally
administered when compared to I.V route.
49

50. Therapeutic Uses:
 It is used to reduce the ventricular arrhythmias and tachycardias.
 It is used as antiarrhythmic effects.
Dose:
 Lorcainide is given orally at a dose 50-100 mg 2-3 times/day after a
meal.
 The drug can be also administered as a slow intravenous injection at
a dose of 1-2 mg for 5-10 min and the dose can be repeated every 8-
12 h.
50

51. CLASS II- ΒETA -BLOCKERS
51

52. Mechanism of Action:
 These drugs act by blocking β-adrenergic receptors present on the
nodal cells (SA and AV node) thereby suppressing the rate of ectopic
pacemaker activity mediated by sympathetic (adrenergic)
stimulation.
 In other words, these drugs control arrhythmias provoked by
sympathetic stimulation or by circulation catecholamines.
 These drugs are considered to be more safer than any other class of
arrhythmic drugs.
 β-blockers used in arrhythmias include Propranolol, esmolol,
Sotalol, and acebutalol.
52

53. Sotolol:
• It is non- selective β-blocker with additional potassium channel
blocking activity. It differs from propranolol in the following
aspects,
• It has no membrane stabilizing effect.
• It increases the ERF of cardiac tissues.
• It enhances the duration of Monophasic action potential in both atria
and ventricles in a dose dependent manner.
• It does not increase the heart rate in isolated cardiac tissue.
• It prolongs QT interval.
53

54. Structure:
IUPAC:N-(4-{1-hydroxy-2-[(propan-2-yl)amino] ethyl}phenyl)
methanesulfonamide
Properties:
White or almost white crystalline powder, soluble in alcohol, water,
insoluble in methylene chloride.
Pharmacokinetics:
It completely absorbed orally. It bypasses first pass metabolism. It is
eliminated unchanged in urine.
54
Molecular formula: C12H20N2O3S

55. Adverse Drug Reactions:
 Blurred vision
 chest pain or discomfort
 confusion
 difficult or labored breathing
 dizziness, faintness, or lightheadedness
 fast, slow, irregular, pounding, or racing heartbeat or pulse
 nausea and vomiting, head ache
 sweating
 swelling of the face, fingers, feet, or lower legs
 tightness in the chest
 unusual tiredness or weakness
 Diarrhea, loss of appetite
55

56. Therapeutic Uses:
 It is used in treatment of hypertension.
 It is used in treatment of angina, arrhythmias.
 It has both β- blocking agent (class-II), Positive blocking agent
(class-III)
Dose:
 I.D: 80 mg b.i.d
 M.D: 240-320 mg day
56

57. CLASS-III- POTASSIUM CHANNEL
BLOCKERS
57

58. Mechanism of Action:
• The prolongation effect is mostly due to the blockade of K+
channel, although enhanced inward Na+ current produces the QT
prolongation.
• The cardiac block of K+ channel increases action potential duration
and reduces normal automaticity.
58

59. Amiodarone:
• Amiodarone is the most preferred board spectrum antiarrhythmic
drug for treating most dreadful ventricular arrhythmias.
• It shows structural resemblance with thyroid hormone owing to the
presence of iodine in its structure.
• Like thyroid hormone, it also possesses affinity towards nuclear
thyroid hormone receptors.
Structure:
IUPAC: {2-[4-(2-butyl-1-benzofuran-3-carbonyl)-2,6-diiodophenoxy]
ethyl}diethylamine
59
Molecular formula: C25H29I2NO3

60. Properties:
White crystalline powder, soluble in chloroform, methylene chloride,
methanol, ethanol, tertrahydrofuran, acetonitrile, water and ether.
Sparingly soluble in propanal, slightly soluble in acetone, carbon
tetrachloride.
Pharmacokinetics:
Oral, I.V route of administration. It is poorly absorbed when
administered through oral route. Its bioavailability is 30%. It is a
highly lipophilic drug gets accumulated in muscle and fat. It is
metabolized in liver and yield an active metabolite des-
ethyamiodarone which exerts similar action as that of parent drug. It
is eliminated primarily by hepatic metabolism and biliary excretion.
A small amount of desethylamiodarone (DEA) is found in the urine.
60

61. Adverse Drug Reactions:
 Headache, Nausea, vomiting
 fatigue
 tremor, lack of coordination, dizziness
 constipation, stomach pain
 insomnia
 decreased sex drive or performance
 uncontrollable or unusual movements of the body
 Photosensitivity,
 When administered through I.V route it causes myocardial
depression and hypotension.
 Pulmonary fibrosis (inner lining of alveoli became thick causing
breathlessness) and pulmonary alveolitis (inflammation of alveoli).
 Blurred Vision
61

62. Therapeutic Uses:
 It is a broad spectrum antiarrhythmic drug as it is proved to be
effective in both ventricular and supraventricular (atrial)
arrhythmias. Resistant ventricular tachycardia and recurrent V-FiB
are the most important indications for which it is commonly
employed.
 It can also be used in artial flutter (to maintain sinus rhythm) and
atrial fibrillations to control ventricular rate) refractory to other
drugs.
 It enhances the refractoriness and hence can be used to abolish AV
re-entrant tachycardia such as WPW-syndrome.
Dose:
 400-600 mg/day through oral route, 100-30 mg at the rate of 5
mg/kg by I.V fusion over 30-60 minutes.
62

63. Reference books
 Text book of Medicinal chemistry volume-1-3rd edition by
V.Alagarasamy.
 Text book of Medicinal chemistry volume-2-3rd edition by
V.Alagarasamy.
 Medicinal chemistry by Rama Rao Nadendla.
 Essentials of Medicinal chemistry 2nd edition by Andrejus Korol
Kovas.
 Faye’s Principles of Medicinal Chemistry- 7th edition by Thoms
L.Lemke, Victoria F.Roche, S. Willam Zito.
 Medicinal Chemistry- 4th edition by Ashutosh Kar.
 Medicinal and Pharmaceutical Chemistry by Harkishan Singh, V.K
Kapoor.
 Wilson and Gisvolid’s Textbook of Organic Medicinal and
Pharmaceutical chemistry-12th edition by John M. Beale, John. H.
Block.
63

64. THANK YOU
64