3rd unit anti-arrhythmic drugs

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

1. 3 rd 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 3 rd Year Semister: 1 st 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

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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 O 2 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 O 2 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. 13 Propranolol 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:C 20 H 24 N 2 O 6 S

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: C 13 H 22 ClN 3 O

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: C 21 H 32 N 3 O 5 P

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: C 14 H 25 ClN 2 O

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: C 11 H 18 ClNO

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: C 11 H 17 ClN 2 O

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:C 15 H 11 N 2 NaO 2

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: C 22 H 28 Cl 2 N 2 O

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- β eta -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: C 12 H 20 N 2 O 3 S

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: C 25 H 29 I 2 NO 3

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-1-3 rd edition by V.Alagarasamy. Text book of Medicinal chemistry volume-2-3 rd edition by V.Alagarasamy. Medicinal chemistry by Rama Rao Nadendla. Essentials of Medicinal chemistry 2 nd edition by Andrejus Korol Kovas. Faye’s Principles of Medicinal Chemistry- 7 th edition by Thoms L.Lemke , Victoria F.Roche , S. Willam Zito . Medicinal Chemistry- 4 th 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-12 th edition by John M. Beale, John. H. Block. 63

64. THANK YOU 64