Chemistry and SAR of Antianginal-Drugs

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ANTI-ANGINAL DRUGS Drugs acting on Cardiovascular system By- Gaurav Kayal ( M.Pharm ) Assistant Professor (Pharmaceutical Chemistry)

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Contents Introduction Angina Pectoris Types of angina Pathophysiology of angina Classification with SAR of following categories: Nitrates Calcum channel blockers Beta blocking agents Adverse effects and contrdictions

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An antianginal drug is any agent which are used in the treatment of angina pectoris. By Gaurav Kayal

Angina Pectoris:

Angina Pectoris Angina pectoris is a clinical syndrome characterized by episodes of chest pain. It occurs when there is a deficit in myocardial oxygen supply in relation to myocardial oxygen demand. Caused by atherosclerotic plaque in the coronary arteries but may also be caused by coronary vasospasm . By Gaurav Kayal

Angina Pectoris:

Angina Pectoris Located substernally but sometimes perceived in the neck, shoulder or epigastrium Primarily caused by imbalance between the oxygen requirement of the heart and oxygen supplied to it by the coronary vessels By Gaurav Kayal

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Types of Angina Classic Angina Variant Angina Unstable Angina By Gaurav Kayal

Pathophysiology of Angina:

Pathophysiology of Angina Therapeutic strategies The defect that causes anginal pain is inadequate O 2 delivery relative to myocardial oxygen requirement Can be corrected in 3 ways 1. Increasing O 2 delivery 2. Reducing O 2 requirement 3. Efficiency of O 2 utilization By Gaurav Kayal

Pathophysiology of Angina:

Pathophysiology of Angina Newer investigational approach Shifting the energy substrate reference of the heart from fatty acid to glucose Partial fatty acid oxidation inhibitors (e.g., Ranolazine, Trimetazidine) By Gaurav Kayal

Treatment of Angina:

Treatment of Angina NITRATES CALCIUM CHANNEL BLOCKERS BETA BLOCKERS By Gaurav Kayal

NITRATES:

NITRATES NITROGLYCERINE (NTG) Active ingredient in dynamite Most important of the nitrates Available forms Sublingual (10-20 min) Transferal (8-10 h) Effect of sublingual NTG results from unchanged drug because it avoids first-pass effect By Gaurav Kayal

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Rapidly denitrated in the liver and smooth muscle Nitroglycerin  (Glyceryl) Dinitrate  Mononitrate First-pass effect is 90% (because of high enzyme activity in the liver) Efficacy of oral (swallowed) NTG results from high levels of glyceryl dinitrate (which have a significant vasodilating effect) By Gaurav Kayal

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Mechanism of Action Denitration causes release of nitric oxide (NO) within smooth muscle cells which stimulates guanyl cyclase and causes an increase in cGMP leading to smooth muscle relaxation. By Gaurav Kayal

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By Gaurav Kayal

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Isosorbide Dinitrate Another commonly used nitrate Available in sublingual and oral form Rapidly denitrated in the liver and smooth muscle to isosorbide mononitrate which is also active By Gaurav Kayal

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Isosorbide Mononitrate Available as a separate drug Oral form Amyl Nitrite Volatile and rapidly acting vasodilator Inhalational route Rarely prescribed By Gaurav Kayal

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Organ System Effects 1. Cardiovascular System Smooth muscle relaxation peripheral venodilation reduced cardiac size and CO through reduced preload Reduced afterload because of arteriolar dilation increase in ejection and further decrease in cardiac size Sensitivity veins >> arteries > arterioles By Gaurav Kayal

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Venodilation decreased diastolic heart size and fiber tension Arteriolar dilation reduced peripheral resistance and BP Overall reduction in myocardial fiber tension, O 2 consumption and double product No direct effects on the cardiac muscle Can cause reflex tachycardia and increased force of contraction when reducing BP By Gaurav Kayal

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2. Other smooth muscle effect Relaxation of the smooth muscle of the bronchi, GIT, GUT Effects are too small to be clinically significant 3. Action on platelets Decrease platelet aggregation 4. Nitrite ion + hemoglobin  methemoglobin Methemoglobin has low affinity for oxygen Pseudocyanosis, tissue hypoxia, death By Gaurav Kayal

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Clinical Uses 1. Sublingual tablet Standard form for treatment of acute anginal pain Duration of action 10-30 minutes   2. Oral (Swallowed) Normal-release Duration of action 4-6 hours Sustained-release Longer duration By Gaurav Kayal

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3.Transferal formulations: Ointment or patch Maintains blood level up to 24 hours Tolerance develops after 8-10 hours with rapidly diminishing effectiveness Remove after 10-12 hours to allow recovery of sensitivity to the drug By Gaurav Kayal

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Toxicities Tachycardia (baroreceptor reflex) Orthostatic hypotension Throbbing headache (from meningeal artery vasodilatation) Interact with Sildenafil (Viagra) and similar drugs promoted for erectile dysfunction Synergistic relaxation of vascular smooth muscle with potentially dangerous hypotension and hypoperfusion of critical By Gaurav Kayal

Calcium Channel Blockers:

Calcium Channel Blockers Nifedipine, Dihydropyridine, Diltiazem, Verapamil Differ markedly in structure but all are orally active with half-lives of 3-6 hours Nimodipine Member of the dihydropyridine family Approved only for the treatment of stroke associated with subarachnoid hemorrhage Bepridil Similar structure to verapamil, Longer duration of action, Greater cardiovascular toxicity By Gaurav Kayal

Chemistry of Ca++ Channel Blockers:

Chemistry of Ca ++ Channel Blockers Five major classes of Ca ++ channel blockers are known with diverse chemical structures: Benzothiazepines: Diltiazem Dihydropyridines: Nicardipine, nifedipine, nimodipine, amlodipine, and many others. There are also dihydropyridine Ca ++ -channel activators Phenylalkylamines: Verapamil Diarylaminopropylamine ethers: Bepridil Benzimidazole-substituted tetralines: Mibefradil By Gaurav Kayal

Calcium Channel Blockers:

Calcium Channel Blockers Mechanism of Action Block voltage-gated “L-type” calcium channels (channel most important in cardiac and smooth muscle) Reduce intracellular calcium concentration and muscle contractility Mibefradil Blocks cardiac “T-type” and “L-type” channels By Gaurav Kayal

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SAR of Calcium Channel Blockers In phenyldihydropyridine derivatives the structural features essential for activity are: the dihydropyridine ring; the secondary nitrogen in the ring; this N remains uncharged at physiological pH; and a bulky substituent (such as phenyl) in the 4-position of the heterocycle. On the other side, the nitro group and the ester moieties are nonessentials. Amlodipine By Gaurav Kayal

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In Verapamil and related drugs the essentials features are: (a) the benzene ring, (b) a tertiary amino nitrogen, which is almost completely charged at physiological pH. (c) The isopropyl group and the ring substituents are not essential for activity. Verapamil hydrochloride By Gaurav Kayal

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Effects Relax blood vessels, and to a lesser extent, the uterus, bronchi and the gut Diltiazem and Verapamil Reduce cardiac rate and contractility (block Ca-dependent conduction in the AV node of the heart) May be used to treat AV nodal arrythmia Nifedipine and other dihydropyridines Evoke greater vasodilation The resulting sympathetic reflex prevents bradycardia and increases heart rate By Gaurav Kayal

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Clinical Use Nifedipine has also been used to abort acute anginal attacks Combined with nitrates in the treatment of atherosclerotic angina Migraine Preterm labor Stroke Raynaud’s phenomenon Prophylactic therapy in effort and vasospastic angina Nimodipine is used for hemorrhagic stroke By Gaurav Kayal

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Toxicities Constipation, pretibial edema, nausea flushing and dizziness Heart failure, AV blockade and sinus node depression (Verapamil) By Gaurav Kayal

BETA BLOCKING DRUGS:

BETA BLOCKING DRUGS β -Blockers Prophylaxis of atherosclerotic anginal attacks Reduce the double product Effects Beneficial effects Decreased heart rate Decreased cardiac force Decreased BP Detrimental effects Increased heart size Longer ejection period By Gaurav Kayal

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Clinical Use Only for prophylactic therapy No value for acute attacks Prevents exercise-induced angina but not the vasospastic form Combination with nitrates reduces the undesirable compensatory effects like tachycardia and increased cardiac force By Gaurav Kayal

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Nonpharmacologic Therapy Myocardial revascularization Coronary artery bypass grafting (CABG) Percutanous transluminal coronary angioplasty (PTCA) Increase coronary flow in atherosclerotic angina By Gaurav Kayal

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SAR for Beta Blockers 1. The O-CH 2 group between aromatic ring and the ethylamino side chain is responsible for the antagonistic property. 2. Replacement of catechol hydroxyl group with chlorine or phenyl ring retains the beta blocking activity. 3 . N,N- di substitution decrease beta blocking activity. Activity is maintained when phenylethyl , hydroxyl phenyl ethyl or methoxy phenyl ethyl groups are added to amine as a part of molecule. By Gaurav Kayal

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4. The two carbon side chain is essential for the activity. 5 . Nitrogen atom should be of secondary amine for optimum beta blocking activity. 6. The carbon side chain having hydroxyl group must be S- configuration for optimum affinity to beta receptor.(Ex- Levobunolol, Timolol). 7 . The aryloxy propanolamines are more potent than aryl ethanolamines. 8. Replacement of ethereal oxygen in aryloxy propanolamines with S, CH2 or N-CH3 is decreased the beta blocking activity. By Gaurav Kayal

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9. The most effective substituents at amino group is isopropyl and tertiary butyl group. 10. The aromatic portion of the molecules could be varied with good activity. 11. Converting the aromatic portion to phenanthrene or anthracene decrease the activity. 12. Cyclic alkyl substituents are better than corresponding open chain substituents at nitrogen atom of amine. 13. Alpha methyl group at side chain decrease activity. By Gaurav Kayal

Adverse Effects & Contraindications:

Adverse Effects & Contraindications May exacerbate heart failure Contraindicated in patients with asthma Should be used with caution in patients with diabetes since hypoglycemia-induced tachycardia can be blunted or blocked May depress contractility and heart rate and produce AV block in patients receiving non-dihydropyridine calcium channel blockers (i.e. verapamil and diltiazem) By Gaurav Kayal

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THANK YOU For Doubts/ Queries- Mr. Gaurav Kayal Assistant Professor (Pharmaceutical Chemistry) (Ph-9009991186 , [email protected])

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