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Vasodilators - Medicinal chemistry for B.Pharm.

The document discusses various classes of cardiovascular drugs, focusing on vasodilators used to treat conditions like angina pectoris and hypertension. It explains the mechanisms of action for these drugs, which involve the relaxation of blood vessel smooth muscles and the decrease of oxygen demand on the heart. Additionally, it highlights specific vasodilators, their properties, uses, and side effects.

Education◦
VASODILATORS
I Antihistaminic agents and Antineoplastic agents II Antianginals, Diuretics and antihypertensive agents III Antiarrythmics IV Drugs acting on Endocrine system V Antidiabetics
Antianginals  Vasodilators  Calcium channel blockers Diuretics Antihypertensives
 An antianginal is a drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease  Angina is characterized by a narrowing of the coronary arteries. Chest pain is its main symptom.  Stable angina and unstable angina  Variant or Prinzmetals angina and Microvasucular angina
Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, which is the narrowing of blood vessels. Vasodilators are used to treat hypertension, heart failure and angina
Vasodilators a. Arterial vasodilators eg. Hydralazine, Minoxidil and Diazoxide b. Venous vasodilators eg. Nitro vasodilators c. Arterial and venous vasodilators eg. Sodium nitroprusside Nitrites and Nitrates (-C-O-NO & -C-O-NO2 ) / Nitro vasodilators i. Amylnitrite ii. Nitroglycerine or Glyceryl trinitrate iii. Pentaerythritol tetranitrate iv. Isosorbide dinitrate Miscellaneous v. Dipyridamole
Treats systemic and pulmonary hypertension, heart failure and angina  Reduces arterial pressure by decreasing systemic vascular resistance  In Anginal patients they reduce after load on the heart  Decrease the oxygen demand of the heart, and thereby improve the oxygen supply/demand ratio
 Reduce venous pressure, which reduces preload on the heart thereby decreasing cardiac output  In angina it is useful as it decreases the oxygen demand of the heart and thereby increases the oxygen supply/demand ratio  Oxygen demand is reduced because decreasing preload leads to a reduction in ventricular wall stress by decreasing the size of the heart
 Vasodilators act on both arteries and veins  Exceptions are hydralazine (arterial dilator) and organic nitrate dilators (venous dilators)  They decrease systemic vascular resistance and arterial pressure with relatively little change in right atrial (or central venous) pressure (i.e., little change in cardiac preload), and they have a relatively little effect on cardiac output
i. Decrease in peripheral vascular resistance (decrease of afterload) ii. Venodilatation (decreased preload) iii. Redistribution of flow to sub endocardium without overall change in coronary flow iv. Preferential dilatation of larger coronary vessels and collaterals favouring distribution of blood to ischemic areas
 BP = CO ˟ PVR BP exerted at three anatomical sites - arterioles, postcapillary venules, and heart. The fourth anatomical control site, the kidney contributes to the maintenance of blood pressure regulating fluid in the body. Baroreceptor reflexes - renin-angiotensin-aldosterone system - co-ordinate function at these four control sites and to maintain Normal B.P. regulation. All antihypertensive/CVS drugs act by interfering with the above specified mechanism.
Cardiac output is a function of heart rate and stroke volume. The resistance produced mainly in the arterioles is known as the systemic vascular resistance (SVR) or the peripheral vascular resistance (PVR). If the pressure in a vessel increases then the blood flow will increase.
 Mechanism of Action : These drugs are rapidly denitrated enzymatically in the smooth cells to release the reactive free radical nitric oxide (NO) (R-NO3) Nitrates– (R-NO2) Nitrites – (R-S-N=O) S- Nitrosothiol- (NO) Nitric oxide –cGMP/cAMP- MLCKphosphorylation-relaxation  Phosphorylated MLCK fails to cause contraction. Relaxation also occurs due to reduced Ca2+ entry.
 All organic nitrates are subjected to first-pass metabolism, by the action of glutathione nitrate reductase in the liver, and in the extra hepatic tissues  Some metabolites of long-acting nitrates are active as vasodilators E.g. Isosorbide dinitrate (Isosorbide-2-mononitrate and Isosorbide-5-mononitrate) It is metabolized primarily in the liver by glutathione nitrate reductase, which also participates in the metabolism of other organic nitrates, catalyzing the denitration of the parent drugs to yield two metabolites, 2- and 5-isosorbate mononitrate
Properties & uses It is a clear yellowish liquid with an ethereal, fruity odour, and pungent, aromatic taste.  It is insoluble in water, but miscible with alcohol, chloroform, or ether.  It is a mixture of isomeric amyl nitrites, but is principally isoamyl nitrite. (rapid effect in 0.5min. On inhalation) It is mainly used to treat angina pectoris. It is also effective in the emergency management of cyanide poisoning by causing the oxidation of haemoglobin to the compound methemoglobin. (CH3)2CHCH2CH2ONO
Properties and uses It is a colourless, odourless liquid with a sweet taste. Glyceryl trinitrate is the trinitrate ester of glycerol Nitroglycerine is used in angina pectoris (2-3 mins to 20mins) and extensively as an explosive in dynamite Rectal ointment to treat the pain that accompanies anal fissures Propane-1,2,3-triyl trinitrate
Properties and uses It is a white or slightly yellowish powder that is practically insoluble in water, soluble in acetone, and slightly soluble in alcohol It is used in the treatment of angina pectoris. It relaxes the smooth muscle of smaller vessels in the coronary vascular tree
Properties and uses: It is a fine white crystalline powder, slightly soluble in water, well soluble in acetone, but sparingly soluble in alcohol It is effective in the treatment of • Angina Pectoris (effect lasts for 4-6hrs) • Coronary Artery Disease Heart Failure • High Blood Pressure 1,4:3,6-dianhydro-D-glucitol 2,5-dinitrate
Properties and uses: It is a bright yellow crystalline powder, which dissolves in dilute solutions of mineral acids, but insoluble in water, soluble in acetone and ethanol. It is a long-acting vasodilator. Its vasodilating effect is selective for the coronary system. It is also used to treat/prophylaxis of angina pectoris • Coronary Artery Disease (CAD) • Postoperative Thromboembolism (Platelet aggregation inhibitor) • Stroke
MOA - The drug inhibits adenosine deaminase in erythrocytes and interacts with the uptake of vasodilator adenosine by erythrocytes. A phosphodiesterase inhibitor Acts as an inhibitor to platelet aggregation. 2,2',2'',2'''-(4,8-di(piperidin-1- yl)pyrimido[5,4-d]pyrimidine- 2,6- diyl)bis(azanetriyl)tetraethanol
 Headache (cerebral arteries)  Nitrite ions: oxidation of hemoglobin to methemoglobin causing reduced blood oxygen  Route of administration (sublingual for nitroglycerin)
 Systemic vasodilation and arterial pressure reduction can lead to a baroreceptor-mediated reflex stimulation of the heart (increased heart rate and inotropy)  This increases oxygen demand, which is undesirable in patients with coronary artery disease  Orthostatic hypotension and syncope upon standing  Renal retention of sodium and water, which increases blood volume and cardiac output with arterial vasodilators (Diuretic and βblocker should be given along with)
Nitrites and Nitrates (-C-O-NO & -C-O-NO2 ) / Nitro vasodilators i. Amylnitrite ii. Nitroglycerine or Glyceryl trinitrate iii. Pentaerythritol tetranitrate iv. Isosorbide dinitrate Miscellaneous v. Dipyridamole
Amyl nitrite Isosorbide dinitrate Glyceryl trinitrate Dipyridamole Pentaerythrytol tetranitrate
Vasodilators - Medicinal chemistry for B.Pharm.
Vasodilators - Medicinal chemistry for B.Pharm.