Tài liệu Color Atlas of Pharmacology (Part 11): Vasodilators pdf

Vasodilators–Overview The distribution of blood within the cir- culation is a function of vascular caliber. Venous tone regulates the volume of blood returned to the heart, hence, stroke volume and cardiac output. The luminal diameter of the arterial vascula- ture determines peripheral resistance. Cardiac output and peripheral resis- tance are prime determinants of arterial blood pressure (p. 314). In A, the clinically most important vasodilators are presented in the order of approximate frequency of therapeu- tic use. Some of these agents possess different efficacy in affecting the venous and arterial limbs of the circulation (width of beam). Possible uses. Arteriolar vasodila- tors are given to lower blood pressure in hypertension (p. 312), to reduce cardiac work in angina pectoris (p. 308), and to reduce ventricular afterload (pressure load) in cardiac failure (p. 132). Venous vasodilators are used to reduce venous filling pressure (preload) in angina pec- toris (p. 308) or cardiac failure (p. 132). Practical uses are indicated for each drug group. Counter-regulation in acute hy- potension due to vasodilators (B). In- creased sympathetic drive raises heart rate (reflex tachycardia) and cardiac output and thus helps to elevate blood pressure. Patients experience palpita- tions. Activation of the renin-angioten- sin-aldosterone (RAA) system serves to increase blood volume, hence cardiac output. Fluid retention leads to an in- crease in body weight and, possibly, edemas. These counter-regulatory pro- cesses are susceptible to pharmacologi- cal inhibition (!-blockers, ACE inhibi- tors, AT1-antagonists, diuretics). Mechanisms of action. The tonus of vascular smooth muscle can be de- creased by various means. ACE inhibi- tors, antagonists at AT1-receptors and antagonists at "-adrenoceptors protect against the effects of excitatory media- tors such as angiotensin II and norepi- nephrine, respectively. Prostacyclin an- alogues such as iloprost, or prostaglan- din E 1 analogues such as alprostanil, mimic the actions of relaxant mediators. Ca 2+ antagonists reduce depolarizing in- ward Ca 2+ currents, while K + -channel ac- tivators promote outward (hyperpolar- izing) K + currents. Organic nitrovasodi- lators give rise to NO, an endogenous activator of guanylate cyclase. Individual vasodilators. Nitrates (p. 120) Ca 2+ -antagonists (p. 122). " 1 - antagonists (p. 90), ACE-inhibitors, AT1- antagonists (p. 124); and sodium nitro- prusside (p. 120) are discussed else- where. Dihydralazine and minoxidil (via its sulfate-conjugated metabolite) dilate arterioles and are used in antihyperten- sive therapy. They are, however, unsuit- able for monotherapy because of com- pensatory circulatory reflexes. The mechanism of action of dihydralazine is unclear. Minoxidil probably activates K + channels, leading to hyperpolarization of smooth muscle cells. Particular ad- verse reactions are lupus erythemato- sus with dihydralazine and hirsutism with minoxidil—used topically for the treatment of baldness (alopecia androg- enetica). Diazoxide given i.v. causes promi- nent arteriolar dilation; it can be em- ployed in hypertensive crises. After its oral administration, insulin secretion is inhibited. Accordingly, diazoxide can be used in the management of insulin-se- creting pancreatic tumors. Both effects are probably due to opening of (ATP- gated) K + channels. The methylxanthine theophylline (p. 326), the phosphodiesterase inhibi- tor amrinone (p. 132), prostacyclins (p. 197), and nicotinic acid derivatives (p. 156) also possess vasodilating activity. 118 Vasodilators Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Vasodilators 119 B. Counter-regulatory responses in hypotension due to vasodilators A. Vasodilators Nitroprusside sodium " 1 -Antagonists ACE-inhibitors Nitrates Dihydralazine Minoxidil Ca-antagonists Venous bed Vasodilation Arterial bed !-Blocker ACE-inhibitors Angiotensin- converting enzyme (ACE) Vasomotor center Vasodilation Blood pressure Blood- pressure Angiotensin II Angiotensinogen Aldosterone Vasoconstriction Vasoconstriction Angiotensin I Cardiac output Blood volume Heart rate Sympathetic nerves Renin-angiotensin-aldosterone-system Renin Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Organic Nitrates Various esters of nitric acid (HNO 3 ) and polyvalent alcohols relax vascular smooth muscle, e.g., nitroglycerin (gly- ceryltrinitrate) and isosorbide dinitrate. The effect is more pronounced in venous than in arterial beds. These vasodilator effects produce hemodynamic consequences that can be put to therapeutic use. Due to a de- crease in both venous return (preload) and arterial afterload, cardiac work is decreased (p. 308). As a result, the car- diac oxygen balance improves. Spas- modic constriction of larger coronary vessels (coronary spasm) is prevented. Uses. Organic nitrates are used chiefly in angina pectoris (p. 308, 310), less frequently in severe forms of chron- ic and acute congestive heart failure. Continuous intake of higher doses with maintenance of steady plasma levels leads to loss of efficacy, inasmuch as the organism becomes refractory (tachy- phylactic). This “nitrate tolerance” can be avoided if a daily “nitrate-free inter- val” is maintained, e.g., overnight. At the start of therapy, unwanted reactions occur frequently in the form of a throbbing headache, probably caused by dilation of cephalic vessels. This effect also exhibits tolerance, even when daily “nitrate pauses” are kept. Excessive dosages give rise to hypoten- sion, reflex tachycardia, and circulatory collapse. Mechanism of action. The reduc- tion in vascular smooth muscle tone is presumably due to activation of guany- late cyclase and elevation of cyclic GMP levels. The causative agent is most likely nitric oxide (NO) generated from the or- ganic nitrate. NO is a physiological mes- senger molecule that endothelial cells release onto subjacent smooth muscle cells (“endothelium-derived relaxing factor,” EDRF). Organic nitrates would thus utilize a pre-existing pathway, hence their high efficacy. The genera- tion of NO within the smooth muscle cell depends on a supply of free sulfhy- dryl (-SH) groups; “nitrate-tolerance” has been attributed to a cellular exhaus- tion of SH-donors but this may be not the only reason. Nitroglycerin (NTG) is distin- guished by high membrane penetrabil- ity and very low stability. It is the drug of choice in the treatment of angina pec- toris attacks. For this purpose, it is ad- ministered as a spray, or in sublingual or buccal tablets for transmucosal deliv- ery. The onset of action is between 1 and 3 min. Due to a nearly complete pre- systemic elimination, it is poorly suited for oral administration. Transdermal de- livery (nitroglycerin patch) also avoids presystemic elimination. Isosorbide dinitrate (ISDN) penetrates well through membranes, is more stable than NTG, and is partly degraded into the weaker, but much longer acting, 5- isosorbide mononitrate (ISMN). ISDN can also be applied sublingually; how- ever, it is mainly administered orally in order to achieve a prolonged effect. ISMN is not suitable for sublingual use because of its higher polarity and slower rate of absorption. Taken orally, it is ab- sorbed and is not subject to first-pass elimination. Molsidomine itself is inactive. Af- ter oral intake, it is slowly converted into an active metabolite. Apparently, there is little likelihood of "nitrate tole- rance”. Sodium nitroprusside contains a nitroso (-NO) group, but is not an ester. It dilates venous and arterial beds equally. It is administered by infusion to achieve controlled hypotension under continuous close monitoring. Cyanide ions liberated from nitroprusside can be inactivated with sodium thiosulfate (Na 2 S 2 O 3 ) (p. 304). 120 Vasodilators Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Vasodilators 121 5-Isosorbide mononitrate, an active metabolite t 1 2 ~ 240 min A. Vasodilators: Nitrates “Nitrate- tolerance” t 1 2 ~ 30 min t 1 2 ~ 2 min NONO Inactivation Route: e.g., sublingual, transdermal Glyceryl trinitrate Nitroglycerin Route: e.g., sublingual, oral, transdermal Isosorbide dinitrate Blood pressure Prevention of coronary artery spasm Preload O 2 -supply Afterload O 2 -demand Venous blood return to heart Venous bed Arterial bed Vasodilation “Nitrates” Peripheral resistance Consumption R – O – NO 2 Release of NO Activation of guanylate cyclase GTP cGMP RelaxationSmooth muscle cell SH-donors e.g., glutathione Active metabolite Molsidomine (precursor) Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Calcium Antagonists During electrical excitation of the cell membrane of heart or smooth muscle, different ionic currents are activated, including an inward Ca 2+ current. The term Ca 2+ antagonist is applied to drugs that inhibit the influx of Ca 2+ ions with- out affecting inward Na + or outward K + currents to a significant degree. Other labels are Ca-entry blocker or Ca-channel blocker. Therapeutically used Ca 2+ an- tagonists can be divided into three groups according to their effects on heart and vasculature. I. Dihydropyridine derivatives. The dihydropyridines, e.g., nifedipine, are uncharged hydrophobic substances. They induce a relaxation of vascular smooth muscle in arterial beds. An effect on cardiac function is practically absent at therapeutic dosage. (However, in pharmacological experiments on isolat- ed cardiac muscle preparations a clear negative inotropic effect is demon- strable.) They are thus regarded as va- soselective Ca 2+ antagonists. Because of the dilatation of resistance vessels, blood pressure falls. Cardiac afterload is diminished (p. 306) and, therefore, also oxygen demand. Spasms of coronary ar- teries are prevented. Indications for nifedipine include angina pectoris (p. 308) and, — when ap- plied as a sustained release preparation, — hypertension (p. 312). In angina pec- toris, it is effective when given either prophylactically or during acute attacks. Adverse effects are palpitation (reflex tachycardia due to hypotension), head- ache, and pretibial edema. Nitrendipine and felodipine are used in the treatment of hypertension. Ni- modipine is given prophylactically after subarachnoidal hemorrhage to prevent vasospasms due to depolarization by excess K + liberated from disintegrating erythrocytes or blockade of NO by free hemoglobin. II. Verapamil and other catamphi- philic Ca 2+ antagonists. Verapamil con- tains a nitrogen atom bearing a positive charge at physiological pH and thus rep- resents a cationic amphiphilic molecule. It exerts inhibitory effects not only on arterial smooth muscle, but also on heart muscle. In the heart, Ca 2+ inward cur- rents are important in generating depo- larization of sinoatrial node cells (im- pulse generation), in impulse propaga- tion through the AV- junction (atrioven- tricular conduction), and in electrome- chanical coupling in the ventricular car- diomyocytes. Verapamil thus produces negative chrono-, dromo-, and inotropic effects. Indications. Verapamil is used as an antiarrhythmic drug in supraventric- ular tachyarrhythmias. In atrial flutter or fibrillation, it is effective in reducing ventricular rate by virtue of inhibiting AV-conduction. Verapamil is also em- ployed in the prophylaxis of angina pec- toris attacks (p. 308) and the treatment of hypertension (p. 312). Adverse ef- fects: Because of verapamil’s effects on the sinus node, a drop in blood pressure fails to evoke a reflex tachycardia. Heart rate hardly changes; bradycardia may even develop. AV-block and myocardial insufficiency can occur. Patients fre- quently complain of constipation. Gallopamil (= methoxyverapamil) is closely related to verapamil in both structure and biological activity. Diltiazem is a catamphiphilic ben- zothiazepine derivative with an activity profile resembling that of verapamil. III. T-channel selective blockers. Ca 2+ -channel blockers, such as verapa- mil and mibefradil, may block both L- and T-type Ca 2+ channels. Mibefradil shows relative selectivity for the latter and is devoid of a negative inotropic ef- fect; its therapeutic usefulness is com- promised by numerous interactions with other drugs due to inhibition of cy- tochrome P 450 -dependent enzymes (CYP 1A2, 2D6 and, especially, 3A4). 122 Vasodilators Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Vasodilators 123 A.Vasodilators: calcium antagonists Smooth muscle cell Ca 2+ Arterial blood vessel Nifedipine (dihydropyridine derivative) Membrane depolarization Na + Ca 2+ 10 -3 M K + Ca 2+ 10 -7 M Verapamil (cationic amphiphilic) Electro- mechanical coupling Impulse conduction Impulse generation Inhibition of coronary spasm Peripheral resistance Contraction Afterload O 2 -demand Blood pressure Vasodilation in arterial bed Selective inhibition of calcium influx Sinus node Ventricular muscle AV-node Contractility AV- conduction Heart rate Reflex tachy- cardia with nifedipine Heart muscle cell Ca 2+ Inhibition of cardiac functions Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. . activity. 118 Vasodilators Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Vasodilators. 304). 120 Vasodilators Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Vasodilators