Color Atlas of Pharmacology (Part 11): Vasodilators

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Color Atlas of Pharmacology (Part 11): Vasodilators

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Vasodilators alogues such as iloprost, or prostaglandin E1 analogues such as alprostanil, mimic the actions of relaxant mediators. Ca2+ antagonists reduce depolarizing inward Ca2+ currents, while K+-channel activators promote outward (hyperpolarizing) K+ currents. Organic nitrovasodilators give rise to NO, an endogenous activator of guanylate cyclase. Individual vasodilators. Nitrates (p. 120) Ca2+-antagonists (p. 122). "1antagonists (p. 90), ACE-inhibitors, AT1antagonists (p. 124); and sodium nitroprusside (p. 120) are discussed elsewhere. Dihydralazine and minoxidil (via its sulfate-conjugated metabolite) dilate arterioles and are used in antihypertensive therapy. They are, however, unsuitable for monotherapy because of compensatory circulatory reflexes. ...

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  1. 118 Vasodilators Vasodilators–Overview alogues such as iloprost, or prostaglan- din E1 analogues such as alprostanil, The distribution of blood within the cir- mimic the actions of relaxant mediators. culation is a function of vascular caliber. Ca2+ antagonists reduce depolarizing in- Venous tone regulates the volume of ward Ca2+ currents, while K+-channel ac- blood returned to the heart, hence, tivators promote outward (hyperpolar- stroke volume and cardiac output. The izing) K+ currents. Organic nitrovasodi- luminal diameter of the arterial vascula- lators give rise to NO, an endogenous ture determines peripheral resistance. activator of guanylate cyclase. Cardiac output and peripheral resis- Individual vasodilators. Nitrates tance are prime determinants of arterial (p. 120) Ca2+-antagonists (p. 122). "1- blood pressure (p. 314). antagonists (p. 90), ACE-inhibitors, AT1- In A, the clinically most important antagonists (p. 124); and sodium nitro- vasodilators are presented in the order prusside (p. 120) are discussed else- of approximate frequency of therapeu- where. tic use. Some of these agents possess Dihydralazine and minoxidil (via different efficacy in affecting the venous its sulfate-conjugated metabolite) dilate and arterial limbs of the circulation arterioles and are used in antihyperten- (width of beam). sive therapy. They are, however, unsuit- Possible uses. Arteriolar vasodila- able for monotherapy because of com- tors are given to lower blood pressure in pensatory circulatory reflexes. The hypertension (p. 312), to reduce cardiac mechanism of action of dihydralazine is work in angina pectoris (p. 308), and to unclear. Minoxidil probably activates K+ reduce ventricular afterload (pressure channels, leading to hyperpolarization load) in cardiac failure (p. 132). Venous of smooth muscle cells. Particular ad- vasodilators are used to reduce venous verse reactions are lupus erythemato- filling pressure (preload) in angina pec- sus with dihydralazine and hirsutism toris (p. 308) or cardiac failure (p. 132). with minoxidil—used topically for the Practical uses are indicated for each treatment of baldness (alopecia androg- drug group. enetica). Counter-regulation in acute hy- Diazoxide given i.v. causes promi- potension due to vasodilators (B). In- nent arteriolar dilation; it can be em- creased sympathetic drive raises heart ployed in hypertensive crises. After its rate (reflex tachycardia) and cardiac oral administration, insulin secretion is output and thus helps to elevate blood inhibited. Accordingly, diazoxide can be pressure. Patients experience palpita- used in the management of insulin-se- tions. Activation of the renin-angioten- creting pancreatic tumors. Both effects sin-aldosterone (RAA) system serves to are probably due to opening of (ATP- increase blood volume, hence cardiac gated) K+ channels. output. Fluid retention leads to an in- The methylxanthine theophylline crease in body weight and, possibly, (p. 326), the phosphodiesterase inhibi- edemas. These counter-regulatory pro- tor amrinone (p. 132), prostacyclins (p. cesses are susceptible to pharmacologi- 197), and nicotinic acid derivatives (p. cal inhibition (!-blockers, ACE inhibi- 156) also possess vasodilating activity. 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- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  2. Vasodilators 119 Venous bed Vasodilation Arterial bed Nitrates Ca-antagonists ACE-inhibitors Dihydralazine Minoxidil "1-Antagonists Nitroprusside sodium A. Vasodilators Sympathetic nerves Vasoconstriction !-Blocker Blood Vasodilation pressure Vasomotor Heart rate center Cardiac Blood- pressure output Blood volume Angiotensinogen Aldosterone Renin Angiotensin- Angiotensin I converting enzyme (ACE) Angiotensin II Vasoconstriction ACE-inhibitors Renin-angiotensin-aldosterone-system B. Counter-regulatory responses in hypotension due to vasodilators Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  3. 120 Vasodilators Organic Nitrates has been attributed to a cellular exhaus- tion of SH-donors but this may be not Various esters of nitric acid (HNO3) and the only reason. polyvalent alcohols relax vascular Nitroglycerin (NTG) is distin- smooth muscle, e.g., nitroglycerin (gly- guished by high membrane penetrabil- ceryltrinitrate) and isosorbide dinitrate. ity and very low stability. It is the drug The effect is more pronounced in venous of choice in the treatment of angina pec- than in arterial beds. toris attacks. For this purpose, it is ad- These vasodilator effects produce ministered as a spray, or in sublingual or hemodynamic consequences that can buccal tablets for transmucosal deliv- be put to therapeutic use. Due to a de- ery. The onset of action is between 1 and crease in both venous return (preload) 3 min. Due to a nearly complete pre- and arterial afterload, cardiac work is systemic elimination, it is poorly suited decreased (p. 308). As a result, the car- for oral administration. Transdermal de- diac oxygen balance improves. Spas- livery (nitroglycerin patch) also avoids modic constriction of larger coronary presystemic elimination. Isosorbide vessels (coronary spasm) is prevented. dinitrate (ISDN) penetrates well Uses. Organic nitrates are used through membranes, is more stable chiefly in angina pectoris (p. 308, 310), than NTG, and is partly degraded into less frequently in severe forms of chron- the weaker, but much longer acting, 5- ic and acute congestive heart failure. isosorbide mononitrate (ISMN). ISDN Continuous intake of higher doses with can also be applied sublingually; how- maintenance of steady plasma levels ever, it is mainly administered orally in leads to loss of efficacy, inasmuch as the order to achieve a prolonged effect. organism becomes refractory (tachy- ISMN is not suitable for sublingual use phylactic). This “nitrate tolerance” can because of its higher polarity and slower be avoided if a daily “nitrate-free inter- rate of absorption. Taken orally, it is ab- val” is maintained, e.g., overnight. sorbed and is not subject to first-pass At the start of therapy, unwanted elimination. reactions occur frequently in the form Molsidomine itself is inactive. Af- of a throbbing headache, probably ter oral intake, it is slowly converted caused by dilation of cephalic vessels. into an active metabolite. Apparently, This effect also exhibits tolerance, even there is little likelihood of "nitrate tole- when daily “nitrate pauses” are kept. rance”. Excessive dosages give rise to hypoten- Sodium nitroprusside contains a sion, reflex tachycardia, and circulatory nitroso (-NO) group, but is not an ester. collapse. It dilates venous and arterial beds Mechanism of action. The reduc- equally. It is administered by infusion to tion in vascular smooth muscle tone is achieve controlled hypotension under presumably due to activation of guany- continuous close monitoring. Cyanide late cyclase and elevation of cyclic GMP ions liberated from nitroprusside can be levels. The causative agent is most likely inactivated with sodium thiosulfate nitric oxide (NO) generated from the or- (Na2S2O3) (p. 304). 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” Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  4. Vasodilators 121 Preload Afterload O2-supply O2-demand Blood pressure Prevention of Venous blood return coronary artery Peripheral to heart spasm resistance Venous bed “Nitrate- Arterial bed tolerance” Route: Route: e.g., sublingual, e.g., sublingual, transdermal oral, transdermal Vasodilation “Nitrates” Glyceryl trinitrate Nitroglycerin Isosorbide dinitrate NO t 1 ~ 2 min t 1 ~ 30 min NO 2 2 Inactivation 5-Isosorbide mononitrate, an active metabolite t 1 ~ 240 min 2 R – O – NO2 SH-donors e.g., glutathione Release of NO Consumption Activation of Active guanylate cyclase metabolite GTP cGMP Molsidomine Smooth muscle cell Relaxation (precursor) A. Vasodilators: Nitrates Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  5. 122 Vasodilators Calcium Antagonists resents a cationic amphiphilic molecule. It exerts inhibitory effects not only on During electrical excitation of the cell arterial smooth muscle, but also on heart membrane of heart or smooth muscle, muscle. In the heart, Ca2+ inward cur- different ionic currents are activated, rents are important in generating depo- including an inward Ca2+ current. The larization of sinoatrial node cells (im- term Ca2+ antagonist is applied to drugs pulse generation), in impulse propaga- that inhibit the influx of Ca2+ ions with- tion through the AV- junction (atrioven- out affecting inward Na+ or outward K+ tricular conduction), and in electrome- currents to a significant degree. Other chanical coupling in the ventricular car- labels are Ca-entry blocker or Ca-channel diomyocytes. Verapamil thus produces blocker. Therapeutically used Ca2+ an- negative chrono-, dromo-, and inotropic tagonists can be divided into three effects. groups according to their effects on Indications. Verapamil is used as heart and vasculature. an antiarrhythmic drug in supraventric- I. Dihydropyridine derivatives. ular tachyarrhythmias. In atrial flutter The dihydropyridines, e.g., nifedipine, or fibrillation, it is effective in reducing are uncharged hydrophobic substances. ventricular rate by virtue of inhibiting They induce a relaxation of vascular AV-conduction. Verapamil is also em- smooth muscle in arterial beds. An effect ployed in the prophylaxis of angina pec- on cardiac function is practically absent toris attacks (p. 308) and the treatment at therapeutic dosage. (However, in of hypertension (p. 312). Adverse ef- pharmacological experiments on isolat- fects: Because of verapamil’s effects on ed cardiac muscle preparations a clear the sinus node, a drop in blood pressure negative inotropic effect is demon- fails to evoke a reflex tachycardia. Heart strable.) They are thus regarded as va- rate hardly changes; bradycardia may soselective Ca2+ antagonists. Because of even develop. AV-block and myocardial the dilatation of resistance vessels, insufficiency can occur. Patients fre- blood pressure falls. Cardiac afterload is quently complain of constipation. diminished (p. 306) and, therefore, also Gallopamil (= methoxyverapamil) is oxygen demand. Spasms of coronary ar- closely related to verapamil in both teries are prevented. structure and biological activity. Indications for nifedipine include Diltiazem is a catamphiphilic ben- angina pectoris (p. 308) and, — when ap- zothiazepine derivative with an activity plied as a sustained release preparation, profile resembling that of verapamil. — hypertension (p. 312). In angina pec- III. T-channel selective blockers. toris, it is effective when given either Ca2+-channel blockers, such as verapa- prophylactically or during acute attacks. mil and mibefradil, may block both L- Adverse effects are palpitation (reflex and T-type Ca2+ channels. Mibefradil tachycardia due to hypotension), head- shows relative selectivity for the latter ache, and pretibial edema. and is devoid of a negative inotropic ef- Nitrendipine and felodipine are used fect; its therapeutic usefulness is com- in the treatment of hypertension. Ni- promised by numerous interactions modipine is given prophylactically after with other drugs due to inhibition of cy- subarachnoidal hemorrhage to prevent tochrome P450-dependent enzymes vasospasms due to depolarization by (CYP 1A2, 2D6 and, especially, 3A4). excess K+ liberated from disintegrating erythrocytes or blockade of NO by free hemoglobin. II. Verapamil and other catamphi- philic Ca2+ antagonists. Verapamil con- tains a nitrogen atom bearing a positive charge at physiological pH and thus rep- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
  6. Vasodilators 123 Smooth muscle cell Afterload O2-demand Blood pressure Contraction Inhibition of Peripheral coronary spasm resistance Ca2+ Arterial blood vessel Vasodilation in arterial bed Na+ Ca2+-3M 10 Membrane depolarization Ca2+-7M 10 K+ Selective inhibition of calcium influx Nifedipine Verapamil (dihydropyridine derivative) (cationic amphiphilic) Inhibition of cardiac functions Impulse Heart rate Sinus node generation Reflex tachy- Ca2+ cardia with nifedipine Impulse AV- AV-node conduction conduction Electro- Ventricular mechanical muscle Contractility coupling Heart muscle cell A.Vasodilators: calcium antagonists Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
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