Page 211 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 197

Blood vessel lumen
Nitrates
Nitrites

Capillary Arginine eNOS Nitric oxide (NO)
endothelial
cells

Ca 2+
Interstitium

Guanylyl
cyclase Nitrates
NO mtALDH Nitrites
Ca 2+ + 2
Sildenafil
Vascular smooth –
muscle cell SNOs
GC* PDE
GTP cGMP GMP
MLCK*

+
+
Myosin
light chains Myosin-LC-PO 4 Myosin-LC
(myosin-LC)
Actin –
ROCK
Contraction Relaxation

FIGURE 12–2 Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in vascu-
*
lar smooth muscle cells. Steps leading to relaxation are shown with blue arrows. MLCK , activated myosin light-chain kinase (see Figure 12–1).
2+
Nitrosothiols (SNOs) appear to have non-cGMP-dependent effects on potassium channels and Ca -ATPase. eNOS, endothelial nitric oxide
*
synthase; GC , activated guanylyl cyclase; mtALDH 2 , mitochondrial aldehyde dehydrogenase-2; PDE, phosphodiesterase; ROCK, Rho kinase.
and increase oxygen delivery to ischemic tissue. In variant angina, The conventional sublingual tablet form of nitroglycerin may lose
these two drug groups also increase myocardial oxygen delivery by potency when stored as a result of volatilization and adsorption to
reversing coronary artery spasm. Newer drugs are discussed later. plastic surfaces. Therefore, it should be kept in tightly closed glass
containers. Nitroglycerin is not sensitive to light.
All therapeutically active agents in the nitrate group appear
NITRATES & NITRITES to have identical mechanisms of action and similar toxicities,
although development of tolerance may vary. Therefore, pharma-
Chemistry cokinetic factors govern the choice of agent and mode of therapy

Diets rich in inorganic nitrates are known to have a small blood when using the nitrates.
pressure–lowering action but are of no value in angina. The agents H C O NO
useful in angina are simple organic nitric and nitrous acid esters 2 2
of polyalcohols. Nitroglycerin may be considered the prototype of HC O NO 2
the group and has been used in cardiovascular conditions for over H C O NO 2
2
160 years. Although nitroglycerin is used in the manufacture of Nitroglycerin
dynamite, the formulations used in medicine are not explosive. (Glyceryl trinitrate)