Pharmacology - HYPERTENSION & ANTIHYPERTENSIVES (MADE EASY) — Transcript

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1. 0:00in this lecture I'm going to talk about pharmacology of antihypertensive drugs
2. 0:05so let's get right into it hypertension or high blood pressure is a
3. 0:10quite common disorder affecting many people who typically don't even notice
4. 0:15any symptoms now in order to gain a better understanding of pharmacology of
5. 0:20antihypertensive agents first we need to review a basic physiology of blood
6. 0:24pressure regulation so when we talk about blood pressure we are generally
7. 0:30referring to the force or tension of blood pressing against the artery walls
8. 0:34now this pressure in the arteries is maintained by among other things
9. 0:38contraction of the left ventricle systemic vascular resistance elasticity
10. 0:44of the arterial walls as well blood volume in other words blood pressure is
11. 0:49simply a product of cardiac output and systemic vascular resistance there are a
12. 0:56couple of major systems involved in blood pressure regulation first arterial
13. 1:01blood pressure is regulated by pressure sensitive neurons called baroreceptors
14. 1:06located in the aortic arch and carotid sinuses so for example if blood pressure
15. 1:13falls too low those baroreceptors can send signals to the adrenal medulla
16. 1:18causing release of catecholamines and thus increase in sympathetic activity through
17. 1:23activation of alpha and beta receptors so activation of beta-1 receptors causes
18. 1:30increase in heart rate and stroke volume and thus increased cardiac output which
19. 1:36leads to increase in blood pressure on the other hand activation of alpha-1
20. 1:40receptors on smooth muscle causes vasoconstriction and thus increase in
21. 1:45vascular resistance which again leads to increase in blood pressure now another
22. 1:51major system involved in blood pressure regulation is the
23. 1:54renin-angiotensin-aldosterone system so we also have baroreceptors in the
24. 2:00kidneys that respond to fall in blood pressure or reduction of blood flow by
25. 2:04releasing enzyme called renin additionally renin secretion is also
26. 2:10stimulated by sympathetic activation of beta-1 receptors
27. 2:13in the kidneys now renin is necessary for the production of angiotensin II
28. 2:19angiotensin II is a very potent vasoconstrictor which constricts systemic
29. 2:24blood vessels thus increasing peripheral resistance angiotensin II also
30. 2:29constricts renal blood vessels and stimulates aldosterone secretion which
31. 2:34leads to sodium and water retention thereby increased blood volume cardiac
32. 2:38output and ultimately increased blood pressure now let's switch gears and
33. 2:43let's talk about antihypertensive agents so there are several major
34. 2:48classes of antihypertensive drugs which work by interrupting different parts of
35. 2:52this blood pressure regulating system first we have alpha-1 blockers such as
36. 2:57Doxazosin and Prazosin which block alpha-1 receptors on the smooth muscle
37. 3:02thus causing decrease in systemic vascular resistance and ultimately
38. 3:07decrease in blood pressure next we have selective beta blockers such as Atenolol
39. 3:13and Metoprolol which selectively block beta-1 receptors on the heart thus
40. 3:18causing decrease in cardiac output and thereby decrease in blood pressure as
41. 3:23you may remember we also have non-selective beta blockers such as
42. 3:27Labetalol and Carvedilol that can additionally block alpha-1 receptors and
43. 3:32thus simultaneously decrease vascular resistance furthermore beta blockers can
44. 3:38inhibit beta-1 receptors present on the kidneys and thus suppress release of
45. 3:42renin formation of angiotensin II and secretion of aldosterone so these
46. 3:48effects result in decrease in systemic vascular resistance and again fall in
47. 3:53blood pressure to learn more about alpha and beta blockers make sure you check
48. 3:57out my video about adrenergic antagonists now the next major class of
49. 4:02antihypertensive agents are centrally acting adrenergic drugs which work by
50. 4:07blocking sympathetic activity within the brain example of drugs that belong to
51. 4:12this class are Clonidine and Methyldopa now Clonidine selectively stimulates
52. 4:18presynaptic alpha-2 receptors thus providing negative feedback to reduce
53. 4:23catecholamine production and release this leads to decrease
54. 4:27in systemic vascular resistance and cardiac output and ultimately decreased
55. 4:32blood pressure Methyldopa on the other hand also lowers blood pressure through the
56. 4:37same mechanism however unlike Clonidine it is not an
57. 4:41agonist itself so first it must be converted to its active metabolite
58. 4:45called methylnorepinephrine now let's move on to another major class of
59. 4:52antihypertensive agents that is calcium channel blockers so calcium channel
60. 4:58blockers are divided into two main subclasses dihydropyridines and
61. 5:03nondihydropyridines now dihydropyridines selectively inhibit L-type calcium
62. 5:09channels in the vascular smooth muscle under normal conditions when calcium
63. 5:15enters the smooth muscle cell it causes it to contract which leads to increased
64. 5:20vascular resistance and thus increase in blood pressure so when dihydropyridine drug
65. 5:26blocks the entry of calcium into the vascular smooth muscle cell the
66. 5:31contraction is inhibited which leads to decreased resistance to blood flow and
67. 5:35thus lowering of blood pressure example of drugs that belong to this group are
68. 5:41Amlodipine Felodipine Nicardipine and Nifedipine when it comes to side
69. 5:48effects of dihydropyridines they're related to systemic vasodilation so you
70. 5:54can expect dizziness headache flushing and peripheral edema another side effect
71. 5:59that may occur with this class is swelling of gums also known as gingival
72. 6:04hyperplasia now let's move on to nondihydropyridines which are non selective
73. 6:10inhibitors of L-type calcium channels in other words they are not only capable of
74. 6:16blocking calcium channels on vascular smooth muscle but also calcium channels
75. 6:20on cardiac cells such as those of SA node and AV node which leads to reduced
76. 6:25myocardial contractility slower heart rate and slower conduction that's why these
77. 6:31agents exhibit significant antiarrhythmic properties for more
78. 6:35details make sure you check out my video about antiarrhythmic drugs
79. 6:40now it's important to remember that even though decreased heart contractions
80. 6:44typically result in decreased cardiac output
81. 6:46nondihydropyridines do not significantly decrease cardiac output
82. 6:51most likely because of the reflex tachycardia that occurs as a result of
83. 6:55vasodilation currently there are only two drugs that belong to this group
84. 7:01namely Diltiazem and Verapamil now when it comes to side-effects nondihydropyridines
85. 7:07can cause excessive bradycardia and cardiac conduction abnormalities
86. 7:12additionally Verapamil which happens to be the least selective calcium channel
87. 7:17blocker can exert significant inhibition of calcium channels in the smooth muscle
88. 7:22that lines the GI tract which can lead to constipation
89. 7:26now the next major class of antihypertensive agents are diuretics there
90. 7:32are three major classes of diuretics that are used in the treatment of
91. 7:35hypertension first we have loop diuretics such as Furosemide which
92. 7:40work by reducing reabsorption of sodium chloride in the kidneys leading to
93. 7:44significant diuresis with less volume in the vascular space less blood returns to
94. 7:49the heart so cardiac output decreases this in turn leads to decrease in blood
95. 7:53pressure particularly in patients with volume-based hypertension and chronic
96. 7:58kidney disease secondly we have thiazide diuretics such as Hydrochlorothiazide
97. 8:03which also reduce reabsorption of sodium chloride in the kidneys but to a much
98. 8:08smaller degree than loop diuretics this leads to initial decrease in
99. 8:13intravascular volume decrease in cardiac output and ultimately lower blood
100. 8:17pressure however the long term effects on blood volume are minimal and
101. 8:21sustained antihypertensive effects are thought to be produced by thiazide induced
102. 8:26vasodilation lastly we have potassium-sparing diuretics such as Triamterene
103. 8:32and Spironolactone which increase diuresis by either interfering with the
104. 8:36sodium potassium exchange in the kidneys or by blocking the actions of
105. 8:40aldosterone potassium-sparing diuretics are often used in combination
106. 8:45with loop and thiazide diuretics to reduce loss of potassium that can occur with
107. 8:50the use of these drugs for more details make
108. 8:54sure you check out my video about diuretics now let's move on to another
109. 8:59group of antihypertensive agents that is agents that work on the
110. 9:03renin-angiotensin-aldosterone system so here we have three pharmacological
111. 9:08targets that can be used to reduce the activity of angiotensin II which is
112. 9:13ultimately responsible for causing blood pressure to increase first we have renin
113. 9:19the enzyme responsible for conversion of angiotensinogen to precursor of
114. 9:24angiotensin II that is angiotensin I so renin is the target of renin inhibitors
115. 9:31which selectively inhibit this enzyme thus decreasing production of
116. 9:35angiotensin II the example of drug that belongs to this class is Aliskiren
117. 9:41secondly we have angiotensin-converting enzyme that is responsible
118. 9:45for conversion of angiotensin I to angiotensin II this enzyme is the target
119. 9:52of ACE inhibitors so just like inhibition of renin inhibition of
120. 9:57angiotensin-converting enzyme also leads to decreased production of angiotensin II
121. 10:02however what makes ACE inhibitors different is that in addition to
122. 10:06lowering angiotensin II levels they can also elevate bradykinin levels
123. 10:10bradykinin is a peptide that causes blood vessels to dilate by stimulating
124. 10:15the release of nitric oxide and prostacyclin
125. 10:18however normally angiotensin-converting enzyme inactives bradykinin so it's
126. 10:24inhibition leads to bradykinin induced vasodilation the example of drugs
127. 10:30that belong to this class are Benazepril Captopril Enalapril
128. 10:35Lisinopril Quinapril and Ramipril finally we have
129. 10:41angiotensin II receptors type 1 or AT1 receptors for short so binding
130. 10:47of angiotensin II to these receptors is actually responsible for most of the
131. 10:53effects of angiotensin II including vasoconstriction and stimulation of
132. 10:57aldosterone release these receptors are the target of angiotensin II receptor
133. 11:02blockers or ARBs for short the example of drugs that
134. 11:07belong to this class are Candesartan Irbesartan Losartan Olmesartan and
135. 11:14Valsartan so in summary the agents that work on
136. 11:19this renin-angiotensin-aldosterone system either block the production of
137. 11:23angiotensin II or block its actions on the AT1 receptors this in turn leads to
138. 11:29decreased systemic vascular resistance but without significant changes in
139. 11:33cardiac output additionally these agents reduce the effects of angiotensin II on
140. 11:39renal hemodynamics specifically angiotensin II constricts the efferent
141. 11:44arteriole thereby generating back pressure in the glomerulus which can
142. 11:49lead to injury so by reducing activity of angiotensin II these agents also
143. 11:55improve renal blood flow and thereby reduce the risk of renal injury now when
144. 12:01it comes to side effects because these agents suppress aldosterone release
145. 12:05their use can contribute to development of hyperkalemia furthermore
146. 12:10ACE inhibitors in particular may cause dry cough or in rare cases angioedema
147. 12:16which can be life-threatening this is thought to be due to increased
148. 12:20levels of bradykinin and substance P now before we end this lecture I wanted to
149. 12:27briefly discuss few other antihypertensive agents that do not fall
150. 12:31into any of the classes that we covered thus far so first we have Bosentan
151. 12:37which is a competitive antagonist of a potent vasoconstrictor called endothelin-1
152. 12:43which acts on the endothelin-A and endothelin-B receptors located
153. 12:48on pulmonary vascular cells by blocking the action of endothelin-1 on
154. 12:53these receptors Bosentan leads to vasodilation which decreases pulmonary
155. 12:58vascular resistance for that reason Bosentan is often a drug of choice for
156. 13:03treatment of pulmonary hypertension next we have Fenoldopam which is a selective
157. 13:11dopamine-1 receptor agonist the dopamine-1 receptors are located on the
158. 13:17smooth muscle cells in the peripheral vasculature
159. 13:20as well as the renal coronary cerebral and mesenteric arteries by stimulating
160. 13:26dopamine-1 receptors Fenoldopam produces generalized arterial vasodilation
161. 13:31which leads to decreased peripheral resistance and thus lower blood pressure
162. 13:37additionally Fenoldopam inhibits tubular sodium reabsorption which
163. 13:41results in natriuresis and diuresis due to its rapid onset of action and
164. 13:47short duration of action Fenoldopam is often used in the
165. 13:51hospitals for short-term management of severe hypertension another fast-acting
166. 13:57agents that are also used for hypertensive emergency are
167. 14:01Sodium Nitroprusside and Nitroglycerin which simply serve as a source of nitric oxide
168. 14:07a potent peripheral vasodilator lastly we have direct acting smooth muscle
169. 14:13relaxants namely Hydralazine with mechanism of action that has not been
170. 14:18entirely determined yet and Minoxidil which works by stimulating opening of
171. 14:23ATP-activated potassium channels in the smooth muscle which leads to membrane
172. 14:28stabilization making vasoconstriction less likely while these agents
173. 14:34significantly decrease peripheral resistance they also produce significant
174. 14:38compensatory reflex tachycardia and renin release for that reason these
175. 14:43drugs are typically administered in combination with a diuretic and a beta
176. 14:48blocker on the flip side topical application of Minoxidil promotes hair
177. 14:53growth which is why this drug is used more often for treatment of baldness
178. 14:57rather than hypertension and with that I wanted to thank you for watching I hope
179. 15:02you enjoyed this video and as always stay tuned for more