Enzymatic inhibition by drugs, Part 1 — Transcript

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1. 0:02hi there and welcome back to
2. 0:03understanding medications in this lesson
3. 0:07we're going to be talking about another
4. 0:08one of the general ways in which our
5. 0:11medications work and specifically in
6. 0:14this lesson we're going to be talking
7. 0:15about enzymatic inhibition
8. 0:18and first of all let's make sure that
9. 0:20you understand what enzymes are enzymes
10. 0:23are proteins that catalyze or in other
11. 0:26words speed up a reaction
12. 0:28so in the body there may be a reaction
13. 0:30that occurs but it may take maybe three
14. 0:33hours
15. 0:34and with the enzyme it may speed up that
16. 0:38reaction and the reaction may occur in a
17. 0:42few milliseconds or a few thousands of a
18. 0:45second
19. 0:46now this is depicted in the really
20. 0:48simplistic diagram here the purple is
21. 0:52the enzyme and the smaller structure in
22. 0:57red is the substrate a substrate means
23. 1:00that it is the substance upon which the
24. 1:02enzyme is acting
25. 1:04and as they come into contact these two
26. 1:08molecular structures have kind of a bond
27. 1:11a molecular bond which allows them to
28. 1:14bond and allows the reaction to occur
29. 1:17and as that happens there's going to be
30. 1:20a cleaving of the substrate into two
31. 1:25different products
32. 1:27enzymes are really important to a range
33. 1:30of biological processes so given that
34. 1:33it's understandable why a lot of our
35. 1:35medications work by inhibiting one of
36. 1:38them so let's try to understand the
37. 1:41basics of enzymatic inhibition as it
38. 1:44applies to our medications when you
39. 1:47think of enzymatic inhibition you should
40. 1:50immediately think of two major types of
41. 1:52enzymatic Inhibitors the reversible
42. 1:55Inhibitors and the irreversible
43. 1:58inhibitors
44. 2:00by far the largest group of enzymatic
45. 2:03Inhibitors is the reversible inhibitors
46. 2:09and those are divided into at least four
47. 2:12subsets
48. 2:13clinically speaking the most important
49. 2:15group of reversible Inhibitors is the
50. 2:19competitive inhibitors
51. 2:21in competitive inhibition the medication
52. 2:23binds to the active site of the enzyme
53. 2:26and prevents The Binding of the
54. 2:29substrate
55. 2:31so it is competing with the substrate
56. 2:36because it is a competition between the
57. 2:39medication and the substrate adding more
58. 2:42substrate would normally increase the
59. 2:44amount of binding of the substrate that
60. 2:47is the largest group of reversible
61. 2:50enzymatic Inhibitors the competitive
62. 2:52Inhibitors and when the medication is
63. 2:55fully metabolized there should be no
64. 2:58further effects
65. 3:00now let's take an example of competitive
66. 3:02inhibition to make sure that you
67. 3:04understand that the structure in purple
68. 3:07is the enzyme let's use the example
69. 3:09acetylcholine esterase the enzyme that
70. 3:13breaks down the neurotransmitter
71. 3:15acetylcholine the structure in red is
72. 3:18the substrate and in this case the
73. 3:21substrate is acetylcholine
74. 3:23when the enzymatic action happens
75. 3:26acetylcholine will degrade to acetate
76. 3:29and choline each molecule of
77. 3:32acetylcholine estrace degrades about 25
78. 3:36000 molecules of acetylcholine per
79. 3:39second and finally the medication is in
80. 3:42yellow the medication is competing for
81. 3:45the active site on the enzyme meaning
82. 3:48that every second that it is in the
83. 3:50active site is a second that the enzyme
84. 3:53is not degrading it's 25
85. 3:56000 molecules of acetylcholine
86. 3:59the other major type of reversible
87. 4:02Inhibitors that is fairly common is a
88. 4:05non-competitive inhibitor in that case
89. 4:08the inhibitor binds to what we call an
90. 4:12allosteric site
91. 4:14it's not the site that's in the active
92. 4:18portion of the enzyme but in a different
93. 4:21portion of the enzyme
94. 4:23this diagram denotes a non-competitive
95. 4:26inhibitor changing the active site so
96. 4:30that the substrate cannot bind now let's
97. 4:32talk about irreversible inhibitors
98. 4:36if a person is given an irreversible
99. 4:39inhibitor of an enzyme the enzyme can no
100. 4:42longer perform its function an
101. 4:44irreversible inhibitor inactivates an
102. 4:47enzyme by binding normally covalently to
103. 4:51the enzyme and normally at the active
104. 4:55site
105. 4:57and you may be thinking right now what
106. 4:59are we going to do without that enzyme
107. 5:01the irreversible enzymatic Inhibitors
108. 5:05are time dependent
109. 5:07So eventually the medication will be
110. 5:11degraded at the active site or the
111. 5:14enzyme will be replaced the time that
112. 5:17this takes is variable but it often
113. 5:19takes much longer than the half-life of
114. 5:22the medication would predict
115. 5:26so from a clinical aspect you could
116. 5:28understand how an irreversible inhibitor
117. 5:32is often going to last a lot longer than
118. 5:35the effects of a reversible inhibitor
119. 5:39an example is the proton pump inhibitors
120. 5:42such as Omeprazole and other medications
121. 5:45that end in the suffix prasol those have
122. 5:49a relatively short half-life of about
123. 5:51one and a half hours and that would
124. 5:54normally mean that the medication would
125. 5:56have to be taken quite frequently
126. 5:59but because it is an irreversible
127. 6:02inhibitor Omeprazole and other
128. 6:04irreversible proton pump inhibitors only
129. 6:07need to be taken on a daily basis
130. 6:11irreversible enzymatic inhibition is
131. 6:13also important in toxins such as
132. 6:16pesticides and anti-infectant agents for
133. 6:21instance many of the nerve gases are
134. 6:23irreversible Inhibitors of the enzyme
135. 6:25that breaks down the neurotransmitter
136. 6:27acetylcholine
137. 6:30and acetylcholine works all the way
138. 6:33through the body but let's just take the
139. 6:35example of what happens at the site of
140. 6:37the muscles
141. 6:39acetylcholine is the neurotransmitter
142. 6:42that's responsible to instruct the
143. 6:45muscles to contract without the enzyme
144. 6:49that breaks down the acetylcholine at
145. 6:51the muscle the acetylcholine continues
146. 6:53to stimulate for instance the
147. 6:55respiratory muscles and remember what we
148. 6:57need in order to breathe we need to be
149. 6:59able to contract the diaphragm but we
150. 7:02need to be able to relax it as well so
151. 7:05contraction relaxation contraction
152. 7:07relaxation and with this nerve gas
153. 7:11that's an irreversible inhibitor of that
154. 7:14enzyme it means that there's constant
155. 7:17excesses in acetylcholine and constant
156. 7:21contraction so the person succumbs to
157. 7:24respiratory distress
158. 7:27we also use irreversible Inhibitors when
159. 7:31we're targeting infective agents for
160. 7:35instance penicillin is an irreversible
161. 7:37inhibitor of an enzyme which only the
162. 7:41bacteria have but humans don't have
163. 7:52we just found out a bit about the
164. 7:54irreversible enzymatic Inhibitors and we
165. 7:58now know that they are time dependent
166. 8:01but I have a problem that many people
167. 8:03puzzle over and I'd like you to think
168. 8:06about it
169. 8:07aspirin is an irreversible enzymatic
170. 8:11inhibitor of the enzyme called
171. 8:14cyclooxygenase and it's abbreviated as
172. 8:16Cox so aspirin inhibits Cox enzyme in
173. 8:21platelets for the entire nine days of
174. 8:25the platelet and that's the reason that
175. 8:27if you're giving blood they ask you if
176. 8:30you have had any aspirin for the past 10
177. 8:33days
178. 8:35they will not use your platelets if you
179. 8:38have had Aspirin because aspirin
180. 8:40irreversibly inhibits the enzyme
181. 8:43cycloxygenase
182. 8:46but the effect of aspirin on that same
183. 8:49enzyme in other tissues doesn't last for
184. 8:52that long otherwise the
185. 8:54anti-inflammatory effect would be much
186. 8:57longer than it is
187. 9:00so why is that can you think of a reason
188. 9:03for the difference
189. 9:06and you were correct if you said that
190. 9:09platelets don't have the ability to make
191. 9:12more enzymes we called it in order to
192. 9:15make new proteins the cell needs a
193. 9:18nucleus that contains the DNA
194. 9:21we make a copy of the relevant portion
195. 9:24of the DNA or in other words we copy the
196. 9:27gene the codes for the protein
197. 9:30and send that information to another
198. 9:32portion of the cell to be translated
199. 9:34into a protein
200. 9:36so the platelet will never do this
201. 9:39because it doesn't have that DNA that's
202. 9:41necessary to make the new enzyme so when
203. 9:45aspirin affects the platelets
204. 9:47cycloxygenase the platelet isn't capable
205. 9:51of degrading the aspirin and it's not
206. 9:54capable of making new cycloxygenase
207. 9:58and as we compare this to what happens
208. 10:02inside cells it's noteworthy that our
209. 10:05cells have ways of degrading drugs and
210. 10:08toxins that are in the cell and if it
211. 10:11cannot degrade the drug this cell is
212. 10:13capable of replacing the irreversibly
213. 10:16inhibited enzyme