Metabolism of Drugs — Transcript

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1. 0:00hi there and welcome back to our
2. 0:02understanding medications we've just
3. 0:04taken a look at the first two processes
4. 0:06of pharmacokinetics the absorption and
5. 0:10distribution of medications and right
6. 0:12now we're going to be taking a look at
7. 0:13the metabolism of drugs
8. 0:16as we concluded our last lesson our
9. 0:18orally administered medication had been
10. 0:21absorbed into the hepatic portal venous
11. 0:24system on the way to the liver
12. 0:26and recall that our medications have no
13. 0:29choice if they're orally administered
14. 0:32because of the fact that any absorption
15. 0:34that occurs from the middle portion of
16. 0:36the esophagus all the way down to the
17. 0:38middle portion of the rectum is going to
18. 0:40go into the hepatic portal venous system
19. 0:43on the way to the liver to be
20. 0:45metabolized and that can be problematic
21. 0:48for a number of different medications
22. 0:50for instance glycerol trinitrite or
23. 0:53nitroglycerin for Angina or sometimes
24. 0:57called angina and also morphine have
25. 1:00what we call a very high first pass
26. 1:04effect and that means that the orally
27. 1:07administered medication is very
28. 1:09significantly altered before it gets to
29. 1:13systemic circulation
30. 1:15for orally administered glycerol
31. 1:17trinitrate the bioavailability is less
32. 1:22than one percent and that means that
33. 1:25less than one percent of the medication
34. 1:27that is orally administered is going to
35. 1:30be reaching systemic circulation
36. 1:33unchanged and that's the reason we most
37. 1:37frequently administer the medication the
38. 1:40sublingually in the form of a spray
39. 1:43spraying it under the tongue avoids that
40. 1:45first pass mechanism and it gets the
41. 1:47medication into the system very quickly
42. 1:50so the bioavailability of the medication
43. 1:53increases dramatically if we administer
44. 1:57it that way
45. 1:58for morphine the bioavailability is
46. 2:01around 30 so we can still administer it
47. 2:04orally but it is oftentimes
48. 2:08intravenously injected resulting in 100
49. 2:12bioavailability
50. 2:15intravenous injections and
51. 2:17intra-arterial injections are the only
52. 2:20types of administration that
53. 2:22consistently achieves 100 percent
54. 2:25bioavailability because nothing can
55. 2:28change the drug from the syringe to the
56. 2:31blood another way that we can get
57. 2:33morphine into the person's system is to
58. 2:37administer a drug that turns into
59. 2:39morphine in the liver codeine is what we
60. 2:43call a pro drug and it does exactly that
61. 2:46it is an inactive drug that has a
62. 2:50bioavailability of 90 percent and the
63. 2:53coding is altered to the active form
64. 2:56which is morphine the first time it
65. 2:59enters one of the liver cells
66. 3:02the liver is a primary site for
67. 3:05metabolism of drugs but it is not the
68. 3:07only site in fact many of the cells of
69. 3:10the git and many cells throughout the
70. 3:12body are also involved in some
71. 3:15metabolism of drugs but the liver has a
72. 3:18full array of the enzymes that are
73. 3:20needed for the drug metabolism and it
74. 3:23receives all of the blood from the git
75. 3:25so we consider it the most important
76. 3:28organ in metabolism of drugs
77. 3:31it's important not to fall into the
78. 3:34habit of thinking that the metabolism of
79. 3:36drugs always makes the drug inactive
80. 3:40like I just doubted in some instances
81. 3:42the first metabolic process in the liver
82. 3:45can make some inactive Pro drugs into
83. 3:49active metabolites it can make active
84. 3:53drugs into more active metabolites it
85. 3:56can make a drug more toxic or it can
86. 3:59make a drug inactive
87. 4:02in each case we are changing the drug
88. 4:05from one molecular form to another so
89. 4:08the main goal of the liver is not to
90. 4:11immediately inactivate the drug but
91. 4:13rather to make it more water soluble and
92. 4:16easier to excrete we can excrete drugs
93. 4:19in a variety of different ways in the
94. 4:22lungs and through our sweat for instance
95. 4:24and we can also excrete in the feces but
96. 4:27the most common way to eliminate drugs
97. 4:30is by the kidneys and in order to
98. 4:32excrete it by that route we need it to
99. 4:35be water soluble
100. 4:37the liver makes the Drug's water soluble
101. 4:40in two stages which are termed phase one
102. 4:42reactions and phase two reactions in
103. 4:46general the phase one reactions involve
104. 4:49cytochrome p450 enzymes the cytochrome
105. 4:53p450 enzymes are a huge super family of
106. 4:57enzymes that induce or unmask a polar
107. 5:01group in other words these reactions
108. 5:04make the molecule more water soluble
109. 5:08besides making the drug more
110. 5:10water-soluble the phase one reaction
111. 5:12also in simplistic terms gives the liver
112. 5:16an additional Target to come back to to
113. 5:20change the molecule even further the
114. 5:23next time that it goes through the liver
115. 5:27in other words the very sight that we
116. 5:30changed the first time is often the
117. 5:34target of other liver enzymes the next
118. 5:37time it goes through the liver
119. 5:40then if the metabolite is still too
120. 5:42lipophilic or in other words too fat
121. 5:44soluble the next time the drug goes
122. 5:47through the liver The Phase 2 reaction
123. 5:49occurs which adds a polar group to the
124. 5:53drug so that it is very water soluble
125. 5:55and we can definitely excrete it by the
126. 5:58kidneys
127. 5:59to picture these reactions let's take
128. 6:01the example of aspirin aspirin is a pro
129. 6:04drug it's taken as acetyl salicylicic
130. 6:07acid in the first pass aspirin is going
131. 6:10to be transformed into salicylicic acid
132. 6:12and that happens mainly in the liver but
133. 6:16it also happens to some extent in the
134. 6:18stomach and the in the intestinal mucosa
135. 6:22of the git and that reaction is termed a
136. 6:25phase one reaction the liver then uses
137. 6:28another enzyme to attach a very polar
138. 6:31molecule to the salicylic acid and in
139. 6:34that case the active metabolite is
140. 6:37changed to a relatively inactive water
141. 6:40soluble substance that can be easily
142. 6:42excreted
143. 6:43and make sure that you reinforce your
144. 6:46knowledge about the metabolism of drugs
145. 6:48by engaging in the quiz for this section
146. 6:51we will see you there and thanks for
147. 6:54joining us
148. 6:57we've just seen that the liver
149. 6:59metabolizes some pro-drugs into active
150. 7:03metabolites and one of the most common
151. 7:05drugs that is a pro drug is aspirin so
152. 7:10right now use your knowledge of
153. 7:12absorption and Metabolism to consider
154. 7:15what would happen in the following
155. 7:17scenario
156. 7:18pushpa has learned that topical
157. 7:20anti-inflammatory agents can help with
158. 7:23arthritis of the fingers she wants to
159. 7:26save money so she mixes aspirin with a
160. 7:29cream and administers it topically will
161. 7:32she get anti-inflammatory effects of the
162. 7:35aspirin in that local area
163. 7:40and you'd be correct if you had said
164. 7:42that she's very unlikely to get direct
165. 7:47anti-inflammatory effects if applied in
166. 7:49that manner drugs are formulated for
167. 7:52specific applications so for instance
168. 7:55intravenous aspirin if aspirin is given
169. 7:58intravenously it is given as lysine
170. 8:02acetylsalicate and not acetyl
171. 8:05salicylicic acid which is the oral form
172. 8:08of aspirin it can be very dangerous to
173. 8:13just assume that a medication made to be
174. 8:16taken orally is safe and effective to be
175. 8:19administered in another way
176. 8:22so if aspirin were to be administered
177. 8:25topically the first problem is that much
178. 8:28of it would not be absorbed
179. 8:30but also remember that aspirin is a pro
180. 8:33drug and as such it needs to be
181. 8:35metabolized into the active form and the
182. 8:38main place for that to occur is in the
183. 8:41liver
184. 8:43so the aspirin that got through the skin
185. 8:45into the interstitial spaces would need
186. 8:48to get into the liver where it would be
187. 8:50metabolized into the active form
188. 8:54let's take one more question to make
189. 8:56sure you understood what happens in the
190. 8:58liver with respect to metabolism
191. 9:01on the first pass through the liver the
192. 9:04enzymes in the liver including the
193. 9:06hundreds of cytochrome p450 enzymes can
194. 9:10make the drug a active B more active C
195. 9:15less active D pharmacologically inert e
196. 9:20more toxic F less toxic G more water
197. 9:25soluble or H all of the above
198. 9:32and you were correct if you had said all
199. 9:35of the above the liver's main job is to
200. 9:38make things more easily excreted so it
201. 9:41makes things more water soluble but in
202. 9:45the process the first step may actually
203. 9:47make the drug more toxic
204. 9:50a good example is the first metabolite
205. 9:52of ethanol the alcohol that we drink
206. 9:55which is acid aldehyde and much more
207. 9:59toxic than ethanol
208. 10:02let's get on to getting a good picture
209. 10:04of the final process of pharmacokinetics
210. 10:07which is the excretion of medications