Pharmcokinetics (PK) and Pharmacodynamics (PD)

When injected intravenously, opioids are rapidly transported to the heart and pulmonary blood vessels from where they are dispersed to various organs and tissues.
After a standard dose of opioid, the interpatient variability of effect is large and is related to a variety of factors, including weight-related parameters (lean and fat body mass), organ function (hepatic and renal function), and cardiac output.
When an opioid is injected into the venous system, there is an initial rapid peak in plasma concentration. Next, the drug rapidly enters multiple organ systems with high blood flow (e.g., the brain, liver, kidney) from which the plasma drug concentration rapidly drops followed by a slower drop caused by redistribution to organs (e.g., the muscles and later, tissues with high fat content) that are less well perfused.
The time needed for the drug's plasma concentration to decrease by 50%, from a steady-state plasma concentration after the drug infusion has stopped, is called the context sensitive half-time (CSt½) (Fig. 19-4: Context-sensitive half-times for remifentanil, fentanyl, and morphine).
1. The CSt½ depends on the duration of the infusion.
2. For fentanyl, the CSt½ increases with the duration of the infusion. For remifentanil, the half-time is independent of the duration.
Metabolism: Which Pathways and Metabolites Are Clinically Relevant?
1. Most opioids are metabolized in the liver through either phase I (oxidative and reductive reactions catalyzed by the cytochrome P450 enzyme system) or phase II reactions (conjugation to a specific substrate).
2. Three aspects of opioid metabolism have clinical importance:
  1. Medications that inhibit or induce the CYP450 system may increase or decrease the clinical effect of opioids by interfering with their metabolism.
  2. Opioid metabolites may either be active or inactive (applies not only to their analgesic effect but also to their unwanted side effects).
  3. Genetic variability in the CYP system has clinical implications.
Morphine undergoes rapid metabolism in the liver, and within minutes after its administration, the two most important hydrophilic metabolites (morphine-3-glucuronide [M3G] and morphine-6-glucuronide [M6G]) appear in the plasma. In humans, M3G is without any analgesic or antianalgesic action. M6G is a full µ-opioid receptor agonist.
Piperidines
1. Fentanyl, alfentanil, sufentanil, and remifentanil are lipophilic opioids that rapidly cross the blood–brain barrier.
2. Fentanyl, alfentanil, and sufentanil are metabolized by the liver catalyzed by the cytochrome P450 enzyme system. The major metabolite of fentanyl is the inactive compound norfentanyl. The polymorphic expression of the CYP3A5 gene accounts for the great variability in alfentanil metabolism and clearance.
3. Remifentanil contrasts with the other piperidines in that it is not metabolized in the liver (contains a methyl ester side chain that is metabolized by within the erythrocyte and by tissue nonspecific esterases). This causes a rapid clearance of the drug (CSt½ of 2 minutes), making it the most rapidly acting opioid currently available (usually administered as a continuous infusion because its plasma level decreases by 50% in as little as 40 seconds).
Methadone is extensively metabolized to an inactive form by CYP2B6, which is also affected by pharmacogenetic variability (there is considerable variation among recipients in the response to the drug).
Naloxone is a nonspecific µ-opioid receptor antagonist that is best administered intravenously (unpredictable bioavailability after oral intake because of an extensive first-pass effect).

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