Analgesic, concentration-time effect

Relating the Time-Course of Plasma Concentrations to the Time-Course of Effect A critical decision to be made after the first human study is whether the compound s speed of onset and duration of action are likely to be consistent with the desired clinical response. Speed of onset is clearly of interest for treatments which are taken intermittently for symptoms rehef, for example, acute treatments for migraine, analgesics, or antihistamines for hay fever. Duration of action phase I is particularly important when the therapeutic effect needs to be sustained continuously, such as for anticonvulsants. The first information on the probable time course of action often comes from the plasma pharmacokinetic profile. However, it has become increasingly evident that the kinetic profile alone may be misleading, with the concentration-time and the effect-time curves being substantially different. Some reasons for this, with examples, include... 

Taking drugs with food may not influence the overall uptake and passage into the plasma (the oral bioavailability), but often reduces the Cmax and increases the time to peak plasma concentration, the Tmax- If you are looking for a rapid effect, for example from an analgesic, it is usually best to take it either one hour before or up to three hours after a meal. 

Buprenorphine is a semi-synthetic derivative of thebaine, one of the opium alkaloids. It is approximately 30 times as potent as morphine. A dose of 0.3 mg intramuscularly has a duration of analgesic action of 6-18 h. Buprenorphine is also effective sublingually. The average bio-availability by this route is about 55%, but absorption is slow and the time to achieve peak plasma concentrations is variable, with a range of 90-360 min. The onset of action is rather slow (5-15 min) after both intramuscular and intravenous administration, possibly due to slow receptor association. Buprenorphine binds to and dissociates from the p receptor very slowly, which may account for its low potential for physical abuse. It also means that buprenorphine-induced respiratory depression is difficult to reverse with naloxone, even with very high doses. Doxapram may in these circumstances be useful. Drowsiness and dizziness are the most common side effects, although they rarely... 

The state-of-the-art approach to controlled release opioid therapy is to provide formulations which exhibit zero order pharmacokinetics and have minimal peak to trough fluctuation in opioid levels with repeated dosing. This zero order release provides very slow opioid absorption, and a generally flat serum concentration curve over time. A flat serum concentration is generally considered to be advantageous because it would in effect mimic a steady-state level where efficacy is provided but side effects common to opioid analgesics are minimized. 

Celecoxib [sel eh COCKS ib] is significantly more selective for inhibition of COX-2 than of COX-1 (Figure 39.16). In fact, at concentrations achieved in vivo, celecoxib does not block COX-1. Unlike the inhibition of COX-1 by aspirin (which is rapid and irreversible), the inhibition of COX-2 is time-dependent and ireversible. Celecoxib was approved for treatment of osteoarthritis and rheumatoid arthritis, but not for analgesia. [Note In some trials, celecoxib had analgesic activity in others it was no more effective than the placebo. Its ability to reduce acute pain is poor.] Unlike aspirin, celecoxib does not inhibit platelet aggregation, and does not increase bleeding time. 

STPs are found to be the major contributor of pharmaceuticals in the Ebro River water. Compounds more frequently detected in the Ebro River basin were analgesics (diclofenac, naproxen, ibuprofen), lipid regulators (gemfibrozil, bezafibrate), antibiotics (azythromycin, trimethoprim, erythromycin, sulfamethoxazole), the antiepileptic carbamazepine, the antihistaminic ranitidine, and the 6-blockers atenolol and sotalol, which are the ones of major consumption in Spain as well as the ones excreted at higher percentages as parent drugs. Concentrations detected in both waste and surface waters are from 100 to 1000 times lower than the levels reported to cause acute toxicity. However, with respect to chronic effects, for some of the most ubiquitous compounds the margin of safety is narrow. As a wide spectrum of pharmaceuticals has been detected in natural waters, effects of mixtures should also be taken into account. 

Still, with all controversies as to mode of administration, choice of drug, dose, concentration or adjuvants, there seems to be proper documentation of analgesic effect from neuraxial glucocorticoids during acute episodes of low back pain and radiating pain. The effect may be evident within a few hours and may last for 1-3 weeks and up to 3-6 months in some studies. However, the analgesic effect does not seem to be superior to placebo when evaluated beyond this time-frame, or in terms of outcome or risk of recurrence. 

Tilidine The effect of voriconazole 400 mg on the pharmacokinetics and analgesic effects of tilidine 100 mg have been investigated in 16 healthy volunteers in a placebo-controlled study f49 ]. Voriconazole caused a 20-fold increase in the serum AUC of tilidine and the AUC of nortilidine increased 2.5-fold the serum concentrations of bisnor-tilidine were much reduced. The onset of analgesic activity occurred later with voriconazole, concordant with the prolonged t ax of nortilidine from 0.78 to 2.5 hours, due to additional inhibition of nortilidine metabolism to bisnortilidine. After voriconazole the AUC under the pain withdrawal versus time curve was reduced compared, mainly because of a shorter withdrawal time. Thus, voriconazole significantly inhibited the sequential metabolism of tilidine, with increased exposure to the active metabolite, nortilidine. Furthermore, the incidence of adverse events was almost doubled after voriconazole and tilidine. 

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