Opioids pharmacodynamics

Basic animal research has provided a better though yet incomplete understanding of the cellular and molecular mechanisms mediating pharmacodynamic opioid tolerance. These mechanisms occur at three levels and have been termed receptor-level tolerance, cellular-level tolerance and system-level tolerance. 

Sporadic use (e.g., for the induction of sleep after a psychostimulant binge) does not require specific detoxification. Sustained use can be treated as described in the previous sections on detoxification from therapeutic or high dosages but with added caution. In mixed opioid and benzodiazepine abuse, the patient should be stabilized with methadone (some clinicians use other oral preparations of opioids) and a benzodiazepine. Buprenorphine should not be administered with benzodiazepines, because a pharmacodynamic interaction is possible (Ibrahim et al. 2000 Kilicarslan and Sellers 2000) and fatalities have been reported with the combination (Reynaud et al. 1998). Sedative-hypnotic withdrawal is the more medically serious procedure, and we usually... 

Pharmacokinetic changes are clinically important only if they engender pharmacodynamic ones. A dramatic example of this linkage is exemplified by the CSS. Previously thought to be uncommon, more than 125 cases of CSS have been reported (Mills, 1997 Mason et ah, 2000, Radomski et ah, 2000). Because of the common usage of SSRIs and co-medications, which include St. John s wort, some pro-serotonergic opioids, and ec-... 

Goldstein A Brown BW (2003). Urine testing in methadone maintenance treatment applications and limitations. Journal of Substance Abuse Treatment, 25, 61-3 Gonzalez JP Brogden RN (1988). Naltrexone a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of opioid dependence. Drugs, 35, 192-213... 

Miotto K, McCann M, Basch J, Rawson R ling W (2002). Naltrexone and dysphoria fact or myth American Journal of Addictions, 11, 151-60 Mitchell TB, White JM, Somogyi AA Bodmer F (2003). Comparative pharmacodynamics and pharmacokinetics of methadone and slow-release oral morphine for maintenance treatment of opioid dependence. Drug and Alcohol Dependence, 11, 85-94 Mitchell TB, White JM, Somogyi AA Bochner F (2004). Slow-release oral morphine versus methadone a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence. Addiction, 99, 940-5 Mitka M (2003). Office-based primary care physicians called on to treat the new addict. Journal of the American Medical Association, 290, 735-6... 

Figure 7.6 Structure of remifentanil and its major metabolite formed by ester hydrolysis. contrast, alfentanil has an intermediate hepatic extraction (0.3-0.5) and alfentanil clearance will be sensitive to changes in both liver blood flow and reduced enzyme capacity in patients with liver disease. Although the kidneys play a minor role in the elimination of most opioids, renal disease can influence their pharmacokinetic profile, secondary to alterations in plasma proteins and intra- and extravascular volumes. Neither the pharmacokinetics nor the pharmacodynamics of remifentanil is significantly altered in patients with liver or renal disease.

While opioid peptides have been very useful for investigating the pharmacology of different opioid receptor subtypes, pharmacological investigations have established that no pharmacodynamic advantage is to be expected from opioid peptides with respect to analgesic activity or side-effects. Furthermore, they have their own shortcomings with respect to potential clinical applications. Most importantly their peptidic structure usually prohibits administration by the oral or transdermal route, which are the routes of choice for pain treatment. 

AstraZeneca is developing a series of selective non-peptidic 5 opioid receptor agonists for the treatment of neuropathic pain. The compounds (e.g. cpd., 1) are in preclinical studies. In vivo, they are effective analgesics with negligible tolerance and dependence. They have parenteral and oral activity with suitable pharmacokinetics and pharmacodynamics. 

Gyr, E., R. Brenneisen, D. Bourquin, T. Lehmann, et al., Pharmacodynamics and pharmacokinetics of intravenously, orally and rectally administered diacetylmoiphine in opioid dependents, a two-patient pilot study within a heroin-assisted treatment program, Int. J. Clin. Pharmacol. Ther., 38(10), 486—491, 2000. 

Kaiko, R.F., Pharmacokinetics and pharmacodynamics of controlled-release opioids, Acta Anaesthe-siol. Scand., 41(1 Pt. 2), 166-174, 1997. 

Cox, E.H. et al. Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effect of synthetic opioids in the rat correlation with the interaction at the mu-opioid receptor. J Pharmacol Exp Ther 1998, 284 1095-1103. 

As with morphine and the benzomorphans, variation of the N-substituent (Chapters 2 and 4) markedly affects opioid pharmacodynamic activity, and (—) 49 (R = OH R = allyl) known as levallorphan or Lorphan is an antagonist several times more potent than nalorphine. Rather than prepare levallorphan by the N-demethylation 49, (R = OH R = Me) and allylation, on a commercial scale 51 (R and R = H) or 51 (R = H R = CH2C6H5) are obtained optically pure.(34) The former may be allylated and cyclized, whereas the latter was cyclized, debenzylated by hydrogenolysis, and finally converted to levallorphan with allyl bromide. 

The pharmacokinetics, pharmacodynamics and adverse effect profile of opioid analgesics are all relevant when considering the risks involved in using these drugs in patients with liver disease. There are also small variations between drugs in relation to pharmacokinetics and side effects, which may affect choice in certain circumstances. The decision to use opioids, the choice of opioid and the dose will therefore depend... 

Antagonistic pharmacodynamic interactions, for example reversal of nondepolarizing muscle relaxants, or reversal of the toxic effects of opioids or of BDZs, are sometimes of value in critical situations. 

Pharmacodynamic interactions. Many TCAs cause sedation and therefore co-prescription with other sedative agents such as opioid analgesics, antihistamines, anxiolytics, hypnotics and alcohol may lead to excessive drowsiness and daytime somnolence. The majority of TCAs can have undesirable cardiovascular effects, in particular prolongation of the QT interval. A similar risk of QT prolongation arises with many other cardiovascular drugs including amiodarone, disopyramide, procainamide, propa-... 

Pharmacokinetic/pharmacodynamic modeling can also assist in identification of the appropriate animal model in which to evaluate the mechanism of action. " Cox and his colleagues have developed a tooth pulp evoked potential (TPEP) rat model in order to investigate the analgesic effects of opioid drugs. The authors utilized a population sigmoidal pharmacody-... 

Neonates, infants, and children are at risk of adverse effects of opioids, owing to pharmacokinetic and pharmacodynamic changes (SEDA-17, 78). Routine use of pulse oximetry is recommended in all children receiving opioids (SEDA-21, 85). 

Important evidence for the role of Pgp at the BBB was obtained from experiments with mdrla(-/-) and mdrla/lb(-/-) mice. The significantly higher accumulation of several drags in the brains of these mice in comparison to most other tissues and plasma demonstrated its important role (62). In addition, increased accumulation of these drags in various tissues can affect their pharmacodynamics (63). This is best illustrated by centrally acting drags. Morphine is often used as a narcotic analgesic for the treatment of pain. It acts at the opioid receptors within the CNS at both the spinal and supraspinal levels. In vitro and in vivo studies have... 

There is little point in testing the tolerability of drugs in normal volunteers, when only patients with the disease of interest are able to demonstrate a relevant pharmacodynamic effect. The doses at which tolerability must be confirmed are unknown until the exposure of patients can indicate the doses that may be effective. The development of potent opioids such as alfentanil, sufentanil and remifentanil as anesthetic agents are a good example. 

---