Pharmacokinetics And Pharmacodynamics – Clinical Applications
Geoffrey K Gourlay, B.Pharm., PhD., FFPMANZCA Objectives 1. 2. 3. 4. 5. Delegates will understand that opioid drugs can activate various opioid and other receptors types and this may explain some of the different pharmacodynamic responses observed. Delegates will understand the pharmacokinetic characteristics of various opioid drugs impacts the on the pharmacodynamic response. Delegates will appreciate the pharmacokinetic characteristics of different routes of administration such as transdermal, spinal, buccal, parenteral, rectal and pulmonary (nebulised). Delegates will understand that the metabolism of opioid drugs may influence pharmacological activity, both positively (ie analgesia) and negatively (ie adverse effects) via the relative activity of parent drug and opioid metabolite(s). Participants will have an understanding how of these factors can influence the choice of opioids in the treatment of chronic and cancer pain.
OVERVIEW Metabolism aspects are increasing in complexity providing considerations of pharmacogenetics, which may influence pharmacological activity, both positively (ie analgesia) and negatively (ie adverse effects) via the relative activity of parent drug and opioid metabolite(s). Concomitantly administered drugs can either increase (competitive inhibition) or decrease (induction of metabolism) the concentration of opioid drugs as seen with methadone. Thus, patients could be placed in different groups with implications for differing pharmacodynamic responses to some opioid drugs. Participants will have an understanding how of these factors can influence the choice of opioids in the treatment of chronic and cancer pain. Morphine is still considered to be the opioid drug of choice by many practitioners, a place it has essentially occupied since recorded history. However, some of the other potent -receptor agonists are gaining popularity for a variety of reasons BINDING PROFILES Molecular biology techniques are providing new information on receptor function and organisation that will lead to an increased understanding of opioid neurotransmission at the molecular level and the factors controlling the development of tolerance to opioid drugs. The binding affinities of a range of opioids to the -, - and - opioid receptors indicates that while the commonly prescribed opioids (agonists and antagonists) bind preferentially to the - receptor, they do associate with all three receptor types. Morphine shows the largest relative preference for the - receptor. Methadone (which also is a potent NMDA receptor blocker) also shows significant binding to - receptors while buprenorphine, and to a slightly lesser extent naloxone, avidly binds to all three receptor types. Codeine and heroin display exceedingly poor binding to opioid receptors which raises the possibility that both are prodrugs. A similar situation probably applies to oxycodone where the oxidative metabolite oxymorphone or the reduction metabolite oxycodol, may be substantially responsible for the pharmacodynamic effects. Alternatively, it has been suggested that the intrinsic nociceptive effects of oxycodone maybe mediated via - receptors. PHARMACOKINETIC ASPECTS Manipulating the absorption of opioids (via formulation approaches) alters the shape of the blood opioid concentrationtime profile as in the case of various sustained release oral morphine, oxycodone and hydromorphone formulations and transdermal fentanyl. The prolonged analgesia associated with these formulations is achieved by altering the absorption profile of the opioids. Oral Dosage Forms Immediate Release Formulations The oral bioavailability (ie proportion of opioid drug absorbed following oral administration compared to a standard parenteral [usually intravenous] dose) for opioid drugs displays significant inter-patient variability. The careful dose titration procedure adopted by pain clinicians to achieve the optimal balance between analgesia the minimum incidence and severity of side effects overcomes the issue of interpatient variability in oral bioavailability for opioid drugs. Sustained or Modified Release Formulations and Bioequivalence. The mean plasma morphine concentration - time profiles following the oral administration of a single dose of various modified release oral morphine formulations is highly variable resulting from the various pharmaceutical approaches that influence the absorption rate. Many of these modified release morphine formulations are NOT bioequivalent. Other Routes of Administration Buccal Formulations Fentanyl has has been successfully administered via the buccal mucosa in a unique formulation (termed a hardened lozenge on a stick) as a non-invasive treatment of acute pain in paediatric patients and also for incident or unpredictable breakthrough pain in adult patient with severe cancer pain. Transdermal Formulations
Fentanyl has desirable physiochemical properties and intrinsic potency that enable analgesic blood concentrations to be achieved following transdermal administration The fentanyl pharmacokinetics from this formulation (Transdermal Therapeutic Systems or TTS - Fentanyl, Durogesic®) are characterised by a slow absorption through the skin (partially controlled by a rate control membrane that forms part of the formulation), but a long duration of effect, up to 3 days. Spinal Administration. The spinal route of administration is used because of a perceived more favourable balance between improved pain relief and the incidence and severity of adverse effects compared to oral opioids due to a selective spinal action. The small opioid doses administered intrathecally (in comparison to oral doses of the same opioid) result in negligible and sub-therapeutic blood opioid concentrations. Intranasal Administration. The absorption of opioid drugs (fentanyl, oxycodone and sufentanil) from the nasal mucosa has been used in the treatment of breakthrough or incident pain and also for pre-operative sedation. Nasal spray bottles that deliver an accurate volume of solution (and therefore dose) as a spray per activation are used for this route of administration. The intranasal bioavailability for oxycodone and sufentanil was 45% and 78% respectively. Pulmonary Administration using Aerosol or Nebulised Solutions. While the lung is not considered to be a normal route of administration for opioid drugs (as opposed to volatile anaesthetic agents), evidence suggests that there is rapid, extensive but variable absorption of both morphine and fentanyl following the inhalation of drug solutions that have been aerosolised. In fact, the mean blood concentrationtime profiles following pulmonary administration were similar to that seen with intravenous administration and raise the possibility of a non-invasive option for breakthrough or incident pain. While these studies used specialised apparatus to create the small droplets that constitute the aerosol, the absorption of opioid drugs from traditionally nebulised solutions is less efficient and results in lower bioavailability and a more variable post-operative analgesia. This approach can also be used to treat dyspnoea. Rectal Administration The rectal route is frequently used in patients who have difficulty swallowing or have significant vomiting despite optimised anti-emetic therapy. While the rectal bioavailability of opioids from solid dosage forms can be extensive (actually greater than oral bioavailability of the same dose), it is highly variable and the precise anatomical location of the suppository in the rectum is a crucial factor governing the extent of avoidance of hepatic first pass metabolism and hence the rectal bioavailability. Various modified release oral formulations have also been administered rectally with variable clinical outcomes. Specific rectal formulations of methadone have been successfully used in the treatment of cancer pain. METABOLISM The liver is the primary site of biotransformation of most drugs, including opioid drugs. Metabolism also occurs to a variable extent (depending on the opioid) in the organs of the body that come into initial contact with the opioid; for example during absorption from the GIT (following oral administration) and lung (pulmonary administration) The resultant metabolites can have pharmacological activity with respect to positive (pain relief) and negative (toxicity) effects. The clearance of the majority of opioids is high and consequently, hepatic blood flow has a major impact on the rate of metabolism. These opioids are frequently grouped together under the term flow limited opioids and require significant hepatic compromise before their pharmacokinetics are influenced. In contrast, the clearance of methadone is much lower and depends on the amount of functional cytochrome P450 isoform 3A4 in the liver and is termed a capacity limited opioid. Consequently, methadone metabolism can be either stimulated or inhibited by environmental factors and the concurrent administration of other drugs that influence 3A4 activity; for example, anticonvulsants (notably phenytoin) and rifampicin markedly stimulate methadone metabolism while fluconazole , HIV-1 protease inhibitors and some of the SSRI’s (fluvoxamine) competitively inhibit methadone clearance resulting in elevated blood methadone concentrations. The terminal half lives for most opioids varies between 2 and 7 hours, the notable exception being methadone where the extremes are as short as 3 hours and as long as 130 hours although most patients will be in a range of 12-60 hours. Methadone is metabolised by N-demethylation predominantly via hepatic cytochrome P450 3A4 to produce a pyrrolidine metabolite that is further metabolised and also excreted in the bile and renally. In almost all countries, methadone is administered as a racemate (ie approximately equal amounts of a d- and l- enantiomer) and the pharmacokinetics of the enantiomers are different. For example, while the terminal half life is longer and the clearance is higher for the analgesically active l- enantioner than for the d- enantiomer the N-demethylation is not stereoselective. However, there were no differences in oral bioavailability between the enantiomers. The l- enantiomer shows between ten and thirty times greater affinity than the d- enantiomer for receptors and is fifty times more potent as an analgesic in humans. Thus, it is generally accepted than the l- enantiomer is the biologically active species at opioid receptors. Methadone was also shown to be a non-competitive NMDA receptor antagonist with activity equivalent to dextromethorphan, but with similar affinitites of both the l- and d- enantiomers for this receptor. Thus, in the light of the NMDA receptor blocking activity, the current view supports the administration of the racemate as the l- and d- enantiomers are active at - and NMDA receptors respectively (agonist and antagonist respectively). Pharmacogenetic Aspects of Cytochrome P450 Metabolism The inter-patient expression of various isoforms of Cytochrome P450’s may well be a major factor in explaining variability in opioid (indeed, any drugs) pharmacokinetics by influencing the rate and extent of metabolism. Cytochrome P450 3A4 is the major isoform in the liver and small intestine where it constitutes 30% and 70% of total Cytochrome P450.
In conclusion, many factors influence the observed pharmacodynamic responses following opioid administration. Available orifices and membranes have been evaluated as possible portals of opioid drug administration and the pharmaceutical industry has ingeniously developed formulations to further utilise these options. Practitioners must understand the pharmacokinetic characteristics of route of administration and formulation if they are to use the options to their fullest extent. Genetic differences in opioid drug metabolism and the role of active metabolites may have a significant impact on analgesia and side effects. Most clinicians will continue to use one or possibly two favourite opioids to treat the majority of cases of cancer and non-cancer chronic pain. However, the effective use of other opioid drugs, routes of administration, formulations and drug combinations requires an understanding of newer aspects of opioid pharmacology. The ultimate beneficiaries will be patients under the care of physicians who take the time to understand these new concepts.