General Principles: Pharmacokinetics continued

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Pharmacokinetics: Opioids

  • 5,6Overview: Opioids:

    • Opioids are commonly used in IV anesthesia. Contemporary agents include fentanyl (Sublimaze) and fentanyl (Sublimaze) derivative such as alfentanil (Alfenta), sufentanil (Sufenta), and remifentanil (Ultiva).  Morphine is considered as the " prototypical" opioid.

    • A primary opioid effect a pharmacological interest is analgesia; however, there are a number of important side effects consider in anesthesia. 

      •  For example, morphine can cause hemodynamic effects including prominent vasodilation (venodilation) which may be sufficient to require transfusion, hypotension or even hypertension.  Other important effects include histamine relieves and quite importantly significant respiratory depression.

      • Fentanyl (Sublimaze),a frequently used agent, exhibits respiratory depression, but does not induce  venodilation or histamine release

      • Fentanyl (Sublimaze) derivatives, sufentanil (Sufenta) in alfentanil (Alfenta), are characterized by more rapid recovery following IV infusion as their plasma concentration decline more rapidly than that observed with fentanyl (Sublimaze).  The shortest acting agent, remifentanil (Ultiva), because of rapid hydrolysis, has an exceedingly short half-life and may require continuous IV infusion to maintain effect.  Another way of looking at this is that with remifentanil (Ultiva) it is easier to "titrate to effect", with rapid in easy adjustment to changing intraoperative requirements.

    • Mechanism of action: Opioids work by interacting with specific opiate receptors that had been designated mu, kappa, and sigma, in terms of major classification types.  Of these, the mu appears most important in terms of analgesia and respiratory depression opioid effects.  The mu receptor type consists of the least two subtypes, mu-1 which probably mediates analgesia and mu-2 which probably mediates respiratory depression, bradycardia, and physical dependence.

      • The G protein second messenger system is activated by opioid agonist binding to the receptor.  Subsequently, activated G protein subunits alter membrane permeability (increasing K+ in decreasing Ca2+ conductance [permeability]) which has the effect of hyperpolarizing the membrane thus inhibiting neuronal activity. 

      • Sites of opioid effects include: medulla, spinal cord, spinal trigeminal nucleus, and periaquaductal grey area which is an integration modulation site from peripheral nerves to the central neuraxis.

  • "There are two primary ascending nociceptive pathways. These are the spinoparabrachial pathway (red), which originates from the superficial dorsal horn and feeds areas of the brain that are concerned with affect, and the spinothalamic pathway (blue), which probably distributes nociceptive information to areas of the cortex that are concerned with both discrimination and affect. Many more less prominent pathways could be added2, 5, 6, 68-72. (A, adrenergic nucleus; bc, brachium conjunctivum; cc, corpus callosum; Ce, central nucleus of the amygdala; Hip, hippocampus; ic, internal capsule; LC, locus coeruleus; PB, parabrachial area; Po, posterior group of thalamic nuclei; Py, pyramidal tract; RVM, rostroventral medulla; V, ventricle; VMH, ventral medial nucleus of the hypothalamus; VPL, ventral posteriolateral nucleus of the thalamus; VPM; ventral posteriomedial nucleus of the thalamus.)"--

  • Figure adapted from: Nature Reviews Neuroscience 2; 83-91 (2001): THE MOLECULAR DYNAMICS OF PAIN CONTROL Nature © Macmillan Publishers Ltd 2001 Registered No. 785998 England

 

 

  • "The descending pathway highlighted originates from the amygdala and hypothalamus and terminates in the periaqueductal grey (PAG). Neurons project from here to the lower brainstem and control many of the antinociceptive and autonomic responses that follow noxious stimulation. (A, adrenergic nucleus; bc, brachium conjunctivum; cc, corpus callosum; Ce, central nucleus of the amygdala; Hip, hippocampus; ic, internal capsule; LC, locus coeruleus; PB, parabrachial area; Po, posterior group of thalamic nuclei; Py, pyramidal tract; RVM, rostroventral medulla; V, ventricle; VMH, ventral medial nucleus of the hypothalamus; VPL, ventral posteriolateral nucleus of the thalamus; VPM; ventral posteriomedial nucleus of the thalamus.)"--

  • Figure adapted from: Nature Reviews Neuroscience 2; 83-91 (2001): THE MOLECULAR DYNAMICS OF PAIN CONTROL Nature © Macmillan Publishers Ltd 2001 Registered No. 785998 England

  • 5,6Morphine  pharmacokinetics:

    • Elimination halftimes for morphine following bolus administration is about 1.7-4.5 hours.  Following bolus administration onset time is relatively slow (15-30 minutes) because:

      1. morphine exhibits relatively low lipid solubility about 2.5% of fentanyl (Sublimaze)

      2. at physiological pH, morphine, a weak base with the pKa of about 8.0, is primarily ionized.  The ionized form does not favor passage through the lipid membrane; accordingly, only about 10%-20% of molecules are un-ionized.

    • Relatively high plasma clearance (15-40 ml/kg/minute) has implicated extrahepatic clearance mechanisms, most likely renal.

Morphine
  • 5,6Fentanyl (Sublimaze) pharmacokinetics:

    • Fentanyl (Sublimaze) is significantly more lipid-soluble, compared morphine and, relative to morphine, has a more rapid onset of action (fentanyl (Sublimaze) is also a weak base and at physiological pH only about 10% of molecules are un-ionized).

    • Clearance of about 10-20 ml/kg/minute is consistent with a primary hepatic mechanism.  Fentanyl (Sublimaze)'s short duration of action following bolus administration is explained by rapid redistribution from brain to other compartments such as skeletal muscle and fat. If, however, fentanyl (Sublimaze) is administered by continuous IV infusion or multiple IV dosing, other non-CNS compartments will saturated and remaining CNS fentanyl will contribute to postoperative ventilatory depression.

Fentanyl (Sublimaze)
  • 5,6Sufentanil (Sufenta) pharmacokinetics:

    •  Sufentanil (Sufenta), in a manner similar to fentanyl (Sublimaze), pharmacokinetics are best represented by a multicompartment (3 compartment) model.

    • IV bolus sufentanil (Sufenta) has a rapid onset of action, similar to fentanyl (Sublimaze),  with rapid redistribution resulting in relatively short-term duration of action.  Elimination halftime is about 2.7 hours and and is associated with high clearance {about 13 ml/kg/minute) which is primarily dependent on hepatic blood flow.  Duration of action is somewhat shorter than for fentanyl (Sublimaze) although sufentanil (Sufenta) is about 5-10 times more potent.

    • Increased sufentanil (Sufenta) potency compared to fentanyl (Sublimaze) is probably related to in part somewhat greater lipid solubility and and higher receptor affinity.  Higher receptor affinity means that to achieve a certain percentage occupancy of the receptor a lower drug concentration is required.

      •  Here we are reminded that potency refers to the drug concentration required to achieve a given level of effect; therefore, a more potent drug can be used in lower dosages to achieve the same effect.  Moreover, potency is different from efficacy in that two drugs could be equipotent but differ in  the maximal effect which may be produced.

      • Sufentanil (Sufenta), is a weak base with a pKa of about 8, indicating that at physiological pH, about 20 percent of the sufentanil molecules are  un-ionized, and are therefore able to readily traverse membrane lipid bilayers.

    • "Context sensitive" halftimes {which are those following termination after continuous infusion} are shorter for sufentanil (Sufenta) compared alfentanil (Alfenta) or fentanyl (Sublimaze). The decline in plasma drug concentration will depend on both redistribution to peripheral (not brain) compartments and metabolism.

    • Other pharmacological issues:

      • Sufentanil (Sufenta) administration may cause a more significant respiratory depression and bradycardia compared to fentanyl (Sublimaze)

      • Sufentanil (Sufenta) given in larger doses [and this point applies to other potent opioids], particularly if administered rapidly, can cause significant  respiratory skeletal muscle rigidity that  may adversely affect the anesthetist's ability to ventilate.

Sufentanil (Sufenta)
  • Since opioid biological actions require the molecule to interact with specific receptors and in the case of anesthesia these receptors of primary interest are localized in the spinal cord and brain, the ionization state of  the drug is a critical importance.  As noted earlier, it is the un-ionized form that more readily moves from the aqueous phase into of the lipid or as we see below "non-polar" component of the membrane.  These non-polar tails form the  transport barrier for polar or formally charged molecules.
Membrane Bilayer Structure

Representation of the lipophilic, hydrophobic core characteristic of biomembrane structure.  

The "tail" component below represents the overall structural barrier, an important cellular physiological membrane property.  This barrier also however, limits access of drugs to their site of action, based on the relative lipophilicity of the drug.  For opioids, which are weak bases, having pKa values of about 8, the relatively small percentage, e.g. 20%, of the opioid molecules are in the optimal, un-ionized form for movement across biological membranes.  We will see the importance of the percentage un-ionized drug as it relates to onset of action time when we compare fentanyl (Sublimaze) and sufentanil (Sufenta) with alfentanil (Alfenta)


Above images courtesy of Professor Steve Wright and the University of Arizona (c) 2001, used with permission.

 

 

  • Alfentanil (Alfenta): pharmacokinetics

    • Alfentanil (Alfenta), another in the fentanyl (Sublimaze) analogue series, is different from fentanyl (Sublimaze) and sufentanil (Sufenta) by virtue of its more rapid onset of action, although it is only 10% as potent as fentanyl (Sublimaze).

      • By contrast to sufentanil (Sufenta) and fentanyl (Sublimaze) which exhibit pKa values above physiological pH, and as a result, and physiological pH are primarily ionized, the pKa for alfentanil (Alfenta) is below (6.5) physiological pH (7.4).  Accordingly, at physiological pH most alfentanil molecules have lost their titratable hydrogen and are un-ionized, i.e. uncharged.  Since the uncharged form readily passes the lipophilic membrane core and given the high percentage of cardiac output directed to the brain, is not surprising that alfentanil (Alfenta), following intravenous administration equilibrates with the brain-target sites in about 1.5 minutes.

      • Short-duration of action occurs as a result of rapid redistribution from the brain to other compartments.  Therefore, if the initial IV bolus is not followed by subsequent administration subtherapeutic effects will be seen within a few minutes.

        • Short-duration of action carried to this extent make alfentanil (Alfenta) very suitable to block physiological response to a single, brief intervention such as intubation or performing a retrobulbar block.

    • Based on alfentanil (Alfenta) pharmacokinetics, the following regimen is an example of how alfentanil (Alfenta) might be used in anesthesia:

      • Induction: intravenous administration of 150-300 ug/kg

      • Maintenance: continuous alfentanil (Alfenta) infusion (25 -150 ug/kg/minute, IV) along with an inhaled agent

    • Clearance: 4-9 ml/kg/minute; alfentanil (Alfenta) metabolites are inactive although numerous; furthermore, significant individual to individual differences in clearance (perhaps 10 fold) may well reflect different gene expressions levels all of the cytochrome P450 isoform responsible for alfentanil (Alfenta) metabolism, namely CYP3A4 (cytochrome P450 3A4 enzyme activity)

Alfentanil
  • Remifentanil (Ultiva):  pharmacokinetics

    • Remifentanil (Ultiva) is unique among the various opioids used in IV anesthesia mainly because of its susceptibility to the ester hydrolysis.  There are two ester-linkages in the molecule one of which is rapidly cleaved by nonspecific plasma and tissue enzymes {different from pseudocholinesterase which hydrolyzes for instance succinylcholine (Anectine) and mivacurium (Mivacron)}

    • This agent is somewhat less soluble than other opioids, contributing factor to its rapid onset of action, onset that occurs within a time frame similar to that seen with alfentanil (Alfenta), i.e. very rapid.  Furthermore, rapid ester hydrolysis limits its duration of action so significantly that, following its redistribution from the brain, its plasma half-life is extremely short.  In fact, the plasma half-life is so short that there is very little redistribution to other compartments.

      • The special degradative pathway is responsible for elimination halftimes on the order of 10-25 minutes -- much less than in other IV agents.

      • The "context sensitive" halftime for remifentanil (Ultiva) is about four minutes and is independent of infusion duration.

    • Remifentanil (Ultiva)'s pharmacokinetic characteristics results in important clinical consequences:

      • The very brief pharmacological activity allows careful titration of dose to effect

      • The drug does not accumulate.  Accumulation is a typical concern following repeated administrations of other drugs.

      • Following continuous intravenous infusion, recovery is rapid limiting the likelihood of postoperative respiratory depression or other complications

Remifentanil (Ultiva)

Remifentanil

Remifentanil showing hydrolysis site

 

Remifentanil (Ultiva)

*Opioid Organ system Effects: see section on Opioid Pharmacology in the Central Nervous System Unit

 

1Katzung, B. G. Basic Principles-Introduction , in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 1-33

2Benet, Leslie Z, Kroetz, Deanna L. and Sheiner, Lewis B The Dynamics of Drug Absorption, Distribution and Elimination. In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 3-27

3Correia, M.A., Drug Biotransformation. in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 50-61.

4Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.

5Dolin, S. J. "Drugs and pharmacology" in Total Intravenous Anesthesia, pp. 13-35 (Nicholas L. Padfield, ed), Butterworth Heinemann, Oxford, 2000

6Stoelting, R. K. and Miller, R.D. Intravenous Anesthetics, in Basics of Anesthesia, 4th edition, pp. 58-69, Churchill-Livingstone, 2000.

 

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