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Hysteresis in drug response
Pharmacology
Hysteresis in drug response
Complex responses Many drug responses are integrated physiological changes, such as a fall in blood pressure after a β-adrenoceptor antagonist such as propranolol. This response involves inhibition of renin release from the kidney, a fall in cardiac output, inhibition of norepinephrine release and a reduction in sympathetic output from the central nervous system (CNS). Although it could be expected that each individual component might be directly related to plasma concentration, there will be no direct relationship to the final integrated response.
Barbara J Pleuvry
Abstract
Hysteresis
Hysteresis may be defined as ‘the retardation or lagging of an effect behind the cause of the effect’. The two main reasons for the lag phase are limited access to the site of drug action or slow receptor kinetics. Both of these characteristics would produce an anticlockwise hysteresis, in which time moves anticlockwise in the change in the relationship between plasma concentration and observed effect with time. An alternative definition would be ‘failure of one of two related phenomena to keep pace with the other’, and would include any situation in which the value of one variable depends on whether the other variable is increasing or decreasing. This definition would take in clockwise hysteresis, which is seen in drug tolerance.
Most drugs have to move into the biophase (site of action) and then occupy receptors or bind with enzymes before they can exert their effect. When the plasma concentration declines, the effects are reversed, but there is a lag phase before the observed effects follow the changes in plasma concentration. This phenomenon is known as hysteresis, which may be defined as ‘the retardation or lagging of an effect behind the cause of the effect’. The two main reasons for the lag phase are limited access to the site of action or slow receptor kinetics. Limited access A few drugs reach the biophase very rapidly, and these equate with the highly lipid-soluble compounds which penetrate through cell membranes rapidly such as intravenous anaesthetic agents. These agents would be expected to show little hysteresis, although interindividual variation in the concentration–effect relationship for thiopental has been ascribed to differences in effect hysteresis. More recently, in children, the decrease in cerebral blood flow velocity during decreasing halothane concentrations was not superimposable on the increasing cerebral blood flow velocity during increasing halothane concentration. A similar finding for propofol has been demonstrated in sheep. Greater hysteresis (Figure 1) is seen with ionized compounds or poorly lipid-soluble compounds such as morphine. This is sometimes termed anticlockwise hysteresis as time runs in the anticlockwise direction. Even drugs whose site of action is outside the CNS can exhibit hysteresis. The slow onset of pancuronium has been ascribed to its slow movement of the ionized compound from the capillary to the junctional cleft. A recent study has demonstrated marked anticlockwise hysteresis with single rectal doses of the weak acid diclofenac, indicative of the effective biophase being within the CNS. The delay to peak analgesia was 300 minutes after administration, whereas the time to peak plasma concentration was 60 minutes. The authors highlighted the possible dangers of co-administration of patient-controlled morphine in which high morphine usage during the time of peak diclofenac plasma concentrations could lead to persistent high concentrations of the active metabolite morphine-6-glucuronide during the peak analgesic activity of the non-steroidal anti-inflammatory drug. This would predispose the patient to respiratory depression. It is important that the phenomenon of hysteresis should be incorporated into pharmacokinetic and pharmacodynamic modelling of intravenous infusion protocols, and the use of context-sensitive half-time is a step in the right direction. Contextsensitive half-times can be defined as the time required for the plasma concentration to decrease by 50% at the end of a specific
Keywords context-sensitive half-times; hysteresis; tolerance
Much of the theory regarding drug concentration–response relationships is derived from experiments using in vitro preparations bathed in physiological solutions in which known quantities of drugs can be added. In this system, the responses of the tissue can be directly related to the concentration in the bathing fluid and the characteristic sigmoid log concentration–response relationship can be obtained. In vivo, different conditions apply. It is usually feasible to measure only plasma concentrations of a drug rather than the drug’s concentration at its site of action. Thus, a direct relationship between plasma concentration and effect is obtainable only when the drug, such as heparin, exerts its effect within the plasma. In view of this, plasma concentrations of a drug are not necessarily a good indicator of drug response. There are a number of reasons for this.
Maximum responses If the drug is a full agonist it is capable of producing the maximum response that activation of that receptor can produce. Concentrations of drug above this maximum concentration will have no further effect.
Irreversible effects If the drug acts irreversibly then the response to its administration will outlast its plasma concentration. Examples of drugs of this type are aspirin, phenoxybenzamine and selegiline.
Barbara J Pleuvry, PhD, is Senior Lecturer in Anaesthesia and Pharmacology at the University of Manchester, UK.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:8
372
© 2008 Elsevier Ltd. All rights reserved.
Pharmacology
Anticlockwise hysteresis loop (i.e. lag effect)
Mechanisms of desensitization and tolerance Mechanism
Response
Conformational change in receptors Binding of agonist but no channel opening Uncoupling from second messenger system Loss of modulator binding site Loss of receptors Physiological adaptation Increased metabolism Plasma concentration Exhaustion of mediators
Concentration–response measurements are made at various times after a dose. The arrows show the direction of time
Example
Nicotinic receptors at the neuromuscular junction β-adrenoceptors and opioid receptors? Benzodiazepine site on GABAA receptor β-adrenoceptors (slow process) and many hormone receptors Acetazolamide Many anticonvulsants induce the enzymes responsible for their own metabolism Indirectly acting sympathomimetics, e.g. amphetamine
Table 1
Figure 1
period of infusion. Some drugs such as remifentanil have context-sensitive half-times which do not change with the duration of the infusion. Others, such as fentanyl, may increase their context-sensitive half-time by 10–12 times after prolonged infusion.
Slow receptor kinetics The best example of a drug that binds slowly to its receptors is buprenorphine, which may take minutes rather than seconds to reach equilibrium. Slower association of vecuronium with the presynaptic receptor governing acetylcholine release than with the postsynaptic receptor mediating muscle fibre contraction has been proposed as an explanation for the hysteresis in train-of-four fade seen between onset and offset of neuromuscular blockade. It is difficult to distinguish this type of hysteresis from the limited access hysteresis described above.
Clockwise hysteresis loop (i.e. tachyphylaxis and tolerance)
Response
Tolerance Tolerance describes the phenomenon in which the effect of a drug declines despite its continuing presence. On a short time-scale, such as a few minutes, this situation is sometimes called desensitization or tachyphylaxis, and on a longer time-scale, such as days or weeks, the term tolerance is preferred. An example is shown in Figure 2, in which, in contrast to Figure 1, the time rotates clockwise. Some authors call this clockwise hysteresis, but in order to do this it is necessary to use an alternative definition of hysteresis. A less physics-based definition would be ‘failure of one of two related phenomena to keep pace with the other’. This would include any situation in which the value of one variable depends on whether the other variable is increasing or decreasing. Tolerance or desensitization can occur as a result of several mechanisms, which are listed in Table 1. ◆
Plasma concentration Concentration–response measurements are made at various times after a dose. The arrows show the direction of time Figure 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:8
373
© 2008 Elsevier Ltd. All rights reserved.
Hysteresis in drug response
Complex responses Many drug responses are integrated physiological changes, such as a fall in blood pressure after a β-adrenoceptor antagonist such as propranolol. This response involves inhibition of renin release from the kidney, a fall in cardiac output, inhibition of norepinephrine release and a reduction in sympathetic output from the central nervous system (CNS). Although it could be expected that each individual component might be directly related to plasma concentration, there will be no direct relationship to the final integrated response.
Barbara J Pleuvry
Abstract
Hysteresis
Hysteresis may be defined as ‘the retardation or lagging of an effect behind the cause of the effect’. The two main reasons for the lag phase are limited access to the site of drug action or slow receptor kinetics. Both of these characteristics would produce an anticlockwise hysteresis, in which time moves anticlockwise in the change in the relationship between plasma concentration and observed effect with time. An alternative definition would be ‘failure of one of two related phenomena to keep pace with the other’, and would include any situation in which the value of one variable depends on whether the other variable is increasing or decreasing. This definition would take in clockwise hysteresis, which is seen in drug tolerance.
Most drugs have to move into the biophase (site of action) and then occupy receptors or bind with enzymes before they can exert their effect. When the plasma concentration declines, the effects are reversed, but there is a lag phase before the observed effects follow the changes in plasma concentration. This phenomenon is known as hysteresis, which may be defined as ‘the retardation or lagging of an effect behind the cause of the effect’. The two main reasons for the lag phase are limited access to the site of action or slow receptor kinetics. Limited access A few drugs reach the biophase very rapidly, and these equate with the highly lipid-soluble compounds which penetrate through cell membranes rapidly such as intravenous anaesthetic agents. These agents would be expected to show little hysteresis, although interindividual variation in the concentration–effect relationship for thiopental has been ascribed to differences in effect hysteresis. More recently, in children, the decrease in cerebral blood flow velocity during decreasing halothane concentrations was not superimposable on the increasing cerebral blood flow velocity during increasing halothane concentration. A similar finding for propofol has been demonstrated in sheep. Greater hysteresis (Figure 1) is seen with ionized compounds or poorly lipid-soluble compounds such as morphine. This is sometimes termed anticlockwise hysteresis as time runs in the anticlockwise direction. Even drugs whose site of action is outside the CNS can exhibit hysteresis. The slow onset of pancuronium has been ascribed to its slow movement of the ionized compound from the capillary to the junctional cleft. A recent study has demonstrated marked anticlockwise hysteresis with single rectal doses of the weak acid diclofenac, indicative of the effective biophase being within the CNS. The delay to peak analgesia was 300 minutes after administration, whereas the time to peak plasma concentration was 60 minutes. The authors highlighted the possible dangers of co-administration of patient-controlled morphine in which high morphine usage during the time of peak diclofenac plasma concentrations could lead to persistent high concentrations of the active metabolite morphine-6-glucuronide during the peak analgesic activity of the non-steroidal anti-inflammatory drug. This would predispose the patient to respiratory depression. It is important that the phenomenon of hysteresis should be incorporated into pharmacokinetic and pharmacodynamic modelling of intravenous infusion protocols, and the use of context-sensitive half-time is a step in the right direction. Contextsensitive half-times can be defined as the time required for the plasma concentration to decrease by 50% at the end of a specific
Keywords context-sensitive half-times; hysteresis; tolerance
Much of the theory regarding drug concentration–response relationships is derived from experiments using in vitro preparations bathed in physiological solutions in which known quantities of drugs can be added. In this system, the responses of the tissue can be directly related to the concentration in the bathing fluid and the characteristic sigmoid log concentration–response relationship can be obtained. In vivo, different conditions apply. It is usually feasible to measure only plasma concentrations of a drug rather than the drug’s concentration at its site of action. Thus, a direct relationship between plasma concentration and effect is obtainable only when the drug, such as heparin, exerts its effect within the plasma. In view of this, plasma concentrations of a drug are not necessarily a good indicator of drug response. There are a number of reasons for this.
Maximum responses If the drug is a full agonist it is capable of producing the maximum response that activation of that receptor can produce. Concentrations of drug above this maximum concentration will have no further effect.
Irreversible effects If the drug acts irreversibly then the response to its administration will outlast its plasma concentration. Examples of drugs of this type are aspirin, phenoxybenzamine and selegiline.
Barbara J Pleuvry, PhD, is Senior Lecturer in Anaesthesia and Pharmacology at the University of Manchester, UK.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:8
372
© 2008 Elsevier Ltd. All rights reserved.
Pharmacology
Anticlockwise hysteresis loop (i.e. lag effect)
Mechanisms of desensitization and tolerance Mechanism
Response
Conformational change in receptors Binding of agonist but no channel opening Uncoupling from second messenger system Loss of modulator binding site Loss of receptors Physiological adaptation Increased metabolism Plasma concentration Exhaustion of mediators
Concentration–response measurements are made at various times after a dose. The arrows show the direction of time
Example
Nicotinic receptors at the neuromuscular junction β-adrenoceptors and opioid receptors? Benzodiazepine site on GABAA receptor β-adrenoceptors (slow process) and many hormone receptors Acetazolamide Many anticonvulsants induce the enzymes responsible for their own metabolism Indirectly acting sympathomimetics, e.g. amphetamine
Table 1
Figure 1
period of infusion. Some drugs such as remifentanil have context-sensitive half-times which do not change with the duration of the infusion. Others, such as fentanyl, may increase their context-sensitive half-time by 10–12 times after prolonged infusion.
Slow receptor kinetics The best example of a drug that binds slowly to its receptors is buprenorphine, which may take minutes rather than seconds to reach equilibrium. Slower association of vecuronium with the presynaptic receptor governing acetylcholine release than with the postsynaptic receptor mediating muscle fibre contraction has been proposed as an explanation for the hysteresis in train-of-four fade seen between onset and offset of neuromuscular blockade. It is difficult to distinguish this type of hysteresis from the limited access hysteresis described above.
Clockwise hysteresis loop (i.e. tachyphylaxis and tolerance)
Response
Tolerance Tolerance describes the phenomenon in which the effect of a drug declines despite its continuing presence. On a short time-scale, such as a few minutes, this situation is sometimes called desensitization or tachyphylaxis, and on a longer time-scale, such as days or weeks, the term tolerance is preferred. An example is shown in Figure 2, in which, in contrast to Figure 1, the time rotates clockwise. Some authors call this clockwise hysteresis, but in order to do this it is necessary to use an alternative definition of hysteresis. A less physics-based definition would be ‘failure of one of two related phenomena to keep pace with the other’. This would include any situation in which the value of one variable depends on whether the other variable is increasing or decreasing. Tolerance or desensitization can occur as a result of several mechanisms, which are listed in Table 1. ◆
Plasma concentration Concentration–response measurements are made at various times after a dose. The arrows show the direction of time Figure 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:8
373
© 2008 Elsevier Ltd. All rights reserved.