When self-regulating physiological systems (generally controlled by negative feedback systems, e.g. endocrine, cardiovascular) are subject to interference, their control mechanisms respond to minimise the effects of the interference and to restore the previous steady state or rhythm: this is homeostasis. The previous state may be a normal function, e.g. ovulation (a rare example of a positive feedback mechanism), or an abnormal function, e.g.
high blood pressure. If the body successfully restores the previous steady state or rhythm then the subject has become tolerant to the drug, i.e. a higher dose is needed to produce the desired previous effect.
In the case of hormonal contraceptives, persistence of suppression of ovulation occurs and is desired, but persistence of other effects, e.g. on blood coagulation and metabolism, is not desired.
In the case of arterial hypertension, tolerance to a single drug commonly occurs, e.g. reduction of peripheral resistance by a vasodilator is compensated by an increase in blood volume that restores the blood pressure; this is why a diuretic is commonly used together with a vasodilator in therapy.
Feedback systems. The endocrine system serves fluctuating body needs. Glands are therefore capable either of increasing or decreasing their output by means of negative (usually) feedback systems. An administered hormone or hormone analogue activates the receptors of the feedback system so that high doses cause suppression of natural production of the hormone. On withdrawal of the administered hormone restoration of the normal control mechanism takes time; e.g. the hypothalamic/pituitary/ adrenal cortex system can take months to recover full sensitivity, and sudden withdrawal of adminstered corticosteroid can result in an acute deficiency state that may be life-endangering.
Regulation of receptors. The number (density) of receptors on cells (for hormones, autacoids or local hormones, and drugs), the number occupied (receptor occupancy) and the capacity of the receptor to respond (affinity, efficacy) can change in reponse to the concentration of the specific binding molecule or ligand,26 whether this be agonist or antagonist (blocker). The effects always tend to restore cell function to its normal or usual state. Prolonged high concentrations of agonist (whether administered as a drug or over-produced in the body by a tumour) cause a reduction in the number of receptors available for activation (down-regulation); changes in receptor occupancy and affinity and the prolonged occupation of receptors by inert molecules (antagonists) leads to an increase in the number of
26 24 Latin: ligare, to bind.
receptors (up-regulation). At least some of this may be achieved by receptors moving inside the cell and out again (internalisation and externalisation).
Down-regulation and the accompanying receptor changes may explain the tolerant or refractory state seen in severe asthmatics who no longer respond to P-adrenoceptor agonists.
Up-regulation. The occasional exacerbation of ischaemic cardiac disease on sudden withdrawal of a p-adrenoceptor blocker may be explained by up-regulation during its administration, so that on withdrawal, an above-normal number of receptors suddenly becomes accessible to the normal chemo-transmitter, i.e. noradrenaline (norepinephrine).
Up-regulation with rebound sympathomimetic effects may be innocuous to a moderately healthy cardiovascular system, but the increased oxygen demand of these effects can have serious consequences where ischaemic disease is present and increased oxygen need cannot be met (angina pectoris, arrhythmia, myocardial infarction). Unmasking of a disease process that has worsened during prolonged suppressive use of the drug, i.e. resurgence, may also contribute to such exacerbations.
The rebound phenomenon is plainly a potential hazard and the use of a P-adrenoceptor blocker in the presence of ischaemic heart disease would be safer if rebound could be eliminated, p-adrenoceptor blockers that are not pure antagonists but have some agonist (sympathomimetic ischaemic) activity, i.e. partial agonists, may prevent the generation of additional adrenoceptors (up-regulation). Indeed there is evidence that rebound is less or is absent with pindolol, a partial agonist P-adrenoceptor blocker.
Sometimes a distinction is made between rebound (recurrence at intensified degree of the symptoms for which the drug was given) and withdrawal syndrome (appearance of new additional symptoms). The distinction is quantitative and does not imply different mechanisms.
Rebound and withdrawal phenomena occur erratically. In general, they are more likely with drugs having a short half-life (abrupt drop in plasma concentration) and pure agonist or antagonist action. They are less likely to occur with drugs having a long half-life and (probably) with those having a mixed agonist/antagonist (partial agonist) action on receptors.
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