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Transcript
Pharmacology-1 PHL 351 Abdelkader Ashour, Ph.D. Desensitization (Tachyphylaxis) and Tolerance The loss of a drug’s effect, when it is given continuously or repeatedly On a short time-scale, such as a few minutes, this situation is called desensitization or tachyphylaxis and on a longer time-scale, such as days or weeks, the term tolerance is preferred. Receptor-mediated responses to drugs and hormonal agonists often desensitize with time, when they are given continuously or repeatedly After reaching an initial high level, the response (eg, cellular cAMP accumulation, Na+ influx, contractility, etc) gradually diminishes over seconds or minutes, even in the continued presence of the agonist This is usually reversible; a second exposure to agonist, if provided a few minutes after termination of the first exposure, results in a response similar to the initial response Desensitization (Tachyphylaxis) and Tolerance, mechanisms 1. Change in receptors (Rapid desensitization): i. A slow conformational change in the receptor, resulting in tight binding of the agonist molecule without the opening of the ionic channel (e.g., ligand-gated ion channels such as nicotinic receptors at the neuromuscular junction) rapid and reversible ii. Phosphorylation of intracellular region of the receptor protein, leading to: Desensitization of ion channel, or Interference with the receptor’s (e.g., GPCR) ability to activate second messenger cascade, though it can still bind the agonist molecule slow and reversible Example: b-adrenoceptors Desensitization (Tachyphylaxis) and Tolerance, mechanisms 2. Loss of receptors (down-regulation) Prolonged exposure to agonists often results in a gradual decrease in the actual number of receptors expressed on the cell surface The vanishing receptors are taken into the cell by endocytosis of patches of the membrane, a process that also depends on phosphorylation It occurs more slowly than rapid desensitization and is less readily reversible. This is because down-regulation involves a net degradation of receptors present in the cell, requiring new receptor biosynthesis for recovery, in contrast to rapid desensitization which involves reversible phosphorylation of existing receptors Many G protein–coupled receptors and many hormone receptors are down-regulated by undergoing ligand-induced endocytosis and delivery to lysosomes Down-regulation generally occurs only after prolonged or repeated exposure of cells to agonist (over hours to days). Example: chronic salbutamol (b2 agonist) can cause internalisation of receptors → less receptors available for stimulation → decreased bronchodilation Desensitization (Tachyphylaxis) and Tolerance, mechanisms 3. Note: Brief periods of agonist exposure (several minutes) can also induce internalization of receptors. In this case, many receptors, including the b-adrenoceptor, do not down-regulate but instead recycle intact to the plasma membrane. This rapid cycling through endocytic vesicles promotes dephosphorylation of receptors, increasing the rate at which fully functional receptors are replenished in the plasma membrane. How about Chronic antagonist administration? Can this lead to UP REGULATION??? ……………………………..YES Example: chronic propranolol (b blocker) can cause increased synthesis of β1 receptors in the heart → less antagonism → decreased drug effect (increased heart rate and blood pressure) Desensitization (Tachyphylaxis) and Tolerance, mechanisms 3. Exhaustion of mediators: 4. depletion of a signaling molecule or an essential intermediate substance required for biological response Example 1: prolonged stimulation of G-protein coupled receptors can lead to depletion of intracellular secondary messengers Example 2: Indirectly acting sympathomimetics (e.g. amphetamine) act by releasing tissue stores of adrenaline and noradrenaline and other amines from the nerve terminal tachyphalaxis occurs because the amine stores become depleted Increased metabolic degradation increase in the rate of metabolism and/or elimination of drug lowers plasma drug concentrations Example: barbiturates and ethanol induce the expression of metabolic enzymes (cytochrome P450s) that degrade the drug low plasma drug concentration Desensitization (Tachyphylaxis) and Tolerance, mechanisms 5. Physiological adaptation A drug’s decreasing effects may occur because it is nullified by a homeostatic response. These homeostatic mechanisms are very common and if they occur slowly the result will be a very gradually developing tolerance. Example 1: the blood pressure-lowering effect of thiazide diuretics is limited because of a gradual activation of the renin-angiotensin system Example 2: It is a common experience that many side effects of drugs such as nausea and sleepiness tend to subside even though administration is continued WHY desensitization? many receptor-effector systems incorporate desensitization mechanisms for preventing excessive activation when agonist molecules continue to be present for long periods. Idiosyncrasy A structural or behavioral characteristic peculiar to an individual or group. Idiosyncratic drug reaction is a qualitatively abnormal, and usually harmful, drug effect that occurs in a small proportion of individuals chloramphenicol causes aplastic anemia in approximately 1 in 50,000 patients In many cases, genetic materials are responsible. Example, individuals with G6PD (an enzyme that maintains the content of GSH in red cells, and thus prevent hemolysis) deficiency cannot tolerate primaquine or some sulfonamide drugs (well tolerated in most individuals) Those individuals will suffer from hemolysis leading to severe anemia Primaquine and related substances reduce red cell GSH harmlessly in normal cells, but enough to cause hemolysis in G6PD-deficient cells