Receptors sensitivity

Nutt DJ, Glue P, Lawson C, et al Flumazenil provocation of panic attacks evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry 47 917-923, 1990... 

Nucleotide changes or coupling to receptor increasing receptor sensitivity... 

Martin, JR., and Takemori, A.E. Chronically administered morphine increases dopamine receptor sensitivity in mice. Eur J Pharmacol 121 221-229, 1986. 

AOS responsiveness to hormonal influences is shown in the action of sodefrin on the lateral nasal sinus of newts (Cynops). The receptors in the accessory pocket are differentially affected by pituitary and ovarian hormones (Toyoda et al., 2000). The local EOG response to the pheromone (Fig. 5.1) was enhanced by the presence of prolactin or of estrogen alone. Receptor sensitivity increase is perhaps an alternate strategy to AOS receptor density increase several alternate routes of signal receptor adaptation (Fig. 7.1) have been hypothesised (Sorenson and Stacey, 1998). 

Tachycardia and increased contractility (due to SNS activation) Increase cardiac output Increased MV02 Shortened diastolic filling time P,-Receptor down-regulation, decreased receptor sensitivity Precipitation of ventricular arrhythmias Increased risk of myocardial cell death... 

Other potential adverse effects from P-blockers include fatigue, sleep disturbances, malaise, depression, and sexual dysfunction. Abrupt P-blocker withdrawal may increase the frequency and severity of angina, possibly because of increased receptor sensitivity to catecholamines after longterm P-blockade. If the decision is made to stop P-blocker therapy, the dose should be tapered over several days to weeks to avoid exacerbating angina. 

The neurotransmitter receptor hypothesis suggests that depression is related to abnormal functioning of neurotransmitter receptors. In this model, antidepressants presumably exert therapeutic effects by altering receptor sensitivity. In fact,... 

Thiazolidinediones are known to increase insulin sensitivity by stimulating peroxisome proliferator-activated receptor gamma (PPAR-y). Stimulation of PPAR-y results in a number of intracellular and extracellular changes, including an increased number of insulin receptors, increased insulin receptor sensitivity, decreased plasma fatty acid levels, and an increase in a host of intracellular signaling proteins that enhance glucose uptake. 

Decreases insulin receptor sensitivity. Insulin resistance... 

It has been generally assumed that therapeutic serum drug concentration ranges based on data obtained in adults were applicable to children. However, in many instances, when drug response is studied in children, differences in drug distribution and metabolism and in receptor sensitivity rendered this assumption invalid [39]. 

Age-related variations in central nervous system (CNS) neurotransmitter production and receptor sensitivity are the most likely explanations for the pharmacodynamic differences observed between children and adults following administration of psychotropic medications [39a], Children have lower phenobarbital ratios than adults, and the ratio increases with gestational age [40,41]. Conversely, a lower therapeutic range for children has been identified for cyclosporine, phenytoin, and digoxin [42]. 

Differences in receptor sensitivity have been offered to explain the spectrum of unexpected drug responses observed in children. Neonates and young children are at increased risk to experience paradoxical CNS stimulation following antihistamine administration. Symptoms observed in pediatric cases of acute overdose include hallucinations, excitation, and seizures. A physiological explanation for this reaction has not been identified. Antihistamines should not be included in over-the-counter (OTC) cough and cold products recommended for infants and young children. 

Farber J., Miller J. D., Crawford K. A., McMillen B. A. (1983). Dopamine metabolism and receptor sensitivity in rat brain after REM sleep deprivation. Pharmacol Biochem. Behav. 18(4), 509-13. 

Henry, D.J., White, F.J. Repeated cocaine administration causes persistent enhancement of D1 dopamine receptor sensitivity within the rat nucleus accumbens. J. Pharmacol. Exp. Ther. 258 882, 1991. 

Neonates and infants may metabolize drugs more slowly, and children may metabolize drugs more rapidly than adults. Lower doses of AEDs are often required in the elderly. Some elderly patients have increased receptor sensitivity to CNS drugs, making the accepted therapeutic range invalid. 

Postsynaptic changes in receptor sensitivity. Studies of many antidepressants have demonstrated that desensitization or downregulation of NE or 5-HT1A receptors may relate to onset of antidepressant effects. 

Semke E., Distel H. and Hudson, R. (1995) Specific enhancement of olfactory receptor sensitivity associated with foetal learning of food odours in the rabbit. Naturwissenschaften 82, 148-149. 

The importance of the changes in receptor sensitivity to our understanding of the chronic effects of psychotropic drugs is discussed on pp. 45-47. 

In SUMMARY, irrespective of the specificity of the antidepressants following their acute administration, it can be speculated that a common feature of all these drugs is to correct the abnormality in neurotransmitter receptor function. Such an effect of chronic antidepressant treatment may parallel the time of onset of the therapeutic response and contribute to the receptor sensitivity hypothesis of depression and the common mode of action of antidepressants. 

Liver disease may decrease hepatic metabolism resulting in enhanced responses to parent chemicals however, for many compounds, metabolism is only slightly impaired in moderate to severe liver disease. Disease-induced alterations in clearance and volume of distribution often act in opposite directions with respect to their effect on half-life. Bioavailability may be markedly increased in liver disease with portal/systemic anastomosis (the connection of normally separate parts so they intercommunicate) so that orally administered chemicals bypass hepatic first-pass metabolism. Altered receptor sensitivity has been observed for some chemical substances in liver cirrhosis. When liver tissue repair is inhibited by chemical co-exposure, even an inconsequential level of liver injury may lead to fulminating liver failure from a nonlethal exposure of hepatotoxic-ants. (Several articles, as reviewed by Dybing and Spderlund 1999.)... 

In turn, whether significant pharmacokinetic differences arising from the pol)nnorphisms translate into relevant alterations in pharmaco-d)mamics (and clinical efficacy) depends on the operating region of the concentration-response relationship, therapeutic index and utility, and whether kinetic variability is outweighed by variability in receptor sensitivity or number, or in the turnover of the natural receptor ligand. 

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