State-dependent drugs

State-dependent block describes the binding of a drug to a certain state of an ionic channel. Tims, the fast Na+ channel switches between a resting and open and inactivated states, the latter being the state to which antiarrhythmic drugs like lidocaine bind. 

Often the stability of a drug in the solid state depends on its physical state (i.e., crystalline or amorphous [8]). If freeze-drying produces an amorphous solid and the amorphous form is not stable, then freeze-drying will not provide an acceptable product. 

Most drugs are ionized in aqueous solution (Table 2.1), and can therefore exist in a neutral or a charged state, depending on the pH of the local environment. Molecules are more lipophilic when neutral than when charged. Ionization is expressed by the aqueous ionization constant, pKa. As pointed out below, log D is a p Independent term for ionizable drugs. Permeability and aqueous solubility are also pKa-dependent. Lipophilicity, pKa, permeability through artificial membranes and... 

Rosecrans JA, Chance WT (1978) The discriminative stimulus properties of n- and m-cholinergic receptor stimulants. In Ho BT, Richards DW III, Chute DL (eds) Drug discrimination and state dependent learning. Academic, New York, pp 119-130 Rosecrans JA, Schechter MD (1972) Brain area nicotine levels in male and female rats of two strains. Arch Int de Pharmacodynamic et de Therapie 196 46-54 Rosecrans JA, Kallman MJ, Glennon RA (1978) The nicotine cue an overview. In Colpaert EC, Rosecrans JA (eds) Stimulus properties of drugs ten years of progress. Elsevier-North Holland, Amsterdam, pp 69-81... 

A good clinical trial is designed to take account of the variability in response (either efficacy or adverse event) that is expected when a new active drug is tested. This response depends on an individual s genetic make-up, and on a number of environmental factors, such as disease state, other drugs and age. The size of the trial and the selection of study subjects are carefully determined to reduce the variability in response to a minimum (i.e. to maximise the sensitivity of the trial) so that the trial endpoints can be determined with as much certainty as possible. 

Jensen HH, Poulson JC Amnesic effects of diazepam drug dependence explained by state dependent learning. Scand J Psychol 23 107-111, 1982 Jensen HH, Hutchings B, Poulsen JC Conditioned emotional responding under diazepam a psychophysiological study of state-dependent learning. Psychopharmacology 98 392-397, 1989... 

Another area of interest are studies on so-called state-dependent learning and memory, i.e. the registration and retrieval of information occurring under the same or different drug treatment conditions. This constitutes a special ease of context-dependent learning and memory because it concerns the question of whether information acquired under the influence of a drug (case (1) above) can be retrieved better or worse when this same substance or placebo is administered before the retrieval phase (case (4)). 

One issue that attracted much interest some 30 years ago is state-dependent learning (SDL) and memory (p.68), which deals with the question of whether any material or behavior acquired under specific conditions (e.g. under the influence of a drug) will be accessible under different, e.g. drug-free, conditions (Weingartner, 1978). Several controlled studies on SDL, with conflicting results, were also performed in ADHD children (Spiegel 1996, p. 203) despite its potential importance, it appears that the topic has not been revisited in the last few years. 

Weingartner, H. Human state dependent learning. In Ho, B.T.. Richards, D.N., Chute, D.L. (eds) Drug Discrimination and State Dependent Learning. Academic Press, New York, 1978, pp. 361-382. 

It appeared that the experimental conditions used in the present study favoured the formation of microspheres of a new type which could be defined as film-type microspheres. They consisted of spherical micromatrices comprising an internal void space and a polymeric membrane of variable thickness where the drug is dispersed in either a molecular or a solid state depending on the payload. 

Clinically, these drugs have hypnotic and relaxant properties. The intoxication is characterized by impeded motor coordination, and the euphoria is not always obvious. To some extent, the attraction of use is more state dependent than in the case of opioids and central stimulants. Diazepam, for instance, is experienced as more rewarding in states of anxiety (negative reinforcement). It is also well known that expectancy factors have a significant role at low blood alcohol concentrations. The low-dose alcohol intake might be experienced as positive to a large extent by what one thinks will happen (Marlatt and Rohsenow 1980). 

LSD first became available for experimental use at about the same time that work on the mechanisms of REM sleep came under scientific scrutiny. Based upon casual reasoning, some predicted that because LSD produced psychotic states, the drug would increase REM sleep and dreaming. But just the opposite happened. Pre-sleep administration of LSD resulted in a dose dependent suppression of REM and a reciprocally marked increase in waking. This experimental insomnia matches the insomnia reported clinically. 

Tao, H. et al. 2006. Efficient characterization of use-dependent ion channel blockers by real-time monitoring of channel state. Assay Drug Dev. Technol. 4, 57-64. 

These findings open new perspectives for the understanding of the action of endogenous DA on state-dependent behavior, as well as of the effects of dopaminergic drugs on sleep and wake regulation, and other functions regulated by hypothalmic networks. 

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