Kinetic parameters also contribute to the abuse liability of drugs. In many cases, differences in absorption, distribution, metabolism and excretion may explain different abuse liability profiles of cheap drugs within the same class. Rapid delivery of the drug into the brain, whether by rapid absorption or intravenous injection, will provide the optimal condition for reinforcing properties and drug re administration. Rapid and complete absorption is associated with a rapid onset of the effects (subjective and objective) of the drugs. Drugs with these characteristics seem to be preferred to the ones for which absorption rate is slow and the immediate subjective effects of the drug are therefore dimini shed. A recent study has conclusively shown that the rate of increase of plasma levels influences the subjective eftects of drugs of abuse in humans.
Drug distribution reflects physio logical factors and physio-chemical properties of the drugs. Drugs with high abuse potential typically have rapid access to their site of action in the brain. Entry to the brain is determined by bloodflow, lipid solubility, molecular size and the presence of active transport . Higher lipid solubility ofbenzodiazepines is associated with more rapid entry into the brain . Drug metabolism is also important. The presence of pharmacologically active metabolites may also play a role in abuse and dependence liability. Pro – drug s (such as halaz ep am, p raz ep am, fluraz ep am) are slowly converted to their active metabolite, N-desmethyldiaz-epam or N-desalkylflurazepam. Clinically this will be observed as a slower appearance of the effects compared with drugs in which the parent compound is also active, and rapidly converted to the metabolite (eg, diazepam). buy asthma inhalers
The elimination kinetics of some drugs are related to both their ability to pro duce physical depend ence and to the appearance of withdrawal. The longer the half-life, the greater the likelihood of physical dependence. The shorter the halflife, the earlier and more severe is the withdrawal syndrome. The balance of these conflicting factors has not been carefully quantified. Benzodiazepines with plasma half-lives of a few hours (eg, triazolam) will not sustain the high level required to produce sufficient physical dependence; therefore withdrawal cannot be observed. However, a short half-l ife drug can produce clinically important physical dependence if the dose is increased or the drug taken frequently. Benzodiazepines with long half-lives (or with active metabolites with long half-lives) (ie, flurazepam, diazepam) will produce physical dependence more easily, even at low doses, but their slower elimination will detay the appearance of the witht drawal symptoms and attenuate their severity . Intermediate half-tife benzodiazepines (8 to 20 h) are the most likely to produce physical dependence and a withdrawal syndrome. Although the relation ship be tween with drawal and self-administration is complex, available data support the view that low dose, persistent, nontherapeutic use ofbenzodiazepines in some individuals has a pharmacological basis and there is a causal relationship between the appearance of discontinuation symptoms and the use pattern . The present study was designed to determine whether differences in the abuse liability ofbenzodiazepines are reflected in epidemiological measures of drug abuse and whether benzodiazepine kinetics play a role in drug selection among drug abusers.