Drugs have half lives - the time over which the drug falls to half its initial concentration within the blood - which determine their efficacy in particular patients. In long release drugs the half life is much influenced by the half life of release; for example, intravenous insulin with a half life of ten minutes, versus insulin subcutaneously, with a half life of four hours.
When considering half life in therapy, it must be remembered that subsequent doses add onto the residue of previous doses, but the half life, by definition, remains the same - this is the nature of an exponential process. Thus, in multiple doses, there comes a point when amount of reduction of plasma levels of a drug between doses equals the amount by which it rises on the next dose, i.e. a steady state is reached.
Increasing the frequency of dosing means that a steady state is reached over the same time frame, but the variation in plasma concentration is damped. As a general rule the steady state takes four or five half lives to reach. Thus, paracetamol reaches a steady state in 40 hours, digoxin in 200 hours and lignocaine in 4 or 5 hours.
Loading doses are used when the time that would be taken to reach the steady state is longer than the physician is prepared to wait.
Thus, the use of slow release formulations - for example morphine continous in pain, will require days to reach proper steady state. Morphine elixir should be used first, illustrating a principle: use a quick release preparation first.
If something reduces the clearence rate, the half life is prolonged, which means that it will take longer to get to steady state, and steady state will be higher. Loading dose should remain the same.
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