This is generally accepted as the term to describe the absorption distribution and metabolism of a drug in vivo and it is these factors which determine how quickly and how much of the administered drug can actually reach its site of action (in the CNS) and be maintained there for the required time (see Fig. 5.4). Experimentally drugs are
Figure 5.4 Pharmacokinetics. The absorption distribution and fate of drugs in the body. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs. To cross the blood-brain barrier, however, drugs have to be in an unionised lipid-soluble (lipophilic) form. This is also essential for the absorption of drugs from the intestine and their reabsorption in the kidney tubule. See text for further details
Figure 5.4 Pharmacokinetics. The absorption distribution and fate of drugs in the body. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs. To cross the blood-brain barrier, however, drugs have to be in an unionised lipid-soluble (lipophilic) form. This is also essential for the absorption of drugs from the intestine and their reabsorption in the kidney tubule. See text for further details usually given intravenously or intraperitonealy, but therapeutically most of them are taken orally.
The speed of onset of action of a drug depends primarily on how quickly it reaches the circulation. For this reason alone it is not surprising that intravenous administration produces the quickest response. Thereafter the rate and degree of absorption depends on the blood flow to the injected site and the surface area of vessels exposed to the drug. The response to an intramuscular injection in humans is quite rapid since our muscles are large and have a good blood supply. In laboratory animals muscle mass is small and so an intraperitoneal administration may be more effective because the drug solution can be given in relatively large volumes which disperse over a large surface area (the abdominal wall and intestinal surfaces).
Drugs taken orally are slow to act. Most are absorbed in the small intestine where the villi, which penetrate into the lumen, present a large surface area. Unfortunately in order to pass through the gut wall into the bloodstream the drug has to become dissolved in its cell's membranes and to achieve this it needs to be lipid-soluble.
Generally it is only the non-dissociated or unionised drug that is lipid-soluble and a drug's degree of ionisation depends on its dissociation constant (pK) and the pH of the environment in which it finds itself. For an acidic drug this is represented by the Henderson-Hasselbalch equation as pK — pH = log conc unionised drug (Cu) (pK — pH = log — for basic drug)
Thus an acidic drug with a relatively low pK of 3 will be largely unionised (hundredfold) in the acidic environment (pH = 1) of the stomach since
but in the more basic intestine it will be ionised, i.e.
It will then depend for its absorption on the large surface area of the intestine.
Drugs absorbed along the length of the gut do not enter straight into the general circulation but pass initially into the portal circulation to the liver where they may be subject to metabolism. In fact a high proportion of some orally administered drugs can be lost in this way without even reaching the main bloodstream but those given sub-lingually (under the tongue) or by suppository into the rectum bypass the portal system. Some drugs can also stimulate the production of microsonal-metabolising enzymes (e.g. phenobarbitone) in the liver and so increase the destruction of other drugs being taken at the same time.
Once in the blood most drugs will leave the circulation by being filtered through pores in the capillaries, provided they have a molecular weight below 6000, which is almost always the case, and are not bound to plasma protein (albumin) which is too large to be filtered. Although such binding, which commonly accounts for over 90% of plasma drug, does restrict movement, it also acts as a drug store. Unfortunately one drug can displace another from such binding and so elevate its free plasma concentration and create the potential for toxicity.
There are two sites in the body where a drug is not able to pass freely into the tissue. One is the placenta and the other the brain where the blood-brain barrier (see Chapter 1) is a formidable hindrance. Without pores in the capillaries a drug can only enter the CNS (or cross the placenta) by virtue of lipid solubility, as in the gut.
Since a drug is a foreign object, the body does its best to get rid of it. As the organ of excretion, the kidney has a copious blood supply and drugs are easily filtered through the glomerular capillaries into the kidney tubule and urine unless they are very large (e.g. hormones, heparin) or bound to plasma albumin. In fact most drugs would be rapidly lost if they were not so bound or showed sufficient lipid solubility to be reabsorbed through the wall of the kidney tubule back into the bloodstream. Thus a drug which is present in the unionised lipid-soluble form is more readily absorbed from the gut, can enter the CNS and is potentially longer acting as it will avoid excretion, unless it is rapidly metabolised.
To increase the chance of removing a drug, the body converts it into a water-soluble, ionised and so excretable form. This is generally a two-stage process involving initial metabolism (e.g. oxidation, reduction or hydrolysis) and then conjugation with something like glucuronic acid. The metabolite may occasionally be as, or more, active than the parent compound but is generally less so and can sometimes even be toxic.
The rate at which a drug is metabolised is generally proportional to its concentration (so-called first-order kinetics) but if there is an excess of drug and the metabolic process becomes saturated, then metabolism proceeds at a constant rate, the maximum possible, irrespective of concentration (zero-order kinetics). With some drugs, such as alcohol, this occurs even at low concentrations. The duration of action of a drug is represented by its half-life (2t) which is a measure of the time taken for its plasma concentration to fall by 50%. Obviously drugs with a short half-life have to be taken more frequently. To use a drug properly it is necessary to know not only what constitutes an effective plasma concentration but also how long that is maintained following dosage. This information can be obtained from pilot studies in humans but since there is considerable variation in how an individual responds to and metabolises a drug the effect of a drug can vary considerably between subjects.
This leads to the concept of therapeutic index. The potency of a drug is almost irrelevant. It is its specificity that matters. Thus if two drugs A and B are effective at the same dose in a patient, say 1 mg, but A produces toxic effects at 10 mg which are only seen with 500 mg of B then B is clearly a much safer drug than A, in that patient. The ratio of toxic to effective dose is the therapeutic index (TI). It is often expressed as toxic dose in 50% of patients effective dose in 50% of patients
In practice it is obviously difficult to actually determine the toxic and effective dose in 50% of treated patients in the same population but the concept of a maximum tolerated dose compared with an effective dose is of great importance.
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