Introduction: pharmacology 3

In this section, you’ll see how we measure the potency of drugs and look at types of drug tolerance that exist. Drugs are often referred to as being potent or very potent, but how is this measured? For drugs that are agonists, that is, they activate a receptor to produce an effect. Drug potency is determined by measuring the EC50 of a drug for a particular effect. The EC50 is the concentration of a drug that produces 50% of the maximal response and reflects both the attraction between the drug and the receptor and the ability of the drug to activate response systems inside the cell.

If we graph the effect of a drug, that is an agonist, with the drug concentration, we get a curve, called a concentration response curve, as shown here. What this means is that eventually we reach concentrations of an agonist, so that if we add any more drug, we will not see any further increase in effect. We can measure the EC50 by looking at what concentration of drug A is 50% of the maximal response. In the case of drug A, it is three. The units are normally expressed in measurement of concentration, such as milligrams per litre or moles per litre. We can also compare different drugs in terms of their potency by comparing their EC50s.

So here is the concentration response curve for drug B. The EC50 for drug B is eight, so the most potent drug out of these two is drug A because the EC50 value, that is the concentration of drug required to produce 50% of the maximal response, is lowest, so drug B is the least potent drug because its EC50 is the largest. This means that we would need a greater concentration of drug B to produce a maximal response than that of drug A. We’ll see in a later week in the course the case of Ari Contos, who has chronic back pain. Ari takes morphine to relieve his back pain, and morphine is an agonist at receptors called opioid receptors.

The EC50 of morphine required to alleviate pain was established many years ago, and that information was used to determine the recommended dose of morphine used today for people like Ari. Thus, the dose given will result in the concentration of morphine rising above the EC50 for morphine. Taking a medicine continually can change the ability of a drug to work. Drug tolerance can be defined as the decreased effect of a drug as a consequence to repeated exposure to that drug. This means that with some medicines, when a person continually takes that medicine at the same dose, it can then lose its effectiveness. This occurs in two main ways. The first is called pharmacokinetic tolerance.

This describes what the body does to the drug. When pharmacokinetic tolerance occurs, the most likely reason for this is that the body, and normally it’s the liver, is breaking down the drug more quickly. Pharmacodynamic tolerance can be summarised as the effect of what the drug does to the body. Pharmacodynamic tolerance results in changes normally at the site of action of the drug, so that the drug then produces less of an effect. The liver is very important in breaking down compounds that originated both inside and outside the body. Over 75% of drugs are broken down in the liver by liver enzymes. Most of these enzymes belong to one family, called cytochrome P450 enzymes or CYPs.

If a drug is broken down by CYPs, continually taking that drug can result in an increased expression of CYPs in the liver. This means that the drug will be more efficiently broken down when taken again, thus less drug will reach its site of action. And the patient will have to take more of the drug to get the same blood concentration.

Some compounds, such as ones containing grapefruit juice, inhibits CYPs and, thus, reduce their ability to break drugs down. This is why grapefruit juice should not be taken with a class of drugs called statins, because statins are broken down by CYPs. We’ll look at a statin, called Atorvastatin, later in this course.

Pharmacodynamic tolerance involves changes normally at the site of action of a drug. For example, continually taking a drug can cause some of the receptors the drug binds to, to then travel from the cell membrane into the cell. This means there are less receptors for the drug to bind to if taken again or it may be that the receptors themselves are less sensitive to the effect of a drug.

As you’ll see later in this course, this is the case for nicotine, the active ingredient in tobacco and is the reason some of the effects of tobacco-smoking are not as strong in chronic smokers, such as the increasing heart rate that can occur, or it may involve the recruitment of processes that limit or oppose the effect of a drug. This may take the form of stopping processes that would normally occur in a cell following drug-binding to receptors. For example, later in the course you’ll see how morphine works to relieve pain, and one of the major problems with morphine is that if a person keeps taking morphine, tolerance occurs, whereby increasing doses of morphine are required to get the same pain relief.

The exact way in which tolerance to morphine occurs has been debated for many years, but several different mechanisms probably play a role. These include changes within cells, such as increased enzyme production, but other changes probably occur as well. So, in this section you have seen how we measure the potency of drugs to the agonists, the concept called drug tolerance, as well as the difference between pharmacodynamic and pharmacokinetic tolerance was also discussed.