McKenna's Pharmacology, 2e

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C H A P T E R 2  Drugs and the body

Drug–carrier molecules (ion transporters) interactions

or decreased cellular activity, changes in cell membrane permeability or alterations in cellular metabolism. Some drugs interact directly with receptor sites to cause the same activity that natural or endogenous chemicals would cause at that site. These drugs are called agonists (Figure 2.1A). For example, insulin reacts with specific insulin-receptor sites to change cell membrane permeability, thus promoting the movement of glucose into the cell. Therefore, agonists are drug molecules that bind to receptors (affinity ) and once bound activate receptors ( efficacy ). This ability to initiate a response after binding with the receptor is referred to as intrinsic activity. Some drugs bind with receptor sites to block normal stimulation, producing no effect. These drugs are called antagonists (Figure 2.1C) . Antagonists are drug mole­ cules that bind to receptors ( affinity ) without causing activation (efficacy ). For example, curare (a drug used on the tips of spears by inhabitants of the Amazon basin to paralyse prey and cause death) occupies receptor sites for acetylcholine, which is necessary for muscle contrac­ tion and movement. Curare prevents muscle stimulation, causing paralysis. Curare is said to be a competitive antagonist of acetylcholine (Figure 2.1B). Still other drugs react with specific receptor sites on a cell and, by reacting there, prevent the reaction of another chemical with a different receptor site on that cell. Such drugs are called non-competitive antagonists (Figure 2.1C). For some drugs, the actual mechanisms of action are unknown. Speculation exists, however, that many drugs use receptor-site mechanisms to bring about their effects. Other drugs act to prevent the breakdown of natural chemicals that are stimulating the receptor site. For example, monoamine oxidase (MAO) inhibitors block the breakdown of noradrenaline by the enzyme MAO. (Normally, MAO breaks down noradrenaline, removes it from the receptor site and recycles the components to form new noradrenaline.) The blocking action of MAO inhibitors allows noradrenaline to stay on the receptor site, stimulating the cell longer and leading to prolonged noradrenaline effects. Those effects can be therapeutic (e.g. relieving depression) or adverse (e.g. increasing heart rate and blood pressure). Selective serotonin reuptake inhibitors (SSRIs) work similarly to MAO inhibitors in that they also exert a blocking action. Specifically, they block removal of serotonin from receptor sites. This action leads to prolonged stimulation of certain brain cells, which is thought to provide relief from depression. Loss of receptor response Prolonged exposure of receptors to drug molecules can result in gradual decrease in the number of receptors. This is often referred to as desensitisation and tachy- phylaxis . There are several mechanisms that give rise

Some drugs are transported inside the cell through an ion transporter or an ion molecule. Ion or drug mole­ cules that are not ipid soluble enough to be transported across the biological cell membrane must be transported. Examples of transporters include those that transport glucose and move sodium and calcium ions out of cells. Other important transporters include those that are involved in the uptake of chemicals acting at nerve ter­ minals, such as noradrenaline, 5-hydroxytryptamine (5-HT, serotonin) and glutamate. Drug–ion channel interactions Ion channels are selective pores in the cell membrane that allow the movement of ions in and out of the cell. Some drugs will block these channels, which ultimately interferes with ion transport and causes an altered phys­ iological response. Drugs working in this way include nifedipine, verapamil and lignocaine. Drug–receptor interactions Receptors are target molecules with which a drug molecule has to combine to illicit a specific effect. The drug molecule combines with and affects the function of the protein molecule thus producing its effect. This is called receptor activation . However, occupation of a receptor by a drug molecule may or may not result in activation of the receptor. The tendency of a drug to bind to receptors is governed by affinity, whereas the tendency for a drug molecule, once bound, to activate the receptor is denoted by its efficacy . More importantly, in order to produce a therapeutic effect, a drug molecule must act selectively on particular cells and tissues. This means that individual drug molecules will only bind to certain targets and individual targets will only recog­ nise certain classes of drug molecules. Receptor sites Many drugs are thought to act at specific areas on cell membranes called receptor sites . The receptor sites react with certain endogenous chemicals ( transmitters and hormones) to cause an effect within the cell. In many situations, nearby enzymes break down the reacting chemicals and make the receptor site ready for further stimulation. To better understand this process, think of how a key works in a lock. The specific chemical (the key) approaches a cell membrane and finds a perfect fit (the lock) at a receptor site (Figure 2.1). The interaction between the chemical and the receptor site affects enzyme systems within the cell. The activated enzyme systems then produce certain effects, such as increased