Drugs Chemicals and Health Course Notes

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Introduction to Pharmacology II
Targets of Drug Action
March 5

How do drugs work? | Nearly all drugs act by interfering or inhibiting natural processes which are required for normal physiological function but which may have been disrupted by disease. | Paul Ehrlich 1845-1915  | Observed that certain chemicals or drugs bound in a selective manner to some but not all cells. He recognised that the cells must have chemical recognition sites for these drugs. The concept of a “receptor” was bornOver the last 100 years we have identified the recognition sites for many known drugs This information has been used to: -design new drugs -understand the biological impact of chemicals -Allowed better understanding of physiological function and disease | Regulatory proteins are the targets 1 Carriers/ transporters2 Enzymes 3 Ion channels 4 Receptors The exception: DNA | There are thousands of known targets and many more to be discovered. | Target 1 Carriers | The body has to move nutrients and waste products into and out of cells and organs This function is often carried out by specialised proteins which sit in cell membranesAlso known as a transporter protein The movement of ions and small organic molecules across cell membranes generally occurs either through channels (see above), or through the agency of a transport protein, because the permeating molecules are often too polar (i.e. insufficiently lipid soluble) to penetrate lipid membranes on their own Examples of particular pharmacological importance include those responsible for the transport of ions and many organic molecules across the renal tubule, the intestinal epithelium and the blood-brain barrier, the transport of Na+ and Ca2+ out of cells, and the uptake of neurotransmitter precursors (such as choline) or of neurotransmitters themselves (such as noradrenaline, 5-hydroxytryptamine [5-HT], glutamate and peptides) by nerve terminals, and the transport of drug molecules and their metabolites across cell membranes and epithelial barriers. |

Target 2 Enzymes | Enzymes: important in regulating protein concentrations and producing bioactive products  Drugs which inhibit enzymes are used in many situations  Drugs which promote enzyme activity are rare; eg MAO inhibitors Many drugs are targeted on enzymes.Often, the drug molecule is a substrate equivalent that acts as a competitive inhibitor of the enzyme (e.g. captopril, acting on angiotensin-converting enzyme)Drugs may also act as false substrates, where the drug molecule undergoes chemical transformation to form an abnormal product that subverts the normal metabolic pathway. An example is the anticancer drug fluorouracil, which replaces uracil as an intermediate in purine biosynthesis but cannot be converted into thymidylate, thus blocking DNA synthesis and preventing cell division. |

Target 3 Ion channels | Ion channels1 are essentially gateways in cell membranes, which selectively allow the passage of particular ions, and which are induced to open or close by a variety of mechanisms. Two important types are ligand-gated channels and voltage-gated channels. The former open only when one or more agonist molecules are bound, and are properly classified as receptors, since agonist binding is needed to activate them. Voltage-gated channels are gated by changes in the transmembrane potential rather than by agonist binding. | In general, drugs can affect ion channel function either by binding to the channel protein itself (to the ligand-binding site of ligand-gated channels, or to other parts of the channel molecule), or they may affect channel function by an indirect interaction, involving a G-protein and other intermediaries (see below). In the simplest case, exemplified by the action of local anaesthetics on the voltage-gated sodium channel, the drug molecule plugs the channel physically, blocking ion permeation. | Small ions are important in maintaining the function of many cells...
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