Medical brain Notes 3

  Drugs and drug target molecules   Drugs need to bind to target molecules. Is there anything remarkable about this statement at all? Well, two things:   1.    It is a surprisingly recent insight – only about 100 years old. (OK, so that is relative – long ago for you, but I'm nearly there.)   2.    It is not generally true.   The idea of defined receptor molecules for drugs or poisons was conceived by Paul Ehrlich (Figure 1.4). Ehrlich worked on a variety of microbes and microbial toxins. He observed  that many dyes used to stain specific structures in micro-bial cells in microscopic examinations also exerted toxic effects on the microbes. This observation inspired him to systematically try every new dye he could get hold of (and new dyes were a big thing in the late 19 th  century!) on his microbes. Although not trained as a chemist himself, he managed to synthesize the first effective antibacterial drug – an organic mercury compound dubbed `Salvarsan' that was clinically used

  Drug molecules may or may not have physiological counterparts   The vasoconstricting action of angiotensin can also be countered at the membrane receptor directly. One such inhibitor that has been around for quite a while is saralasin (Figure 1.6c).   Saralasin illustrates that the structure of the physiological mediator or substrate is a logical starting point for the syn-thesis of inhibitors. However, it is not a completely satisfac-tory drug, because it cannot be orally applied – can you see why? The more recently developed drug valsartan (Figure 1.6d) is orally applicable, but has very limited similarity to the physiological agonist.   Enalapril and valsartan represent the two practically most important functional groups of drugs, respectively – en-zyme inhibitors, and hormone or neurotransmitter receptor blockers. Another important group of drugs that act on hormone and neutotransmittor receptors are `mimetic' or agonistic drugs. However, there is no clinically useful ex-amp

  Synthetic drugs may exceed the corresponding physiological agonists in selectivity Angiotensin is an example of a peptide hormone. Peptide hormones and neurotransmitters are very numerous, and new ones are constantly being discovered, as are new loca-tions and receptors for known ones. While several drugs exist that act on peptide receptors (most notably, opioids), drug development generally lags behind the physiological characterization. The situation is quite different with an-other group of hormones / transmitters, which are small-er molecules, most of them related to amino acids. With many of these, the availability of drugs has enabled the characterization of different classes of receptors and their physiological roles. The classical example is the distinction of α - and  β -adrenergic receptors (which we will consider in more detail later on in this course). While both epinephrine and norepinephrine act on either receptor (though with somewhat different potency), the distinctio

  Metabolism of physiological mediators and of drugs So far, we have encountered two reasons for designing drug molecules that are structurally different from physiological mediators:   1.    Turning an agonist into an inhibitor, and   2.    Increasing receptor selectivity.   Both these reasons relate directly to the interaction of the drug molecule with its target. A third rationale for varying the structure of the drug molecule is that most physiological mediators are rapidly turned over in the organism, which is usually undesirable with drugs. E.g., angiotensin lives only for a few minutes (as does saralasin); the same applies to epinephrine and norepinephrine 2 . With these, one impor-tant pathway of inactivation consists in methylation (Figure 1.10).   The drug phenylephrine (Figure 1.10, right) lacks the cru-cial hydroxyl group that normally initiates inactivation of epinephrine and therefore persists for hours rather than minutes in the organism, making it more practically usefu

  Strategies of drug development   Drug development strategies may be classified as follows:   1.    Rational design   2.    Brute force   3.    Traditional medicine / natural products   4.    Mere chance.   Note that these distinctions are not really sharp in practice. E.g., the development of H 2 -receptor blockers described above would be a mixture of strategies 1 and 2. In reality, one will always try to rationally make use of as much infor-mation as possible and then play some kind of lottery to do the rest.   An example of the rational approach to drug design is pro-vided by the development of HIV (human immune defi-ciency virus) protease inhibitors. HIV protease cleaves vi-ral polyproteins – the initial products of translation – into the individual protein components and thus is essential for the maturation of virus particles. The crystal structure of HIV protease was used to design synthetic molecules that would snugly fit into the active site. Figure 1.11 shows the inhibitor s

  Pharmacokinetics   Whatever the actual mechanism of action of a drug may be, we will want to know: Does the drug actually reach its site of action, and for how long does it stay there? This is governed by three factors:   1.    Absorption: Uptake of the drug from the compartment of application into the blood   2.    Distribution: Transport / equilibration between the blood and the rest of the organism   3.    Elimination: Filtration and secretion in the kidneys; chemical modification in the liver   Broadly speaking, absorption and distribution determine the whether a drug will be available at its target site at all, while elimination determines for how long the drug effect will last. The issues of drug absorption, distribution and elimination are collectively referred to as `pharmacoki-netics'.

  Drug application and uptake   You are certainly aware that drugs are applied by various routes; the choice depends largely on the pharmacokinetic properties of the drug in question. Table 2.1 lists some characteristics of the major routes.   We will look at the various routes of application in turn. Oral uptake is the most common one, so let's start with this one.   Oral drug application   Inside the digestive tract, drug molecules encounter a quite aggressive chemical milieu. E.g., the acidic pH in the stom-ach (pH ~2) and the presence of proteases and nucleases in the gut preclude the application of proteins, nucleic acids, and other labile molecules. The gut mucous membrane presents a barrier to uptake; many drugs are not able to ef-ficiently cross it by way of diffusion.   For those drugs that make it from the gut lumen into the blood, the liver presents another formidable barrier. All blood drained from the intestines (as well as the spleen and the pancreas) is first passed