Notes

  1. You may have heard of Lipinski’s “rule of five”, which stipulates a molecular weight of ≤500 Da, places limits on the number of polar atoms, and so forth, stating all of these constraints using numbers that are multiples of five. These additional aspects of drug molecular structure will be considered in Chapter 3. ↗
  2. Indeed, excess gastric acid was considered the cause of gastric ulcers, since the bacterial pathogen Helicobacter pylori had not yet been discovered. H. pylori damages the gastric mucous membrane and initiates ulceration, and antibacterial therapy is now key in the treatment of ulcers. However, since ulceration is promoted by gastric acid, its reduction remains important as well. ↗
  3. If you are intrigued by the tetrazole group in the losartan structure, you can find out more about it in slide 14.2.2. ↗
  4. The Deutschmark was not only fiscally but also artistically superior to the Euro. Maybe when the Euro finally collapses, we can get it back. ↗
  5. I suppose that something might happen in anaerobic cultures, with their reducing conditions. I have not looked into the literature on this question, however. ↗
  6. Stigler’s law of eponymy states that “no scientific discovery is named after its original discoverer.” Stigler himself names Robert Merton as the original discoverer of Stigler’s law. ↗
  7. While covalent and irreversible binding coincide with the great majority of drugs, there are exceptions; see for example slide 15.3.3. ↗
  8. In case you aren’t, just think of all the money you had no time to spend while deriving it. ↗
  9. This assumption neglects the turnover of the receptor by degradation and synthesis, which will typically be slow relative to the reaction and turnover of the drug. ↗
  10. If we define Kintr as the ratio of active fraction over inactive fraction, then an active fraction of 0.2 in the absence of ligand corresponds to Kintr = 0.2/0.8 = 0.25. ↗
  11. This is analogous to the oxygen binding kinetics of hemoglobin vs. myoglobin, which is commonly treated at length in introductory biochemistry classes. ↗
  12. These assumptions follow [8], with the addition of explicit two-state behavior for the receptor. ↗
  13. The acetylation reaction is straightforward and is carried out with acetyl chloride or acetic anhydride. Police routinely track shipments of these compounds in order to ferret out illicit heroin-producing labs. ↗
  14. The transport protein that takes l-DOPA across the blood brain barrier also transports tryptophan and phenylalanine and is referred to as the l-aromatic amino acid transporter. This same transporter is also involved in the pathogenesis of phenylketonuria (see slide 10.2.2). ↗
  15. The lobules are separated by thin septa of connective tissue, which are stained bright-red in this tissue sample. ↗
  16. These finest, uppermost bile duct branches are so thin that they can only be visualized using special histological stains or electron microscopy. ↗
  17. Amoxicillin is ampicillin with an aromatic hydroxyl group attached. Surprisingly, it has better oral availability than ampicillin. There may be a rational explanation for this, but I have not found it. ↗
  18. As noted above, albumin transports fatty acids. Ibuprofen looks a bit like a fatty acid, and it competes with a fatty acid (arachidonic acid) for binding to the active site of cyclooxygenase (see Chapter 9). ↗
  19. A somewhat old-fashioned method to accelerate the excretion of such compounds is osmotic diuresis, that is, the application of an osmolyte such as mannitol that is quantitatively filtrated and retained in the urine, and thus increases the urine volume due to its osmotic effect. ↗
  20. An even faster way to eliminate phenobarbital is the oral application of copious amounts of charcoal, also described in [16], which works by “reverse absorption” into the intestines. ↗
  21. Probenecid was developed to slow down the elimination of penicillin, which is eliminated in the same way as p-aminohippurate, though not quite at the same rate. ↗
  22. You may recall that nicotinamide cosubstrates (NAD and NADP) can only accept or donate electron pairwise, whereas flavin coenzymes (FAD and FMN) can accept or donate them both singly and in pairs. Flavins therefore can mediate between NAD or NADP and iron-containing hemes or iron-sulfur clusters that can only accept single electrons. In addition to cytochrome P450 reductase, we find this arrangement also in nitric oxide synthase and in the mitochondrial respiratory chain. ↗
  23. The ligand does not seem to be rifampicin itself but a similar compound, although it is referred to as rifampicin in the pdb file. ↗
  24. Interestingly, the major cytochrome P450 isoform responsible for acetaminophen oxidation is 2E1, which is induced by ethanol and acetone and also degrades both these inducers. ↗
  25. On the other hand, individual GPCRs may also couple to more than one G protein; compare slide 2.5.4. ↗
  26. One might wonder why a protease was not used to activate the receptor. The reason may be the inherent difficulty in selectively cleaving the receptor without also cleaving and activating plasma coagulation factors. The use of a peptide receptor agonist avoids this problem. ↗
  27. In much of the literature on GPCR oligomers, these are assumed to be dimers, but most studies do not contain experiments that would stringently distinguish between dimers and larger oligomers. When we talk about dimers below, we simply follow the authors of the cited studies, without examining whether or not they have proven a strictly dimeric subunit stoichiometry. ↗
  28. The authors of the study cited did not interpret their findings in terms of receptor oligomerization; however, oligomerization of muscarinic receptors has since been demonstrated [34]. ↗
  29. Dendron is the Greek word for tree. ↗
  30. Otherwise, heart transplants would be impossible, since the transplanted heart will be disconnected from those neuronal inputs. ↗
  31. The Nernst equation is really just an application of the Gibbs equation to electrochemical gradients—all you need to derive it is the Gibbs equation itself and the definition of the voltage: Δ E = Δ G/zF, with z as the number of charges per ion and F as Faraday’s constant. ↗
  32. This time is variable; both opening and inactivation are stochastic processes, with separate rate constants; the rate constant for opening is greater than that for inactivation. ↗
  33. This reactivation again takes a bit of time; therefore, the membrane will not be excitable for a short period immediately after repolarization. This time interval is the refractory period. ↗
  34. Note, however, that we do find different channel populations on different cell types, and this gives rise to action potentials that differ in shape and duration. On nerve and skeletal muscle cells, action potentials last only a few milliseconds; on heart muscle cells, half a second, and several seconds on smooth muscle cells. In skeletal muscle, a contraction is sustained by a repetitive burst of action potentials; in contrast, in the heart and in smooth muscle, each action potential is sustained for the entire duration of the contraction. ↗
  35. The lower parts of the excitation-conduction system can also spontaneously produce action potentials, but do so at a slower rate, and their internal timers get reset each time an action potential arrives from above. However, when the sinoatrial node fails, another center—usually the atrioventricular node—kicks in with its own, somewhat slower rhythm. ↗
  36. Note that this still works out to a flow rate of ~6×106 ions per second. Unlike glucose transporters etc., which undergo conformational changes with each molecule transported, ion channels just remain static as the ions zip through in rapid succession. ↗
  37. The “ir” stands for “inward rectifier”, meaning that these channels let K+ ions in more readily than out. However, the difference between the inward and the outward currents is not very large, and it is actually the outward permeability that is responsible for their main physiological function. ↗
  38. Mibefradil was withdrawn from the market due to strong inhibition of cytochrome P450 3A4 [44]. ↗
  39. Such low specificity occurs with channels that transport hydrated ions. The same is also observed with the nicotinic acetylcholine receptor and some other ligand-gated channels. ↗
  40. The rubidium isotope 86Rb is radioactive and thus is easily quantified. It is often used instead of K+ because none of the potassium radioisotopes have experimentally convenient half lives. ↗
  41. The mediators are endocannabinoids; we will discuss them in more detail later (see slide 9.7). ↗
  42. As an interesting aside, in neuromuscular synapses, a single presynaptic action potential is sufficient for triggering a postsynaptic action potential. This agrees with the fact that a skeletal muscle cell receives input only from a single nerve cell. ↗
  43. If we assume equal permeabilities for sodium and potassium, we would, according to slides 6.2.2 and 6.2.4, expect that the EPSP created by the NAR would top out at about −15 mV. This is still negative, so how can it trigger opening of the adjacent NaV channels? The answer is that full membrane depolarization is not required for those channels to respond, since their firing level is at −55 mV. ↗
  44. As you may know, tetanus is caused by tetanus toxin, a protein toxin produced by an anaerobic soil bacterium, Clostridium tetani. Tetanus occurs when wounds are infected with this bacterium. The toxin is a protease that cleaves synaptobrevin, a membrane-associated protein essential for transmitter exocytosis. Tetanus can be lethal because it interferes with the alternation of muscular contraction and relaxation required for breathing. Preventive immunization with tetanus toxoid, which is chemically or genetically inactivated tetanus toxin, protects against the disease. ↗
  45. This might be the last time I’m showing you the structure of cocaine—but no guarantees. ↗
  46. Aside from reserpine, verapamil and quinidine also inhibit ABC transporters. Intriguingly, the primary targets of all three drugs are transport proteins other than ABC transporters. ↗
  47. The decompression of the tiny canal of Schlemm, which drains surplus fluid from the eyeball, occurs as a side effect of the contraction of the ciliary muscle that modulates the shape and refractive power of the lens. Muscarinic receptors induce contraction of this muscle. ↗
  48. Muscle relaxants obviate the need for suppressing pain reflexes in the spinal cord. The dosage of inhalation narcotics can then be reduced to the lower amount required for suppressing consciousness in the brain. ↗
  49. An orally applicable ganglion blocker is mecamylamine (slide 3.4.7). ↗
  50. The cells in the anterior pituitary are specialized for the production of individual hormones; accordingly, since tumors originate from single cells, most hypophyseal tumors also secrete only individual hormones. On the other hand, damage to the pituitary usually causes lack of several or all hypophyseal hormones at once. ↗
  51. Birth should proceed within one day after the amniotic sac has burst; if it does not, oxytocin may be used. It is my impression that this is not too successful and quite often still ends with a Cesarean section—performing the latter right away may be the more sensible option. ↗
  52. From these biochemical effects, it is understandable that excessive thyroid hormone secretion will experience tachycardia, weight loss, and sweating. ↗
  53. Radioactive iodine isotopes, both 131I and 129I, are formed by uranium fission in nuclear reactors. In case of reactor disasters, people are supposed to swallow large amounts of non-radioactive iodide in order to saturate their thyroids and prevent accumulation of radioactive iodine. Thyroid cancer induced by 131I was the most common form of cancer observed after the Chernobyl reactor meltdown in 1986. ↗
  54. It also used to be popular among weight lifters and other competitive athletes, but it no longer is because it can readily be detected by blood tests. ↗
  55. Interestingly, this even seems to apply to males—see [59]. ↗
  56. The photochemical formation of cholecalciferol proceeds only in the skin. Photons absorbed by skin pigment are lost to cholecalciferol formation; this likely created the selective pressure for Homo sapiens to lose most of the skin pigment after leaving Africa for more Northern climates. Persons with dark skin who live in less sunny regions should be diligent about vitamin D supplementation. ↗
  57. This appears to be another example of agonist-specific coupling, this time by the vitamin D receptor; however, I have not been able to find detailed experimental studies on this point. ↗
  58. Bisphosphonates also have useful antimicrobial activity with some parasites such as Trypanosoma species; this effect seems to be caused by inhibition of the hexokinase enzymes of these parasites [60]. ↗
  59. Abatement of nitrate tolerance during the weekend was the basis of the Monday headache in those who worked in Mr. Nobel’s nitroglycerin manufacture. ↗
  60. Arachidonic acid is eicosatetraenoic acid; it is the most important precursor. Eicosapentaenoic acid, docosahexanoic acid and other ω-3 fatty acids contribute, but will not be considered here any further. ↗
  61. Inhibitors of thrombocyte aggregation or plasmatic blood coagulation are sometimes referred to as “blood thinners.” This metaphor is overly simplistic and misleading. As Einstein remarked, we should strive to make things as simple as possible, but not simpler. We here have a case of “too simple.” ↗
  62. In a combined immunodeficiency, both cellular immunity, which is mediated by T-killer cells and other effector lymphocytes, and humoral immunity, that is, formation of antibodies, are compromised. ↗
  63. Most solid tumors are treated first with conventional surgery, which removes most of the malignant cell mass. In contrast, lymphomas and leukemias are treated with cytotoxic drugs right away; large numbers of malignant cells are thus killed simultaneously, and the nucleic acids contained within them enter degradation all at once. ↗
  64. Abbreviations: NeuNAc, N-acetylneuraminic acid; Gal, galactose; GlcNAc, N-acetylglucosamine; Man, mannose; Fuc, l-Fucose. ↗
  65. Various sugar-binding proteins, or lectins, are found on macrophages. They serve to recognize polysaccharides on microbial cell surfaces, which then mediates phagocytosis and destruction of the microbes. ↗
  66. Literally translated: the “raging fireball” ↗
  67. Combination therapy is absolutely essential in the treatment of tuberculosis and leprosy. The hardy mycobacteria that cause these diseases succumb to antibiotics only slowly, and their prolonged survival increases their chances of acquiring mutations that confer resistance. ↗
  68. For an individual carrier plasmid or bacteriophage, the range of host species will often be quite narrow. However, transposons help resistance genes to move from one carrier molecule to the next, and thus to cross multiple species barriers successively. ↗
  69. The “toxic” effect of endotoxin results not from any intrinsic biochemical activity of the LPS molecule but instead from a violent response of the non-specific immune system to it. ↗
  70. The two types of pumps cooperate synergistically in extruding drugs from the cell—see [85] and references therein. ↗
  71. The outer membrane in Gram-negatives excludes crystal violet, and therefore prevents the bacteria from staining dark blue in the Gram stain procedure. In contrast, Gram-positives absorb and retain the dark-blue dye. ↗
  72. The thick cell wall enables the mycobacteria to persist inside host phagocytes, which further impedes access of drugs to bacterial targets. ↗
  73. KatG has both superoxide dismutase and catalase activity, that is, it catalyzes both of the reactions 2O2O2+H2O2 and 2H2O2H2O+O2. I have not found a precise equation for the KatG-mediated conversion of INH to the radical intermediate; the one given in the slide is not to be taken literally. ↗
  74. A crosslinked, stable cell wall is necessary to contain the high osmotic pressure of the bacterial cytoplasm. If crosslinking is inhibited with vancomycin or β-lactam antibiotics, the cells will suffer osmotic lysis at physiological extracellular salt concentrations. Osmotic lysis can be prevented by adding 600 mM sucrose to the medium. In this way, cell wall-less protoplasts (with Gram-positive bacteria) or spheroplasts (with Gram-negatives) can be generated. ↗
  75. Bacterial cells have no ER, and synthesis of membrane or secreted proteins occurs directly at the cytoplasmic membrane. ↗
  76. The antibiotic used in this experiment is not amphotericin B itself but the related polyene antibiotic pimaricin. ↗
  77. This ROS toxicity may account for the benefit of glucose-6-phosphate dehydrogenase deficiency in malaria—lacking regeneration of reduced glutathione prevents scavenging of ROS, which then inflict damage on the parasites. ↗
  78. The crystallization seems to be initiated by lipids in the parasite’s vacuolar membranes, but the exact role of the lipids is still a bit contentious [98,99]. ↗
  79. Radiation therapy is similar in its mode of action to DNA-modifying cytotoxic drugs. “Ionizing” radiation creates not only ions but also radicals, which are the actual cytotoxic agents that react with DNA to induce strand breaks and other kinds of modifications. ↗
  80. Some of them, of course, don’t stay. From first-hand experience, I would recommend securing tenure before too many of them are gone. ↗
  81. Chemical name: 2,5-bis-(5-hydroxymethyl-2-thienyl)-furan ↗
  82. The “G” in G1 and G2 denotes “gap”. While these phases are gap phases with respect to change in cellular DNA content, the cell is not idle in these stages. The G1 phase, in particular, can be very long and comprises the time during which a cell performs its specific physiological role. ↗
  83. RXR cooperates also with other nuclear hormone receptors besides RARA, such as thyroid hormone receptor (slide 7.3.1) and the pregnane X receptor (slide 4.3). ↗
  84. The translocation, and therefore PML-RARA, is somewhat molecularly heterogeneous, and not all variants respond to the treatment equally well. ↗
  85. Sounds complicated? It is actually simplified—see reference [109] for more detail. ↗
  86. The cells that one aims to destroy in immunosuppressive therapy are lymphocytes, which mediate the autoimmune reactions. The principle is similar as in anticancer treatment, in that the cells are driven into apoptosis through interference with DNA replication. ↗
  87. Some of the analogues used in antiviral treatment, such as dideoxyadenosine for example, were indeed originally conceived as anticancer drugs. ↗
  88. Cellular proteins get tagged for degradation by ligation to the small protein ubiquitin. The protein MDM2 (slide 12.2) is a ubiquitin ligase that tags p53 for proteosomal degradation. ↗
  89. Melphalan also contains a phenylalanine moiety, which makes it a substrate for amino acid transporters. Cyclophosphamide undergoes metabolic conversion to another N-mustard derivative plus acrolein (CH2=CHCHO), which is an alkylating agent in its own right. ↗
  90. Fatalities due to chloramphenicol bone marrow toxicity are actually no more frequent than fatal outcomes of penicillin allergy. Nevertheless, chloramphenicol is shunned, while penicillin is accepted. I suspect that this is because penicillin allergy kills instantaneously, and the unfortunate victim will therefore rapidly leave the scene. In contrast, bone marrow failure due to chloramphenicol is a slow and drawn-out affair that will cause much dismay and anxiety among a larger number of attendant personnel. ↗
  91. If you are wondering now how this can be done without suppressing the orderly termination of translation at the regular stop codon, we have no answer for you, but nevertheless commend you for paying attention. If you were not wondering about this, you were probably not really studying but just cramming for an exam. ↗
  92. Some viruses, such as rotaviruses, possess a double-stranded genome to begin with. However, most RNA viruses have single-stranded genomes; one wonders how much RNA interference may have done to favor the emergence of single-strandedness during evolution. ↗
  93. The physiological significance of this is that the most common cause of inflammation is infection, and many plasma proteins, such as antibodies and complement proteins, are involved in fighting infections. ↗
  94. Leuprolide acetate is a GnRH receptor agonist. However, GnRH receptor stimulation must occur in a pulsatile fashion in order to trigger release of LH and FSH from the pituitary. If present continuously, an agonist causes receptor desensitization and decreased LH and FSH secretion; this is the principle of long term leuprolide acetate application. ↗