Chapter 1 - Drugs and drug targets: an overview Drug (Medicine) - a natural or artificial substance given to treat or prevent disease or to lessen pain, a substance other than food (?) that causes a physiological change inthe body, use can beshort term (acute problems) or regular (chronic problems) Drugs are classified in various ways. All drugs have some side effects and can possibly lead to addiction. Examples of various types of medicines 1 For the gastrointestinal tract (digestive system) 2 For the cardiovascular system 3 For the central nervous system 4 For pain and consciousness (analgesic drugs) 5 For musculo-skeletal disorders 6 For the eye Almost any chemical can 7 For the ear, nose and oropharynx affect a living organism. 8 For the respiratory system Any chemical that can 9 For endocrine problems affect the body is, in a 10 For the reproductive system or urinary system sense, a "lead" compound. 11 For contraception The more we know how a 12 For obstetrics and gynecology drug works (its mechanism 13 For the skin of interaction) the better 14 For infections and infestations we can direct its usefulness 15 For the immune system and control its side effects. 16 For allergic disorders 17 For nutrition 18 For neoplastic disorders (tumors, benign or malignant) 19 For diagnostics 20 For anesthesia 21 For euthanasia 1 Anatomical Therapeutic Chemical Classification System (ATC) - assigns ATC code = an alphanumeric code that assigns a drug to a specific class. Code = jargon, language of experts, not a common language of everyday people. First level The first level of the code indicates the anatomical main group and consists of one letter. There are 14 main groups: A Alimentary tract and metabolism O B Blood and blood forming organs C03CA01 C Cardiovascular system HO D Dermatologicals O G Genito-urinary system and sex hormones H Systemic hormonal preparations, excluding sex hormones and insulins HN S NH2 J Antiinfectives for systemic use L Antineoplastic and immunomodulating agents O M Musculo-skeletal system O Cl N Nervous system P Antiparasitic products, insecticides and repellents Furosemide (Lasix) used to treat fluid build- R Respiratory system up due to heart failure, liver scarring, or S Sensory organs kidney disease. It may also be used for the V Various treatment of high blood pressure. It has also been used to prevent and treat race horses for Example: C Cardiovascular system exercise-induced pulmonary hemorrhage. Second level The second level of the code indicates the therapeutic main group and consists of two digits. Example: C03 Diuretics Third level The third level of the code indicates the therapeutic/pharmacological subgroup and consistsofoneletter. Example: C03C High-ceiling diuretics Fourth level The fourth level of the code indicates the chemical/therapeutic/pharmacological subgroup and consists of one letter. Example: C03CA Sulfonamides Fifth level The fifth level of the code indicates the chemical substance and consists of two digits. Example: C03CA01 Furosemide 2 Drugs can be differentiated by: How they are administered ‐ consumed (liquid or solid by stomach or intestines), dissolved under tongue or in eyes, injected, inhaled, absorbed (patch, cream or ointment), insufflation (snorted), rectally (as a suppository), vaginally Sources –plants, whole or parts (herbs and spices from stems, leaves, flowers, roots) or extracted substances (about 70% of pharmaceutical drugs come from natural products), organic synthesis (vast topp),ic), synthesis by microorganisms (alcohol by y,yeast, penicillins, cephlosporins, cyphamycins, cyclosporins by fungi = yeast/molds, etc.), toxins (snakes, spiders, frogs, insects, puffer fish, algae red tides, etc.), genetically modified bacteria or yeast (to synthesize human insulin), animals (bovine or porcine insulin, Premarin as Hormone Replacement Therapy from horse urine, blood thinning drug called ATryn, is made in the milk of genetically altered goats). Often regulated into 3 categories: over the counter (OTC) available in supermarkets without any restrictions, behind the counter (BTC) can be dispensed by a pharmacist without doctor's prescription prescription only medicine (POM) prescribed by licensed pharmacist (a doctor) 3 Full shells (or subshells) Review Topics: Polarity and Shape control the chemistry. This is the goal. H Atomic attraction for electrons He (Where does polarity come from?) +1 +2 n = 1 valence electrons = bonding electrons (attracted by Zeffective) core electrons = full inner shells that shield Ztotal Ztotal = 1 Ztotal = 2 shielding = 0 Attractions are stronger across a row because the effective nuclear charge is larger. shielding = 0 Zeffective = 1 Zeffective = 2 radius = 52 pm radius = 31 pm Li Be B C N O F Ne n = 2 +3 +4 +5 +6 +7 +8 +9 +10 Z = 6 Z = 7 Z = 8 Z = 9 Z = 10 Ztotal = 3 Ztotal = 4 Ztotal = 5 total total total total total shielding = -2 shielding = -2 shielding = -2 shielding = -2 shielding = -2 shielding = -2 shielding = -2 shielding = -2 Z = 4 Z = 5 Z = 6 Z = 7 Z = 8 Zeffective = 1 Zeffective = 2 Zeffective = 3 effective effective effective effective effective radius = 167 pm radius = 112 pm radius = 87 pm radius = 67 pm radius = 56 pm radius = 48 pm radius = 42 pm radius = 38 pm Na Cl Ar Attractions are stronger up a n = 3 column because thevalence +11 electrons are closer to the same effective nuclear charge. +17 +18 Ztotal = 11 other radii other radii other radii Ztotal = 17 Ztotal =18 shielding = -10 K (243 pm) Br (94 pm) Kr (88 pm) shielding = -10 shielding = -10 Zeffective = 1 Cs (298 pm) I (115 pm) Xe (108 pm) Zeffective = 7 Zeffective = 8 radius = 190 pm radius = 79 pm radius = 71 pm 4 Full shells (or subshells) Review Topics: Polarity and Shape control the chemistry. This is the goal. H Atomic attraction for electrons He (Where does polaritycome from?) +1 +2 n = 1 valence electrons = bonding electrons (attracted by Zeffective) core electrons = full inner shells that shield Ztotal Ztotal = 1 Ztotal = 2 shielding = 0 Attractions are stronger across a row because the effective nuclear charge is larger. shielding = 0 Zeffective = 1 Zeffective = 2 radius = 52 pm radius = 31 pm Li Be B C N O F Ne n = 2 +3 +4 +5 +6 +7 +8 +9 +10 Z = 6 Z = 7 Z = 8 Z = 9 Z = 10 Ztotal = 3 Ztotal = 4 Ztotal = 5 total total total total total shielding = -2 shielding = -2 shielding = -2 shielding = -2 shielding = -2 shielding = -2 shielding = -2 shielding = -2 Z = 4 Z = 5 Z = 6 Z = 7 Z = 8 Zeffective = 1 Zeffective = 2 Zeffective = 3 effective effective effective effective effective radius = 167 pm radius = 112 pm radius = 87 pm radius = 67 pm radius = 56 pm radius = 48 pm radius = 42 pm radius = 38 pm Na Cl Ar Attractions are stronger up a n = 3 column because the valence +11 electrons arecloser to the same effective nuclear charge. +17 +18 Ztotal = 11 Ztotal = 17 Ztotal = 18 shielding = -10 shielding = -10 shielding = -10 Zeffective = 1 Zeffective =7 Zeffective = 8 radius = 190 pm radius = 79 pm radius = 71 pm other radii other radii other radii K (243 pm) Br (94 pm) Kr (88 pm) Cs (298 pm) I (115 pm) Xe (108 pm) 5 Electronegativity, (chi), is the property that indicates an atoms attraction for electrons in chemical bonds with other atoms. Approximate electronegativity values for some main group elements. (atoms in red have some biological significance) Group 1A Group 2A Group 3A Group 4A Group 5A Group 6A Group 7A Group 8A Z = +3 Zeff = +1 Zeff = +2 eff Zeff = +4 Zeff = +5 Zeff = +6 Zeff = +7 Zeff = +8 H = 2.2 V Cr Mn Fe He = none Li = 1.0 Be = 1.5 Co Ni Cu Zn B = 2.0 C = 2.5 N = 3.0 O = 3.5 F = 4.0 Ne = none Na = 0.9 Mg = 1.2 1.65-1.90 Al = 1.5 Si = 1.9 P = 2.2 S = 2.6 Cl = 3.2 Ar = none K = 0.8 Ca = 1.0 3d elements Ga = 1.6 Ge = 2.0 As = 2.2 Se = 2.5 Br = 3.0 Kr = 3.0 Rb = 0.8 Sr = 0.9 4d elements In = 1.8 Sn = 2.0 Sb = 2.0 Te = 2.1 I = 2.7 Xe = 2.6 Simplistic estimate of bond polarities using differences in electronegativity between two bonded atoms. A B bond polarity based on = A B 0.4 considered to be a pure covalent bond (non-polar) 0.4 < < (1.4 - 2.0) considered to beapolar covalent bond (permanent charge imbalance) (1.4 - 2.0) < considered to be an ionic bond (cations and anions) Br Mg Br H F = = H Mg Br Rules can be F ambiguous. = = 1.8 = = 1.8 o o TBP = 711 C TBP =20C (ionic salt) (molecular) o o CuI (TBP = 1290 C NH3 (TBP = -33 C 6 1. Dispersion forces / van der Waals interactions / London forces (nonpolar attractions) Dispersion forces are temporary fluctuations of negative electron clouds from one direction to another, relative to the less mobile and more massive positive nuclear charge. These fluctuations of electron density induce fleeting, weak dipole moments. Polarizability is the property that indicates how well this fluctuation of electron density can occur about an atom. In a nonpolar molecule the and are centered, on average. This would seem to indicate that in nonpolar molecules there is no polarity or attraction between molecules. Dispersion Forces So why do such substances liquify and and are not centered solidify? Why aren't they always gases? creating tempory polarity. Fast moving electrons shift position relative toslow - - moving nuclei, creating a + + temporary imbalance of charge, +Z +Z +Z +Z which induces a similar distortion of the electron clouds in neighbor structures +Z = nuclear protons Weak, fluctuating polar forces and a weak attraction for of attraction between molecules. = electron cloud neighbor molecules.