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 yy,east, 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.
7 Periodic trends in polarizability, .
C NOF
Zeff = +4 Zeff = +5 Zeff = +6 Zeff = +7 F is like a marble.
Polarizability is larger with smaller Zeff Cl because the electrons are not held as Polarizability is tightly, so they are more easily greater because distortable. Zeff = +7 there is a weaker hold on the electrons because they are Features that increase polarizability: farther away from Br the same effective 1. smaller Zeff, favors C > N > O > F nuclear charge, so they are more easily 2. valence electrons farther from the Zeff = +7 distortable. nucleus when Zeff issimilar I > Br > Cl > F. I I is like a cotton ball.
Zeff = +7 8 Phase at room temperature The halogenmolecules are similar in shape and nonpolar. There is a smooth, increasing trend in 250 F2 = gas He = gas Cl = gas Ne = gas both melting and boiling points. This is suggestive 2 of some factor increasing the forces of attraction 200 Br = liquid Ar = gas 2 bp between molecles of the halogen family as they get I2 = solid Kr = gas larger. The smooth trend in melting point is not 150 I typical, because itcanvarysomuch with differences 2 in shapes. The even change in melting points is 100 mp observed here because the halogen molecules all have a similar, rigid shape. 50 X X Temp. o Br room temp 25 C (oC) 0 2 -50
Cl The Noble gas molecules are similar in shape and -100 2 nonpolar. There is a smooth, increasing trend in both melting and boiling points. This is suggestive -150 Kr of some factor increasing the forces of attraction Ar bp between molecles of the halogen family as they get mp larger. The smooth trend in melting point is not -200 typical, because it can vary so much with differences F2 Ne in shapes. The even change in melting points is -250 observed here because the halogen molecules all He have a similar, spherical shape. -273 absolute zero=0 K
9 Dispersion forces are cumulative, so when the contact surface area is larger, the interactions are stronger (because there are more of them). Higher molecular weight alkanes have more carbon atoms to interact than lower molecular weight alkanes (even though only similar weak dispersion forces are present in both).
Alkane boiling point Alkane boiling point From the examples above, you can see that even the weak methane, CH -162 tridecane, C H 235 dispersion forces of attraction become significant when a 4 13 28 large number of them are present. ethane, C2H6 -89 73 tetradecane, C14H30 254 propane, C3H8 -42 47 pentadecane, C15H32 271 butane, C4H10 0 42 hexadecane, C16H34 287 CH4 CH4 Larger molecules have morecontactsurface area pentane, C5H12 36 36 heptadecane, C17H36 302 hexane, C H 69 33 octadecane, C H 316 with neighbor molecules. 6 14 18 38 CH3CH2CH2CH2CH2CH3 Greater dispersion forces heptane, C7H16 98 29 nonadecane, C19H40 330 mean a higher boiling point. octane, C8H18 126 28 icosane, C20H42 343 CH3CH2CH2CH2CH2CH3 nonane, C9H20 151 25 henicosane, C21H44 356 decane, C10H22 174 23 doicosane, C22H46 369 CH3CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH3 undecane, C11H24 196 22 tricosane, C23H48 380 dodecane, C12H26 216 20 triacotane, C30H62 450 CH CH CH CH CH CH CH CH CH CH CH CH tetracotane, C40H82 563 3 2 2 2 2 2 2 2 2 2 2 3 350 Boiling Point o 300 Temp ( C) 250 200 150 100 bp of water 50 0 mp of water -50 -100 -150
C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 Straight chain alkanes 10 In alkane isomers (having the same number of atoms, CnH2n+2), more branching reduces contact with neighbor molecules and weakens the intermolecular forces of attraction. Linear alkanes have stronger forces of attraction than their branched isomers because they have a greater contact surface area with their neighbor molecules. Branches tend to push neighbor molecules away. The strength of these interactions falls off as the 6th power of distance. A structure twice as far away will only have 1/64 the attraction for its neighbor. CH H2 H2 H2 H H 3 6 H C C CH H C C C CH 2 2 1 reference 3 3 3 3 H3C C C CH3 = 1 o 1 distance bp = -42 C o H3C C CH3 bp = -0.5 C bp = -0.5oC H 6 bp =-12oC 1 = 1 2 64 More atoms increase the contact Less branching increases contact surface area with neighbor surface area with neighbor molecules (not isomers). molecules in these isomers.
150oC Stronger dispersion forces because of greater surface contact area in linear chain bp = +126 (higher bp). More efficient packing in lattice structure due to compact rigid shape bp = +106 100oC 100oC boiling point = closer contact mp = +101 (higher mp).
hot dog? Temp T = 75oC (oC) your finger? 50oC
25oC room temp water
0oC 0oC freezing point
-50oC mp = -57 11 Hybridization explains the shapes we observe in organic and biochemistry. 3 2 sp sp sp sp2 sp sp2 H H H H H H H C C CC H C C H Ca Cb Ca H H H H H H H allene ethane ethene trigonal planar carbon atoms tetrahedral carbon atoms trigonal planar carbon atoms ethyne linear carbon atoms at the ends and a linear carbon atom in the middle HCH bond angles 109o HCH bond angles 120o (116o) o o o HCC bond angles = 180o HCC bond angles 109 CCH bond angles 120 (122 ) o HCaH bond angles 120 o HCaCb bond angles 120 o CaCbCa bond angles = 180
Lone pairs can occupy a similar space to a bonded atom. (Zeff(C) = +4, Zeff(N) = +5, Zeff(O) = +6) H H H H C N H H H H CN H C N Ca Cb N H H hydrogen cyanide H methanamine methanimine ethenimine
H H H C O CO C O H O C O H H methanol methanal carbon monoxide carbon dioxide
12 Resonance occurs through parallel p orbitals and stabilizes positive charge, negative charge, free radicals and neutral conjugated pi systems. allylic carbocation enolate anion (2D and 3D structures) (2D and 3D structures) H H H H
H2C C CH CH H C C O 2 H2C C 2 2 H2C C O
H H H H H H H H CC CC CC CC H C H H C H H O H O H H
allylic free radical bezene resonance (2D and 3D structures) (2D and 3D structures) H H equivalent structures H2C C CH 2 H2C C CH2
H H H H H H H H CC CC C C C C H C H H C H H C C H H C C H H H CC CC 13 H H H H 2a. Dipole-dipole interactions (in between polarity) - Dipole moments are less than full charges and the bonds are very directional (not "omni"), so attractions for neighbor molecules are weaker than is found in ionic salts. However, polar molecules usually have stronger attractions than nonpolar molecules of similar size and shape. Boiling points are a better indication of the strength of attractions among neighbor molecules than melting points (when other factorsare similar). A higher boiling point indicates stronger attractions. Molecular dipole moments are indicators of charge imbalance due to a difference in electronegativity , bond length and molecular shape.
nonpolar polar more polar H H H H C C O O o resonance Tbp = 84 C C C C C H H H H H H H H = 0.0 D =2.3D versus o bp = -104oC bp = -20 C O o mp = -169oC mp = -92 C C H2O sol. = 2.9mg/L H2O sol. = 400g/L H H pKa = 44 pKa =NA
nonpolar H polar more polar H C N N C C resonance C C C H H H H = 0.0 D versus o = 2.98 D bp = -81oC Tbp = 107 C bp = +26oC N mp = -84oC mp =-13oC C H2O sol. = insoluble H H2O sol. = miscible pKa = 25 pKa = 9.2 14 What is the effect of "R" groups? Do they make the molecule more polar, less polar or no different? Electron donation or electron withdrawal through sigma bonds is called an inductive effect.
N nonpolar H polar more polar C N C N H3C C resonance C C H C H C 3 versus 3 H3C H = 0.78 D = 3.92 D C o o o bp = -23 C Tbp = 104 C bp = +81 C C mp = -102oC mp = -46oC H3C H2O sol. = insoluble H2O sol. = miscible
O polar O polar O polar O O O resonance resonance resonance C C C C C C H3C H H C H H C CH H H H H 3 3 3 H3C CH3 = 2.3 D = 2.68 D = 2.91 D o bp = -20 C bp = +20oC bp = +56oC o mp = -92 C mp = -123oC mp = -94oC H2O sol. = 400g/L H2O sol. = very sol. H2O sol. = very sol.
15 2b. Hydrogen bonds - Hydrogen bonds represent a very special dipole-dipole interaction. Molecules that have this feature have even stronger attractions for neighbor molecules than normal polar bonds would suggest. Solvents that have an O-H or an N-H bond are called "protic solvents" and can both donate and accept hydrogen bonds (because they also have lone pairs of electrons). They generally have higher boiling points than similar sized structures without any "polarized hydrogen atoms". We call such interactions "hydrogen bonds". A molecule that has such a polarized hydrogen is classified as a hydrogen bond donor. A molecule that has a partial negatively charged region that can associate with such a hydrogen is classified as a hydrogen bond acceptor.
H accepts Hydrogen bonding holds the molecules more tightly O hydrogen to one another. This can be seen in higher boiling H bond points among similar structures where hydrogen H donates O H bonding is possible versus not possible. Many examples hydrogen below show this property. bond H O donates H hydrogen H H Cl donates O bond accepts hydrogen accepts hydrogen hydrogen H bond donates H accepts bond bond hydrogen hydrogen O H O bond bond H O H3C H3C C CCH3 C C C H H O H O H3C CH3 three hydrogen bonds in G-C base pair H two hydrogen bonds in A-T base pair H N O H N N N H O N N H N N DNA N N N H N DNA N N N H O DNA guanine adenine H cytosine thymine O DNA Which base pair binds more tightly, GC, AT or are they about the same? 16 Provide an explanation for the different boiling points in each column. 4B 5B 6B 7B 8B o 100 H2O boiling points ( C) CH4 NH3 H2O HF He o bp = -164oC bp = -33oC bp = +100oC bp = +20oC bp = -269 C o 50 mp =- 182oC mp = -78oC mp = 0oC mp =-84oC mp = -272 C Temp HF = 0.0 D = 1.42 D = 1.80 D = 1.86 D = 0.0 D o ( C) H Te = 0.3 = 0.8 = 1.2 = 1.8 = NA 0 2 SbH3 PH NH H2Se SiH4 3 H2S HCl Ne 3 HI o o o o bp = -112oC bp = -88 C bp = -60 C bp = -85 C bp = -246 C -50 o H S AsH3 o mp = -132oC o mp = -114 C mp = -249oC 2 SnH4 mp =- 185 C mp = -82 C HCl HBr = 0.0 D = 1.0 D = 1.0 D = 0.0 D PH = 0.0 D -100 3 GeH4 = 0.0 = 0.4 = 1.0 = NA = 0.3 SiH AsH HBr Ar 4 GeH4 3 H2Se o o -150 bp = -88oC bp = -62oC bp = -41oC bp = -67 C bp = -185 C o CH Kr mp = -165oC mp =- 111oC mp = -66oC mp =-87oC mp = -189 C 4 Ar = 0.0 D = 0.0 D = ? D = 0.8 D = 0.0 D -200 = 0.2 = 0.0 = 0.4 = 0.8 = NA
SnH4 SbH3 H2Te HI Kr -250 Ne o o bp = -52oC bp = -17oC bp = -2oC bp = -35 C bp = -153 C He o o o mp = -51oC mp = -157oC mp =- 146 C mp = -88 C mp = -49 C -300 = 0.0 D = ? D = 0.4 D = 0.0 D = 0.0 D row row = 0.5 = NA row row = 0.2 = 0.2 = 0.1 2 3 4 5
Column shifted down one row.
17 Offer explanations for the following observations.
H 2 H2 C O C H H C CH H3C CH3 3 3 H3C O = 0.08 D = 1.30 D = 1.69 D o = 20oC o o bp = -42 C bp = -22 C = 100 C bp =+78oC o o mp = -188 C mp =-141C mp = -114oC H2O sol. = 0.004 mg/L H O sol. = 71g/L 2 H2O sol. = miscible
H2 H2 H C C O H C C CH H3C O CH3 3 3 3 C C H C C C C H H H2 H2 H2 H2 2 2 = ? D = 1.15 D = 1.66 D o o o bp = +36oC = -1 C bp =+35oC = 83 C bp = +118 C o mp = -130oC mp = -116oC mp = -90 C H2O sol. 0 mg/L H2O sol. = 69 g/L H2O sol. = 73 g/L
18 The types of interactions between molecules depends on functional groups and solvation. Organic functional groups are mostly similar to biochemical functional groups. O O O O O O C H R N C H C C C R C R O R O R R O R Cl H carboxylic acids anhydrides esters acid chlorides amides (1o, 2o, 3o)
O O H R C N H H R N C C R O R H R R R S H nitriles aldehydes ketones alcohols thiols amines (1o, 2o, 3o)
R O R R X R O N R S X = F, Cl, Br, I R O N R O thioethers halogen ethers sulfides compounds nitroso compounds nitro compounds
H H There is chemical logic N for all of these functional C C R C C H groups. You have to understand how they react R H to plan strategies in drug alkenes alkynes heteroaromatic design. aromatic 19 Biochem structures are more like names of your classmates. Every one has to be learned individually. (* = chiral center). Stereochemistry is critical part of each structure. HO HO HO HO OH * * O * O * O HO O * * * * HO OH HO O OH * * * * * * * * * hemi-acetal * * HO OH HO OH HO OH HO OH aldose 4 acetal 2 stereoisomers pyranose 10 5 2 stereoisomers and 2 stereoisomers OH HO multiple ways to attach hemi-ketal * OH HO ketal OH O OH * O HO OH * O * * * OH O OH * * * HO * * * HO O * * HO OH * OH ketonse furanose * HO OH 3 4 2 stereoisomers 2 stereoisomers HO glycosides H H H 29 stereoisomers and 3 3 3 H N 4 multiple ways to attach N 4 9 N 9 H2N N 4 9 N 2 N N 1 2 2 5 8 8 8 2 N 1 N 1 HN 1 N N N 4 N steriods 5 6 5 7 5 6 7 6 7 3 hormones purine NH imidazole proteins 2 adenine O guanine fatty acids glycerides NH O 2 O R H neurotransmitters 4 and on and on... 3 5 C O N HN N HN H2N S C
2 6 OH N O O O N 1 N N amino acids H H H (20 essential, pyrimidine cytosine thymine uracil there are 100s of others) 20 Famous Drugs Psychoactive drugs - chemical substances that affect the function of the central nervous system, altering perception, mood or consciousness: ethanol (depressant: wine beer, hard liquor, chough medicines, etc.), nicotine (stimulant: cigarettes, cigars, pipes, patches, drops, etc.) and caffeine (stimulant, estimated used by 90% of the population: coffee, tea, chocolate, etc.) are the most widely consumed psychoactive drugs used worldwide and are also considered recreational drugs since they are used for other than medicinal purposes O CH3 H H 2 H3C N C N N H3C OH CH3 ethanol O N N N caffeine nicotine CH3
21 Other recreational drugs: hallucinogens (LSD), opiates (morphine, heroin) and amphetamines (phenethylamine has been used to treat ADHD, narcolepsy and obesity, methamphetamines), also use can be spiritual or religious (mescaline from peyote used by indigenous peoples for about 6,000 years, cannabis (THC = tetrahydrocanabinol) used for spiritual purposes for about 4,000 years) Lysergic acid diethylamide morphine phenethylamines (LSD) (and heroine) mescaline HO (hugevariety) 2 R R O NH N O 2 H R3 N H RN O H O R H R4 R6 N N O CH3 CH3 5 HO R H Methylphenidate (ritalin) Epinephrine, also known as adrenalin O O HN OH H H HO N N tetrahydrocanabinol CH3 OH THC H CH3 HO
H H N CH3 methamphetamine (racemic, free base) O levomethamphetamine (weaker) and CH3 dextromethamphetamine (stronger)
22 Therapeutic Index = toxic dose (50% of subjects) / effective dose (50% of subjects), a safe drug has a high number and a dangerous drug has a low number. Or, some define it as the safe amount of drug in the blood.
Digoxin cardiac glycoside from foxglove plant: 0.8 to 2.0 ng/mL O O therapeutic amount = 2 x 10-9g / mL HO C H O 38 58 14 = 3 x 10-12 moles / mL Mol. Wt.: 738.86 = 8 x 10-5g / 40L H
O O H OH complicated O medicine HO O O O H
HO HO HO -5 23 17 molecules (8x10 g / 40L)(1 mol/800g)(10 molecules/mol) = 1x10 molecules 1x106 molecules cell = = 100,000,000,000 cells cell lithium citrate - used to treat bipolar depression O OH O Li lithium: 0.8 to 1.2 meq/L (toxic over 1.5 meq/L) C6H5O7Li3 Li -3 therapeutic amount = 1 x 10 meq Li / L Mol. Wt.: 201 O O = 0.33 x 10-3 mmoles salt / L O O = 0.2 g salt / 40L simple Li medicine older method
LD50 = lethal dose, 50% of subjects ED50 effective dose, 50% of subjects 23 Water distribution in people is estimated to be 48 ±6% for females and 58 ±8% water for males (averages). Water constitutes as much as 73% of the body weight of a newborn infant. Body water and salt is regulated by hormones (anti‐diuretic hormone = ADH = vasopressin), aldosterone and atrila natriuretic peptide.
Body water can be broken down into the following compartments:
Intracellular fluid (about 2/3 of body water). Per Guyton: in a body containing 40 liters of fluid, about 25 liters is intracellular, which amounts to 62.5% (5/8), close to the 2/3 rule of thumb
Extracellular fluid (1/3 of body water). Per Guyton: in a body containing 40 liters of fluid, about 15 liters is extracellular, which amounts to 37.5%, close to the 1/3 rule of thumb.
Plasma (1/5 of extracellular fluid). Per Guyton: of the 15 liters of extracellular fluid, plasma volume averages 3 liters. Interstitial fluid (4/5 of extracellular fluid), transcellu lar flu id (k(a.k.a. "hid"third space," normally idignored in callilculations ), iidinside organs, gastrointestinal, cerebrospinal, peritoneal and ocular fluids.
Estimates are for about 6 quarts of blood flow per minute, 83 gallons per hour and 2,000 gallons per day. Blood circulates through the body in about 1 minute. Video of blood flow: http://www.brainstuffshow.com/blog/how‐fast‐does‐blood‐flow‐ throughout‐the‐human‐body/ 24 Pain relivers = analgesia, relief from pain. (many possibilities, example here = Tylenol) Tylenol or paracetamol or acetaminophen or APAP - most commonly used medication for pain and fever
H The good: It is used to treat pain and fever and appears to act centrally in the brain, rather than peripherally in nerve endings. It is often sold in N combination with other drugs (cold medications and opioid pain medications for cancer or after surgery). Its mechanism of action is not well understood. It is thought to inhibit COX enzymes (cyclooxygenase O 1 (has isoleucine at position 523 in active site) and cyclooxygenase 2 HO (has smaller Val523 there), 65% homologous and very similar active sites), which prevents metabolism of arachidonic acid to 'unstable' Tylenol protaglandin H2, which is converted to pro-inflamatory compounds. It also may inhibit the uptake of anandamide, increasing concentrations of Toxic metabolite endogenous cannabinoids, modulating pain pathways and lowering body temperature. It may also block synthesis of nitric oxide. The half life inadults isabout 3 hours, but is longer in infants, so the dose gets progressively lower the younger the patient. H The bad: Use at high dosages can cause liver failure. It is the most N common cause of liver failure in the US and UK.Damage to the liver, or hepatotoxicity, results not from acetaminophen itself, but from one of its metabolites, N-acetyl-p-benzoquinoneimine (NAPQI). which O depletes the liver's natural antioxidant glutathione and directly O damages cells in the liver, leading to liver failure. N-acetyl-p-benzoquinoneimine (NAPQI)
25 We need this from our diet. 2 4 6 2 HO 4 6 O 1 3 5 HO 1 3 5 7 7
8 8 HO 1 3 5 O O 2 4 linoleic acid (LA) 9 enzyme enzyme 6 reactions 9 reactions 18:2n-6 -linolenic acid (LA) dihomo--linolenic acid (LA) 7 20:3n-6 10 18:3n-6 10 8 18 11 18 19 17 9 17 17 11 20 18 16 10 16 12 12 14 16 15 13 11 15 13 14 14 15 13 Our bodies 12 Linoleic acid is an essential, can do this as polyunsaturated fatty acid used in the part of our O enzyme biosynthesis of arachidonic acid (AA) fatty acid reactions and thus some prostaglandins, metabolism. O leukotrienes (LTA, LTB, LTC), and HO N 1 3 5 thromboxane (TXA). It is found in the H 2 4 6 HO 1 3 5 lipids of cell membranes. It is 2 4 6 7 enzyme abundant in many nuts, fatty seeds and reactions arachidonic acid (AA) 7 8 their derived vegetable oils. It 20:4n-6 8 comprises over half (by weight) of 19 17 9 20 18 19 17 9 poppy seed, safflower, sunflower, 16 10 20 18 16 10 corn, and soybean oils. It must be 15 13 11 consumed for proper health. A diet 14 12 15 13 11 only deficient in linoleate (the salt 14 12 form of the acid) causes skin scaling, anandamide - fatty acid neurotransmitter and found hair loss, and poor wound healing in 9 enzyme as the natural receptor for -THC compounds in O reactions rats cannabis (tetrahydrocannabinol in marijuana). R HO 1 3 5 8 2 4 6 oxygen R 9 R 9 O or 8 8 7 9 O O prostaglandin H2 9 P-450 O O 10 10 (blood clotting, immune response) 8 10 10 O O O R 11 12 12 20 12 R 11 R 11 18 16 14 11 19 17 15 13 12 prostaglandin H2 OH 26 https://en.wikipedia.org/wiki/Prostaglandin_H2 (prostaglandins are 20 carbon compounds that do many thing,gs, stop bleeding, part of immune response, cause inflammation, temperature control, etc.)
27 How does acetaminophen cause liver damage? We need to look at some related biomolecules. You are not responsible for these mechanisms.
FAD / FADH2 - Flavin adenine dinucleotide (oxidation - reduction) - used to deliver hydride to C=C or take hydride from CH-CH (fatty acid metabolism,etc.) simplified structures for FAD and FADH2 H B R R R R
FAD - flavin dinucleotide H B R C C R (a hydride acceptor) C C N H R R H H
Hydride transfer hydride transfer N reduces FAD to N from FADH2. N FADH2. reduces C=C, R H makes FAD R R N N R C C R C C B H H R B R R FADH2 - flavin dinucleotide (a hydride donor) O O FAD - flavin dinucleotide O P O P O N (a hydride acceptor) O NH2 O O N HO OH N HO N OH OH
N N O actual structure NH N 28 O Aldopentoses - 5 carbon aldehyde carbohydrates, naturally occuring carbohydrates tend to be D, 3 chiral centers leads to 8 possible stereoisomers (naturally occurring aminoacids tend to be L with "S" chirality) OH OH OH OH
* * * HO * O HO * * * * * * * O HO O HO * O OH OH OH OH OH OH OH OH D-arabinose D-lyxose D-ribose D-xylose O H O O H H O H S HO H S R R HO H H OH H OH R H OH S R S HO H H OH HO OH R R H OH R R H OH H OH H OH H C 2 H2C H C OH 2 H2C OH OH OH enantiomer enantiomer enantiomer enantiomer Ketopentoses - 5 carbon ketone carbohydrates, naturally occuring carbohydrates tend to be D, 2 chiral centers leads to 4 possible stereoisomers (naturally occurring aminoacids tend to be L with "S" chirality) OH OH NH2 * * * * * HO OH HO * OH 5-phosphate N N O OH O OH O D-ribulose D-xylulose O P O N N OH OH 5 adenosine O O 4 1 O O H H ribose R S H 3 2 H H OH HO H OH OH R R adenosine monophosphate (AMP) H OH H OH
H C 2 H2C OH OH enantiomer enantiomer 29 Keto / Enol tautomerization is a common transformation, happens twice in glycolysis.
H B
H B H H HO O OH OH HO O OH HO O
H H H
OH H OH OH OH OH O OH OH O H B B D-glucose endiol D-fructose
O O H B O
O P H B O P H P H O O O O O O O O O O
H H H H OH O O H B B D-glyceraldehyde-3-phosphate endiol dihydroxyacetonephosphate
30 NAD+ and NADP+ - nicotinamide adenine dinucleotide (hydride acceptor)
4 CONH2 NH2 5 3 Why is C N 4 N similar role in electrophilic? O O 6 = organic chem: 2 Jones, PCC, N 1 N H2C O P O P O CH2 N Swern oxidation O N OH R HO O O H H O simplified H H structure actual OH OH NADP+ has a structure phosphate here.
NADH and NADHP - nicotinamide adenine dinucleotide (hydride donor) H H4b H4a CONH2 NH2 H N similar role in N organic chem: Why is H4 = O O nucleophilic? NaBH4, LiAlH4 N H2C O P O P O CH2 N N O N OH HO O O H H R O H H OH OH NADPH has a phosphate here.
H B H B H B N N N Transfers 2e-s and 2H, possibly as hydride and a NADH NADH N proton or in free NAD+ N radical transfers. reverse H FAD N FAD (simplified) H R N FADH2 (simplified) oxidized R N H R N oxidized H H (simplified) reduced H
31 O H B fatty acid catabolism - most reactions in biochemistry are under enzyme control H FAD O H B B fatty acid chain N BH O O H R acyl-CoA O mixed anhydride enzyme O high energy thioester N O R O ester O O hydrolysis H O H O R P ENZ-1 O O S O O O O R R H R H H OP OP OPO B triglyceride - fatty acid BH S ENZ-1 N chains are often 16-18 ATP O O O B H carbons long
acyl CoA N (2 carbons shorter, B cycle repeats) -ketothioester -hydroxythioester H FADH2 O B ,-unsaturated thioester BH ENZ-2 H O S H O O ENZ-1 R O O H ENZ-1 S ENZ-1 S NAD+ R BH S R H R O H H H H H H N R BH O ENZ-1 B S H NADH S ENZ-2 B H H CoA S N R B H H All of this is "Co-A" O O O O
HS O P O P O N O N N O NH ENZ-1 S H H 2 CoA O O N S H OH Thiol esters form here. This is an acetyl CoA - involved acetyl group N in many biochemical actual N repeat O HO cycles in the body HS Co-A structure OH simplified Acetyl Co-A = structure S CoA
32 fatty acid structures saturated fatty acid chain (no C=C bonds)
O O 12 10 8 6 4 2 O 11 9 7 5 3 1 1 R HO 3 5 7 9 11 Lauric acid, C12 O 4 6 8 10 12 dodecanoic acid O O
O R HO 1 3 5 7 Myristic acid, C O 9 11 13 14 4 6 8 10 12 14 tetradecanoic acid O R triglyceride - triester of glycerol HO 1 3 5 7 9 11 13 15 Palmitic acid, C16 O 4 6 8 10 12 14 16 hexadecanoic acid O O R Stearic acid, C O HO 1 3 5 7 9 11 13 15 17 18 4 6 8 10 12 14 16 18 octadecanoic acid O O O = D = double bond R 9 5 3 1 7 2 8 6 4 cis-9-Octadecenoic acid O P CH3 1 3 HO 5 7 9 10 12 14 16 18 Oleic acid, 18:1 cis-9 4 6 8 11 13 15 17 O CH HO N 3 O CH3 9 7 6 4 2 8 5 3 1 diglyceride - phosphatidyl choline HO 1 3 5 7 9 10 17 Linoleic acid, 18:2n-6 12 13 15 4 6 8 11 14 16 18 18:2 cis,cis-9,12 2 4 6 O 9 10 HO 1 3 5 oleic acid (LA) 7 18:1n-9 7 8 11 12 8 HO 1 3 5 O 6 2 4 6 5 13 14 linoleic acid (LA) 9 18:2n-6 arachidonic acid (AA) 7 4 15 20:4n-6 3 16 10 8 O 19 17 2 18 9 1 What came first in life? 17 18 17 11 20 18 amino acids proteins, 16 10 16 12 HO nuclotide bases RNA DNA, 14 15 13 11 fats & lipids membranes, 15 13 14 12 carbohydrates structure, energy, ...or some combination of all of these 33 Example of cytochrom P-450 oxidative enzymes, common in the liver, protoporphyrin, the iron sits in the middle of a complicated heme molecule. There are over 21,000 distinct P-450 enzymes known.
N +3 N Fe simplified structure, N +3 N N binds to enzyme N through a sulfur Fe enzyme, cysteine +3 N N Fe
S All extraneous parts are left HO C Enz out to show only the iron 2 atom in an oxidized state. S CO2H H ready for oxidation reactions shown below Enz B (symbolic cytochrom P-450 enzymess)
The proteins are complicated and can hold iron‐heme complexes.
34 Steps shown below in cytochrome P-450 oxidations (and next slide) 1. Ferric iron ion abstracts an electron from flavin mononucleotide (FADH2), an enzyme co-factor, and is reduced from +3 to +2. 2. Iron gives up an electron to make a bond with oxygen. (+2 to +3). 3. Oxygen atom abstracts an electron from flavin mononucleotide (FADH FAD),anenzymeco-factor. 4. FAD gets reduced by NADH (hydride donor) and picks up a proton to reform FADH2 5. The basic oxygen anion picks up a proton (or two?) from an acidic enzyme site. 6. A weak O-O bond breaks homolytically or heterolytically, and releases water. 7. An electron is supplied from iron to stabilize the oxidized oxygen atom. +3 to +4, which is now ready to oxidize bio-molecules. 1e- 1 O O FADH O BH +3 2 O O Fe O FADH +2 2 +3 3 Fe Fe +3 Fe +H+ NAD+ NADH 5 4 FAD H O H 2 H BH heterolytic H O O O O reactive +3 8, 9, 10 O peroxide Fe (see next) +4 7 6 +3 Fe +3 Fe homolytic Fe Possible leakage of hydroxyl radicals (extremely dangerous Every step represents a protein target for a in the body), but also part of H medicine. Side effects occur when other body's immune defense in all O biochemical reactions are also affected. out warfare, collateral damage possible. 35 8. The free radical-like oxygen atom converts a C-H bond to an C-OH bond via free radical chemistry 9. The free radical-like oxygen atom converts a C=C bond to an epoxide via free radical chemistry 10. The free radical-like oxygen atom converts a N or S lone pair to an N-O or S-O bond. The iron is reduced back at Fe+3 to begin the process all over again.
8 sp3 C-H bonds alcohols
H C H O C O H C O
Fe +3 Fe Fe +4 +4 The free radical-like oxygen atom abstracts a hydrogen The carbon free radical abstracts hydroxyl (OH) from iron, atom from a C-H bond in the enzyme cavity, forming an making an C-OH bond where a C-H bond had been. The iron is O-H bond and a carbon free radical. reduced back at Fe+3 to begin the process all over again. R H 9 R B R R R OH R R O H R C R C C C R C CC C R R HO R O O O R R R Diols are much more alkenes or aromatics BH +3 water soluble, can be Fe +4 Fe +4 epoxides Fe eliminated from the body. The free radical-like oxygen atom adds to a C=C The carbon free radical abstracts the oxygen atom from the iron, making an bond (alkene or aromatic) in the enzyme cavity, epoxide ring. The iron is reduced back at Fe+3 to begin the process all over forming a O-C bond and a carbon free radical. again. Reactive epoxides can be opened up to diols (more water soluble).
10 S O R S R O R R N O sulfur O R/H +3 S substrate Fe R R sulfur R (1e-) substrate R Fe +4 Fe +4 sulfoxides, further oxidation is N-oxides, further oxidation is (nitrogen too) -2 -1 possible, all the way to sulfate, SO4 possible, all the way to nitrate, NO3
36 Toxicity of acetaminophen N-hydroxylation by cytochrome P-450 (too much acetaminophen uses up all the capacity of the enzyme to oxidize target molecules) H H H Fe +3 H O N O N O O H N O ( 20%) Fe +4 O Fe +4 HO HO acetaminophen O HO gluconidation sulfonation H conjugation conjugation ( 30%) ( 50%) H N Too much acetaminophen uses up the P-4450 oxidizing power B H N O of the liver. Other compounds H that need oxidation are not O O O oxidized and can build up to HO N O toxic levels. O S O O OH O HO H O makes these B O more water soluble OH Conjugation joins xenomolecules with biomolecules, usually helps to eliminate them from the body in the urine (kidneys) or feces (intestines). N Toxic metabolite (see next slide) Furanocoumarins are found in O citrus fruits and can cause O similar problems when taking N-acetyl-p-benzoquinoneimine (NAPQI) O O O certain medicines. Psoralen is a mutagen found in grapefruit, and is used for this purpose in molecular biology research. Psoralen intercalates into the DNA and, on exposure to ultraviolet (UVA) radiation and can form monoadducts and covalent interstrand cross-links (ICL) with thymines preferentially at 5'-TpA sites in the genome, inducing apoptosis (cell death). 37 glutathione (5mM in cells) Glutathione is an important reducing agent in body (can (about 12 billion / cell) HS provide electrons from sulfur). O H O Glutathione also protects HO C against toxicity by 2 N S N R H conjugating with OH metabolites, making them glutathione water soluble and H N O 2 glutamic acid H (tripeptide) excreting them. The (backwards) cysteine glycine bodies store of glutathione is used up glutathione conjugation with NAPQI reacting with NAPQI. H B H B S N R H N R S glutathione O O HO O Other important anti-oxidants found in the body: glutathione, vitamin C and vitamin E. All protect against free radical damage in the body. Food can be medicine too, and food can be toxic!
HO O O vitamin E (-tocopherol) electron rich anti-oxidant HO HO fat soluble (membranes) OH HO vitamin C (ascorbic acid) O electron rich anti-oxidant water soluble (blood and cytosol) 38 Possible membrane damage from free radicals and possible protection from vitamins E and C.
HO O The damage O OH saturated fatty acid chain saturated fatty acid chain
dangerous O O HO O uncontained O free radical O O diglycerides in cell membranes Free radicals reacting with unsaturated fatty acid pi bonds unsaturated cis fatty acid can possibly cross link fatty chains in cell membrane acid chains, making cell membranes more rigid and less functional over time, leading to cell death. HO O O OH saturated fatty acid chain saturated fatty acid chain
O O OH O O
O O
continued unsaturated cis fatty acid damage chains in cell membrane
39 hydroxyl free radical The protection HO resonance and inductive effects stabilize radical so it does not do damage O H O O H H
O O R resonance O R O R
vitamin E located HO HO H O in cell membranes hydroxide is quenches radicals H B neutralized by O vitamin C reduces body's buffer H O vitamin E back to system normal and ultimately HO O O O washes out of the body H O R O O O H O H O H O O B resonance H O R H O R H O R B protects a O R second time O vitamin E is recharged O and still in cell membrane O oxidized vitamin C form washes out of the body
O R
40 = diglycerides, helps compartmentalize aqueous regions in the body, cell membranes, mitochondria, vacules, nucleus, etc. cell membrane (lipid bilayer) OH exocytosis - cell transports proteins to outside cholesterol - endocytosis - cell transports proteins to inside helps stabilize membrane proteins cell membrane and source of all other body steroids. OH endocellular protein HO Na+ mitochondria ion channels golgi apparatus
ribosomes HO nucleus G protein complex, 1/3 of all medicines act on G proteins. OH NH3 DNA O2C xocellular histones ribosomes protein endoplasmic chromosomes reticulum chromatin transscription RNA lysosome HO OH translation vacule proteins
+ +2 K carbohydrates Ca ion channels fats, lipids, other mitochondria ion channels biochemicals
cell membrane Biomolecules: proteins (aminoacids), carbohydrates (sugars), lipids (cholesterol) and fats (diglycerids, triglycerids), DNA and RNA, vitamins, co-factors, minerals, combinations of all of the above, etc.
41 Can be the key that turns on the enzyme engine. Can amplify 100s to 1000s of cycles. allosteric activator allosteric activator
allosteric binding at allosteric site enzyme allosteric site enzyme site active enzyme turns on enzyme active enzyme site catalyst site catalyst A
substrate allosteric substrate binds activator at catalytic site allosteric enzyme site A active enzyme reacts site again substrate catalyst reacts substrate
allosteric allosteric activator activator
allosteric product allosteric enzyme site releases enzyme site active active site enzyme B enzyme catalyst site catalyst product B
reaction 1 reaction 2 reaction 3 A enzyme a B enzyme b C enzyme c D (x 100) (x 100) (x 100) 1A 100 B 10,000 C 1,000,000 D possible amplification of signal
possible feedback inhibition
42 Problem - The terms "hydrophilic" and "hydrophobic" are frequently used to describe structures that mix well or poorly with water, respectively. Biological molecules are often classified in a similar vein as water soluble (hydrophilic) or fat soluble hydrophobic). The following list of well known biomolecules are often classified as fat soluble or water soluble. Examine each structure and place it in one of these two categories. Explain you reasoning. a b O
OH O P OH O O vitamin A OH
c O
N HO O d vitamin B6 (pyridoxine) HO H
HO OH
O
vitamin C OH (ascorbic acid) vitamin E (-tocopherol)
43 Problem - Bile salts are released from your gall bladder when hydrophobic fats are eaten to allow your body to solubilize the fats, so that they can be absorbed and transported in the aqueous blood. The major bile salt glycolate, shown below, is synthesized from cholesterol. Explain the features of glycolate that makes it a good compromise structure that can mix with both the fat and aqueous blood. Use the 'rough' 3D drawings below to help your reasoning, or better yet, build models to see the structures for yourself (though it's a lot of work).
OH O
H H H N synthesized in many, H H many steps in the body H H cholesterol O HO HO OH glycolate O 1. source for steroids and bile acids syntheses in the body H (bile salt) 2. important constituent of cell membranes 2. transported in blood to delivery sites via VLDL LDL HDL All polar groups are on the same face. Which side VLDL = very low density lipoprotein, has high cholesterol concentration faces water and which side faces fat molecules? LDL = low density lipoprotein, has medium cholesterol concentration (See structures below.) HDL = high density lipoprotein, has low cholestero contcentration
CO2 OH representation of cholesterol OH representation of bile acid (glycolate) as as a long flat shape a long bent shape havingtwo different faces, one polar and one nonpolar HO OH
H2O blood HO H2O Glycolate has a nonpolar, hydrophobic OH blood blood face that can cover the inside of a fat ball HO H O and a hydorphilic face that can point H2O OH 2 HO outward toward the aqueous blood, which OH allows fats to be transported throughout O2C CO2 the body to reach fat storage cells and blood nonpolar fats blood other essential locations. There is a whole and cholesterol family of bile acids that are produced from inside H O cholesterol. The body produces about 1 2 gram of cholesterol each day and about H2O O2C half of that is converted into bile acids that HO CO2 are released into the intestine to help H2O OH absorb fats. About 12-18 grams of bile HO blood acids are released each day and most of blood OH H O that is reabsorbed and recirculated (95%). HO 2 H O OH blood The rest is lost in the feces. The body's 2 store of bile acids is about 4-6 grams. 44 blood H2O = water molecule G = H - TS Water molecules rigidly order nonpolar themselves around a nonpolar molecule. This is an entropy expense (S is lower) and increase free energy, G (less favorable). nonpolar Weak dispersion forces. Water nonpolar molecules associate hydrophobic effect together, the water molecules are less structured, more disordered. nonpolar This is an entropy gain (S is higher)and free energy, Gismore nonpolar negative (favorable). Nonpolar molecules are said to be hydrophobic. The nonpolar compoundsfloator sink based on relative density. compound density dipole moment water 1.0 g/cm3 1.8 D octane 0.8 g/cm3 0 D carbon tetrachloride 1.6 g/cm3 0 D
45 Biopharmaceutics Classification System - classifies drugs according to their solubility and permeabilty or absorption properties. This system restricts the prediction using the parameters solubility and intestinal permeability. The solubility classification is based on a United States Pharmacopoeia (USP) aperture. The intestinal permeability classification is based on a comparison to the intravenous injection. All those factorsarehighly important because 85% of the most sold drugs in the United States and Europe are orally administered.
According to the Biopharmaceutics Classification System, drug substances are classified as follows:
Class I - high permeability, high solubility. Compounds that arewell absorbed and their absorption rate is usually higher than excretion. Example: metoprolol
Class II - high permeability, low solubility. The bioavailability of these products is limited by their solubility. A correlation between the in vivo bioavailability and the in vitro solubility can be found. Examples: glibenclamide, bicalutamide, ezetimibe, phenytoin
Class III - low permeability, high solubility. The absorption is limited by the permeation rate but the drug is solvated very fast. If the formulation does not change the permeability or gastro- intestinal duration time, then class I criteria can beapplied. Example: cimetidine
Class IV - low permeability, low solubility. These compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected. Example: hydrochlorothiazide, Bifonazole
46 Class I - high permeability, high solubility Metoprolol, (tradename Lopressor) is used to treat high OH blood pressure, various heart problems and migraine H headaches. It may be combined with the diuretic O N hydrochlorothiazide. Metoprolol was first made in 1969. It is available as a generic drug. In 2013, it was the 19th most prescribed medication in the United States. O Class II - high permeability, low solubility O O O S O O N N H H
N Glibenclamide is an antidiabetic drug in a H class of medications known as sulfonylureas, closely related to sulfonamide antibiotics. It was developed in 1966.
Cl Class III - low permeability, high solubility H N Cimetidine (Tagamet) is a histamine H2 receptor N antagonist that inhibitsstomach acid production. It is N mostly used in the treatment of heartburn and peptic N S C ulcers. It was discovered in 1971 and marketed in N N 1976. H H Class IV - low permeability, low solubility N
N Bifonazole is an imidazole antifungal drug. Bifonazole is marketed under the trade mark Canespor in ointment form.
47 Pharmacokinetics - what the body does to the drug (the fate of the drug in the body)
Pharmacodynamics - what the drug does to the body (mechanism of drug action on the target site)
A common descriptor describing the fates of drugs inside the body is ADME
Absorption - the process of a substance entering the blood circulation.
Distribution - the dispersion or dissemination of substances throughout the fluids and tissues of the body.
Metabolization (or biotransformation, or inactivation) – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into secondary metabolites.
Excretion - the removal of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue.
The two phases of metabolism and excretion can also be grouped together under the title elimination. The study of these distinct phases involves the use and manipulation of basic chemical concepts in order to understand the process dynamics. For this reason in order to comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act as excipients (substances added to stabilize the drug), the characteristics of the appropriate biological membranes and the way that substances can cross them, or thecharacteristics of the enzyme reactions that inactivate the drug.
Pharmacokinetics blood brain barrier? Pharmacodynamics drug mouth stomach intestines blood liver kidneys urine interaction target feces various interstitial lymphatic system tissues tissues 48 Naming systems Letters and numbers are used for drugs in early research (lead compounds). Letters are specific to the research company undertaking the research and numbers are for the specific compound being studied. Book examples of anti-HIV drugs. Ro31-8959 ABT-538 MK-639 (Roche) (Abbott) (Merck) early research saquinavir ritonavir indinavir names in testing
Fortovase Norvir Crixivan Trade names
Fortovase 200 mg of saquinavir in a gel-filled beige-colored capsule. different formulations Invirase 200 mg of saquinavir as the mesylate salt in a brown/green capsule Generic drugs are not allowed to use the trade name used by the originator of the drug.
49 saquinavir ritonavir N indinavir H2N O S OH H N N S N O O O HN HN O OH NH HN O N OH N H OH HN O N H N O N O H O H NH
Saquinavir is an antiretroviral drug used Ritonavir isanantiretroviral medication used Indinavir isaprotease inhibitor used together with other medications to treat along with other medications to treat as a component of highly active or prevent HIV/AIDS. Typically it is HIV/AIDS. The combination treatment is antiretroviral therapy to treat taken orally with ritonavir or known as highly active antiretroviral therapy HIV/AIDS. Unfortunately, indinavir lopinavir/ritonavir. It is in the protease (HAART). It is taken by mouth and used to wears off quickly after dosing, so inhibitor class and works by blocking inhibit the enzyme that metabolizes other requires very precise dosing every the HIV protease. Saquinavir was first protease inhibitors. leading to higher eight hourstothwartHIVfrom sold in 1995. As of 2015 it was not concentrations of those other medications. It forming drug-resistant mutations. available as a generic medication and first came into use in 1996 and costs between wholesale cost is about $4.50 per day $10 and $55 per day, depending on the dose ( $1500/year). ( $11,000/year).
50