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  1. Drug Absorption, Distribution, Metabolism, Elimination Chapter 3

  2. Physical/Chemical Properties of Drugs Ability to Approach Receptors

  3. Drug Mol’s  Receptors • Bloodstream (cardiovascular system) • Bulk flow transfer • Fast, long-distance • Chem nature of drug not impt • Short distances • Diffusion • Chem properties impt

  4. Chem Properties Impt to Diffusion • Aqueous diffusion delivers most drug mol’s • Rate of diffusion dependent on molec size • Diffusion coeff = 1/ qMW • BUT: Most drugs 200-1000 MW, so little difference • Ability to cross barriers • Cell membr’s mostly lipid • Drug hydrophobicity impt

  5. Absorption = Movement Across Cell Barriers • Cell membr’s separate aqueous compartments • Movement through cell involves traversing at least 2 lipid bilayers • Some tight junctions between cells • Ex: CNS, placenta, testes • Some freely permeable • Ex: Liver, spleen • Vascular endothelium differs in permeability

  6. Small Mol’s Cross Cell Membr’s • Diff’n  lipid • Diff’n  aqueous pores traversing lipid bilayer • BUT most pores too small to accomm most drugs • Transmembr carrier prot • Pinocytosis • Not impt for small mol’s

  7. Diffusion • Number mol’s crossing membr per unit area in unit time; depends on • Permeability coefficient (P) • Diffusivity • Diffusion coefficient • Doesn’t differ much between drugs • Solubility in membr • Partition coefficient (solubility oil/solubility water) • Most impt to pharmacokinetics • Used as predictor of drug properties

  8. barbital secobarbital thiopental

  9. pH and Ionization • Many drugs are weak acids/bases • Can be ionized, unionized • Varies w/ pH of environment • Acids release H+ • Strong: All H+ released • Weak: Some H+ released • Ka quantitates strength of acid

  10. Weak acid ionization (HA  H+ + A-) • Ka = [H+][A-]/[HA] • Negative log and rearrangement: • Log [H+] = log Ka + log [A-]/[HA] • pH = pKa + log [A-]/[HA] • Henderson/Hasselbach equation • pKa = pH when drug 50% dissoc’d • Weak base ionization (BH+  H+ + B) • Ka = [H+][B]/[BH+] • Negative log and rearrangement • pH = pKa + log [B]/[BH+]

  11. Rearrangement if known pH, pKa allows deter’n ionized/unionized ratio at any pH environment

  12. pH Differences between Body Compartments • Environmental pH effects ability to release H+ (ionization) • Ionized species have low lipid solubility • Most: uncharged can traverse cell membr’s • So each environment’s pH effects drug dist’n between them • Ion trapping •  Compartment equilibrium

  13. Ex: Stomach  Blood • Assume weak acid drug (HA) w/ pKa=6.0 • Assume [HA]=1.0 • Stomach pH=1.0 • 1.0-6.0=log [A-]/[HA] • 1.0x10-5=[A-] • Little ionized drug • Blood pH=7.0 • 10=[A-] • Much ionized drug • Expect stomach-to-plasma traverse BUT not plasma-to-stomach

  14. Book ex: more basic drug (how do we know?) Plasma  Digestive Tract

  15. Acidic drugs concent’d in high pH compartment • Site of highst dissoc’n H+ (ionization) • Can’t traverse membr to escape • Basic drugs concent’d in low pH environment • Largest D pH between compartments  largest D [drug] • BUT not total impermeability • AND not total equilib • Most impt to gi, renal

  16. Carrier Mediated Transport • Specialized for physiologically impt mol’s • Sugars, neurotransmitters, metals, etc • Transmembr prot • Binds mol(s) • Changes conform’n • Releases to other side of membr • Diff kinetics than simple diffusion • Can become saturated • Subject to competition between ligands

  17. Two types of carriers allow • Facilitated diff’n • Along concent gradient • Active transport • Against gradient • Cell uses chem energy • Carriers impt pharmacologically • Renal tubule • Biliary tract • Blood-brain barrier • GI tract • P-glycoprotein impt drug transporter • Renal tubular cells, bile canaliculi, brain microvessels

  18. Drug Administration

  19. Two Major Routes • Enteral • Via gastrointestinal tract (gi) • Oral • Sublingual • Buccal • Parenteral • Via injection • IV • IM • Subcu • Intrathecal

  20. Oral Administration • Convenient; includes most drugs • Little absorption until small intestine • Are most drugs weak acids or bases? • Abs’n from small intestine • Passive transfer dependent on • Ionization • Lipid solubility • Some carrier-mediated transport • Levodopa through carrier for phenylalanine • Fluorouracil through carrier for pyrimidines • Fe, Ca

  21. Rates abs’n after oral admin depend on • Gi motility • Some disorders  gastric stasis • Some drugs affect motility (incr or decr) • Meals • Splanchnic blood flow • Drug particle size/formulation • Capsules/coated tablets • Timed release formulations • Physicochemical factors • Tetracycline binds Ca  milk prevents abs’n • Drug interactions

  22. Bioavailability • Proportion of drug that passes into systemic circ’n after oral admin • Dependent on • Absorption • Local metab by small intestine enzymes • Indiv pts’ physiology impt • Activity intestinal metab enz’s • pH variations • Motility

  23. Differs w/ type dose (oral, IV) • Oral dosing  further metab • Book: First pass effect through liver • = AUCoral/AUCIV x doseIV/doseoral • AUC = Area Under Curve of drug plasma concent vs. time • “Bioequivalence” used to compare generic drugs to patented

  24. Other Types of Drug Admin • Sublingual • Impt when • Rapid response req’d • Drug unstable at gastric pH • Drug rapidly metab’d by liver • Pass straight into systemic circ’n • Don’t enter liver portal system (so no first-pass effect)

  25. Ex: glyceryl trinitrate relieves angina • Metab  NO release • NO act’s soluble guanylate cyclase (sim to ad cyclase) •  incr’d cGMP  act’n prot kinase G •  biochem cascade in smooth muscle •  dephosph’n myosin light chains, sequestering Ca •  vascular smooth muscle relaxation • Also relaxes cardiac muscle •  decr’d bp, so red’d preload, cardiac afterload • So decr’d cardiac O2 consumption • Also redist’n coronary blood flow toward ischemic cardiac areas

  26. Rectal • Abs’n unreliable • Often for local action • Useful in pts vomiting, unable to take by mouth (infants) • Cutaneous • Local effect on skin req’d • Abs’n occurs  systemic effects • Suitable for lipid-soluble mol’s • Ex: estrogen patch

  27. Nasal sprays • Abs’n through mucosa overlaying lymphoid tissue • Impt for drugs inact’d in gi • Ex: peptide hormone analogs, ADH, calcitonin • Inhalation • Large surface area and high blood flow • No gi inact’n • BUT also route of elim’n • Ex: volatile, gaseous anesthetics • Ex: locally acting drugs • Ex: inhaled human insulin being tested

  28. Admin by Injection • Subcutaneous, intramuscular • Faster than oral • Rate abs’n depends on site admin, local blood flow • Red’n or prolonging systemic action poss by altering drug mol or prep’n or giving w/ another agent • Intrathecal • Into subarachnoid space via lumbar puncture • Ex: regional anesthetics • Ex: cancer chemotherapeutics • Ex: antibiotics for NS infections

  29. Intravenous (IV) fastest, most certain • Bolus  high concent R heart, lung, systemic circ’n • Peak concent depends on rate injection • Common ex: antibiotics, anesthetics • Most uncomplicated to understand distribution, pharmacokinetics

  30. Distribution of Drugs in the Body Pharmacokinetics

  31. Experimental Finding • Rates drug abs’n, dist’n, elim’n gen’ly directly proportional to physio concent • First order kinetics • Rate varies w/ first power of concent dC(t)/dt = -kEC(t) where dC(t)/dt = rate change [drug] kE = elimination constant (neg sign due to decr [drug] w/ elim’n) • Note: rate elim’n may be zero order (independent of concentration) • Ex: ethanol

  32. Kinetics Meas’d w/ Single IV Dose • Single bolus over 5-30 sec • Periodic blood samples analyzed for [drug] • Time ~0 – highest concent • Dist’n drug in circulation  equilib • Complete by sev passes through heart (sev min) • Later time – concent decr’s due to • Dist’n  tissues • Dist’n  other body fluids • Metab  other cmpds • Excr’n unchanged drug (renal, biliary, lung)

  33. (Concent (y axis) reflects free drug + drug bound to plasma prot’s) • Conversion to log concent  more linear curve • Non-linear portion – dist’n phase (a phase) • Rapid decr plasma concent • Linear portion – elimination phase (b) • Grad decr plasma concent

  34. Eq’n line for elim’n phase: C(t) = C0e-kEt • Where C(t) = Concent drug @ time (t) C0 = Concent @ time 0 e = nat’l log base kE = rate const for phase (elim’n rate const) t = time • Y int = C0; slope = -kE/2.3 • Can be used to deter rate dist’n when a phase included

  35. With Oral Admin… • Plot differs in a phase • Initial: [plasma] = 0 • Swallowing, dissolution, abs’n take time • Rapid abs’n  rate b phase incr’s • First order: rate incr w/ incr’d [drug] • Peak concent at rate abs’n = rate elim’n

  36. Body Fluid Compartments: Sites of [Drug] • Total body water=50-70% total body wt • Intracell highest • Extracell: • Interstitial = between cells • Plasma = blood + lymph • Transcell = cerebrospinal, intraocular, synovial, etc. • Fat is also compartment • BUT poorly perfused

  37. Dug mol’s exist ionized/unionized, free/bound in each compartment • Dist’n pattern for each drug dependent on • Membrane permeability/transport • Binding w/in compartment • pH partitioning • Fat/water partitioning

  38. Specialized Compartment – Blood Brain Barrier • History: Ehrlich -- dyes injected IV stained most tissues; brain unstained • Contin layer endothelial cells w/ tight junctions • Non-brain – fenestrations • Specific transport for small organics • Safety buffer • Throughout brain, spinal cord • Except floor of hypothal, area postrema

  39. Inaccessible to many drugs unless high lipid solubility • BUT inflamm’n can disrupt integrity • AND some peptides increase bbb permeability • Intrathecal injection sometimes circumvents

  40. Volume of Distribution • Vol fluid req’d to contain drug in body at same concent as that present in plasma • May indicate drug binding to plasma prot or other tissue constituents • Vd = D/C0 • Where Vd = vol dist’n (L) D = dose w/ IV injection (mg) C0 = blood concent @ 0 time (mg/L)

  41. Most impt: free drug in interstitial fluid • Drug values vary greatly • Molecular wt • More impt: binding plasma prot’s

  42. Drug Binding to Plasma Proteins • Reflected in Vd • If high binding, drug “trapped” in plasma • High C0 on graph (Y reflects bound + unbound drug) • For Vd=D/C0, Vd very low (2-10L) • Ex: warfarin (anticoagulant) • If low binding, drug free to disperse  tissues • Low plasma concent (= low C0) • Vd high (40,000 L) • Ex: furosemide (diuretic)