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  1. 1. Pharmacokinetics
  2. 2. Component Processes Absorption – entry of a drug from its site of administration to the systemic circulation Distribution – process by which a drug enters the interstitium or tissues from the blood Metabolism / Biotransformation – processes by which a drug is changed: to its active form or to its removable form Excretion – removal of the drug from the body
  3. 3. Drug ABSORPTION into Plasma DISTRIBUTION to Tissues Bound Drug Free Drug Tissue Storage Sites of Action Drug METABOLISM: Liver, Lung, etc Drug EXCRETION: Renal, Biliary, etc. Drug Biodisposition / Pharmacokinetics
  4. 4. Permeation  Permeation – travel of a drug across cellular membranes, influencing its biodisposition; is dependent on: Solubility Ionization Concentration gradient Surface area Tissue vascularity
  5. 5. Drug Permeation Solubility Lipid solubility – ability to pass through lipid bilayers Water solubility – in aqueous phases Partition coefficient – ratio of lipid to aqueous solubility : the higher the partition coeff, the more membrane soluble the drug Ionization The Henderson–Hasselbach equation – determines the percentage of ionization (ionized=water-soluble; nonionized=lipid-soluble) Drugs are either weak acids or weak bases, & can exist as charged or neutral particles in equilibrium, depending on pH & pKa Ionization increases renal clearance of drugs
  6. 6. Drug Permeation Concentration gradient – diffusion is down a concentration gradient; the greater the concentration gradient, the faster the diffusion/permeation Surface area – the available area for permeation; the greater the surface area, the faster the diffusion / permeation Tissue Vascularity – density of blood supply & speed of blood flow – the better/more the tissue vascularity, the better the permeation
  7. 7. Absorption Passive diffusion – most common Aqueous diffusion: Fick’s Law: Flux (J) = (C1 – C2) x S.A. x P. coefficient Thickness  J = molecules per unit time  C1= higher concentration  C2 = lower concentration  S.A. = surface area available for diffusion  P. Coefficient = permeability coefficient / partition coefficient  Thickness = length of the diffusion path
  8. 8. Absorption Lipid diffusion: the Henderson–Hasselbalch equation log (protonated / unprotonated) = pKa – pH *for acids: pKa = pH + log x concentration [HA] unionized concentration [A] *if [A] = [HA], then pKa = pH + log (1); log (1) = 0, so pKa = pH *for bases: pKa = pH + log x concentration [BH+] ionized concentration [B] *if [B] = [BH+], then pKa = pH + log (1); log (1) = 0, so pKa = pH
  9. 9. weak Acids & weak Bases  A weak acid is a neutral molecule that dissociates into an anion & a proton (H+) so that its protonated form is neutral, more lipid-soluble  A weak base is a neutral molecule that can form a cation by combining with a proton so its protonated form is charged, water-soluble weak acids pKa weak bases pKa Phenobarbital 7.1 Cocaine 8.5 Pentobarbital 8.1 Ephedrine 9.6 Acetaminophen 9.5 Chlordiazepoxide 4.6 Aspirin 3.5 Morphine 7.9
  10. 10. Diffusion Aqueous diffusion within large aqueous compartments across tight junctions across endothelium thru pores (MW20,000 - 30,000) molecules tend to move from an area of higher to an area of lower concentration plasma protein-bound drugs cannot permeate thru aqueous pores charged drugs will be influenced by electric fields Lipid diffusion higher partition coefficient = easier for a drug to enter lipid phase from aqueous charged drugs – difficulty in diffusing thru lipid uncharged – lipid-soluble lower pH relative to pKa, greater fraction of protonated drug (protonated form of an acid is neutral; protonated form of a base is charged) A weak acid at acid pH & a weak base at alkaline pH will be more lipid-soluble
  11. 11. Carrier – mediated Transport Facilitated diffusion – passive (no E expended) carrier-mediated transport. saturable; subject to competitive & non-competitive inhibition used by peptides, amino acids, glucose Active (uses E) carrier-mediated transport saturable subject to competitive & non-competitive inhibition against a concentration gradient  e.g. Na – K pump
  12. 12. Endocytosis & Exocytosis ENDOCYTOSIS  entry into cells by very large substances (uses E)  e.g. Iron & vit B12 complexed with their binding proteins into intestinal mucosal cells EXOCYTOSIS  expulsion of substances from the cells into the ECF (uses E)  e.g. Neurotransmitters at the synaptic junction
  13. 13. Ion Trapping Ion trapping or reabsorption – delays excretion Kidneys:  nearly all drugs are filtered at the glomerulus  most drugs in a lipid-soluble form will be reabsorbed by passive diffusion  to increase excretion: change urinary pH to favor the charged form of the drug (not readily absorbed) – weak acids are excreted faster in alkaline pH (anion form favored) – weak bases are excreted faster in acidic pH (cation form favored) Other sites: body fluids where pH differs from blood pH, favoring trapping or reabsorption  stomach contents ▪ aqueous humor  small intestines ▪ vaginal secretions  breast milk ▪ prostatic secretions
  14. 14. Distribution First pass effect – decreased bioavailability of drugs administered orally because of initial absorption into the portal circulation & distribution in the liver where they may undergo metabolism or excretion into bile Extraction Ratio – magnitude of the first pass effect. ER = cl Liver / q (hepatic blood flow) Systemic drug bioavailability – determined from extent of absorption & ER. F = f x (1 – ER)
  15. 15. Distribution Volume of Distribution – ratio between the amount of drug in the body (dose given) & the concentration of the drug in blood plasma. Vd = drug in body / drug in blood Factors influencing Vd: drug pKa (permeation) extent of drug-plasma protein binding lipid solubility (partition coefficient) patient age, gender, disease states, body composition
  16. 16. Drug – Plasma Protein Binding Most drugs are bound to some extent to plasma proteins Albumin, Lipoproteins, alpha 1 acid glycoprotein Extent of protein binding parallels drug lipid solubility Binding of drug to Albumin is often non- selective, Acidophilic drugs bind to Albumin, basophilic drugs bind to Globulins drugs with similar chemical/physical properties may compete for the same binding sites Volume of distribution is inversely proportional to protein binding
  17. 17. Distribution Non-ionized (hydrophobic) drugs cross biomembranes easily Binding to plasma proteins accelerates absorption into plasma but slows diffusion into tissues Unbound / free drug crosses biomembranes Competition between drugs may lead to displacement of a previously bound drug  higher levels of free/unbound drug  better distribution Distribution occurs more rapidly with high blood flow & high vessel permeability
  18. 18. Distribution Special barriers to distribution: placenta blood-brain barrier Many disease states alter distribution: Edematous states – cirrhosis, heart failure, nephrotic syndrome – prolong distribution & delay Clearance Obesity allows for greater accumulation of lipophilic agents within fat cells, increasing distribution & prolonging half-life Pregnancy increases intravascular volume, thus increasing distribution hypoAlbuminemia allows drugs that normally bind to it to have increased bioavailability Renal failure may decrease drug bound fraction (metabolite competes for protein binding sites) & thus ↑ free drug levels
  19. 19. Blood Brain Barrier (BBB): Only lipid-soluble compounds get through the BBB. Four components to the blood-brain barrier:  Tight Junctions in brain capillaries  Glial cell foot processes wrap around the capillaries  Low CSF protein concentration ------> no oncotic pressure for reabsorbing protein out of the plasma.  Endothelial cells in the brain contain enzymes that metabolize, neutralize, many drugs before they access the CSF. – MAO and COMT are found in brain endothelial cells. They metabolize Dopamine before it reaches the CSF, thus we must give L-DOPA in order to get dopamine to the CSF.
  20. 20. Exceptions to the BBB. Certain parts of the brain are not protected by the BBB:  Pituitary, Median Eminence  Supraventricular areas  Parts of hypothalamus Meningitis: It opens up the blood brain barrier due to edema. Thus Penicillin-G can be used to treat meningitis (caused by Neisseria meningitides), despite the fact that it doesn't normally cross the BBB. Penicillin-G is also actively pumped back out of the brain once it has crossed the BBB. Sites of Concentration: can affect the Vd Fat, Bone, any Tissue, Transcellular sites: drug concentrates in Fat / Bone / non-Plasma locations  lower concentration of drug in Plasma  higher Vd
  21. 21. Metabolism Biotransformation of drugs (usually in the Liver; also in the Lungs, Skin, Kidney, GIT)) to more polar, hydrophilic, biologically inactive molecules; required for elimination from the body.  Phase I reactions – alteration of the parent drug by exposing a functional group; active drug transformed by phase I reactions usually lose pharmacologic activity, while inactive prodrugs are converted to biologically active metabolites  Phase II reactions – parent drug undergoes conjugation reactions (to make them more soluble) that form covalent linkages with a functional group: glucuronic acid, acetyl coA, sulfate, glutathione, amino acids, acetate, S-adenosyl-methionine
  22. 22. Metabolism Phase I  reaction products may be directly excreted in urine or react with endogenous compounds to form water-soluble conjugates  mixed function oxidase system (cytochrome P450 enzyme complex: Cyt P450 enzyme, Cyt P450 reductase) requires NADPH (not ATP) as E source, & molecular O2; [drug metabolizing enzymes are located in hepatic microsomes: lipophilic, endoplasmic reticulum membranes (SER)]  Phase I enzymes perform multiple types of reactions:  OXIDATIVE REACTIONS  REDUCTIVE REACTIONS  HYDROLYTIC REACTIONS
  23. 23. CYTOCHROME-P450 COMPLEX:  There are multiple isotypes.  CYT-P450-2, CYT-P450-3A are responsible for the metabolism of most drugs.  CYT-P450-3A4 metabolizes many drugs in the GIT, decreasing the bioavailability of many orally absorbed drugs.  INDUCERS of CYT-P450 COMPLEX: Drugs that increase the production or ↓ degradation of Cyt-P450 enzymes.  Phenobarbital, Phenytoin, Carbamazepine induce CYT-P450-3A4  Phenobarbital, Phenytoin also induce CYT-P450-2B1  Polycyclic Aromatics (PAH): Induce CYT-P450-1A1  Glucocorticoids induce CYT-P450-3A4  Chronic Alcoholism, Isoniazid induce CYT-P450-2E1. important! this drug activates some carcinogens e.g. Nitrosamines. *Chronic alcoholics have up-regulated many of their CYT-P450 enzymes.
  24. 24.  INHIBITORS of CYT-P450 COMPLEX Inhibit production: Ethanol suppresses many of the CYT-P450 enzymes, explaining some of the drug-interactions of acute alcohol use. Non–competitive inhibition: Chloramphenicol is metabolized by Cyt P450 to an alkylating metabolite that inactivates Cyt P450 Competitive inhibition: Erythromycin inhibits CYT-P450-3A4. Terfenadine (Seldane) is metabolized by CYT-P450-3A4, so the toxic unmetabolized form builds up in the presence of Erythromycin. The unmetabolized form is toxic and causes lethal arrhythmias. This is why Seldane was taken off the market; Cimetidine, Ketoconazole – bind to the heme in Cyt P450, decreasing metabolism of Testosterone & other drugs Steroids: Ethinyl estradiol, Norethindrone; Spironolactone; Propylthiouracil (PTU): inactivate Cyt P450 by binding the heme
  25. 25. Metabolism Phase II  Drug Conjugation reactions: “detoxification” rxns: non- microsomal, primarily in the liver; also in plasma & GIT – usually to glucuronides, making the drug more soluble.  conjugates are highly polar, generally biologically inactive (exception: morphine glucuronide – more potent analgesic than the parent compound) & tend to be rapidly excreted in urine or bile  “Enterohepatic recirculation”: high molecular weight conjugates are more likely to be excreted in bile  intestines, where N flora cleave the conjugate bonds, releasing the parent compound into the systemic circulation delayed parent drug elimination & prolongation of drug effects  conjugation, hydrolysis, oxidation, reduction
  26. 26. Reaction Reactant transferase substrate Example Glucuron- idation Glucuronic acid Glucuronyl transferase Phenols, alcohols, carbolic acids, hydroxylamines, sulfonamides Morphine acetaminophen diazepam digitoxin meprobamate Acetylation Acetyl CoA N-Acetyl- transferase Amines Sulfonamides isoniazid clonazepam dapsone mescaline Glutathione conjugation Glutathione GSH- S- transferase Epoxides, nitro groups, hydroxylamines Ethacrynic acid bromobenzene
  27. 27. Reaction Reactant transferase substrate Example Sulfate conjugation Phospho- adenosyl phospho- sulfate Sulfo- transferase Phenols, alcohols, aromatic amines Estrone warfarin acetaminophen methyldopa methylation S-adenosyl methionine Trans- methylases Catecholamines phenols, amines Dopamine epinephrine histamine thiouracil, pyridine
  28. 28. Toxicity  drugs are metabolized to toxic products  hepatotoxicity exhibited by acyl glucuronidation of NSAIDS N-acetylation of Isoniazid Acetaminophen in high doses – glucuronidation & sulfation are usual conjugation reactions in therapeutic doses, but in high doses, these get saturated so Cyt P450 metabolizes the drug, forming hepatotoxic reactive electrophilic metabolites  fulminant hepatotoxicity & death (antidote: N-acetylcysteine)
  29. 29. Reduction in Bioavailability First pass effect Intestinal flora metabolize the drug Drug is unstable in gastric acid e.g. Penicillin Drug is metabolized by digestive enzymes e.g. Insulin Drug is metabolized by intestinal wall enzymes e.g. sympathomimetic drugs / catecholamines
  30. 30. Excretion Clearance – CL – removal of drug from the blood, or the amount of blood/plasma that is completely freed of drug per unit time over the plasma concentration of the drug CL = rate of elimination of drug plasma drug concentration especially important for ensuring appropriate long-term dosing, or maintaining correct steady state drug concentrations Renal clearance - unchanged drug, water-soluble metabolites – glomerular filtration, active tubular secretion, passive tubular reabsorption of lipid-soluble agents Hepatic clearance – extraction of drugs after GIT absorption
  31. 31. Excretion KIDNEY GLOMERULAR FILTRATION: Clearance of the apparent volume of distribution by passive filtration.  Drug with MW < 5000 ------> it is completely filtered.  Inulin is completely filtered, and its clearance can be measured to estimate Glomerular Filtration Rate (GFR). TUBULAR SECRETION: Active secretion.  Specific Compounds that are secreted: – para-Amino Hippurate (PAH) is completely secreted, so its clearance can be measured to estimate Renal Blood Flow (RBF). – Penicillin-G is excreted by active secretion. Probenecid can be given to block this secretion.
  32. 32. Excretion Half life (t ½) – time required to decrease the amount of drug in the body by 50% during elimination or during a constant infusion; useful in estimating time to steady-state: approximately 4 half-lives to reach 94% Estimation of time required for drug removal from the body Estimation of appropriate dosing interval: drug accumulation occurs when dosing interval is less than 4 half-lives Affected by Chronic renal failure – decreases clearance, prolongs half-life  increasing Age – Vd changes, prolongs half-life Decreased plasma protein binding shortens half-life
  33. 33. Half – Life The half-life is inversely proportional to the Kel, constant of elimination. The higher the elimination constant, the shorter the half-life.
  34. 34. Drug Elimination Zero order kinetics – rate of elimination of the drug is constant regardless of concentration i.e. constant amount of drug eliminated per unit time so that concentration decreases linearly with time examples: ethanol, phenytoin, aspirin First order kinetics – rate of elimination of the drug proportional to concentration i.e. constant fraction of the drug eliminated per unit time so that concentration decreases exponentially over time
  35. 35. that’s all for now. . .