OzEMedicine - Wiki for Australian Emergency Medicine Doctors

see also:

• pharmacokinetics

• The distribution of a drug throughout the body is governed by the affinity it has for various constituents of the tissues:
  • involvement in enteric circulations (eg. enterohepatic shunt) which increase persistence in the body, preventing distribution elsewhere;
  • aqueous & lipid solubility (as for absorption);
  • binding to extracellular substances;
  • intracellular uptake;
• The rate of reaching equilibrium distributions b/n drug in the blood & in a tissue depends largely on the rate of blood flow through the tissue: (lung, brain, liver & kidney) > muscle > adipose;
  • eg. single bolus thiopentone time to reach plasma-tissue equilibrium is: brain - minutes; muscle 30 min.; fat 4-8 hours;

• The volume of fluid a drug would occupy if the total amount in the body were in solution at the same concentration as in plasma;
  • ie. Vd = total amount in body / plasma concentration
• Vd may correspond to a body compartment:
  • plasma protein bound drug: Vd = 0.06 L/kg body wt. = 3L ~ plasma vol.
    • eg. warfarin 99% - Vd = 10L; frusemide 99% - 8L; tolbutamide 96% - 7L;
  • ECF only: Vd = 0.2 L/kg = 14L
    • eg. mannitol, amoxil - Vd 15L; keflex/gentamicin/indomethacin - 18L;
    • may increase if abn. accumulation of ECF eg. ascites, oedema, pleural effusion
    • Vd tobramycin depends on LEAN body wt as doesn't penetrate adipose tisue well.
  • Passes into all cells non-selectively, non-bound, evenly distributed, then Vd = 0.6 L/kg = body water = 42L - depends on body wt NOT LEAN body wt;
    • eg. ethanol; lithium - 55L; metronidazole - 52L;
  • If highly bound to tissue, then Vd is only a mathematical concept as may be several hundred times body volume - drug not homogeneously distributed!!
    • eg. digoxin 440L (dependant on LEAN body mass);
    • tricyclics 1600L; carbamazepine 98L; diazepam 99% pp.bound - 77L;
    • morphine 230L;

• At the pH of plasma, albumin has a net anionic charge, and has high capacity but low affinity for binding most cationic drugs, however, many acidic acids bind strongly but may have only a low capacity.
• Many lipid soluble drugs bind strongly to hydrophobic side-chains of the amino acid residues;
• A number of endogenous substances are bound to albumin, & their presence affects the binding of drugs (eg. amount of fatty acids);
• > 98% bound: Brufen (acidic), diazepam (basic);
• 95-98%: fluclox; lasix; warfarin; indocid; tolbutamide; bupivicaine;

• raises apparent solubility of drugs in plasma
• if affinity high & rate dissolution slow, then hepatic & renal elimination is slowed, increasing plasma half-life;
• may serve as a depot for the drug in the body (eg. suramin);
• reduction of pharmacological activity in general;

• hypoalbuminaemia → high unbound conc., high Vd & clearance;
• uraemia → decreases binding of: digoxin, morphine, phenytoin;
• age: fetus - hypoalbuminaemia; neonate - bilirubin present;
• displacement by others eg bilirubin, uric acid, fatty acids;
  • eg. kernicterus due to salicylates/sulphonamides;
  • uricosuric action of brufen;

• Drugs need to get into cells before they can bind to i/cellular proteins, etc.:
  • Keratin:
    • high content of cystein, thus, sequesters drugs that bind to sulphydryl groups: arsenic, mercury, griseofulvin;
  • Melanin: binds chloroquine, phenothiazines;
  • Nucleic Acids: mepacrine binds avidly;
  • Mucopolysaccharides: are acidic & bind cations: eg. mepacrine;
  • Collagen: binds sulphasalazine;
  • Haemoglobin: binds anions;
  • Organelles:
    • such as vesicles, granules, mitochondria may take up selective substances: vital stains, transmitter-like;

• Adipose:
  • account for ~20% of body wt → bind much lipid soluble
  • drugs: insecticides, DDT, dieldrin;
• Bone:
  • calcium may bind: tetracycline;
  • drugs may replace Ca in crystals: Pb, Ra, strontium;
• Marrow:
  • cells actively proliferating take up phosphate;
• Pancreas: sequester ~7% of selenomethionine;
• Parathyroid: takes up selenomethionine, toluidine blue;
• Thyroid: takes up iodide & related anions (technetium);
• Kidney:
  • drugs actively taken up by renal tubular cells & secreted into urine are sequestered by kidney:
    • IVP drugs;
• Liver:
  • drugs that undergo hepatic metab. & biliary excretion are selectively concentrated in liver & biliary tract;
• Spleen: sequesters damaged RBC's;
• Lung: sequesters: tricyclics; 30-50 m IV particles;
• CNS:
  • generally only lipid soluble nonionized drugs pass blood brain barrier, except for metabolic substrates such as Na, K, Cl, glucose, amino acid-like, choline, transmitter-like which are actively transported;
  • certain types of neurones may selectively bind drugs such as: chlorpromazine;
  • Penicillin penetrates poorly unless meninges are inflamed;
  • Quaternary N atom generally do not pass blood/brain barrier;