OzEMedicine - Wiki for Australian Emergency Medicine Doctors

see also:

• pharmacokinetics

• Water soluble substances pass through aqueous “pores” in cell membranes or b/n cells at a rate according to Ficks' Law:
  • m/t = Pk A (Co-Ci) , where,
    • m = amount of substance passing through an area A of interface over period of time t;
    • Co & Ci are conc. outside & inside the membrane;
    • Pk = permeability constant;
• For small molecules, the aqueous diffusion coefficient is inversely prop. to square root of MW;
• For macromolecules (eg. proteins), it is inversely prop. to cube root of MW;
• Ionized molecules are also effected by:
  • water of hydration increases effective molecular size;
  • trans-membrane potential;
  • factors imposed by Gibbs-Donnan equilibrium;
• Also, the association of water molecules by dipole bonding to nonionized hydrophyllic groups (eg. hydroxyl) decreases the rate of aq. diffus. of substances containing these groups (& greatly decreases their lipid solubility (see below));

• Lipid soluble substances are taken up at one interface according to their lipid/water partition coefficient, diffuse across the lipid phase (the membrane) according to their concentration gradient, and are redistributed in accord with their lipid/water partition coefficient at the opposite interface;
• The higher the partition coefficient, the faster the diffusion;
  • Eg. Inorganic ions, endog.end products (urea) ~0; thiopent.~100;
• The rate follows Fick's Law, & is proportional to concentration gradient b/n the 2 aqueous phases;
• If partly ionized, the gradient is of the nonionized particle concentration (as ionized particles are not lipid soluble):
  • log (PN/PO - 1) = pH - pKa, where,
    • PN, PO are the nonionized P.Coeff., & the observed overall P. coefficient;
    • pH is pH of aqueous phase;
    • pKa is ionization constant for substance;
  • The higher the pH, the higher the ionization of acidic drugs;
  • Absorption is rapid even if only 0.01% is in non-ionized form;
  • The lower the pKa for acids, the more acidic; (vv for bases);
  • Bases with pKa > 5, or acids with pKa < 2 are scarcely absorbed from the stomach as effective pH at absorbing surface is ~3.5;
  • Intestinal effective pH is ~5, thus bases with pKa < 8, or acids with pKa > 3 will be rapidly absorbed;

• Active transport is involved in the uptake of certain nutrients such as nicotinic acid, nicotinamide, pyridoxine, riboflavine, thiamine, folic acid, amino acids, pyrimidines (eg. uracil);
• Drugs that are chemically related may be actively transported:
  • methyldopa & L-dopa (via amino acid transport);
  • phenytoin (folate);
  • 5-FU (pyrimidines);

• A few drugs with very high lipid solubility maybe absorbed together with long chain fatty acids, monoglycerides, cholesterol and fat-soluble vitamins:
  • digitoxin;
  • griseofulvin;
  • drugs incorporated into liposomes;

• Drugs with large MW, or which exist in solution in molecular aggregates, are probably taken up by pinocytosis:
  • botulinum toxin;
  • intrinsic factor + vitamin B12 complex;

• intestines (200m2) » stomach;
• thus, although the properties of a drug may favour gastric absorption per unit area (eg. acid with low pKa), a large proportion may be absorbed in the intestines;

• on empty stomach increases conc. → absorption

• penicillin; procaine, other esters, but chlorazepate is activated → diazepam!;

• insulin, etc;

• azo bonds in food dyes; glucuronide conjug.; some sulphon.;

• SO4 conjugating enzymes: isoprenaline; (chlorpromazine; methyldopa, L-dopa, oestrogens);
• amino acid decarboxylase: L-dopa (esp. gastric>intestinal);
• hydrolytic enzymes: glyceryl trinitrate; (methadone, pethidine, dextropropoxyphene);

• blood flow through submucosal capillaries is a limiting factor of drugs that have low aqueous solubility;
• binding to plasma proteins;

• non-propulsive movements increase disintegrat./dissol.;

• maxalon, atropine increase intestinal absorption;
• NB. although aspirin (pKa 3) is largely nonionised in stomach, it's solubility is low so that ~50% is absorbed from intestines where it is more soluble although more ionized - maxalon increases absorption rate by enhancing gastric emptying;

• Absorption of lipid soluble drugs is rapid, and one may facilitate absorption of ionizable drugs by suppressing their ionization by giving a pH buffer (range pH 3.5 to 9), thus avoiding 1st pass effect of hepatic metabolism as bypass portal circulation;

• The degree of uptake of an inhalation anaesthetic from alveolar gas into pulmonary blood is determined by:
  • concentration in alveolar gas;
  • blood/gas partition coefficient - the higher, the greater the uptake into blood, but the lower the blood saturation;
  • rate of pulmonary flow;
  • Aerosol particle size determines the degree of penetration into respiratory tract:
    • > 10 microm trapped in URT;
    • 2-10 microm trapped in small bronchi & bronchioles;
    • < 2 microm enter alveoli;
    • Eg. nicotine in cigarette smoke is mainly solid particles less than 1 microm diam. but extremely rapid & almost complete transfer from the particles reaching the alveoli into blood!

• Only drugs with high lipid solubility penetrate the epidermis unless ionized drugs are driven by electrophoresis;

• Spreading of the injected mass is facilitated by including hyaluronidase which then allows infusion rates up to 10ml/min;
• After injection, drugs with MW > 20,000 are mainly taken via lymphatics, whilst those < 3,000 are taken up by capillaries;
• Rate of systemic distribution dependent on blood flow, solubility, binding to colloid particles, presence of oil in injectate, rate of dissolution of injectate (eg. implant);

• As for subcutaneous, but less painful as less nerve supply and usually higher blood flow thus more rapid onset of action
• eg. adrenaline should be given IM rather than s/c in Rx of anaphylaxis