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pk_absorption

Absorption of drugs

see also:

Passage Of Drugs Through Membrane Barriers:

1. Aqueous diffusion:

  • 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));

2. Lipid Diffusion:

  • 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;

3. Active Transport

  • 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);

4. Co-absorption with lipid micelles in intestinal mucosa:

  • 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;

5. Pinocytosis:

  • 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;

Other factors effecting absorption:

Surface area of absorbing surface:

  • 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;

Drug concentration

  • on empty stomach increases conc. → absorption

Hydrolysis by gastric acids:

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

Proteolyic enzymes destroy polypeptides

  • insulin, etc;

Bacterial metabolism in intestines

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

Metabolism during absorption may inactivate drugs

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

Clearance/binding after absorption increases conc. gradient

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

Motility

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

Transit time

  • 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;

Other sites of drug administration:

Sublingual/Nasal/Rectal:

  • 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;

Lungs:

  • 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!

Skin:

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

Subcutaneous:

  • 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);

Intramuscular:

  • 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

Intravenous:

Intraarterial:

Intrathecal:

pk_absorption.txt · Last modified: 2008/11/09 06:00 by 127.0.0.1

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