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Transfer of the drugs across membranes

Transfer of the drugs across membranes. Prepared by Prof. Abdulkader.H.El Daibani. Transfer of the drugs across membranes. Absorption For drugs to produce their action they must reach their target sites by crossing biological membranes. Mechanism of drug transfer.

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Transfer of the drugs across membranes

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  1. Transfer of the drugs across membranes Prepared by Prof. Abdulkader.H.El Daibani

  2. Transfer of the drugs across membranes Absorption • For drugs to produce their action they must reach their target sites by crossing biological membranes.

  3. Mechanism of drug transfer Mechanism of drug transfer: 1) Passive diffusion: a) Aqueous diffusion (filtration ) • transfer of drugs through pores across endothelium of capillaries and depend on conc. Gradient ,only drug with M.W< 100 can be transferred by aqueous diffusion e.g. urea, ethanol. It's imp. For glomular filtration in renal excretion not common because most drugs have M.W > 100.

  4. Mechanism of drug transfer b) Lipid diffusion: • the higher lipid solubility of drug expressed by oil to water P.C( partition coefficient), Drug with P.C> 1 e.g. sodium thiopentone cross cell membrane at high rate of diffusion. • The lipid diffusion is most imp. Mechanism of drug transfer because membrane are lipid in nature.

  5. Mechanism of drug transfer Characteristics: • depend on drug conc. gradient (1st order kinetics). • No energy is required. • Doesn't become saturated. • Not inhibited by other substance.

  6. Mechanism of drug transfer Cut off phenomena across S.I • Drugs must have some water solubility as well as lipid solubility to be absorbed from S.I. • Lipid solubility of drugs is enhanced by presence of non polar groups of benzene ring, hydrocarbon chain, steroid , nucleus or halogen (Br, Cl, F), while water solubility of drugs is increased by presence of polar groups such as alcoholic (-OH), amide(-CONH2) or carboxylic(-COOH) groups and formation of glucuronide and sulphate conjugates.

  7. Mechanism of drug transfer Most drugs are week organic acids or weak organic bases. • For week acids: HA ↔ A- +H+ Non ionized ionized • For week bases BH+↔ B+H+ Ionized non ionized pka = -logKa pH = -log [H].

  8. Mechanism of drug transfer • The ionization of drugs is determined by ionized constant (Ka) of the drug express as pka= - log Ka and pH of medium. • pKa=Ph of medium when rate of ionized to non ionized is 1:1. • Gastric juice pH (1.4), plasma pH(7.4) urine pH (4.5-8). Ionized drugs are hydrophilic and non ionized drugs are lipophilic, so non ionized drugs can cross membrane readily. Acidic medium and basic drug ionized in acidic medium.

  9. Mechanism of drug transfer • The rate of non ionized to ionized fraction is calculated by Hasselback equation: • For week acids log non ionized form/ionized form=pKa-PH. or pH-pKa=log-I/NI. • For basic drug log ionized form/non ionized form=pKa-Ph or pH-pKa=log NI/I.

  10. Mechanism of drug transfer Examples: • If PB (week acid) with pKa=7.4, what is the ration of non ionized to ionized form when the urine pH is 6.4. log non ionized/ionized=pKa-PH log non ionized/ionized=7.4-6.4=1 antilog of 1=10 non ionized/ionized= 10/1. % of non ionized=10/11*100=90%.

  11. Mechanism of drug transfer • Therefore alkalization of urine with NaHCO3 is used in treatment of toxicity of acidic drugs e.g. aspirin and acidification of urine with ascorbic acid or NH4Cl is used in treatment of toxicity with basic drugs e.g. amphitamine, quinidine and pethidine.

  12. Mechanism of drug transfer • Some drugs do not have ionized groups and not affect by pH of medium e.g. digoxin and chloramphenicol, other drugs are strongly ionized at all pH and called polar drugs and passes –vly charged e.g. (acidic heparin) or +vly charged (basic ipratropium, tubocurarine.

  13. Mechanism of drug transfer 2)Carrier-mediated diffusion: • Drugs with large molecular size or drugs insoluble in lipid need a carrier for transport across cell membrane. Two types: active( energy) carrier mediated transport: Characteristics: • 1)selectivity. • 2)Require energy in the form of ATP, • 3)Competition between drugs transported by some carrier. • 4)Saturable. • 5)Can be against conc. gradient. • e.g. NA uptake by adrenergic neurons • uptake of amino acids into C.N.S e.g. L-dope.

  14. Mechanism of drug transfer • Renal tubular excretion of organic acids e.g. uric acid, penicillin and probencid. • Absorption of iron, α methyl dopa and 5-FU from G.I.T. • Uptake of iodine inro thyroid gland. • 5-FU→5-Flurouracil(anticancer drug

  15. Mechanism of drug transfer b)Facilitated diffusion: • similar to active transport, does not require energy. • Drugs are not transferred against conc. gradient e.g. absorption of Ca++ from G.I.T Uptake of glucose by tissues.

  16. Mechanism of drug transfer 3) Penocytosis (Endo or exocytosis) Formation and movement of vessels across cell membranes. Large molecules enter by endocytosis e.g. absorption of iron and vit.B12 in small intestine. Exocytosis: • Is the reverse process e.g. release of neurotransmitter.

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