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PHYSICOCHEMICAL PRINCIPLES OF DRUG ACTION

PHYSICOCHEMICAL PRINCIPLES OF DRUG ACTION. INTRODUCTION. Drug molecules interact with biological structures. drug effect. lipoproteins/enzymes. membranes. nucleic acids. DRUG EFFECT. Drug effect is preceded by drug transport. from site of application to site of action.

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PHYSICOCHEMICAL PRINCIPLES OF DRUG ACTION

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  1. PHYSICOCHEMICAL PRINCIPLES OF DRUG ACTION

  2. INTRODUCTION Drug molecules interact with biological structures drug effect lipoproteins/enzymes membranes nucleic acids

  3. DRUG EFFECT Drug effect is preceded by drug transport from site of application to site of action and is dependent on physicochemical properties

  4. PHYSICOCHEMICAL PROPERTIES Interatomic distances Intermolecular forces Stereochemistry Partition coefficient Solubility All affect pharmacokinetics Ionization

  5. PHARMACOKINETICS TO UNDERSTAND ALL THIS WE MUST UNDERSTAND PHYSICOCHEMICAL PROPERTIES ABSORPTION Receptors Tissue Depots unbound drug unbound drug Plasma unbound drug bound drug bound drug bound drug metabolites EXCRETION METABOLISM

  6. PHYSICOCHEMICAL PROPERTIES  Interatomic distances  Intermolecular forces  Stereochemistry Partition coefficient Solubility Ionization

  7. PARTITION COEFFICIENT Hydrophobic bonding interactions are critical Can be approximated by partition coefficient PC Drug (W) Drug (O) [drug]O Thus, PC describes the entire drug. PC = [drug]W

  8. PARTITION COEFFICIENT Useful to know the hydrophobic bonding properties of substituent groups. Hydrophobic bonding constant  for a substituent is obtained as a difference In log P.  = log PX - log PH Thus, describes the substituent. PX = PC for substituted compound PH = PC for parent compound

  9. REPRESENTATIVE VALUES

  10. SOLUBILITY Drugs must be in solution to interact with receptors. Drugs have some degree of solubility in both aqueous and lipid compartments (PC). Solubility is a function of: ionization molecular structure molecular weight stereochemistry electronic structure

  11. SOLUBILITY of WEAK ELECTROLYTES Solubility will be affected by pH.

  12. SOLUBILITY of WEAK ELECTROLYTES indomethacin tetracycline Aqueous solubility chlorpromazine 2 6 12 pH

  13. PREDICTING WATER SOLUBILITY Empiric method Analytic method Solubility in water ionic compounds, i.e. salts of WA, WB polar compounds, i.e. those that H-bond

  14. EMPIRIC METHOD Solubility Properties of Na Salts of Common Organic Acids

  15. EMPIRIC METHOD Solubility Properties of Na Salts of Common Organic Acids H2O solubility can be increased by salt formation

  16. EMPIRIC METHOD Solubility Properties of Common Organic Acids COOH brings into solution 5 – 6 C’s to extent of 1%

  17. EMPIRIC METHOD Solubility Properties of Common Alcohols ROH brings into solution 5 – 6 C’s to extent of 1%

  18. EMPIRIC METHOD Solubility Properties of Common Amines N brings into solution 6 – 7 C’s to extent of 1%

  19. EMPIRIC METHOD Solubility Properties of Common Phenols ArOH brings into solution 6 – 7 C’s to extent of 1%

  20. BASIS OF EMPIRIC METHOD For monofunctional compounds a single functional group (capable of H-bonding) will bring into solution 5 – 7 carbons to the extent of 1%. but Drugs are usually not simply monofunctional. Simple summation of “water-solubilizing” potential may not give accurate predictions.

  21. EMPIRIC METHOD Water Solubilizing Potential of Functional Groups solubility defined as  1%

  22. EMPIRIC METHOD tyrosine Prediction: 17 – 20 C should be brought into solution. Only 9 C present, so should be >1% soluble. Experimental Results: 0.045% solubility WHY?

  23. EMPIRIC METHOD intramolecular ionic bonding reduces solubility pH adjustment increases solubility Polyfunctional data compensates for intra- and inter- molecular bonding.

  24. EMPIRIC METHOD Mono 5 + 5 + 5 + 7 + 7 = 29 6 + 6 + 5 + 7 = 24 soluble soluble Poly 2 + 2 + 2 + 3 + 4 = 13 3 + 3 + 2 + 3 = 11 insoluble insoluble

  25. ANALYTIC METHOD [drug]octanol log P is a measure of the solubility of the whole drug log P = [drug]water  is the log P of the fragment logPcalc =  fragments solubility defined as >3.3% if calc. logP is > +0.5 then compound is H2O insoluble if calc. logP is < +0.5 then compound is H2O soluble

  26. ANALYTIC METHOD  Values for Organic Fragments solubility defined as >3.3%

  27. ANALYTIC METHOD 1. table is only a brief compilation 2.  values are approximations 3.  values depend on whether fragment aromatic or aliphatic 4.  values are obtained under nonionizing conditions 5. intramolecular H-bonding must be considered 6. values for heterocycles can be estimated

  28. ANALYTIC METHOD procaine solubility defined as >3.3% insoluble +2.3

  29. ANALYTIC METHOD chlorpromazine solubility defined as >3.3% Exp. +5.3 Calc. +5.0

  30. ANALYTIC METHOD amobarbital solubility defined as >3.3% Exp. +2.1 Calc. +2.1

  31. ANALYTIC METHOD penicillin V solubility defined as >3.3% Exp. +2.1 Calc. +2.4

  32. ANALYTIC METHOD glycerol solubility defined as >3.3% Exp. –1.7 Calc. -1.5

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