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Lecture 4.ppt

The document discusses factors that influence the rate and extent of drug absorption from the gastrointestinal tract. It explains the pH-partition theory, which states that the proportion of ionized vs. non-ionized drug depends on the drug's pKa and the pH of the environment. According to this theory, weak acids are absorbed in the stomach while weak bases are absorbed in the intestine. However, other factors like surface area, dissolution rate, and lipid solubility also impact drug absorption. The document also discusses complexation, stability in the GI tract, and adsorption - which can negatively affect drug bioavailability.

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2 ‫الكليـــــــــــــة‬ ‫رؤيــــــــــــة‬ ‫الكليــــــــــــة‬ ‫رســـــــــــــــالة‬ ‫الريادة‬ ً ‫محليا‬ ً ‫واقليميا‬ ً ‫ودوليا‬ ‫لالرتقاء‬ ‫بصحة‬ ‫االنسان‬ ‫من‬ ‫خالل‬ ‫استخدام‬ ‫االب‬ ‫تكارات‬ ‫فى‬ ‫مجال‬ ‫التعليم‬ ‫والبحوث‬ ‫العلمية‬ ‫والممارسات‬ ‫التطبيقية‬ . ‫توفير‬ ‫أفضل‬ ‫الممارسات‬ ‫في‬ ‫مجال‬ ‫التعليم‬ ‫والتعلم‬ ‫والتدريب‬ ‫وإستمرارية‬ ‫خلق‬ ‫ف‬ ‫رص‬ ‫للطالب‬ ‫والخريجين‬ ‫بإبتكار‬ ‫ونشر‬ ‫وتطبيق‬ ‫المعرفة‬ ‫الحديثة‬ ‫المرتكزة‬ ‫على‬ ‫البحوث‬ ‫وال‬ ‫تطبيقات‬ ‫في‬ ‫العلوم‬ ‫الصيدلية‬ ‫واإلكلينيكية‬ ‫واإلجتماعية‬ ‫للنهوض‬ ‫بالصحة‬
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4 Upon successful completion of this course the student should be able to;  Describe the physicochemical and physiological factors that influence the absorption of drugs from extra and intravascular routs of administration, their distribution within the body, and the irroutes and mechanisms of elimination.
5 The pH - partition theory explains the influence of GI pH and drug pKa on the extent of drug absorption. A. pH - Partition Theory As most drugs are weak electrolytes, the unionized form of weakly acidic or basic drugs (i.e. the lipid- soluble form) will pass across the gastrointestinal epithelia, whereas the gastrointestinal epithelia is impermeable to the ionized (i.e. poorly lipid-soluble) form of such drugs.
6 According to the pH-partition hypothesis, the absorption of a weak electrolyte will be determined chiefly by the extent to which the drug exists in its unionized form at the site of absorption.
7 The extent to which a weakly acidic or basic drug ionizes in solution in the gastrointestinal fluid is determined by: its pKa & the pH at the absorption site and may be calculated using the appropriate form of the Henderson- Hasselbach equation
8 What is acid? acid is a substance that liberates hydrogen ions [H+] in solution. What is a base? A base is a substance that can bind H+ and remove them from solution. pH = - log [H+] Strong acids, strong bases, as well as strong electrolytes are essentially completely ionized in aqueous solution. Weak acids and weak bases are only partially ionized in aqueous solution and yield a mixture of the undissociated compound and ions.
9 HA H+ + A- Ka = [H+] [A-] [HA] In solutions of weak acids equilibria exist between undissociated molecules and their ions. The ionization constant Ka of a weak acid can be obtained by applying the Law of Mass Action:
10 pKa = pH - log [A-] [HA] log [A-] [HA] = pH - pKa Henderson - Hasselbalch Equation pKa = the negative logarithm of Ka From the pKa, one can calculate the proportions of drug in the charged and uncharged forms at any pH: For acidic drugs, the lower the pKa the stronger the acid
11 Some Typical pKa Values for Weak Acids at 25 °C pKa Weak Acid 4.76 Acetic 3.49 Acetylsalicyclic 9.24 Boric 2.73 Penicillin V 8.1 Phenytoin 2.97 Salicyclic 7.12 Sulfathiazole
12 In solutions of weak bases equilibria exist between undissociated molecules and their ions. The ionization constant Ka of a protonated weak base can be obtained by applying the Law of Mass Action: B + H+ BH+ Ka = [H+] [B] [BH+]
13 pKa = the negative logarithm of Ka From the pKa, one can calculate the proportions of drug in the charged and uncharged forms at any pH: pKa = pH - log [B] [BH+] Henderson - Hasselbalch Equation log [B] [BH+] = pH - pKa For basic drugs, the higher the pKa the stronger the base
14 Therefore, according to these equations: a weakly acidic drug, pKa 3.0, will be: predominantly unionized in gastric fluid at pH 1.2 (98.4%) and almost totally ionized in intestinal fluid at pH 6.8 (99.98%), a weakly basic drug, pKa 5, will be: almost entirely ionized (99.98%) at gastric pH of 1.2 and predominantly unionized at intestinal pH of 6.8 (98.4%).
15 This means that, according to the pH-partition hypothesis, a weakly acidic drug is more likely to be absorbed from the stomach where it is unionized, and a weakly basic drug from the intestine where it is predominantly unionized. However, in practice, other factors need to be taken into consideration.
16 Lipid solubility :weak acids and weak bases HA <==> H+ + A- B + HCl <==> BH+ + Cl- [ UI ] [ I ] [ UI ] [ I ] pKa=pH + log (HA/A-) pKa= pH + log(BH+/B) ASPIRIN pKa = 4.5 (weak acid) 100mg orally 99.9 = [ UI ] [ UI ] Stomach pH = 2 Blood pH = 7.4 0.1 = [ I ] Aspirin is reasonably absorbed Strychnine not absorbed until from stomach (fast action) enters duodenum 0.1 = [ UI ] [ UI ] Blood pH = 7.4 99.9 = [ I ] STRYCHNINE pKa = 9.5 (weak base) 100mg orally Stomach pH = 2
17 Limitations of the pH-partition hypothesis  Weak acids are also absorbed from the small intestine due to:  The significantly larger surface area that is available for absorption in the small intestine in contrast to stomach  The longer small intestinal residence time  The microclimate pH, that exists at the surface of the intestinal mucosa and is lower than that of the luminal pH of the small intestine
18  The pH -partition hypothesis cannot explain the fact that certain drugs (e.g. tetracyclines) are readily absorbed despite being ionized over the entire pH range of the gastrointestinal tract. One suggestion for this is that such drugs interact with endogenous organic ions of opposite charge to form an absorbable neutral species - an ion pair - which is capable of partitioning into the lipoidal GIT barrier and be absorbed via passive diffusion.
19 Barbitone and thiopentone, have similar dissociation constants - pKa 7.8 and 7.6, respectively - and therefore similar degrees of ionization at intestinal pH. However, thiopentone is absorbed much better than barbitone. WHY? the absorption of drugs is also affected by the lipid solubility of the drug. Thiopentone, being more lipid soluble than barbitone, exhibits a greater affinity for the gastrointestinal membrane and is thus far better absorbed. B. Lipid Solubility of Drugs
20 An indication of the lipid solubility of a drug, and (its absorption) is given by its ability to partition between a lipid-like solvent (usually octanol) and water. This is known as the drug's partition coefficient, and is a measure of its lipophilicity. How can we measure lipid solubility??
21 The partition coefficient P is the ratio of the drug concentration in the organic phase to its concentration in the aqueous phase Partition coefficient (p) = [ L] conc / [W] conc [ L] conc is the concentration of the drug in lipid phase, [W] conc is the concentration of the drug in aqueous phase. The higher p value, the more absorption is observed. Polar molecules, i.e. those that are poorly lipid soluble and relatively large, such as heparin are poorly absorbed after oral administration and therefore have to be given by injection.
22 A prodrug is a chemical modification, frequently an ester of an existing drug. The ester linkage increases the lipophilicity of the compound thus enhances the absorption. A prodrug has no pharmocological activity itself but it converts back to the parent compound as a result of metabolism by the body. (e.g. Rivampicillin a prodrug for ampicillin) The drug is too hydrophilic, what can be done?? Prodrug is one of the options that can be used to enhance p value and absorption as sequence.
23 So far we have looked at the transfer of drugs in solution in the G-I tract, through a membrane, into solution in the blood. However, many drugs are given in solid dosage forms and therefore must dissolve before absorption can take place. C. Drug Dissolution
24 The rate of solution may be explained using Fick’s First Low of Diffusion: It is the rate at which a dissolved solute particle diffuses through the stagnant layer to the bulk solution If absorption is slow relative to dissolution then all we are concerned with is absorption. However, if dissolution is the slow, rate determining step (the step controlling the overall rate) then factors affecting dissolution will control the overall process.
25 Fick's first law By Fick's first law of diffusion: D diffusion coefficient, A surface area, Cs solubility of the drug, Cb concentration of drug in the bulk solution, h thickness of the stagnant layer. As Cb is much smaller than Cs the equation reduces to : Solid Stagnant Layer Cs Cb h Bulk Solution
26 There are a number of factors which affect drug dissolution: Surface area, A The surface area per gram (or per dose) of a solid drug can be changed by altering the particle size. e.g. a cube 3 cm on each side has a surface area of 54 cm2. If this cube is broken into cubes with sides of 1 cm, the total surface area is 162 cm2.
27 Generally as A increases the dissolution rate will also increase. Improved bioavailability has been observed with griseofulvin, digoxin, etc. Methods of particle size reduction include mortar and pestle, mechanical grinders, fluid energy mills, solid dispersions in readily soluble materials (PEG's).
28 Diffusion layer thickness, h This thickness is affected by the agitation in the bulk solution. In vivo we usually have very little control over this parameter. It is important though when we perform in vitro dissolution studies because we have to control the agitation rate so that we get similar results in vitro as we would in vivo.
29 Diffusion coefficient, D The value of D depends on the size of the molecule and the viscosity of the dissolution medium. Increasing the viscosity will decrease the diffusion coefficient and thus the dissolution rate. This could be used to produce a sustained release effect by including a larger proportion of something like sucrose or acacia in a tablet formulation.
30 Drug solubility, Cs Solubility is another determinant of dissolution rate. As Cs increases so does the dissolution rate. We can look at ways of changing the solubility of a drug:
31 base, therefore if the drug can be given as a salt the solubility can be increased and we should have improved dissolution. One example is Penicillin V. D. (1) Salt Form If we look at the dissolution profile of various salts. Salts of weak acids and weak bases generally have much higher aqueous solubility than the free acid or
32 Some drugs exist in a number of crystal forms or polymorphs. These different forms may well have different solubility properties and thus different dissolution characteristics. Chloramphenicol palmitate is one example which exists in at least two polymorphs. E. (2) Crystal Form
33 Plot of Cp versus Time for Three Formulations of Chloramphenicol Palmitate The B form is apparently more bioavailable. This is attributed to the more rapid in vivo rate of dissolution. The recommendation might be that manufacturers should use polymorph B for maximum solubility and absorption.
34 In addition to different polymorphic crystalline forms, a drug may exist in an amorphous form. Because the amorphous form usually dissolves more rapidly than the corresponding crystalline forms there will be significant differences in the bioavailabilities. e.g. antibiotic novobiocin. The more soluble and rapidly dissolving amorphous form of novobiocin was readily absorbed. However, the less soluble and slower-dissolving crystalline form of novobiocin was not absorbed to any significant extent thus therapeutically ineffective.
35 Acid and enzymatic hydrolysis of drugs in GIT is one of the reasons for poor bioavailability. Penicillin G (half life of degradation = 1 min at pH= 1) Rapid dissolution leads to poor bioavailability WHY? (due to release large portion of the drug in the stomach, pH = 1.2) How to protect the drug from the gastric juice? 1. Enteric coating the tablet containing the drug. 2. Prodrug that exhibits limited solubility in gastric fluid but liberates the parent drug in intestine to be absorbed. F. Drug Stability and Hydrolysis in GIT
36 G. Adsorption Certain insoluble substances may adsorb co-administrated drugs leading to poor absorption. Charcoal (antidote in drug intoxication).
37 Complexation of a drug in the GIT fluids may alter rate and extent of drug absorption. 1. GIT component- drug interaction: Intestinal mucosa + Streptomycin = poorly absorbed complex 2. Food-drug interaction: Calcium + Tetracycline = poorly absorbed complex 3. Tablet additive – drug interaction: Carboxyl methylcellulose (CMC) + Amphetamine = poorly absorbed complex H. Complexation
38 4. Complexing agent + polar drugs: Dialkylamides + prednisone = well-absorbed lipid soluble complex 5. Lipid soluble drug + water soluble complexing agent Miconazole + cyclodextrine = water soluble complex
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