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Biopharmaceutics Dr. Rana Abu Dahab Lecture -6- Menas Abu Alhalawa We were talking in the previous lecture about the oral drug absorption and we mentioned the physiological variables ; physiological factors that influence drug absorption from the gastrointestinal tract; the first one of them is the gastric emptying, the gastric emptying rate ,the the presence of food and the gastric secretions. We did mention previously that the duodenum is the major site for absorption of nutrients, and the major site for absorption of drugs ; thus the reservation of the drug in the duodenum crucially determines the rate of appearance of the drug in the systemic circulation; So whatever dose I’m providing the body with got to get to the duodenum as fast as possible in order to me to get the highest rate of drug absorption, so we need that drug emptying in the stomach and the intestinal emptying , and any delay in gastric emptying would delay dug absorption factors that we said before can affect the rate but could also affect the extent. Another factor is how long the drug’s stable in the stomach. And we also said that The gastric emptying rate (gastric emptying time) is a highly valuable parameter and it’s the cause for intersubject variability in the plasma concentration time profile. Now the stomach differ in the fed and the fasting statuses; in the fasting status goes through 4 phases; in the 3rd stage there’d be an emptying from the stomach to the duodenum, in order for emptying to Page 1 of 9 happen we need contractions of the stomach and relaxation of the pyloric sphincter so that there’d be a transfer of the chime from the stomach to the major site of absorption, the stomach in stage 1,2,4 isn’t going through any active contractions (the stomach in an almost silent position) and we’d wait for stage 3 for the emptying to happen, and that’s the cause of the variability when people take the dosage form at fasting status. Whilst other statuses(fed statuses) there are those regular contractions that mixes the food in the stomach and empties the food from the stomach to the duodenum however those contractions and emptying are dependent on the existing food. Variability when having a drug at fasting status comes from the phase (1,2,3 or 4) we’re in. So when we talk about mild moderate meals; light meals like breakfast , then the drug taken with these meals would go under contractions and emptying, however we’re talking about foods that are potent inhibitors for gastric emptying , and the drug’s taken after such a large meal; a meal with inhibitor for gastric emptying again there’d be a delay for the drug till reaching the systemic circulation. The factors that affect the gastric emptying are numerous and today we’d focus on the ones that are mostly related to food starting with 1-the volume of the meal ; now the gastric emptying is an exponential process meaning that the more volume the Biopharmaceutics Dr. Rana Abu Dahab Lecture -6- Menas Abu Alhalawa stomach is being filled with for the first emptying from the stomach to the duodenum, now the duodenum with it’s mechanoreceptors gets stretched and the mechanoreceptors causes a negative feedback on the stomach; so the duodenum whilst emptying of a large volume alerts the stomach to stop. Emptying stops to enable the duodenum to control the amount it already still has , then there’d be a processing from the stomach to the duodenum. Duodenum deals with whatever it has, then another amount of food empty from the stomach to the duodenum again for other process of digestion and absorption. So, the correlation between the stomach and duodenum is that the stomach doesn’t empty until the duodenum is done with the digestion and the absorption. One of the important terms is the 1)volume : for example, after fasting first thing people tend to do is to drink large quantity of liquids (which is not recommended claiming that it causes a premature satiation feeling; because of the at once emptying of the duodenum and that’s it. That the stomach afterwards would instantly be full.) secondly2)the type of meal(mostly the fatty meals; when we’d have large amounts of triglycerides or unsaturated fatty acids, that fat is a potent inhibitor for gastric emptying; mainly digestion of Page 2 of 9 fat is slower than digestion of carbohydrates and proteins, and fat is absorbed in the duodenum, so whenever we take a fatty meal due its slow digestion in the duodenum whatever is in the stomach doesn’t get quickly emptied so it prevents the gastric emptying, so in the case of giving a solid dosage form along with fatty meal it’d be waiting for the contraction for it’s emptying and this explains why would some people(especially for their kids) have a fatty nutrients for Suhoor taking in consideration the time spent without eating during the day of fasting. Now, if a unit dosage form (a tablet ; one not to be dissolved; a coated tablet form not suspension lets say) was taken by me after a fatty meal it’s emptying will definitely be delayed (no rapid appearance of the drug in the circulation) (carbohydrates have less complications than fats yet have a high osmotic pressure so are the amino acids osmotic pressure reduction in the rate of emptying dependent on the conc. Of salts and non electrolytes , physical state of gastric content, the larger solid is the gastric content the larger gastric emptying there is; since reducing the size of big particles is the function of the stomach, while the emptying would be fast when we have something like soup Biopharmaceutics Dr. Rana Abu Dahab Lecture -6- Menas Abu Alhalawa or something sweety for Futoor so the goal from having soup at first for Futoor is to have a quick emptying and absorption for the sugars that’d been taken the thing that’ll lead to a refreshing sensation (the secret behind the importance of starting with something light at the beginning of the Futoor) Food has important function in terminating gastric emptying and gastric emptying rates, Sometimes we actually “recommend the patient to take the drug along with food” ; if the drug itself was an irritant or causes gastric upset, we might need such recommendations as some sort of compromising seeking for some sort of balance even when in this case it might actually decrease the bioavailability in exchange for some limitation in the side effects And in other times we might need to rapid the appearance of the drug in the systemic circulation (we recommend it taken half an hour before the meal or an hour afterwards; in case of drug-food interactions so that there wouldn’t be any complexations from drug-food interactions, so we do that to decrease the effect of food on the rate of appearance of drug in the systemic circulation,so this one is of important biological matters) Page 3 of 9 So now, back to Distinguishing in the gastric emptying between different dosage forms. Liquids and small particles usually empty quite rapidly irrespective of 1)Fed status 2) if the pyloric sphincter was relaxed or contracted (11:46) ; so when I take solutions, or suspensions or dosage form that rapidly disintegrates in the stomach , all of these disperse in the GIT and emptied irrespective of the fed status meaning that pyloric sphincter won’t make the stomach totally sealed; there’s some space which allows passage of liquids such as water(and that’s how liquids and small particles are dealt with during the gastric emptying, no problems happen) Now the more sensitive to gastric emptying are the larger particles the ones larger than the few millimeters; those need contraction of stomach along with relaxation of the pyloric sphincter so that they transfer from stomach to the duodenum . The more challenging would be the nondigestable very large solids just like the Ibuprofen ®800 tablet and the antibiotic tablets in grams housekeeper wave that’d transfer them from the stomach to the duodenum; what makes them more sensitive to the gastric emptying in the presence of food while the small particles on the other hand don’t really get effected by that . Another parameter intestinal motility Biopharmaceutics Dr. Rana Abu Dahab Lecture -6- Menas Abu Alhalawa Now we previously said that drugs are absorbed from duodenum. drug absorption, it’s more of a residual area for drug absorption. Now, afterwards the chime reaches the intestines a sufficient residency must be achieved in order to absorption to fully happen; now the drugs are in the lumen of the intestines in the salts of the chime and the muscles there are operating the mixing so drug is mixed and dissolved and during the mixing also it approximates on the surface of the mucosa to allow to the absorption meaning that not everything in that tube(intestines) is going to be absorbed that instantly; it actually needs to approach the mucosa and get absorbed. So we talked so far about the biological variable number one : the gastric emptying and the gastric motility So Residency in the intestines(which is 34hrs, although it could be prolonged in the fed status up to 12hrs also in case of any diseases that residency can be even shorter than normal) is important for: –Residency in the intestine allows for complete dissolution and complete absorption. So lets say our patient does have a GIT disease; an infection or lets assume it’s a diarrhea in this case: the drug isn’t supposed to be given orally because there won’t be a sufficient residency nor suction for a fully absorption so it’s favored to be given as injection(if possible). Then comes The Colon with a residency time that’s up to 35hrs (longest) influenced by amounts of food and fibers, it has been also said that colon isn’t a major site for Page 4 of 9 Secondly The effect of food in GIT: (now we know that presence of food effects the bioavailability and absorption . Effects are: 1)Alteration of the rate of gastric emptying , and usually a delay in the rate of absorption An example : (important*) -The stomach(with it’s acidic PH is excellent for dissolution of weakly basic drugs ) PROS: the ionized molecules are usually better dissolved), if we had a weak basic drug with low solubility then the longer they stay in the stomach the higher would be it’s solubility, just like the nitropheratol which is a weak basic drug with poor water solubility(which makes it not dissolve in the duodenum secretions and yet dissolves better at the lower PH of the stomach; it’s given with fruit (given with food generally) so that we delay the gastric emptying (which would increase it’s dissolution although I’d witness a reduction in the rate, but usually the extent is higher) for a complete dissolution, now since I kept it in the stomach longer I’d find a lower absorption at first that’d be lifted by the extent . Biopharmaceutics Dr. Rana Abu Dahab Lecture -6- Menas Abu Alhalawa To sum up the example: Giving the drug with food => delayed gastric emptying => drug stays in stomach for longer time => higher opportunity for dissolution in the acidic conditions of the stomach => eventually leads to higher extent of absorption (bioavailability) because high dissolution which compensates the delay in gastric emptying. “Delay in gastric emptying is NOT always Unfavorable”: meaning we referred to delay as unfavorable earlier above, but in this case of a weak basic and poorly soluble drug(so they’d need to stay longer time in the stomach to allow their dissolution); so then it’s favorable. -if a substance was very ***(18:00) it won’t be absorbed 2)Stimulation of gastric secretions , a type of pancreatic secretions which are important => bile salts that are secreted upon the ingestion of food especially a presence of high proportion of fat; now the structure of bile salts explains their aactivity as surface active agents, they operate on fats until they reduce the size of globules of fatty droplets to allow their digestion then absorption, because they’re amphephiles surfactants and improve the dissolution of hydrophobic drugs , it might be ok with the ingestion of food along with the given dosage form; because the bile salts are capable on stimulating the solublization of hydrophobic agents , so they may improve solubility of some drugs of low solubility, bile salts have short form insoluble Page 5 of 9 complexes with some drugs reducing their bioavailability, they might complex with drugs forming insoluble complexes (drugs that form insoluble complexes with bile salts: neomycin, kanamycin). Bile salts may improve absorption or reduces it. “bile salts always improve drug solubility” => this statement is false. The anti-fungal “ Greaseofalvin” is a very hydrophobic drug, to overcome this problem we recommend the patient to take it with a very fatty meal a slow emptying rate, but the presence of the bile salts has been noted to improve the dissolution of that drug and improves the bioavailability of the drug , after the stimulation of secretions there’d be competition between drugs for specialized absorption and food components If the drug is absorbed by carrier mediated mechanism and another nutrient existed which is absorbed by the same mechanism they may compete. 3)food increases the viscosity of the GI content and reduction in dissolution rate and diffusion to reach cell membranes: If the drug is taken without food and only with a glass of water then the chime will be thinner and the diffusion of the drug across the chime would be faster , diffusion is dependent on viscosity and the absorption would be fast however the presence of food to the chime more viscous that the drug has to fuse across the chime until it Biopharmaceutics Dr. Rana Abu Dahab Lecture -6- Menas Abu Alhalawa reaches the surface and get absorbed, that’s why kind of drug administration in relation to food is important here two things must be noted a)safety(when we have irritant drugs) b)efficacy :rate and extent of drug absorption , then we balance between them and decide what is suitable . The GI PH : the PH of the fluids vary along the GIT (1[stomach]7-8[colon]) When it comes to the drug that’s taken orally we have to remember that it has to go through all these variations of PH, the GI PH variability is quite high (some migh have it as 1 and others as 2.5 and the diurnal changes between day and night;, it depends on the general health of the individual ; emotional status ,stress ,localized disease situations ,types of food ingested(for example: spicy food diet leads to a lower PH) and on anti- cholinergic agents that influence the PH of the GIT). PH of the GIT is important for : 1)Dissolution of weak acids and weak bases 2)determining the ratio of ionized and nonionized for the weak acids and weak bases (remember: the weak bases are solublized better in the stomach and the weak acids are solublized better in the intestine) Another important parameter besides the PH ; which is according to the PKa of the drug molecule is the ratio of the non ionized and the ionized ; whilst the non ionized are usually more lipophilic so they cross the membrane easier and here we Page 6 of 9 have two opposite functions the first one is dissolving in the aqueous media so that its absorbed secondly is the fraction of the non ionized so that it passes the membranes, and both of these are influenced by the PH, which we cannot call it “unpredictable” but it is highly variable which might be due to variability of drug absorption (that’s why sometimes the best absorption can be sometimes at the initial part of the duodenum or the last part of it; the surface are also can affect absorption. Gastric PH can affect drug absorption in different ways ; ionization and solubility of acids and bases and the chemical stability of drugs in low gastric PH ,and that’s a problem because most of drugs that aren’t stable in the stomach are in enteric-coated, that coat sometimes effects the rate of absorption of drugs because because the drug is not emptied from the stomach to the duodenum until the coat is dissolved so that the drug is available for absorption. Other secretions(bile and pancreatic, bile have PH between 7.8-8.6 concentrated in the bile , bile has bile salts, bilirobin, components of hemoglobin, electrolytes, cholesterol, phospholipids promotes the dissolution of lipophilic drugs and dosage forms like the “Grisofulvin”, it improves membrane permeability; if I had lipophilic drug and was put with the phospholipids , the phospholipids might form micelles and trap some drug inside and this may promote drug absorption,,,, or the opposite formation of insoluble complexes of bile Biopharmaceutics Dr. Rana Abu Dahab Lecture -6- Menas Abu Alhalawa salts reducing their bioavailability so the ffect here is negative. And the last secretions are the pancreatic secretions, the major component is the enzymes, they might reduce the bioavailability of drugs which are made out of proteins, proteins undergo digestion by the pancreatic secretions . Drugs overcome a lot of barriers, and some drugs even may reach 100% bioavailability!, to achieve 100% bioavailability by oral route the drug got to be => *chemically(PH related) stable in the GIT , they also got to be stable in the gut lumen (gut lumen metabolism; whatever secreted in the lumen drug got to be stable to these lumen enzymes, we’re mostly talking about proteolytic enzyme that’d metabolize proteins, carbohydrates, gluconucleotides *drug got to be stable to gut wall metabolism; in gut wall metabolism where we have 2 factors; 1)brush border enzymes that are on the surface ,2) and inside of the cell we have active heterocytes (living) have sip enzymes, enzymes that drug got to be stable to these sip enzymes. Drug moves from lumen trough endothelial cells, blood vessels, portal circulation then goes to the liver (hepatic metabolism; first pass effect which is another challenge for the drug ,if the drug had lower bioavailability than 100% by oral route, I’d give it in higher doses than in IV to compensate hepatic meatbolism, or we try to give it IV from the beginning. Effect of disease status on drug absorption Page 7 of 9 (drugs that are taken orally must cross the GIT; biological variables, gastric emptying and others, drug has to be stable at the high PH range and to be stable to secretions, once drug’s absorbed goes through the first past effect which afterwards it’d be available in the systemic circulation (those are our biological variables determining drug absorption) another parameters that could be determining drug absorption are the effects of disease status on the drug availability (Pharmacokinetic studies are done on healthy humans and it is done by gathering small group of healthy people and get them tested for a certain drug effect IV then Orally administered in order to see whether the drug is absorbed or not, and most of the bioequivalence and the studies that monitor the plasma concentration time profile are done on young and healthy individuals, now in reality the patients aren’t always healthy; taking in consideration the ones above sixty of them, the ones that had undergone a certain surgery or even more, the ones with a disease or two taking a drug or more then the medication rate problems might appear more (effecting the appearance of drug in circulation and variations in the side effects) so keep in mind that there are some disease conditions do have an effect over the drug availability 1)Parkinson’s disease : patients have problems in swallowing dosage forms and esophageal dismotilitized (motility in the Biopharmaceutics Dr. Rana Abu Dahab Lecture -6- Menas Abu Alhalawa esophagus is quite slow) so these patients are unfavorably to be prescribed an oral dosage forms except for solutions and are searched for a faster methods to the drug to reach the stomach (e.g.: using a tube) , also all the secretions and the gastric emptying rate is slower in this disease, if I wanted the drug dissolution to happen in the stomach then to get emptied by reduction of secretions in the stomach might not be available in the case of this disease’s condition, so drugs in this case might be directly administered to the stomach and won’t fully disintegrate or dissolve, conc. of solution dosage forms or liquid dosage forms to account for the differences in the stomach motility 2) acholrohydric patients (patients with achlorohydria) ; the acid in the stomach is surely important for the fluids within the stomach and the acidic PH is important for dissolution of weak bases , those patients have poor acid secretions , the reason could be parietal cell that secrete the protons, so we can’t dependent on the acidity of the stomach to dissolve the drug in this case; as we’ve been saying that for weak basic drugs we depend on stomach acidity for an optimum drug dissolution. 3) congestive heart failure have reduced splanchnic blood flow ; edema in the bowel wall – (normal status)one of the most important variables that allow simple passive diffusion is the presence of a concentration gradient ; presence of mesenteric blood vessels with a very high capacity that transfers the drug from the GI Page 8 of 9 bowl to the portal-circulation to the systemic circulation,,, patients have a lower drug absorption because of the accumulated fluids and then there wouldn’t be a concentration gradient that’d allow a rapid simple passive diffusion . 4) inflammatory bowel diseases (in general) are divided into two subtypes : Crohn's disease (the inflammatory disease of the distal small intestine and colon , regions of thickening of the bowel wall overgrowth of bacteria sometimes causes destruction of the bowel, so the whole area to which the drug to be absorbed is deteriorated , so we’d find some areas where the wall’s thin is where the absorption is fast and others that are thick with mucous secretions where absorption is slowed down (some drugs absorption in this case is the same, and some are increased or reduced; mostly this absorption is unpredictable ) one of the drugs that are mentioned with Crohn’s disease in which we have higher plasma concentration in the case of Crohn’s disease is Propranolol, which would result in concentration in the plasma that’s higher ; the first explanation to that was presence of thin areas that make absorption faster others say that because it’s an inflammatory disease so as an inflammatory disease it’d increase the plasma protein ; such as specific α-1 glycosidic protein that increases in the inflammatory situations which the propanolol binds to and when it does it’s elimination is reduced and the plasma levels that are persistently higher in theses patients. Biopharmaceutics Dr. Rana Abu Dahab Lecture -6- Menas Abu Alhalawa and Celiac disease : inflammatory disease effecting mostly the proximal small intestine (example on sucha disease is the sensitivity to gluten that causes inflammation in the small intestines ; the material in cereals, those patients are known for their increased gastric emptying time increased and permeability’s usually increased resulting in a higher drug absorption , those patients must be monitored (for effects and side effects) and doses should be adjusted ; their plasma concentration and their drug dosages. one of the popular cases is the intestinal infections (usually cause diarrhea which during it the content residency is lower than usual) then I’d suspect the drug absorption to be incomplete ,,,,,oral contraceptives which are 99.999% effective in contraception aren’t recommended to be used during diarrhea because the drug then won’t be fully absorbed and then the plasma level of estrogen will reduce again and there might be a possible ovulation , so contraceptives are pretty effective unless there was a case of diarrhea. 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