bio pharmaceutis paper Flashcards
Outline barriers to drug absorption in the colon. (13 marks)
The lumen, unstirred water layer, GI membrane and presystemic metabolism may cause problems when considering absorption in the colon. The pH of fluids in the lumen varies considerably along the length of the gastrointestinal tract. Gastric fluid is highly acidic (around pH 1 – 3.5 in healthy people in the fasted state, around pH 3 – 7 after a meal). Omeprazole degrades rapidly at acidic pH, however, this has been overcome by using enteric-coated dosage forms. The primary enzymes found in gastric juice is pepsin. Pepsin along with proteases are responsible for the degradation of peptide drugs in the lumen. This however may be exploited in that bacteria in the lumen are able to excrete enzymes responsible for the breakdown of sulfasalazine (prodrug) to produce its active metabolites (used in IBD). Complexation may occur in the lumen, whereby a drug is able to complex (sometimes irreversibly) to a substance such as calcium or iron. An example of this is tetracycline complexing with calcium or iron, hence patients are told to avoid milk or products containing Ca/Fe. If the complex formed is water soluble this have little effect on drug absorption. Bile salts present in the lumen can act as surfactants and increase dissolution of poorly soluble drugs, but forms insoluble complexes with neomycin, kenamycin and nystatin. Increased viscosity of gastrointestinal contents will decrease rate of diffusion and dissolution.
The mucus and the unstirred water layer is a barrier before drugs can permeate across the epithelial surface. The thickness of this layer varies along the length of the GI tract (30-100μm), therefore diffusion time will also vary. Some drugs can complex with the mucous in this layer reducing their availability for absorption.
The GI membrane is itself a barrier to drug absorption. There are two type of transport. These are transcellular (through cells) and paracellular (between cells). Transcellular is the most common, and it involves transporting substances across a lipid bilayer by means of passive diffusion, carrier-mediated transport, active transport, facilitated diffusion, endocytosis, pinocytosis, receptor-mediated endocytosis, phagocytosis and transcytosis. This is for mainly lipid soluble drugs. Paracellular is the movement of drug through small aqueous pores (tight junctions) accounting for 0.01% of the total surface area of the GI tract. It is important for the transport of small hydrophilic charged drugs. (This route may be increased in celiac’s disease. Efflux pumps are able to pump drugs back into the lumen. One of the key counter-transport proteins is P-glycoprotein. This may be a reason for a development of resistance to anti-cancer drugs, which are rapidly pumped back out by efflux pumps upon absorption.
Presystemic metabolism can also be a barrier for drug absorption. Certain foods may increase the bioavailability of drugs susceptible to presystemic inesstinal metabolism by interacting with the metabolic process. Grapefruit juice, for example is capable of inhibiting the intestinal CYP3A family and thus will reduce metabolism of all drugs susceptible to this, such as Simvastatin
In relation to biopharmaceutics define the terms MTC, MEC, Cmax and duration of action. (4marks)
MTC – Maximum Therapeutic Concentration (the maximum dose considered to have therapeutic effect)
MEC – Minimum Effective Concentration (the minimum dose considered to have therapeutic effect)
Cmax – The peak concentration value. At Cmax the rate of drug input = the rate of drug output.
Duration of action – the amount of time the drug is within the therapeutic range.
Outline the effective of disease states and physiological disorders can affect gut absorption and hence, bioavailability. (5 marks)
Bioavailability the proportion of a drug or other substance which enters the circulation when introduced into the body and so is able to have an active effect. Therefore if a drugs absorption in the GI tract is reduced its bioavailability is also reduced. Local diseases cause alterations in gastric pH that can affect the stability, dissolution and absorption of drugs. Partial or total gastrectomy results in drugs reaching the duodenum more rapidly than in normal individuals, at a much higher pH level. AIDS patients often have over-secretion of gastrin and thus a lower pH which can adversely affect the dissolution and hence bioavailability of weakly basic drugs such as the anti-fungal ketoconazole. Lower pH values are often seen in disease states of the colon such as Crohn’s disease and ulcerative colitis. In Celiacs disease there is an increased permeability of the GI tract via the paracellular route, caused by the loosening of tight junctions.
State and explain 3 limitations of the pH partition hypothesis (6 marks)
Despite the state of ionisation, weakly acid drugs are well absorbed from the small intestine. This is due to the large surface area in the small intestine compared to the stomach, the longer small intestine residence time and the microclimate pH at the surface of intestinal mucosa with a lower pH. Another limitation is that drug absorption is limited by drugs having to cross a mucosal unstirred layer before crossing the membrane. Its movement through here can be influenced by Complexation and MW (viscosity). Convection flow of water or solvent drug is another limitation which affects absorption. Greatest effect in the jejunum where water movement is greatest. Also affects lipid soluble drugs, in that water moves out of the intestine concentration lipid soluble drugs and therefore driving the diffusion.
Outline the influence of food on intestinal absorption. (8 marks)
The presence of food in the gastrointestinal tract can influence the rate and extent of absorption, either directly or indirectly via a range of mechanisms.
Direct Mechanisms
Drug absorption may be decreased due to increased competition of receptor sites by the food. Food will also increase the viscosity of gastrointestinal contents and hence there will be a decrease in diffusion and a reduction in dissolution (both will cause a decrease in bioavailability). In some cases food may be able to complex with the drugs. Usually this is reversible and so has little effect on bioavailability however, in some situations the complexation between food and drug will result in the irreversible formation of an insoluble complex. In such cases, the fraction of administered dose becomes unavailable for absorption and bioavailability is decreased (tetracycline able to bind to divalent cations, so avoid milk). Another potential problem is that foods being consumed with drug administration will lead to an increase in HCl in the stomach. This is liable into decrease in pH may cause pH sensitive drugs to be further degraded and lower bioavailability.
Indirect Mechanisms
Food can induce changes in pre-systemic metabolism. Examples of this may include the inhibition of CYP3A4 by grapefruit juice, leading to reduction in drug metabolism which would normally be enzymatically degraded (e.g. Simvastatin). Food induces changes in blood flow. Blood flow after a meal increases to the GI tract and liver. As drug is presented faster to the liver, it will be more likely to bypass the liver un-metabolised due to the swamping of enzymatic systems. This will lead to an increase in bioavailability. On the other hand, some drugs (e.g. propranol) are sensitive to their rate of presentation around the body and may be degraded at a faster rate, decreasing bioavailability.
