Drug Absorption and Distribution PDF

Absorption of drug  Transfer of drug across biological membranes Drugs diffuse across a cell membrane from a region of high concentration (gastrointestinal fluids) to one of low concentration (blood).  Diffusion rate is directly proportional to the gradient but also dep...

Absorption of drug  Transfer of drug across biological membranes Drugs diffuse across a cell membrane from a region of high concentration (gastrointestinal fluids) to one of low concentration (blood).  Diffusion rate is directly proportional to the gradient but also depends on : The molecule's lipid solubility, Size Degree of ionization The area of absorptive surface Passage of drug across cell membranes influenced by Physiochemical factors include: I)Characteristics of drug molecule: 1- Molecular size and shape. 2-Degree of lipid solubility II)The cell membrane: The cell plasma membrane is a common barrier to drug transfer. It is formed of two outer layers of protein and lipid center with many minutes' pores.  Processes of crossing the cell membrane 1- Passive transport This takes place when molecules diffuse across the cell membrane by travelling through specific transport proteins. It occurs down a concentration gradient - molecules move from an area of high to lower concentration. This does not require a supply of energy because diffusion is a spontaneous process.  An example of passive transport is the uptake of glucose by liver cells. Glucose diffuses from the blood into the cytoplasm of liver cells via a transport protein called GLUT4. 1- Passive transport  2- Active transport This occurs when molecules are moved across the cell membrane from an area where they are at a low concentration to an area where they are at a high concentration by specific transport proteins.  This movement is against the concentration gradient so the transport proteins require an energy supply. Energy is provided by the breakdown of ATP inside the cell.  An example of active transport is the action of a transport protein called the sodium- potassium pump. Lots of copies of this protein are found in the cell membrane of nerve cells. The proteins pump sodium out of the cells and potassium into the cells. This helps nerve cells to transmit nerve impulses.  3- Facilitated diffusion Facilitated diffusion is a type of diffusion in which the molecules move from the region of higher concentration to the region of lower concentration assisted by a carrier. Non lipid soluble drugs can diffuse through the lipid matrix by the help of a carrier system of enzymes from extracellular to intracellular fluid along the concentration gradient. 3- Facilitated diffusion  4-Pinocytosis Pinocytosis may be responsible for the movement of large lipid-insoluble molecules (30 nm) between blood and interstitial fluid Briefly, cell membranes endocytosis the external substances and collect them inside the membrane-bound vesicles, which are then transferred inside the cell. This is an energy-consuming process and could play a minor role in the transport of drugs (excluding protein molecules).  Factors affecting absorption related to drug related to the patient animals  Factors affecting absorption 1- Factors related to drug A- Physiochemical properties of the drug 1- Lipid solubility 2- Degree of ionization 3- Molecular weight and valiancy. 4- Chemical nature, organic or inorganic  B- Pharmaceutical form of drug: Solutions are rapidly absorbed than suspensions and then powder according to particle size.  2- Factors related to the patient animals a- Pathological condition of the absorbing surface b-Rate of general circulation c-Specific factors d-Route of drug administration  DRUG DISTRIBUTION After absorption drugs pass to various body compartments as: 1- Free in blood plasma. 2- Free in extracellular fluid. 3- Free in intracellular fluid. 4- Bound to plasma proteins. 5- Bound to tissue proteins. 6- Stored in fat depots.  Distribution in extra or intracellular fluid is according to PH gradient of the two fluids. Some organs are impermeable to certain drugs by their barriers.  Blood barriers Glial cells in the capillaries of certain organs, selectively permeable to certain drugs, and not to others. Barriers include mainly the blood brain and blood placental barriers. Others as intestinal, serous and milk barriers also exist.  Blood brain barrier (BBB) This includes the C.N.S. and C.S.F. Quaternary ammonium compounds cannot pass this barrier as neostigmine while anaesthetics easily pass it. Drugs intended to act on the C.N.S. must be capable to pass the blood brain barrier.  Blood placental barrier Drugs capable to pass this barrier reach the fetus and may result in resorption, abortion, malformation or fetal depression. Drugs intended for use in pregnants must not pass this barrier.  Storage depots Drugs may be stored in the body in : 1-Plasma proteins : Albumin and other plasma proteins may bound to drug molecules remaining inactive, not metabolized or excreted as phenylbutazone  2-Extracellular depots : Connective tissue bound to ionic muco polysaccharides. Hair, bones and teeth may act as a reservoir to heavy metals and tetracyclines.  3-Tissue proteins : Certain drugs bound to tissue proteins more than plasma as digitalis in cardiac muscles. 4-Fat: Is an important store for lipid soluble drugs as thiopental. Redistribution of drugs to other sites than its site of action terminates its effect, as thiopental from brain to fats.  Protein bounding It is a specific affinity which is variable for different drugs and in different species of animals. This variation may account for the differences in the rates of drug absorption, distribution, biotransformation or excretion. It is a reversible process and the protein bound drug molecule is inactive as cannot cross biological membranes to the site of action. It cannot be metabolized or excreted.  Effects of protein bounding on drug kinetics: 1- Facilitation of absorption: by low concentration of free molecules. 2- Facilitation of distribution: acting as a carrier for drugs insoluble in plasma to their sites of action as steroids. 3- Prolongation of drug action: by buffering the drug concentration, slow metabolism or excretion.  4- Increasing initial doses: to reach the therapeutic dose of unbound drug. 5- Lowering the dose in hypo proteinaemia : to avoid drug toxicity. 6- Drug interaction by replacing other protein bound drugs by higher affinity resulting in toxicity, as phenylbutazone and dicoumarol or salycilates and thyroxin.