DRUG ABSORPTION, HOW DIFFERENT DRUGS ARE OBSORBED

Describing how drugs are absorbed from the site of administration into the systemic circulation

1. DRUG ABSORPTION JACQUELINE NJERI MUCHIRI MSc, PGDME, BPHARM

2. ABSORPTION Absorption is the passage of a drug from the site of administration into the systemic circulation (Plasma). Unless a drug acts topically (i.e. at its site of application) It must first enter the bloodstream and then be distributed to its site of action. The mere presence of a drug in the blood does not lead to a pharmacological response.

3. Cont……… To be effective, the drug must leave the vascular space and enter the intercellular or intracellular spaces To reach its site of action, a drug must cross a number of biological lipid barriers & membranes Processes, such as binding to plasma proteins, tissue storage, metabolism, and excretion, determine the amount of drug finally available for interaction with specific targets.

4. Absorption of drugs can occur by: Facilitated transport- movement of substances across a biological membrane by help of carriers or channels. Active transport- movement across a membrane against the concentration gradient by help of energy (ATP) Pinocytosis - a type of endocytosis where cell engulfs small molecules dissolved in extracellular fluid. Diffusion- the net movement of particles from a region of higher to a region of lower concentration.

5. Properties of drugs that influence their absorption Particle size Larger particles will need much more time to dissolve before they can be absorbed through biological membranes as compared to small particles

6. Drug formulation Different drug formulations will be absorbed at different rates For example solutions are designed to be absorbed much faster than tablets because they are ready to diffuse Tablets may have a resistant coating to resist degradation by gastric acid and be absorbed in the intestines.

7. Physical factors influencing absorption Blood flow to absorption site Blood flow to the intestines is much more than what flows to the stomach, thus much absorption occurs in the intestines than the stomach. Total surface area available for absorption The intestines has a surface area about 1000 times than that of the stomach, thus absorption of drugs across the intestines is more efficient compared to that of the stomach.

8. Contact time at the absorption surface. If the drug moves through the absorption surface like the GIT quickly as in cases of diarrhoea, the rate of absorption will be reduced. Any condition that delays the transport of drug from the stomach to the intestines delays its absorption. The intestine is the major area of drug absorption

9. Absorption of drugs from the GIT Oral cavity Drugs absorbed from the oral cavity enter the general circulation directly. Although the surface area of the oral cavity is small but diffusion is faster. Absorption can be rapid if the drug has a high lipid–water partition coefficient and therefore can readily diffuse through lipid membranes.

10. For instance, the weak base nicotine reaches peak blood levels four times faster when absorbed from the mouth (pH 6) than from the gastrointestinal tract (pH 1–5) The extensive network of blood vessels in the oral cavity facilitates rapid drug absorption Sublingual administration is the route of choice for a drug like nitroglycerin whose coronary vasodilator effects are required quickly in cases of angina

11. Absorption from the Stomach Facilitated by: the rich blood supply to the stomach wall. Affected by: the stomach emptying time Emptying time can be altered by many factors (e.g., volume of ingested material, type and viscosity of the ingested meal, body position, gastric emptying time), The low pH of the gastric contents (pH 1–2) The extent of gastric absorption will vary from patient to patient as well as at different times within a single individual.

12. Absorption from the Small Intestine The small intestine is composed of a single layer of cells called enterocytes. Enterocytes consists of many villi and micro-villi There is a complex supply of blood and lymphatic vessels into which digested food and drugs are absorbed. Most drug absorption occurs in the proximal jejunum (first 1–2 m in humans). The pH of the intestinal fluid (pH 5) will strongly influence the rate of drug absorption

13. weak acids like phenobarbital are more readily absorbed from the small intestine due to the large surface area. Conditions that shorten intestinal transit time (e.g., diarrhea) decrease intestinal drug absorption Increases in transit time will enhance intestinal absorption by permitting drugs to remain in contact with the intestinal mucosa longer

14. Absorption from the Large Intestine The large intestine has a considerably smaller absorptive surface area than the small intestine Little absorption occurs from this site, due to solid nature of the intestinal contents The extensive vascularity of the rectal mucosa facilitates drug absorption The most distal portion of the large intestine, the rectum, can be used directly as a site of drug administration.

15. Factors affecting the rate of GIT absorption Gastric Emptying Time Gastric emptying time markedly influences the rate at which drugs are absorbed Factors that accelerate gastric emptying time, thus permitting drugs to reach the large absorptive surface of the small intestine sooner, will increase drug absorption unless the drug is slow to dissolve.

16. Intestinal Motility Increased gastrointestinal motility may facilitate drug absorption by thoroughly mixing intestinal contents and thereby bringing the drug into more contact with the mucosal surface. However , the opposite may also occur in that an increase in motility may reduce contact time in the upper portion of the intestine where most of drug absorption occurs.

17. Food Absorption of most drugs from GIT is reduced or delayed by the presence of food in the gut. Drugs such as the tetracyclines can complex with Ca 2+ ions in food, or milk, reducing absorption Drugs like those used for worm elimination (ant helminthes) are usually taken on empty stomach to achieve desired effects. However some drugs may require the presence food to avoid gastric irritation

18. Formulation Factors Drugs administered in aqueous solution are absorbed faster and more completely than tablet, capsules or suspension forms. Suspensions of fine particles (microcrystalline) are better absorbed than are those of larger particles.

19. Absorption from the lungs The lungs serve as a major site of absorption for a number of agents given for both local and systemic effects. Such drugs can be inhaled as gases (e.g., volatile anesthetics) or as aerosols (suspended liquid droplets or solid particles) Facilitated by: the large surface area of the pulmonary alveolar The limited thickness of these membranes and, The high blood flow to the alveolar region.

20. Absorption through the skin Most drugs incorporated into creams or ointments are applied to the skin for local or systemic effects The diffusion rate of a drug through the skin is largely determined by the lipid–water partition coefficient of the drug The outer layer of the skin, forms a barrier against the rapid penetration of most drugs into the skin This is due in large part to the relatively close-packed cellular arrangement and decreased amount of lipid in these cells The hair follicles and sweat glands facilitate absorption through the skin

21. Absorption of drugs after parenteral administration IM and Subcutaneous Administration Because of the high tissue blood flow, drug absorption generally is more rapid after IM than after subcutaneous injection. Drug absorption from IM and subcutaneous sites depends on the quantity of drug given and the rate of vascular perfusion of the area

22. Intravenous Administration Intravenous drug administration ensures immediate pharmacological response Problems of absorption are avoided because the entire quantity of drug enters systemic circulation directly. This route is useful for: Drugs that are poorly absorbed (lipophobic) Those extremely irritating to tissues Those rapidly metabolized before or during their absorption from other sites. The rate of injection should be slow enough, to prevent excessively high local drug concentrations

23. A serious disadvantage of IV drug administration becomes clearly apparent when an overdose is given. Neither can the drug be removed nor its absorption retarded. Other disadvantages include the possibilities of embolism (particularly if an insoluble drug is given) Introduction of bacteria The possible introduction of the human immunodeficiency virus (HIV) is a well-known consequence of intravenous drug administration

24.   Bioavailability Bioavailability is the portion of the administered drug that reaches systemic circulation. However, this does not apply for intravenous administration because all the drug is applied directly into systemic circulation, hence bioavailability for IV route is 100%. It is expressed as a fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. For example if 100mg of a drug is administered orally and 70mg of the same drug is absorbed unchanged, the bioavailability of that drug is 70%.

25. Factors influencing bioavailability First-pass hepatic metabolism When the drug is absorbed across the GIT, it enters portal circulation before entering systemic circulation. If the drug is rapidly metabolised by the liver, the amount of unchanged drug that gains access to systemic circulation is decreased. This reduces bioavailability, eg propranolol or Lidocaine are rapidly metabolised by the liver.

26. Solubility of the drug For a drug to be rapidly absorbed, it must be largely lipophilic yet have some solubility in aqueous solutions. Chemical instability Some drugs like penicillin are unstable in the acidic pH of the stomach. Others like insulin may be destroyed in the GIT by degrading enzymes.

27. THE END