Drug Absorption Processes PDF

ABSORPTION OF DRUGS Dr. Salma Naqvi Asst. Prof., Pharmacology GMU, Ajman Learning Objectives: At the end of the lecture the student should be able to: Define absorption and explain different processes by which absorption can occur. List vario...

ABSORPTION OF DRUGS Dr. Salma Naqvi Asst. Prof., Pharmacology GMU, Ajman Learning Objectives: At the end of the lecture the student should be able to: Define absorption and explain different processes by which absorption can occur. List various factors affecting drug absorption. Explain how ionization of a drug affects its absorption. Describe various factors which may affect bioavailability of a drug. Understand the significance of plasma half life of a drug  ABSORPTION Absorption is the process by which drugs enter the systemic circulation (Blood) from the site of administration. The drug has to cross the biological membranes in order to get absorbed from the site of administration. The process of drug absorption applies to all routes of administration, except for the topical route, in which drugs are applied directly on the target tissue, and intravenous administration, in which the drug is given directly in the bloodstream. Orally administered drugs are absorbed from small intestine - portal vein - liver - systemic circulation.  Processes of Absorption Passive diffusion: The drug diffuses across the membrane in the direction of its concentration gradient, the membrane playing no active role in the process. This is the most important mechanism for majority of drugs. Lipid diffusion is a process by which highly lipophilic drug dissolves in the lipid components of the cell membranes. Aqueous diffusion/Filtration: It occurs by passage through aqueous pores in cell membranes. Lipid-insoluble drugs cross biological membranes by filtration if their molecular size is smaller than the diameter of the pores. Majority of cells (intestinal mucosa, RBC, etc.) have very small pores and drugs with MW > 100 or 200 are not able to penetrate and absorb. Active transport: Active transport requires a carrier molecule (transmembrane proteins which serve as carriers) and a form of energy. Active transport can transfer drugs against a concentration gradient. Facilitated diffusion: It also requires a carrier molecule, but no energy is needed. Thus drugs or substances cannot be transferred against a concentration gradient but diffuse faster than without a carrier molecule present. Illustration of passive diffusion and filtration across the lipoidal biological membrane with aqueous pores Fig. 2.5: Illustration of different types of carrier mediated transport across biological membrane ABC—ATP-binding cassettee transporter; SLC—Solute carrier transporter; M— Membrane A. Facilitated diffusion: the carrier (SLC) binds and moves the poorly diffusible substrate along its concentration gradient (high to low) and does not require energy B. Primary active transport: the carrier (ABC) derives energy directly by hydrolysing ATP and moves the substrate against its concentration gradient (low to high) C. Symport: the carrier moves the substrate ‘A’ against its concentration gradient by utilizing energy from downhill movement of another substrate ‘B’ in the same direction D. Antiport: the carrier moves the substrate ‘A’ against its concentration gradient and is energized by the downhill movement of another substrate ‘B’ in the opposite direction  FACTORS AFFECTING DRUG ABSORPTION 1. Particle size: Small particles absorb faster. 2. Drug concentration: Concentrated solutions are absorbed faster as compared to dilute solutions. 3. Lipid Solubility: Lipid soluble drugs are easily absorbed by passive diffusion (because the cell membrane is made up of phospholipids) 4. Water solubility: Water soluble drugs are poorly absorbed 5. Drug solubility: drugs given in aqueous solutions are more rapidly soluble than when given in oily solution, suspension or solid form 6. Dosage form: Tablets and capsules, rate of disintegration and dissolution is limiting factor in their absorption. After dissolution, smaller the particle size, more efficient will be absorption 7. Area of absorbing surface: Most drugs are well absorbed from small intestine due to large surface area  FACTORS AFFECTING contd.. 6. Vascularity of the absorbing surface: Increased blood flow increases drug absorption. 7. Route Of Administration: Oral route: Slow and erratic absorption. Sublingual, I.V. : Immediate and complete absorption 9. Presence of food: Decreases absorption 10.Degree of ionization: Non–ionized drugs are better absorbed than ionized. Note: Lipid soluble and unionized drugs are easily absorbed than water soluble and ionized drugs  Ionization & pH Acidic drugs remain unionized in acidic medium and are easily absorbed e.g. Aspirin absorbed from the stomach; Iron salts are absorbed from acidic medium Basic drugs remain unionized in basic and are easily absorbed e.g. alkaloids absorbed from the small intestine Lipid soluble(hydrophobic), uncharged, unionized will cross the membrane rapidly than lipid insoluble(hydrophilic or water soluble), charged and ionized. Acidic drugs are ionized more in alkaline urine—do not back diffuse in the kidney tubules and are excreted faster. Accordingly, basic drugs are excreted faster if urine is acidified. Functional integrity of the GIT: Increased peristaltic activity as in diarrhea reduces drug absorption Increased gastric emptying time: absorption will be more.  BIOAVAILABILITY It is the fraction of the dose that reaches the circulation in unchanged form. Bioavailability of orally administered drugs is less than 100% because of incomplete absorption and first pass metabolism. Bioavailability of drugs is 100% when given by intravenous or sublingual route Factors which increase drug absorption increase the bioavailability and those which decrease absorption decrease the bioavailability of the drug Main organ of metabolism is liver Specific drugs are metabolized in gut wall, skin, lungs  Factors affecting Bioavailability First-pass hepatic metabolism: when a drug is absorbed across GIT, it enters the portal circulation before entering the systemic circulation. If the drug is rapidly metabolized by the liver ,the amount of unchanged drug that gains access to the systemic circulation is decreased Absorption Solubility of the drug: hydrophobic drug will absorb more so bioavailability will be more Chemical instability: some drugs are unstable in pH of the gastric contents. Others are destroyed in GIT by degradative enzymes e.g. insulin Particle size: smaller the particle size more absorption will be there.  Plasma Half Life (t1/2) The time required for the concentration of drug in the plasma to decrease to one half of its initial value. For example if the initial conc. of drug is 100mg and if the half life is 1 hr, only 50mg will remain in the plasma at the end of 1 hr, 25mg at the end of 1 hr  Significance of Plasma t1/2 It denotes how quicky a drug is removed from the plasma by biotransformation or excretion Since drug require a minimum conc. in the plasma to produce pharmacological action, a drug which is eliminated quickly requires more frequent dosing than a drug with a long half life. It thus indicates the duration of action of drug and therefore it determines the frequency of administration of dose of the drug for therapeutic effectiveness.  Points to Remember ❖ Transfer across Membrane by 3 processes ❖ Absorption means drug reaching the blood, which is affected by various factors. ❖ Lipid soluble and unionized drugs are easily absorbed. ❖Ionization of the drug and pH of the medium plays important role in the absorption and excretion of the drug. ❖ Bioavailability means fraction of total dose reaching the blood. It varies depending upon different factors. ❖t1/2 is important to determine the concentration of drug in the plasma at a given time References: Brenner and Stevens’ Pharmacology, 5 th edition, Chapter 2 (https://www.clinicalkey.com/#!/content/book/3-s2.0- B9780323391665000025?scrollTo=%23hl0000503 ) Tripathi K.D., Essentials of Medical Pharmacology, 7th Edition, 2013, 2, p 10-17.  Revision 1. Alkalinization of urine hastens the excretion 3. The most important factor governing of : absorption of a drug from intact skin is : a. Weakly basic drugs a. Molecular weight of the drug b. Weakly acidic drugs b. Site of application c. Strong electrolytes c. Lipid solubility of the drug d. Nonpolar drugs d. Nature of the base used in formulation 2. Diffusion of drugs across cell membrane : 4. What kind of substances can’t permeate a. Is dependent upon metabolic activity of membranes by passive diffusion? the cell a. Lipid-soluble b. Is competitively inhibited by chemically b. Non-ionized substances related drugs c. Hydrophobic substances c. Is affected by extent of ionization of d. Hydrophilic substances drug molecules d. Exhibits saturation kinetics 5. Which route of administration of drug will provide highest bioavailability? 6. Which route of drug administration is most likely lead to the first-pass effect? 7. Which of the following factor does not influence the oral bioavailability of the drugs a. metabolism by gut wall enzymes b. Decomposition by hydrolytic gut enzymes c. Chelation with existing food in stomach d. Plasma half life 8. A 60-year-old woman complained of weakness, lethargy and easy fatigability. Investigation showed that she had iron deficiency anaemia (Hb. 8 g/dl). She was prescribed cap. ferrous fumarate 300 mg twice daily. She returned after one month with no improvement in symptoms. Her Hb. level was unchanged. On enquiry she revealed that she felt epigastric distress after taking the iron capsules, and had started taking antacid tablets along with the capsules. What could be the possible reason for her failure to respond to the oral iron medication? THANK YOU