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Physiological factors effecting bioavailability{ndds.2(1)}

Physiological factors such as the route of administration, gastrointestinal pH, motility and emptying time, presence of food, and disease states can impact drug absorption from the gastrointestinal tract. The route determines the absorption site and potential for first-pass metabolism. Gastrointestinal pH and surface area affect drug solubility and ionization state. Motility and emptying time influence drug contact with the mucosa. Food and disease can modify gastrointestinal conditions and blood flow, altering drug dissolution and permeability. These physiological factors must be considered for optimal drug bioavailability.

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Physiological Factors Affecting Drug bioavailability presented by M.pharm(2 sem) Dept of pharmaceutics
• Physiological Factors Affecting Drug Absorption (1) Routes of drug administration (2) Membrane Physiology i) Nature of cell membrane ii) Transport processes (3) pH and surface area of GIT (4) Gastric emptying time. (5) Gastrointestinal motility (6) Splanchnic blood flow (7) Drug stability in GIT (8) Effect of food and nutrients (9) Disease state (10) Drug interaction
. Routes of Administration and Drug Absorption • The route of administration (ROA) that is chosen has a large impact on how fast the drug is taken up and how much of it arrives at its destination in an active form. • The route of administration is determined by the physical characteristics of the drug, the speed at which the drug is absorbed, as well as the need to bypass hepatic metabolism and achieve high conc. at particular sites • Oral: Drug is taken orally. • Features: Absorption takes place along the whole length of GIT (i.e. large surface area) • Absorption site: Gastrointestinal epithelia
• . Buccal/Sublingual: Drug is place in mouth or under tongue. Features: Rapid absorption avoiding first-pass effect. Drugs which are highly lipid-soluble and subject to high first-pass effect if swallowed are given through this route (e.g. Nitroglycerine) • Absorption site: Buccal/ Sublingual mucosa • Inhalation: The drug is inhaled and absorbed through the lungs Features: large surface area and rapid absorption -Avoids first pass-metabolism. • -Volatile and gaseous drugs are given in this route (e.g Absorption site: Alveoli of lung • Intranasal: drug is given into the nasal cavity • Absorption site: Nasal membrane • Rectal: Drug is given into rectum e.g. suppositories • Feature: absorption process avoids first-pass metabolism • Absorption site: epithelia of rectal wall
• Parenteral routes: Biotechnology-derived drugs (e.g. insulin, erythropoietin, somatotropin) are given through parenteral route because they are too labile in GIT to be given orally. • Intravenous (IV): placing a drug directly into the blood stream Features: no absorption required, 100% bioavailable, rapid onset of action Intramuscular (IM): drug injected into skeletal muscle; absorption is faster then SC but slower than IV Absorption site: striated muscle fiber Subcutaneous (SC): Absorption of drugs from the subcutaneous tissues Absorption site: Subcutaneous tissue
. No single method of drug administration is ideal for all drugs in all circumstances The oral route is the most popular route of administration of drug because of its- • Large surface area for absorption • Compartments with different pH that accommodate the drugs of different solubility • Convenient, easy and efficient route compared to other routes
• 2. Membrane physiology •For systemic drug absorption drug molecules must cross the cell membrane (oral route-intestinal epithelium). •Drug molecules may pass either transcellular pathway or paracellular pathway. •The permeability of a drug at the absorption site into systemic circulation depends on : -molecular structure and properties of the drug. -physical and biochemical properties of cell membrane. •So the biological membranes pose a significant barrier to drug delivery. i) Nature of cell membrane ii) Transport processes
• . i Structure of cell membrane • Cell membranes are generally thin,approximately 70 to 100 Å in thickness. • Composed of primarily of phospholipids in the form of a bilayer interdispersed with carbohydrates and protein groups. • There are several theories as to the structure of cell membrane such as Danielli-Davson model, Unit membrane model, Fluid mosaic model . ii. Transport Process Passage of drugs across cell membranes: 1.Passive diffusion. 2.Carrier mediated transport • Active transport • Facilitated diffusion 3.Ion pair formation. Others are: - Endocytosis -Exocytosis
• A. Passive diffusion • Passive diffusion is the process by which molecules spontaneously diffuse from a region of higher concentration to a region of lower concentration. • It does not require energy. • Drug molecule diffuses according to Fick’s law of diffusion: dQ/dt= DAK (Cg-Cp)/ h • Passive diffusion is the major absorption processes for most of the drugs.
• B.carrier mediatedTransport • . Carriy a carrier present at the absorption site. •Numerous specialized carrier mediated systems are present in the body especially in the intestine for the absorption of ions and nutrients required by the body. • •It is two types: -Active transport (energy dependent). -Facilitated diffusion(not energy dependent).
i. Active Transport • Active transport requires a carrier molecule and a form of energy. The energy is provided by the hydrolysis of adenosine tri phosphate. •Active transport can transport a drug against a concentration gradient i.e. from regions of low drug concentration to regions of high drug concentration.
• .Sodium, Potassium, Calcium ions, glucose, amino acids vitamins like niacin, ascorbic acid are absorbed by this way. • Drugs like methotrexate (anti cancer drug)-structurally similar to folic acid, 5- fluorouracil (antineoplastic drug)- structurally similar to uracil are absorbed by this way. • Only a few drugs are absorbed by active transport mechanism.
i. Facilitated Diffusion • Facilitated diffusion also requires a carrier molecule. But it does not require energy. • Here the drug moves along a concentration gradient. • Some cephalosporin antibiotics such as cephalexin undergo facilitated diffusion by an oligopeptide transporter protein located in intestinal epithelial cells.
• C . Ion-Pair Formation • Ion-pair formation is the main pathway for ionized drugs specially for which maintain ionized state at any pH. • These drugs penetrate the membrane poorly. So the charged drug forms a complex with oppositely charged ligand and becomes neutral. • This neutral complex can easily cross the absorption barrier by passive diffusion. • Ligand + drug→ ion-pair→ absorption barrier→ drug +ligand • Ex: propranolol forms ion pair with oleic acid.
• D. Endocytosis • In endocytosis membranes invaginate or pinch in to form a vesicle enclosed the moving materials inside the cell.
• E. Exocytosis • •Exocytosis is the process of a cell exporting material using vesicular transport. Intracellular vesicle moves to the plasma membrane, where they fuse with the membrane and release their contents into surrounding fluids. •Cells of stomach and pancreatic cells secrete digestive enzymes through exocytosis. •Certain neurotransmitters (such as nor-epinephrine) are stored in membrane bound vesicles in the nerve terminal. They are released by exocytosis.
• .21. pH AND SURFACE AREA OF GIT
• ORAL CAVITY • Saliva is the main secretion of the oral cavity • pH 7 • Contains ptyalin which digests starch. e.g fentanyl citrate, nitroglycerin etc (lipid soluble drug) • .ESOPHAGUS • It connects the pharynx and the cardiac orifice of stomach • pH 5-6 • Very little drug dissolution occurs in it
• .. STOMACH • Fasting pH 2-6 • pH in presence of food is 1.5-2 • Intrinsic factor enhances vit B-12 absorption & gastric enzymes initiate digestion • Basic drugs are solubilized rapidly in presence of acid • pH may be increased due to certain drugs e.g omeprazole • Ethanol easily crosses cell membrane & efficiently absorbed from the stomach • e.g ibuprofen,aspirin etc absorbed here
• INTESTINE • pH 5-8 • Large area for drug absorption • pH is optimum for enzymatic digestion of protein and peptide containing food. Hence protein type drug (e.g insulin) can’t be administered orally • The influence of absorptive surface area is much prominent than pH. • e.g vitamine,diazepam,quinidine etc absorb here
• COLON AND RECTUM • pH 5.5-7 • Colon promotes melting of oily drugs to form emulsion. • e.gIn crohn’s disease prednisolone,hydrocortisone for infammatory bowel disease • Rectums pH is 7 and virtually has no buffer capacity • Oral SRDF are well absorbed in colon (e.g theophylline) • Suppositories are well absorbed in rectum
IONIZATION of DRUG • Acidic drugs are absorbed faster in acidic pH as they remain unionized in acidic medium of stomach. So they can be absorbed through lipidic cell membrane.e.g aspirin ,ibuprofen • Basic drugs are not absorbed well in acidic pH because they ionized in acidic medium. • Basic drugs remain unionize in basic medium (small intestine) and can be easily absorbed.e.g codein • Acidic drugs ionize in basic medium so can’t be absorbed. • Highly acidic or basic drug ionize at all pH hence poorly absorbed in GIT.e.g disodium cromogylate.guanethidine etc
• GASTRIC EMPTYING TIME • The time taken for stomach contents to be passed into the duodenum influenced by gastric motility,activity of pyloric sphincter etc • If acidic drugs remain for long time into stomach, they get absorbed at a faster rate. • And if basic drug remains for a short time in stomach and being more time in small intestine, they get easily absorbed. • for acidic drug gastric emptying time should be more and for basic drug less. • Example: penicillin is unstable in acid and decomposes if stomach emptying is delayed. Other drugs, such as aspirin, may irritate the gastric mucosa during prolonged contact.
• . FACTORS INFLUENCING GASTRIC EMPTYING TIME Factors Influence on Gastric Emptying volume The larger the starting volume, the greater the initial rate of emptying, after this initial period, the larger the original volume, the slower the rate of emptying. Type of meal Reduction in rate of emptying to an extent directly dependent upon concentration of carbohydrate,lipid and protein type food Osmotic pressure Reduction in rate of emptying to an extent dependent upon concentration for salts and nonelectrolytes Physical state of gastric contents Solutions or suspensions of small particles empty more rapidly Body position Rate of emptying is reduced in a patient lying on left side. Viscosity Rate of emptying is greater for viscous solutions.
• . Contd. Factors influence on Gastric Emptying Emotional states Aggressive or stressful emotional states increase stomach contractions and emptying rate; depression reduces stomach contraction and emptying. Disease states Rate of emptying is reduced in some diabetics and in patients with local pyloric lesions and hypothyroidism; gastric emptying ratei s increased in hyperthyroidism. drugs Anticholinergic,narcotic analgesic etc decrease emptying
. GASTROINTESTINAL MOTILITY • It tends to move the drug through the alimentary canal • This movement helps drug particle to come in contact with mucosa and absorbed • The excessively rapid movement of GIT impairs absorption.
• Gastrointestinal Motility Disorders • Achalasia • Gastroesophageal Reflux Disease (GERD) • Functional chest pain • Gastroparesis / Delayed gastric emptying • Rapid gastric emptying • Idiopathic vomiting / Cyclic vomiting syndrome • Functional dyspepsia • Constipation • Diarrhoea • Irritable bowel syndrome • Fecal incontinence
• . INTESTINAL MOTILITY • It mix the contents of the duodenum, bringing them into intimate contact with the mucosal cells. • The drug must have a sufficient time at the absorption site for optimum absorption. • In case of high motility(e.g diarrhea) the drug has a very brief residence time and less opportunity for adequate absorption
• . Factors affecting intestinal motility a.Physical activity b.Food c.Emotional condition d.Age, gender e.Disease state,drug etc It is very important in absorption and bioavalability of SRDFs,enteric coated dosage forms and drugs which are absorbed by carrier mediated transport systems of small intestine.
• . Intestinal Motility Disorders • Intestinal pseudo-obstruction • Irritable bowel syndrome • Fecal incontinence • Constipation
.SPLANCHNIC BLOOD FLOW • Some drugs are achieving higher plasma conc. after food, this is because food increase splanchnic blood flow. • e.g propranolol, chloramphenicol, lithium carbonate. • The absorption of some drugs is reduced due to presence of food (e.g ampicillin, aspirin, L-dopa) • In hypovalemic state, the splanchnic blood flow is reduced. So absorption of the drug is also decreased
• . DRUG STABILITY IN GIT • Metabolism or degradation by enzymes or chemical hydrolysis may adversely affect the drug absorption. • Destruction in gastric acid (e.g penicillin)
• . EFFECT OF FOOD • The presence of food in the GI tract affects the bioavailability of oral drugs. • Some effects of food on the bioavailability of the oral drugs include: • Delay in gastric emptying time • Stimulation of bile flow • Change in the pH of GI tract • Increase in splanchnic blood flow • Change in luminal metabolism of drug substances • Physical/chemical interaction of metal with drug substances
• . Contd. • The nutrient and caloric contents of the meal, meal volume, meal temperature etc affect drug product transit time, luminal dissolution, drug permeability and systemic availability. Thus it affects drug absorption. • Absorption of some antibiotics decreases when administered with food (e.g. penicillin, tetracycline)
• Contd. • Absorption of some lipid soluble drugs increases when administered with food. e.g. metazalone. • The presence of food in the GI lumen stimulates the flow of bile which increases the solubility of fat soluble drugs by forming micelle. • The presence of food in the stomach lowers the pH which causes rapid dissolution and absorption of basic drugs with limited aqueous solubility. e.g. cinnarizine
• Contd. • Drugs irritating to GI mucosa (e.g: erythromycin, aspirin, NSAIDs etc) given with food to reduce the irritation by decreasing the rate of drug absorption. • In the presence of food, enteric coated and non disintegrating drug products can not reach the duodenum rapidly, thus they delay drug release & systemic drug absorption.
• . Contd. • Food can also affect the integrity of dosage form which causes an alteration in the release rate of the drug. e.g. theophylline. • Timing of drug administration is important as taking a medication either 1 hr before or 2 hr after meals , avoid any delay in drug absorption.
• . Effect of nutrients on drug absorption • Absorption of water soluble vitamins (e.g. B- 12, folic acid) in the stomach are facilitated by forming complex with intrinsic factors. • Absorption of calcium in the duodenum is facilitated by vita-D by increasing calcium binding protein which binds calcium in the intestinal cell & transfer it to the blood circulation.
• . Contd. • Grape juice contains various flavonoids e.g. naringin which inhibits cytochrome P-450 enzymes . Thus it inhibits absorption of some drugs.
• EFFECT OF DISEASE STATES • Drug absorption differs in any disease which causes changes in – • 1. Intestinal blood flow • 2.Gastrointestinal motility • 3.Changes in stomach emptying time • 4.Gastric Ph • 5.Intestinal pH • 6. Permeability of gut wall • 7. Bile secretion • 8.Digestive enzyme secretion • 9.Alteration of normal GI flora
• . Contd. • Patient with Parkinson’s disease have difficulty swallowing & greatly diminished GI motility • Patient on tricyclic antidepressants & antipsychotic drugs reduce GI motility which delay drug absorption • In achlorhydric patient weak-base drugs remain undissolved in stomach because no adequate acid e.g. Dapsone
• . Contd. • In patient with acid reflux disorder ,PPI such as omeprazole , render stomach achlorhydric, may affect drug absorption • HIV-AIDS patients are prone to a number of GI disturbances e.g. increased gastric transit time, diarrhea • CHF patient with persistent edema reduce blood flow to the intestine & intestinal motility results in decrease absorption e.g. furosemide
• . Contd. • Crohn’s disease causes impaired absorption due to reduce surface area & thicker gut wall e.g. higher plasma propranolol conc. observe in crohn’s • . • .permeability of small intestine • Cephalexin absorption increase in Celiac disease
• DRUGS THAT AFFECT ABSORPTION OF OTHER DRUGS • Metoclopramide stimulates stomach contrac tion & increases intestinal peristals • Decrease the peak drug conc. by reducing effective time for absorption • For example, digoxin absorption is reduced by metoclopramide but increased by propantheline bromide
• Contd. • Anticholinergic drug (propantheline bromide) may slow stomach emptying &motility of small intestine • Tricyclic antidepressants & phenothiazines with anticholinergic side effects cause slower peristalsis & stomach emptying may delay in drug absorption • Antacid not given with cimetidine,tetracycline because reduce absorption
• . Contd. • PPI e.g. omeprazole rais gastric pH • Interfere with drugs for which gastric pH affects bioavailability (e.g.ampicillin)& enteric- coated drug product (e.g. aspirin) • Cholestyramine is a nonabsorbable ion- exchange resin for the treatment of hyperlipemia • It binds warfarin,thyroxine,thereby reducing absorption of these drugs.
• . Contd. • Erythromycin inhibits the hepatic metabolism of a number of drugs e.g. Digoxin. • Antibiotic eliminates a species of intestinal flora that inactivates digoxin,thus leading to greater reabsorption of drug from the enterohepatic circulation.
Physiological factors effecting bioavailability{ndds.2(1)}