Drug Absorption Mechanisms PDF

D: diffusion coefficient. (corrected slide lecture 1) Related to the size and lipid solubility of the drug and the viscosity of the diffusion medium. Lipid solubility or molecular size D thus dM/dt A: surface area. The surface the rate of diffusio...

D: diffusion coefficient. (corrected slide lecture 1) Related to the size and lipid solubility of the drug and the viscosity of the diffusion medium. Lipid solubility or molecular size D thus dM/dt A: surface area. The surface the rate of diffusion x: membrane thickness. the quicker the diffusion. Concentration difference. The drug concentration in blood or plasma will be >> [S], max* [ S ] dc   dt then Kc + [S] can be dt K c  [S ] considered as Kc. dc = rate of absorption dt dc max = Max.rate of abs. at high drug conc. dt dc Kc = affinity const. of drug to carrier    K  [S ] [S] = drug conc. dt As Kc and dc/dt max are const. Active transport is unidirectional In vitro testing of absorption mechanisms  Facilitated passive diffusion Certain molecules with low lipid solubility (eg, glucose) penetrate membranes more rapidly than expected. A carrier molecule in the membrane combines reversibly with the substrate molecule releasing the substrate at the interior surface. Does not require energy expenditure  Mechanisms of absorption Ion-pair transport Highly ionized molecules at intestinal pH. Forms with cations a more lipophilic complexes. (e.g.mucin endogenous) Counter ion acts as organic carrier for hydrophilic mol. Then pass by passive diffusion (acc. to conc. grad. Substances like cholate, deoxycholate, taurocholate can act as binding agents.  Ion - pair absorption High Lower concentration concentration Intestinal Cell interior Cell membrane lumen Drug+ Ion- Drug+ ion- Drug+ Ion- Examples: quaternary ammonium compounds, tetracyclines, ampicillin, chloramphenicol, doxorobucin, timolol maleate, the formation of an ion pair for propranolol (basic drug) with oleic acid  Pinocytosis The only transport mechanism in which a drug compound must not be in aqueous solution to be absorbed. Vesicular transport:  It is the process of engulfing particles. -Pinocytosis: refers to the engulfment of small molecules or fluid. -Phagocytosis: refers to the engulfment of larger particles or macromolecules.  The cell membrane - invaginates to surround the material, - engulfs the material into the cell forms a vesicle or vacuole. Endocytosis and exocytosis are simultaneous process  Energy expenditure is required. Vesicular transport is the proposed process for vitamins A, D, E, and K, peptides  Pinocytosis High Lower concentration concentration Cell membrane Intestinal Cell interior lumen Drug Drug vacuole  Combined absorption models A drug may be absorbed by more than one mechanism. e.g. Vit B12 facilitated transport and passive diffusion. Cardiac glycosides are absorbed by active and passive diffusion Small molecules might be absorbed by passive diffusion and by convective transport. Combined absorption models (cont) Mouth cavity Stomach Passive and convective All mechanisms Small intestine Large intestine and rectum Passive and convective and pinocytosis  Distribution A B Drug S endothelial structure of O Blood capillaries (directly) or R P Lymphatic ducts (indirect) T I O N Systemic circulation Metabolism DISTRIB- and excretion UTION Into the tissue (distribution)  Distribution Distribution is the movement form central compartment (BLOOD) to the peripheral compartment (TISSUE) where the drug should be present S1 S2 Drug properties affecting its Distribution Apparent volume of distribution Vd= Parameter representing if a drug will remain in the plasma or redistribute to other tissue compartments. It is a constant relating the total amount of drug in the body to the plasma concentration of the drug at a given time. Vd = Amount of drug in the body (mg) / Plasma concentration of drug (mg/L)  Low Vd drugs – not lipophilic enough to bind to tissues – highly bound to plasma proteins versus tissue – restricted to the bloodstream and extracellular fluid and do not enter the tissue cells in sig. amounts. Moderate Vd drugs – are moderately lipophilic, so they permeate into cells, and are moderately bound to plasma protein and tissue components. They distribute evenly throughout the blood and tissues High Vd drugs – drugs are highly lipophilic – are highly permeable into cells and highly bound to tissue components versus plasma proteins.  After a drug enters the systemic circulation, – it is distributed to the body’s tissues. Distribution is generally uneven because of differences – in blood perfusion, – tissue binding, – regional pH, permeability of membranes. After equilibrium, drug concentrations in tissues and in extracellular fluids are reflected by the plasma concentration. Well perfused organs e.g. liver, heart, kidneys, lungs Poorly perfused organs e.g. fat tissues, bones PERFUSION After a drug entered tissues, drug distribution to the interstitial fluid is determined by perfusion. - Richly vascularized areas: distribution equilibrium between blood and tissue (rapid) - Poorly perfused tissues (eg, muscle, fat), distribution is very slow, BINDING The extent of drug distribution into tissues depends on -plasma protein binding distribution -tissue binding. Distribution of Hydrophobic small molecules HIGH Hydrophilic large molecules LOW Drugs bind also to body fat Fat is poorly perfused, Equilibration time is long, especially for lipophilic drugs. – Accumulation of drugs in tissues prolong drug action because the tissues release the accumulated drug as plasma drug concentration decreases.  Factor affecting drug distribution  Plasma protein and tissue binding  Age (total body water, fat content, organ composition, plasma protein content )  Pregnancy  Obesity  Diet  Disease state  Penetration of Drugs Through Blood Brain Barrier Drugs reach the central nervous system (CNS) via brain capillaries and cerebrospinal fluid (CSF). - Lipid-soluble drugs (eg, thiopental) enter the brain readily, - Polar compounds do not. Although the brain receives about one sixth of cardiac output, drug penetration is restricted because of the brain’s permeability characteristics. 47  Blood brain barrier The CNS circulation is made by blood capillaries structurally different from the tissues blood capillaries – Capillaries of the brain and spinal cord lack the small pores – Lined with a layer of special endothelial cells sealed with tight junctions. – Surrounded by astrocytes Special cells of supporting tissue at the base of endothelial membrane. BBB is further reinforced by a high concentration of P-glycoprotein (Pgp), active -drug-efflux-transporter protein BUT inflamm’n can disrupt integrity Penicillin large water soluble molecule (doesn‘t cross BBB in normal cond.)  Biopharmaceutics of different routes Sublingual / Buccal route Sublingual route: the dosage form is placed beneath the tongue. Buccal route: Dosage form is placed between the cheek and teeth or in the cheek pouch. Oral mucosal regions are highly vascularised therefore rapid onset of action 10/10/2024 52  SUBLINGUAL / BUCCAL ROUTE Avoidance of first pass effect …. Passive diffusion Thickness of oral epithelium: Sublingual absorption is faster than buccal, because former region is thinner than buccal mucosa. Designed to dissolve slowly to minimize possibility of swallowing the dose. Exception include: Nitroglycerin, Isosorbide dinitrate tablets which dissolves within minutes in buccal cavity to provide prompt treatment of acute anginal episodes. 10/10/2024 53  Oral epithelium characteristics. Tissue Structure Thickness Bloodflow (µm) (mL/min/ cm2) Buccal Non keratinized 500 – 600 2.4 Sublingual Non keratinized 100 – 200 0.9 Gingival Keratinized 200 1.5 Palatal Keratinized 250 0.9 10/10/2024 54  Factors limiting buccal drug administration 1. Limited mucosal surface area. 2. Taste of medicament and discomfort. EXAMPLES: Nitroglycerin, Isosorbide dinitrate, Progesterone, Oxytocin, Fenosterol, Morphine. 10/10/2024 55  Dosage forms for the oral cavity  Mucoadhesive patches  Chewable formulations  Gums  Tablets. method for prolonging drug release some antifungals comparison with liquids (antacids) 10/10/2024 56  Colon and colon delivery The large intestine is responsible for water absorption Parts are – ascending, transverse, descending and sigmoid portions of the colon, and finally the rectum. 10/10/2024 57 10/10/2024 58  Organ time Stomach 0.3-5hr. Small intestine 1-5 (av.3hr.) Large intestine Up to 24hr or more 10/10/2024 59 Problems of the colon: - Low dissolution volume - Reduced SA - Sluggish movement eventhough - Local action in colon balanced by the slower transit. - Systemic action? 10/10/2024 60  Nasal drug delivery It is the organ of smell (but a very small area is dedicated for this task) and has an important role in respiration.  Heating and humidification of air is done in the nose  Heating by the abundant blow flow  Humidification by mucous secretion 10/10/2024 61  It is divided by middle (or nasal) septum into two symmetrical halves, each one opening at the face through nostrils and extending posterior to the nasopharynx. Both symmetrical halves consist of four areas 1- Nasal vestibule 2- Atrium 3- Respiratory region 4- Olfactory region 10/10/2024 62 3. Respiratory region Humidification and temperature regulation of inhaled air. It contains globet cells, mucus Epithelial cells are covered on their apical surface with microvilli and cilia. Microvilli enhance the respiratory surface area, Cilia are essential to transport the mucus toward the nasopharynx. 10/10/2024 63 4- Olfactory region Olfactory epithelium contains specialized olfactory receptor cells for smell perception. Small serous glands (glands of Bowman) secretions acting as a solvent for odorous substances. This area is mostly lined with mucous membrane. It contains the nerve cells A receptor potential in the cell is generated initiating a nerve impulse in the olfactory nerves to the brain. Direct CNS transport 10/10/2024 64 Nasal mucus layer It is of 5 μm thick 2 distinct layers: – an external, viscous and dense, (gel layer) – an internal, fluid and serous (sol layer). The protective action by – adhesive characteristics of mucus – to attract inhaled particles or pathogens, Removed towards the nasopharynx – by nasal MCC. (mucociliary clearance) 10/10/2024 65  Nasal lymphatic system and importance for vaccination The nasopharyngeal region possesses a very rich lymphatic plexus, 10/10/2024 66  Advantages of Nasal delivery  Nose can be used as a route for systemic drug delivery.  It is an easy acceptable route.  It avoids the first pass effect.  Intranasal administration of drugs  As alternative for injection (children)  For elderly  Small molecules are absorbed at a very rapid rate (IV)  Volume, conc. viscosity, pH(5.5-6.5), tonicity 10/10/2024 68 Concerns about nasal route - Regardless of the mechanism by which drug is administered to the nose, any absorbed drug will either be blown out of the nose, or will clear to the gastrointestinal tract. - Accordingly, the consequence of gastrointestinal absorption should always be considered when administering any drug to the nose - Pathological conditions affecting mucociliary functions: Rhinitis, Asthma, Sinusitis Nasal polyps (prevent humidification and temperature control) 10/10/2024 69  Nasal drug delivery  Drugs are absorbed by passive diffusion.  Rapid onset of action but limited time of absorption.  Increase residence time by (increasing viscosity by the use of viscosity modifiers, thermoreversible gels and use of mucoadhesives PAA, hyaluronic acids)  Site for  Topical administered drugs e.g local decongestant local vasoconstricting action  Drugs for systemic administration, e.g. hormones, antiemetic drugs, sedative drugs, antimigraine drugs 10/10/2024 70  Nasal drug delivery Formulation Concerns  Permeation enhancers can also enhance absorption of macromolecules. Preservatives??? Bioadhesives Dosage forms 10/10/2024 71  Lung drug delivery Lung membrane -Alveolar surface 80- 140 m2, much larger than that of the nose (about 180 cm2) -Alveolar membrane thickness 0.1 and 0.2 µm -Highly perfused organ 5 l/min -Avoid first-pass effect -Some metabolism occurs -Permeable to water, most gases and lipophilic substances. - Tight junctions, endothelial junctions with gap junction - pH 6-7.6 72  Lung and drug delivery The size of the alveolar surface varies between 80 and 140 m2, and much larger than that of the nose (about 180 cm2) Another advantage of the lung is the thin alveolar epithelium. The thickness of this epithelium in most regions is between 0.1 and 0.2 µm* Furthermore, the lung is perfused with a blood volume of about 5 l/min at rest without a first-pass effect, Some metabolism takes also place in the lung 10/10/2024 73 10/10/2024 74