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Class drug absorption

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Class drug absorption

  1. 1. Dr. RAGHU PRASADA M S MBBS, MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1
  2. 2. PHARMACOKINETICS: Pharmacokinetics is the science of the kinetics of drug absorption, distribution, and elimination (i.e, excretion and metabolism). PHARMACODYNAMICS: Pharmacodynamics refers to the relationship between the drug concentration at the site of action (receptor) and pharmacologic response. ABSORPTION: “The process of movement of unchanged drug from the site of administration to systemic circulation is called as absorption”. It can also be defined as the process of movement of unchanged drug from the site of administration to the site of measurement i.e plasma.
  3. 3. The process whereby drug moves from the muscle, digestive tract or other site of entry into the body towards the circulatory system Drugs are administered away from their site of action . To reach their site of action they are permeate from one compartment to another by crossing the different barriers. So the drugs have to cross the cell membranes.
  4. 4. Fluid bi-layer of phospholipids. Scattered membrane protein molecules embedded in bi-layer serve as Receptors--- selective targets for drug action Ion channels Transporters Lipid molecules are capable of lateral movement. It is flexible Has high electrical resistance Relatively impermeable to highly polar molecules Highly permeable to lipid soluble drug molecules
  5. 5. 1. Passive diffusion Lipid diffusion Aqueous diffusion 2. Carrier mediated transport Active transport Facilitated diffusion 3. Pinocytosis Endocytosis Exocytosis
  6. 6. Pores of about 10 nm and 50 to 70 nm were inferred to be present in membranes based on capillary membrane transport studies. These small pores provide a channel through which water, ions, and dissolved solutes such as urea may move across the membrane. Passive Diffusion: Passive diffusion is the process by which molecules spontaneously diffuse from a region of higher concentration to a region of lower concentration. This process is passive because no external energy is expended
  7. 7. Important for drug molecules too large or too insoluble in lipid to diffuse passively through membranes. Carriers are trans-membrane proteins. The drug molecules chemically related to naturally occurring peptides, amino-acids, or sugars can use these carriers. Carrier binds one or more molecules or ions, changes conformation & releases them on the other site of membrane.
  8. 8. Main sites: Renal tubule. Biliary tract. Blood brain barrier. (BBB) Gastrointestinal tract. (GIT) Types: Active Transport Facilitated Diffusion:
  9. 9. Active transport: The characteristics are: Against the concentration gradient Energy dependent , obtained from hydrolysis of ATP Carrier is required Selective Saturable Competitive inhibition by another drug binding to same carrier.
  10. 10. Reverse transporters: Carriers specialized in expelling foreign molecules as the enter the cells. One large family is ABC (ATP binding cassette ) family It includes P-glycoprotein or multidrug resistance type 1 (MDR1) transporter, found in the brain, testis & other tissues and in some drug resistant neoplastic cells It can be inhibited by grape fruit juice & certain drugs i.e VERAPAMIL. 2. Multidrug resistance –associated protein (MRP) transporters play important role in excretion of drug or its metabolites into urine or bile.
  11. 11. Facilitated Diffusion: A mechanism to enhance diffusion of drugs with low lipid solubility. Along a concentration gradient Carrier mediated: Carrier increases lipid solubility of drug →↑rate of diffusion Not energy dependent Saturable Competitive inhibition e.g. Glucose entry into the cell by Glucose transporters- GLUT1-GLUT5
  12. 12. Specific receptors for transport proteins must be present for this process to work. Endocytosis: Drugs which have very large molecules (macromolecules) can be engulfed by the cell membrane in a vesicle & carried into the cell & released within the cell by pinching off the vesicle & breakdown of its membrane. Examples: Transport of vitamin B12 with a binding protein ( intrinsic factor) across gut wall. Iron is transported into hemoglobin synthesizing RBCs precursors with transferrin.
  13. 13. Exocytosis is the reverse of endocytosis.It is responsible for secretion of many substances from cells. e.g. Expulsion of neurotransmitters into the synaptic cleft. The neurotransmitter substances are stored in membrane bound vesicles in nerve endings to protect them from metabolic destruction . Appropriate activation of nerve ending causes expulsion of its contents in to the synaptic cleft.
  14. 14. Solid dosage form Granules or aggregates Fine particles Drug in solution At absorption site Ionic drug Ionic drug Non-ionic drugNon-ionic drug1 2 3 3 3 4 BloodGI Lumen GI Barrier Sequence of events in the absorption of drugs from orally administered solid dosage forms
  15. 15. Physicochemical/ Pharmaceutical factors: Drug solubility & dissolution rate Particle size & effective surface area Polymorphism & amorphism Pseudoploymorphism (hydrates/solvates) Salt form of the drug Lipophilicity of the drug pH- Partition-hypothesis pKa of drug & gastrointestinal pH Drug stability
  16. 16. Physicochemical/ Pharmaceutical factors : Disintegration time (tablets/capsules) Dissolution time Manufacturing variables Pharmaceutical ingredients (excipients/adjuvants) Nature & type of dosage form Product age & storage condition
  17. 17. Pharmacokinetic factors : Route of administration Membrane physiology a) Nature of cell membrane b) Transport processes Age Gastric emptying time and Intestinal transit time Gastrointestinal pH Disease states Blood flow through the GIT Gastrointestinal contents: a) Food- drug interactions b) Fluids c) Other normal GI contents Presystemic metabolism by: (first pass metabolism) a) Luminal enzymes b) Gut wall enzymes
  18. 18. PHYSICOCHEMICAL/PHARMACEUT- ICAL FACTORS 1) Drug solubility & dissolution rate : The rate determining steps in absorption of orally administered drugs are: 1. Rate of dissolution 2. Rate of drug permeation through the biomembrane. Dissolution is rate determining step for hydrophobic & poorly aqueous soluble drugs. E.g. Griseofulvin & Spironolactone. Permeation is the rate determining step for hydrophilic & high aqueous soluble drugs. E.g. cromolyn sodium OR Neomycin.
  19. 19. 2) Particle size and effective surface area: Particle size may play a major role in drug absorption. Dissolution rate of solid particles is proportional to surface area Smaller particle size, greater surface area then higher will be dissolution rate, because dissolution is thought to take place at the surface area of the solute( Drug). Particle size reduction has been used to increase the absorption of a large number of poorly soluble drugs E.g. Bishydroxycoumarin, digoxin, griseofulvin
  20. 20. We have to reduce the size of particles up to 0.1 micron to increase surface area of absorption. So these can be achieved by “micronisation process’’. a) HYDROPHILIC OR b) HYDROPHOBIC a) HYDROPHILIC DRUGS: In hydrophilic drugs the small particles have higher energy than the bulk of the solid resulting in an increased interaction with the solvent. Examples, 1.Griesiofulvin – Dose reduced to half due to micronisation. 2.Spironolactone – the dose was decreased to 20 times
  21. 21. 3.Digoxin – the bioavailability was found to be 100% in micronized tablets. After micronisation it was found that the absorption efficiency was highly increased b) HYDROPHOBIC DRUGS: In this micronisation techniquies results in decreased effective surface area & thus fall in dissolution rate. The hydrophobic surface of the drugs adsorbs air on to their surface which inhibits their wettability. Ex Cyclosporin
  22. 22. Drug stability: A drug for oral use may destabilize either during its shelf life or in the GIT. Two major reasons for poor bioavailability -Degradation of the drug into inactive form and -Interaction with one or more different component(s) either of the dosage form or those present in the GIT to form a complex that is poorly soluble or is not absorbable
  23. 23. Many drugs are weak acids/bases Can be ionized, unionized Varies with pH of environment Acids release H+ Strong: All H+ released Weak: Some H+ released Ka quantitates strength of acid
  24. 24. Oral – 5<100% bioavailability First pass effect is significant Absorption in small intestine is primarily dependent on physico-chemical properties Non ionised compounds –ethyl alcohol and Low molecular weight substances –urea readily cross cell membrane Rectal -30<100% bioavailability Only about 50% of the rectal dose may pass through liver (external haemorrhoidal veins). Barriers here are colonial mucosa, anaerobic organisms and enzymatic activity E.g. Metoclopramide, ergotamine, lidocaine
  25. 25. Absorption of Drugs Lung – gases, liquid droplets 5<100% bioavailability The drug can have local effects - Epinephrine for asthma. The drug can have systemic effects - general anesthetics. Large surface area, limited thickness of pulmonary membrane and high blood flow allow for almost instant absorption by diffusion Avoid first pass effect Lungs are also site of first pass excretion Bioavailability characteristics with different routes
  26. 26. Intra-arterial: nearly 100% bioavailable Intra-arterial injection is used to deliver drugs directly to organs, for example, in cancer chemotherapy, and in the use of vasopressin for GI bleeding. Intrathecal: nearly 100% bioavailable Injection directly into the cerebrospinal fluid (CFS) ensures complete CNS bioavailability for drugs that can not cross the blood-brain barrier. E.g. Mepivacaine and prilocaine for spinal anesthesia. Intravenous (IV): nearly 100% bioavailabe IV administration introduces drug directly into the venous circulation. IV bolus is used for immediate therapeutic effect, typically for general anesthesia and for treatment of cardiac arrhythmia.
  27. 27. Intramuscular (IM): nearly 100% bioavailable For drugs and vaccines that are not absorbed orally, for example, aminoglycosides, insulin and hepatitis vaccine. The IM route is often used for sustained medication and specialized vehicles, such as aqueous suspensions, oily vehicles Topical route: Transdermal: 80<100 % bioavailable Continuous release of drug over a specified period, low presystemic clearance, and easy drug withdrawal by simply removing the device, and good patient convenience and compliance.
  28. 28. Intranasal: Intranasal administration may be used for local or systemic effects. Local effects include treatment of nasal allergies, rhinitis, and nasal congestion. Nasal delivery for systemic effects is established for a small number of drugs E.g. Vasopressin analogues and oxytocin are commercially available for intranasal dosage. Vaginal: vaginal absorption can give rise to rapid and efficient systemic delivery. E.g. vaginal rings and biodegradable microspheres
  29. 29. Sublingual/Buccal: Drugs can be absorbed from the oral cavity itself or sublingually. Absorption from either route is rapid, sublingual more so apparently because of greater permeability of sublingual membranes and rich blood supply. E.g. organic nitrates, barbiturates, papaverine, prochlorperazine, benzodiazepines.
  30. 30. Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route Factors influencing bioavailability First pass metabolism Solubility of drug Chemical instability Drug formulation Enzyme induction Individual variation
  31. 31. The tmax is independent of dose and is dependent on the rate constants for absorption (ka) and elimination (k) At Cmax, sometimes called peak concentration, the rate of drug absorbed is equal to the rate of drug eliminated. Therefore, the net rate of concentration change is equal to zero AUC is a measure of the body’s exposure to a drug 32
  32. 32. The AUC-Area Under Curve is expressed in the units of mg-hr/ml Planimeter –an instrument for measurement of area of plane figures Cut and weigh method- that means to cut out the area under the entire curve on rectilinear graph paper and weigh it on analytical balance Mathematical –using trapezhoid rule
  33. 33. When drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation. Here some part of drug gets metabolized and amount of unchanged drug that gains access to the systemic circulation is decreased. Ex- lidocaine, morphine, nitroglycerine, propranolol
  34. 34. THANKYOU Download slides from Authorstream-raghuprasada Slideshare-raghuprasada Youtube-raghuprasada

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