pharmacokinetics, overview pharmacokinetics: the study of the movement of drugs in the body,...
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- Slide 1
- Pharmacokinetics, Overview Pharmacokinetics: the study of the movement of drugs in the body, including the processes of absorption, distribution, localization in tissues, biotransformation and excretion Learning pharmacokinetics is of great practical importance in the choice and administration of a particular drug for a particular patient, e.g., one with impaired renal function
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- Drugs need to achieve an adequate concentration in their target tissues. The two fundamental processes that determine the concentration of a drug at any moment and in any region of the body are: translocation of drug molecules chemical transformation by drug metabolism and other processes involved in drug elimination These are critically important for choosing appropriate routes of administration Pharmacokinetics, Introduction Translocation of drug molecules: drug molecules move around the body in two ways: bulk flow transfer (i.e. in the bloodstream) The chemical nature of a drug makes no difference to its transfer by bulk flow. diffusional transfer (i.e. molecule by molecule, over short distances) Diffusional transfer (transmembrane movement of the drugs): ability to cross hydrophobic diffusion barriers is strongly influenced by lipid solubility. delivering drug molecules to and from the non-aqueous barriers is influenced by water solubility
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- The Movement of Drug Molecules Across Cell Barriers Gaps between endothelial cells are packed with a loose matrix of proteins that act as filters, retaining large molecules and letting smaller ones through. In some organs (e.g. the liver and spleen) endothelium is discontinuous, allowing free passage between cells. In other organs, especially in the CNS (blood brain barrier) and the placenta (placental barrier), There are tight junctions between the cells the endothelium is enclosed in an impermeable layer of periendothelial cells (pericytes). These features prevent potentially harmful molecules from leaking from the blood into these organs and have major pharmacokinetic consequences for drug distribution. Aqueous Diffusion: It occurs within the larger aqueous compartments of the body (interstitial space, cytosol, etc) and across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores. It is probably important in the transfer of gases such as carbon dioxide
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- The Movement of Drug Molecules Across Cell Barriers Passage of drugs across cell membranes 1) Passive transfer: a. Simple diffusion: The vast majority of drugs gain access to the body through this mechanism. Drugs must be first in aqueous solution to gain access to the lipid membrane Drugs pass along concentration gradient No energy or carrier is required It is not inhibited by metabolic inhibitors It is not saturable. It depends on: concentration gradient lipid solubility degree of ionization, thickness of membrane molecular size. Concentration gradient is maintained by removal of the drug from other side of the membrane. Lipid solubility is measured by lipid/water partition coefficient (ratio of drug concentration in lipid phase and water phase when shaken in one immiscible lipid/water system). Ionized drugs generally have low lipid/water coefficient.
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- The Movement of Drug Molecules Across Cell Barriers, Lipid solubility: weak acids and weak bases / Clinical Significance K a K a HA H + + A - BH + B + H + [UI] [I] [I] [UI] pK a =pH+log(HA/A - ) pK a =pH+log(BH + /B) ASPIRIN pK a = 3.5 (weak acid) 100mg orally 99.9 = [ UI ][ UI ] Stomach pH = 2 Blood pH = 7.4 0.1 = [ I ] Aspirin is reasonably absorbed Strychnine is not absorbed until from stomach (fast action) enters duodenum 0.1 = [ UI ] [ UI ] Blood pH = 7.4 99.9 = [ I ] STRYCHNINE pK a = 8.0 (weak base) 100mg orally Stomach pH = 2
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- In drug poisoning, renal elimination of drugs can be enhanced by changing urinary pH to increase drug ionization and inhibits tubular re-absorption. Alkalinization of urine by NaHCO 3 increases excretion of acidic drugs e.g. aspirin. Acidification of urine by vitamin C or NH 4 Cl increases excretion of weak base drugs e.g. amphetamine. The Movement of Drug Molecules Across Cell Barriers, Lipid solubility: weak acids and weak bases/ Clinical Significance, contd.
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- The Movement of Drug Molecules Across Cell Barriers, contd. b. Filtration: In capillaries, pores have large size and so nearly all free drugs in plasma can be filtered. It depends on hydrostatic and osmotic pressure, so it is limited by blood flow but not by lipid solubility and it is not saturable 2) Specialized transport: - Substances that are too large or poorly lipid soluble as amino acids and glucose are carried by specialized carriers. - a. Facilitated diffusion: is similar to simple diffusion but requires a carrier and it is saturable. - A carrier molecule is a transmembrane protein which binds one or more molecules or ions, changes conformation and releases them on the other side of the membrane. - Carrier molecules facilitate entry and exit of physiologically important molecules, such as sugars, amino acids, neurotransmitters and metal in the direction of their electrochemical gradient
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- The Movement of Drug Molecules Across Cell Barriers, contd. b. Active transport: where drugs pass against concentration gradient, so it requires: energy, carrier (thus it is saturable) Example: many drugs, especially weak acids (e.g., penicillin, uric acid) and weak bases (e.g., histamine), are actively secreted into the renal tubule, and thus more rapidly excreted MechanismDirectionEnergy requiredCarrierSaturable Passive diffusionAlong gradientNo Facilitated diffusionAlong gradientNoYes Active transportAgainst gradientYes
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- The Movement of Drug Molecules Across Cell Barriers, contd. c. Pinocytosis: It involves invagination of part of the cell membrane and the trapping of a small vesicle containing extracellular constituents within the cell The vesicle contents can then be released within the cell, or extruded from its other side Examples: Pinocytosis of vitamin B12 (complexed with intrinsic factor). It is important for the transport of some macromolecules (e.g. insulin, which crosses the bloodbrain barrier by this process)
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- Plasma level curve C max = maximal drug level obtained with the dose. t max = time at which C max occurs. Lag time = time from administration to appearance in blood. Onset of activity = time from administration to blood level reaching minimal effective concentration (MEC). Duration of action = time plasma concentration remains greater than MEC. Time to peak = time from administration to C max.
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- 1- Absorption It is the process of entry of drug from site of administration into systemic circulation. Factors influencing absorption A- Factors related to drug a) Physicochemical properties: 1-Degree of ionization: highly ionized drugs are poorly absorbed. 2-Degree of solubility: High lipid/water partition coefficient increases absorption. 3-Chemical nature: inorganic iron is better absorbed than organic iron. 4-Valency: ferrous salts are more absorbed than ferric, -so vitamin C increases absorption of iron. b) Pharmaceutical form of drug: Absorption of solutions is better than suspensions or tablets.
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- 1- Absorption, Factors Influencing Absorption, contd B- Factors related to the patient: 1-Route of administration: absorption is faster from i.v. > inhaled > i.m. > oral > dermal administration 2-Area and vascularity of absorbing surface: absorption is directly proportional to both area and vascularity. Thus absorption of the drug across the intestine is more efficient than across the stomach, as intestine has more blood flow and much bigger surface area than those of the stomach 3-State of absorbing surface: e.g. atrophic gastritis and mal-absorption syndrome decrease rate of absorption of drugs. 4-Rate of general circulation: e.g., in shock, peripheral circulation is reduced and I.V. route is used. 5-Specific factors and presence of other drugs: e.g. intrinsic factor of the stomach is essential for vitamin B12 absorption from lower ileum and adrenaline induces vasoconstriction so delay absorption of local anesthetics. secondsminuteshours
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- Bioavailability It is the fraction of drug that reaches systemic circulation in an unchanged form and becomes available for biological effect following administration by any route. It is 100% after IV administration. It is calculated by comparison of the area under the plasma concentration time curve (AUC) after IV dose of a drug with that observed when the same dose is given by another route e.g. oral. Area under the curve (AUC) oral x 100 Oral bioavailability = Area under the curve (AUC) I.V. Oral bioavailability depends on amount absorbed and amount metabolized before reaching systemic circulation (first pass metabolism) Bioequivalence: Bioequivalence occurs when two formulations of the same compound have the same bioavailability and the same rate of absorption
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- 2-Distribution Distribution of a drug from systemic circulation to tissues is dependent on lipid solubility, ionization, molecular size, binding to plasma proteins, rate of blood flow and special barriers The body compartments include extracellular (plasma, interstitial) and intracellular which are separated by capillary wall and cell membrane Intracellular compartment Interstitial compartment Intravascular
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