PoDA 2 Study Guide PDF

PoDA 2 Study Guide -- Mira Haddad START OF EXAM 1 Chapter 1: Introduction to Physicochemical Properties 1. Understand the importance of dosage form development to the practice of pharmacy The ultimate goal is a reproducible and predictable therapeutic response within the population...

PoDA 2 Study Guide -- Mira Haddad START OF EXAM 1 Chapter 1: Introduction to Physicochemical Properties 1. Understand the importance of dosage form development to the practice of pharmacy The ultimate goal is a reproducible and predictable therapeutic response within the population Need for dosage forms include: ○ High potency and low dosage of most therapeutic agents ○ Help the drug stability, solubility, ionization, osmolarity and tonicity, concealing bad taste 2. Define a therapeutic range and understand the physiologic factors that contribute to pharmacokinetic and pharmacodynamic variability Therapeutic range: the plasma or blood [ ] range associated with an acceptably high probability of therapeutic success AND acceptably low probability of an adverse effect, not considered in absolute terms ○ Steady state: rate in= rate out, fluctuate between same peak [ ] and same trough [ ] ○ The larger the range, the safer the drug Pharmacokinetic: what the body does to the drug, ADME→ [ ] vs time graph ( usually 1st order) Pharmacodynamics: what the drug does to the body → effect vs log [ ] graph (sigmoidal) ○ Effect vs time = PK and PD data The relationship between dose and effect is significantly more variable than is the relationship between [ ] and effect ([ ] and effect correlated but not linear) 3. List the most important physicochemical properties of a drug and dosage form that will determine its biological performance Organoleptic properties: color, taste, smell: alter to help patient compliance, should not affect performance ○ All salts do not taste salty ○ Low MW = salty, High MW = bitter ○ High hydroxyl groups = sweeter Particle size (surface area), solubility, dissolution, partition coefficient, ionization constant, crystal properties, stability 4. Recite pertinent examples of how the physicochemical properties of a drug affect the performance of the drug or dosage form in patients REDUCING particle size, INCREASES specific surface area (surface area per unit weight), in turn increasing the rate of dissolution → affects absorption ○ Poorly soluble drugs will be affected by particle size because dissolution is their rate limiting step (RLS) ○ If a drug has good solubility, then the dissolution rate will be fast and the absorption rate (permeating the membrane) will be the RLS ○ Noyes Whitney Equation: shows which variables can affect dissolution rate K = partition coefficient: lipophilic character of a drug Cs = [ ] of drug in stationary layer, C = [ ] of drug in bulk fluid 1  PoDA 2 Study Guide -- Mira Haddad Chapter 2: States of Matter 1. Understand the atomic and intermolecular forces that govern molecular structure and the physicochemical properties of drugs Interaction between two molecules involves both repulsive and attractive forces Latent heat of vaporization: heat that is absorbed (taken up) when a liquid vaporizes or heat liberated when gas condenses Latent heat of fusion: heat that is absorbed when a gram of solid melts or liberated when it freezes Boiling point (BP): the temperature at which thermal agitation can overcome the attractive forces between the molecules of a liquid (the temperature at which vapor pressure of the liquid equals the external or atmospheric pressure) Melting point (MP): the temperature at which a solid passes into the liquid phase Freezing point: the temperature at which a liquid passes into the solid phase ○ Melting and freezing point = same values 2. List and describe the types of Van der Waals forces Van der Waals interactions = attractive forces, increase with increasing number of atoms in the molecules Theses forces are weak compared to covalent bonds but there are many Dipole-dipole interactions: hydrogen bonding, partial charges that are opposite attract Debye interactions: dipole induced- dipole interaction, permanent dipoles are capable of inducing an electric dipole in non polar molecules London force: induced dipole-induced dipole, interaction between two non polar molecules (no inherent electric dipole) 3. Explain how molecular weight (MW) and carbon number affect melting point, boiling point, solubility, etc. Boiling point ○ INCREASES with an increase in MW, higher #C = higher BP ○ H-bonding is a stronger interaction and can account for higher BP Melting point ○ INCREASES with an increase in MW (normal saturated hydrocarbons), higher #C = higher MP ○ Odd number of carbon atoms are packed less efficiently so they are LOWER than even numbered Solubility ○ Larger side chains causes less interactions with other molecules (intermolecular forces) and more interactions with the solvent ○ Larger side chains INCREASE solubility but DECREASE MP because of steric hindrance (pack less tightly) 4. Illustrate the use of cocoa butter in the manufacture of suppositories and the relationship to polymorphs Polymorphs: substances that exist in more than one crystalline form, but still chemically identical, the forms can differ in MP and solubility Cocoa butter is a solid at 23oC and when heated to 34oC a drug can be added and it can then be cooled down to form a suppository ○ If heated 35oC or above, the unstable structure forms, this causes the melting point to change (15oC) and it is no longer a solid at room temperature, which makes it a poor suppository as it will be a liquid at room temperature 5. Understand and recite the physical mechanisms providing for drug delivery from pharmaceutical aerosols Drug in volatile solution: under pressure, propellent = liquid form, drug is dissolved ○ The pressure forces the solution to expel, and once it evaporates it leaves just the drug Inert gas: liquid concentrate and compressed inert gas 2  PoDA 2 Study Guide -- Mira Haddad ○ Small dry particles are expelled (ex. inhalers) 6. Define terms related to phase diagrams and the Phase Rule Phase: homogeneous, state of matter, distinct portion of system Phase Rule: F = C - P + 2 ○ C= number of components ○ F = degrees of freedom, how many variables are needed to identify a point on the diagram F= 2 when given one state of matter F= 1 when given two states of matter (along the curve) F= 0 at the triple point ○ P= how many phases are present 7. Calculate the proportion of phases existing in a two component system containing liquid phases and/or solid phases See practice problems/HW on carmen 3  PoDA 2 Study Guide -- Mira Haddad 8. Predict the state of a physical system containing a liquid and solid given knowledge of the [ ] and temperature of the system See practice problems/HW on carmen Chapter 3: Solution Dosage Forms 1. Be able to define a solution Solution: a mixture of two or more components that form a homogeneous molecular dispersion (one phase system) 2. Be able to list the nine basic types of solutions Gas in gas: air Liquid in gas: water in oxygen Solid in gas: iodine in air Gas in liquid: coke, beer Liquid in liquid: alcohol in water Solid in liquid: NaCl solution Gas in solid: hydrogen in palladium Liquid in solid: mineral oil in parafin Solid in solid: gold-silver mixtures, alums 3. Which (of the above answer) are the most pharmaceutically relevant Gas in liquid Liquid in liquid Solid in liquid → most pharmaceutically relevant 4. Be able to discern differences between different types of solutions i.e. how does a simple solution differ from a syrup Simple solution: solid drug dissolved in a liquid solvent (pharmaceutically relevant) Syrups: concentrated aqueous solutions of sugars/sugar substitutes (pharmaceutically relevant) Elixirs: sweetened, hydroalcoholic solutions which hold both water soluble and alcohol soluble drug in solution (pharmaceutically relevant) Tinctures: alcoholic or hydroalcoholic solutions prepared from plant/vegetable materials or chemical substances Fluidextracts: alcoholic preparations of plant/vegetable materials such that 1mL contains 1g of the standard drug Spirits: alcoholic or hydrochloric solutions of volatile substances (e.g. oils) (high alcohol content) 4  PoDA 2 Study Guide -- Mira Haddad Aromatic waters: saturated aqueous solutions of volatile substances (e.g. perfumes) 5. What properties make a syrup naturally resistant to bacterial growth The sugar content is very high and prevents the bacteria from being able to grow 6. Be able to list and define the seven types of solutions (and based on route of administration) Oral solutions: systemic and local by mouth Ophthalmic solutions: local by eye Otic solutions: local by ear Nasal solutions: local and some can be systemic by nose Topical solutions: systemic and local by skin Rectal solutions: systemic and local by rectum Irrigation solutions: local for cleaning wounds 7. Be able to list and describe the 5 types of pharmaceutical waters Purified Water, USP: purified by distillation, ion exchange, or reverse osmosis ○ For compounding solutions, NOT for parenterals Water for Injection, USP: purified water that is pyrogen free ○ Used for production of injectable products, NOT sterile, sterilized after production Sterile Water for Injection, USP: same as WFI but sterile ○ Used for reconstitution or dilution of parenterals Bacteriostatic Water for Injection, USP: same as SWFI but contains microbial agent ○ Used in small volume parenterals due to possible toxicity, not used in newborns Sterile Water for Irrigation, USP: same as SWFI ○ Packaged for irrigation use, larger volumes Chapter 4: Physicochemical Properties of Solutions 1. Distinguish between the different components and types of solutions Solvent: component of solution that determines the phase of the solution, usually the liquid (major component) Solute: component of solution that is homogeneously dispersed as molecules throughout solvent, usually the solid (minor component) 2. Be able to define and/or describe the following terms: Electrolyte: substances that form ions in solution, conducts an electrical current, demonstrate atypical changes in colligative properties Non-electrolyte: substances that do not yield ions when dissolved in water and do not conduct an electric current Ideal solution: a solution in which there is NO CHANGE in the properties of the components of the solution, other than dilution, when they are mixed to form the solution, NO HEAT evolved or absorbed ○ (100mL + 100mL = 200mL) ○ Strength of attractive forces between the solute-solvent must be identical to solute-solute and solvent-solvent Non-ideal (real) solution: a solution in which their is a CHANGE in properties of the components, other than dilution, when they are mixed to form a solution, HEAT is evolved or absorbed ○ (100mL + 100mL = 180mL) Negative deviation: adhesive attraction between molecules of different species exceeds the cohesive attraction of like molecules resulting in LESS than expected vapor pressure ○ Solute-solvent has the greatest attraction (compared to solvent-solvent and solute-solute) Positive deviation: interaction between solute-solvent molecules is less than that between pure constituents resulting in GREATER than expected vapor pressure ○ Solute-solute and solvent-solvent are the greater attraction (compared to solute-solvent) 5  PoDA 2 Study Guide -- Mira Haddad 3. Be able to calculate and express [ ] in terms of molarity, molality, mole fraction, percent, and milliequivalents Molarity: the number of moles of solute contained in 1000mL of solution (M or moles/L) ○ Values change with temperature due to expansion/contraction of liquids Molality: the number of moles of solute contained in 1000g of the solvent (m or moles/kg) Mole fraction: the ratio of the number of moles of one component of a solution (i.e. solute) to the sun of the number of moles of all the components of the solution (i.e. solute + solvent) (no units) Percent expressions ○ Mole percent: mole fractions * 100 ○ % by volume (v/v): mL of solute in 100mL of solution ○ % by weight (w/w): grams of solute in 100g of solution ○ % by weight in volume (w/v): grams of solute in 100 mL of solution ○ Mg %: mg of solute in 100 mL of solution (w/v * 1000) 4. Be able to distinguish between additive, constitutive, and colligative properties Additive: depend on the total contribution of the atoms in the molecules or on the sum of properties of the components in solution ○ MW is the sum of masses of constituent atoms of a molecule ○ Total mass is the sum of masses of individual components Constitutive: depend on the structural arrangement of the individual atoms or functional groups of the molecule ○ Optical rotation, viscosity, surface tension, vapor pressure, freezing point, boiling point Colligative: depend mainly on the number of particles in a solution (a change in a constitutive property but not the constitutive property themselves) ○ Vapor pressure lowering, freezing point depression, boiling point elevation, osmotic pressure 5. List and describe 4 colligative properties Vapor pressure lowering ○ Vapor Pressure: The pressure exerted by molecules in the vapor state when in equilibrium with molecules in a liquid or solid state at a constant temperature, measure of escaping tendency of the components of the solution, need to acquire sufficient energy to overcome attractive forces to escape to form a gaseous phase, liquids exert a greater vapor pressure compared to solids since it is easier for liquids to go to a vapor state ○ When a non-volatile solute is combined with a volatile solvent it alters the ability of the solvent molecules to escape from the surface, nonvolatile solvent addition results in REDUCED vapor pressure ○ The more solute dissolved, the greater the DECREASE in vapor pressure Freezing point depression ○ When a solute is added to a solvent, a DECREASE in the freezing point occurs in proportion to the [ ] of the solute Boiling point elevation ○ Boiling point: temperature at which vapor pressure of the liquid reaches equilibrium with the atmospheric pressure ○ Solution needs to be heated to a HIGHER temperature for the vapor pressure to reach atmospheric pressure → as more solute is dissolved the bond between solute-solvent is greater than solvent-solvent Osmotic pressure ○ Most clinically relevant → ophthalmic, parenteral, nasal, and topical dosage forms 6  PoDA 2 Study Guide -- Mira Haddad ○ Osmosis: process by which solvent molecules pass through a semipermeable membrane from a region of low solute to a region of higher solute [ ] ○ Osmotic pressure: pressure applied to pure solvent in order to prevent it from passing into the given solution by osmosis → can be used to express [ ] of solution ○ Colligative property in itself 6. Explain using Raoult's Law/own terms how the addition of solute to a solution changes the colligative properties Adding more solute to a solution changes the vapor pressure because it changes the escaping tendency of the components of the solution → changes bond strengths Raoult's Law → addition of partial pressure of each component in a solution is equal to total vapor pressure → partial pressure = mole fraction x pure component Vp As the components of the solution change so will the total vapor pressure, making it a colligative property Chapter 5: Osmolarity and Tonicity 1. Define the behavior of red blood cells in the presence isotonic, hypotonic, and hypertonic solutions HypOtonic ○ A solution that has a LOWER osmotic pressure (solute [ ]) than body fluids ○ Causes swelling and BURSTING of the cell as water rushes in Isotonic ○ A solution that has the SAME osmotic pressure (solute [ ]) as body fluids ○ Eg sodium chloride 0.9% or dextrose 5% HypErtonic ○ A solution that has a HIGHER osmotic pressure (solute [ ]) as body fluids ○ Causes SHRINKAGE of the cell as water is drawn out ONLY WHEN blood cells are impermeable to the solute and permeable to the solvent 2. Distinguish between isotonic and isoosmotic solutions Isotonic ○ A solution that has the SAME osmotic pressure as a BIOLOGICAL membrane ○ As long as the membrane is impermeable to the solute of the solution Isoosmotic ○ A solution that has the SAME osmotic pressure as another solution A solution that is ISOOSMOTIC with BLOOD is ISOTONIC ONLY when the RBC is IMpermeable to the solute molecule 3. Define units of osmolality and tonicity ( and define terms) Osmolality ○ Milliosmol ○ Measures [ ] of all solutes (penetrating and non-penetrating) in a solution → osmotic pressure Tonicity ○ NO UNITS ○ Biological effect ○ Measures [ ] of non-penetrating solutes in a solution 4. Know normal serum osmolarity numbers Normal serum osmolarity values: 275-300 mOsmol/L This DOES NOT guarantee isotonicity→ ONLY if solute is impermeable to membrane will this range be considered isotonic Liquid dosage forms should be close to this range → minimize discomfort 7  PoDA 2 Study Guide -- Mira Haddad 5. Be able to calculate milliosmoles/L and adjust pharmaceutical solutions for tonicity (i.e. calculate the amount of sodium chloride or other osmotic agents necessary to make a solution isotonic) Calculate the amount of sodium chloride represented by the ingredients Calculate the amount of sodium chloride alone that would be contained in an isotonic solution of that volume The amount of sodium chloride you need = second step - first step If an agent other than sodium chloride is used, adjust to tonicity by dividing step 3 by sodium chloride equivalent of other substance 6. Be able to calculate sodium chloride equivalents MW of substance * NaCl’s i value / MW of NaCl * substance’s i value = 1/X ○ X = sodium chloride equivalent 7. Be able to perform isotonicity calculations using freezing point (0.52 * MW) / (1.86*i ) = g of solute/ 1000 g of water ○ -0.52oC → freezing point of both human blood and lacrimal fluid ○ When 1 mole of a nonelectrolyte is dissolved in 1000g of water, the freezing point of solution is about 1.86oC below the freezing point of pure water Chapter 6: Drugs as Acids and Bases 1. Distinguish between strong and weak electrolytes Strong electrolytes: acids or bases that have acidity or basicity constants greater than about 10-2 ○ Completely ionized (100%) when placed in water ○ pKa = - log (Ka) ○ pKa or pKb < 2 Weak electrolytes: acids or bases that have acidity or basicity constants less than 10-2 ○ Tend to ionize less when placed in aqueous solution, and are likely to show changed in the degree of ionization in the range of pH encountered in the human body ○ pKa or pKb > 2 2. Given the appropriate information be able to calculate Ka Kb pKa and pKb Acid dissociation constant , Ka ○ Ka = [H+] [A-] / [HA] → pKa = - log (Ka) Base dissociation constant, Kb ○ Kb = [BH+] [-OH] / [B] → pKb = - log (Kb) Henderson-Hasselbach Equation ○ pH = pKa - log ([HA] / [A-]) = pKa - log (unionized/ionized) 3. Describe how changes in pH affect the extent of ionization of weak acids and bases Important because unionized form can cross biological membrane and ionized cannot, so absorption will occur at a greater rate for unionized species Weak acids ○ HA↔ H+ + A- ○ LOW pH = UNIONIZED, HIGH pH = IONIZED Weak bases ○ BH+ ↔ H+ + B ○ LOW pH = IONIZED, HIGH pH = UNIONIZED 4. Explain how the extent of ionization affects solubility and absorption Absorption ○ Want to be unionized in order to cross biological membrane easier ○ Weak acids: LOW pH is FAVORABLE for absorption because its in its UNIONIZED state 8  PoDA 2 Study Guide -- Mira Haddad ○ Weak bases: HIGH pH is FAVORABLE for absorption because its in its UNIONIZED state Solubility ○ Want to be ionized in order to be more soluble in water → charges attract water (aid in dissociation ) ○ Weak acids: HIGH pH is FAVORABLE for solubility because its in its IONIZED state ○ Weak bases: LOW pH is FAVORABLE for solubility because its in its IONIZED state 5. Be able to calculate the extent of ionization of a compound at different pHs % Ionization for weak acids ○ 100 / 1+ 10^(pKa-pH) % Ionization for weak bases ○ 100 / 1+ 10^(pH-pKa) 6. Describe how the pKa of a drug will affect its absorption in different parts of the gastrointestinal tract Drugs are absorbed in GI tract by passive diffusion depending on fraction of unionized drug present at the pH of the intestines Acidic drugs ○ Best absorbed from acidic solution (stomach, LOW pH) → pH < pKa ○ LOW pKa = HIGH ionization at any pH Basic drugs ○ Best absorbed from higher pH (intestines) → pH > pKa ○ HIGH pKa = HIGH ionization at any pH LARGE SURFACE AREA of SMALL INTESTINE is able to compensate for unfavorable pH changes, which allows both weakly acidic and weakly basic drugs to be ABSORBED FASTER in SI 7. Describe how urine pH affects the elimination of weak acids/bases from the body How drugs move through the kidney ○ Glomerulus: filtration → remove drug from blood and place in urine for elimination ○ Proximal tubule: active secretion → remove drug from blood and place in urine for elimination ○ Distal tubule: reabsorption → allows filtered and secreted substances to go back into blood Passive reabsorption → occurs due to [ ] gradient between high drug [ ] in the urine and low drug [ ] in the blood, depends on physicochemical properties of drug and on pH of urine (pH = 5-8) → only drug close to this range will be affected by urine pH Weak acids ○ LOW urine pH = less ionized, MORE reabsorbed (less eliminated) ○ HIGH urine pH = more ionized, LESS reabsorbed (more eliminated) Weak bases ○ LOW urine pH = more ionized, LESS reabsorbed (more eliminated) ○ HIGH urine pH = less ionized , MORE reabsorbed (less eliminated) 8. List the conditions necessary for renal absorption for weak acids/bases Weak acids ○ pKa between 3-7.5 ○ HA must be non-polar ○ Fraction of drug excreted from urine must be high (kidney metabolism) Weak bases ○ pKa between 6-12 9  PoDA 2 Study Guide -- Mira Haddad ○ B is non-polar ○ Fraction of drug excreted in the urine must be high (kidney metabolism) 9. Define buffer, buffer action, and buffer capacity Buffer: compounds or mixtures of compounds that, by their presence in solution, RESIST changes in pH upon the addition of small quantities of acid or base → commonly made from weak acids and their salts Buffer action: resistance to a change in pH Buffer capacity: the ability of a buffer to resist a change in pH upon addition of acid or base ○ Not a fixed value (depends on amount of acid or base added) ○ Greatest when the pH = pKa of buffer system (salt/acid ratio is 1) ○ Dependent on the [ ] of buffer constituents ○ The SMALLER the change in pH caused by addition of given amount of acid or base, the GREATER the buffer capacity ○ Buffer capacities of 0.01-0.1 are acceptable for most pharmaceutical liquid dosage forms ○ B= 2.3*C*( Ka [H+] / (Ka + [H+])2 ) C = total buffer [ ]: sum of molar [ ] of the acid and the salt 10. List the properties of a good buffer Good buffer properties ○ Demonstrate pKa values near the pH found in the body ○ Significantly resist changes in pH at [ ] that are non-irritating and non-toxic ○ Readily available at an affordable cost ○ Stable under the conditions needed for sterilization 11. Calculate the pH change upon addition of acid/base to a buffer pH = pKa + log ([salt] / [acid]) → final pH ○ Adjust the [ ] of salt and acid based on what is being added If adding acid: add [ ] to acid and subtract [ ] from salt If adding base: add [ ] to salt and subtract [ ] from acid pH = pKa + log ([salt] / acid] ) → initial pH -- before buffer Final - initial = change in pH 12. Given the appropriate information be able to calculate the amount of constituents necessary to make a buffered system See practice problems/HW on carmen See objective 9 Chapter 7: Solubility 1. Describe how various factors (temperature, pressure, addition of salts, chemical reactions, pH, molecular surface area, solubility parameter, particle size, solvent properties, enthalpy, presence of co-solvents, solubilizing agents) affect the solubility of gas in liquid, liquid in liquid, and solid in liquid Solubility of Gas in Liquid ○ Pressure: the solubility will INCREASE with an INCREASE in pressure ○ Temperature: the solubility will DECREASE with an INCREASE in temperature ○ Presence of salts: the solubility will DECREASE with an INCREASE in salts ○ Chemical Reaction: the solubility will INCREASE with an INCREASE of chemical reactions Solubility of Liquid in Liquid ○ See next objective Solubility of Solid in Liquid ○ Solute properties: MP, heat of fusion, polarity, molecular SA affect solid’s solubility “like dissolves like” 10  PoDA 2 Study Guide -- Mira Haddad Molecular SA: INCREASE in SA = INCREASES solubility Salt forms Weak acids react with strong bases If salt form is sodium= drug is weak acid Weak bases react with strong acids If salt form is sulfate, HCl, phosphate = drug is weak base Particle size: DECREASE in particle size = INCREASE in apparent solubility ○ Solvent Properties: polarity, dielectric constant, capability for H-bonding, solubility parameter Solubility parameter: helps predict solubility The closer the solubility parameter of a solute and solvent, the greater the mutual solubility of the pair ○ Enthalpy ENDOthermic: INCREASE in temperature = INCREASE in solubility EXOthermic: INCREASE in temperature = DECREASE in solubility ○ pH: changes in their solubility with changes in the pH of solution S = overall solubility of drug So = solubility of UNionized species (intrinsic solubility) IONIZED= MORE soluble Weak acids: INCREASE in pH = MORE soluble pH = pKa + log ( S-So / So) Weak bases: DECREASE in pH= MORE soluble pH = pKa + log ( So / S-So) These equations can be used to find min pH (weak acids) or max pH (weak bases) that must be maintained in order to prevent precipitation ○ Cosolvents INCREASE in cosolvents = INCREASE in solubility See objective 6 for how to calculate ○ Solubilizing agents INCREASE in surfactants = INCREASE in solubility Surfactants form micelles at critical micelle [ ], allowing hydrophobic material to be able to dissolve in the hydrophobic core 2. Distinguish between complete miscibility, partial miscibility, and practically immiscible Miscibility: the solubility of a liquid in liquid Complete miscibility: where two liquids are miscible in all proportions, forms a solution (i.e. alcohol in water) Partial miscibility: where the miscibility is a function of temperature (i.e. phenol in water) Relatively immiscible: not soluble, cannot form a single phase system, do not mix (i.e oil in water) 3. Distinguish between solubility, saturation, unsaturated, and super saturated Solubility: [ ] of solute present in the solvent that occurs at saturation at a specified temperature Saturation: solution in which the dissolved solute is in equilibrium with the solid solute Unsaturated: solution containing the dissolved solute at a [ ] BELOW that necessary for complete saturation at a specified temperature Supersaturated: a solution containing the dissolved solute at a [ ] HIGHER than the [ ] it would normally contain at a specified temperature (very unstable, not as likely) 4. Understand solubility kinetics and thermodynamics Enthalpy(△H): amount of heat that is evolved or absorbed as the drug goes into solution Entropy (△S): the order of randomness of the system 11  PoDA 2 Study Guide -- Mira Haddad Free energy(△G): indicates if the reaction (drug dissolving) is spontaneous or not ○ Negative: spontaneous, drug dissolution will occur, WANT △G to be NEGATIVE ○ Positive: not spontaneous, drug dissolution is not favored ○ △G = △H - T* △S Cohesive factors ○ Favor SOLUTE-SOLUTE and SOLVENT-SOLVENT interactions ○ Crystal lattice enthalpy (△HCL) ○ Corresponds to heat required to separate molecules, need to break those bonds in order to form solute-solvent bonds Is always POSITIVE (i.e △HCL > 0) Adhesive factors ○ Forces that favor SOLUTE-SOLVENT interactions ○ Solvation enthalpy (△HSOLV) ○ Corresponds to heat absorbed when the solute molecules are immersed in the solvent Is alway NEGATIVE (i.e △HSOLV < 0) △HCL > △HSOLV → △H will be POSITIVE and solubility will NOT be favored, ENDOTHERMIC △HCL < △HSOLV → △H will be NEGATIVE and solubility will be favored, EXOTHERMIC △HCL = △HSOLV → △H will be ZERO, IDEAL solution ○ Values are absolute 5. Be able to interpret phase solubility analysis data and calculate the proportion of components in a multicomponent mixture See practice problems/HW on carmen [ ] where precipitate starts to occur/when solubility is reached = solubility / fraction present ○ Can use to find which component will reach solubility first: SMALLEST value will reach its solubility first 6. Be able to design multi-solvent systems with drug in solution f1= fraction of solvent 1, S1= solubility of solvent 1 … etc Solve by assigning each solvent a term, make sure all units are the same Sum of all f’s have to be 1, so can use that equation to substitute and solve for one f at a time See practice problems/HW on carmen 12  PoDA 2 Study Guide -- Mira Haddad Chapter 8: Dissolution 1. Recite the steps of the dissolution process Disintegration: the drug breaking apart into small pieces (granules) → fast Deaggregation: the granules break apart into smaller pieces (fine particles) → fast Dissolution: the particles dissolving into solution → slow These steps occur simultaneously 2. Explain why the process of dissolution is important for drug delivery The rate of dissolution is the most important Since dissolution is usually the RLS (particularly for poorly soluble drugs), it will determine how fast the drug is able to reach systemic circulation 3. Be able to describe the effect of each variable in the Noyes-Whitney equation on the rate of dissolution dM/dt= (D*K/ h ) * SA * (Cs-C) → divide by volume (C=M/V) dC/dt= (D / V* h) * SA * (Cs-C) ○ See Ch 1 objective 4 for meaning of each term ○ K = 1 for dissolution ○ INCREASING D, SA, or (Cs-C) will INCREASE the dissolution rate ○ INCREASING V or h will DECREASE dissolution rate 4. Identify which variables that control the dissolution process can be manipulated to affect absorption in vivo and in vitro In vitro methods determine the dissolution rate of solid dosage forms In vitro goal is to predict in vivo performance of dosage form Surface area of undissolved solid (SA) ○ INCREASE in surface area = INCREASE in dissolution rate Solubility of solid in the medium ○ Properties of solute/solvent, temperature, pH, cosolvents, solubilizing agents all can affect solubility See Ch 7 objective 1 [ ] of solute in solution (“sink conditions”) (Cs-C) ○ “Sink conditions” refers to a large [ ] gradient ○ Want Cs- C to be large for dissolution INCREASE in Cs will INCREASE dissolution rate INCREASE in C will DECREASE dissolution rate Increasing volume of bulk media or replacing of the dissolution media (more physiologically relevant) will help keep C low ( want C to approach 0) Thickness of boundary layer (h) ○ Want h to approach 0 ○ Degree of agitation INCREASE agitation = DECREASE in layer = INCREASE in dissolution rate ○ Viscosity of dissolution media DECREASE viscosity = DECREASE in layer = INCREASE in dissolution rate Diffusion coefficient (D) ○ Viscosity ( want it low) ○ Size of drug particles (want it low) ○ Temperature ( want it high) ○ INCREASE D = INCREASE in dissolution rate 5. Explain how the addition of a hydrophilic diluent to a hydrophobic powder mass increases the dissolution rate 13  PoDA 2 Study Guide -- Mira Haddad Normally dissolution of a hydrophobic powder will only occur around the surface of the mass ( low dissolution rate), because the hydrophobic nature of the contents will impede penetration of GI fluids With addition of a very soluble DILUENT throughout mass, the diluent will dissolve in GI fluid leaving a porous mass of drug, this then allows GI fluid to penetrate the mass → effective surface area of drug causing INCREASE in dissolution rate 6. Distinguish between USP and non-USP tests related to dissolution NON USP ○ Disintegration Apparatus (basket rack assembly) Tests time required for a solid dosage form to disintegrate in a solvent Not really used because may not relate to dissolution rate of drug USP ○ Apparatus 1 ( basket method ) Drug put in a rotating basket and put in a medium ○ Apparatus 2 (paddle method) Drug put in a medium with a rotating paddle ○ Then medium is sampled to test for how much of the drug is present ○ Apparatus 3 and (flow through cell system) Apparatus 4 also exist ○ In vivo bioequivalence studies are best method to compare drug products 7. Know the differences and similarities between case I-IV drugs in the biopharmacies classification system Case I: HIGH solubility and HIGH permeability ○ RLS is rate of gastric emptying Case II: LOW solubility and HIGH permeability ○ RLS is dissolution rate Case III: HIGH solubility and LOW permeability ○ RLS is rate of gastric emptying Case IV: LOW solubility and LOW permeability ○ Worst kind, significant problems for oral delivery Highly soluble: highest unit dose of drug will completely dissolve in 250mL of solvent Highly permeable: extent of absorption that is greater than 90% Chapter 9: Drug Stability 1. Describe the USP and FDA standards for dosage form manufacturer Content uniformity: making sure that each manufactured tablet has the same amount of drug (active ingredient) ○ Average should contain 85-115% of the claimed quantity of active ingredient ○ Relative standard deviation no more than 6% of the claimed quantity of active ingredient ○ No individual unit should fall outside 75-125% of the claimed quantity of active ingredient 2. List potential factors influencing the rate of drug degradation Temperature (i.e. storage conditions) ○ INCREASE in temp usually means INCREASE in degradation Humidity Light (i.e photochemical degradation) pH (i.e. acid or base catalyzed degradation) ○ Specific acid base catalysis: when drug degradation is influenced by the [H+] or [OH-] Hydrogen ion catalysis predominates at LOW pH Hydroxyl ion catalysis predominated at HIGH pH 14  PoDA 2 Study Guide -- Mira Haddad An optimum pH usually exists in between these extremes where rate of drug degradation is minimal ○ General acid base catalysis: when drug degradation is influenced by [ ] of a buffer component Contamination (e.g. bacterial or fungal) Presence of cosolvents ○ Can replace water thus DECREASE the probability of hydrolysis which MAY DECREASE degradation Presence of additives (i.e. buffer salts to maintain formulation) ○ Usually in instances when the drug molecule is in charged solution ○ Reactions of ions with LIKE charge will INCREASE degradation ○ Reactions of ions with OPPOSITE charge will DECREASE degradation Addition of surfactants (leading to formation of micelles) ○ Can INCREASE or DECREASE degradation ○ Can affect rate of hydrolysis 3. Define and distinguish between the rate of reaction, rate constants, and the order of reaction dC/dt = -k * Cn ○ dC/dt = rate of reaction: speed/velocity at which reaction occurs, change in [ ] over time Positive with increase in degradation product Negative with decrease in drug concentration Units are amount* volume-1*time-1 ○ k = rate constant: proportionality constant relating to rate of change in drug [ ] to drug [ ] present ALWAYS a positive number Units depend on order of reaction Zero order: amount*volume-1 *time-1 First order: time-1 Second order: volume*amount-1*time-1 ○ n = order of reaction: number of species present that influence rate of reaction Zero order: dC/dt = -k Rate of change in drug [ ] with time is INDEPENDENT of drug [ ] Losing drug at constant amount regardless of [ ] First order: dC/dt = -k * C Rate of change in drug [ ] with time is DIRECTLY PROPORTIONAL to [ ] of drug present, constantly changing Rate is faster with higher [ ] and slower with lower [ ] Second order: dC/dt = -k * C2 Rate of change in drug [ ] with time is DIRECTLY PROPORTIONAL to SQUARED [ ] or [ ] of BOTH reactants required to form product Squared could mean drug dimerizes Both reactants could mean a drug and water etc. 4. Discern between zero, first, and second order rates of reaction and degradation 15  PoDA 2 Study Guide -- Mira Haddad 5. Determine the reaction order and calculate the pertinent parameters (i.e. half-life, rate constant, and intercepts) to describe data collected from drug degradation studies Three ways to determine reaction order 16  PoDA 2 Study Guide -- Mira Haddad ○ Graphical method: graph [ ] vs time, lnC vs time, and 1/C vs time, and match the line up with how it would look in its appropriate reaction order (i.e. a straight line for [ ] vs time would indicate zero order whereas a straight line for lnC vs time would indicate first order etc.) ○ Substitution method: solve for k with each reaction order equation using various data points and the equation that yields a constant k is that reaction order Zero order: rise over run y2-y1 / x2-x1 First order: take ln y for the data points in rise over run Second order: take 1/y for the data points for rise over run ○ Half life method: calculate half life for several data points Zero order: half life will be LONGER at higher drug [ ] First order: half life is CONSTANT → does not depend on drug [ ] Second order: half life will be SHORTER at higher drug [ ] 6. Calculate the drug concentration at any time during drug degradation processes that occur by zero or first order mechanisms See practice problems/HW on carmen Use the reaction order’s equation to find rate constant k (slope) and initial [ ] Co (intercept) ○ Then can use equation to solve for any concentration 7. Predict the effect of temperature and pH on the stability of drugs and dosage forms Arrhenius Equation ○ a method to use data from studies at high temperatures to predict stability at low temperatures ○ The rate of most drug degradation reactions increase 2-3 times with each 10o rise in temperature ○ Use correct reaction order equation when solving for shelf life See objective 2 for pH effect on stability 8. Be able to calculate the rate, rate constant, half life, shelf life, and concentrations for zero, first, and second order data See practice problems/HW on carmen See objective 4 for the equations to use for each order reaction 9. Demonstrate/explain how a first or second order degradation process can “appear” to degrade be a zero or first order process respectively 17  PoDA 2 Study Guide -- Mira Haddad First Order ○ Apparent Zero Order: suspensions are special in which the solid drug is in equilibrium with a saturated solution of the drug→ the drug [ ] will not change until drug reservoir (solid drug) is gone No way of knowing mathematically, would have to look at the suspension Half life and shelf life are zero order After reservoir is gone it will revert back to first order since solid drug is no longer replacing the drug being degraded Second Order ○ Apparent First Order: special case when two species (e.g. drug and water or drug plus excipient) are required for degradation to occur AND their initial [ ] are not equal dC/dt = -k*Cdrug*CH20 Manifest as first order due to the presence of excess amounts of one of the reactants→ water will be so much higher than the drug that it will essentially remain constant through degradation Half life and shelf life are first order 10. Calculate rate constants and shelf life using the Arrhenius equation and the Q10 method See objective 7 for Arrhenius equation and how to solve for rate constant and shelf life Q10 ○ Less accurate, but more convenient way to estimate shelf life based on temperature ○ Can only be used to examine the effect on temperature in 10o increments ○ Use correct reaction order equation when solving for shelf life ○ Can use 2 and 4 as Q10 values because activation energies usually fall within 12-24 kcal/mol with most drugs being within 19-20 kcal/mol → those Ea values correspond with the Q10 values of 2 and 4 Chapter 10: Introduction to and Properties of Solids 1. List the advantages of oral solid dosage forms Patient acceptance-most preferred route of delivery Taste Storage/stability 2. Describe what happens after a solid dosage form is swallowed Drug is taken and dissolution has to occur for drug to be in SOLUTION (i.e solubility) Drug has to be UNionized to be passively diffused (most common route) Drug enters GI tract and has to pass GI tract membrane to get to blood 18  PoDA 2 Study Guide -- Mira Haddad ○ pH partition hypothesis Drug enters blood stream and has other barriers (tissue type/membranes) to distribute in tissues and get to site of action ○ Metabolites in blood→ metabolites in urine ○ Unchanged drug excreted through urine Drug reaches site of action and elicits response Drug starts to be removed from body the moment it enters ○ By metabolism in liver ○ By excretion in kidneys 3. Define the following terms: Maximal tolerated [ ]: max [ ] where therapeutic effects occur without reaching toxicity Minimal effective [ ]: min [ ] where therapeutic effects start to occur Therapeutic window: plasma [ ] range where the therapeutic effect of drug is found, below would be no effect where above would start to have toxic effects Cpmax: max plasma [ ] of drug Tmax: time that it takes to reach Cpmax Duration of action: the time in which drug [ ] in plasma is in its therapeutic window Absorption phase: when drug is being absorbed, plasma [ ] is INCREASING Elimination phase: when drug is being eliminated, plasma [ ] is DECREASING Area under the plasma [ ]- time curve: the extent of the drug’s absorption into body Bioavailability: how much of a dose reaches the systemic circulation intact, rate of absorption affects this Bioequivalence: when two drugs have the same bioavailability, Tmax, Cpmax, and AUC, has to be ALL OF THESE parameters to be bioequivalent 4. Discern between AUC, bioequivalence, and bioavailability AUC: the total amount of drug the body is exposed to Bioavailability: how much drug absorbed by systemic circulation, can be found with AUC Bioequivalence: used to compare two drug formulations, must meet SAME criteria for ALL required parameters 5. Explain the potential for bioavailability differences based on dosage form The greater complexity of a dosage form then the greater potential for differences in bioavailability ○ Depends on drug properties and body ○ Different extents and rates of absorption can occur 6. Understand the concept of specific surface area 19  PoDA 2 Study Guide -- Mira Haddad Sw: surface area per unit weight ○ Sw = 6 / p*d ( density * diameter) The SMALLER the particle size, the GREATER the specific surface area 7. Define the different types of mixtures Positive Mixtures ○ Two ingredients mix spontaneously and irreversibly by diffusion and tend to form a perfect mix ○ No energy input required with unlimited mixing time ○ Ex: any kind of solution, two gases, two miscible liquids Negative Mixtures ○ Components will tend to separate out ○ May occur rapidly and require energy input Ex. suspensions, calamine lotion ○ May occur slowly Ex. emulsion, cream, viscous suspension Neutral Mixtures ○ Static in nature ○ No tendency to mix spontaneously or segregate once work put it to mix them ○ Ex. powders, pastes, ointments 8. What are the mechanisms of mixing and how long should a mixture be mixed Convection: transfer of particles as might occur by the blades of a blender Shear: occurs when a layer of material moves over another Diffusive: result of dilation of the powder bed and gravity 9. Define segregation and be able to describe how it occurs and how it can be prevented Segregation: opposite of mixing, needs to be AVOIDED in pharm processes (“demixing) ○ Differences in particle size, density, and shape can lead to segregation Density: more dense material will move downward Shape: more spherical particles have greatest flowability but also segregate easier ○ Perculation: smaller particles fall through the voids of larger particles ○ Trajectory: larger particles have greater kinetic energy ○ Elutriation: “dusting out”, fine particles are blown upwards Prevention of segregation ○ Selection of similar particle size fractions ○ Milling (aggregation) → particles < 30um ○ Controlled crystallization (particle shape and size) ○ Selection of excipients (similar densities) ○ Granulation ○ Reduction of agitation after mixing ○ Production of an ordered mix (cohesive/adhesive forces between constituents) 10. Understand the concept of flow and how it applies to the manufacture of solid dosage forms (define and calculate the angle of repose, what is the best particle size and/or angle of repose for ideal flow) Flow: how well the powder flows through all the machinery used to make solid dosage form, needs to be pourable/movable ○ Angle of repose is the angle the powder makes when being poured and can be used to quantify flow ○ As the angle of repose INCREASES, the flow DECREASES ○ tanθ = h/r 20  PoDA 2 Study Guide -- Mira Haddad h= height, r = radius ○ Ideal Angle of repose around 25o → have the best flow >50o → unsatisfactory flow 25-50o may or may not be good flow ○ Best particle size 250-2000 um → flow freely is shape not issue 100-250 um → may flow freely depending on shape fup) Can be low or high E CLTS = CLR- CLGF Tubular Reabsorption: moved drug from tubular lumen into plasma ○ Primarily occurs in distal tubule, although there are a few exceptions ○ Generally passive process (driven by [ ] gradient) ○ In series with GF and TS ○ Determinants Intrinsic efficiency of reabsorption is primarily determined by passive diffusion pH of urine (normally 4.5-7.5) and pKa of drug (unionized form enhances reabsorption) Urine flow: INCREASED flow DECREASES reabsorption due to decreased [ ] gradient and shorter residence time in tubule Total Renal Clearance ○ CLR = (CLGF +CLTS) * (1 - ETR) ETR = fraction of the drug in urine that is reabsorbed ○ Renal clearance of a drug may involved 1,2, or all 3 of these processes ○ Determinants of renal clearance of a drug depend on which of the processes are involved and how large of a contribution each makes ○ Need to know which processes are involved in clearance of drug to be able to predict impact of changes in physiological determinants 4. Define and be able to calculate Eratio Eratio: the ratio of total renal clearance to the clearance by glomerular filtration ○ NOT THE SAME THING AS EXTRACTION RATIO ○ Eratio = CLR / CLGF ○ Eratio = 1 → drug is only filtered or that secretion and reabsorption exactly offset each other 61  PoDA 2 Study Guide -- Mira Haddad ○ Eratio >1 → drug is filtered and secreted, if also reabsorbed, reabsorption < secretion ○ Eratio < 1 → drug is filtered and reabsorbed, if also secreted, secretion < reabsorption Additional information ○ If CLR is [ ] dependent → secretion ○ If CLR is decreased by co-administration of other drugs that are known to be secreted (competition) → secretion ○ If CLR changed with urine flow rate or urine pH changed → reabsorption ○ Eratio =1 with NO competition (or [ ] dependence) and/or no effect of urine pH and flow rate effect → filtration only ○ Eratio >1 with NO effect of urine pH or flow rate changes → filtration and secretion only ○ Eratio>1 with urine pH and/or flow rate changes → filtration, secretion, and reabsorption with net secretion ○ Eratio IBW, use adjusted BW (if ABW > 1.2*IBW) AdjBW = IBW + 0.4*(ABW-IBW) ABW= actual body weight IBW= ideal body weight = 23H2 (males), 21H2 (females) → H in meters Salazar- Corcoran Equation MDRD Equation GFR in mL/min/1.73m2, age in years, SCr and SUN in mg/dL, and Alb in g/dL 63  PoDA 2 Study Guide -- Mira Haddad Chapter 25: One Compartment Model 1. Be able to describe what a PK model is and why it is useful PK models are used to PREDICT certain drug [ ] /values when parameters are changing ○ Many different models exist 2. Given the proper data, be able to calculate clearance, volume of distribution half-life, plasma [ ], etc. from IV data Plasma [ ] / KE ○ lnCp = lnCpo - KEt KE = CL/V → - slope of lnC vs time graph ○ Cpo = Dose/V Cpo DOES NOT depend on CL INCREASE in V will DECREASE Cpo Half life ○ t1/2= 0.693/KE → 0.693V /CL Half life and KE will depend on CL and V ○ INCREASE in CL will INCREASE K E ○ INCREASE in V will DECREASE K E ○ INCREASE in CL will DECREASE t1/2 ○ INCREASE in V will INCREASE t1/2 3. Describe and calculate the area under the plasma [ ] time curve (AUC) Area under the curve (AUC): area under the plasma [ ] vs time curve AUC= Dose/CL ○ Only dependent on CL INCREASE in CL will DECREASE AUC ○ NOT dependent on V Trapezoidal Method ○ Summation of following equation with different trapezoids from under the curve 4. Understand the process of absorption and the equations that describe it One Compartment Model- Absorption input ○ KE = elimination rate ○ ka = absorption rate ○ ka has to be bigger than KE by at least a factor of 4 (the usual) OR KE has to be bigger than ka by at least a factor of 4 ○ The slope of the log linear portion (toward bottom of line) represents the slope of the smaller value (usually KE) ○ See next objective for how to calculate 64  PoDA 2 Study Guide -- Mira Haddad 5. Be able to define and calculate Cp, Cmax, Tmax, AUC, F, t1/2, KE, and ka from absorption data Cmax: then the rate in equals the rate out (peak plasma [ ] ) ○ If ka INCREASES then Cmax will INCREASE ○ If KE INCREASES (because of an INCREASE in CL) Cmax will DECREASE ○ If KE INCREASES (because of a DECREASE in V) Cmax will INCREASE Tmax: the time when the rate in equals the rate out ○ Tmax = ln (ka/KE) / ka-KE ○ INCREASE in ka or KE will DECREASE Tmax AUC ○ Independent of absorption rate constant and volume of distribution ○ Two things will change AUC Bioavailability (INCREASE F, INCREASES AUC) CL (INCREASE CL, DECREASES AUC) AUC = (F*Dose) / CL t1/2: half life ○ t1/2 = (0.693*V) / CL → t1/2= 0.693/K E ka/ KE ○ Graphical analysis: method of residuals/ feathering/ peeling ○ If ka > 4KE First: extrapolate KE line from the Cp points → do this by getting slope (lnC2 - lnC1/ t2-t1) of linear portion (toward bottom of line) Use that slope to find new Cp values (use KE to find plasma [ ] at earlier times → lnC = lnCo - KEt ) Use new values on KE line and subtract corresponding Cp values from original line (use the same time points) Use those new values to find the slope (lnC2 - lnC1/ t2-t1) at those time points and that will give you the ka If ka < 4KE → then flip everything and the first slope will be ka etc. 65  PoDA 2 Study Guide -- Mira Haddad 6. Be able to determine how changes in dose, clearance, volume of distribution, and ka affect the above parameters Cp vs T 1. Important concepts from this lecture Cmax and Cmin are especially important when pharmacodynamic effect is relatively immediate… and when either effect or toxicity relate directly to peak or trough [ ] Peak and troughs happen with intermittent drug administration Cpss (plasma [ ] in the steady state) may be more relevant parameter in drugs with delayed effect or long half lifes, where continuous effect is more clinically relevant than isolated peak or trough ○ Medications where peak/trough or not relevant compared to Cpss: birth control, warfarin, amiodarone, SSRIs ○ Cpss,avg cannot be directly measured Independent Variables ○ Clearance ○ Volume of Distribution ○ Bioavailability Dependent variables → all determined by CL, V, and/OR F ○ Elimination rate constant ○ Maximum drug [ ] ○ Minimum drug [ ] ○ Average steady state drug [ ] ○ Area under the [ ] vs time curve (AUC) Cmax calculations ○ Can find cmax (1) by doing dose/volume ○ cmax(2) is found differently because the next dose is not administered when [ ] is at zero → plasma [ ] are additive (add trough plus cmax(1) ) ○ See equation sheet 2. Important trends/graphs from this lecture 66 PoDA 2 Study Guide -- Mira Haddad 67  PoDA 2 Study Guide -- Mira Haddad Chapter 26: Infusion Dosing 1. Understand the kinetics of accumulation When infusing a drug at a constant rate, the amount of drug in the body can be determined by the difference between the rate in and the rate out dA/dt= rate in - rate out (Ko - KEA) Ko = input rate → (amount/time) KEA = rate out If input rate is continued long enough, a plateau is reached and the rate in is equal to the rate out Cpss = Ko /CL When drugs are infused at the same rate ( one compartment model assumed) ○ All drugs with the SAME CL will have the SAME Cpss ○ Young and old people have the same Cpss if infused at the same rate… what differs is the amount of drug in the body and time it takes to get to that [ ] 68  PoDA 2 Study Guide -- Mira Haddad ○ LARGE Vd means LARGER amount of drug in the body, even if Cpss is the same Accumulation kinetics ○ Cp,inf = Cpss (1-e-KEt) (1-e-KEt) → accounts for accumulation ○ Can also use: Cp,inf = Cpss (1-(½)n ) n=number of half lives 2. Be able calculate an input rate necessary to achieve a desired plasma [ ] for a drug Ko=CL*Cpss → Cpss = Ko/CL ○ Volume does NOT affect Cpss Half life will change Not starting at zero ○ INCREASE in Ko will INCREASE Cpss → proportionally Half life unaffected Not starting at zero ○ INCREASE in CL will DECREASE Cpss → proportionally Half life will change Not starting at zero See practice problems/HW on carmen 3. Be able to calculate plasma drug [ ] during an infusion Cp,inf = Cpss (1-e-KEt) After infusion → one compartment model → Cp=Cpo * e-KEt See practice problems/HW on carmen 4. Be able to calculate the time required to reach steady state If we start at a [ ] zero (or double the Cpss) then after 3.3 half-lives 90% of the Cpss is obtained If we start at a [ ] that is NOT zero the time to +/- 10% of the Cpss differs from 3.3 half lives ○ -10% if starting from [ ] below Cpss ○ +10% if starting from [ ] above Cpss Plasma [ ] at any time after bolus + infusion ○ Cp = Cpo* e-KEt + Css (1- e-KEt) Solving for time to get to Cpss ○ Given Cpo and Cpss the time to reach any Cp can be calculated from (Css-Cp)/(Css-Cpo) = e-KEt= (½)n Cp is desired target [ ] (+/- 10%) Cpo is current [ ] in body n = number of half lives Can solve for time or # of half lives 5. Understand the concept of a loading dose and be able to calculate a proper loading dose Loading dose: a dose given to get patient at steady state immediately ○ Cp = Amount/Volume ○ Ass = Cpss*Vd OR Ass = Ko/K E Ass = amount of drug to get to steady state (i.e loading dose needed) 6. Be able to estimate CL,V,KE, and t1/2 for/from the continuous input regime Can get CL,KE, and V if given plasma levels measured during infusion ○ CL= Ko/Cpss ○ Can get KE from the slope of Ln(Cpss-Cp) vs Time -slope = KE ○ V = CL/KE 69  PoDA 2 Study Guide -- Mira Haddad ○ t1/2 = 0.693/KE START OF EXAM 4 Drug Interactions 1. Types of drug interactions Pharmacodynamic drug interactions: drugs amplify or cancel each other's pharmacological effect ○ Additive (synergistic): effects because of shared mechanism of drug action → potentiates response ○ Antagonism: effects because of opposing mechanisms of drug action → block response ○ WILL NOT interfere with Vd, CL, or F (i.e. metabolism of drug/ADME) ○ Usually can NOT be managed by dose-spacing (that will not avoid the interaction) Both drugs active in body 3.3 times the half lives after last dose is given Avoidance of one drug is probably best/only solution Pharmacokinetic drug interactions: interactions wherein one or both drugs pharmacokinetic parameters (F,Vd, or CL) are altered by the presence of another drug (i.e. ADME) ○ Alter plasma drug [ ] via changing: bioavailability, volume of distribution, metabolism (liver clearance), or excretion (kidney clearance) 2. Types of PK interactions Bioavailability Interactions ○ F can increase (more drug reaches systemic circulation) or decrease (less drug reaches systemic circulation) ○ pH effects (increase or decrease F) Dose spacing MAY avoid SOME pH related interactions IF the pH change is BRIEF (ex. Can dose space with antacids because effect only lasts a few hours, but can NOT dose space with PPIs because effects last longer) ○ Inhibition of pre-systemic metabolism or an efflux pump (increases F) If metabolism of drug is inhibited, more drug will be absorbed, meaning more drug will reach systemic circulation and elicit a response (can be too much drug) Ex. inhibition of a CYP 450 enzymes or P-glycoproteins Probably NOT avoidable by dose spacing Interactions will persist for 3.3 times the half life of the causative drug Understand how to identify the causative drug (drug causing the interaction) and the affected drug (drug affected by interaction.. i.e. drug who has a change in F) ○ Grapefruit juice interactions also inhibit gut wall enzymes and are irreversible (increases F) 70  PoDA 2 Study Guide -- Mira Haddad DO NOT recommend dose spacing with grapefruit juice CYP3A4 substrates with low bioavailability are high risk drugs ○ Changes in drug solubility or drug chelation (decreases F) Absorption interactions involving solubility or chelation often CAN be managed by dose spacing → give at least 1-2 hours apart to avoid physical contact between the two drugs ○ Induction of pre-systemic metabolism (decreases F) Can NOT be managed by dose spacing Metabolism is increased, so drug leaves body faster and elicits response for less amount of time, drug is less absorbed Clearance Interactions ○ Clearance interactions involve one drug changing the hepatic or renal clearance of another drug ○ Typically involve either inhibition or induction of the liver CYP450 enzymes ○ Liver enzyme INHIBITION interactions Most common type of interactions Inhibition is usually competitive and reversible Results in DECREASED metabolic capacity via decreased CLint,u → increases plasma drug [ ] For High E drugs, CL= Q so will probably NOT change unless extraction ratio is reduced substantially For Low E drugs, CL=Clint and thus CL probably WILL change As inhibition ceases, the half life of the affected drug will decrease and return to normal → new Cpss of (formerly) inhibited drug will occur in 3.3 (new) half lives The onset of competitive inhibition interactions is typically IMMEDIATE Interaction begins with first dose of inhibitor Interaction lasts until the causative drug is eliminated from the body (3.3 times the half life of the last dose of the inhibitor) → this is when drug dose can be returned back to normal (original dose) ○ Liver enzyme INDUCTION interactions Causes increased gene expression for synthesis of oxidative enzymes in gut wall or liver smooth endoplasmic reticulum Result is INCREASED metabolic capacity via increased CLint,u → decreases plasma drug [ ] For High E drugs CL= Q but, even though enzyme induction does occur CL will probably not change For Low E drugs CL=CLint and this CL probably WILL change The onset of induction takes DAYS TO WEEKS Offset of induction interactions also takes days to weeks and depends on the rate of turnover of enzyme proteins ○ Clearance interactions are NOT avoidable with dose spacing The interaction will persist for 3.3 times the half-life of the causative drug, after its last dose Renal Excretion Interactions ○ Can not interfere with CLGF but CAN interfere with CLTS (because proximal tubule contains drug transporters) 71  PoDA 2 Study Guide -- Mira Haddad ○ Usually if drug interferes with urinary excretion of a drug, it is via inhibition of active tubular secretion This will DECREASE the renal (and total) clearance of affected drug Usually competitive and reversible once drug is eliminated from system Very unlikely that a drug interaction will increase a drug’s renal clearance These interactions are handled the same way hepatic clearance interactions would be handled 3. Important notes to make about PK interactions Common source of error with calculations ○ Understand percent differences Ex: Amiodarone reduces Warfarin's clearance from 3.1 ml/min to 1.4 ml/min This means that Warfarin’s clearance is 45% of normal (1.4/3.1 x 100) or (new/old x 100) → this is the same thing as saying there is a 55% reduction in Warfarin’s clearance Cpss,avg = F*Ko / CL → so if clearance is 45% of normal (0.45*CL) then Cpss is going to increase by 2.2 fold or by 120% ( 1/0.45 because CL is on the bottom of the equation) The goal is to ALWAYS keep Cpss,avg,UNBOUND the SAME → need to keep ratio UNCHANGED ○ Do whatever is necessary to make this happen (adjusting dose in correct manner) Use AUC = F (Dose) / CL to adjust scheduled doses Use Cmax = F (Dose) / V to adjust PRN doses ○ Continuing off Warfarin example from above In order to keep Cpss,avg,u the same we would need to decrease the dose to 45% of normal ( reduce the dose by 55%) Cpss,avg,u (same) = F*0.45Ko*fup / 0.45CL → 0.45/0.45= 1 so that Cpss,avg,u remains unchanged Other ways to use the adjusted information ○ To calculate a new half life, even if you do not have KE or V Ex. if the original half life was 6 hours and now CL is 40% of normal then… The new t1/2 = 0.693*V / (0.4*CL) so… 6 hours / 0.4 = 15 hours and that is the new half life Cpss,avg = F*Ko / CLT ○ For a drug with linear (first order) clearance, changes in dose, F, or total clearance will cause proportional changes in Cpss,avg Using AUC data ○ Captures both changes in F and CL ○ If AUC data is available, use them to change maintenance doses, NOT FOR ONE TIME doses Changes in half life do not tell us about changes in F Changes in single or first dose Cmax represent only F and Vd → provide no information if CL has changed also Single and PRN Dosing 1. Information about PRN dosing/loading doses Rapid onset of effect to achieve an effect → intention is to relieve symptoms and then not give more drug until/unless symptoms return Giving a loading dose or PRN dose does NOT guarantee that drug [ ] will be therapeutic ○ SIZE of dose MATTERS 72  PoDA 2 Study Guide -- Mira Haddad Usually dosing regimes involve a loading dose followed by a maintenance dose, so the loading dose does not have to reach steady state (in one dose) ○ Do not get to steady state faster with loading dose → still 3.3 times the half life ○ Loading dose helps to stay in steady state→ depending on size and frequency of the maintenance regimen that follows (separate issues) Most important premise of PRN dosing is that plasma [ ] has presumably fallen to near zero before each new dose → the patient takes another dose only when the effect wears off → significant drug accumulation should not occur Drug interactions can occur with PRN dosing, but they are handled differently ○ Induction of clearance with PRN doses will NOT reduce Cmax (drug effect), but duration of effect may be SHORTER → patients will ask for doses more frequently ○ Inhibition of clearance with PRN dosing will NOT increase drug effect, but the duration effect will be longer → patients will ask for doses less frequently ○ Induction of pre-systemic enzymes (decreases F) with PRN dosing will reduce Cmax and the drug effect, but duration of effect may be unchanged → patient will tell you the medication does not work ○ Inhibition of pre-systemic enzymes (increases F) with PRN dosing will increase Cmax and the drug effect, but duration of effect may be unchanged → patients are at risk of toxicity from the high peak [ ] ○ Summary If CL changes → do NOT change dose If F changes → CHANGE dose 2. Adjusting PRN dosing Magnitude of effect → related to size of dose Time at which it breaks through → dictated by dosing interval When assessing pain control → ask about BOTH immediate control (adequacy of dose) and duration of control (dosing interval) ○ Each variable can be changed independently, depending on symptoms Morphine example from slides illustrates the following ○ How larger PRN doses given less frequently may result in both side effects and loss of effect ○ How smaller PRN doses given more frequently approach a continuous infusion ○ Lower Cmax and higher Cmin may provide good efficacy without loss of effect at the end of each dosing interval Chapter 27: Multiple Dosing 1. Calculate the amount/ [ ] during the accumulation phase of a multiple dosing scenario 73  PoDA 2 Study Guide -- Mira Haddad 2. Calculate the amount/ [ ] maximum and minimum values at steady state during a multiple dosing regime 3. Calculate the average amount/ [ ] in the body at steady state during a multiple dosing regime Average at ss is not the same as the numerical average because there is an exponential decline 74  PoDA 2 Study Guide -- Mira Haddad 4. Understand the concepts of and be able to calculate the accumulation index, the fluctuation index, and the fraction of steady state Accumulation Index (AI): the ratio of Ass,max to F*Dose → unitless ○ For a substance with a very long half life relative to its dosing interval there is a lot of accumulation (AI is HIGH) → dosing more than drug is being cut in half ○ The smaller the interval of tau to t1/2 → less fluctuation a dosing regime provides and the closer the peaks and troughs ○ High accumulation = very close peaks and troughs → shorter dosing intervals ○ Ex. if the AI=9 that means it takes 9 doses to reach ss Fluctuation Index (FI): ratio of Ass,max to Ass,min → unitless ○ Characterizes how far the [ ] drops over a dosing interval ○ High fluctuation = very far peaks and troughs → longer dosing intervals Fraction of Steady State (fss) ○ The peak level after any dose divided by the max peak (Ass,max) ○ Just a fraction of achievement of steady state 5. Know when a loading dose is necessary When a loading dose IS needed → Loading dose = Ass,max / F 75  PoDA 2 Study Guide -- Mira Haddad ○ When AI is large because need to fill body to get to ss When half life is larger than dosing interval (large accumulation) ○ Therapeutic index is large ○ Long half life ○ Based on patient needs: if critical or life sustaining/time sensitive 6. Be able to develop a dosing regime using the various methods described in lecture Antibiotics 1. Premise/background of antibiotics Based on bacterial MIC (minimum inhibitory [ ] ) and tolerable drug [ ] in plasma, the lab will assign a sensitivity designation to this particular organism--drug combination ○ MIC < tolerable amount → then sensitive and may treat infection This does not ensure infection will be treated with antibiotic → based on a lot of factors 76  PoDA 2 Study Guide -- Mira Haddad ○ MIC > tolerable amount → then resistant ○ If intermediate susceptibility → infection may still be able to resolve IF: Patient has intact immune system If antibiotics are administered in a manner that compliments their activity 2. Drug concentration-dependent vs drug-concentration independent Concentration-DEPENDENT killing ○ Bacteria counts (or CFUs) decline more rapidly as antibiotic concentrations rise progressively above the MIC ○ Higher drug concentrations = more effective at lowering CFUs ○ Exhibit post antibiotic effect A period of time after drug concentration has lowered where there is no bacteria growth → buys time and allows for longer dosing intervals ○ MAXIMUM DRUG [ ] (Cpeak) matters → affects bacterial killing efficiency Peak to MIC ratio of 10:1 appears to be optimal Peak [ ] is primarily determined by dose size BIGGER DOSE is better → all about peak [ ] ○ Drugs in this class (* most common) Aminoglycosides* Quinolones*, Rifampin*, Metronidazole, Azalides, Streptogramins, Ketolides Concentration-INDEPENDENT killing ○ Bacteria counts DO NOT decline more efficiently/rapidly as antibiotic [ ] increases above the MIC ○ High drug concentrations → are NOT more effective at lowering CFUs ○ Most do NOT exhibit a post-antibiotic effect So [ ] below the MIC allows bacteria to grow ○ Time > MIC is the key → TIME ABOVE MIC matters Time above MIC should be greater than 50% for each dosing interval DOSING INTERVAL is more important than peak [ ] 3. Considerations when adjusting dosing regimen of antibiotic Aminoglycosides→ toxicity associated with TROUGH levels Adjusting doses ○ NEVER adjust FIRST dose with diminished CL especially for antibiotics → need to reach MIC May reduce interval Reduced dosing recommendations should be applied after initial loading dose is administered Chapter 28, Part 1: Two Compartment Model 1. Be able to explain the plasma [ ] - time profile of a two compartment drug After IV bolus administration a distribution and elimination phase is often observed Distribution is found in two compartments ○ Dose enters first compartment (central) and distributes quickly → rapid distribution for the highly perfused tissues throughout a piece of the body ○ Then distributes slowly into second compartment (peripheral) as it undergoes elimination ○ This yields the bi-exponential plasma [ ] time curve ○ Dose dumped into compartment 1 and then is eliminated and distributed to compartment 2 at the same time until compartment 1 and 2 reach an equilibrium → distribution ends → post distributive phase (log linear) is when compartment 2 starts to feed back into compartment 1 to be eliminated 77  PoDA 2 Study Guide -- Mira Haddad ○ Bend in graph = the [ ] in compartment 2 coming to a pseudo equilibrium with [ ] in compartment 1 2. Differentiate between the various volume of distribution terms and assess their relevance (understand concepts of loading dose for two compartment drugs) Helpful for deciding loading doses Vss2c ○ Sum of V1 and V2 ○ Only works at one instant time after iv bolus where [ ] in compartment 1 = [ ] in compartment 2 Vd ○ Volume of distribution of compartment 1 LD = Vss x Cdesired = OVERdose LD = V1 x Cdesired = UNDERdose → use this because it is the safer option 3. Distinguish between and describe the relevance of the alpha and beta half lives 𝛼 half life (t1/2𝛼) ○ Measure of the time it takes for distribution to finish 𝛽 half life (t1/2𝛽) ○ True biological half life and is analogous to the half-life from