FALL23_PKAdrugSTABILITY_NRAN80323.pptx

pKa & DRUG STABILITY Gregory Collins, DNP, CRNA PHYSICAL SCIENCE IN NURSE ANESTHESIA NRAN 80323 pKa & DRUG STABILITY READING: Baker M, Naguib M, Warltier D. Propofol. Anesthesiology. 2005;103(4):860-876. OBJECTIVES: DRUG INCOMPATIBILITY IONIZATION / ACIDBASE Equilibrium Constant pKa Curves Ion Tr...

pKa & DRUG STABILITY Gregory Collins, DNP, CRNA PHYSICAL SCIENCE IN NURSE ANESTHESIA NRAN 80323 pKa & DRUG STABILITY READING: Baker M, Naguib M, Warltier D. Propofol. Anesthesiology. 2005;103(4):860-876. OBJECTIVES: DRUG INCOMPATIBILITY IONIZATION / ACIDBASE Equilibrium Constant pKa Curves Ion Trapping DESOLVATION Propofol DRUG INCOMPATIBILITY DRUG INCOMPATIBILITY PRIMARY CONCERNS… 1) IONIZATION (pKa) / ACID-BASE REACTIONS 2) DESOLVATION OF NON-IONIC, ORGANIC DRUGS 3) SALTING OUT REACTIONS DRUG INCOMPATIBILITY PRIMARY CONCERNS… 1) IONIZATION (pKa) / ACID-BASE REACTIONS 2) DESOLVATION OF NON-IONIC, ORGANIC DRUGS 3) SALTING OUT REACTIONS IONIZATION / ACIDDRUG pH BASE Most anesthetic drugs are WEAK BASES DRUG pKa DRUG PREPARATION Altering pH of solution Changes in stability / H2O solubility pH OF TARGET IONIZATION / ACIDBASE ANESTHESIA PHARMACOLOGY & pK a How do IONIZED drugs behave? How do NON-IONIZED drugs behave? Why does it matter? DISSOCIATION pKa IN (pK ) CONSTANT a PHARMACOLOGY IONIZED pH NON-IONIZED pH AT WHICH 50% OF DRUG IS IONIZED & 50% OF DRUG IS NON-IONIZED INHERENT CHARACTERISTIC OF DRUG IONIZATION BH H +B pH < pKa < pH + HA H + + THIOPENTAL / WEAK ACID / pKa 7.4 LIDOCAINE / WEAK BASE / pKa 7.9 + IONIC SOLUTIONS 10 DISSOCIATION CONSTANT (pK ) a HENDERSON-HASSELBACH H+ + HCO3- EQUATION H2CO3 H20 CO2 + K = EQUILIBRIUM CONSTANT Expressed in moles / Simple math / Results lack context & usability pH = pK + log ( [HCO3-] / [CO2] ) Expressed in pH scale 0-14 / logarithmic calculation / Usable, contextual DISSOCIATION CONSTANT (pK ) a K = EQUILIBRIUM CONSTANT Allows for calculation and prediction of REVERSIBLE REACTION aA + bB cC + dD pK = log of the equilibrium constant (in context of pH) DRUG IONIZATION DRUG “A” WEAK BASE pKa 7.0 7. 4 DRUG IONIZATION 7. 4 DRUG “B” WEAK BASE pKa 9.0 DRUG IONIZATION 7. 4 DRUG “C” WEAK ACID pKa 7.0 DRUG IONIZATION DRUG “D” WEAK ACID pKa 9.0 7. 4 DRUG IONIZATION DRUG IONIZATION DRUG IONIZATION DRUG IONIZATION LOCAL ANESTHETICS LIDOCAI NE WEAK BASE pKa 7.9 ION TRAPPING CAN OCCUR BETWEEN ANATOMIC FLUID COMPARTMENTS (WITH DIFFERENT pH) SEPARATED BY LIPID MEMBRANE BASIC DRUGS CAN BE TRAPPED IN MORE ACIDIC ENVIRONMENTS ACIDIC DRUGS CAN BE TRAPPED IN MORE BASIC ENVIRONMENTS NORMAL pH OF FLUID ION TRAPPING FENTANY L WEAK BASE pKa 8.0 DRUG IONIZATION MANIPULATING pH OF ENVIRONMENT TO CLINICAL ADVANTAGE: INCREASING pH TO INCREASE LIPOPHILICITY AND PROMOTE DIFFUSION Adding 1ml NaHCO3 to 9ml 2% lidocaine to convert labor epidural for CS DRUG IONIZATION CLINICAL APPLICATION OF pKa: 1) Is the drug a WEAK ACID or WEAK BASE? 2) What is the pKa of the drug? DRUG IONIZATION BUPIVACAIN E WEAK BASE pKa 8.1 DRUG INCOMPATIBILITY PRIMARY CONCERNS… 1) IONIZATION (pKa) / ACID-BASE REACTIONS 2) DESOLVATION OF NON-IONIC, ORGANIC DRUGS 3) SALTING OUT REACTIONS DESOLVATION • Many NON-IONIC drugs are INSOLUBLE in water • Must be formulated in ORGAINIC SOLVENTS or EMULSIONS • Solutions may be FRAGILE and very DESOLVATION ETOMIDATE DESOLVATION PROPOFOL 2,6 – diisopropylphenol AVERAGE DROPLET SIZE 0.15 – 0.3  m PROPOFOL Composition of EMULSION: • • • • • 2,6-diisopropylphenol Soybean oil Egg lecithin Glycerol Antimicrobial agents PROPOFOL • PHOSPHOLIPIDS in egg lecithin are AMPHIPATHIC (contain hydrophilic AND hydrophobic end) • NEGATIVE polar regions interact with H2O • Allow for DISPERSION in aqueous solution PROPOFOL DESTABILIZING FACTORS: • INCREASED TEMPERATURE • DECREASED pH • FREEZE-THAW FLOCCULATION • ELECTROLYTE CONTAMINATION COALESCENCE PROPOFOL CREAMING: Large oil droplets form and rise to surface CRACKING: Droplets break and free oil formed on surface 10  m High risk for FAT EMOLISM with CREAMING/CRACKING of propofol emulsion Capillary diameter 5-7  m BOTTOM LINE… DO NOT ADD/MIX ANY DRUG WITH PROPOFOL! DRUG INCOMPATIBILITY PRIMARY CONCERNS… 1) IONIZATION (pKa) / ACID-BASE REACTIONS 2) DESOLVATION OF NON-IONIC, ORGANIC DRUGS 3) SALTING OUT REACTIONS SALTING OUT REACTION • Involves uneven distribution of electrons due to VAN DER WAAL FORCES between molecules including PLASMA PROTEINS • Causes ELECRTRON CONCENTRATION and GREATER CHARGE, results in SALT FORMATION • Large SALT CRYSTALS increase risk of endothelial damage and EMBOLIZATION • Most common: CEFTRIAXONE (Rocephin) + CALCIUM (particularly in neonates) NO CEFTRIAXONE WITH CALCIUM OR CALCIUM SUMMARY UNDERSTANDING: What are the 3 primary concerns regarding drug incompatibility in anesthesia? Describe pharmacology of IONIZED and NON-IONIZED drugs. What is pKa? What does HENDERSON-HASSELBACH and pH equation measure? Describe and define EQUILIBRIUM CONSTANT. Describe relationship of pKa curves to degree of ionization and pH. How do local anesthetics cross cell membrane and reach receptor? What is ION TRAPPING and why is it significant? Describe the formulation of non-ionic, organic drug compounds. What are the components and functions of propofol emulsion? What destabilizes propofol emulsion and what are the dangers associated with such?