Final Presentations of Pharm PDF

Clinical Pharmacokinetics Neisha M Rodriguez OD, PHD, MPH Clinical Pahrmacokinetics • Pharmacological effects of a drug and concentration of the drug in an accessible body compartment (e.g., in blood or plasma) as these change in time • Provides • Quantitative relationship between dose and effect...

Clinical Pharmacokinetics Neisha M Rodriguez OD, PHD, MPH Clinical Pahrmacokinetics • Pharmacological effects of a drug and concentration of the drug in an accessible body compartment (e.g., in blood or plasma) as these change in time • Provides • Quantitative relationship between dose and effect • Drug concentration in body fluids and their adjustments • Therapeutic efficacy and avoidance of unwanted effects Clinical Pahrmacokinetics • Parameters of drug disposition • • • • Bioavailability Volume of distribution Clearance Elimination Parameters of Drug Distribution • Bioavailability • Indicate the fractional (F) extent to which a drug dose reaches its site of effect action. uncharged drugimolecule • F = Qty of drug reaching systemic circulation Qty of drugs administered • Area under the plasma concentration The more quantity en drug,theno • The concentration of the drug in the plasma over time ? sope wan you es of and dose E dag ease plasmaovertime on doug Parameters of Drug Distribution • Apparent volume of distribution • Volume into a drug distributes and Liver • Vd = Amount of drug in the body (gm) Plasma drug concentration (gm/L) ht seae Parameters of Drug Distribution • Clearance • If bioavailability is complete, steady-state concentration of a drug will be achieved when the rate of elimination equals the rate of drug administration • Rate of elimination to the plasma concentration CL = Rate of elimination of a drug (Units=Vol per unit time) Plasma drug concentration *clearance is usually assumed to remain constant in a medically stable patient Volume of biological fluid from which drugs have completely removed • Total clearance Cltotal = Clrenal + Clhepatic + Clother Parameters of Drug Distribution • Clearance example • Drug X is infused at 5mg/min, producing a plasma rate concentration of 8mg/L. What is the clearance rate for this drug? CL = Rate of elimination of a drug (Units= Vol (mL) per unit time (min)) Plasma drug concentration en Parameters of Drug Distribution • Clearance example Case: An 80 Kg patient with a negative medical history has orbital cellulitis. Cephalexin is administered as a treatment. The drug plasma excretion concentration of unchanged drug is 93%, and the plasma clearance is 12 mL/min/Kg. What is the plasma clearance for this patient? · (12mL/min (kg) (80kg) - 960x . = 960m/min 93=892 . 8m2 Parameters of Drug Distribution • Half-life (t1/2) • The time it takes plasma concentration to be reduced to 50% • Constant for drugs that follow First order kinetics • t1/2 = 0.693 x Vd = (Units = Time) CL • Steady state • The rate of elimination is balanced with the rate of administration • Usually, at 4 t1/2 time frame Steady State • Drug X is administered every 8 hours in a formulation of 25 mg. The half-life of drug X is known to be 6 hrs. What would be the total amount of drug administered to achieve the steady state? üSteady-state is achieved 4 t ½ üThen 6 x 4 = 24 hrs. ü24 / 8 = 3 (doses) ü3 X 25mg = 75 mg • Dose regimen • Plan of administration over a period of time • Therapeutic window • Concentration range that provides efficacy without toxicity • Importante in long-term therapy Ocular Bioavailability Neisha M Rodriguez OD, MPH-G, PhD Ocular Bioavailability • Bioavailability • Fraction of administered drug gain access to systemic circulation chemically unchanged • FDA “the rate and extent to which the active ingredient or active is mostly absorbed from a drug product and becomes available at the site of action • In ocular therapy • Bioavailability is used to measure the side effects and toxicities and not an indication of therapeutic efficacy gang ciesrmiculnaitmioaln ophtai ↳from ophtalmic dreg Ocular Bioavailability Low toxicity • Topical ocular delivery • Low bioavailability • Low local and systemic effects • Physiological protective mechanisms from the eye comaspecto -blinting, Ocular Bioavailability • Physiological factors affecting ocular drug bioavailability • Factors • Pre-corneal clearance • Low corneal permeability • Blood-ocular barrier (BOB) Ocular Bioavailability • Physiological factors affecting ocular drug bioavailability • Pre-corneal clearance • Poor bioavailability less 5% • Tear turnover and drainage • Dilution by tear flow • Reflex blinking • Drug induced lacrimation 6 7 Ocular Bioavailability • Physiological factors affecting ocular drug bioavailability • Cornea as barrier • Mayor route for absorption • Corneal epithelium permeability • Tight intercellular junctions • Molecules cross • Simple diffusion • Paracellular and/or transcellular route • Hydrophilic drugs • Lipophilic drugs Retrieved from:www. duncaneye.com • Blood ocular barrier (BOB) 8 Ocular Bioavailability • Physicochemical factors affecting ocular drug bioavailability • Molecular solubility • Max amount of solute dissolved under standard conditions of temperature, pressure and pH • Topical ophthalmic drugs mainly absorbed by cornea, some through conjunctiva and sclera. • Deferential solubility dictates type of molecules • Intracellular • Intercellular Ocular Bioavailability • Physicochemical factors affecting ocular drug bioavailability • Molecular size and shape • Determinant in ocular permeation • Epithelium diameter • 2 nm • Large molecules • Fluorescein • Determinant rate of diffusion Ocular Bioavailability • Physicochemical factors affecting ocular drug bioavailability Yout • pH and dissociation • Aqueous solubility depends • Solution pH, pKa, pKb ee • Tear pH 17 . mantande • Ophthalmic solutions The chemical equilibrium - state in which the nonionized (more lipophilic) portion is in balance with the ionized, (more hydrophilic) portion • Weak acid or bases • Non-ionized form § estas Matformed a dang partOf Inon-isnined Duane's Ophthalmology 11 Ocular Bioavailability • Physicochemical factors affecting ocular drug bioavailability • pH § Indispensable for the chemical and physical stability § Buffers in formulations counteract shift in pH § In addition, buffer systems may momentarily alter the pH of tears after instillation § Irritation Ocular Bioavailability • Physicochemical factors affecting ocular drug bioavailability • Formulation factors dongJozorh • Instilled volume • 1 drop = 30 µL • Tear volume = 11 µL • Type • Bottle tip or dropper design • Dispensing rate • Angle of the bottle • 45° angle smaller than vertical position optifocralmachiulaetvetionhbottl e di p e Siste en ↳adquateo ↳ optimal t red you Nasolacrimal Drainage Area Canaculi 0.6 cm2 Drop 25-56 µl (30 µl) 1.5-2.0 cm2 Conjunctiva 18 cm2 Nasolacrimal Duct 0.8-1.6cm2 150-200 cm2 14 Ocular Bioavailability • Physicochemical factors affecting ocular drug bioavailability • Formulation factors • Viscosity • Drug retention cul de sac • Increase contact time • Cohesiveness with the ocular surface tends to increases trans corneal penetration 15 to 30 cps optimal (centistokes) (greater viscosity slower velocity of flow displacement) Ocular Bioavailability • Physicochemical factors affecting ocular drug bioavailability • Formulation factors • Osmolarity § Hypertonic solutions with a tonicity greater than the equivalent to 5% saline solution concentration – usually cause decrease drug concentration at the corneal surface § Hypotonic formulations with a tonicity under the equivalent of 5% solution undergo rapid dissolution upon instillation, thus offsetting adverse symptoms Isotonic formulations less irritating to eyes do not alter osmolarity • 290 osmol (0.9% saline sol) 16 17 Systemic Pharmacodynamics Neisha M Rodriguez OD, PHD, MPH Pharmacodynamics • Studies drugs' biochemical, cellular, and physiological effects and their mechanisms of action • Interactions with macromolecules • Receptors or drug targets Pharmacodynamics • Nature of drugs • • • • • Inorganic ions Nonpeptide organic molecules Small peptides and protein Nucleic acids, Lipids and carbohydrates • Size and molecular weight • From 7 to 50,000 (MW) • Most common between 100 and 1,000 Pharmacodynamics • Receptors and their sites • Specialized cell surface molecule targeted by a drug that mediates its pharmacologic actions • Large molecules of biochemical processes • Types • Ligand-gated ion • G proteins • Enzyme linked • Intracellular Pharmacodynamics • Physiological receptors • Agonist • Mimic regulatory effect of endogenous signaling • Primary agonist • Allosteric agonist • Partial agonist • Lower response than a full agonist • Antagonist • Block or reduce the action of the agonist Pharmacodynamics • Physiological receptors • Competitive antagonist • Compete with agonists • Noncompetitive antagonists • Prevents response of an agonist without competing with the agonist Pharmacodynamics • Potency • An expression of the activity of a drug in terms of the concentration or amount needed to produce a defined effect • ED50 • Efficacy • The maximal response produced by a drug