IntroductiontoPharm notes.pdf

INTRODUCTION TO PHARMACOLOGY ANES 629 Travis Laffoon, DNP, APRN, CRNA PHARMACOKINETICS/PHARMACODYNAMICS Pharmacokinetics What the body does to the drug A- Absorption D- Distribution M- metabolism E- excretion Pharmaco...

INTRODUCTION TO PHARMACOLOGY ANES 629 Travis Laffoon, DNP, APRN, CRNA PHARMACOKINETICS/PHARMACODYNAMICS Pharmacokinetics What the body does to the drug A- Absorption D- Distribution M- metabolism E- excretion Pharmacodynamics What the drug does to the body MOA, effects, potency, etc.  TERMINOLOGY Receptor: protein or other substance binding to an endogenous chemical or drug (ligand) ligand binds to receptors not every receptor needs to be bound to ilicit an effect Reversible binding vs. Irreversible binding Aspirin birds irreversibly to platelet receptor + only lose effect by making new platelets Affinity- attraction of drug to the receptor site Potency- amount of drug needed to produce effect Efficacy (intrinsic activity)- ability of drug to produce desired response Tolerance- increased amount of drug is needed to produce a given response Tachyphylaxis- acute tolerance/rapid decrease in response to given dose nitroglycerine  TERMINOLOGY ED50- effective dose in 50% of population, ED99- effective dose in 99% of population TD50- toxic dose in 50% of population LD50- lethal dose in 50% of population, LD1- lethal dose 1% of population Ceiling Effect- dose beyond which no effect is seen after which we see more unwanted effects Therapeutic window/index- dosage range that provides safe therapy toxic = unwanted effects  g protein coupled receptors most cornon RECEPTORS Bonds with a receptor fall into these categories from weakest to strongest Van der Waals, hydrophobic, hydrogen, ionic, and covalent 'non reversable receptor bond Most common site of receptor is in the cell membrane For intravenous drugs, sufficient amounts of drug required for a maximum response are delivered to site within 1 minute but they don't immediatly bint Occupancy theory- magnitude of drug’s effect is proportional to number of receptors occupied Square receptor concept- relationship between number of receptors bound and response is nonlinear response may not increase to the same magnitude as more receptors are bound  RECEPTOR BINDING Partial agonist Inverse agonist binds to receptor causes opposite Antagonist- binds to a Agonist/Antagonist- bind to a effect Agonist- binds to a receptor receptor and blocks its receptor and stimulate it but and stimulates its function function only have a fraction of the potency of pure agonist Lock and key Affinity but no efficacy Affinity and some efficacy Affinity and efficacy Competitive vs. Noncompetitive Nalbuphine, butorphanol ∅ amount of /produces Icompetes or agonism Attaches to a response receptor sire can overcome receptor I high agonist Levels What primarily determines the duration of action of a irreversible antagonist? A) Metabolism of the agent B) Speed at which new receptors are produced C) The pKa of the agent D) Diffusion of the drug away from the SOA E) The half-life of the agent ANTAGONISM Competitive antagonism Agonist and antagonist have affinity for same receptor Ex: Neuromuscular blocker and Acetylcholine Physiologic antagonism Two agonist drugs binding to different receptors that stimulate opposite functions constrict dilate Ex: phenylephrine & nitroglycerin Chemical antagonism Drugs action is blocked but no receptor is involved Ex: protamine and heparin  DRUG INTERACTION TERMINOLOGY Addition Combined effect of two drugs 1+1=2 with same mechanism produces effect equal to that expected Synergism Combined effect of two drugs is 1+1=3 greater than sum of individual effects Potentiation Enhancement of action of one 1+0=3 drug by another that has no detectable action of its own Antagonism The action of one drug opposes 1+1=0 another  UP & DOWN REGULATION Continued stimulation of receptors with agonists generally results in a state of desensitization, also referred to as refractoriness or down-regulation Subsequent exposure to the same dose of drug produces lower response Less receptors and less sensitive Continued administration of an antagonist results in up-regulation as a response to chronic blockade Patient again experiences tolerance which requires higher doses for continued antagonism More receptors and more sensitive THERAPEUTIC INDEX TI= ________/__________ Range between the concentration that produces a desired effect and one that produces a toxic effect The larger the TI the safer the drug PROPERTIES INFLUENCING DRUG ACTIVITY Molecular size- molecules with molecular weights greater than 200 generally don’t cross cell membranes Active or passive transport Protein binding- doesn’t allow passage through blood vessels Acidic drugs primarily bind to _____________ Basic drugs bind primarily to _____________ & __________________ Protein binding generally parallels lipid solubility because hydrophobic drugs are more likely to bind to proteins and fat Number of sites is finite- can overcome binding by adding more drugs Drugs with 90% protein binding (or higher) can have unexpected intensifications if displaced from proteins (usually clinically irrelevant) Theoretically, reductions in protein content from liver disease, poor nutrition, CHF, last trimester of pregnancy can have similar effects Drug/Protein Displacement % bound % free New % New % free Relative % bound increase Drug A 98 2 96 4 100% Drug B 60 40 58 42 5% Drug C 90 ___ 70 ___ ___  IONIZATION Drugs are typically salt forms of either weak acids or weak bases Charged (ionized) form is water soluble, uncharged (nonionized) form is lipophilic Ionized doesn’t penetrate lipid membranes (may in very small quantities) Nonionized does penetrate lipid membranes pKa is the pH at which a drug exists as 50% ionized and 50% nonionized pKa is a value that DOES NOT change, but its proximity to the pH of the environment it is in determines the percentage of the drug that will exist in a soluble form pKa DOES NOT tell you if a drug is an acid or base  IONIZATION Basic drugs entering a more basic environment (than its pKa) will become more nonionized Acidic drugs entering a more acidic environment (than its pKa) will become more nonionized Basic drugs entering a more acidic environment (than its pKa) will become more ionized Acidic drugs entering a more basic environment (than its pKa) will become more ionized If the difference between the pKa and pH of the solution is 1 or greater, it is nearly 100% something (ionized/unionized) If the difference is 0.5 it is 75% something (ionized/unionized) pH & pKa the same it is 50%/50% DRUG COMPOUNDS Weak acids unite with positively charged ions such as Na+, Mg++, Ca++. If you notice one of the following: sodium drug, calcium drug, magnesium drug- you could assume the drug is the salt form of a weak acid. Ex: Sodium pentobarbital is the salt of a weak acid Weak bases unite with negatively charged ions such as Cl- or SO42-. If you notice one of the following: drug chloride, drug sulfate- you could assume the drug is the salt form of a weak base. Ex: morphine sulfate and lidocaine hydrochloride are the salts of weak bases pKa Equation Examples Weak Acid pKa 4 placed into pH of 11 = _____% ____________ pKa 4 0 14 pH 11 pKa 10 0 14 pH 9.5 Weak Acid pKa 10 placed into pH 9.5 = _____% ___________ Difference in pKa & pH % form (ionized or unionized) 0 50/50 0.1 55 0.2 60 0.3 65 0.4 70 0.5 75 0.6 80 0.7 85 0.8 90 0.9 95 1.0 99-100% An acidic drug with a pKa of 7.4 is administered into an environment of 7.4. What is the percentage of the drug in the ionized form? A) 100% B) 75% C) 50% D) 25% E) 0% A basic drug with a pKa of 3.4 is given IV. What is the percentage of the drug in the ionized form? A) > 99% B) 75% C) 50% D) 25% E) < 1%  ION TRAPPING Degree of ionization of a specific agent can vary based upon the membrane it crosses An agent that crosses a membrane into an environment that favors its conversion to an ionized form can ”trap” it in that area Ex: Lidocaine (base pKa 7.9) given to mother → crosses the placenta → lidocaine becomes more ionized (pH in the fetus is lower than that of the mother ) → now trapped in the fetus and can’t cross back through placenta membrane  ABSORPTION Defines the uptake of a drug across tissues and its movement into the bloodstream Influenced by drug characteristics (pKa, solubility, formulation), dose, site, bloodflow, surface area, first pass metabolism, etc. Ficks law: rate of diffusion across a specific membrane depends on concentration gradient, area of membrane, solubility of drug, thickness of membrane, and molecular weight of drug Bioavailability- fraction of the administered drug that actually reaches the systemic circulation. FIRST PASS EFFECT Drug absorbed from GI tract first pass through portal venous system and then through the liver prior to entering systemic circulation If drug is extensively metabolized by the liver, then little reaches systemic circulation  DISTRIBUTION Involves the instantaneous distribution of drug into the blood volume and subsequent partitioning of drug into tissues Described by compartment models which depict the body as composed of distinct sections One compartment model represents the entire body, through which homogeneous distribution occurs Two compartment model is composed of a central compartment and a peripheral compartment Drugs obey the law of mass action When plasma concentration exceeds tissue concentration the drug moves from plasma to tissue and vice versa TWO COMPARTMENT MODEL Central compartment is composed of intravascular fluid and highly perfused tissues (heart, lungs, brain, liver, kideys, endocrine organs) 10% of body mass Receives 75% cardiac output (vessel rich group) Peripheral compartment composed of muscle and vessel poor tissues (fat, bone) 90% body mass Receives 25% of cardiac output VOLUME OF DISTRIBUTION The apparent theoretical volume in which the drug is distributed once it is introduced into the body Reflects the volume into which the drug would need to distribute to account for the observed plasma concentration Relates the amount of drug in the body to the serum concentration Vd= dose/plasma concentrationT=0 Extracellular fluid= 14L (interstitial 10L & plasma 4L), Intracellular fluid= 28L (70kg)= 42L TBW Normal Vd for for a 70kg adult = 42L/70kg=0.6L/kg If Vd is >0.6 L/kg then drug is likely largely distributed and lipid soluble If Vd is 0.6 Capacity dependent- extraction ratio