Pharmacology in Anesthesia Part 1

1. Pharmacology in AnesthesiaPart 1 Juan E. Gonzalez, CRNA, MS Assistant Clinical Professor

2. Pharmacokinetics • Pharmacokinetics (PK): describes relationship b/w dose of drug given & its observed [plasma] and/or [tissue]. • PK: what the BODY “does” to the drug • Clinical PK: describes Absorption (A), Distribution (D), Metabolism (M), Elimination (E) of drugs. (ADME) • Information about PK parameters (e.g. Vdss,CLtot) allows the prediction of [plasma] following different dosing regimens (dose individualization)

3. Pharmacodynamics Pharmacodynamics (PD): describes relationship b/w [drug] and the response (pharmacological effect) PD: what the DRUG “does” to the body PD effects: responsible for desired (therapeutic efficacy) and undesired (toxicity) clinical outcomes Examples of PD measurements: changes in BP during HTN Tx, decreases in HR during Beta-blocker Tx, changes in PT and INR during coumadin Tx drug + receptor drug-receptor complex response

4. PK & PD Both PK & PD are sources of variability in drug responses among pts (inter-patient variability: e.g., age, concurrent illness, concomitant medications)

5. PK & PD • Dosing regimen • PK • [drug] in the body (exposure) • PD • PD response • Therapeutics • Clinical outcome

6. PK concepts • When a drug is given extravascularly it must be absorbed across biological membranes to reach systemic circulation • PO: from GI tract into capillaries longer • Transdermal: from skin into capillaries • Transfer of drug across membranes based on: • drug properties: molecular size, degree of ionization, lipid solubility, protein binding • other factors: amount of blood flow to target tissue, [gradient] of drug across the membranes • Vasculature = transport of drug molecule to site of activity

7. Transport

8. Ionization • Most drugs are salts of weak acids or weak bases • For both weak acids and weak bases the total concentration of a drug is greater on the side of the membrane on which the drug is more ionized • Degree of ionization of a drug (whether acidic or basic drug) at a particular site is determined by the dissociation constant (pKa) of the drug and the pH of the environment the drug is in

9. Weak base If pH>pKa: unionized form predominates If pH=pKa: unionized=ionized If pH<pKa: ionized form predominates eg: Basic Drug (diazepam) pKa 3.3 In stomach: pH=1.3 In plasma: pH=7.4 Greater [diazepam] in GI compartment than in plasma Weak acid If pH>pKa: ionized form predominates If pH=pKa: unionized=ionized If pH<pKa: unionized form predominates pH, pKa, ionization

10. PK concepts • Once intravascular (IV): • Drug can leave vasculature (penetrate tissues) or • Drug can remain in blood • Drug may bind to endogenous proteins (e.g. albumin) • Binding is usually reversible (equilibrium b/w protein-bound drug and unbound drug) • Unbound drug in blood is driving force of distribution of agent into body tissues

11. PK concepts • If unbound drug leaves the bloodstream and distributes to tissue: • drug may become tissue-bound • drug may bind to receptor (pharmacologic or toxic response) • drug may bind to a nonspecific site (no effect) • drug may remain unbound in tissue • drug may be rendered inactive and/or eliminated from the body (if tissue can metabolize or eliminate the drug)

12. PK concepts • Organs (e.g. liver, GI tract wall, lung) have enzymes that metabolize drugs. Resulting metabolites may be active (biological effect) or inactive (no effect) • Blood has esterases: enzymes that cleave ester bonds in drug molecules  inactive

13. Metabolism • Metabolism (usually in the liver) via one or both types of reactions” • Phase I reactions • make the drug more polar and water soluble  more prone to elimination by the kidney (e.g. oxidation, hydrolysis, reduction) • Phase II reactions • Inactivate the pharmacologic activity of the drug and may make it more prone to elimination by the kidney (e.g., conjugation to form glucuronides, acetates, sulfates)

14. Linear PK • Most drugs follow linear pharmacokinetics: • [drug] in serum change proportionally with daily dosing (e.g., If “X” [drug] were doubled from 400mg/d to 800mg/d, the patient’s serum [drug] would double • If drug is given via continuous IV infusion, serum [drug] will increase until equilibrium b/w drug dosage rate and the rate of drug elimination • e.g., if pt receiving theophylline at a rate of 40mg/hr (dose), the serum [theophylline] will increase until the pt’s body was eliminating theophylline at 40mg/hr. When [serum] reaches a constant value  STEADY STATE

15. Compartmental PK • Describes the body as a system of hypothetical compartments linked by transfer rate processes (assumed to be first-order: proportional to the concentrations in their initial compartments) • Linear or dose-proportional PK (e.g. [drug] is proportional to the dose given) • These PK compartments group together several physiological compartments (tissues) that have similar kinetic properties • Each compartment is characterized by its size (volume). Each compartment has homogeneous concentrations.

16. One-compartment model Only one Compartment Drug given Drug Eliminated

17. Two-compartment model Peripheral Compartment (vessel-poor group) 90% body mass 25% cardiac output Central Compartment (vessel-rich group) 10% body mass 75% cardiac output Drug given Drug Eliminated -Central Compartment: Can be sampled through the blood. Made up of intravascular fluid and organs/tissues highly perfused with blood, e.g: lungs, liver, kidneys, heart, brain (rapid equilibrium distribution with blood) -Peripheral Compartment: Cannot be usually sampled. Made up of organs/tissues poorly perfused with blood, e.g: muscle, skin, fat, bone (slow equilibrium distribution with blood)

18. Fluid Composition • There are basically two water compartments in the body: • Extracellular 17% of body weight (12 liters)* • Plasma 4% of body weight (3 liters) • Interstitial 13% of body weight (9 liters) • Intracellularly 41% of body weight (28.5 liters) *Total body water (58% of body weight) or (40.5 liters) (based on 70 kg man)

19. Definitions • Volume of Distribution (Vd): volume necessary to account for the total amount of drug in the body if the drug were present throughout the body in the same concentration as in plasma. Absorption must be rapid and one assumes there is no elimination. • Vd is the apparent volume in which the drug is distributed after it has been introduced into the system. • This hypothetical value is calculated from the total dose divided by the plasma concentration at zero time. Vd = Q/CT=0 where Q: dose of drug CT=0: [drug] in plasma at time 0 Units: liters/kg

21. Definitions • Clearance (Cl): theoretical volume of plasma that is completely cleared of drug at a given time. Measure of the body’s ability to eliminate drug. • Units: ml/min • Elimination Half-Time (T1/2 beta): time it takes for the [drug] in plasma to fall by one half (only accounts for time to a 50% decrease in central compartment concentration) • Elimination Half-Life: (t1/2) time it takes for the total amount of drug in the body to decrease by 50% after absorption and distribution are complete. Plasma concentration of a drug reaches steady state in 4 to 5 half-lives. Elimination also takes 4 to 5 half-lives

22. References • The Chemistry of Drugs for Nurse Anesthetists (2005)by L.B. Kier & C.S. Dowd, AANA Publishing , Inc.Available only through AANA Bookstore: http://www.aana.com/bookstore/books.asp • http://www.med.howard.edu/pharmacology/handouts/pharmacodynamics.htm • http://cdds.georgetown.edu/programs/guphm/ligand/ • http://pharmacy.creighton.edu/pha443/pdf/Default.asp • Nagelhout & Zaglaniczny: Nurse Anesthesia, 3rd edition