Exam 1 Flashcards
Pharmacokinetics
What the body does to the drug
Absorption
How the drug gets in
Bioavailability
Relative amount of drug that reaches systemic circulation
= 1 for parenteral (IV or IM)
First-pass metabolism
Occurs before drug reaches systemic circulation
Liver: very significant for enteral administration
Lung: fentanyl uptake, propofol metabolism
Plasma esterases/pseudocholinesterase
First-Pass of sublingual route
Direct absorption into systemic venous system, avoids portal circulation
NO FIRST-PASS
Distribution of cardiac output
VRG: 75% and is 10% BW
Muscle: 19% and is 50% BW
Fat: 6% and is 20% BW
VP: 0% and is 20% BW
Redistribution
Single doses of lipophilic drugs have short CNS DOA as they redistribute to peripheral tissues
Larger doses=longer apparent DOA
Decrease in plasma concentration becomes dependent on elimination from body instead of redistribution
Albumin
Carrier protein produced in the liver
Binds most acidic/neutral drugs, some basic(ex:benzos, SSRI’s)
Alpha-1-acid glycoprotein
Binds most basic drugs
Pt with low protein levels
Higher free drug levels
Cell Membrane make up
Lipid bilayer
Small lipophilic drugs pass freely
Hydrophilic drugs require channel (except in CNS, as they must undergo active transport)
Passive transport
Movement of drug down its concentration gradient
Generally limited by blood flow
Drug will diffuse as quickly as it can be delivered
Facilitated diffusion
Needs carrier proteins, NO ENERGY REQUIREMENT
Active transport
Carrier proteins use energy to move drug, even against concentration gradient
Both lipophilic and lipophobic drugs need active transport to deal with concentration gradients
Acid-Base
H(+) + A- HA
H(+) + B HB(+)
CHARGED SPECIES DONT CROSS MEMBRANES WELL
pKa
pH where ionization occurs
“50-50 point”
Ex: if pKa = 6 and pH = 2, excess protons will drive equation to RIGHT
If pKa = 6 and pH = 7.4, equation will shift to LEFT
Biotransformation
Alteration of the drug via a metabolic process (usually in liver)
Most drugs need to be HYDROPHILIC for excretion
Phase 1 Biotransformation
Oxidation, reduction, hydrolysis
Increase polarity of molecule to make the drug water soluble for excretion in urine
CYP
Enzyme that catalyzes most phase 1 rxns
Activity increases with ongoing drug exposure
Can be inhibited when drugs compete for same CYP subtype
CYP3A4/5
Subtype of CYP family
Metabolizes many opioids, benzos, LA’s
Phase 2 Biotransformation
Conjugation with a polar substance
(Attachment of glucuronate, acetate, glutathione group) –> water soluble for excretion in urine
Neonate Biotransformation
Neonates through 1 year have diminished phase 1 and 2 activities
Hepatic Drug Clearance
Volume of blood that the liver could cleanse of drug in given amount of time
Hepatic blood flow x extraction ratio
Hepatic blood flow
Dependent on CO and BP
Hepatic extraction ratio
Fraction of drug removed from the blood as it passes through the liver
High Extraction Ratio
“Flow-limited” (e.g. Etomidate, propofol)
Hepatic clearance nearly equal to hepatic blood flow
Low CO states will show diminished hepatic elimination
Clearance remains unchanged unless metabolic capacity (Vm) is severely compromised
Low extraction ratio
“Capacity limited” (e.g. Thiopental, diazepam)
Clearance NOT significantly affected by changes in hepatic blood flow
Clearance limited by fact that liver can only handle a fraction of the drug it sees
Changes in Vm will produce a nearly proportional effect on clearance
Renal drug clearance
Autoregulation maintains constant renal flow over wide range of CO
Renal clearance small fraction of renal blood flow, due to protein binding
Renal tubular active transporters allow renal clearance to approach RBF
Decreased Renal function and dosing
Altered drug dosing required to avoid accumulation of parent compounds and metabolites
Drugs with significant renal excretion
Aminoglycosides Atenolol Cephalosporins Digoxin Edrophonium Nadolol Neostigmine Pancuronium PCNs Procainamide Pyridostigmine Quinolone Rocuronium Sugammadex
First-order kinetics
Fixed PERCENTAGE/FRACTION of existing drug removed per unit of time
AMOUNT depends on serum levels
FRACTION removed does NOT depend on serum levels
Ex: if 10% removed per minute, k=0.1min^-1
Zero-order kinetics
Fixed AMOUNT of drug removed per unit of time
INDEPENDENT of serum levels
Found in certain drugs (e.g. Phenytoin, alcohol)
Can occur at high serum levels of drugs (notably thiopental) especially when concentration exceeds body’s capacity to metabolize drug
Half-life
Time required for serum concentration to change by a factor of 2
= ln 2/k
After 5 half-lives, drug 97% reduced in serum
Volume of distribution
Quantifies extent of drug distribution
= amount given/serum concentration
Describes capacity of tissues for absorbing certain drug
Depends on tissue mass and the affinity of that drug for the tissue
Numeric index of extent of distribution, describing behavior of drug in body
Vd of lipophilic drugs
Generally larger Vd than other classes
Loading dose
Vd x target concentration
Elimination clearance
(ClE) theoretical volume of flood from which drug is completely and irreversibly removed in a unit of time
= dose given/area under concentration vs time curve
Elimination half-life
(t 1/2 beta) amount of time it takes for the amount of drug IN THE BODY to decrease by a factor of 2
Depends on both distribution and elimination
= ln 2 x (Vd/ClE)
Does not say anything about termination of EFFECT (which depends on SERUM concentration), only elimination of drug from the body
Two- compartment model
Central compartment (VRG + plasma) and peripheral compartment
Initial spike in serum concentration after injection
Quick decline = distribution phase (alpha phase)
Slower decline = elimination phase (beta phase)
Pharmacodynamics
What the drug does to the body
ED50
Does required to produce a specific effect in 50% of the population (like MAC)
LD50
Dose required to cause death (or toxicity) in 50% of population
Therapeutic index
LD50/ED50
Measure of safety
Our drugs often have two-tailed therapeutic index
There are both low (awareness) and high (overdose) toxicities to avoid
Receptor model
Drug + receptor Drug - Receptor –> Effect
Agonist (X) binds to receptor (R) and produces an effect
Potency
How much drug you need to get an effect
Usually due to differing affinity for receptor
Efficacy
Max degree of effect a drug can cause
Partial Agonist
Produces a lower maximal response than a full agonist
Lower efficacy
Competitively inhibits response produced by full agonist
Redundancy
Generally an excess of receptors
Max effect typically occurs at FAR BELOW MAXIMUM receptor binding
Tolerance
Diminished response to a drug dose due to chronic exposure
Cellular tolerance (adaptation)
Enzyme induction (change in metabolism)
Depletion of neurotransmitters
Tachyphylaxis
Acute tolerance after only a few doses
Antagonists
Bind to receptor without producing an effect
Competitive antagonist
(Y) Binds reversible to same binding site
Effect can be overcome by increasing concentration of agonist
Decreases agonist potency, but efficacy is not changed
Non-competitive antagonist
(Z) some bind irreversibly to receptor
Some bind to allosteric site
Reduce both potency and efficacy
Cannot be completely overcome by increasing concentration of agonist
TBW
Actual BW of PT
Can lead to drug overdose in morbidly obese pts
Especially inappropriate for dosing water-soluble agonists
Succinylcholine
Cisatracurium
Neostigmine
LBW
Fat mass subtracted from TBW
Correlates with better CO and drug clearance
Does not account for obesity-related cardiomyopathy
Males: 1.1 x weight -128 x (weight/height)^2
Females: 1.07 x weight - 148 x (weight/height)^2
IBW
Based on height
Useful in pts with BMI<40
Males: 50kg + 2.3kg for every inch over 60
Females: 45.5kg + same
Vecuronium Cisatracurium Rocuronium Morphine Acetaminophen
Ideal IV Anesthetic
Water soluble and stable
Lack of pain on injection; no tissue damage with extravasation
Low incidence of histamine release or hypersensitivity
Rapid smooth onset
Rapid metabolism to inactive metabolites
Minimal cardiac/respiratory depression
Decreases ICP/CMRO2
Rapid smooth recovery
Minimal side effects
Propofol
Inhibitory transmission (GABA)
Emulsion in intralipid (soybean oil, glycerol, egg lecithin)
Lecithin is from YOLK, most allergies are to egg WHITE (protein)
Supports bacterial growth
Discard open vial & tubing after 12 hours
Fospropofol
Aquavan: prodrug, water soluble,
Side effect: perineal burning
Propofol pharmacokinetics
Absorption: IV
Distribution: highly lipid soluble; very fast redistribution (<8mins)
Biotransformation: exceeds hepatic blood flow - implies extrahepatic metabolism (lungs?)
Up to 10x faster than thiopental
Liver conjugation (inactive metabolites), but not affected by moderate cirrhosis
Excretion: renal (but not affected by CRF)
Dose: 1.5-2.5 Mg/kg
25-75 mcg/kg/min for sedation
100-200 mcg/kg/min for GA - target plasma concentration of 4-6 mcg/mL
Some risk of awareness when used as sole agent, higher risk of pt movement
Propofol Infusion Syndrome
Lactic acidosis usually after prolonged high-dose infusions (>75 mcg/kg/min, >24 hours)
Lipemia, rhabdomyolysis, metabolic acidosis, death
May reflect a genetic susceptibility
Effects of Propofol (CV)
CV: decreased SVR, contractility, preload –> hypotension
Worse with rapid injection, old age, LV failure
Potential for bradycardia, but often tachycardia with induction