Pharmacokinetics Flashcards
What is the equation for volume of distribution?
Vd = amount of drug/desired plasma concentration
What is the total distribution of body water in a 70 kg patient?
42L
How many liters of fluid are located in the intracellular region?
28
How many liters of fluid are located in the extracellular fluid?
14L
Of the extracellular fluid, how many liters are located in the interstitial fluid?
10L
Of the extracellular fluid, how many are located in the plasma volume?
4L
A drug with a Vd that > TBW (> 0.6 L/kg or > 42L) is assumed to be what?
Lipophilic
A drug with a Vd < TBW (<0.6 L/kg or < 42L) is assumed to be what?
Hydrophilic
What are some key traits about a drug that is lipophilic with a high Vd (>42L)?
It distributes into the total body water as well as into the fat
What is the equation for the loading dose of a drug?
Loading dose = Vd x desired plasma concentration/ 1
(this is assuming it is an IV drug with 100% bioavailability)
What are the most important clearing organs?
Liver
Kidney
Organ independent (Hoffman)
What is clearance directly proportional to?
Blood flow to cleaning organ
Extraction ratio
Drug dose
What is clearance inversely proportional to?
Half-life
Drug concentration in the central compartment
What does a steady state mean?
The amount of drug entering body = amount of drug eliminated from body
As a general rule, when is steady state achieved?
5 half-lives
When looking at the plasma concentration curve, what does the alpha phase represent?
Distribution
What looking at the plasma concentration curve, what does the beta phase represent?
Elimination
What is the concept of context sensitive half-time?
It’s the time required for the plasma concentration to decline by 50% after the infusion is stopped
What is the Ionization of a drug is dependent on what two factors?
The pH of the solution
The pKa of the drug
What exactly is pKa?
It’s a constant property of a molecule
A drug’s pKa equals the pH where 50% of the drug is ionized and the other 50% is non-ionized.
What is the Henderson-Hasselbach equation?
pH= pKa + log (base) / conjugate acid
What are some properties of an ionized molecule? Traits
Solubility: water (hydrophilic)
Pharmacological effect: not active
Hepatic Biotransformation: less likely
Renal Elimination: More likely
Diffuses across lipid bilayer: BBB, GI tract, or placenta —> no
What are some properties of a non-ionized molecule?
Solubility: lipophilic
Pharmacologic effect: yes, active
Hepatic bio transformation: more likely
Renal elimination: no
Diffuse across a lipid bilayer: BBB, GI tract, Placenta —> yes
Which local anesthetic is most likely to undergo fetal ion trapping? Which is the least likely?
Most likely: Lidocaine
Least likely: chloroprocaine (d/t it’s high pKa and rapid metabolism)
What are some key facts about albumin in terms of plasma protein binding?
Most plentiful plasma protein
Determines oncotic pressure
1/2 life: 3 weeks
Negative charge
Primarily binds to ACIDIC drugs
In what conditions is albumin decreased?
Liver disease
Malnutrition
Renal dx
Old age
PREGNANCY
What are some key facts about a1- Acid Glycoprotein?
Binds with basic drugs
When is a1 acid Glycoprotein increased? What decreases it?
Increased: surgical stress
MI
chronic pain
RA
Advanced age
When is it decreased: pregnancy neonates
What is the equation to determine changes in plasma protein binding?
Percent change= New value - Old Value / old value x 100%
What is zero order kinetics? What are some examples?
A constant AMOUNT of the drug is metabolized per unit time
Ex: asa, phenytoin, alcohol, warfarin, heparin, theophylline
What is first order kinetics?
A constant FRACTION of the drug is metabolized per unit time
Most of our drugs are this.
What is the key organ for metabolism? What is another important site?
Key: Liver
Plasma
What is the primary role of metabolism?
Change a lipid-soluble, active compound to a water soluble, inactive compound
What is it called when the body converts an inactive molecule into a pharmacologically active molecule?
Prodrug!
What are the 3 phases of metabolism?
Phase 1: Modification
Phase 2: Conjugation
Phase 3: Elimination
What are the three types of phase 1 reactions?
Oxidation —> removes electrons
Reduction —> adds elections
Hydrolysis —> adds water to split
What does it mean to be perfusion dependent?m in terms of hepatic elimination?
This is for drugs with a high hepatic extraction ratio (> 0.7) ~ clearance depends on liver blood flow.
^ liver blood flow = ^ clearance
Decrease in blood flow = decrease in clearance
What does it mean to be capacity dependent on terms of hepatic elimination?
Drugs that have a low hepatic extraction ratio (< 0.3). Clearance is dependent on the ability of the liver to extract the drug from blood. Changes in hepatic enzymes and/or protein binding affect clearance
^ enzyme induction = ^ clearance
Enzyme inhibition = decrease clearance
What are examples of high hepatic extraction rations and/or perfusion-dependent drugs?
Most anesthetics/opioids
Propofol
Fent
Ketamine
Morphine
Lidocaine
BBS
CCBs
What are examples of low hepatic extraction ratio? An/or drugs that are capacity-dependent?
Roc
Diazepam
Lorazepam
Methadone
Thiopental
Theophylline
Phenytoin
What are two specific enzymes of the P450 system that pertain to anesthesia? They are important
CYP 3A4 (most of our anesthetics)
CYP 2D6 (some opioids) morphine, oxycodone, hydrocodone
Name some examples of enzyme inducers? What do these do?
Increase clearance —> decrease drug level —> may need increased dose
Tobacco
Barbiturates
Ethanol
Phenytoin
Rifampin
Carbamazepine
St. John’s Wort
What are examples of an enzyme inhibitor? What does it do?
Inhibits enzyme activity —> decreases clearance —> increased plasma levels—> smaller dose may be required
Grapefruit juice
Cimetidine
Omeprazole
Isonaizid
SSRIs
Erythromycin
Ketoconazole
Cipro
Acidic urine favors what? Think elimination
Reabsorption of acidic drugs
Excretion of basic drugs
AAA (Acids are better Absorbed in an Acid medium)
Basic urine favors what? Think elimination
Reabsorption of basic drugs
Excretion of acidic drugs
BBB: Basic drugs are Better absorbed in a Basic medium)
What drugs are metabolized by pseudocholinesterases?
Sux
Mivacurium
Ester local anesthetics (cocaine, tetracaine)
What drugs are eliminates by non-specific esterases?
Esmolol
Remi
Atracurium (+ Hoffman)
Etomidate
Clevidipine
What describes the relationship b/t effect-site concentration and the clinic effect?
Pharmacodynamics
“What the drug does to the body”
What describes the relationship b/t the drug dose and plasma concentration?
Pharmacokinetics
“What the body does to the drug”
(Think absorption, distribution, metabolism, elimination)
What is one the x axis when looking at the dose-response curve?
Potency
What is on the y axis is on dose-response curve?
Efficacy
What is the ED50? What is the ED90?
ED 50 —> dose required to achieve a given affect in 50% of the population
ED 90 —> dose required to achieve a given affect in 90% of the population
When considering the dose-response curve, what does a left-shift mean?
Increased potency —> lower dose required
When considering the dose-response curve, what does a right shift mean?
Lower potency —> higher dose is required.
What is efficacy?
Measure of the intrinsic ability of a drug to elicit a given clinical effect
What does the slope on the dose response curve indicate?!
Slope tells you how many receptors must be occupied to elicit a clinical effect.
Steep slope: most receptors must be fully occupied
What is an example of addition?
Effect of two drugs given at the same time are added to each other (1+1=2)
Morphine + hydromorphone
What is an example of synergism?
The effect of two drugs given at the same time is greater than their individual effects.
(1+1=3)
Propofol and midazolam
What is potentiation?
Effect of one drug is enhanced by a drug that has no effect of its own
1+0=3
PCN and probenecid
What is antagonism?
Simultaneous administration of one drug negates the effect of a second drug
1+1=0
Fent and naloxone
How do you calculate therapeutic index?
Therapeutic index= LD50 / ED50
What is the TD50?
The dose that will produce toxicity in 50% of the population
What is the LD50?
The dose that produces death in 50% of the population.
What is a racemic mixture?
It’s a mixture that contains two enantiomers in equal amounts.
What are some examples of enantiomers?
Ketamine
Thiopental
Isoflurane
Desflurane
Mepivacaine
What are two exceptions that are prepared as single enantiomers instead of as racemic mixture?
Ropivacaine
Levobupivacaine
What are ways you can acidify the urine?
What are ways you can alkaline the urine?
Acidify: ammonium chloride or cranberry
Alkalize: acetazolamide
