Pharmokinetics Flashcards
What is the relationship between a drugs dose and the plasma concentration?
volume of distribution
What two things does volume of distribution assume?
- drug distributes instantaneously
2. the drug is not subject to biotransformation or elimination before it fully distributes
How would a drug with a low volume of distribution be described?
< 0.6mL/kg or < 42L
Where do drugs with a low Vd distribute?
some or all of the body, but not the fat. “hydrophilic”
Does a drug with a low Vd need a larger or smaller dose to achieve a desired plasma concentration?
smaller
What is one class of a drugs with a low Vd?
NMB
The ____ the Vd the ___ the loading dose to achieve a desired plasma concentration.
higher, higher
What is the formula for Vd?
Vd= amount of drug / desired plasma concentration
What is the formula used to calculate loading dose?
IV loading dose = Vd x (desired plasma concentration / bioavailability)
How would a drug with a high Vd be described?
> 0.6L/kg or > 42L
Where do drugs with a high Vd distribute to?
into body water and fat. “lipophilic”
Do drugs with a higher Vd need a smaller or larger dose to achieve a desired plasma concentration?
higher
What is an example of drug with a high Vd?
propofol
How is TBW distributed? TBW = Extracellular= Intracellular= Plasma= Interstitial=
TBW = 42L Extracellular= 14L Intracellular= 28L Plasma= 4L Interstitial= 10L
What is the volume of plasma that is cleared of drug per unit time?
clearance
What are the three major clearing organs?
liver
kidney
organ independent (Hoffman elimination and ester hydrolysis in plasma)
What occurs when the amount of drug entering the body equals the amount being eliminated?
steady state
How many half lives must occur to reach steady state?
5 half lives
What is drug clearance directly proportional to?
blood flow to clearing organ
extraction ratio
drug dose
What is drug clearance inversely related to?
half life
drug concentration in the central compartment
What describes the alpha phase?
distribution of a drug.
What occurs during the alpha phase?
the drug rapidly distributes from the central compartment (plasma) to the peripheral compartments (tissues)
What determines the slope of alpha distribution?
Volume of distribution
Describe the alpha phase slope of a lipophilic drug.
larger volume of distribution, steeper slope
What occurs during the beta phase?
eliminiation
As a drug is being eliminated from the central compartment and the plasma concentration declines. What will eventually happen?
concentration gradient reverses and drug will redistribute from the tissues back into the central compartment.
Does the beta phase slope represent elimination from the central compartment, peripheral, or both?
central
What is the speed at which a reaction occurs? “how fast the molecules move b/w compartment”
rate constants
Drug transfer from the central to peripheral compartment is K___
K12
Drug transfer from the peripheral to central compartment is K___
K21
Drug elimination from the body is K___
Ke
The time it takes for 50% of the drug to be removed from the body after IV injection
elimination half life
The time it takes for 50% of the drug to be removed from the plasma during the elimination phase (beta phase)?
elimination half time
Elimination half times is only applicable to what compartment model?
one compartment
What is the time required for the plasma concentration to decline by 50% after infusion is stopped?
context sensitive half time
What narcotic is quickly metabolized by plasma esterases, and has a context sensitive half time independent of infusion time?
Remifentanil
Arrange Fentanyl, Sufentanil, Remifentanil, and Alfentanil from longest to shortest centext sensitive half time.
fentanyl - longest
alfentanil
sufentanil
remifentanil - shortest
What ions are weak acids paired with?
sodium, calcium, and magnesium (all positive ions)
What ions are weak bases paired with?
chloride, sulfate (all negative)
When pKa and pH are the same, what percentage of the drug will be ionized and nonionized?
50%, 50%
What does an acidic drug donate?
H+
What does a basic drug donate?
OH-
What is the process where a molecule gains a positive or negative electron and this molecular charge affects a molecules ability fo diffuse through lipid membranes.
ionization
Describe solubility of ionized and non-ionized drugs.
ionized are hydrophilic and lipophobic
nonionized are hydrophobic and lipophilic
Are ionized or nonionized drugs active?
nonionized
What type of drugs are more likely to undergo hepatic biotransformation?
nonionized
What type of drugs are more likely to undergo renal elimination?
ionized
What type of drugs can diffuse across lipid bilayers?
nonionized
An acidic drug in a basic solution will be highly ionized or nonionized?
ionized
An acidic drug in a acidic solution will be highly ionized or nonionized?
nonionized
A basic drug in a acidic solution will be highly ionized or nonionized?
ionized
A basic drug in a basic solution will be highly ionized or nonionized?
nonionized
What circumstance creates the strongest gradient for passage of LA from mother to fetus?
maternal alkalosis, fetal acidosis
What part of a drug can diffuse across the cell membrane?
lipophilic, nonionized
What part of a drug can diffuse across the cell membrane?
lipophilic, nonionized
Can ionized drugs cross cell membranes?
no
What are the three major plasma proteins?
albumin, a1-acid glycoprotein, beta globulin
Which plasma proteins bind to basic drugs?
a1-acid glycoprotein and beta globulin
What plasma protein binds acidic drugs mainly?
albumin
What is the primary determinant of plasma oncotic pressure?
albumin
Which plasma protein is a measure of protein synthesis, has a negative charge, and a half life of 2 weeks?
albumin
What situations cause a decrease in albumin?
liver disease, renal disease, old age, malnutrition, pregnancy
What increases a1-acid glycoprotein?
surgical stress, myocardial infarction, chronic pain, RA, old age
What decreases a1-acid glycoprotein?
neonates and pregnancy
How is % change of a bound and unbound drug calculated?
% change = (new unbound value - old unbound value) / new unbound value
What causes changes in plasma protein binding?
decreased plasma protein content, or competition to binding sites
The Vd and plasma protein content have what type of relationship?
inverse
Is the metabolism and elimination of highly protein bound drugs slower or faster compared to drugs with decreased protein binding?
slower
What order kinetics is described by a drug being eliminated at a rate of 5mg/h?
zero order kinetics
When there is more drug than enzyme, the drug is eliminated by which order kinetics?
zero order
What drugs undergo zero order kinetics?
aspirin, phenytoin, alcohol, warfarin, heparin, theophylline
A drug that is eliminated at a rate of 50%, undergoes which order kinetics?
first order kinetics
Is there more enzyme or drug in first order kinetics?
more enzyme. the enzyme metabolizes the drug at a constant fraction
What are the three phases of drug reactions?
phase 1: modification
phase 2: conjugation
phase 3: elimination/excretion
What are the most common sites of drug metabolism?
liver #1 and plasma
The P450 system is located where?
smooth endoplasmic reticulum
What types of drug metabolism occurs in the plasma?
Hoffman elimination, hydrolysis reactions,
How does metabolism facilitate drug elimination?
metabolism changes a lipid soluble compound into a H20 soluble, inactive byproduct
Why does metabolism transform drugs into H2O soluble compounds?
H2O soluble drugs have greater ionization, which decreases Vd, increasing delivery to the kidney for elimination
What are the three stages of phase 1 reactions?
oxidation- removes electrons
reduction- adds electrons
hydrolysis- adds H20 to split apart
Most phase 1 reactions are carried out by which system?
P450
What occurs during conjugation? Phase 2 reactions
H20 is added to the molecule. It becomes highly H20 soluble, inactive and ready for elimination
What is enterohepatic circulation?
Drugs like diazepam are excreted in the bile, reactivated in the intestine, then reabsorbed into circulation
What do phase 3 reactions require to transport drugs across cell membranes?
ATP dependent carrier proteins
Which drug has higher efficacy?
Which drug needs to occupy fewer receptors to cause a response?
Efficacy: A
Response: B
Which drug is more potent?
Drug A
What drugs undergo perfusion dependent hepatic elimination?
fentanyl, lidocaine, propofol
What two drugs undergo capacity dependent elimination?
diazepam and Roc
What is the extraction ratio?
how much drug is delivered to clearing organ vs how much is removed by that organ.
What does an extraction ratio of 1.0 and 0.5 represent?
1 means 100% delivered in cleared
0.5 means 50% of drug delivered is cleared
What two factors determine hepatic clearance?
blood flow and extraction ratio
What extraction ratio signifies flow limited extraction?
ER > 0.7
What extraction ratio signifies capacity limited extraction?
ER < 0.3
What does an ER > 0.7 mean?
clearance is dependent on liver BLOOD FLOW
What does an ER < 0.3 mean?
clearance is dependent on the livers ability to extraction drug from the blood.
What has a significant impact on hepatic clearance if the drug has a ER < 0.3?
enzyme activity and protein binding
What drugs have an ER < 0.3 so they are enzyme dependent?
Rocuronium, Diazepam, Lorazepam, Methadone, Thiopental, Theophylline, Phenytoin
What are examples of drugs with an intermediate ER?
Versed, Vec, Alfentanil, methohexital
What are drugs with a ER > 0.7, blood flow dependent elimination?
Fentanyl, Sufentanil, Morphine, Meperidine, Naloxone, Ketamine, Propofol, Lidocaine, Bupivacaine, Metoprolol, Propranolol, Alprenolol, Nifedipine, Diltiazem, Verapamil
What is the most important mechanism of drug biotransformation in the body?
P450 enzymes
Where are P450 enzymes located?
hepatocyte smooth ER. Also lungs, skin, kidneys, adrenal gland, and GI tract.
What is the most important cytochrome P450 enzyme?
CYP 3A4
What are the three effects of enzyme inducers?
increase clearance, decrease plasma levels, may need higher doses.
What are examples of enzyme inducers?
tobacco, barbiturates, ethanol, phenytoin, rifampin carbamazepine
What do enzyme inhibitors do?
compete for binding sites on an enzyme and reduce clearance.
What are the three effects of enzyme inhibitors?
decrease clearance, increase plasma levels, need smaller doses.
What are examples of enzyme inhibitors?
grapefruit juice, cimetidine, omeprazole, isoniazid, SSRI’s, erythromycin, ketoconazole
What are examples of drugs that undergo metabolism by CYP 3A4?
Fentanyl, Alfentanil, Sufentanil, Methadone
Midazolam, Diazepam
Lidocaine, Bupivacaine, Ropivacaine
What are examples of drugs that undergo metabolism by CYP 2D6?
codeine, oxycodone, hydrocodone
What are examples of drugs that undergo metabolism by CYP 1A2?
Theophylline
What are some CYP 3A4 inhibitors and inducers?
inducers: phenytoin, carbamazepine, dexamethasone
inhibitors: isoniazid, SSRI’s, Quinidine
What are some CYP 1A2 inhibitors and inducers?
inducers: tobacco, cannabis, ethanol
inhibitors: erythromycin, ciprofloxacin
What type of drugs are excreted unchanged?
hydrophilic
What type of drugs must undergo biotransformation before they can be eliminated?
lipophilic
What drugs are freely filtered at the glomerulus?
those not bound to proteins
What are the organic anion transporters?
furosemide, thiazide diuretics, & penicillin
What are the organic cation transporters?
morphine, meperidine, & dopamine
What determines whether drugs are excreted in the urine or reabsorbed into peritubular capillaries?
urine pH
How does the pH of the urine determine reabsorption and excretion of drugs?
acidic urine reabsorbs acidic drugs, eliminated basic drugs
basic urine reabsorbs basic drugs, eliminated acidic drugs
What medications acidify urine and leads to elimination of basic drugs?
ammonium chloride and cranberry juice
What medications will alkalinize urine and eliminate acidic drugs?
sodium bicarbonate and acetazolamide
What are the three main metabolic pathways in the plasma?
pseudocholinesterase, nonspecific esterases, alkaline phosphatase
What metabolic pathway does not involve enzymes?
Hoffman elimination
Pseudocholinesterase deficiency extends the duration of action of what three drugs?
succinylcholine, mivicurium, and ester LA’s (1 “i” in their name)
What drugs undergo metabolism by nonspecific esterases?
remifentanil, esmolol, etomidate, atracurium
What drug undergoes metabolism by nonspecific esterases and hepatic metabolism?
etomidate
What drug undergoes metabolism by nonspecific esterases and Hoffman elimination?
atracurium
What medication is converted to a prodrug by alkaline phosphatase?
fospropofol
