Pharmacokinetics I & II Flashcards
Define pharmacokinetic phase of drug action and four factors that determine it. What is it often referred to as?
determines the concentration of a drug and its time course of action
- absorption 2. distribution 3. metabolism 4. excretion (ADME)
“what the body does to the drug”
Define pharmacodynamic phase of drug action. What is it often referred to as?
concentration of a drug and its interaction with receptors in target tissues determines the magnitude o fits effect (dose-response relationship)
“what the drug does to the body”
What are the important factors to determine the dose and dosing regimen of a drug?
pharmacokinetic and pharmacodynamic features
What are the goals of dose and dosing regimen?
to maintain the concentrations of a drug in plasma (or target tissue) at the therapeutic ranges
What are physiochemical properties of the following types of small molecule drugs vs biologics?
small molecule drugs:
- molecular size < 500 daltons
- weak acid or base
- low water solubility, lipophilic
- mostly orally active
biologics:
- molecular size > 1000 daltons
- peptides, peptidomimetics, proteins, nucleotides
- administered by IV, IM, SC
- orally inactive
What are the 4 routes of drug administration?
- enteral - drug placed directly into the GI tract; oral; sublingual; rectal
- parenteral - routes that bypass the GI tract (iv, I’m, sc, intrathecal)
- inhalation
- topical - eye, intranasal, skin
What are two general ways drugs cross the cell membrane?
- passive transport
2. specialized transport
What 5 factors affect drug absorption via passive diffusion?
- size of drug
- lipoid solubility
- polar
- degree of ionization
- pH of the local fluid of body
In terms of membrane polarity, do non-ionized or ionized drugs diffuse more effectively?
Acidic drugs are more permeable at an ____ pH. Opposite for basic.
Non-ionized
acid drugs are more permeable at an acid pH. (will be non-ionized here)
What is the Henderson-Hasselbalch equation?
log ([A-]/[AH]) = pH - pKa
where AH is non-ionized drug, A- is ionized drug
Absorption of acid drugs is greater at _______. (opposite for bases)
lower pH
Describe the “first-pass effect” (metabolism) and how it affects the bioavailability of orally-administered drugs.
enteral administration of drugs undergoes partial inactive or elimination during their ‘first past’ through GI tract to liver; decreases the amount of drug that can reach systemic circulation
How can you avoid the “first pass effect”?
using alternative routes of drug administration
FDA required bioavailability of a drug to be greater than __.
5%
Define drug distribution. What 6 factors affect it?
- movement of a drug from systemic circulation into various tissues and body fluids
- tissue perfusion rate (organ blood flow)
- capillary/tissue membrane permeability
- tissue mass
- regional differences in pH
- transport mechanisms
- binding of drug to plasma or tissue proteins
What is the ultimate outcome of a plasma protein-bound drug?
eliminated through excretion (binding is usually reversible and nonselective)
Only ___ drug can exert a pharmacologic effect and undergo ____ clearance.
Free
passive clearance
Why does the brain have a limited drug distribution?
due to the blood-brain barrier
Define volume of distribution (Vd).
What is the formula to determine Vd?
What does it indicate?
an apparent volume of fluid in which a drug seems to be distributed in the body
Vd = dose of drug/peak plasma concentration
indicates the relative size of the body compartment containing the drug
What is Vd influenced by?
protein binding, lipid solubility of drug, body composition (varies with age, sex, etc)
What can happen if there is a pH difference across a membrane?
the ionized fraction of a drug may be greater on one side than on the other; acidic drugs accumulate on the more basic side –> ionic trapping in body fluids whose pH differs from blood
What is important for drug diffusion across brain capillaries?
lipid solubility
What two things affect permeability of BBB?
- age
2. inflammation
What is placental exchanged related to? What type of drugs cross more readily?
- concentration gradients
- rate of drug delivery
lipid-soluble drugs cross readily
How can a drugs’s effects be terminated?
- biotransformation (metabolism) in the liver
2. excretion in the kidney
Define Phase I reaction
aka functionalization; Phase I - alter and creates functional groups (through oxidation and reduction) to make the drug more receptive to conjugation; drugs become less lipophilic (all cases) and less active (in most cases)
What is a pro drug?
inactive compounds that are converted to pharmacologically active moieties by metabolic processes. metabolic transformation may result in detoxification or generation of more toxic forms of the drug
What cytochrome P450 isozyme is responsible for 50% of drug metabolism?
CYP3A4/5
What are the 3 reaction class mechanisms to make a drug hydrophilic in Phase I reactions of metabolism? (Remember the goal o Phase I)
goal of phase I is to make/alter functional groups
oxidation
reduction
hydrolysis
When does microsomal enzyme induction occur?
occurs when prior administration of an agent increases the total amount of enzyme due to increased protein synthesis or substrate stabilization
Define autoinduction
when a drug induces metabolism of other drugs as well as its own self
Which of the following can be induced?
- Phase I enzymes
- Phase 2 enzymes
- non-microsomal enzymes
- and 2. are microsomal enzymes (enzymes that metabolize drugs and are looked on SER)
- cannot be induced
What is the clinical importance of enzyme induction?
faster rate of metabolism can reduce drug concentrations below their therapeutic levels
Describe the two ways that enzyme inhibition can occur.
- Metabolism-based (reversible) inhibition: addition of a drug with greater affinity for the enzyme inhibits metabolism of the primary drug in a competitive reversible manner
- Mechanism-based (irreversible) inhibition: inhibitor drug is metabolized by enzyme to form a reactive species that binds irreversibly to the enzyme and prevents further metabolism; this inhibition lasts for the life of the enzyme, inhibitor and enzyme need to be degraded and a new enzyme needs to be produced
What is the clinical importance of enzyme inhibition?
because it slows the rate of drug metabolism and can elevate the drug’s concentration in the body which can eventually lead to toxicity
What are 3 things that inhibit CYP3A4>
erythromycin, ketoconazole, grapefruit juice
What may contribute to interindividual variability in drug metabolism & pharmacological response?
genetic polymorphisms
What are the clinical consequences of genetic polymorphisms?
may metabolize slower or faster or not at all; affects therapeutic range so need to keep in mind when administering a dose
Define Phase II reactions of metabolism
aka conjugations; couple a drug or metabolite to an endogenous substrate (such as an amino acid, acetic acid, glucouronic acid, or sulfate); attachment of these hydrophilic groups usually makes the drug more polar and less active (readily excrete)
What are factors that affect drug metabolism?
- concomitant drug therapy (can lead to enzyme induction or inhibition)
- social factors (age, gender, nutrition, alcohol)
- health (liver dz)
- environmental factors
- genetics (polymorphisms on drug metabolizing enzymes)
Rate of drug excretion in the urine is the net result of which 3 processes?
- glomerular filtration (passive, only unbound drug)
- active tubular secretion (via transporters)
- reabsorption
What are the four different mechanisms that may be involved in renal excretion of drugs?
What is the formula for drug excretion?
- glomerular filtration - removes all unbound drugs of low molecular weight (charged are filtered at slower rates)
- passive reabsorption - depends on lipid solubility, most drugs are passively reabsorbed in the distal renal tubules; non-ionized, lipophilic drugs are extensively resorbed into plasma
- active tubular secretion - involved in renal excretion of some drugs, actively transport some drugs (like penicillin) into renal tubule
- active tubular reabsorption
drug excretion = filtration - reabsorption + secretion
Acidification of a the urine promotes excretion of ______ whereas alkalinization promotes excretion of _____.
weak bases
weak acids
What can prolong the duration of action of a drug in the body?
enterohepatic recycling of drugs (conjugates undergo bacterial hydrolysis before reabsorbed into portal circulation (liver))
What are the 5 important pharmacokinetic parameters?
bioavailability kinetics of elimination volume of distribution half-life clearance
What is the key parameter to determine the bioavailability of drugs?
area under the curve (AUC) on a conc. vs. time plot
The therapeutic range is between which two minimums?
Minimum effective concentration (MEC)
and
Minimum toxic concentration (MTC)
What is bioavailability (BA)?
the fraction/percentage of a drug dose that reaches the systemic circulation unchanged; compares amount of a drug “available” to body after administration by different routes
For intravenous drug dose, __% reaches the blood stream.
100%
What is the formula of bioavailability (BA) when comparing oral and IV?
F = (AUC)oral / (AUC)iv x (IV dose) / (oral dose)
oral dose = (IV dose)/F
Kinetics of Elimination
Define Zero-order and First-order
zero-order: constant amount of drug in body is eliminated per unit time
dA/dt=-k
first-order: constant fraction of drug present in the body is eliminated per unit time, regardless of the concentration (most drugs)
dA/dt=-kA
*where k is the rate of elimination
What happens when he capacity for drug elimination becomes saturated?
kinetics may change from first order to zero order where a constant amount (not fraction) of drug is eliminated per unit of time; drugs overdosed
(cannot calculate half life)
What is volume of distribution (Vd)?
an apparently volume of fluid in which a drug seems to be distributed in the body; indicates the relative size of the body compartment contain the drug; influenced by protein binding and lipid solubility of the drug; useful for calculating the dose of a drug required to achieve an effect plasma concentration
What is elimination half-life (t 1/2)?
Time required for the plasma concentration to decrease by one-half (50%); only first order
useful for determining the dosing interval and time required to reach steady state after repeated drug administration
What is steady state?
when drug is given repeatedly at intervals that are too short to allow complete clearance; plateau will eventually be reached when the amount of drug administered equals the amount eliminated in a given time unit
During a continuous infusion or when multiple drug doses are given, the steady state is attained after approximately how many half-lives?
4 to 5 half lives
thus half life is useful in determining dosing frequency
How can you promptly raise the plasma drug concentration?
administer a loading dose followed by a maintenance dose
