Pharmacokinetics Flashcards
pharmacokinetics
the actions of the body on the drug
these properties determine how rapidly and for how long the drug will appear at the target organ
- absorption
- distribution
- metabolism
- excretion
routes of administration determined by:
properties of the drug (solubility, ionization, etc.), therapeutic objectives (rapid onset, chronic administration, restriction to a local site, setting in which it will be used)
2 major routes of administration
- enteral
- parenteral
enteral administration
administration by mouth; simplest and most common method; swallowed or placed under tongue
oral administration advantages
- easily self-administered
- easier to overcome overdoses
- large surface area for absorption
oral administration disadvantages
-complicated pathway to absorption- harsh environment of stomach, metabolism by liver
oral administration: some drugs are absorbed from ___, major site of absorption and entry into systemic circulation is ___; ____ for absorption
stomach;
small intestine;
large surface area
most drugs absorbed in GI tract enter ____ circulation prior to entering ____ circulation; called ____
hepatic;
general;
first pass metabolism
sub-lingual administration advantages
- rapid absorption
- easily administered
- low incidence of infection
- avoid stomach and first pass metabolism- preferred route of enteral administration for drugs that undergo extensive first-pass metabolism
parenteral administration
introduction of drugs directly across the body’s barrier defenses into the systemic circulation or other vascular tissue (bypass GI tract); any way of administration not by mouth
parenteral administration used for:
- drugs that are poorly absorbed from the GI tract and/or are unstable in the GI tract
- treatment of unconscious patient
- when rapid onset of action is required
parenteral administration advantages
- have the highest bioavailability
- not subject to first-pass metabolism
- provides the most control over the actual dose delivered
parenteral administration disadvantages
- irreversible
- can cause pain, fear, and/or infection
3 major parenteral routes
- intravascular (IV or IA)
- intramuscular (IM)
- subcutaneous (SC)
most common parenteral route
intravenous
intravenous characteristics
- rapid effects
- not easily recalled (greater potential for toxic overdose)
- potential for infection
- rate of infusion must be carefully controlled
- similar concerns apply to IA drugs
intramuscular characteristics
-can be aqueous solutions (fast absorption) or depot preparations (slow absorption)
depot preparations
- suspension of drug in a non-aqueous vehicle
- vehicle diffuses out of muscle leaving the drug to precipitate at site of injection
- drug dissolves slowly (not fully dissolved)
subcutaneous characteristics
- injection under the skin
- slower than IV but less risk
- often combined with epinephrine (acts as a local vasoconstrictor and decreases removal of the drug from the site of administration)
other routes of administration
- inhalation
- intranasal
- intrathecal
- intravitreous
- topical
- transdermal
- rectal
inhalation
- rapid delivery (almost as fast as IV)
- used for gases or aerosol
intrathecal
introduction directly into cerebrospinal fluid
transdermal
- through skin, usually a patch
- used for sustained delivery
- variation in absorption rate
rectal
- minimizes first pass metabolism- 50% of drainage bypasses liver
- good for meds that induce vomiting or in a patient that is vomiting
absorption
transfer of a drug from its site of administration to the bloodstream
absorption is ___ for IV drug (___ dose reaches circulation); all other routes have ____ absorption and thus lower bioavailability
complete;
total;
lower
passive diffusion
- drug moves from area of high concentration to area of low concentration
- does not involve a carrier molecule, is not saturable, and is not specific; can be through a channel or pore
- does not require energy
facilitated diffusion
- moves from high concentration to low concentration
- requires carrier molecule (usually large molecules)
- does not require energy
active transport
- drugs move from area of low concentration to area of high concentration
- depends on a carrier protein and is energy dependent
- requires ATP
endocytosis/pinocytosis
large molecules are engulfed by the cell membrane and transported into the cell by a vesicle; exocytosis is the reverse
most drugs are either ____ or ____
weak acids; weak bases
pKa is a measure of ____; lower means the drug is more ___; higher means more ___
strength of interaction with a proton; acidic; basic
drugs pass through membranes more readily if they are ____
uncharged (non-ionized)
weak acids will be non-ionized in environments with ___ pH; absorb better from ___
low; stomach
acids like acids!
weak bases will be non-ionized in environments with ___ pH; absorb better from ___
high; intestine
bases like bases!
higher blood flow to absorption site= ____;
blood flow to intestine is ____ than that of stomach;
blood flow through deltoid muscle is ____ than through the gluteal muscle
greater absorption;
greater;
greater
greater surface area= ____;
surface area of intestine is ____ that of stomach;
gluteal muscle can accommodate a ____ volume of drug
greater absorption;
1000-fold;
larger
contact time at the absorption site: if a drug moves through the GI tract very quickly, it is ____
not well absorbed
anything that delays movement from stomach to intestine ____ the rate of absorption: sympathetic input (exercise, medications), presence of food
delays
____ absorption in areas of high expression of P-glycoprotein
reduced
P-glycoprotein is a ____ whose main job is ____
membrane transporter protein; to get a foreign molecule and kick it out again
P-glycoprotein is located in many systems
- liver
- kidneys
- placenta
- intestines
- brain capillaries
bioavailability
the fraction of drug that reaches systemic circulation; only a portion of an orally administered drug is free to be used
how is bioavailability determined?
determined by comparing plasma levels of a drug after a particular route of administration with levels after IV injection (100% available after IV injection);
can plot plasma levels over time on a graph –> gives “area under the curve” (AUC); curve reflects extent of drug absorption;
bioavailability= AUC oral/AUC injected x 100
factors affecting bioavailability
- first pass metabolism
- solubility of the drug
- chemical stability
- formulation of the drug
- concentration
first pass metabolism
drugs absorbed from the GI tract enter the hepatic circulation before systemic circulation
if rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is ____
decreased
even one pass through the liver can ___ many drugs
alter
hydrophilic drugs are absorbed ____
poorly- cannot cross cell membrane (unless membrane pore or carrier molecule present)
extremely hydrophobic drugs are absorbed ____
poorly- cannot dissolve in aqueous body fluids, cannot gain access to cell surface
to be readily absorbed, must be ___ soluble but also have some solubility in ____
lipid; aqueous solutions
a drug that is lipophilic will have ___ absorption
greater
drugs must be formulated to withstand ____
acidity of stomach and actions of enzymes
ex: insulin can not be given orally- susceptible to enzyme degradation, Penicillin G is not acid stable
along with chemistry, absorption can be altered by:
- particle size (smaller is easier)
- binders or dispersing agents
- enteric coatings
- salt form
- others…
absorption can be increased by ____ the concentration of the drug
increasing (up to a certain point)
bioequivalence
two drugs that demonstrate comparable bioavailability and similar times to achieve peak blood concentrations; has nothing to do with how well the drugs work, just how much is available for the body to use
therapeutic equivalence
two drugs that are comparable in efficacy and safety; bioequivalence does not necessarily equal therapeutic equivalence
drug distribution
the process by which a drug diffuses from systemic circulation into the extracellular fluid and/or the cells of the tissues
drug distribution is dependent on:
- blood flow
- capillary permeability
- protein binding
- lipid solubility of the drug
there is a wide variation in rate of _____ to various tissues, resulting in ____ to various organs
the rate of blood flow;
an unequal distribution
greater blood flow to ____
brain, liver, and kidneys
____ has the slowest rate of blood flow
adipose tissue
the ability of a drug to diffuse out of capillaries is determined by:
- the structure of the capillary wall
- the chemical structure of the drug
capillary structure is ____ from organ to organ
different
typical capillary structure
- single layer of endothelial cells resting on a basement membrane; no surrounding smooth muscle or elastic tissue
- slit junctions and fenestrations; expose the basement membrane and allow for transport out of the capillary
in the brain, capillaries have no _____, but rather ____
junctions or fenestrations; zonulae occludens (tight junctions)
in the liver and spleen, capillaries have ____, which allows ____
large slit junctions;
large plasma proteins to pass through
blood brain barrier
- tight junctions and zonulae occludens prevent diffusion of many substances from the circulation into the CNS
- must pass through endothelial cells or be transported in by specific transporters
____ molecules readily pass through into the CNS (BBB will not keep them out)
lipid-soluble
placental barriers
- blood flow is limited from mother to placenta
- delayed equilibration of a drug between mother and fetus (10-15 mins at least)
- assume all drugs cross the placental barrier as well as breast milk (unless explicitly stated otherwise)
blood aqueous barrier
- capillaries of the choroid and ciliary processes are fenestrated, all others are not
- selective inhibition of movement of solutes from ocular vasculature into anterior chamber
- no back flow from Schlemm’s canal
- capillaries of iris and retina are impermeable
- most systemic drugs have a difficult time getting into the eye (few exceptions)
chemical nature of the drug strongly influences ____
ability to cross cell membranes
hydrophobic (lipophilic) molecules ____ across most biologic molecules (including BBB); ____ is major factor influencing distribution
readily move;
blood flow
hydrophilic (lipophobic) molecules _____ across cell membranes; they must ____
do not readily move;
go through slit junctions/fenestrations
binding of drugs to plasma proteins is usually ____
reversible
binding of drugs to plasma proteins ____
sequesters the drug in a non-diffusable form (too large to pass through any membranes) and thus slows the transfer out of the vascular compartment
protein binding to drugs can cause:
- decreased clearance
- increased half-life
- drug-drug interactions- displacement of one drug by another
____ is main plasma protein that binds drugs
albumin
bound drugs are ____
pharmacologically inactive
volume of distribution
- hypothetical volume of fluid into which a drug is dispersed
- once a drug enters the body, it has the potential to distribute into any one of three functionally distinct compartments of body water or to become sequestered in a cellular site
____ are “trapped” within the plasma (vascular) compartment; plasma volume is about ____ of body weight
large molecular weight drugs or drugs that bind extensively to plasma proteins; 6%
if a drug has a low volume of distribution, it will likely be found in _____
circulation in the blood
____ can be found in the extracellular fluid;
they move through capillaries into interstitial fluid but can not cross _____;
distribute into ____;
____ of body weight
low molecular weight, hydrophilic drugs;
lipid membranes of cells;
plasma water & interstitial fluid;
20%
____ can be found in total body water;
can move through ____;
distributes into about ____ of body weight
low molecular weight, hydrophobic drugs;
cell membranes and into intracellular fluid;
60%
drugs that have a large volume of distribution can be found ____
anywhere (plasma, interstitial fluid, and in cells themselves)
calculation for volume of distribution
V= amount of drug in body (dose)/ plasma concentration
in reality, drugs are eliminated and plasma concentrations have 2 phases:
- distribution phase
- elimination phase
effect of a large V:
- drug elimination depends on _____
- if V is large, most of the drug is in the ____ and ____ to the excretory organs
- any factor that increases the volume of distribution can lead to ____ half-life and ____ the duration of action of a drug
the amount of drug delivered to the liver or kidney per unit of time; extra-plasmic space; is unavailable; an increased half-life; extend
metabolism
- any chemical that is foreign to our body will be subject to elimination
- most drugs must be biotransformed (metabolized) before they can be eliminated
most drugs must be made more ____ before they can be eliminated
polar and/or water soluble (charged and/or hydrophilic)
metabolism often results in ____, but some are actually ____
inactivation and excretion;
made more active (prodrug)
many metabolites ____
are either pharmacologically active or cause side effects
____ is major site for drug metabolism, although some drugs undergo metabolism in other organs (ex: ____)
liver;
kidney, intestines
first order kinetics metabolism
- rate of metabolism is proportional to concentration of the free drug
- rate of metabolism increases as concentration of drug increases
zero order kinetics metabolism
- rate of metabolism is constant over time
- dose independent
lipophilic drugs are ____ from kidney, making them ____; must be transformed to ____;
2 types of reactions: ____
easily reabsorbed;
more difficult to eliminate;
more polar substances;
Phase I, Phase II
Phase I reactions convert _____;
most often catalyzed by _____ in the _____
lipophilic molecules to more polar molecules;
the Cytochrome P-450 system;
liver
Cytochrome P450 system:
- enzymes are located in most cells but primarily found in ____
- responsible for metabolism and biotransformation of ____
- many different ____
- enzymes are ____ for one particular substrate
liver and GI tract;
endogenous compounds and xenobiotics;
enzymes;
not specific
the CYP450 system exhibits considerable ____ variability; basis for ____
genetic;
differing dosing requirements, therapeutic responsiveness, and risk of adverse events between patients
the CYP450 system is one source of ____ interactions, with ____ and _____
drug-drug;
inducers; inhibitors
inducers
increase CYP activity, leading to decreased plasma concentrations of many drugs (being broken down more rapidly)
inhibitors
decrease CYP activity, leading to increased plasma concentrations of the drug (being broken down less rapidly)
other Phase I reactions
- oxidations
- dehydrogenations (ex: ethanol)
- deamination
- hydrolysis
(CYP450 enzymes are most important Phase I reaction)
Phase II reactions; most are ____
conjugations- attaches an endogenous substrate to molecule to form highly polar conjugate (larger);
glucuronic acid, sulfuric acid, acetic acid, or an amino acid often added
_____ is the most common and most important Phase II reaction; it makes ____
glucuronidation;
lipophilic molecules more readily excretable in urine
not all drugs undergo ____ reactions
Phase I and then Phase II
some may skip phase I, some may undergo phase II first
individual differences in rates of drug metabolism require ____
variations in drug dose
factors that influence an individual’s rate of drug metabolism
- genetic factors- enzyme polymorphisms
- diet and environmental factors- certain foods induce or inhibit CYP enzymes (grapefruit juice, cigarettes, many others…)
- age and sex
- drug interactions
- disease
drugs may be removed from the body by a number of routes
- kidney (main organ for drug elimination)
- liver (either biotransformation or bile)
- lung
- “other”
glomerular filtration:
- drugs enter kidney through ___
- free drug (not bound) flows into ____ as part of glomerular filtrate
- lipid solubility and pH ____ the passage of drugs into the glomerular filtrate (only ___)
renal artery;
Bowman’s space;
do not influence;
molecule size
proximal tubular secretion:
- larger drugs not transferred into the filtrate leave the glomeruli through ____
- secretion occurs by ____
efferent arterioles; active transport (requires energy, non-specific- competitive)
distal tubular secretion:
- concentration of drug ____ as it moves towards distal convoluted tubule
- may diffuse out of nephric lumen, back into systemic circulation if ____
- can manipulate _____ to increase elimination of certain drugs
increases;
unchanged;
pH of urine
can manipulate pH of urine to increase elimination of certain drugs, “ion trapping”
for weak acids, increase pH;
for weak bases, decrease pH
clearance
predicts the rate of elimination in relation to drug concentration
clearance formula
CL= 0.693 x V/half-life
rate of drug delivery is constant with ____
IV infusion
in most cases, the elimination obeys ____ order kinetics
first (constant fraction removed per unit time)
steady state concentration
plasma level increases until elimination rate equals infusion rate
steady state is ____ to the rate of infusion
directly proportional
steady state is ____ to the rate of clearance
inversely proportional
decrease clearance = ____ steady state concentration
increased
increase clearance = ____ steady state concentration
decreased
dosing with continuous infusion can be achieved via:
- IV
- oral fixed-dose/fixed-time intervals (ex: one tablet every 4 hours)
steady state is the point at which the amount of drug being administered/absorbed equals ____;
____ with IV;
____ with oral fixed dosage
the amount being eliminated;
remain constant;
fluctuate around a mean
half-life
time required for the drug concentration to change by 50% (usually used as an elimination term)
common assumption is that it takes ____ for a drug to reach steady state concentration
5 half-lives
rate of approach to steady state ____ by the rate of drug infusion
is not affected
for most drugs, the half-life can help approximate ____
how long it will take a drug to reach its full effect after the patient starts treatment
any changes in half-life of a drug due to abnormal states may require ____
dosage adjustments
half-life can be ____;
usually by ____;
anything that effects _____
increased or decreased;
disease states;
CL or V
when drug infusion is discontinued, the decrease in plasma concentration to zero parallels ____
the same time course as that observed with the drug achieving steady state concentration
rational dose regimens:
- based on ____
- calculation would be easy for ____
assumption of Target Concentration (TC); continuous infusion (but very inconvenient for patient!)
fixed-dose/fixed-time regimens:
- often more ____
- result in ____
convenient;
time-dependent fluctuations in the circulating level of a drug
fixed-dose/fixed-time regimens:
- using smaller doses at shorter intervals ____
- SS concentration and rate at which SS is approached ____ by frequency of dosing
reduces the amplitude of the swings in drug concentration;
are not affected by
maintenance dose:
- dose of the drug administered to ____
- drugs administered at ____
- for drugs not administered via IV, must account for ___
establish the desired steady state concentration for therapeutic effectiveness;
intervals;
bioavailability
dosing rate formula
Dosing Rate= CL x TC (target concentration)
maintenance dose formula
Maintenance Dose= Dosing Rate/bioavailability x Dosing Interval (bioavailability is usually a known quantity (given))
loading dose:
- a desired plasma concentration level may be delayed due to ____
- one can administer a loading dose to ____
binding to plasma proteins or metabolism;
achieve rapid therapeutic levels (any method of delivery)
loading dose formula
Loading Dose = V x TC
loading dose can be given as ___
a single dose or a series of doses
if loading dose is given too rapidly, ____ can occur, especially if a drug has ____;
calculated amount does not give rate of administration!
toxic reactions; a rapid rate of absorption (like for IV infusion)
____ is the most important factor determining drug concentrations
clearance
clearance is determined by:
- dose
- organ blood flow
- kidney and liver function
