Pharmacokinetic- Elimination/Pharmacodynamics Flashcards
what factors affect the affinity a drug has to a particular receptor relative to many other different binding sites in the patient??
size, shape, and electrical charge of a drug determine its binding affinity to a particular receptor
If tau is much longer than t1/2, all of drug is effectively eliminated before next dose and fluctuation ____
is maximal
what is the clinical use of t1/2
- designing dose regimens
- time to reach SS or to be eliminated
- prediciting fluctuations in Cp
what is a partial agonist
- Partial agonists are drugs that occupy the same receptor as the full agonist but bring about less than the maximum response (i.e., that produced by full agonists), even at full dosage levels.
- These drugs are thus less efficacious, and 100% occupancy of the receptors produces a lesser response. A partial agonist [C] may be more potent (as in the figure below), less potent, or equally potent.
*potency and efficacy can vary independently
an abstract volume, not necessarily a physiological volume. It is inversely related to the amount of drug in the plasma.
Vd
using the derivated equation of 1st order kinetics, how do you determine the the rate and Cp0
- rate = slope of the graph of lnCp vs time = ke
- Cp0= y intercept
lnC= -ket + lnCp0
This type of antagonist can bind irreversibly (covalently) or pseudoirreversibly (with very high affinity-slow dissociation) to the active site of the receptor or can bind reversibly or irreversibly to an allosteric site
noncompetitive anagonist
at high doses, drug metabolism is __ order-that is, ____ and ___ of the drug dose
zero order
constant and independent
Receptor theory allows determination of quantitative relation between ____ and ____ via use of dose-response curves
dose or concentration of drug
its pharmacologic effects
major mechanisms of transduction and amplification
- Ligand-gated ion channels: A very fast response (msec) via opening (or closing) of ion channel that changes membrane potential
- G-protein-coupled receptors: A fast response (sec) via change in activity of G-protein linked enzyme system that produces effector molecules (2nd messengers) such as cyclic AMP, cyclic GMP, or inositol triphosphate (IP3)
- Kinase-linked receptors or hormone (nuclear) receptors: A slower response (hours) brought about by changes in gene transcription and protein synthesis
what happens to the agonist dose vs percent of maximum curve in the presence of agonist + competitive antagonist
- shifts curve to right
- the EC50 of agonist [A] increases, which is equivalent to a decrease in potency. However, the maximal efficacy (Emax) of the agonist [A] is unchanged
T1/2 useful in ____ estimating an appropriate dosing interval (tau) for maintenance therapy
qualitatively
how do you attain a Cpss sooner (ie. for a drug with a long half-life)
loading dose is administered followed by the normal maintenance dose schedule
Most commonly activates or blocks a distinct receptor that mediates a physiologic response that is opposite to that of activation of the receptor for the agonist.
physiologic antagonist
____ refer to antagonists that bind to the SAME receptor as the agonist
Receptor antagonists
*also called pharmacologic anatgonist
how do you calculate a loading dose?
An initial estimate of an appropriate loading dose (LD) can be calculated using the Vd for the drug and the desired Cp as follows:
LD [mg] = Cp0 [mg/L] X Vd [L]
how do you determine the magnitude of fluctuations between doses?
*1/fraction of drug remaining at end of dosing interval [Cp2/Cp1]
Fold - Fluctuation = 2^x
- where x = number of half-lives in the dosage interval
what are the clinical uses of Vd
- calculating LLD
- converting Dose (mg) to Cp (mg/L)
The most important concept in pharmacokinetics is the principle that
governs the rate of elimination of drugs from the body
When t = t1/2, then by definition C2 =
½ C1
what is the clinical use of clearance
calculating MD
Potency of a drug depends in part on the ___ and ___
- affinity (Kd) of receptors for binding the drug and
- in part on the efficiency of this drug-receptor complex to generate a response [the intrinsic efficacy of the drug] and is designated by the EC50
___ are responsible for selectivity of drug action
Receptors
[increase in benefit: risk ratio]
elimination of a constant FRACTION (per cent) of drug per unit of time
first-order elimination
how can zero-order drugs be dangerous
- Drugs eliminated by zero order kinetics do not have half-lives
- can present dose adjustment challenges, especially at the upper end of the therapeutic range of narrow therapeutic index drugs, where a small change in dose can produce large changes in plasma concentrations and subsequent toxicity
For a drug with a t1/2 of 3 hours, how much drug would remain in the plasma after 3 hrs if the initial dose was 1000mg/ml
500mg/ml
types of nonreceptor antagonists
- physiological antagonist
- chemical antagonist
when do changes in hepatic blood flow affect clearance?
- If metabolism is not efficient (i.e., LOW EXTRACTION DRUG) changes in hepatic blood flow do not significantly influence clearance
- If metabolism is very efficient (i.e., HIGH EXTRACTION DRUG) alterations in hepatic blood flow will have a major influence on total body clearance
what features of a (receptor) protein allow for greatest specificity of drug “fit”
secondary and tertiary structural features of protein such as:
- Hormone and NT
- Receptor or voltage gated ion channels (EX. NICOTINIC CHOLINERGIC OR 5HT3-SEROTONIINERGIC)
- Enzymes (ex. angiotensin converting enzyme, carbonic anhydrase, Na+-K+-ATPase0
- Transport proteins (ex. carrier molecules like the kidney Na+/K+/2Cl- co transporter)
- structural proteins (ie. tubulin)
If drug A’s EC50 is greater than that of drug B (partial agonist), which drug is more pharmacologically potent?
Drug B
provides information on how much drug (dose) will be required to produce a given effect
the potency
*the more potent a drug, the less that is needed for any given effect. EC50 values are utilized when comparing potencies of different drugs
what are effectors
the components of the biologic system that accomplishes the biologic effect after being activated by the receptor,
i.e., they are molecules that translate the drug-receptor interaction into a change in cellular activity
A receptor that is bound by a noncompetitive antagonist can no longer respond to agonist binding, so the curve shifts ____ and therefore the maximal efficacy (Emax) of the agonist is ___
However, there is no shift of the curve on the x-axis unless there are spare receptors present in the system where a shift to ___ (decrease in apparent potency of agonist - increase in EC50) may be seen, but effect is generally minimal.
“shifts downward”
the maximal efficacy (Emax) of the agonist is reduced
“shift to the right”
what is the clinical use of ke
prediciting change in Cp with time
what is the units of clearance
L/hr/kg
what is ke
ke is the fraction of drug leaving body per unit time via all elimination processes
*aka-a number or constant that allows us to calculate the amount of drug remaining at any time during the elimination process
clearance is best thought of as:
a proportionality constant that makes the average plasma concentration [Cp(ss)] at steady state equal to the rate of administration (maintenance dose [MD] per dosage interval [tau or τ])
MD/tau= CL x Cpss OR
CL= (MD/tau)/ Cpss
what factors influence hepatic clearance?
- blood flow to liver
- protein-drug binding
- intrinsic hepatic metabolic activity (subject to co-administration of inducers and inhibitors)**
distinguish the different pharmacokinetic phases and components using a graph of ln concentration vs time
- distribution phase (α) -an initial curvilinear portion (representing the of drug equilibrating between blood and tissue)
- elimination phase (β)- linear portion
- Ke= slope of B elimination phase
with what type of antagonist can increasing the concentration of agonist overcome the antagonism?
-Competitive antagonist
NOT noncompetitivie
Why do we see changes in Emax, EC50, and potency w/ competitive reversible anatongists
- Emax is unchanged-bc the agonist concentration can be increased to counteract (“outcompete”) the antagonist thereby “washing out” the effect of the antagonist.
- EC50 is increased
- Potency is decreased
- competitive antagonist competes for receptor binding, reducing apparent agonist affinity for receptor (decrease in potency), but doesn’t affect the number of receptors available to contribute to response.
The drug receptor theory states:
- the greater the number of receptors occupied by drug the greater the response produced
- the response obtained by administration of any drug is proportional to the amount of receptors occupied by drug. When the dose of drug is high enough to occupy all of the receptors, no further increase in response can be obtained, i.e., Emax has been reached.
- To understand the drug-receptor interaction, it is necessary to ____ the relationship between drug dose and effect.
- When choosing among therapeutic drug options, it is necessary to know their relative ____ and ____
quantify
potency (dose)
therapeutic efficacy (maximum effect)
If tau is much shorter than t1/2, then there is ____ fluctuation
little
what is the unit of half-life
hours or minutes
an examination of the hyperbolic shape of the dose-response curve indicates that:
- The curve is relatively linear (straight) at low doses of drug-low doses of drug (below the EC50, which generally constitutes the therapeutic range of doses) the response usually increases in direct proportion to the dose
- The curve levels off at high drug doses -there is a limit to the increase in response that can be achieved by increasing the drug dose
0 order kinetics most often occurs due to saturation of hepatic metabolic enzyme systems by drug administration. This enzyme saturation occurs with therapeutic doses for only a few drugs including:
- ASA
- phenytoin
- ethanol
- toxic doses for many -hepatically eliminated drugs
how do you measure elimination off a graph?
Cp vs Time
- slope= rate of elimination (mg/ml per time)
- rapid (steep) initially when Cp is high, then slows (becomes less steep) as drug is eliminated, i.e., displays first order kinetics
describe how a drug infusion works
When a drug is administered by infusion at a constant rate the plasma concentration [Cp] initially rises with time. However, as plasma concentration continues to rise, the rate of elimination, driven by drug plasma concentration, also rises. This rise continues UNTIL the increasing drug concentration produces a rate of elimination just equal to the constant rate of infusion (i.e., the rate of administration) at which time a condition of STEADY STATE is said to exist.
at low doses, drug metabolism is ___ order- that is __ to the drug dose
first
proportional
-When a drug is eliminated by first order kinetics, its ____ changes constantly as will the ____
absolute rate of elimination
amount of drug eliminated
describe competitive reversible antagonist
Antagonist [B] binds reversibly to the active site of a receptor, but does not stabilize the conformational change required for receptor activation. The antagonist [B] blocks an agonist [A] from binding to its receptor and maintains the receptor in the inactive conformation
what happens to Emax, EC50, and potency w/ noncompetitive anatongists
Emax is decreased
EC50 unchanged
Potency unchanged
Example of what type of pharmacologic action? Agonist or antagonist?
Metoprolol is not an agonist and does not activate receptors, but can lower heart rate by blocking the action of the endogenous agonist norepinephrine at β1 adrenergic receptors in the heart.
Antagonist
how do you determine systemic clearance?
aka total clearance
add the clearance from all organs
CL(renal)+CL(hepatic)+CL(allother routes)
ex of what type of nonreceptor antagonist?
-EDTA (a chelating agent) combining with lead ions
-Antacid bases neutralizing excessive stomach acid
-Osmotic diuretics
Protamine (positively charged molecule) countering effects of heparin (negatively charged molecule)
Chemical antagonist
The average SS concentration is the same for intermittent infusion as it is for continuous infusion.
-With intermittent drug administration, however, the plasma concentration fluctuates between doses, and the size of the fluctuation increases as _____
the dosage interval increases
what is zero-order kinetics
Describes the process in which the rate of elimination of drug from the body is independent of the amount of drug in the body (NOT first order).
-The AMOUNT of drug removed per unit time is constant, i.e., is independent of drug concentration
what is clearance
The volume of plasma (Vd) which is completely cleared of drug in a given period of time by the combined processes of tissues such as kidney (excretion) and liver (drug metabolism) with some contribution from other tissues such as lung, muscle, etc
half-lives provide quick rule-of-thumb estimates of:
- Time for elimination of drug from plasma (4-5 half-lives)
- Time to reach steady state plasma drug levels following multiple doses (4-5 half-lives)
- Fluctuations in plasma levels between doses (number of half-lives in dosing interval)
*to more precisely calculate the amount of drug that remains use the derived 1st order kinetics equation
what is the relationship between R-D and response
RD is proportional to response
what is first order kinetics
rate of elimination [mg/hr] is proportional to the concentration of the drug in the plasma [mg/L]
ex. If the concentration of the drug is doubled, the rate of elimination is doubled; if the concentration is halved, the rate of elimination is halved
* complicated by the fact that, as the drug is eliminated from the body, its concentration is constantly changing, and therefore its rate of elimination also changes constantly
describe the Dose-response curve
- increasing doses (or concentrations) of a drug [D] and then measuring the specific response [e] produced (e.g., heart rate increase, pain relief, blood pressure decrease)
- The data are then plotted as the percent of the maximum response possible in the test system [e / Emax] (y-axis) versus each dose [D] (x-axis).
____ include physiological antagonists that bind to a different receptor and chemical antagonists that bind the agonist molecule directly and do NOT involve any receptor binding
Nonreceptor antagonists
examples of physiological responses that come from D-R binding
muscle contraction or relaxation, neurotransmitter release, glandular secretory activity, etc.
If tau is less than or equal to t1/2, then plasma levels will fluctuate ____ during that dosing interval.
*Most drugs are dosed in this manner.
less than 50%
Does not involve receptor binding. The antagonism occurs via inactivation of the agonist itself by modifying it or sequestering it so it is no longer capable of binding to and activating the receptor
chemical antagonist
overview cascade of pharmacodynamics
drug–> recognition and binding to receptor–> signal transduction via G-proteins or other effectors–> amplification–> physiological response
when does zero-order kinetics most often occur?
occurs due to saturation of hepatic metabolic enzyme systems by drug administration
What effect does increasing MD have
increasing MD dose will NOT allow SS to be reached sooner, but will cause the Cpss to be higher when it is reached
The vast majority of agonist drugs in use in clinical practice are __ agonists
FULL
what is EC50 or ED50
- EC50 and ED50 are used interchangeably
- analogous w/ kd, the concentration of drug at which 50% of the receptors are occupied by drug (ie. bound)
*Although kd (measure of binding affinity for the receptor) is not precisely equivalent to EC50 / ED50 (dose to produce 50% of maximal response), in clinical usage it is often used interchangeably
fundamentally, how are hepatic and renal elimination different
hepatic: enzymatic transformation of drug into metabolites
renal: excretion of unchanged drug
what factors influence renal clearance?
- renal function-generally creatinine clearance (CrCl) OR serum creatinine (SCr) is used as measure of kidney function
* Changes in renal function will alter clearance of renally eliminated drugs and necessitate dose changes to prevent drug accumulation
the component of the biologic system to which a drug binds to bring about a change in the function of the system
a drug receptor
In choosing between 2 drugs the prescriber considers their relative ___ rather than ___
efficacies rather than relative potencies
what happens to Emax, EC50, and potency w/ competitive reversible anatongists
- Emax is unchanged
- EC50 is increased
- Potency is decreased
virtually all drugs are eliminated according to ___ order kinetics. Why?
first (when given in doses within the therapeutic dosage range)
-bc the major biologic processes responsible for drug elimination, hepatic metabolism and renal excretion, are first order processes
In therapeutics, efficacy refers to ___
-For example?
the extent a given clinical effect can be achieved in an intact patient.
ex. the diuretic efficacies of different agents are compared even though they act on distinct membrane transporters at different segments of the nephron. Thus, furosemide, an inhibitor of the Na+-K+-2Cl- cotransporter is said to be a more efficacious or more powerful diuretic than hydrochlorothiazide, an inhibitor of the Na+-Cl- cotransporter.
If the half-maximal effect of drug x (EC50x) occurs at a concentration that is one-tenth the half-maximally effective concentration of drug y (EC50y), which drug is more potent?
drug x is more potent than drug y
describe how the distribution and elimination phases are played out when prescribing a drug
-and how it is used to determine Vd
- A known dose of the drug is given intravenously. This will result in very high initial concentrations, which rapidly fall off as the drug quickly distributes itself into those spaces in the body that it can enter (α-phase for distribution).
- After the initial rapid drop due to redistribution from plasma, plasma concentrations will fall with first order kinetics (β-phase for elimination) at a rate dependent on the half-life of the particular drug.
- Extrapolation of this line back to zero time provides the Cp0, i.e., the plasma concentration which would have been present had distribution throughout the body been instantaneous, and this value can be used to calculate Vd.
The more t1/2’s (not the more hours) in a dosage interval the ___ the fluctuation.
greater
For some narrow therapeutic index drugs the calculated LD may result in toxicity due to transiently high plasma levels during the α-distribution phase out of the plasma compartment.
How do you prevent toxicity from a loading dose?
divide the LD and give over a longer interval
- still reaches desired Cp much sooner than 4-5 half-lives
- e.g., digoxin [t1/2 = 36 hr] can be loaded over 12-24 hr reaching therapeutic levels in a day vs 6-7 days with a maintenance dose only
what largely determines the dose necessary to administer to the patient
pharmacologic potency
*For therapeutic purposes, the potency of a drug is usually expressed in dosage units for a particular therapeutic endpoint (e.g., 20 mg of lisinopril will lower BP by 10-15 mm Hg).
In clinical use, it is important to distinguish between a drug’s potency and its efficacy. The clinical EFFECTIVENESS of a drug depends on _____ AND ____ (pharmacokinetic profile in a given patient).
its maximal efficacy (not its potency)
its ability to reach the relevant receptors at its site of action
Time to reach SS plateau and time to eliminate all drug is related to
the half-life of a drug only and is INDEPENDENT of drug dosage
**increasing MD dose will NOT allow SS to be reached sooner, but will cause the Cpss to be higher when it is reached
Changes in the chemical structure of a drug will significantly alter affinity for _____ with consequent alterations in ____
ex.?
different classes of receptors
the therapeutic and toxic effects of the drugs
ex: Dobutamine will interact with β1-adrenergic receptors on the heart, but will have no effect on acetylcholine or adenosine receptors (at normal therapeutic doses)
___ is often used interchangeably with efficacy to describe the ability to initiate a response
power
For ____ , the receptor is unable to respond to the agonist due to antagonist interference.
a noncompetitive allosteric site antagonist
*Even high concentrations of agonist will be unable to activate the receptor, thus an allosteric antagonist exhibits noncompetitive antagonism regardless of the reversibility of the binding
Even high concentrations of agonist will be unable to activate the receptor, thus an allosteric antagonist exhibits ____ regardless of the reversibility of the binding.
noncompetitive antagonism
what is the difference between specialized receptors and generalized receptors
specialized receptors- molecules like membrane proteins or ion channels designed to detect chemical signals and initiate a response via signal transduction pathways
generalized receptors- biological molecules with any function including enzymes, lipids, or nucleic acids
The extent of the effect of an antagonist will depend on ____
the level of “normal tone” mediated by the agonist in that tissue
*A pharmacologic antagonist will have NO effect in the absence of the agonist for that receptor.
For a drug with an oral bioavailability of 50% (F=0.5), the IV dose that would produce the desired Cp would need to be ____ to calculate the oral dose necessary.
ex. IV dose of drug is 100mg, then oral dose would be?
divided by 0.5
100 mg / 0.5 == 200 mg
In systems where the two drugs do not both produce the maximal response characteristic of the tissue, the observed maximal response is a function of their ____
relative intrinsic efficacies
For ____, a functional receptors have been “removed” from the system, limiting the number of available receptors that can contribute to the response regardless of agonist concentration
a noncompetitive ACTIVE site antagonist
The relative potency of two agonists, drug x and drug y, obtained in the same tissue is a function of their ___
relative affinities for the receptor and their intrinsic efficacies
how can fluctuations in plasma levels be blunted?
by slowing absorption via controlled or extended release preparations
when are spare receptors found to exist
if the maximal drug response (Emax) occurs at less than maximal occupation of the receptors (Bmax) as indicated by an EC50 that is less than the Kd
Example of what type of pharmacologic action? Agonist or antagonist?
Dobutamine binds to β1-adrenergic receptors on the heart and increases heart rate in the same manner as the endogenous ligand Norepinephrine
Agonsit
Spare receptors are found to exist if the maximal drug response (Emax) occurs at less than maximal occupation of the receptors (Bmax) as indicated by an EC50 that is less than the Kd. 2 mechanisms whereby this may occur are:
- if the duration of action of the effector is much greater than that of the drug-receptor interaction
- when the actual number of receptors exceeds the number of available effector molecules. These spare receptors would increase sensitivity to the agonist as the likelihood of drug-receptor interaction increases in proportion to the number of receptors available
__ is the fraction of total drug that is eliminated per unit time, therefore ____ gives the fraction of the volume of distribution that is completely cleared of drug per unit time
ke
ke x Vd
*this volume stays constant through the course of elimination of the drug
A drug that activates its receptor upon binding and brings about the characteristic tissue response
agonist
how do drugs mediate actions of pharmacologic agonists and antagonists?
- some drugs can bind to and regulate the function of receptor macromolecules as agonists, in the same manner as the natural endogenous ligands (e.g., neurotransmitters and hormones) promoting that receptor function.
- Other drugs can act as pharmacologic antagonists, binding to receptors but unable to generate the characteristic response. The effect of an antagonist then results from preventing the binding of endogenous agonist molecules to the receptor and blocking their biologic actions
types of receptor molecules
- proteins (greatest specificity)
- Nucleic acids (lower specificity)
- Membrane lipids (lower specificity)
what is the relationship between t1/2 and ke in order to appreciate the rate at which the drug is eliminated
convert ke to t1/2
t1/2= 0.963/ke
The conformational change in the receptor leads to the _____ that alters cellular function via effector molecules.
transduction step
what is the most important determinant of a drugs clinical utility?
efficacy
*as potency simply determines what dose is necessary to achieve the desired level of response
____ reflects the limit of the dose-response relationship on the response axis (y-axis). It indicates the relationship between binding to the receptor and the ability to initiate a response at the molecular, cellular, tissue or system level
Maximal Effect or Maximal Efficacy [Emax]
Explain the derivated equation of 1st order kinetics:
ln(C2/C1)= -ket
that the log of the fraction of drug remaining in the body [C / Cp0] is equal to the rate constant of elimination for the drug [ke] multiplied by the time elapsed [t]. In actual use, Cp0 and C can be drug concentrations at any two times during the first order elimination of a drug with C1 is the first (higher) of the two and C2 is the second (lower) drug concentration
ex of what type of nonreceptor antagonist?
The effect of histamine (via HISTAMINE receptors) to produce constriction of bronchiolar smooth muscle and the antagonistic action of epinephrine (via ADRENGERIC receptors) to produce bronchodilation when used in the treatment of anaphylactic
physiologic antagonist
Drug receptor theory assumes that the interaction follows
simple mass action relationships, binding is reversible, and response is proportional to receptors [R] occupied by drug [D]
RD is proportional to response
what a full agonist
-Full agonists are drugs that occupy receptors and bring about a full or maximal response.
The maximal response is usually defined as that produced by the most powerful agonists in that tissue, or that produced by a drug classically associated with the response
Dose-response curve:
response can be plotted as a function of either the drug concentration or the drug dose. If the drug concentration is used, an __ will be determined; if the drug dose is used, an __ will be determined
EC50
ED50
Elimination by first order kinetics has the characteristic that a _____ and this is ____ of the Total Amount of Drug Present.
CONSTANT Fraction of drug is eliminated per unit time
Independent
Clearance ranges from
just above zero to a maximum determined by blood flow (cardiac output) to organs of elimination
According to drug-receptor theory, all receptor sites would be occupied and response could no longer increase with increasing doses with what?
maximal efficay
____ mediate the actions of pharmacologic agonists and antagonists.
Receptors
the amount of fluctuation that can be tolerated for any given drug is determined by ____
its therapeutic index
what are advantages of the Log Dose-response curve?
- Allows a wide range of doses to be plotted allowing easy comparison of different drugs
- Dose-response relationship is a nearly a straight line over large range of doses (generally corresponding to the therapeutic range).
effect of an antagonist results from
results from preventing the binding of endogenous agonist molecules to the receptor and blocking their biologic actions
the concentration (EC50) or dose (ED50) required to produce 50% of that drug’s individual maximal effect (NOT the 100% value of that system), i.e., e/Emax = 1/2
potency
what is an antagonist
- a drug that inhibits the action of an agonist but has no effect in the absence of an agonist.
- Antagonists can be divided into receptor and non-receptor antagonists
elimination of a constant AMOUNT of drug per unit of time
zero-order elimination
for drugs that exhibit 1st order kinetics, how long would it take for a drug to reach steady state
4-5 half lives (same pace for elimination)
- 50% of [SS] reached after 1 half-life
- 75% after 2 half-lives
- over 90% at 4 half-lives
what happens upon a drug binding to its receptor
The specificity of fit of drug to receptor (recognition) induces conformational change in receptor protein
what order processes is hepatic metabolism and renal excretion?
1st order kinetics
what drugs do not have half lives?
those that display zero order kinetics because elimination is of a CONSTANT amount of drug per unit of time (independent of Cp)
amplification of a signal transduction via G proteins or other effectors can occur via:
- transport of ions or molecules
- transcription factors
- enzyme activation or deactivation
- protein synthesis
- release of neuroactive agents
