Basic Principles of Pharmacology Flashcards
Pharmacokinetics describes…
the relationship between drug
dose and drug concentration in plasma or at the site of drug
effect over time
What processes make up pharmacokinetics?
Absorption, distribution and elimination (metabolism and excrection)
What is the volume of distribution? How to calculate?
The volume of distribution (Vd) is the apparent size of the tank in which a known amount of drug distributes to produce a measured drug concentration once the drug has had enough time to thoroughly mix within the tank.
Volume of distribution = Amount of dose (t) / Concentration (t)
(t) = at a given time
Usually in mg/L
If drug elimination occurs as a first-order process (i.e., elimination is proportional to the concentration at that time), in a tank model, the volume of distribution calculated by will be … over time
constant
The more soluble a drug is in peripheral tissue relative to blood or plasma, the … the peripheral volumes of distribution
larger
Clearence describes …
the rate of drug removal from the
plasma/blood, is defined as the volume of plasma cleared of a drug over a specified time period
What is systemic clearence? And intercompartimental clearence?
Systemic clearance permanently removes drug from the body, either by eliminating the parent molecule or by transforming it into
metabolites.
Intercompartmental clearance moves drug
between plasma and peripheral tissue tanks
What is the difference between clearence and elimination rate?
Clearance is defined in units of flow, that is, the volume completely cleared of drug per unit of time (e.g., L/min).
Clearance is not to be confused with elimination rate (e.g., mg/min).
The elimination rate is not an accurate method of describing the mass of drug removed over time. For example, assuming a first-order process, when plasma concentrations are high, the rate of drug elimination is high. When low, the rate is also low.
Clearance is a better descriptor as it is independent of drug concentration
How clearance can be calculated at the steady state during a continuous infusion?
Clearance= Infusion rate / Css
Css is the plasma concentration at steady state
How the the first-order elimination rate constant can be calculated?
K = CL / Vd
Where CL is clearance with units of volume/time (L/min), Vd is the compartment distribution volume with units of liters (L),
In a physiologic model of clearance, how the total clearance can be obtained?
The total clearance is the sum of each clearance by metabolic organs such as the liver, kidney, and other tissues
To calculate a metabolic organ clearance:
Clearance= Q (Cin −Cout) / Cin
- Q is the blood flow to metabolic organs;
- Cin is the concentration of drug delivered to metabolic organs;
- Cout is the concentration of drug leaving metabolic organs
Obs: The fraction of inflowing drug extracted by the organ [ (Cin−Cout) / Cin ] is called the extraction ratio (ER), so:
Clearance = Q x ER
Describe the relation between hepatic extraction ratio (ER), blood flow and drug metabolism
- For drugs with an ER of nearly 1 (e.g., propofol), a change in liver blood flow produces a nearly
proportional change in clearance.
If nearly 100% of the drug is extracted by
the liver, this implies that the liver has a very large metabolic capacity for the drug. In this case, the rate-limiting step in metabolism is the flow of drug to the liver, and such drugs are
said to be “flow limited.” As a consequence, any reduction in liver blood flow due to circulatory effects of anesthetic agents or changes in circulatory volumes in cases of perioperative bleeding or other situations of excessive fluid loss can be expected to reduce liver-dependent drug clearance. - For drugs with a low ER (e.g., alfentanil), clearance is nearly independent of the rate
of liver blood flow.
For these drugs, clearance is limited by
the capacity of the liver to take up and metabolize drug. These drugs are said to be “capacity limited.” Clearance will change in response to any change in the capacity of
the liver to metabolize such drugs, as might be caused by liver disease or enzymatic induction
What is the zero and the first order kinetics?
With zero-order kinetics, drug is eliminated at a constant rate, regardless of the plasma concentration, following a linear elimination phase as the system becomes saturated.
A simple analogy would be an athlete signing an autograph on a picture. Regardless of the total amount of photographs that must be signed, the athlete can only sign one autograph every 15 seconds. The rate-limiting factor of this analogy and zero-order kinetics is time.
With first-order kinetics, drug is eliminated at a rate proportional to the amount of drug
present at that time.
To utilize the same analogy, now the entire team can sign the photographs. The more hotographs there are to sign, the more athletes can sign. The rate-limiting factor of this analogy and in first-order kinetics is the initial concentration
- In the case of the autographs, if the amount of needed autographed photos exceeds the number of available athletes, the first-order elimination then becomes zero-order
How to calculate de elimination half-life of a drug with first-order kinetic from a compartment?
t1/2 = 0.693 / k
k is the first-order kinetic elimination rate constant
Front-end kinetics
Front-end kinetics refers to the description of intravenous drug behavior immediately following administration.
- How a drug rapidly moves from the blood into peripheral tissues directly influences the peak plasma drug concentration.
The amount of drug that moves to the peripheral tissue commonly surpasses the amount that is eliminated during the first few minutes after drug administration
Back-end kinetics
Back-end kinetics provides descriptors of how plasma drug concentrations decrease once a continuous infusion is terminated. An example is decrement time, which predicts the time required to reach a certain plasma concentration once an infusion is terminated. Decrement times are a function of infusion duration
Hysteresis refers to
Hysteresis refers to the time delay between changes in plasma concentration and drug effect. Hysteresis accounts for the time required for drug to diffuse from the plasma to the site of action plus the time required, once drug is at the
site of action, to elicit a drug effect.
This lag between the plasma concentration and effect usually results in the phenomenon called hysteresis in which two different plasma concentrations correspond to one drug effect or one plasma concentration corresponds to
two drug effects
Kinetic micro rate constants used to describe biophase include k1e and ke0. The k1e describes …, and ke0 describe the …
drug movement from the central compartment to the effect site
elimination of drug from the effect-site compartment
To create a pharmacodynamic model, the hysteresis loop is collapsed using modeling techniques that account for the lag time between plasma concentrations and the observed effect. These modeling techniques provide an estimate of the lag time, known as the…, and an estimate of the effectsite concentration (CE) associated with a 50% probability of drug effect (C50).
t1/2ke0
Most concentration effect relationships in anesthesia are described with a sigmoid curve. The standard equation for this relationship is the “Hill Equation,” also known as the “sigmoid Emax relationship”:
Effect=E0 + (Emax −E0) * (C^g/(C50^g +C^g))
- E0 is the baseline effect
- Emax is the maximal effect,
- C is the drug concentration
- γ or g (gamma) represents the slope of the concentration-effect relationship.
Gamma (γ) is also known as the “Hill coefficient.” For values of γ < 1, the curve is …; for values of γ > 1, the curve is …
Obs: ^ is used to denote coefficient
hyperbolic
sigmoid
Potency describes …
the amount of drug required to elicit an effect. The C50 is a common parameter used to describe potency
For drugs that have a concentration-versus-effect relationship that is shifted to the
left (small C50), the drug is considered to be … potent;
For drugs that have a concentrationversus-effect relationship shifted to the right, the drug is considered to be … potent.
more
less
Efficacy is …
a measure of drug effectiveness at producing an effect once it occupies a receptor. Similar drugs
that work through the same receptor may have varying degrees of effect despite having the same receptor occupancy
Describe the dynamic range
the concentration range where changes in concentration lead to a change in effect
- Concentrations outside the dynamic range do not yield much change in drug effect
The therapeutic index of a drug is defined as
ratio between the LD50 and the ED50
- ED50 is the dose at which there is a 50% probability of effect
- LD50 is the dose with a 50% probability of death
A term used to characterize the continuum of drug concentrations across various combinations of drug pairs (X in combination with Y) is the …
isobole
A common isobole is the 50% isobole line. It represents …
all possible combinations of two-drug effect-site concentrations that would lead to a 50% probability of a given effect
- Other isoboles are of more clinical interest. For example, the 95% isobole for loss of responsiveness represents the concentration pairs necessary to ensure a 95% probability of unresponsiveness
Additive isoboles are lines connecting equi-effective concentrations CX and CY of the agents X and Y.
Subadditive effects (antagonism) are indicated by … and superadditive (synergism) effects by …
elliptical isoboles located above the additivity line
hyperbolic isoboles located below the additivity line
Hendrickx and colleagues surveyed the literature for work in both humans and animal models that described anesthetic drug interactions for opioids, sedative hypnotics, and inhalation agents.
They found several interesting features of anesthetic drug combinations.
First, inhalation agents when combined are strictly 1…, suggesting a common mechanism of action, except for 2…, which has an infra-additive interaction with other inhalation agents.
Second, interactions between various
intravenous drugs and inhalation agents are 3… except for 4…
Third, interactions between different classes of intravenous drugs (e.g., opioids and sedative hypnotics) are primarily 5…, except for 6…
1) additive
2) nitrous oxide
3) synergistic
4) nitrous oxide and GABA sedative hypnotics
5) synergistic
6) ketamine and benzodiazepines
The dose of propfol in obese patients should be adjusted. Of the many available dosing scalars, authors recommend … for bolus dosing (i.e., during induction) and … for infusions
LBM (lean body mass)
TBW (total body weight) or CBW (corrected body weight)
- Obs: CBW for infusions may underdose
In obese patients, although not clinically validated, Greenblatt and associates recommend that bolus doses of midazolam should be scaled to … and other dosing scalars may lead to inadequate effect. On the other hand, with a fixed elimination, continuous infusion rates should be dosed to …
TBW
IBW
Studies suggest that dosing of dexmedetomidine, which is calculated using
TBW, can be … in obese patients
overdosing
For an obese patient, dosing scaled to … resulted in almost identical remifentanil effect-site concentrations as in the lean patient dosed according to TBW.
Dosing scaled to LBM in the obese individual resulted in … effect-site concentrations than those in a lean individual dosed according to TBW
FFM (fat free mass)
lower
Morphine dose adjsutment in obese
de Hoogd and colleagues performed a population pharmacokinetic analysis of intravenous morphine in morbidly obese individuals. They found that morphine
pharmacokinetics were comparable to those of healthy volunteers. They concluded that no weight-based dosing adjustments were necessary. However, they also found
that the elimination of pharmacologically active metabolite was decreased, resulting in an increased exposure to active metabolite with prolonged administrations. They concluded that the clinical relevance of this phenomenon
was not clear