Definition of therapeutic index
Range of doses from the minimum effective concentration to the toxic threshold.
Wider the range, safer the drug
Definition of bioavailability. Which parameters influence it?
It’s an estimation of the fraction of a drug reaching the systemic circulation from an extravasal site in its unmodified form.
There are 3 parameters:
- Cmax: maximum concentration of the drug. It’s the peak of the curve
- Tmax: time at which Cmax is reached
- AUC: area under plasma concentration-time curve. It’s the amount of active principle released in the blood
OPEN QUESTION: draw a graphical comparison of the administration of a drug through:
- intravenous route
- intramuscular route
- oral route
Which factors can limit the oral bioavailability
- Poor drug dissolution: release of the active principle from the pharmaceutical preparation.
The active principle can be trapped inside the pharmaceutical form and it’s not available for the absorption. - Limited stability or inactivation of the active principle in the gastro-enteric tract (may be attenuated by “coating”). Some coating applied on some pills can limit the absorption of the active principle in the gastro-enteric tract
- Physico-chemical characteristics: ex:lipophilicity can limit the absorption
- Enteric drug transporters that can facilitate or limit the absorption of certain drugs and during the passage into the bowel
- Enteric and liver biotransformations that can occur in the bowel and also in the liver, that is the main organ for biotransformations (“first pass effect”).
- It’s important to consider the pH of the stomach in order to know how much the drug will be dissociated.
Definition of half life. Why it’s important?
It’s a measure of the rate of drug elimination, it is the time (in hours) taken for the plasma concentration of a drug to decline by 50%.
The posology and the therapeutic protocol of a drug are heavily affected by its half-life, thanks to this value we can know exactly when we have to/can administrate the drug again in order to maintain a therapeutic effect.
Definition of volume of distribution. Which are the consequence of this parameter?
It is the volume of fluid (usually water) in which a drug can be dissolved, expressed in litre or litre/kg.
Higher is the value, better will be the distribution of the drug into the tissues.
Definition of body clearance
It is a measure of the body’s ability to remove a drug, it depends on various elimination processes.
Explain the postulates on which is based the one-compartment open model
- The body is considered as a single, kinetically homogenous unit with no barriers opposing to the drug movement.
- The equilibrium between drug, plasma and other body fluids is attained instantaneously and always maintained.
- The anatomical reference compartment is the plasma and any change in drug plasma concentration is expected to reflect a proportional change in all body tissues.
- The input (availability) and the output (excretion) are unidirectional.
Drug is administered in one way and eliminated following the same direction,
What is the Ke?
It’s the constant of elimination, it depend on drug’s concentration in plasma
How can we calculate the volume of distribution?
Vd=(D (injected drug dose))/(C (drug plasma concentration) )
Which is the relation between drug clearance and half-life?
They’re inversely related: the higher the clearance, the shorter the half-life.
Clearance=0,693/(half-life)
How do we intend the body in the two compartment model?
In this model we intend the body as two boxes:
- A central one (liver, kidney, lungs, heart) with a good vascularization, with a high rate of blood
- A peripheral one (fat, intestine, muscles, etc.), where the perfusion is less.
Drug normally distribute rapidly to a limited number of tissues (in general, the highly perfused ones) and then, at a lower rate, to the other less perfused tissues (peripheral part).
The communication between these 2 parts is continuous, drugs move back and forth between these compartments to maintain equilibrium.
Which are the postulates for the two compartment model?
- Drugs enter the body and leave the body only via the central compartment
- C and V are drug plasma concentrations and Vd of either compartment
- K1,2 and K2,1 are the elimination rate constants from central to peripheral compartment, and vice versa, respectively
- Ke is the elimination rate constants of drug from central compartment to outside the body
- The drug rapidly distributes in the central compartment where an equilibrium is almost immediately attained at T=0, C1 = D1/V1 and C2 = 0
- The drug transfer from the central to the peripheral compartment and vice versa (K1,2 and K2,1) as well as the elimination from the central compartment (Ke) occurs according to first order kinetics
OPEN QUESTION: draw the plot of the two compartment model. Which phases can you recognize? What does the intercept on Y allow to calculate?
- α-phase (distribution phase): steep slope directly related to a rapid decline in plasma drug concentration due to the distribution into the peripheral compartment and, to a lesser extent, to the elimination from the central compartment.
- Steady state: drug’s plasma concentration equals tissue drug concentration
- β-phase (elimination phase): less steep curve, drugs begin to continuously flow back into the central compartment, where they are eliminated
The intercepts on Y axis allow to calculate the main pK parameters for both distribution and elimination phases
What happens if a drug don’t fit neither the 1-compartment nor the 2-compartment model?
sometimes there are three-compartment models with a γ-phase, in which the peripheral compartment has a subdivision in two different peripheral compartments (very less perfused tissues and intermediate perfused tissues).
