Pharmacokinetics Flashcards
Pharmacokinetics
is part of the pharmacology that studies the pagh of drugs in the body , their absorption, distribution and elimination.
Crossing biological membranes
The body can be considered as consisting of a series of compartments separated by biological membranes. Crossing biological membranes is a process
that underlies all pharmacokinetic processes.
Cell membranes are lipid bimolecular structures that separate aqueous media. Drugs can cross these biological membranes in several ways,
1 ) passively or
2) through active mechanisms, depending on their biochemical characteristics.
3) Other forms of crossing biological membranes involve the involvement of aqueous pores.
At the level of cell membranes there are a series of aqueous pores or water channels called aquaporins (AQP).
crossing plasma membranes
Passive diffusion
1 ) Simple (passive) diffusion involves the passage, without energy consumption, of the drug directly through the membrane, in the direction of the
concentration gradient, until the drug concentrations are equalized in the two separate compartments of the biological membrane.
- The diffusion is more intense -> the higher the concentration gradient, -> the more liposoluble the drug and the larger the surface area of the membrane involved in the absorption process.
* The drug must also be hydro-soluble, otherwise the drug remains in the cell membrane without passing into the other aqueous compartment.
- Drugs that are able to dissociate in solution - the more a drug dissociates, the more hydro-soluble, the less liposoluble it becomes, and the less likely it is to
cross biological membranes by diffusion.
*The dissociation capacity depends on
1) the dissociation coefficient of the substance (pKa) a 2) pH of the medium in which it is dissolved.
The existence of compartments with different pH directs the diffusion of drugs - it is possible to change for therapeutic purposes the pH of certain
compartments in order to direct the circulation of drugs.
The alkalinization of urine favors the -> elimination of acidic drugs, while
its acidification, -> of alkaline ones, in both cases by : increasing the proportion of the polar form, water-soluble, and the consequent decrease of the tubular reabsorption.
Crossing biological membranes
Active transport
Active transport involves crossing biological membranes with energy
consumption and against the concentration gradient. Active transport is
performed by certain proteins inserted in the cell membrane called carrier proteins
or transporters.
A particular form of active transport is facilitated diffusion, which is in fact
an active transport performed in the direction of the concentration gradient.
Absorption of drugs
Drug absorption is the pharmacokinetic process by which drugs enter the bloodstream from the site of administration, involves crossing biological
membranes being an essential process for choosing the route of drug administration.
In situations where the drugs are administered directly into the blood (intravenously or, less frequently, intraarterially), there can be no talk of absorption.
* Lipo-soluble and small-molecule drugs are usually well absorbed, regardless of the route of administration, provided they are not inactivated at the
site of administration.
**The absorption is better the higher the concentration at the site of administration, the higher the absorption surface and the richer the vascularity.
1) Oral Administration
2) Parental Administration ( IV , I.m. + subcutaneous )
3) Administration on skin + mucosa
4) Inhalatory administration
Oral administration
It is the most convenient route of administration and
can be influenced by a number of local factors:
1) gastric acidity, enzymes of digestive juices.
2) If the drug molecules are lipo-soluble, they are generally absorbed quickly and completely.
3) If they are polar, their absorption is lower the higher the polarity of the molecule.
4) When the polarity of the molecule is
intermediate, the absorption is partial, but if it is good enough, it can allow oral administration but the absorption can be influenced by the motility of the
digestive tract: it increases when transit is slowed and decreases when transit is accelerated.
Parenteral administration
is recommended when oral administration is
not possible or not advantageous: drugs that are not absorbed or destroyed in the digestive tract, uncooperative patients, the need for a very fast and intense effect, contraindication for oral administration, etc.
1) Intravenous administration does not involve absorption and it is considered that the entire amount of drug injected reaches the bloodstream right from the moment of administration.
2) Intramuscular and subcutaneous administration involve absorption that may be influenced by the nature of the drug and the vascularity of the area.
3 ) In the case of intramuscular injection the absorption is faster than in the case of subcutaneous administration, the muscle being much better vascularized
Administration on skin and mucosa
is used in the case of drugs with local action, drugs that are highly metabolized at the first liver pass, to bypass the portal circulation (eg nitroglycerin), or in case of substances that are destroyed in the digestive tract (catecholamines, vasopressin, etc.).
Inhalatory administration
achieves very rapid absorption, if the drug is
lipo-soluble and small in size (anesthesiology), or is used in the case of inhaled antiasthmatic drugs (they must remain at the site of administration).
Distribution of drugs
The distribution of the pharmacokinetic process in which the drug reaches
the bloodstream is transported throughout the body. Many drugs in the blood bind to plasma proteins.
1) Usually the drugs bind reversibly to albumin, and the bound form is inactive, available for action being only the free, unbound form.
2) The free form is that which penetrates into various tissues and is eliminated from the body
by metabolism or urinary excretion.
3) The more a drug binds to plasma proteins,
the lower the concentration of free form, the less active the drug is in the blood and the less it passes to the tissues.
Hypoalbuminemia
- (which may occur in nephrotic syndrome, liver failure, etc.) may increase the toxicity of drugs that bind closely to plasma proteins by increasing the concentration of the free form.
- It can also increase the concentration of the free form when co-administering drugs that bind to a large percentage of the same site on proteins, with one of the substances displacing the other and increasing its pharmacodynamic effect.
Elimination of drugs
Elimination of drugs is the pharmacokinetic process by which drugs are eliminated from the body.
1) Most drugs are eliminated from the body through
urinary excretion or metabolism, most often hepatic.
2) Other elimination routes are possible, but are usually not quantitatively important for the elimination of the drug.
3) Elimination of drugs by urinary excretion can be done by glomerular filtration and / or tubular secretion. 4) Most drugs are small enough to filter glomerular. However, only the free form, unbound to plasma proteins, filters glomerularly, because proteins do not filter glomerularly. If the drug is non-polar
(lipo-soluble), it undergoes intense tubular reabsorption processes,
- its urinary elimination being limited, or conversely,
- if it is polar (hydro-soluble), the tubular reabsorption is minimal, reaching to eliminate perhaps even the entire glomerular filtered amount.
5) Urinary excretion is the main way to eliminate water-soluble drugs from the body. In case of renal insufficiency, the risk of toxicity of these drugs increases, requiring an adjustment of the doses and the interval between administrations, depending on the degree of renal insufficiency.
6) Fat-soluble drugs are slightly eliminated by urinary excretion.
7) On the one hand, it binds a lot to
plasma proteins and filters a little glomerularly, on the other hand, being fatsoluble, it is reabsorbed a lot in the tubular so that only a small part of the
glomerular filtrate is excreted in the urine.
8) Lipo-soluble drugs are usually eliminated by hepatic metabolism.
9) Drug metabolism can take place in various structures (blood, digestive tract mucosa, etc.) but in most cases metabolism takes place in the liver.
elimination of drugs continuation
10 ) Most often, the metabolism results in biologically inactive substances with increased polarity that can be more easily eliminated by urinary excretion.
11) Sometimes completely inactive substances are administered from a biological point of view that become active in the body through bioactivation. These substances are usually called prodrugs or prodrugs
12) The ability of the liver to metabolize certain drugs depends on the enzymatic baggage of this organ and the chemical structure of the drug.
13) For certain drugs, the liver has the ability to completely metabolize that drug on its
first passage through the liver, a phenomenon known as first-pass liver disease.
Drugs that suffer from a first-pass hepatic phenomenon are usually inactive if administered orally (by swallowing), because by absorption they pass into the portal vein which transports them to the liver where they are completely inactivated.
Pharmacokinetic Parameters
1) Plasma concentration.
The plasma concentration of the drug is obtained by directly measuring the concentration of the drug in the plasma.
- The plasma concentration of a drug varies over time. For comparisons between patients, between drugs, or between different routes of administration for the same drug, the peak plasma concentration (Cmax) or the area under the plasma concentration-time curve (AUC) is usually used. AUC of a drug is generally
considered a measure of a person’s exposure to that drug.
2) Apparent volume of distribution. Knowing the plasma concentration and the dose administered intravenously, the apparent volume of distribution Vd of a drug can be calculated according to the formula:
Vd = D/Cp
where Vd = apparent volume of distribution, D = intravenous dose and Cp = maximum plasma concentration after dose D.
3 ) Bioavailability. Bioavailability (BA) is the percentage of the amount of drug administered that reaches the blood and is thus available for action.
BA = (Qx/Qiv)100
where Qx represents the amount and, respectively, the plasma concentration of the drug for the route of administration considered (oral, intramuscular, etc.) and
Qiv for the route of intravenous administration.
Very important is the timing of determining the plasma concentration and therefore, either the peak of the plasma concentration is used, or, best of all, the
area under the time variation curve of the plasma concentration (AUC) is used.
In the latter case the bioavailability formula becomes:
BA = (AUCx/AUCiv)100
Knowing the bioavailability of a drug allows, among other things, the relationship between the doses of drug administered by various routes of administration. For example, if a drug has a 50% bioavailability after oral administration, the dose for oral administration will be double the dose for intravenous administration.
4) Drug clearance. Clearance of a drug is probably the most important pharmacokinetic parameter. The clinic usually works with the plasma clearance
of the drug which represents the volume of plasma completely treated by the drug per unit time and is calculated based on the variation of the plasma concentration of the drug over time after a single administration, according to the formula:
Cl = D/AUC where Cl is the plasma clearance of the drug, D is the administered dose, and
AUC is the area under the plasma concentration curve over time. Plasma clearance of a drug allows the determination of the doses necessary to maintain a
constant plasma concentration of the drug.
5) Plasma half-life (t1/2), defined as the time required to halve the plasma concentration.
In first order kinetics this parameter has a constant value for the same substance, regardless of the total amount of drug in the body.
In principle, if after each t1/2 the plasma concentration reaches half, theoretically it never reaches the value 0, but tends towards this value. After a time 4 – 5 times higher than t1/2, it is estimated that a drug is completely eliminated from the body
