Absorption of drugs

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I/- Introduction :

Between the time of drug administration and that of obtaining the effect ; the drug passes through several stages grouped into three phases :

The stage biopharmaceutical : includes the steps of the availability of the drug of the active organism. These steps are combined in the release of active substance from the pharmaceutical form and its dissolution.

For example the solid form (tablets) : the solution formatting steps are : the decay and disintegration (particles of small sizes) shape then the dissolution ( dispersion in the molecular state in an aqueous medium) the active ingredient.

The pharmacokinetics stage : is descriptive and quantitative study of the future of medicine in the body over time. It therefore includes the study of the absorption, distribution, metabolism, the elimination of drugs in the body (concept ADME).

The pharmacodynamic Phase : it is the study of the biochemical and physiological effects of the active ingredients and their mechanisms of action

II/- Definition of absorption :

The absorption or resorption is a phenomenon that is the transfer of the active ingredient from its site of administration into the systemic circulation. The passenger in eimplique biological membranes.

Except for the intravenous and intra arterial, all administartion routes are affected by the phenomenon of absorption.

III/- The physico-chemical properties involved in drug absorption :

1- The ionization state :

The active ingredients of drugs have generally, either a weak acid or weak base character, Example :

BY folic pKa basic AP pKa
ampicillin 2.5 Strychnine 8.0
Aspirin 3.0 Paracetamol 9.5
Ibuprofen 4.4 Procaine 9.0

They are therefore likely to ionize depending on the medium pH where there are, and their pK. according to the equation of Henderson-Hasselbalch :

For weak acids :

PH = PKa + log {ionized form} / {nonionized}

For weak bases :

PH = PKa + log {nonionized} / {ionized form}

2- Liposolubilité :

Ks partition coefficient information about fat solubility which is carried by the non-ionized fraction of the drug molecule.

Ks = Drug concentration in a non-polar solvent / drug concentration in a polar solvent

More Ks is high, the drug is more soluble.
More Ks is high, over the PA pass a lipid membrane

3- The hvdrosolubilité :

The poorly water-soluble substances are poorly absorbed in the digestive system as the amount is in solution is very limited, therefore the water solubility is a limiting factor in the dissolution of drugs in the digestive milieu.

4- Molar mass :

The transfer rate of a drug is inversely proportional to its molecular weight.

The active ingredients dissolved unionized and sufficiently soluble cross
biological membranes of the absorption site

IV/- The mechanisms involved in drug absorption :

The main barrier is that the drug meets the plasma cell membrane, composed of a lipid bilayer.

Drugs can cross membranes either by passive processes or mechanisms involving the participation of membrane components.

a- The passive diffusion :

It is the most important mechanism by which the active ingredient molecules pass through the membrane when these molecules are not electrically charged.

  • Concerns molecules liposilubles unionized.
  • Is in the direction of the concentration gradient.
  • Does not require energy and transport.
  • The drug physicochemical properties determine passive diffusion.

b- Facilitated passive diffusion :

  • The transfer of the molecules is in the direction of the concentration gradient.
  • It is a phenomenon that requires a carrier (a membrane protein).
  • It is a saturable and specific phenomenon.

c- Active transport :

  • Is in the opposite direction of the concentration gradient.
  • Carrier Required (a membrane protein) , and energy
  • Active transport is specific and saturable.

d- filtration :

  • Passage of molecules through pores in cell membranes.
  • Interested water and the molecules of low molecular weights ( < 150 D)
  • The passage is a function of hydrostatic pressure gradient or osmotic.
  • Lack of saturation phenomena and specificity.

e- La pinocytose :

This is the transmembrane passage of large molecules entrapped in the vesicles formed by invagination of the plasma membrane.

V /- The absorption of drugs by different routes of administration :

A/- absorption of oral drugs :

1- Anatomical elements involved in digestive absorption of drugs :

elements

anatomic

physiological characteristics PH Vascularisation
The stomach
  • Consisting of a thick membrane with a small absorption surface (1 m )
  • Under normal conditions, gastric emptying is fast and the role of the stomach in the absorption of the drug is modest
1-3 Low (Blood flow = 0,2 1/me)
Duodenum
  • a material exchange surface
  • Presence of bile promoting dissolution of the active ingredients
4-5 Important
The intestine

hail

  • the membrane is thin with a large absorbing surface (microvillosité) (200 m2).
  • The small intestine is the most important site for drug absorption
5-8 very Important (Blood flow = 1 1/me)

The passage of the active ingredients through the mucosa gastrointestinal involves all transmembrane transport mechanisms : diffusion passive ; active transport ; facilitated diffusion ; filtration et pinocytose.

2- Diffusion medications pH effect :

Only the non-ionized and soluble fraction passes through the digestive barrier into the blood (pH = 7.4), nature of lipid-proteique (by passive diffusion).

The pH varies between 1 and 8 in the gut, according to this pH value, the ratio of the ionised and unionized forms depends on the pKa of the compound.

For low-acid :

Example 1 : Drug pKa = 3

• In acidic medium : Vionisation low, the non-ionized fraction greater, the drug will best cell membranes.
• In basic medium : ionization is important, where a fraction ionized greater, thereby limiting the transmembrane portion of the substance.

For a weak base :

• In acidic medium : ionization will be greater, where a fraction ionized greater, the drug will harm cell membranes.
• In basic medium : ionization is low, the drug will be fine cell membranes.

N.B : before it is absorbed a certain amount of active ingredient can be metabolized or transformed under the effect of certain enzymes in the gut (Disaccharisadases , Dipeptidases, enterokinase, Cytochromes) or enzymes of the intestinal flora by transformation products called metabolites "It is the effect of intestinal first-pass"

After absorption, the active ingredients reach the portal vein that goes to the liver. At this level, a fraction can be metabolize (= Chemically transformed). This phenomenon called "the first-pass effect" can significantly reduce the amount of these active substances before reaching the bloodstream.

3- The factors modifying drug absorption :

a- The physicochemical properties of drugs :

  • PKa and the degree of ionization of the active ingredient
  • Liposolubilité.
  • Dissolution (limiting step).
  • Pharmaceutical form: (Ex: liquid forms; resorption is faster).

b- physiological factors :

1- The physiological components of digestion :

Digestive secretions (PH stomacal acide; intestinal flora…) may lead to physicochemical changes drug molecules.

2- food :

There are difficult to predict the influence of diet on gastrointestinal absorption of drugs.

Taking a meal causes the following changes :

  • Increased splanchnic blood flow
  • Decreased gastric emptying (high-fat meal)
  • Increased biliary secretion.

3- Gastric emptying :

Factors influencing gastric emptying are :

  • food
  • Physical exercise
  • Body position
  • Drug interactions

4- Splanchnic blood flow :

It directly influence the absorption of fat-soluble drugs

c- Pharmacokinetic drug interactions phases :

This is the result of changes made by one of the partners drugs limiting factors the digestive absorption of drugs, to know : dissolution ; gastric emptying ; and intestinal blood flow.

d- Medical conditions :

The absorption of drugs may be altered by the intestinal transit disruptions, secretions and the state of the intestinal mucosa.

The level of disturbance Examples Result
digestive secretion Lack of secretion of intrinsic factor Decreased absorption of vitamin B12
Absence of bile secretion Decreased absorption of vitamin K
intestinal mucosa Degeneration of the intestinal villus (Crohn's disease) Decreased absorption of all medications
Transit intestinal Decreased drug contact time with the intestinal mucosa (diarrées). Decreased absorption of all medications

B/- The absorption sublingually :

The drug is placed under the tongue, region defined by a mucous membrane similar to that of the gastrointestinal tract, conditions conducive to drug absorption at this level :

—► Epithélium mince.
—► PH weakly acidic.
—► vasculatures rich allowing passage through the oral mucosa to the blood medium

Any drug absorbed by this route, prevent :

  • The action of various gastric PH.
  • digestive enzymes.
  • bacterial flora.
  • hepatic metabolism (hepatic first pass)

C/- Absorption rectal :

– It is done by passive diffusion.
– Hemorrhoidal veins lower and medium lead to internal iliac veins that drain into the inferior vena cava avoiding the first pass liver.
– Hemorrhoidal veins above are connected to the inferior mesenteric vein, which supplies blood to the portal vein and then to liver.

Note : it is difficult to predict with certainty the amount of drug administered rectally avoiding the first pass liver.

D/- Absorption through the lungs :

The lungs are an excellent absorption by their body :

* Large exchange surface (the number of cells varies between 300 at 400 millions).
* Very high permeability
* very important vascularization The absorption by this route of administration is by passive diffusion at the alveolar membrane

E/- Absorption by parenteral :

The drug absorption is generally rapid injection of drugs directly into the body (with the exception of intravenous and intra arterial). And while avoiding the removal by the gastrointestinal tract. However, drugs administered directly into the systemic circulation can undergo elimination of first pass through the lungs before being distributed to the rest of the body. On distingue:

1- The absorption of the drug intramuscularly :

Absorption is by passive diffusion or facilitated.

The active ingredients are absorbed rather quickly depending : their lipid solubility and vascularization and blood flow from the injection site.

2- subcutaneously Absorption :

Absorption is by passive diffusion or facilitated, the resorption rate is less than intramuscularly because of the viscosity of the ground substance of connective tissue (adding an enzyme: hyaluronidase which decreases the viscosity)

Dr GHARBI's course. M – Faculty of Constantine