Principles of Gastro-Intestinal Drug Absorption Part 5

Physiological Factors Affecting Drug absorption

Clincal Pharmacy, Biopharmaceutics section

Done By Ismail Mortada

A study in biopharmaceutis dedicated for professionals & students

We mentioned before the factors affecting drug absorption in past articles, those factors related to the drug itself 7 the absorption media also, now in this coming series of lectures, I’ll discuss the natural original physiological factors which still affects the drug absorption, we can start by looking at the following

A) GIT structure & surface area available for absorption
B) GIT Components
C) GIT Viscosity or content viscosity
D) GIT PH
E) The Rate of Gastric Emptying

A) GIT STRUCTURE & PHYSIOLOGY

The GIT is a major system in the human body, the digestive system in general will not start from the stomach as people think, but it will start from the saliva & the oral cavity itself, in general we need to know that the PH of the stomach is acidic (low PH) as well known & it increases while going to the intestines & that the bile ducts will secrete bile salts from the Gall bladder + enzymes taken from the pancreas

So the route in which food or oral drugs will pass is starting from the oral cavity (mouth + saliva) reaching the stomach of low PH through the esophagus, then to the deudenum, than the jejunum reaching the colon at the end

The following are the details of the Digestive elements

Regarding the PH range is as the following

A) For buccal cavity the PH is approximately 7
B) Esophagus PH is 5-6
C) Stomach Ph is 1-3, decomposition of some drugs occurs here & weak acids are un-ionized
D) Duodenum PH is 6-6.5 contains ducts & surfactant properties
E) Small Intestine PH is around 7-8
F) Large Intestine PH is about 5.5-7

Regarding The Membrane Nature

A) Buccal Cavity having a thin membrane
B) Esophagus having very thick membrane with no absorption capacity
C) Stomach, duodenum & small intestine have a normal membranes

Regarding the Blood Supply

A) Buccal cavity having a good, fast absorption with low dose
B) Stomach, dudenum, small intestine & large intestine have good blood supply

Regarding the Surface Area

A) Buccal cavity, esophagus & stomach have a small surface area
B) Duodenum have a very large surface area
C) Small intestine have a very large 10-14 ft, 80 cm square\cm of surface area
D) The large intestine doesn’t have very large area, about 4-5 ft

Regarding the Transit Time

A) Buccal Cavity have a short unless controlled time
B) Esophagus have a short time
C) Stomach have 30-40 minutes (small time) with reduced absorption
D) Duodenum have a very short window effect
E) The small intestine have about 3 hours
F) The large intestines have a long one up to 24 hours

Regarding by-passing liver

A) The buccal cavity will not pass liver first effect
B) All the rest will pass except lower colon & superfecial rectum area

Note that in a place like the buccal cavity we use drugs which are biodegradable or potent lipophilic agents normally such as steroids & nitroglycerin agents, as the drug pass via the GIT, it faces different enviroments with respect to structure, components, viscosity or consistency as well as PH, the GIT is composed of the following briefly

A) THE STOMACH

Composed of smooth epithelial cells surface, Since the stomach has a small surface area & the resident time of the drug in the stomach is short, then its role in drug absorption is limited some how & it’s not considered the major site for drug absorption, Only weak acidic drugs which exist in un-ionized, lipid soluble form are absorbed to some extent in the acidic PH of the stomach which is normally between 1-3, this PH is stimulated by the Vagus nerve when food is indigested

The main role of the stomach is store, mix & reduce ingested food into a slurry or paste with the aid of gastric secretions & than emptying or pumping these contents into the small intestine

B) THE SMALL INTESTINE

The most important site for drug absorption in GIT composed basically of the deudenom (5-7) & jejunum (5-6) or aapproximately +\- 1, because it exhibits large surface area, The intestinal lumen is composed of numerous mucosal foldings, known as foldings of Kircking, each fold comprises a large number of finger like projections known as villi & projecting from these villi are numerous fine structure known as micro-villi

The presence of such large numbers of villi & micro-villi will provide the small intestine with a large surface area of about 120 m square, The small intestine is also the most important region for carrier mediated transport, and as seen in the pictures, those villi & projections are having rich blood supply which increases the vasculaarity of the whole region

C) THE LARGE INTESTINE

Similar to the stomach, the large intestine has smaller surface area as it does not contain any villi or micro-villi & little drug absorption takes place in this region, the large intestine have 2 basic functions as the following

A) For the absorption of water, electrolytes & bile salts which takes place in the proximal part of the large intestine the ascending & transverse colon
B) The storage & elimination of faecal matters which occur in the distal part, the descending colon & the rectum

Now the absorption from the colon is very low as just mentioned & in this region higher viscosity of the content occurs

B) THE GIT COMPONENTS

GI fluid is composed of various components which may affect the drug absorption, some of these are as the following

A) The Bile Salts
B) The Enzymes
C) The Mucin

A) THE BILE SALTS

Being surface active agents, the bile salts enhance the absorption of poorly wettable drugs (hydrophobic drugs) by enhancing their wettability, the dissolution rates of such drugs can be facilitated; for example, When Griseofulvin is taken after meals, its absorption is enhanced, due to the increase of bile salts excretion which promotes the dissolution rate of the drug, In addition generally meals reduce the rate of gastric emptying which decreases the rate of drug absorption without affecting the extend of absorption

On the other hand bile salts were observed to reduce the absorption of certain drugs, through the formation of non-absorable complexes; for example; Aminoglycosides (streptomycin & Kanamycin), neomycin & nystatin form a non-absorable complex with bile salts

B) ENZYMES

Since GIT fluid contains large concentration of enzymes needed for food digestion, it should be expected that some of these enzymes will act on drugs, for example the enzyme Esterase (secreted by pancreas) will hydrolyse a number of ester derivative drugs such as aspirin & propoxyphene in the intestine & also digestive enzymes may break some proteinic like drugs such as protein-insulin

C) MUCIN

This is a viscous muco-polysaccharaide (glycoprotein) that lines the GIT mucosa for protection & lubrication purposes, it may form non-absorable complex with certain drugs for example aminoglycosides, while it may form an ion-pair with certain cationic drugs such as Quaternary Ammonium Compounds leading to their absorption, because mucin it self is holding a negative anionic charges

C) GIT VISCOSITY OR CONSISTENCY

As the drug passes through the GIT, the viscosity or consistency of GIT contents changes from fluid like to semi-solid paste due to the continous absorption of water, So drug particles which have not dissolved for any reason in the stomach or the upper part of the duodenum may encounter a difficulty in their dissolution & hence their absorption, because by increasing the viscosity of the medium absorption will decrease

D) GIT PH

The PH of the GIT varies from PH (1-3) in the stomach to PH (5-8) in the small & large intestines approximately, as always mentioned; the PH at the absorption site is very important for drug absorption, According to the PH partition theory, the un-ionized lipid soluble form can permeate the GIT membrane, Thus weakly acidic drugs such as Sulphonamides, barbiturates & some anti-inflammatory agents (non-steroidal)for example phenyl butazone, salicylates & naproxin are absorbed to a good extent in the stomach, while weakly basic drugs such as anti-histamines (diphenhydramine), anti-depressants (imipramine) & phenothiazines (chlorpromazine) are well absorbed from the small intestine

E) RATE OF GASTRIC EMPTYING

The rate of gastric emptying influences drug absorption to varying extent, depending on the following factors

A) The nature of the drug
B) The mechanism of absorption of the drug
C) The site of release of the drug from the dosage form

A) THE NATURE OF THE DRUG
If the drug is acidic in nature, which is absorbed from the stomach, then any delaying in the gastric emptying will enhance the amount of the drug absorbed; as the resident time of the drug in the stomach is increased, whereas any acceleration or stimulation of gastric emptying may reduce the amount absorbed this is a general sentence because acidic drugs are also absorbed from the small intestine due to the higher surface area cause of the villi, For basic drugs which are mainly absorbed from the small intestine, any delaying in the rate of gastric emptying will delay their arrival to the small intestine & will delay their absorption rates

If the drug is un-stable or degradable in the gastric medium; then any delaying in the rate of gastric emptying will enhance the degradation of such drugs & reduce the amount of drug absorbed, for example the bioavailibility of L-Dopa & Erythromycin (which are degradable in the stomach PH) were observed to be reduced, while any increase in gastric emptying will reduce degradation & hence increase bioavailibility of such drugs

In case of Hydrophobic drugs which are poorly water soluble; then the delaying of gastric emptying will permit a longer contact time of the drug with GIT which will give such drugs enough time to dissolve, also it will permit longer contact of the drug with the bile salts which will enhance the wettability & hence the disssolution rate of such drugs, also longer contact of the drug with the GIT will enhance the absorption of the drug, for example the delaying of gastric emptying (by taking food) were found to enhance the absorption rates of hydrophobic drugs such as griseofulvin & nitrofurantion

B) THE MECHANISM OF ABSORPTION OF THE DRUG
In case of drugs which are absorbed by Active trnasport ( a caarier-mediated form); any delaying of gastric emptying will increase the contact time of such drugs with their aabsorption sirte, where the carrier is concentrated & hence resulting in enhanced drug absorption, The absorption of vitamin B12 (which is actively transported) was found to be enhanced when the drug is taken with viscous fluids or food which will delay the gastric emptying & hence enhance the absorption of the vitamin

C) THE SITE OF RELEASE OF THE DRUG FROM THE DOSAGE FORM
Drugs which are formulated as enteric coated tablets (to control its release) are also effected by rate of gastric emptying, delaying in the rate of gastric emptying will delay the arrival of such enteric coated tablets to the intestines (which is the absorption site for them) so a delay in their absorption will occur, while enhancing the gastric emptying will accelerate the arrival of the enteric coated tablets to the intestine & thus increasing their rate of absorption

NOTE that even the pharmacodynamics of the drug effect the whole absorption mechanism for some drugs which acts locally or at the same time with other drugs like fibers which might decrease the absorption of any general drug or supplement

SOME FACTORS AFFECTING THE RATE OF GASTRIC EMPTYING INCLUDE THE FOLLOWING

A) The type, volume & temperature of food
B) The acidity of the gastric fluid
C) The psychological state of the person
D) Diseases
E) Drugs

A) THE TYPE, VOLUME & TEEMPERATURE OR FOOD
It had been found under experiments that generally the intake of food & viscous fluids retard the rate of gastric emptying & the effect of food type (in retarding gastric emptying) follows the following sequence according to increasing the gastric emptying

Fats> Proteins> Carbohydrates

And that the larger the volume of food or fluids taken; the slower is the gastric emptying, generally warm meals enhance gastric emptying while very hot & very cold meals will retard gastric emptying rate

B) THE ACIDITY OF THE GASTRIC FLUIDS
Generally the rate of gastric emptying is retarded by increasing the aciddity of the stomach, through the intake of lemon or orange juice, while the intake of antacids may enhance the rate of gastric emptying

C) THE PSYCHOLOGICAL STATE OF THE PERSON
It has been observed (experimentally) that mental depression, trauma & brain concusion will retard the rate of gastric emptying, while agitation or excitation enhances the rate of gastric emptying

D) DISEASES
Diseases such as gastric ulcers, hypothyroidism & mental depression were observed to retard gastric emptying, while hyperthyroidism enhances gastric emptying

E) DRUGS
Certain drugs were found to retard gastric emptying through a central mechanism such as the following

A) Anti-cholinergic drugs such as atropine & propantheline
B) Anti-histamines such as chlorpheneramine & diphenhydramine
C) Narcotics such as morphine
D) Major tranquilizers such as chlorpromazine
E) Ethanol

On the other hand, some drugs promote gastric emptying such as the following

A) Cholinergic drugs such as metoclopramide, called plasil
B) Antacids such as magnesium carbonate, magnesium oxide or magnesium trisilicate
C) Drugs which cause local gastrointestinal motility & hence promotes gastric emptying such as chloroquine, metronidazole, nitrofurantoin & aspirin

Some examples showing the effect of some drugs which affects the rate of gastric emptying on the absorrption rate of other co-administered drugs such as the following

A) The absorption rate of paracetamol & ethanol was observed to be reduced when these drugs are separately co-administered with the anti-cholinergic propantheline
B) The absorption rate of paracetamol & ethanol was observed to be enhanced when these drugs are separately co-administered with cholinergic drug metoclopramide
C) Chloroquine was found to enhance the rate of absorption of paracetamol & ampicillin
D) Metronidazole enhances the absorption of ampicillin
E) The amount of absorbed L-Dopa had been found to be enhanced when the drug is co-administered with antacids, this is because antacids enhance gastric emptying hence reducing the resident time of the drug in the stomach (where it is degraded) hence reducing the amount degraded & increasing the absorption

Principles of Gastro-Intestinal Drug Absorption Part 5

Physiological Factors Affecting Drug absorption

Clincal Pharmacy, Biopharmaceutics section

Done By Ismail Mortada

A study in biopharmaceutis dedicated for professionals & students

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التصنيفات : Biopharmaceutical studies | السمات:Biopharmaceutics, drug absorption, GIT absorption, git anatomy, git phsyiology, git structure
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