Factors Affecting Oral Absorption

1. Biological factors2. Physiological factors3. Physico-chemical factors4. Pharmaceutical factors

ByDeepak Kumar, M-Pharm(AACP)

(Pharmaceutics).

Biological Factors:-a. Penetration of drugs through the GIT.b. Penetration of drug through the blood brain

barrier.c. Penetration of drug through the placental

barrier.d. Penetration of drug through the skin.e. Penetration of the drug through the eyes.f. Penetration of drugs from the mucous

membrane.

Overall picture of drug absorption, distribution, and elimination

a)Penetration of drug through the GIT:-

1.The GI mucosa,is a semipermeable membrane,across which transport of various nutrients as well as substances foreign to the body takes place.

2.These compounds are normally absorbed across this membrane into the blood by- Passive diffusion

Active diffusion Pore transport Pinocytosis,etc

b)Penetration of drug through the blood brain barrier:-

1. BBB is a sheath of endothelial cells lining the capillaries.2. Penetration of drugs depends on-size of molecules,lipid solubility.3. Highly lipid soluble drugs like thiopental,reach the brain very soon.4. Rate of penetration is proportional to the size of the molecule. ex-Insulin penetrates slowly,urea penetrate rapidly.

Blood brain barrier:-

Example:-

c)Penetration of drug through the placental barrier:-

1.Placenta is the membrane separating foetal blood from the maternal blood.2.Passage of drugs occur by -simple diffusion -Active transport -Pinocytosis -Filtration Examples,of drugs of moderate to high lipid solubility are sulphonamides, barbiturates,anticonvulsants,narcotic analgesics,antibiotics & steroids.

Placental Barrier

d)Penetration of drugs across the skin:- A) Through epidermis(Trans-epithelial absorption) Layers of epidermis:-

-Basal layer-Prickle cell layer-Granular layer-Horny layer / stratum corneum

=Absorption of a drug is proportional to be lipid solubility,since the epidermis behaves as a lipid barrier,the mechanism of absorption being passive diffusion.

=Absorption through skin could be enhanced by:- 1)Innuction 2)Iontophoresis 3)Sonophoresis 4)Magnetophoresis.1)Innuction-It involves suspending the drug in an oilly vehicle and rubbing

the resulting preparation on the axis.2)Iontophoresis- Transfer of drugs that ionize |Transfering of positively charged drug across the skin,an anode is placed in

contact with the drug dissolution |voltage is applied

+vely charged drugs repell from anode |

Penetrates through the skinSystemic circulation

B) Via the hair follicles (Pilosebaceous absorption) Factors affecting percutaneous absorption:-

1)Thickness of horny layer - The horny layer is thickest on the palms and soles and thinnest on the face.

2)Skin condition - Permeability of the skin is affected by age,disease state,climate and injury.

3)Hydration of skin - Hydration of the skin by use of wetting agent or occlusion promotes drug absorption.

4)Skin temperature - The permeability of drugs increases with increase in skin temperature.

5)Chemical form of the drug and the vehicle - Fluocinolone acetonide which when used topically is over 100 times as active as hydrocortisone and is useful for treating psoriasis.

6)Incorporation of permeation enhancers - Dimethyl sulphoxide,a surfectantwhich is miscible with water as well as organic solvents enhances percutaneous absorption of drug.

3)Sonophoresis- This makes use of sound waves to enhance the penetration.

4)Magnetophoresis- It involves the application of magnetic field and enhancing the absorption of drugs.

e)Penetration across the eyes :-->The cornea,lens and vitreous body of the eye are all transparent media with no blood

vessels . Oxygen and nutrients are transported to these non vascular tissues by the aqueous humour which has a high oxygen tension and same osmotic pressure as blood.

->The intraocular bioavailability of topically applied drugs is extremely poor due to - presence of lachrymal fluids in the cul-de-sac

- nasolacrimal drainage - interaction of drugs by other substances->Penetration depends upon the polarity of the vehicle Ex-Absorption of dexamethasone from acetate buffer is faster than from phosphate buffer which is more polar.

f)Penetration through the mucous membrane:-

->The mucous membrane is generally highly vascular in nature.The barrier for drug absorption is the capillary endothelial cell membrane which is lipoidal and consists of pores.Thus,lipid soluble drugs can easily penetrate by the process of diffusion and small drug molecules can penetrate by pore transport.

REFERENCES:-

Textbook of BIOPHARMACEUTICS & PHARMACOKINETICS(Dr.Shobha Rani).

BIOPHARMACEUTICS & PHARMACOKINETICS(F.V.Manvi, K.Nanjwade,K.Patel)

Physiological Factors Affecting Oral Absorption.Article by- A. S. Adebayo, Ph.D

Kulkarni

Questions:-

1.Discuss in detail the biological factors of drug absorption?(10,20 Marks)

2.With the help of a neat labelled diagram explain the Blood Brain Barrier?(10 Marks)

3.How can the penetration of the drugs through the skin can be enhanced?(5 Marks)

4.What factors affect absorption of drugs through the skin?(5 Marks)

***END OF PRESENTATION***

THANK YOU

Physiological Factors:-

a. Patient factorsb. Gastrointestinal physiologyc. pH of Gastrointestinal tractd. Presystemic Metabolisme. Absorption sitesf. Protein Bindingg. Gastrointestinal Transith. Circadium Rhythm

1)Age:- Absorption,distribution,metabolism and elimination decline with age. On the otherhand young children may not absorb some drugs as

systems are not developed.

2)Sex:- In pregnancy the total body water increases(6-8 L);secondly variations in hormones,weight distribution may have direct or indirect effect on

drug distribution.During the luteal phase of the menstrual cycle and during pregnancy when progesterone levels are high there is a

delay in GI transit.

3)Body weight:- Whether the body weight is lean body mass or fat mass significantly affects drug distribution.Patient with smaller volumes of body fluids and of lighter weight usually have higher blood drug levels.

4)Activity and Posture:- The activity and posture dependent changes in plasma volume or blood flow rate may show variation in pharmacokinetics of certain drugs.

.

a)Patient Factors:-

Continued:-

5)Food:- Absorption is maximum from the empty stomach.Food reduces rate of absorption of drug but doesnot changes the extent of absorption.ex-Aspirin,acetaminophen,phenobarbital sodium and rifampin.In fasted state the volume of fluid is low.So,a meal can rise ph

to 3-Milk to-6.

6)Medicines:- Any drug that influences the rate of gastric emptying can change drug absorption.The increase in gastric pH may

increase the solubility of acidic drugs and decrease the solubility of basic drugs.

7)Disease conditions:- GI secretions and GI transit differ during different disease like-GI ulcer,acidity,diarrhoea,constipation. Aspirin and paracetamol have good absorption from small intenstine

b)Gastrointestinal physiology:-Characteristics of G.I physiology :-

pH Membrane Blood Supply Surface Area Transit Time By-pass liver

BUCCAL approx 7 Thin Good, fast absorption with low

dose

small Short unless controlled

Yes

ESOPHAGUS 5 - 6 Very thick, no absorption

- small Short -

STOMACH 1 - 3 Normal good small 30 - 40 minutes, reduced

absorption

no

DUODENUM 6 - 6.5 Normal good very large very short (6" long),

window effect

no

SMALL INTESTINE

7 – 8 Normal good very large 10 - 14 ft, 80 cm 2 /cm

about 3 hours no

LARGEINTESTINE

5.5 - 7 - good not very large 4 - 5 ft

long, up to 24 hr lower colon

Gastrointestinal Physiology:-

c)Gastrointestinal pH:- Average pH values at different locations in GIT:-

GI fluid pH influence drug absorption in a several ways:-

1.Disintegration-With enteric coated formulations,the coat dissolves in the intestine followed by disintegration of the tablet.

2.Dissolution- A pH that favours formation of salts of the drug enhances the dissolution.

3.Absorption- Depending upon the drug pKa and whether it is an acidic or basic drug the GI pH influence drug absorption by determining the amount of drug that would exist in unionized form at the site of absorption.

4.Stability- Stomach pH->Acidic->Degradation of penicillinG & erythromycin

Location Average pH in fasted stage Average pH in the fed state

1.Stomach 1.3 4.9

2.Duodenum 6.5 5.5

3.Jejunum 6.6 5.2-6.0

4.Ileum 7.4 7.5

d)Presystemic Metabolism:- For drugs administered orally,two main reasons for its decreased

bio-availability are- 1.Decreased absorption 2.Pre-systemic metabolism/First-pass

effect.

->Presystemic metabolism of drug can occur in GIT or in membrane.

->The loss of drug through biotransformation by such eliminating organs during its passage to systemic circulation is called as first pass/pre-systemic metabolism.

->The four primary systems which affect pre-systemic metabolism of the drug are:-

1.Luminal enzymes2.Gut wall enzymes/mucosal enzymes3.Bacterial enzymes4.Hepatic enzymes

->If a drug is subject to rapid metabolism in liver,then a reduced absorbed dose reaches in blood circulation.

e)Absorption sites:-

Drugs are having a particular site for maximum absorption.The following table summarizes the comparative drug absorption from different regions of GI tract.

Drug Stomach Jejunum Ileum Colon

Furosemide **** - ** *

Isradipine ** ** **** ****

Nifedipine ** ** - ****

Omeprazole - * ** ***

Phenytoin - * ** ***

Theophylline *** ** - **

f)Protein binding:-

->The drug bound to the proteins in blood(plasma),membranes or tissues is difficult to diffuse,absorb,reach to the site of action and interact with receptors.

->The rate of biotransformation and elimination are also decreased because of protein binding.

->The protein binding is usually reversible and it releases drug from the protein until drug in the extravascular water equilibrates with free drug in the plasma.

->Binding may be competitive where one drug displaces another drug,eg-aspirin dispalces penicilin.

->Infants and adults show difference in plasma protein binding and tissue binding of drugs,eg- Local Anesthetics

Sulfaphenazole-> Albumin is the main component ,which binds to a wide variety of drugs.

g)Gastrointestinal Transit:-

->Apart from dissolution of drug and its penetration through the biomembrane, passage from stomach to small intestine called as gastric emptying.

->Rapid gastric emptying is advisable where, 1) Rapid onset of action is desired. 2) Dissolution of drugs require in the intestine. 3) The drugs are not stable in gastric fluids.ex-penicillinG and erythromycin. 4) The drug is best absorbed from the distal part of the small intestine.

->Delayed gastric emptying is recommended in particular where, 1)Food promotes drug dissolution and absorption. ex-Griseofulvin. 2)Disintegration and dissolution of dosage form is promoted by gastric

fluids. 3)The drugs dissolve slowly. ex-Griseofulvin. 4)The drug irritating gastric mucosa. ex-aspirin,nitrofurantoin. 5)The drugs are absorbed from the proximal part of the small intestine and

prolong drug absorption site contact is desired.ex-vit-B12,C.

Factors Affecting Gastric Emptying :-

Volume of Ingested Material As volume increases initially an increase then a decrease. Bulky material tends to

empty more slowly than liquids

Type of Meal

Fatty food Decrease

Carbohydrate Decrease

Temperature of Food Increase in temperature, increase in emptying rate

Body Position Lying on the left side decreases emptying rate. Standing versus lying

(delayed)

Drugs

Anticholinergics (e.g. atropine) Decrease

Narcotic (e.g. morphine) Decrease

Analgesic (e.g. aspirin) Decrease

Parameters used to quantify gastric emptying:-

1)Gastric emptying rate:- Speed at which the stomach contents move into intestine.

2)Gastric emptying time:- It is the time required for the gastric content to empty into the intestine.

3)Gastric emptying:- It is the time taken for half the stomach to emptying Drugs affecting Gastric Emptying time:-

Decrease gastric emptying rate Increase gastric emptying rate Antihistamines Anticholinesterases Antimuscarenic drugs -Atropine,Propantheline -Neostigmine -Phyostigmine Ganglion blocking drugs Dopamine antagonists - Hexamethonium - Domperidone Opiod analgesics - Metoclopramide - Diamorphine,Morphine Iproniazid Reserpine Sodium bicarbonate Phenothiazines Sympathomimetics - Isoprenaline

h)Circadium Rhythm:-

-> The functions of body including body secretions and pharmacokinetics display its own time schedule per day and over entire life period,called as circadium rhythm.

->Diseases such as bronchitis,ischemic heart attacks,allergic conditions(asthma attack),rheumatoid arthritis display circadium dependent symptoms in early morning hours

->Acidity gradually increases from 4pm and it is max at midnight.Patients suffering from sleeping disorders need second dose at around 2am. ->NSAID,theophylline,nifedipine,oral nitrates and propranolol have been reported to have higher Cmax and shorter Tmax when administered in the morning than evening.

->It was correlated with the faster gastric emptying which carry drug to efficient absorption sites of small intestine .

REFERENCES:-

Textbook of BIOPHARMACEUTICS & PHARMACOKINETICS(Dr.Shobha Rani).

BIOPHARMACEUTICS & PHARMACOKINETICS(F.V.Manvi, K.Nanjwade,K.Patel)

Physiological Factors Affecting Oral Absorption.Article by- A. S. Adebayo, Ph.D

Kulkarni

Questions:-

1.Discuss in detail the physiological factors of drug absorption?(10,20 Marks)

2.What is gastric emptying?In which condition rapid and delayed gastric emptying is advisable?(10 Marks)

***END OF PRESENTATION***

THANK YOU