PATIENT RELATED FACTORS AFFECTING ON DRUG ABSORPTION

Physiologic Factors Related to Drug Absorption:  

The systemic absorption of a drug is dependent on  

1. The physicochemical properties of the drug,  
2. The nature of the drug product, and  
3. The anatomy and physiology of the drug absorption site. 

1. Membrane Physiology

A. Nature of Cell Membrane 

• The fluid mosaic model, proposed by , explains the transcellular diffusion of polar molecules.  
• According to this model, the cell membrane consists of globular proteins embedded in a dynamic fluid, lipid bilayer matrix.
• These proteins provide a pathway for the selective transfer of certain polar molecules and charged ions through the lipid barrier. 
• As shown in , transmembrane proteins are interdispersed throughout the membrane. Two types of pores of about 10 nm and 50 to 70 nma were inferred to be present in membranes based on capillary membrane transport studies. These small pores provide a channel through which water, ions, and dissolved solutes such as urea may move across the membrane.

B. Trasport Processes 

i. Passive Diffusion:

• lipophilic drug may pass through the cell or go around it. If the drug has a low molecular weight and is lipophilic, the lipid cell membrane is not a barrier to drug diffusion and absorption. 
• Passive diffusion is the process by which molecules spontaneously diffuse from a region of higher concentration to a region of lower concentration. This process is passive because no external energy is expended. 

ii. Carrier-Mediated Transport:

• Theoretically, a lipophilic drug may pass through the cell or go around it. If the drug has a low molecular weight and is lipophilic, the lipid cell membrane is not a barrier to drug diffusion and absorption. 
• In the intestine, drugs and other molecules can go through the intestinal epithelial cells by either diffusion or a carrier-mediated mechanism. Numerous specialized carrier-mediated transport systems are present in the body, especially in the intestine for the absorption of ions and nutrients required by the body. 

iii. Active Transport 

• Active transport is a carrier-mediated transmembrane process that plays an important role in the gastrointestinal absorption and in renal and biliary secretion of many drugs and metabolites. 
• A few lipid-insoluble drugs that resemble natural physiologic metabolites (such as 5-fluorouracil) are absorbed from the gastrointestinal tract by this process. Active transport is characterized by the transport of drug against a concentration gradient—that is, from regions of low drug concentrations to regions of high concentrations. 
• Therefore, this is an energy-consuming system. In addition, active transport is a specialized process requiring a carrier that binds the drug to form a carrier–drug complex that shuttles the drug across the membrane and then dissociates the drug on the other side of the membrane

iv. Vesicular Transport 

• An example of exocytosis is the transport of a protein such as insulin from insulin-producing cells of the pancreas into the extracellular space. The insulin molecules are first packaged into intracellular vesicles, which then fuse with the plasma membrane to release the insulin outside the cell. 

v. Pore (Convective) Transport

• Very small molecules (such as urea, water, and sugars) are able to cross cell membranes rapidly, as if the membrane contained channels or pores. Although such pores have never been directly observed by microscopy, the model of drug permeation through aqueous pores is used to explain renal excretion of drugs and the uptake of drugs into the liver. 

vi. Ion-Pair Formation

• Strong electrolyte drugs are highly ionized or charged molecules, such as quaternary nitrogen compounds with extreme pKa values. Strong electrolyte drugs maintain their charge at all physiologic pH values and penetrate membranes poorly. When the ionized drug is linked up with an oppositely charged ion, an ion pair is formed in which the overall charge of the pair is neutral. This neutral drug complex diffuses more easily across the membrane.  
• For example, the formation of ion pairs to facilitate drug absorption has been demonstrated for propranolol, a basic drug that forms an ion pair with oleic acid, and quinine, which forms ion pair with hexylsalicylate 

2. Gastro-Intestinal Physiology

A. Gastric emptying rate:-

• Anatomically, a swallowed drug rapidly reaches the stomach.  
• Eventually, the stomach empties its contents into the small intestine. Because the duodenum has the greatest capacity for the absorption of drugs from the GI tract, a delay in the gastric emptying time for the drug to reach the duodenum will slow the rate and possibly the extent of drug absorption, thereby prolonging the onset time for the drug.  
• Some drugs, such as penicillin, are unstable in acid and decompose if stomach emptying is delayed. Other drugs, such as aspirin, may irritate the gastric mucosa during prolonged contact. 
• Gastric emptying rate is faster in case of solution & suspensions than solid & nondisintegrating dosage forms. 
• Factors that influence gastric emptying rate are: - 

• Volume of meal 
• Composition of meal 
• Physical state and viscosity of meal 
• Temperature of meal 
• Gastrointestinal pH 
• Electrolyte and osmotic pressure 
• Body posture 
• Emotional state 
• Disease state. 

 B. Intestinal motility: - 

• Normal peristaltic movements mix the contents of the duodenum, bringing the drug particles into intimate contact with the intestinal mucosal cells. 
• The drug must have a sufficient time (residence time) at the absorption site for optimum absorption. In the case of high motility in the intestinal tract, as in diarrhea, the drug has a very brief residence time and less opportunity for adequate absorption. 

C. Drug stability in GIT: - 

• Metabolism or degradation by enzymes or chemical hydrolysis may adversely affect the drug absorption and thus reduces B.A. 
• Destruction in gastric acid. 
• Generally a problem with orally administered drugs. 

 D. Intestinal transit: - 

• Long intestinal transit time is desirable for complete absorption of drug e.g. for enteric coated formulation & for drugs absorbed from specific sites in the intestine.
• Peristaltic contraction promotes drug absorption by increasing the drug membrane contact and by enhancing dissolution especially of poorly soluble drugs.
• Influenced by food, disease and drugs. e.g. metoclopramide which promotes 
• intestinal transit &thus enhance absorption of rapidly soluble drugs while anticholinergic retards intestinal transit and promotes the absorption of poorly soluble drugs. 

 E. Blood flow to GIT:  

• Once the drug is absorbed from the small intestine, it enters via the mesenteric vessels to the hepatic-portal vein and the liver prior to reaching the systemic circulation. Any decrease in mesenteric blood flow, as in the case of congestive heart failure, will decrease the rate of drug removal from the intestinal tract, thereby reducing the rate of drug bioavailability. 
• GIT has higher perfusion rate because it is extensively supplied by blood capillary network. 
• Therefore help in maintaining sink conditions &concentration gradient for drug absorption by rapidly removing of drug from site of action.
• Blood flow is imp for actively absorption of drugs.
• Highly permeable drugs or drugs that absorbed through pores –GI perfusion is rate limiting while the drugs with poor permeability GI perfusion is not imp.
• Perfusion increases after meals & persist for few hours but absorption is not affected. 

F. Effect of Food

• The presence of food in the GI tract can affect the bioavailability of the drug from an oral drug product. Digested foods contain amino acids, fatty acids, and many nutrients that may affect intestinal pH and solubility of drugs. The effects of food are not always predictable and can have clinically significant consequences. Some effects of food on the bioavailability of a drug from a drug product include:
• Delay in gastric emptying
• Stimulation of bile flow 
• A change in the pH of the GI tract
• An increase in splanchnic blood flow 
• A change luminal metabolism of the drug substance
• Physical or chemical interaction of the meal with the drug product or drug substance
• The absorption of some antibiotics, such as penicillin and tetracycline, is decreased with food; whereas other drugs, particularly lipid-soluble drugs such as griseofulvin and metazalone, are better absorbed when given with food containing a high fat content.
• Propranolol plasma concentrations are larger after food than in fasted subjects. This may be an interaction with the components of food. 

G. pH and surface area of GIT: 

3. Age

In infants, the gastric pH is high and intestinal surface and blood flow to the GIT is low resulting in altered absorption pattern in comparison to adults. 

In elderly persons, causes of impaired drug absorption include altered gastric emptying, decreased intestinal surface area and GI blood flow, higher incidents of achlorhydria and bacterial over growth in small intestine.

A. Clinical Factors:- 

i. Diseases 

• Parkinson's disease may have difficulty swallowing and greatly diminished gastrointestinal motility. A case was reported in which the patient could not be controlled with regular oral levodopa medication because of poor absorption. Infusion of oral levodopa solution using a j-tube gave adequate control of his symptom. 
• Patients on tricyclic antidepressants (imiprimine, amitriptyline, and nortriptyline) and antipsychotic drugs (phenothiazines) with anticholinergic side effects may have reduced gastrointestinal motility or even intestinal obstructions. Delays in drug absorption, especially with slow-release products, have occurred. 
• Achlorhydricpatients may not have adequate production of acids in the stomach; stomach HCl is essential for solubilizing insoluble free bases. Many weak-base drugs that cannot form soluble salts will remain undissolved in the stomach when there is no hydrochloric acid present and are therefore unabsorbed. Salt forms of these drugs cannot be prepared because the free base readily precipitates out due to the weak basicity. 
• Dapsone, itraconazole, and ketoconazole may also be less well absorbed in the presence of achlorhydria. In patients with acid reflux disorders, proton pump inhibitors, such as omeprazole, render the stomach achlorhydric, which may also affect drug absorption. Co-administering orange juice, colas, or other acidic beverages can facilitate the absorption of some medications requiring an acidic environment. 
• HIV-AIDS patients are prone to a number of gastrointestinal (GI) disturbances, such as increased gastric transit time, diarrhea, and achlorhydria. Rapid gastric transit time and diarrhea can alter the absorption of orally administered drugs. Achlorhydria may or may not decrease absorption, depending on the acidity needed for absorption of a specific drug. Indinavir
• for example, requires a normal acidic environment for absorption. The therapeutic window of indinavir is extremely narrow, so optimal serum concentrations are critical for this drug to be efficacious.
• Congestive heart failure (CHF) patients with persistent edema have reduced splanchnic blood flow and develop edema in the bowel wall. In addition, intestinal motility is slowed. The reduced blood flow to the intestine and reduced intestinal motility results in a decrease in drug absorption. For example, furosemide (Lasix), a commonly used loop diuretic, has erratic and reduced oral absorption in patients with CHF and a delay in the onset of action.
• Crohn's disease is an inflammatory disease of the distal small intestine and colon. The disease is accompanied by regions of thickening of the bowel wall, overgrowth of anaerobic bacteria, and sometimes obstruction and deterioration of the bowel. The effect on drug absorption is unpredictable, although impaired absorption may potentially occur because of reduced surface area and thicker gut wall for diffusion.

ii. Drugs

• Anticholinergic drugs in general may reduce stomach acid secretion. Propantheline bromide is an anticholinergic drug that may slow stomach emptying and motility of the small intestine. Tricyclic antidepressants and phenothiazines also have anticholinergic side effects that may cause slower peristalsis in the GI tract. 
• Slower stomach emptying may cause delay in drug absorption.
• Metoclopramide is a drug that stimulates stomach contraction, relaxes the pyloric sphincter, and, in general, increases intestinal peristalsis, which may reduce the effective time for the absorption of some drugs and thereby reduce the peak drug concentration and the time to reach peak drug concentration. For example, digoxin absorption from a tablet is reduced by metoclopramide but increased by an anticholinergic drug, such as propantheline bromide. Allowing more time in the stomach for the tablet to dissolve generally helps with the dissolution and absorption of a poorly soluble drug, but would not be helpful for a drug that is not soluble in stomach acid.
• Antacids should not be given with cimetidine, because antacids may reduce drug absorption. Antacids containing aluminum, calcium, or magnesium may complex with drugs such as tetracycline, ciprofloxacin, and indinavir, resulting in a decrease in drug absorption. To avoid this interaction, antacids should be taken 2 hours before or 6 hours after drug administration. As mentioned, proton pump inhibitors, such as omeprazole, render the stomach achlorhydric, which may also affect drug absorption.
• Cholestyramine is a nonabsorbable ion-exchange resin for the treatment of hyperlipemia. Cholestyramine adsorbs warfarin, thyroxine, and loperamide, similar to activated charcoal, thereby reducing absorption of these drugs. 
• Absorption of calcium in the duodenum is an active process facilitated by vitamin D, with calcium absorption as much as four times more than that in vitamin D deficiency states. It is believed that a calcium-binding protein, which increases after vitamin D administration, binds calcium in the intestinal cell and transfers it out of the base of the cell to the blood circulation.