JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD Pharm. D IV Year BIOPHARMACEUTICS AND PHARMACOKINETICS Previous Question Paper (April/May - 2019 - R08)

Patient-related factors significantly influence the oral absorption of drugs by altering the physiological, pathological, and biochemical environment of the gastrointestinal tract (GIT). These factors can be categorized as follows:

1. Age: Physiological changes across the lifespan affect absorption. In neonates, gastric pH is higher (less acidic), which decreases the absorption of acidic drugs but increases the absorption of acid-labile drugs. In the elderly, reduced gastric acid secretion, decreased gastric emptying rate, and reduced intestinal blood flow can delay or decrease the extent of drug absorption.
2. Gastric Emptying Rate: The rate at which the stomach empties into the small intestine is a critical determinant. Since the small intestine is the primary site of absorption due to its large surface area, rapid gastric emptying generally leads to faster drug absorption. Factors like food, posture, and drugs (e.g., metoclopramide vs. propantheline) significantly alter this rate.
3. Intestinal Transit Time: The duration a drug remains in the small intestine affects the extent of absorption. If transit is too rapid, as in cases of diarrhea, the drug may not have sufficient time to be absorbed, leading to reduced bioavailability.
4. Gastrointestinal pH: The pH of the GIT varies from the stomach (pH 1-3) to the colon (pH 7-8). According to the pH-partition hypothesis, drugs are absorbed primarily in their non-ionized form. Changes in pH due to disease or diet can shift the ionization state of weak acids or bases, thereby affecting their membrane permeability.
5. Pathological Conditions: Gastrointestinal diseases such as Crohn's disease, celiac disease, or achlorhydria can alter the mucosal surface area, permeability, and transit time. Furthermore, conditions like congestive heart failure can reduce splanchnic blood flow, limiting the transport of absorbed drugs away from the site of absorption.
6. Presence of Food: Food can affect absorption through various mechanisms: delaying gastric emptying, altering GI pH, increasing bile secretion (which aids the dissolution of lipophilic drugs), or forming non-absorbable complexes with the drug (e.g., tetracyclines with calcium).
7. First-Pass Metabolism: The extent to which a drug is metabolized by enzymes in the gut wall (e.g., CYP3A4) or the liver before reaching systemic circulation directly impacts the final bioavailability of the administered dose.

Drug distribution is the reversible transfer of a drug between the blood and the extravascular fluids and tissues of the body. The extent and rate of distribution are influenced by several physiological and physicochemical factors:

1. Physicochemical Properties of the Drug:

Lipophilicity is a primary determinant; highly lipophilic drugs easily cross cell membranes via passive diffusion, leading to extensive tissue distribution. Molecular size also plays a role, as smaller molecules diffuse more rapidly. Furthermore, the degree of ionization at physiological pH dictates distribution, as only the unionized form of a drug can readily permeate lipid membranes.

2. Physiological Factors:

Blood flow (perfusion) is critical; organs with high blood flow, such as the heart, liver, kidneys, and brain, receive the drug rapidly (the perfusion-limited model). Conversely, poorly perfused tissues like adipose tissue or resting skeletal muscle exhibit slower distribution. Capillary permeability also varies; for example, the blood-brain barrier is highly restrictive due to tight junctions, whereas liver sinusoids are highly permeable.

3. Plasma Protein Binding:

Drugs bind to plasma proteins like albumin (for acidic drugs) and alpha-1-acid glycoprotein (for basic drugs). Only the free, unbound fraction of the drug is pharmacologically active and capable of crossing membranes. High protein binding acts as a reservoir, limiting the volume of distribution and slowing the elimination process.

4. Tissue Binding and Affinity:

Certain drugs show high affinity for specific tissues, leading to accumulation. For example, tetracyclines have a high affinity for bone and teeth, while chloroquine accumulates in the liver and retina. This binding can result in a large apparent volume of distribution.

5. Disease States:

Pathological conditions significantly alter distribution. Hypoalbuminemia (due to liver disease or malnutrition) reduces protein binding, increasing the free drug fraction. Renal failure can alter membrane permeability and fluid balance, while congestive heart failure reduces cardiac output, thereby decreasing blood flow to peripheral tissues and limiting drug delivery.

6. Age and Body Composition:

Neonates have a higher percentage of total body water and lower body fat compared to adults, which affects the distribution of water-soluble and lipid-soluble drugs, respectively. In elderly patients, changes in body composition and reduced plasma protein levels often necessitate dosage adjustments.