Pharmacokinetics - Drug Absorption & Distribution PDF

Patients related factors by oral route e) Gastric emptying time ↑gastric emptying time → ↓ rate of absorption food & Drugs Metoclopramide increases gastric motility and accelerates gastric emptying and hence aid in rapid absorption While fatty meal, antimotility drugs (Atropine), exercise & stress c...

Patients related factors by oral route e) Gastric emptying time ↑gastric emptying time → ↓ rate of absorption food & Drugs Metoclopramide increases gastric motility and accelerates gastric emptying and hence aid in rapid absorption While fatty meal, antimotility drugs (Atropine), exercise & stress can slow gastric emptying and delay the rate of absorption and onset of action f) Destruction of drug in GIT • Benzyl penicillin is destroyed by gastric HCL • Insulin is destroyed by proteolytic enzymes Patients related factors by oral route (g) Nature of drug & pH of the media (GIT) ▪ Acidic drug in acidic pH more absorption (in Stomach) ▪ Acidic drug in alkaline pH less absorption (in intestine) ▪ Basic drug in acidic pH less absorption (in stomach) ▪ Basic drug in acidic pH less absorption (in stomach) (h) First-pass metabolism / pre-systemic elimination ↑first pass metabolism-----------↓ absorption and BA Factor affecting absorption form parenteral site (Except I/V): i. Site of injection: I/M→ more absorption S/C→ Less than i/m. ii. Blood flow to absorptive area Muscle (I/M) → more absorption Sub cutaneous tissue (s/c) → Less absorption. iii. Formulation: SR formulation → Slow absorption Aqueous solution → Rapidly absorption. V. Torniquet →↓ Blood supply →↓ absorption VI. Application of heat message →↑ Blood flow →↑ absorption. Drug Absorption - Summary ▪ Most drug absorption occurs through passive absorption ▪ Lipid soluble drugs are more readily absorbed than non-lipid soluble drugs ▪ Non-polar drugs are more readily absorbed than polar drugs ▪ Non-ionized drugs are more readily absorbed than ionized drugs ▪ Basic drugs are more readily absorbed in the small intestine than acid drugs; acid drugs in the stomach ▪ Overall, the majority of drug absorption occurs in the small intestine, especially the duodenum Distribution Drug distribution is the process by which a drug reversibly leaves the blood stream and enters into interstitium (ECF)&/or the cell of the tissues. ▪ Distribution is represented by a parameter called apparent volume of distribution (Vd) Major compartment of distribution A. Fluid compartment (70%) Plasma compartment, ECF, Total body water/TBW B. Solid compartment (30%) Bone, Muscle, Fat (25% of TBW) Volume of Distribution (Vd) • Vd /apparent Vd is defined as the (theoretical) volume that would contain the total body content of the drug (Q) at a concentration (C) equal to that present in the blood, plasma etc. Vd = Q/C • It is expressed in units of l/ kg or l/ 70 kg • Small Vd indicates that the drug is present mostly in vascular compartment. Eg. Warfarin – 10 l / 70 kg • Large Vd indicates that the drug is distributed more into the tissues or extravascular compartment. Eg. Chloroquine - 13,000 l/70 kg, Erythromycin - 55 l/70 kg Factors affecting drug distribution a) Lipid solubility of drugs Drugs with high lipid solubility → widely distributed in the body (High Vd) b) Ionization at physiological pH Polar/ionized drug – less lipid solubility – extracellular distribution Nonpolar/unionized drug – high lipid solubility – intracellular distribution c) Plasma protein binding Plasma protein that are responsible for drug binding: Albumin: Usually binds with acidic drugs e.g. phenytoin, Warfarrin α1 glycoprotein: Usually binds with basic drugs e.g. Prazosin, Verapamil. Other special Plasma proteins: Thyroid binding globulin (TBG) Corticosteroid binding globulin (CBG) Plasma protein binding ▪ Protein bound drug are inactive & acts as reservoir. ▪ They are not responsible for the pharmacological actions of drug ▪ Sustain and long duration of action ▪ Produces prolong toxic action ▪ No biotransformation ▪ No excretion ▪ Important in drug interaction. Factors affecting drug distribution d) Tissue protein binding (storage of drugs in tissues) ▪ Many drugs accumulate in tissues (by binding to proteins) than in extracellular fluids (high Vd). ▪ Acts as reservoir – slowly released into blood as concentration falls & produce prolong effects. ▪ For example Chloroquine: Liver and retina Digoxin, Chloroquine: Kidney Tetracyclines: Bone & teeth Lipid soluble drugs (Thiopentone): Adipose tissue Factors affecting drug distribution f) Capillary permeability In liver and spleen: endothelial cells have high intercellular pores, through which even large plasma protein can pass; as a result majority of drugs enter liver and spleen Factors affecting drug distribution Blood Brain Barrier (BBB) In brain: Capillary endothelium is continuous with tight junctions; as a result all the drugs can not enter the brain(restricted entry) ▪ This barrier restricts the entry of water soluble / lipid insoluble drugs like streptomycin, neostigmine, etc ▪ Highly lipid soluble drugs can easily crosses BBB & enter CNS. Eg: Thiopentone Factors affecting drug distribution Passage across placenta ▪ Lipid soluble drugs can easily cross placental membranes whereas polar/water soluble drugs poorly cross placental membrane. ▪ However, placental barrier is incomplete compared to BBB. - Water soluble drugs at high concentration can crosses placental barrier & enter into fetal circulation - Drugs which enter into fetal circulation can produce adverse effects on growing fetus or newborns (teratogenicity). ▪ Care should be exercised while prescribing drugs to pregnant women.