Pharmacokinetics: Membrane Transport and Drug Absorption

This lecture covers the principles of pharmacokinetics with a focus on membrane transport and drug absorption. It aligns with CBME guidelines of the NMC and includes essential concepts frequently tested in past year questions (PYQs) and NEET PG exams, providing a strong foundation for understanding drug behavior.

1. Pharmacokinetics: Membrane Transport Dr. Shivankan Kakkar , MD

2. Introduction to Pharmacokinetics Pharmacokinetics : The quantitative study of drug movement in, through, and out of the body. Key Concept : The intensity of drug response is linked to the concentration of the drug at the site of action , which depends on pharmacokinetics. Pharmacokinetic Properties Determine : Route of administration Dose and frequency Latency of onset Time to peak action Duration of action Dr. Shivankan Kakkar, MD 2

3. Dr. Shivankan Kakkar, MD 3 Pharmacokinetics Includes: (Mnemonic: ADME ) A bsorption D istribution M etabolism E xcretion Note: Some scientists prefer to include D issolution of drugs in pharmacokinetics, referred to as DADME .  

4. Biological Membranes – Structure Membrane Composition : Phospholipid Bilayer (~100 Å thick) Polar heads on the surface , nonpolar hydrocarbon chains in the core Cholesterol molecules interspersed within the bilayer Proteins in Membrane : Intrinsic proteins span the full membrane thickness Extrinsic proteins are adsorbed on the surface Glycoproteins or glycolipids attach to sugars/sialic acids Dr. Shivankan Kakkar, MD 4

5. Membrane Properties and Dynamics Membrane Properties : High electrical resistance and relative impermeability to most substances Dynamic Structure : Proteins and lipids can move laterally within the membrane Protein Functions : Form aqueous pores , act as carriers , enzymes , or receptors Enable signal transduction and specialized transport functions Dr. Shivankan Kakkar, MD 5

6. Drug Transport Across Membranes Transport Mechanisms : Passive Diffusion : Drug moves down concentration gradient Filtration : Movement through aqueous pores or between cells (paracellular) Specialized Transport : Carrier transport – Facilitated Diffusion & Active transport Vesicular transport – Endocytosis & Exocytosis Significance : All pharmacokinetic processes involve crossing these biological membranes. Dr. Shivankan Kakkar, MD 6 Most Common Drugs Absorbed by Active Transport Levodopa α-Methyldopa NEET PG

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8. Passive Diffusion in Drug Transport Definition : Passive diffusion is the process where drugs diffuse across a membrane from high to low concentration without active participation from the membrane . Importance : This mechanism is crucial for the majority of drugs (xenobiotics), as the body develops specialized mechanisms for normal metabolites . Dr. Shivankan Kakkar, MD 8

9. Mechanism of Lipid-Soluble Drug Diffusion Lipid Solubility : Lipid-soluble drugs diffuse by dissolving in the lipoidal matrix of membranes. The rate of transport is proportional to the lipid : water partition coefficient . Key Example : A drug with higher lipid solubility achieves a higher concentration in the membrane and diffuses more quickly. Important Point : The greater the concentration difference across the membrane, the faster the diffusion occurs. Dr. Shivankan Kakkar, MD 9

10. Influence of pH on Drug Ionization Weak Electrolytes : Most drugs are weak electrolytes ; their ionization is pH dependent . Ionization Equation : The ionization of a weak acid (HA) can be described as: log [A¯]/[HA]=pH− pKa Explanation : This equation indicates that the ratio of ionized form ([A¯]) to the non-ionized form ([HA]) of a weak acid change with pH. The pKa is the pH at which the drug is 50% ionized . When the pH increases relative to the pKa , the drug becomes more ionized ; conversely, when the pH decreases , less of the drug is ionized . Dr. Shivankan Kakkar, MD 10

11. Implications of pH on Drug Absorption Absorption Dynamics : Acidic Drugs : e.g., aspirin ( pKa 3.5) is largely non-ionized in acidic gastric pH , facilitating absorption. Basic Drugs : e.g., atropine ( pKa 10) is largely ionized in gastric pH and is absorbed only in the intestines. Important Point : The process known as ion trapping occurs when a unionized drug crosses a membrane , reverts to an ionized form, and becomes trapped, as seen with aspirin’s potential to cause gastric mucosal damage . Dr. Shivankan Kakkar, MD 11

12. Dr. Shivankan Kakkar, MD 12 Weakly Acidic Drugs: NSAIDs (Aspirin) Barbiturates Methotrexate Sulfonamides Penicillin V Weakly Basic Drugs: Atropine Morphine Amphetamines Ephedrine Chloroquine Polymyxin B Vancomycin Major Factors Responsible for Drug Absorption: Lipid Solubility (Drugs with high lipid solubility are absorbed faster) Non-Ionisation (Only non-ionised drugs can easily cross cell membranes)   Non-Ionisation Depends on pH: A cidic Drugs become non-ionised in a cidic medium B asic Drugs become non-ionised in b asic medium NEET PG NEET PG Henderson-Hasselbalch Equation Inference when pKa = pH: At this point, 50% of the drug is in the ionized form and 50% is in the non-ionized form . NEET PG

13. Excretion of Drugs Based on pH Differential Excretion : Acidic Drugs : Are excreted faster in alkaline urine due to increased ionization, which prevents back diffusion in the kidneys. Basic Drugs : Are excreted faster if the urine is acidified . Key Example : Lipid-soluble nonelectrolytes like ethanol and diethyl-ether readily cross biological membranes and their transport is pH independent . Dr. Shivankan Kakkar, MD 13 pH independent transport is seen for – Ethanol and Diethyl ether Alcohol absorption is from – Small Intestine > Stomach Alkalinisation of Urine: Promotes the excretion of acidic drugs . Acidification of Urine: Can enhance the excretion of basic drugs . Not practically advised due to increased risk of renal stone formation . NEET PG NEET PG

14. Filtration in Drug Transport Overview : Filtration allows drugs to pass through pores or paracellular spaces in membranes. Acceleration : Enhanced by hydrodynamic flow under hydrostatic or osmotic pressure in capillaries. Size Constraints : Lipid-insoluble drugs filter if their size is smaller than pore diameter . Cellular pores (4 Å) restrict entry for drugs with MW > 100-200 . Capillary pores (40 Å) permit passage of most drugs, including albumin . Drug diffusion in capillaries is driven by blood flow rate , not by lipid solubility or pH . Dr. Shivankan Kakkar, MD 14

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16. Specialized Drug Transport Types of Transport : Carrier-mediated transport Vesicular transport (endocytosis and exocytosis) Importance : Specialized transport mechanisms are crucial for moving ions, nutrients, metabolites , and xenobiotics (including drugs) across cell membranes. Dr. Shivankan Kakkar, MD 16

17. Carrier Transport Mechanism Transmembrane Proteins : All cell membranes contain transmembrane proteins that function as carriers or transporters for physiologically important substances. Mechanism : Transporters undergo a conformational change after transiently binding to their substrate, allowing passage across the membrane. Key Features : Specific for substrates (e.g., organic anions) Saturable and competitively inhibited by analogues Slower than channel flux Dr. Shivankan Kakkar, MD 17

18. Types of Carrier Transport Facilitated Diffusion : Energy Requirement : Passive, no energy needed Direction : Moves substrates down their electrochemical gradient (high to low) Example : Entry of glucose into muscle and fat cells via the GLUT 4 transporter. Active Transport : Energy Requirement : Requires energy, inhibited by metabolic poisons Direction : Moves substrates against their gradient (low to high) Examples : Levodopa and methyl dopa are actively absorbed from the gut by the aromatic amino acid transporter . P-glycoprotein (P- gp ) handles the transport of various xenobiotics .   Dr. Shivankan Kakkar, MD 18 NEET PG

19. Primary vs. Secondary Active Transport Primary Active Transport : Energy Source : Directly from ATP hydrolysis Transporters : ABC transporters , which mediate solute efflux from the cytoplasm. Secondary Active Transport : Energy Source : Derived from the movement of another solute (mostly Na+ ). Types : Symport/Cotransport : Both solutes move in the same direction (e.g., Na+ and glucose). Antiport/Exchange Transport : Solutes move in opposite directions (e.g., Na+ and calcium). Dr. Shivankan Kakkar, MD 19

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21. Vesicular Transport Mechanism Overview : Transport of substances into (endocytosis) or out of (exocytosis) the cell using vesicles . Mechanism : A binding protein on the membrane complexes with the substance, initiating vesicle formation. The vesicle detaches from the membrane and can: Remain stored within the cell Release its contents into the cytoplasm Move to the opposite membrane to release substances across the cell. Dr. Shivankan Kakkar, MD 21

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23. Applications & Examples Transported Substances : Proteins and Large Molecules : Vesicular transport is essential for larger substances, contributing minimally to drug transport. Vitamin B12 : Absorbed from the gut after binding to intrinsic factor (a protein). Exocytosis : Hormones : Example includes insulin , which is secreted from pancreatic cells. Neurotransmitters : Such as noradrenaline , released from nerve endings. Dr. Shivankan Kakkar, MD 23

24. Pharmacokinetics: Absorption of Drugs Dr. Shivankan Kakkar , MD

25. Drug Absorption Overview Definition : Absorption is the movement of a drug from its site of administration into the circulation. Importance : Both the fraction of the administered dose that gets absorbed and the rate of absorption are crucial for therapeutic effectiveness. Dr. Shivankan Kakkar, MD 25

26. Factors Affecting Absorption Aqueous Solubility : Drugs in solid form must dissolve in an aqueous phase before absorption. Examples : Poorly Water-Soluble Drugs: Aspirin and griseofulvin : Their rate of dissolution governs the rate of absorption . Microfine tablets enhance absorption . Ketoconazole : Requires gastric acid for dissolution and absorption. Concentration : Passive diffusion is driven by the concentration gradient.. Area of Absorbing Surface : Larger surface areas lead to faster absorption. Vascularity of the Absorbing Surface : Increased blood flow enhances absorption by maintaining the concentration gradient. Route of Administration : Each route (oral, intravenous, etc.) has unique characteristics affecting absorption. Dr. Shivankan Kakkar, MD 26 Explain Why Why particle size of drug in a solid form is important in case of certain drugs like aspirin ?

27. Oral Drug Absorption Barrier : The epithelial lining of the gastrointestinal tract is lipoidal, presenting a barrier to drug absorption. Drug Types : Lipid-Soluble Drugs : Ethanol is readily absorbed from both the stomach and intestine . Acidic Drugs : Aspirin and barbiturates are predominantly ionized in alkaline medium , leading to poor absorption. Basic Drugs : Atropine and Morphine are largely ionized in the stomach (acidic medium) and absorbed in the duodenum . Dr. Shivankan Kakkar, MD 27 Explain Why Explain Why Basic drugs are absorbed only when they reach the intestine Acidic drugs are poorly absorbed in alkaline medium Most Common Site of Drug Absorption The upper duodenum is the most common site for drug absorption due to its larger surface area and thinner mucosa compared to the stomach. NEET PG NEET PG NEET PG

28. Factors Affecting Oral Absorption Gastric Emptying : Faster gastric emptying accelerates absorption; absorption is slower in the stomach due to thick mucosa and small surface area. Food Presence : Food can dilute drugs and form poorly absorbed complexes (e.g., tetracyclines with calcium in milk) , leading to reduced absorption . Exception : Fatty foods can enhance absorption of certain drugs like lumefantrine. Dr. Shivankan Kakkar, MD 28 Short Note Effect of food on absorption of drugs Food Decreases Absorption of: Tetracycline Ampicillin Captopril Digoxin Isoniazid Levodopa Rifampicin Food Increases Absorption of: Lumefantrine Carbamazepine Griseofulvin (especially with fatty food) Lithium Nitrofurantoin Riboflavin Fibrates Erlotinib NEET PG

29. Factors Affecting Oral Absorption Degradation in GI Tract : Drugs like penicillin G and insulin are degraded in the GI tract and ineffective orally. Solutions : Use of enteric-coated tablets or sustained-release formulations. Efflux Transporters : The efflux transporter P-glycoprotein (P- gp ) can extrude absorbed drugs back into the intestinal lumen. Examples : Low oral bioavailability of digoxin and cyclosporine can be affected by P- gp . Inhibitors (e.g., quinidine) can enhance absorption, while inducers (e.g., rifampin ) can reduce it. Drug Interactions : Concurrently ingested drugs can alter absorption by forming insoluble complexes or affecting gut motility . Examples : Tetracyclines with calcium salts and phenytoin with sucralfate. Dr. Shivankan Kakkar, MD 29 NEET PG

30. Subcutaneous and Intramuscular Absorption Direct Drug Delivery : Drugs are deposited near capillaries for effective absorption . Lipid Solubility : Easily absorbed : Lipid-soluble drugs cross capillary membranes. Large molecules : Absorbed through lymphatics . Absorption Rates : Subcutaneous ( s.c. ) : Slower than intramuscular ( i.m. ) but more consistent than oral. Intramuscular ( i.m. ) : Faster and more reliable absorption . Factors Influencing Absorption : Increased Blood Flow : Heat/exercise accelerates absorption. Vasoconstrictors (e.g., adrenaline ): Slow absorption of local anesthetics . Hyaluronidase : Enhances spread from s.c. injections. Depot Medications : Examples : Benzathine penicillin, depot progestins. Dr. Shivankan Kakkar, MD 30

31. Topical Drug Absorption Lipid Solubility : Critical for systemic absorption through skin and membranes. Examples of Effective Drugs : Hyoscine, fentanyl, testosterone, and estradiol . Potential for Systemic Effects : Corticosteroids can lead to pituitary-adrenal suppression . Rubbing or using occlusive dressings can enhance absorption. Toxicity Concerns : Organophosphate insecticides can lead to systemic toxicity . Abrasions (e.g., tannic acid on burns) may cause hepatic necrosis. Ocular Absorption : Physostigmine penetrates cornea ; neostigmine does not . Timolol eye drops may induce bradycardia. Mucosal Absorption : Estrogen cream can lead to gynaecomastia in male partners . Dr. Shivankan Kakkar, MD 31

32. Bioavailability Definition : Bioavailability is the fraction of an administered drug that reaches systemic circulation in unchanged form. Oral Administration Process : When a drug is taken orally, it is absorbed into the portal circulation and reaches the liver. First Pass Metabolism : Some of the drug may be metabolized in the liver before entering systemic circulation. Drugs with high first pass metabolism include nitrates, hydrocortisone, lignocaine, propranolol, salbutamol, and morphine. Dr. Shivankan Kakkar, MD 32 Short Note Key Determinants: Reduced absorption and first pass metabolism significantly influence bioavailability. Explain Why Oral dose of some drugs are several fold higher than their Parenteral dose Short Note First Pass Metabolism NEET PG NEET PG

33. Intravenous ( i.v. ) Route : Bioavailability is 100% since the drug directly enters systemic circulation. Calculating Bioavailability : Compare the AUC (Area Under the Plasma Concentration-Time Curve) for the i.v. route to that of the specific route. Dr. Shivankan Kakkar, MD 33 AUC tells about the extent of absorption of the drug. Tmax . tells about the time to reach maximum concentration, i.e. rate of absorption Cmax . is the maximum concentration of a drug that can be obtained NEET PG NEET PG

34. The route with the highest first-pass metabolism is oral administration . The most common site for first-pass metabolism is the liver . First-pass metabolism in the small intestine occurs with Levodopa . Rectally administered drugs absorbed through the external hemorrhoidal vein bypass first-pass metabolism . Dr. Shivankan Kakkar, MD 34 NEET PG

35. Bioequivalence of Drugs Same Drug, Different Brands Example: Phenytoin (Tab. Dilantin vs. Tab. Eptoin ) Bioequivalence Definition Difference in bioavailability < 20% = Bioequivalent Bioavailability Rate and extent drug reaches the bloodstream Similar Plasma Levels Ensures comparable therapeutic effects Interchangeability Can be substituted without affecting efficacy or safety Dr. Shivankan Kakkar, MD 35 Short Note