Drug Chemistry, Absorption and Distribution

This presentation explores the fundamental principles of drug chemistry and its critical role in drug absorption and distribution within the body. Understanding these concepts is essential for optimizing drug efficacy, safety, and therapeutic outcomes.

The slides cover:

Key physicochemical properties of drugs, including solubility, lipophilicity, ionization, and molecular size, which influence how drugs behave in the body.

Mechanisms of drug absorption across biological membranes, including passive diffusion, facilitated transport, and active transport.

Factors affecting bioavailability, including first-pass metabolism and formulation characteristics.

Drug distribution principles, such as plasma protein binding, tissue permeability, blood flow, and special barriers like the blood-brain barrier and placenta.

The concept and clinical significance of volume of distribution (Vd).

Practical applications in dosing, formulation design, and individualized therapy.

This resource is designed for pharmacy students, medical professionals, and anyone interested in pharmacology, providing clear diagrams, key points, and clinical relevance for better understanding of how drugs reach and act in the body.

1. Pharmacology I  Nisha Adhikari Lecturer School of pharmacy B. Pharmacy

2. Unit-II: Pharmacokinetics Topic: Drug Chemistry, Absorption and distribution

3. Fundamental Terms in Pharmacokinetics Ionization: Ionization is the process by which a molecule gains or loses a proton (H⁺) and becomes charged (ionized) . Ionized drugs → have a charge (either + or -) Unionized drugs → are neutral , no charge

4. Why does it matter? Ionized drugs : Water-soluble , do NOT easily cross cell membranes Unionized drugs : Lipid-soluble , EASILY cross cell membranes Only unionized forms of drugs are absorbed well through lipid membranes (like the GI tract or blood-brain barrier). 1. Ionization

5. In Chemistry: pKa is the negative base-10 logarithm of the acid dissociation constant (Ka) of a substance: pKa = − log 10 ​(K a ​)​ Ka (acid dissociation constant) measures how strongly an acid donates a proton (H⁺) in water. pKa is a more manageable way to express the strength on a log scale. 2. pKa (Acid Dissociation Constant)

6. 2. pKa (Acid Dissociation Constant) In Pharmacology: What is pKa? pKa is the pH at which 50% of the drug is ionized and 50% is unionized . Think of it as the “threshold pH” for ionization.

7. A low pKa → strong acid → dissociates easily → more ionized in water A high pKa → weak acid → doesn’t dissociate much → less ionized 2. pKa (Acid Dissociation Constant)

8. Example: Hydrochloric acid (HCl): pKa ≈ -7 (strong acid) Acetic acid (vinegar): pKa ≈ 4.75 (weak acid) Phenol: pKa ≈ 10 2. pKa (Acid Dissociation Constant)

9. How pKa relates to ionization: When pH = pKa → 50% ionized, 50% unionized When pH < pKa → Acidic drugs = unionized , Basic drugs = ionized When pH > pKa → Acidic drugs = ionized , Basic drugs = unionized 2. pKa (Acid Dissociation Constant)

10. Example: Aspirin (pKa ~3.5) Stomach pH ~1-2 → more unionized → better absorption in stomach. 2. Morphine (pKa ~8) Intestinal pH ~7-8 → more unionized → better absorption in intestines. pH and pKa

11. LINK

12. pH and pKa Drug Type pKa Relationship to pH Ionization Status Membrane Permeability Acidic pH < pKa Mostly unionized Crosses easily Acidic pH > pKa Mostly ionized Crosses poorly Basic pH < pKa Mostly ionized Crosses poorly Basic pH > pKa Mostly unionized Crosses easily

13. 3. Henderson–Hasselbalch Equation Used to calculate the ratio of ionized to unionized drug . For acidic drugs : pH = pKa + log [A⁻] / [HA] Where: A⁻ = ionized form HA = unionized form

14. For basic drugs : pH = pKa + log [B] / [BH⁺] Where: B = unionized base BH⁺ = ionized form This helps in predicting drug absorption and urinary excretion . 3. Henderson–Hasselbalch Equation

15. Examples and Questions Equation for Acidic Drugs : For an acidic drug (HA) : HA = unionized form (protonated acid). A⁻ = ionized form (conjugate base). Rearranged:

16. Equation for Basic Drugs: For a basic drug (B) : B = unionized base. BH⁺ = ionized form (protonated). Rearranged: Examples and Questions

17. 4. Ion Trapping When a drug moves from one pH compartment to another, it may become ionized and get trapped , unable to cross back. Example: A basic drug like morphine moves into the acidic stomach → becomes ionized → can't leave easily → trapped Used clinically in poisoning to enhance drug excretion

18. Summary Table of Key Terms Term Meaning Example Ionized Charged molecule (water-soluble, poor absorption) Aspirin in basic pH Unionized Uncharged molecule (lipid-soluble, absorbed easily) Aspirin in acidic pH pKa pH at which drug is 50% ionized/unionized Aspirin pKa ≈ 3.5 pH Acidity of the environment Stomach ≈ 1–3, Intestine ≈ 6–8 Ion trapping Drug becomes ionized in a compartment and is trapped Basic drug trapped in stomach Henderson–Hasselbalch Equation to calculate ionization Useful in drug absorption & excretion

19. Drug Diffusion Q. What is Diffusion? Diffusion is the movement of molecules from an area of high concentration to an area of low concentration until equilibrium is reached. When we take a drug (like a tablet, injection, etc.), it needs to move from where you put it into the blood or tissues where it can do its job. This movement often happens by diffusion .

20. Drug Diffusion 🩸 Key Points for Drug Diffusion: Passive Process : Diffusion does not need energy from the cell. Concentration Gradient : Drugs move from areas of high concentration to low concentration . For example, if there’s more drug outside a cell, it will diffuse into the cell. Lipid Solubility : The cell membrane is made of lipids (fats). So, drugs that can dissolve in fats (lipophilic) can diffuse more easily. Size and Charge : Small, non-polar (uncharged) drugs diffuse faster than large, charged ones.

21. A. Active Processes (Energy Required) 1. Active Transport: Uses ATP to move drugs from low → high concentration. Needs carrier proteins (pumps). Example: levodopa (with amino acid transporter), ion pumps. Diffusion of Drugs

22. 2. Vesicular Transport (Endocytosis/Exocytosis): For very large molecules (proteins, large drugs). Uses the cell membrane to engulf (endocytosis) or release (exocytosis) the drug. Example: Therapeutic antibodies, some vaccines. Diffusion of Drugs

23. B. Passive Processes (No Energy Required): Simple Diffusion: Small, lipid-soluble drugs move directly across membranes. No carrier proteins involved. Moves from high → low concentration. Example: gases (O₂, CO₂), alcohol. Diffusion of Drugs

24. 2. Facilitated Diffusion: Drugs need carrier proteins or channels to pass. No energy used. Moves from high → low concentration. Example: glucose transporters. Diffusion of Drugs

25. Key Differences Table (Quick Overview) Transport Type Energy? Direction Carrier Protein? Example Active Transport ✅ Yes Low → High ✅ Yes Levodopa, sodium-potassium pump Endocytosis/Exocytosis ✅ Yes In/Out of cell (large molecules) ✅ Membrane vesicles Antibody therapies, large proteins Simple Diffusion ❌ No High → Low ❌ No Alcohol, gases Facilitated Diffusion ❌ No High → Low ✅ Yes Glucose, some vitamins

26. Water Solubility and Lipid Solubility Water-Soluble Drugs (Hydrophilic): Dissolve easily in plasma. Do not easily cross cell membranes. Mostly excreted via urine . Examples: aminoglycosides, atenolol.

27. Water Solubility and Lipid Solubility Lipid-Soluble Drugs (Lipophilic): Cross membranes easily. Accumulate in fat-rich tissues . Undergo extensive hepatic metabolism . Examples: diazepam, propranolol. Key Concept: A drug must be lipid-soluble and unionized to cross most biological membranes (like GI tract, BBB, placenta).

28. Organs Involved in Drug Ionization Organ pH Impact Stomach 1.0–3.5 Acidic: favors absorption of weak acids (like aspirin). Small intestine 5.5–8.0 Weak bases and many drugs absorbed here due to large surface area. Blood ~7.4 Drugs distribute and may ionize depending on pKa. Kidneys Varies (acidic/alkaline urine) Affects drug reabsorption and excretion . Ionized drugs are excreted more. Liver ~7.4 Important for metabolism, not primary ionization. Ionization depends on pH of body fluids and pKa of the drug.

29. Absorption Definition: Absorption is the process by which a drug enters the bloodstream from the site of administration. Factors Affecting Absorption: Drug Form : Solution > suspension > tablet Route of Administration : IV > IM > oral Blood Flow : Better perfusion = faster absorption Surface Area : Intestine > stomach Ionization : Unionized drugs are absorbed better Food & pH : Can delay or enhance absorption

30. Absorption Common Routes: Oral (most common) Intramuscular (IM) Subcutaneous (SC) Intravenous (IV) – 100% bioavailable Topical / Transdermal / Inhalation

31. Distribution Definition: Distribution is the process by which the drug moves from the blood to tissues and organs.

32. Factors Affecting Distribution: Blood flow to tissues Plasma protein binding (e.g., albumin) Bound drug = inactive Free drug = active Tissue binding Lipid solubility pH of the tissue Blood-Brain Barrier (BBB) : Only lipophilic , small , and unionized drugs can pass (e.g., benzodiazepines) Distribution

33. Volume of Distribution ( Vd ): Indicates how extensively a drug distributes into tissues. Low Vd : Drug remains in blood (e.g., heparin) High Vd : Drug distributes to fat/muscle (e.g., amiodarone) Distribution

34. Metabolism (Biotransformation) Definition: Metabolism converts lipophilic drugs into more water-soluble compounds for easier excretion. Organs Involved: Liver (primary site) Lungs, kidneys, intestines also contribute.

35. Phases: Phase I (Functionalization) : Oxidation, reduction, hydrolysis Involves cytochrome P450 enzymes (CYP450) Phase II (Conjugation) : Adds polar groups (e.g., glucuronic acid, sulfate) Increases water solubility Metabolism (Biotransformation)

36. First-Pass Metabolism: Significant metabolism in the liver or gut wall before drug reaches systemic circulation. Reduces bioavailability of oral drugs (e.g., propranolol, morphine). Metabolism (Biotransformation)

37. Excretion Definition: Excretion is the process of removing drugs and their metabolites from the body. Organs Involved: Kidneys (major route – urine) Filtration, secretion, reabsorption Ionized drugs are excreted easily Liver (via bile → feces) Lungs (volatile drugs like anesthetics) Saliva, sweat, breast milk (minor)

38. One of the major elimination pathways for drugs Occurs in nephrons of the kidney Involves 3 key processes: Glomerular filtration : Free drugs only Tubular secretion : Active transport Tubular Reabsorption : Unionized drugs may re-enter blood Excretion

39. 1. Glomerular Filtration: Occurs at glomerulus Passive process (no energy required) Only free (unbound) drugs are filtered Bound drugs (e.g. to albumin) are not filtered Example: Free penicillin filtered here Excretion

40. 2. Tubular Secretion: Occurs at proximal tubule Active transport — requires energy (ATP) Secretes ionized and un-ionized drugs Separate transporters for acids and bases Example: Penicillin, uric acid, creatinine Excretion

41. 3. Tubular Reabsorption: Occurs at distal tubule Unionized (lipid-soluble) drugs are reabsorbed into the blood Ionized drugs remain in urine for excretion Reabsorption depends on drug pKa and urine pH Excretion

42. Urine pH and Drug Ionization Acidic urine = enhances excretion of basic drugs Alkaline urine = enhances excretion of acidic drugs Example: Alkalinize urine to treat aspirin overdose

43. Clinical Relevance Drug dosing must consider renal function Creatinine clearance helps estimate kidney filtration Renal excretion is crucial for: Water-soluble drugs Drugs with low metabolism Toxic drug removal in overdose

44. 1. Acidic Drugs 📖 Definition: Drugs that donate protons (H⁺) in solution. They are more ionized in basic (alkaline) pH and more lipid-soluble (unionized) in acidic pH . 🔬 Chemical Groups: Carboxylic acids (-COOH) Phenol (-OH) groups Enols, sulfonamides, barbiturates

45. 🧫 Solubility: More soluble in alkaline media (because they ionize). Absorbed better in acidic environments when unionized (like the stomach ), though major absorption happens in intestine due to large surface area. 1. Acidic Drugs

46. 🩺 Pharmacokinetic Implications: Bind to albumin in plasma. Ionize in alkaline urine → more excreted May require pH-dependent formulations (e.g., enteric coating for aspirin) 1. Acidic Drugs

47. 💊 Examples : Drug Use Aspirin NSAID Phenobarbital Anticonvulsant Penicillin Antibiotic Warfarin Anticoagulant Salicylates Anti-inflammatory 1. Acidic Drugs

48. 2. Basic Drugs 📖 Definition: Drugs that accept protons (H⁺) . They are more ionized in acidic pH , and more lipid-soluble (unionized) in basic pH . 🔬 Chemical Groups: Amines (-NH₂, -NH, tertiary amines) Nitrogen-containing heterocycles

49. 🧫 Solubility: More soluble in acidic media (due to ionization). Absorbed better when unionized in alkaline (basic) pH , such as intestinal fluid . 2. Basic Drugs

50. 🩺 Pharmacokinetic Implications: Bind to α₁- acid glycoprotein in plasma Ionize in acidic urine → can be excreted quickly Ion trapping in acidic compartments (e.g., stomach, lysosomes) 2. Basic Drugs

51. 💊 Examples : Drug Use Morphine Pain relief (Opioid) Diazepam Anxiety/Seizures Lidocaine Local anesthetic Ephedrine Decongestant Propranolol Beta-blocker (hypertension) 2. Basic Drugs

52. 3. Neutral Drugs 📖 Definition: These drugs do not ionize in physiological pH range. They are neither acidic nor basic , and their solubility and absorption do not depend on pH. 🔬 Chemical Characteristics: Lack functional groups that ionize in biological pH range. Remain uncharged → generally lipophilic

53. 🧫 Solubility & Absorption: pH-independent Absorbed well due to lipophilicity May require solubilizing agents/formulation modifications 3. Neutral Drugs

54. 🩺 Pharmacokinetic Implications: Diffuse freely across membranes Not subject to ion trapping Formulation depends on solubility profile, not pKa 3. Neutral Drugs

55. 💊 Examples : Drug Use Chloral hydrate Sedative-hypnotic Nitroglycerin Anti-anginal DMSO Solvent & anti-inflammatory 3. Neutral Drugs

56. 📊 Comparison Table Property Acidic Drugs Basic Drugs Neutral Drugs Functional group -COOH, -OH -NH₂, tertiary amines None (non-ionizable) pKa Range 3–7 7–11 N/A Solubility More in alkaline More in acidic Not pH-dependent Unionized in Acidic pH (stomach) Basic pH (intestine) Always uncharged Protein binding Albumin α₁- acid glycoprotein Variable Excretion strategy Alkalinize urine Acidify urine Not pH-sensitive Example Aspirin, Penicillin Morphine, Diazepam Diazepam, Nitroglycerin

57. 📌 Summary Points Acidic drugs: Donate protons , better absorbed in stomach , bind to albumin , better excreted in alkaline urine . Basic drugs: Accept protons , absorbed mainly in intestine , bind to α1- acid glycoprotein , better excreted in acidic urine . Neutral drugs: No ionization , pH-independent absorption, often lipophilic.