Lecture 1 Pharmacokinetics: Absorption and Distribution

Pharmacokinetics and the LADME Framework

• Pharmacokinetics (PK) is the study of how the body handles a drug, often described through five distinct stages represented by the acronym LADME.
• L = Liberation: The release of a drug from its pharmaceutical dosage form.
• A = Absorption: The process by which a drug enters the bloodstream without being chemically altered, or the movement of a drug from its site of administration into the blood or lymphatic system.
• D = Distribution: The movement of the drug to and from the blood and various tissues of the body, such as fat, muscle, and brain tissue.
• M = Metabolism: The chemical conversion of a drug into compounds (metabolites) that are easier for the body to eliminate.
• E = Excretion: The elimination of the unchanged drug or its metabolites from the body via renal (kidneys), biliary (liver/bile), or pulmonary (lungs) processes.

Liberation

• Liberation characterizes how a drug is released from its administered form. There are three primary release types:
  • Immediate release: The drug is released without any intentional delay.
  • Delayed release: The drug is released at a specific time after it is ingested rather than immediately.
  • Extended release: The drug is released slowly over a prolonged period.
• A critical clinical consideration is that certain formulations, particularly extended-release or delayed-release versions, must not be split or crushed, as this would destroy the intended liberation profile and potentially cause a toxic surge of the medication.

Routes of Drug Administration

• The Route of Administration (ROA) is the path by which a medication is brought into contact with the body. The chosen route has a profound effect on the drug’s onset of action.
• ROAs are generally divided into two major categories: Enteral and Parenteral.

Enteral Routes

• Enteral administration involves absorption through the gastrointestinal (GI) tract via active or passive transport.
• Oral (PO): Meaning "by mouth."
• Buccal (Buc): Placing the medication between the gums and the cheek.
• Sublingual (SL): Placing the medication under the tongue.
• Rectal (PR): Administered per rectum.

Parenteral Routes

• Parenteral administration typically involves injection or other non-GI methods.
• Intravenous (IV): Injection directly into a vein. This provides the fastest onset as it bypasses absorption barriers.
• Intramuscular (IM): Injection into the muscle.
• Subcutaneous (SC): Injection into the fatty tissue layer just under the skin.
• Inhalation: Drug delivery through the lungs.
• Intrathecal: Injection directly into the cerebrospinal fluid (CSF). The most common form is an epidural (outside the dura) or a spinal injection (intrathecal space).
  • Advantages: Bypasses the blood-brain barrier.
  • Disadvantages: Higher risk of infection, requires highly skilled personnel and strict aseptic technique.

Biochemical Principles of Absorption

• Drug absorption is heavily dependent on the ability of a molecule to cross the phospholipid bilayer of cell membranes.
• The phospholipid bilayer consists of hydrophilic (water-loving) heads facing outward and hydrophobic (water-fearing) tails facing inward.

Essential Terminology

• Hydrophilic: Polar substances with a tendency to mix with or dissolve in water.
• Hydrophobic: Non-polar substances that aggregate in aqueous solutions and exclude water molecules.
• Lipophilic: The ability of a substance to combine with or dissolve in lipids or fats.
• Lipophobic: Substances that are not soluble in lipids or other non-polar substances.
• Polarity: A state in a molecule where electrons are unevenly distributed in a chemical bond, creating dipoles with unequal charges (e.g., $H_2O$).
• Ionized: A molecule possessing a positive or negative charge because the number of protons does not equal the number of electrons.
• Protonation: The addition of a proton ($H^+$) to an atom, molecule, or ion, which is a common occurrence in acid-base reactions.

Fick’s Law and Permeability

• Fick’s Law of Diffusion describes the passive movement of molecules down a concentration gradient (from high concentration to low concentration).
• Rate of transport across membranes is dependent on:
  • Molecular size: Smaller molecules diffuse more rapidly.
  • Lipophilicity: Hydrophobic (lipophilic) molecules pass through the lipid bilayer more easily.
  • Degree of ionization: Unionized (uncharged) molecules pass more easily; ionized molecules are blocked.
  • Blood flow to the area.
  • Protein binding.
• Relative Permeability Rank:
  • Easiest: Gases ($CO_2$, $N_2$, $O_2$) and hydrophobic/non-polar molecules (Benzene).
  • Moderate: Small polar molecules (Ethanol, $H_2O$, Urea).
  • Difficult: Large polar molecules (Glucose, Amino acids).
  • Impermeable: Charged molecules/Ions ($Na^+$, $K^+$, $Cl^-$, $Mg^{2+}$, $Ca^{2+}$, Amino acids, $ATP$).

pH, pKa, and Ion Trapping

• Most drugs are either weak acids or weak bases and exist in equilibrium between charged (ionized) and uncharged (unionized) forms.
• $pKa$ is defined as the $pH$ at which $50\%$ of the drug is non-ionized. A lower $pKa$ indicates a more acidic substance.

Henderson-Hasselbalch Relationship

• If $pH = pKa$: The drug is at equilibrium.
• If $pH < pKa$: Weak acids ($HA$) remain unionized and can diffuse; weak bases ($BH^+$) become protonated and ionized, failing to diffuse.
• If $pH > pKa$: Weak bases ($B$) remain unionized and can diffuse; weak acids ($A^-$) become ionized and fail to diffuse.
• Ion Trapping Example: Aspirin ($pKa = 3.5$) in the stomach ($pH = 1$). In the highly acidic stomach, aspirin is unionized and diffuses easily across the gastric mucosal barrier. Once it reaches the plasma ($pH = 7.4$), the higher $pH$ causes the drug to become ionized. Because ionized molecules cannot cross back through the lipid membrane, the drug becomes "trapped" in the plasma.

Membrane Transport Mechanisms

Passive Transport

• Simple Diffusion: Movement across the membrane down a concentration gradient; no energy required.
• Facilitated Diffusion: Requires a carrier protein or channel protein to move the solute, but still requires no energy. It can be saturated and competitively blocked.

Active Transport

• Movement against an electrochemical gradient.
• Requires energy in the form of Adenosine Triphosphate (ATP).
• Involves ATP-driven pumps or coupled transporters.

First-Pass Metabolism and Bioavailability

First-Pass Metabolism

• This refers to the hepatic metabolism of a drug when it is absorbed from the GI tract and delivered to the liver via the portal circulation before reaching the systemic circulation.
• A larger first-pass effect results in less drug reaching the systemic circulation.
• Affected routes: Oral and (partially) Rectal.
• Extraction Ratio ($ER$): Quantifies the magnitude of first-pass metabolism.
  • $CL_H = Q \times ER$
  • $CL_H$: Hepatic clearance (volume of blood in liver from which drug is removed per unit of time, measured in $L/hr$).
  • $Q$: Rate of hepatic blood flow ($L/hr$).
  • $ER = \frac{CL_H}{Q}$

Bioavailability (F)

• Bioavailability is the fraction of an administered dose that reaches the systemic circulation in an unchanged form.
  • $F = \frac{\text{Amount of drug reaching systemic circulation}}{\text{Amount of drug administered}}$
  • $F = f \times (1 - ER)$, where $f$ is the fraction of drug absorbed.
• Factors affecting $F$ include drug solubility in the administration site, gastric $pH$ effects, and the extraction ratio.
• Intravenous medications have a bioavailability of $1.0$ ($100\%$).

Pharmacokinetic Parameters

• Area Under the Curve (AUC): The actual total body exposure to a drug after a dose.
• $C_{max}$: Maximum plasma concentration reached.
• $T_{max}$: The time at which $C_{max}$ is achieved.
• MEC: Minimum Effective Concentration.
• MTC: Minimum Toxic Concentration.
• Therapeutic Range: The concentration window between the MEC and MTC.

Drug Distribution

• Distribution is the delivery of a drug from the systemic circulation to the tissues. It occurs in two phases: the distribution phase and the elimination phase.

Factors Affecting Distribution

• Blood flow: High-perfusion organs (brain, heart, kidneys) receive drugs rapidly. Low-perfusion tissues (fat, bone) receive drugs slowly.
• Organ size: Large organs like skeletal muscle can hold significant quantities of drug at steady-state.
• Capillary permeability: Determined by the physical structure of the capillaries.
• Solubility and Protein Binding: Drugs bound to plasma proteins (like albumin) cannot leave the intravascular space.

Blood-Brain Barrier (BBB)

• A specialized astrocytic sheath and tight junctions between endothelial cells regulate substance flow into the brain.
• Most non-ionized, lipid-soluble drugs enter the brain readily.
• Water-soluble drugs diffuse very slowly and often require specific transport proteins (e.g., for glucose or amino acids).

Four-Compartment Model

1. Blood: Initially high concentration, falls rapidly.
2. Vessel-Rich Group (VRG): Usually the first to accumulate drug (brain, heart, liver, kidneys).
3. Muscle: Larger compartment but less perfused than VRG.
4. Fat: Lowest perfusion; drug often metabolized and excreted by the time it distributes here.

Volume of Distribution (Vd)

• $V_d$ is a theoretical fluid volume required to contain the total amount of drug in the body at the same concentration as that present in the plasma.
• It is a proportionality constant calculated at steady state:
  • $V_d = \frac{\text{Amount of drug in the body}}{\text{Plasma concentration}}$
• Total body fluid in a 70 kg male is approximately $42\,L$ ($60\%$ of body mass), divided into:
  • Intracellular fluid (ICF): $2/3$ of total fluid (~$28\,L$).
  • Extracellular fluid (ECF): $1/3$ of total fluid (~$14\,L$).
    • Interstitial fluid: $80\%$ of ECF.
    • Plasma: $20\%$ of ECF (~$3\,L$).

Interpreting Vd Values

• $V_d \leq 42\,L$ (~$0.6\,L/kg$): Suggests the drug stays largely within the systemic circulation.
• $V_d > 42\,L$ (~$0.6\,L/kg$): Suggests the drug is widely distributed into tissues.
• Examples for a 70 kg adult:
  • Gentamicin: $17.5\,L$ ($0.25\,L/kg$)
  • Vancomycin: $49\,L$ ($0.7\,L/kg$)
  • Azithromycin: $2240\,L$ ($32\,L/kg$)

Clinical Significance of Vd

• Drugs with high $V_d$ leave the blood and enter tissues; therefore, plasma levels only increase significantly once tissues are saturated.
• A high $V_d$ usually requires a higher initial "loading dose" to establish therapeutic plasma levels quickly.

Questions & Knowledge Checks

• Q: Should you crush an extended-release tablet?
  • A: No. Crushing destroys the extended-release mechanism, leading to rapid absorption that could be dangerous.
• Q: Which factors affect drug absorption?
  • A: All of the following: Route of administration, rate of liberation, drug formulation, and physical factors.
• Q: Which molecule will diffuse across a lipid bilayer the fastest?
  • A: Small and lipophilic.
• Q: In the stomach (pH = 1), will Aspirin (pKa = 3.5) have low or high absorption?
  • A: High (because it is unionized in an acidic environment).
• Q: Which route involves the largest degree of first-pass metabolism?
  • A: Oral.
• Q: Which factors affect drug distribution?
  • A: Blood flow to the tissue, solubility of the drug, capillary permeability, and protein binding.