Pharmacokinetics and Drug Administration

Pharmacokinetics

• Pharmacokinetics is the study of what the body does to a drug.
• It describes the changing concentrations or amounts of a drug and its metabolites in blood, plasma, urine, and other body tissues and fluids.
• Key processes include:
  • Absorption
  • Distribution
  • Metabolism
  • Excretion (ADME)

Routes of Drug Administration (RofA)

• Absorption is how the body takes in a drug.
• Enteral routes:
  • Oral (swallowed)
  • Sublingual (under the tongue)
  • Buccal (between cheek and gum)
  • Rectal (inserted into rectum)
• Parenteral routes:
  • Intravenous (IV)
  • Intramuscular (IM)
  • Subcutaneous (SQ/SC)
  • Inhalation
  • Epidural
  • Intra-articular
  • Topical/Transdermal (applied to skin or mucous membrane)
  • Ocular
  • Otic (into the ear)
  • Parenteral (bypassing gut, often requiring injection)

Bioavailability (F)

• Bioavailability quantifies the fraction of a drug that reaches systemic circulation after administration.
• IV administration has 100% bioavailability because it bypasses absorption.
• Oral administration has less than 100% bioavailability due to first-pass metabolism (metabolism in the liver before reaching systemic circulation).
• Other factors impacting bioavailability include:
  • incomplete absorption
  • gastric acid
  • enzymatic destruction
  • intestinal barriers

First-Pass Metabolism

• First-pass metabolism refers to drug metabolism in the liver before reaching systemic circulation.
• This process can significantly impact the therapeutic effect of a drug, often reducing its bioavailability when administered orally.

Oral Ingestion (Absorption)

• Absorption is governed by factors such as:
  • surface area for absorption in the intestine
  • blood flow
  • drug concentration
  • physical state of drug
• Occurs primarily via passive diffusion.
• In theory, weak acids are best absorbed in the stomach, and weak bases are best absorbed in the intestines.
• In reality however absorption is greater in the intestines due to surface area and organ function.
• Form of oral drugs affects rate of absorption:
  • Liquids (syrups, elixirs) are the fastest
  • Powders are rapid
  • Pills/Capsules are the slowest.

Rate of Appearance in Blood

• Affected by rate of dissolution and absorption from the GI tract.
• Timed-release or enteric-coated pills alter the rate at which the drug appears in the blood.

Effect of Changing Rate of Gastric Emptying

• Cold water ingestion accelerates gastric emptying, leading to increased drug absorption.
• Fatty meals and other factors can slow gastric emptying.

Rectal Administration

• Useful for vomiting or unconscious patients.
• Approx. 50% of the drug bypasses the liver.
• Disadvantages include irregular/incomplete absorption, irritation, and patient aversion.

Sublingual Administration

• Absorption from the oral mucosa has significance for drugs like nitroglycerin.
• This route bypasses first-pass metabolism.

Subcutaneous Administration

• Slow and constant absorption.
• Suitable for slow-release pellets.
• Needs non-irritating drugs.

Intramuscular Administration

• Rapid absorption from aqueous solutions, with rates varying among muscle groups (e.g., gluteus, deltoid).
• Slow absorption with oil-based solutions or suspensions.

Intra-arterial Administration

• Used to target a drug to a specific organ (e.g., for tumors, cancers).
• Requires specialized expertise/experience, is usually reserved for a limited number of cases.

Intrathecal Administration

• Necessary when blood-brain or blood-CSF barriers are present.
• Injection into spinal subarachnoid space.
• Used in spinal anesthesia for acute CNS infections.

Intraperitoneal Administration

• Peritoneal cavity offers large surface area for absorption.
• Seldom used clinically due to high infection risk.

Pulmonary Absorption

• Used for inhaled gaseous and volatile drugs.
• Almost instantaneous absorption.
• Avoids first-pass metabolism.

Topical Application

• Used for mucous membranes (eye, nose, vagina etc).
• Intended for local effects.
• Systemic absorption (e.g., antidiuretic hormone through nasolacrimal canal) possible.
• Also used for skin application.

Topical Application (Skin)

• Limited number of drugs are absorbed.
• Absorption is proportional to the surface area and is increased with inflammation and abrasions.
• Oily vehicles enhance absorption by aiding penetration into the skin.

Topical Application (Eye)

• Often for local effects.
• Systemic absorption through the nasolacrimal canal is undesirable.
• Bypasses first-pass metabolism.

Molecular Size (Absorption)

• Smaller molecules diffuse more readily across cell membranes than larger ones, inversely proportional to square-root of molecular weight.
• This pertains to passive diffusion, and not to specialized transport mechanisms.
• Tight junctions have low molecular weight passage.

Lipid Solubility (Absorption)

• Lipid solubility (oil:water partition coefficient) is vital for crossing cell membranes.
• A more lipid-soluble drug will usually cross more readily.

Ionization (Absorption)

• Most drugs are weak electrolytes (acids/bases).
• The degree of ionization varies with pH.
• Non-ionized forms of drugs cross cell membranes more easily.

Ionization (2):

• Ionized form of drugs = polar = water-soluble.
• Non-ionized form = less polar = more lipid-soluble.
• pKa= Acid dissociation constant, at which 50% of the molecules are ionized.

Henderson-Hasselbalch Equation

• A relationship between pH, pKa, and the ratio of ionized/non-ionized forms.

Membrane Transfer

• Methods of drug movement across cell membranes include passive diffusion, carrier-mediated transport, active transport, pinocytosis and endocytosis.

Facilitated Diffusion

• Carrier-mediated process without energy requirement
• Movement can't be against the gradient
• Necessary for compounds to cross membranes by simple diffusion.

Special Carriers

• Important for transporting substances that are too large for simple diffusion.
• Examples include peptides, amino acids, and glucose.
• Saturable and inhibited transport mechanisms.
• Active transport requires energy. Facilitated diffusion does not.

Drug Absorption and Bioavailability

• Absorption describes how much/how quickly a drug leaves its administration site.
• Bioavailability (F) describes how much of a drug reaches its site of action or a biological fluid where it would have access to its target.
• Bioavailability is measured by the Area Under the Curve (AUC).

Factors Modifying Absorption

• Drug solubility
• Local conditions (pH, temperature)
• Local circulation.
• Surface area.

Bioequivalence

• Drugs are bioequivalent if they have similar rates and extents of bioavailability after administration, regardless of formulation.
• This is vital for different formulations of a drug to be interchangeable.

Distribution

• Once absorbed, drugs are distributed into interstitial and cellular fluids.
• The distribution pattern is influenced by physiological and physicochemical properties of the drug.

Phases of Distribution

• Initial phase: reflects cardiac output, mostly to heart, brain, liver, and kidney.
• Next phase: slower delivery to tissues like muscle, viscera, skin, and fat, involving a larger proportion of the body.

Drug Reservoirs

• Body areas accumulating drugs, like plasma proteins, cellular reservoirs (adipose, for lipid-soluble drugs), bone, or transcellular trapping (ion trapping).
• Dynamic impact on drug availability.

Protein Binding

• Drugs can bind to plasma proteins (e.g., albumin) or tissue proteins.
• Only unbound drug can diffuse across membranes.

Plasma Proteins

• Albumin and α1-acid glycoprotein are important binding proteins.
• Binding impact depend on the concentration of the protein, binding affinity, and the number of binding sites.

Plasma Proteins (2) Example

• Thyroxine (T4) is significantly bound to plasma proteins, particularly to thyroxine-binding globulin (TBG).

Bone Reservoir

• Tetracycline antibiotics and divalent metal ion-chelating agents can store in bone.
• Eventually incorporated into the crystal lattice, serving as a slow release reservoir.

Adipose Reservoir

• Lipid-soluble drugs are stored in fat tissue, which can act as a reservoir, especially in patients with high body fat content.

Thiopental

• Highly lipid-soluble intravenous anesthetic.
• Quickly distributed to brain, and subsequently to other tissues, like muscle.
• Rapid accumulation in fat.
• Can lead to slow elimination and potential prolonged effects.

GI Tract as Reservoir

• Weak bases can concentrate in stomach due to pH.
• Some drugs are excreted in bile and can be reabsorbed or are stored in the GI tract.

Placental Transfer

• Drugs cross the placenta via passive diffusion, mostly lipid soluble and non-ionized drugs.
• Transfer rates tend to increase toward term as tissue layers between maternal and fetal blood capillaries thin.

Clinical Pharmacokinetics

• A relationship exists between the pharmacological or toxic response to a drug and the accessible drug concentration in the blood.
• Important parameters are volume of distribution, clearance, and bioavailability.

Volume of Distribution

• Relates the amount of drug in the body to the plasma concentration.
• The apparent volume of distribution often doesn't correspond to a real anatomical space.

Total Body Water

• Compartments include plasma, interstitial, and intracellular fluids.

Elimination (Clearance)

• Clearance is the volume of blood or plasma cleared of drug during a time period.
• Affected by drug's concentration, and rate of elimination.
• Rates are usually constant (1st-order kinetics) and proportional to drug concentration.

Clearance (2)

• Clearance does not mean the drug is completely removed; rather, it represents the volume of blood cleared per unit time.
• The rate of elimination is directly proportional to the drug concentration.

Clearance (3) / (4) / (5) Examples

• Different drug clearance example are given.

Clearance in Organ

• Rate of elimination = blood flow to organ X (arterial drug concentration minus venous drug concentration)

Kinetics of Drug Elimination

• Zero-order kinetics shows a constant rate of removal.
• First-order kinetics displays proportional removal with decreasing concentration.