Pharmacokinetics - ADME

Objectives

  • Outline the stages of pharmacokinetics:
    • Absorption
    • Distribution
    • Metabolism
    • Excretion
  • Describe significant factors affecting:
    • Absorption
    • Distribution
    • Metabolism
    • Excretion
  • Define:
    • CmaxC_{max}
    • T1/2T_{1/2}
    • TmaxT_{max}
    • Onset of action
    • Clearance
    • Volume of distribution
    • Bioavailability of a drug
  • Define:
    • MEC (Minimum Effective Concentration)
    • MTC (Minimum Toxic Concentration)
    • Therapeutic range of a drug

Lecture Overview

  • How drugs enter the body.
  • What happens to drugs inside the body.
  • How the body eliminates drugs through:
    • Metabolism
    • Excretion
  • These processes affect:
    • Onset of drug action
    • Duration and intensity of drug action

ADME

  • A = Absorption
  • D = Distribution
  • M = Metabolism
  • E = Excretion
  • Absorption:
    • Drugs are absorbed from the small intestine.
    • They enter the portal vein.
    • Pass through the liver, where different enzymes either deactivate or activate the drug.
    • This process is known as first-pass metabolism.

Route of Administration and Drug Absorption

  • Intravenous (IV):
    • Administered through veins.
    • 100% bioavailability (e.g., 10 mg administered = 10 mg available).
    • Fastest route of administration.
    • Immediate administration.
    • No first-pass metabolism.
  • Oral:
    • Most complex and common route.
    • Involves many barriers.
    • Patients can self-administer.
    • Reduced bioavailability due to first-pass metabolism.
    • Absorption occurs through the digestive system (stomach, intestine).
  • Inhalation:
    • Drugs are well absorbed if good air entry.
    • Fast, bypasses the digestive system, and no first-pass metabolism.
    • Example: Inhalers.
  • Intramuscular/Subcutaneous:
    • Variable absorption depending on circulation and tissue pH.
    • Injected into muscle (intramuscular) or fat tissue (subcutaneous).
    • Slower than IV as drugs need to dissolve into the bloodstream.
    • Tissue pH is important as most drugs are ionized (charged).
  • Rectal:
    • Faster than oral, bypasses first-pass metabolism.
    • Used for patients who cannot take oral medication.
    • Aims to avoid liver metabolism.
    • May bypass side effects associated with oral administration.
    • Erratic absorption due to variable blood supply.
  • Sublingual:
    • Under the tongue, absorbed into the mucous membrane.
    • Very fast absorption.
    • Bypasses the digestive system, entering directly into the bloodstream.
    • Rapid action with good blood supply.
  • Topical:
    • Variable absorption, usually slow as the skin acts as a barrier.
    • Lipid-soluble substances (ointments) are absorbed better than aqueous creams.

Intravenous (IV) Administration

  • Advantages:
    • Very rapid.
    • Precise control (100% bioavailability).
    • Avoids absorption problems or drug breakdown before entering the blood.
      • Avoids enzymes in the liver.
      • No loss of dose.
    • Suitable for drugs that are too irritating for oral intake or tissue injection.
  • Disadvantages:
    • Requires skill (e.g., to prevent air embolism).
      • Air embolism: Air in the bloodstream, can block and be fatal.
    • Requires healthcare professional.
    • Careful preparation needed (sterile, non-particulate).
    • Most hazardous due to no recall.
      • 100% bioavailability can lead to overdose and can be fatal.
      • Non-reversible.

Oral (PO) Administration

  • Most common route, accounting for 80% of all prescriptions.
  • Advantages:
    • Safest, most convenient, and economic.
  • Disadvantages:
    • Slow (1/2 - 3 hours for effect).
    • Unpredictable regarding rate, extent, and reproducibility.

Plasma Drug Concentration Curve

  • Absorption phase: drug enters the portal vein.

Drug Physiochemical Properties

  • Solubility in lipids and water is important for absorption, distribution, and excretion.
  • Non-polar or ionized state influences by pH.
  • Chemical structure affects susceptibility to metabolism.

Typical Biological Membrane

  • Many lipid membranes exist between tissue compartments.
  • Small, uncharged, and lipid-soluble drugs distribute faster and more widely than bulky, ionized, less lipid-soluble drugs.

Main Mechanisms of Transport Across Biological Membranes

  • Passive Diffusion:
    • Most important mechanism.
    • Applies to non-polar drugs (i.e., lipid-soluble).
    • Concentration gradient is the driving force.
    • No energy required.

pH and Membrane Permeability

  • Unionized drug crosses lipid biological barriers (e.g., membranes) better than ionized drug.

Facilitated Diffusion

  • For some drugs, movement occurs faster than predicted.
  • Depends on an oscillating transporter protein.
  • Depends on concentration gradient.
  • No energy required (passive transport).
  • Sugars and amino acids are usual substrates.
    * Example: Cephalexin via oligopeptide transporter in the intestine.

Active Transport

  • Can proceed against concentration gradient.
  • Requires energy (ATP).
  • Membrane transporter proteins and channels are involved.
    * Limited amount, easily saturated.
  • Saturation can lead to decreased absorption.
  • Drugs may accumulate, leading to off-target toxicity.
  • Specific organs involved: Liver, kidney, gut epithelium.
  • Allows cells to:
    • Accumulate essential compounds for growth (e.g., sugars, amino acids, vitamins, and drugs like methotrexate, glucuronides).
    • Remove waste products.

Intestinal Drug Transporters

  • Most important: P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
  • BCRP limits drug absorption.
    • Inhibition of BCRP increased oral absorption of sulphasalazine.
    • Curcumin is a BCRP inhibitor.
    • Sulphasalazine is an anti-inflammatory medication used for arthritis.

Endocytosis

  • Internalization of large molecules by the cell.
  • Mainly for drugs with molecular weight > 1000 (e.g., cytokines, hormones, growth factors, immunoglobulins).
  • Involves 3 steps:
    • Substrate binds to receptor.
    • Invagination of receptor-substrate complex.
    • Budding off and delivery of vesicle into the cell.

Filtration

  • Most drugs pass through cells to cross biological barriers, except in:
    • Blood capillaries:
      • Contain fenestrations that allow rapid interchange between blood and interstitial fluid.
    • Glomerular capillaries:
      • Extremely porous, allowing passage of all plasma constituents except macromolecules with MW > 30,000.

Drug Absorption

  • Refers to the passage of a drug from its site of administration into the general circulation.
    • Except for drugs applied directly to the target tissue.
  • An intravenously injected drug is immediately and completely (100%) absorbed.
  • Orally administered drugs face several barriers to absorption, making absorption delayed and incomplete.

Measurement of Absorption

  • Measured via bioavailability.
    • Percentage of the original drug that reaches plasma as active (bioavailability = F%).
  • Brand drugs and generic drugs must have the same bioavailability (bioequivalence).

Absorption: Rate and Extent

  • Rate: How rapidly the drug gets from its site of administration to the general circulation.
  • Extent: How much of the administered dose enters the general circulation (% bioavailability = F).
  • Possible effects of rate and extent of absorption on pharmacological action.

Factors Influencing the Oral Absorption of Drugs

  • Decomposition in acidic gastric juices.
  • Decomposition by hydrolytic gut enzymes (e.g., proteases, lipases).
  • Degradation by gut microorganisms.
  • Food in the gut may alter absorption rate and amount (e.g., interact to form a complex).
  • Metabolism by gut wall enzymes.
  • Drug formulation.

Patient Factors Influencing Absorption

  • Stomach emptying rate:
    • Major factor in determining the rate of absorption.
    • Rate increased by hunger, mild exercise, other drugs.
    • Rate decreased by hot meals, vigorous exercise, pain, migraine, labor, and drugs (narcotics, anticholinergics, tricyclics).
  • Intestinal motility:
    • Increased motility due to gastroenteritis and diarrhea.
      • Decreased transit time (important for drugs with low H2OH_2O solubility such as digoxin) leads to decreased bioavailability.
    • Decreased motility by various drugs (narcotics, anticholinergics, tricyclics).
  • Interactions with food:
    • Example: Chelation of tetracycline with metal ions (Ca2+, Fe2+).
  • Effect of food on erythromycin bioavailability:
    • AUC decreased by a mean of 50% with breakfast.
  • Effect of food on Metoprolol bioavailability:
    • AUC increased by a mean of 60% with breakfast.
  • Effect of a large or small volume of water on drug bioavailability.

Capillary Permeability

  • Most capillaries are relatively porous.
  • Drugs leave the blood regardless of being poorly soluble, charged, or polar.
  • Brain capillaries have no pores and have an additional layer of glial cells.
    • Only lipid-soluble drugs diffuse across brain capillaries unless they undergo active transport.

Body Fluid Compartments

  • Drug distribution and blood flow.
  • Tissue receiving more blood receives more drug.
  • Rate of distribution to tissues depends on relative blood flow.
    • Heart, lungs, brain, liver, and kidney receive drug very rapidly.
    • Slower rate to less well-perfused organs, such as muscle, skin, and fat.
  • Tissue uptake:
    • Lipid-soluble drugs are taken up into fat (e.g., 70% thiopentone present in fat 3 hours after administration).
  • Various tissue proteins reversibly bind drugs (e.g., albumin).
    • Albumin used as a novel carrier for drug delivery.
  • Tissue binding may have adverse effects:
    • Example: Tetracycline binds to bone and teeth, weakening and discoloring them (contraindicated in children).
  • Volume of distribution (VDV_D):
    • Apparent volume that drug is distributed into based on the concentration measured in plasma.
    • Hypothetical volume.
    • Concentration=amountgiven(dose)volumeConcentration = \frac{amount given (dose)}{volume}
    • VD=amountgivenconcentrationinplasmaV_D = \frac{amount given}{concentration in plasma}
    • Drug isn't evenly distributed, so VD often exceeds total body water.

Blood-Brain Barrier (BBB)

  • Endothelial cells lining the microvasculature of the central nervous system (CNS) constitute the BBB.
  • Selectively excludes circulating drugs and toxic agents from entering the neural parenchyma but allows essential nutrients, hormones, and some drugs into the brain.

Blood-Brain Barrier to Drugs

  • Example: Histamine accumulation in intestinal tissues but no apparent accumulation in the brain due to the BBB preventing histamine from entering.

Drugs Penetrating BBB

  • The likelihood of BBB transport of a molecule is determined by the molecular weight (MW), structure, and interaction with transporters.
  • Central nervous system (CNS) drugs.

CNS Infection and BBB

  • Normally, the BBB limits the entry of many substances, including antibiotics (e.g., penicillin), into the CNS.
  • During CNS infections like bacterial meningitis, the inflammation of the meninges increases the permeability of the BBB, allowing antibiotics like penicillin to penetrate more effectively.