Lecture 5: Pharmacokinetics I
Fundamental Concepts of Pharmacokinetics and Pharmacodynamics
Pharmacokinetics is defined as what the body does to the drug. It is characterized by the following outcomes:
Too low concentration: Results in no therapeutic effect.
Too high concentration: Results in side effects.
Different drugs display different pharmacokinetic profiles depending on an individual's genetic makeup.
Pharmacodynamics involves the mechanism of action and the resulting effects on cellular functions, specifically targeting:
Receptors
Ion channels
Enzymes
Transporters
Physicochemical properties of a drug influence both pharmacodynamics and pharmacokinetics:
In pharmacodynamics, these properties affect Affinity, Efficacy, and Potency.
In pharmacokinetics, these properties affect the ADME process, which determines drug concentration.
ADME is the acronym for the four major stages of pharmacokinetics:
Absorption
Distribution
Metabolism
Excretion
Mechanisms of Drug Transfer and Absorption
Movement of drugs between body compartments usually requires the penetration of lipid diffusion barriers, specifically cell membranes.
These barriers determine where a drug will be present in the body and for what duration following administration.
Transfer mechanisms throughout the body include:
Bulk flow transfer: Movement through the bloodstream via the cardiovascular (CV) system.
Diffusion: Passive movement across membranes.
Pinocytosis: Internalization of molecules into the cell.
The Diffusion Coefficient is determined by the molecular weight (MW) of the substance according to the following principle:
Physicochemical Determinants of Absorption: Lipid Solubility and Diffusivity
Lipid solubility is considered one of the most critical determinants of the pharmacokinetic characteristics of small molecule drugs.
Major factors affecting diffusion through lipids include:
Partition coefficient: Reflecting the lipid solubility of the drug.
Diffusion coefficient: Reflecting the diffusivity of the drug.
Molecular charge dictates membrane penetration:
Non-polar (uncharged) molecules dissolve freely in lipids and penetrate cell membranes without assistance.
This determines the rate of absorption from the gut, penetration into the brain and other tissues, and the rate of renal elimination.
The Impact of pH and Ionization on Drug Movement
Many drugs exist as weak acids or weak bases.
Weak acids (HA) dissociate in a reversible reaction:
The Henderson-Hasselbalch Equation describes the relationship between pH and ionization:
Only uncharged (un-ionized) species can cross lipid membranes. At a low pH, weak acids remain in their un-ionized form, facilitating membrane crossing.
pH affects the steady-state distribution of drugs between aqueous compartments through the "ion trapping" effect:
Basic environments (where pH > 7) favor the dissociation (ionization) of acids. Therefore, weak acids become "trapped" in basic compartments such as the renal tubules.
Urinary acidification retards the excretion of weak acids.
Clinical application in Aspirin poisoning ():
Increasing plasma pH (e.g., using sodium bicarbonate) causes weakly acidic drugs like aspirin to be extracted from the Central Nervous System (CNS) into the plasma.
Once in the basic plasma, they become trapped, preventing as much neurotoxicity.
Routes of Drug Administration and Bioavailability
Bioavailability is defined as the fraction of an ingested dose that gains access to the systemic circulation.
Routes and their characteristics:
Oral: Drug travels from the gut through the portal system straight to the liver, where it is metabolized. Peptides like Insulin cannot be taken orally because they would be digested; they must be injected.
Rectal/Suppositories: Can be used if a patient is vomiting or is a baby.
Intravenous (IV): Drug goes straight into the blood, bypassing the gut. It provides immediate circulation but requires a doctor and can be uncomfortable.
Intramuscular: Deeper injection (e.g., for certain vaccinations) allowing for quicker distribution than subcutaneous routes, but requires a bigger needle.
Subcutaneous: Injection right under the skin. Distribution is slow due to poor local circulation.
Intrathecal: Injection into the spine (e.g., during labor). It requires medical professionals but the patient remains conscious.
Inhalation: Used for limited sites of action (e.g., inhalers for the lungs). Drugs may be expired into the air.
Percutaneous (Skin): Absorption through the skin. This can be uncomfortable and may require specialists.
Carrier-Mediated Transport Systems
Drugs can be transported via passive or active mechanisms by specific carriers:
Solute Carrier (SLC) transporters.
ATP-binding cassette (ABC) transporters.
These transporters typically handle endogenous substrates like sugars, amino acids, metal ions, and neurotransmitters.
Over 300 human genes are believed to code for these transporters.
When transporters act on foreign chemicals (xenobiotics or drugs), absorption and elimination are affected by:
Saturation of the transporter.
Competitive inhibition at the transporter site.
Drug transporters often have extensive binding affinity for a broad spectrum of small molecule substrates and inhibitors, which has significant implications for drug-drug interactions.
Example: Genetic variants of organic cation transporter 1 (OCT1) affect responses to Metformin (a diabetes drug). Patients with a polymorphism that impairs OCT1 function show less effective glucose regulation when taking Metformin.
Fluid Compartments and Principles of Drug Distribution
Drugs distribute between the four main fluid compartments of the body. Only "free," un-ionized drug can cross between these compartments.
At equilibrium, the concentration in each compartment depends on four factors:
Permeability across tissue barriers.
Protein binding within the compartments.
pH partition.
Fat:water partition.
Plasma protein binding (specifically Albumin, which mainly binds acidic drugs) can reduce the concentration of "free" drug.
Albumin has a high capacity.
If protein binding sites become saturated, a small increase in dose can lead to an unexpectedly large increase in the concentration of free, active drug.
High protein binding slows down the drug's elimination.
Tissue-Specific Distribution: CNS and Body Fat
The Blood-Brain Barrier (BBB) limits distribution to the CNS:
Endothelial cells in the CNS blood vessels form tight junctions that are impermeable to water-soluble molecules.
Lipid-soluble molecules, such as Ethanol and Caffeine, cross the BBB easily.
Tight junctions can become "leaky" during inflammation. For example, IV penicillin can be used to treat Meningitis because the barrier is compromised by the infection.
Partitioning into body fat:
Body fat acts as a store for lipid-soluble drugs.
Lipid-soluble general anesthetics are highly lipophilic.
Individuals with large fat stores will absorb lipid-soluble drugs into that fat.
For individuals with very little fat, even a low dose of a lipid-soluble drug could cause saturation of the storage site.
Summary of Principles
Most drugs must cross lipid membranes/cellular barriers to reach their targets.
Crossing occurs via passive diffusion or carrier-mediated transfer.
Passive diffusion is dependent on lipid solubility, ionization, and pH:
Weak acids accumulate in compartments with high pH.
Weak bases accumulate in compartments with low pH.
Binding to plasma proteins, bone, or food reduces free drug concentration and can cause non-linear dose-concentration relationships due to saturation.
Absorption and bioavailability depend on the route of administration; gut absorption specifically depends on motility, pH, particle size, and interactions with gut contents.
Lipid-insoluble drugs are generally confined to plasma and interstitial fluids and have limited access to the CNS.
Lipid-soluble drugs enter all compartments and tend to accumulate in fat.