Pharmacology - Pharmacokinetics

Pharmacokinetic Modelling

• What amount to give to the patient to sooth their symptoms.

• Using math to predict drug concentration over time in the body, so one can choose the right dose and dosing schedule.

Pharmacokinetic Studies

• The introduction of a new drug.

Enteral

• A route of drug administration.

• Involving or passing through the intestine, either naturally via the mouth and esophagus, or through an artificial opening.

  • Consists of oral, sublingual, and rectal.

Oral (Enteral)

• Most common route; first pass effect (30-90 minutes).

  • Takes time for the drug to create an effect.

Sublingual (Enteral)

• Rapid absorption route; bypasses ‘first pass” effects despite taking orally.

  • Under the tongue.

• Rapid delivery (3-5 minutes).

Rectal (Enteral)

• Allows rapid systemic effects (5-30 minutes).

• ~50% of the drug that is absorbed from the rectum will bypass the liver.

• Takes some time but not as much as oral.

• Not all of the drug is subjected through first pass.

Parenteral

• A route of drug administration.

• Administered by any way other than through the mouth.

  • Consists of intravenous and intramuscular/subcutaneous routes.

Intravenous (Parenteral)

• Delivery directly into the systemic circulation, very rapid onset of action (seconds to minutes).

  • Directly into the blood.

Intramuscular/Subcutaneous (Parenteral)

• Injection into muscle/ just below the skin; rate of absorption depends on blood flow to site (10-20 minutes).

Other Routes

• There are other routes of drug administration.

  • For example, inhalation and topical/transdermal (ointment/patch).

Inhalation (Other)

• Absorption is through epithelium in the lungs and can be very rapid (2-3 minutes).

  • i.e. asthma, anesthesia.

Topical/Transdermal (Other)

• Convenient, slow absorption (minutes to hours) and sustained exposure.

• Comes in the form of a ointment/patch.

  • i.e. topical treatments.

Absorption & Elimination

• The drug needs to be absorbed from its site of administration.

• It then needs to travel in the body to reach its target tissue.

• Over time the effects of the drug ‘wear off’ because the drug is eliminated from the body.

Therapeutic Window

• The overall range between the minimum effective concentration and the toxic concentration that defines the safety limits of a drug.

• Defines the upper and lower boundaries of safe drug exposure.

• Describes what is allowable, not what is actively targeted.

Therapeutic Concentration/Range

• The target drug concentration maintained within the therapeutic window to ensure effectiveness while avoiding toxicity.

• Represents the optimal level clinicians aim to maintain.

• Describes what is actively targeted, not the full safety limits.

Time Course of Drug Action (Oral)

• As more time passes, more of the drug is absorbed; the initial upward slope is the absorption phase.

• Plasma drug concentration increases with time until Cmax, the maximum concentration achieved.

• After Cmax, the concentration decreases as time passes.

• Therapeutic effect occurs only while the concentration remains above the minimal therapeutic effect.

Absorption Phase

• Initial upward portion of the curve.

• Plasma drug concentration increases with time.

• Occurs as the drug is absorbed into systemic circulation.

Cmax

• The maximum plasma concentration achieved after dosing.

• Occurs at the peak of the curve.

• Must remain below the toxic threshold.

Tmax

• The time at which Cmax occurs.

• Marks the end of the absorption phase.

• Indicates how quickly peak concentration is reached.

Minimal Therapeutic Effect (Minimum Effective Concentration)

• The lowest plasma concentration that produces a therapeutic effect.

• Below this level, the drug has no clinical effect.

• Forms the lower boundary of the therapeutic window.

Duration of Therapeutic Effect

• The time the drug concentration remains above the minimal therapeutic effect.

• Corresponds to the effective portion of the curve.

• Determines how long the drug produces benefit.

IV Bolus

• Drug is given all at once.

• Administered intravenously.

• Entire dose enters systemic circulation immediately.

• No absorption phase.

IV Bolus: Time Course of Drug Action

• Plasma drug concentration is highest at time zero (C₀).

• Concentration begins decreasing immediately after administration.

• Decline reflects drug elimination over time.

• No rising phase is present on the curve.

IV Infusion

• Drug is given over time, not all at once.

• Administered intravenously.

• Drug enters systemic circulation continuously.

• Dose rate is controlled.

IV Infusion: Time Course of Drug Action

• Plasma drug concentration increases over time.

• Amount of drug eliminated = amount of drug injected, producing steady state concentration (Css).

• Concentration goes up but plateaus at steady state.

• Takes approximately 5 half-lives to reach steady state concentration.

Elimination Rate Constant (Ke)

• Describes the rate at which drug is eliminated from the body.

• It is obtained from the slope of the log-transformed concentration–time plot for an IV bolus.

• The slope of this straight line equals –Ke.

• Larger Ke = faster elimination.

Calculating Ke

• Two concentrations (C1 at t1, C2 at t2) are selected from the linear portion.

• The slope is calculated using the change in ln(concentration) over time.

• Formula:

  • –Ke = (ln C2 − ln C1) / (t2 − t1)

  • or –Ke = ln(C2 / C1) / (t2 − t1)

• Ke is reported as a positive value (rate constant).

Conceptual Meaning of Ke

• Ke represents the fraction of drug eliminated per unit time.

• A Ke of 0.462 hr⁻¹ means ~46% of the remaining drug is eliminated per hour.

• Elimination is proportional to how much drug is present (first-order).

Active Transport

• Done by transporters by using energy (ATP), move against the concentration gradient (e.g. ABC transporters - Digoxin).

  • Digoxin is a heart medication.

Facilitated Transport

• Move down the concentration gradient via a transporter without a need for energy (ATP) (e.g. amino acid transporter - Levodopa).

  • Going from high to low concentration using a transporter.

Diffusion

• Move down the concentration gradient without a need for transporter.

• Highly lipophilic drugs (e.g. Amiodarone).

  • Serious arrythmia medication.

Paracellular Transport

• Occurs via tight junction between the cells.

• The drug finds spaces between the cells and squeezes through.

• Small, hydrophilic drugs (i.e. Metformin).

  • Used for diabetes type 2 treatment.

Three Factors Governing Drug Distribution:

1. Concentration gradient of free drug between blood and target organ/compartment.

2. Solubility of drug in the target organ/compartment (relative water/fat solubility).

3. Blood flow to the target organ.

1. Concentration Gradient of Free Drug

• Determined by the concentration gradient of free drug between blood and the target organ/compartment.

• Only the unbound (free) fraction is pharmacologically active.

• Plasma protein binding reduces the amount of active drug; bound drug is inactive.

• Highly protein-bound drugs can have small effects despite large amounts present (e.g., Warfarin ~99% bound).

2. Solubility of Drug in Target Organ/Compartment

• Depends on the drug’s relative water vs fat solubility.

• Lipophilic drugs preferentially accumulate in fat-rich tissues.

• Accumulation is favored when solubility in the tissue is high.

• Example: Amiodarone, which accumulates in fat tissue.

3. Blood Flow to the Target Organ

• Distribution depends on how well the tissue is perfused.

• Highly perfused tissues accumulate drug more readily.

• Poorly perfused tissues accumulate drug more slowly.

• Examples: Brain (highly perfused) vs fat tissue (poorly perfused).

Viscera

• Highly perfused organs (vessel-rich group) - rapid distribution of drugs.

Muscle

• Drugs perfuse well here.

• Large mass, quick distribution despite low lipid content.

Fat

• Drugs with high lipid solubility will accumulate in fat, but distribution to this compartment is slow due to poor blood supply.

Blood-Only Beaker

• The volume of solution is unknown.

• When you calculate the volume, it represents the amount of water the drug has distributed into.

• This is the apparent volume, not the actual physical volume of the beaker.

• It reflects how widely the drug has proliferated outside the blood.

Blood + Extravascular Beakers

• The total volume of solution includes blood plus extravascular compartments.

• The drug distributes between these compartments.

• The measured concentration in blood is lower because the drug is spread out.

• This corresponds to the drug being distributed in ~100 L of water (apparent).

Apparent Volume of Distribution (Vd)

• The total volume of solution includes blood plus extravascular compartments.

• The drug distributes between these compartments.

• The measured concentration in blood is lower because the drug is spread out.

• This corresponds to the drug being distributed in ~100 L of water (apparent).

Volume of Distribution (Vd) Formula

• For an IV bolus, Vd = Dose / C₀, where C₀ is the initial plasma concentration.

• From the graph, C₀ = 100 mg/L and Dose = 1000 mg.

• Vd = 1000 mg / 100 mg/L = 10 L.

• Rearranging to Dose = Vd × C allows calculation of the loading dose needed to reach a target plasma concentration.