Pharmacokinetics

Overview of Pharmacokinetics

• Definition: The relationship between drug dose and plasma concentration over time.

• What does the body do to the drug?

• Four Main Components:

  • Absorption

  • Distribution

  • Metabolism (Biotransformation)

  • Elimination

Acid-Base

• An acid is a substance that donates a proton: HA$\lrArr$ H+ + A-

• a base is a subsance that accepts a proton: B + H+ $\lrArr$ BH+

• Ionization is dependent on two Factors:

  1. The pH of the solution

  2. The pKa of the drug

     

Ion Trapping

• Only un-ionized, lipophilic drugs diffuse across membranes. Upon crossing, they ionize based on local $pH$ and $pKa$, resulting in varying drug concentrations and ionization levels on each side of the membrane.

• After it does, it will ionize based on pKa and pH of the solution on this side of the membrance.

• Therefore, the drug concentration and the degree of ionization will differ on each side of the membrane.

  

• Fetal Ion Trapping

  • Mechanism: Un-ionized drugs cross the placenta and become ionized in the relatively acidic fetal environment. Once ionized, they cannot diffuse back, leading to drug accumulation in the fetus.

  • Key Factors:

    • Maternal alkalosis increases the risk.

    • Lidocaine is highly susceptible to trapping.

    • Chloroprocaine is least likely to be trapped due to its high pKa and rapid metabolism in maternal blood.

Absorption

• Definition: The process of drug movement from the site of administration to the bloodstream (plasma).

• Bioavailability:

  • Definition: The fraction of the drug dose that reaches systemic circulation.

  • Example: Intravenous (IV) administration has a bioavailability of 1 (or 100%).

• Factors Affecting Absorption:

  • Un-ionized drugs absorb better than ionized drugs.

  • Acidic drugs are better absorbed in the acidic stomach, while basic drugs are absorbed in the alkaline intestine.

• First-Pass Metabolism:

  • Venous drainage from stomach and small intestines flows to the liver, leading to first-pass metabolism.

  • Venous drainage from the mouth and esophagus goes to the superior vena cava, bypassing the liver.

  • Rectal administration partially bypasses the portal system, making it a useful option for children or individuals who cannot take oral medications.

  • Note: Rectal administration can be erratic and may cause irritation to the rectal mucosa.

• Transdermal Administration:

  • Provides extended release.

  • The stratum corneum (first sub-layer of the epidermis) is a barrier to most medications except lipid-soluble drugs (e.g., nitroglycerin, scopolamine, fentanyl, EMLA, clonidine).

• Subcutaneous Absorption:

  • Relies on diffusion from the injection site to the bloodstream.

  • Diffusion rate is affected by blood flow to the injected tissue and the drug formulation (solutions [already ready] are absorbed faster than suspensions[must be broken down first before being absorbed]).

  • IV administration bypasses absorption entirely, avoiding first-pass metabolism.

Distribution

• Definition: After absorption, drugs are distributed throughout the body via the bloodstream.

• Distribution Characteristics:

  • The vessel-rich group (brain, heart, liver, kidneys) receives a greater portion of cardiac output (75%) but constitutes only 10% of body mass.

    • This leads to faster equilibration with plasma concentration due to increased blood flow

  • The muscle and skin constitute 50% of body mass but receive only 19% of cardiac output.

  • Fat (20% body mass) receives 6% of cardiac output.

  • The vessel-poor group (bone, ligaments, cartilage) is 20% body mass and receives <1% of cardiac output.

  • Fat and skin have a larger capacity for storing lipophilic drugs, which leads to a larger reservoir after infusion or a large bolus dose.

• Law of Mass Action:

  • When plasma concentration exceeds tissue concentration, drugs move down their concentration gradients (vice versa).

• Volume Distribution (Vd):

  

  • Definition: Relationship between drug dose and the resulting plasma concentration, indicating how much a drug spreads after entering the body.

  • Formula: $V_d = \frac{\text{Amount of drug}}{\text{Desired plasma concentration}}$

  • Characteristics:

  • Small volume distribution = drug remains primarily in the bloodstream.

  • Large volume distribution = drug disperses into tissue (fat/muscle).

  • Vd assumes two things:

    • 1) drug distributes instanataneously

      • Full equilibration at time = 0

    • 2) drugs aren’t subject to biotransformation or elimiation before it’s fully distributed.

• Affecting Factors of Vd:

  • Drug characteristics: molecular size, ionization, protein binding.

  • Patient characteristics: pregnancy, burns, etc.

• Body Water Distribution:

  • Total body water in a 70 kg male = 42 liters, subdivided into:

    • Intracellular fluid: 28 liters

    • Extracellular fluid: 14 liters (4 liters plasma volume, 10 liters interstitial fluid).

      

• Lipophilic Drugs:

  • Volume distribution greater than total body water indicates higher lipophilicity, requiring increased doses.

  • Example: Propofol.

• Hydrophilic Drugs:

  • Volume distribution less than total body water indicates higher hydrophilicity, allowing for reduced doses.

  • Example: Neuromuscular blockers.

• Loading Dose:

  • Purpose: Achieve a predetermined plasma concentration.

  • Formula: $\text{Loading Dose} = \frac{\text{Desired plasma concentration}}{\text{Bioavailability}} \times V_d$

• IV Anesthetics:

  • Display two compartments (central and peripheral).

  • Volume distribution at steady state involves both compartments.

    • The central compartment represents the plasma and highly perfused organs, while the peripheral compartment includes less perfused tissues. This multi-compartmental model helps in understanding the distribution kinetics of IV anesthetics and optimizing dosage regimens.

  • Compartment Models:

    • Two-compartment model shows biphasic decrease in plasma concentration after IV bolus (alpha distribution and beta elimination with differing slopes).

      

    • Three-compartment model expands this concept further, accounting for a third compartment, often representing slowly equilibrating tissues, which provides an even more accurate representation of the drug's pharmacokinetics in complex biological systems.

      

Elimination

• Definition: The process of removing drugs from the body.

• Contect-Sensitive Half-Life:

  • Definition: Time required for 50% of the drug to leave the body after a rapid IV injection. Measures a constant fraction and NOT a constant amount.

  • Different from elimination halftime (the time for 50% removal during the elimination phase, applicable to one-compartment models).

    

• Context-Sensitive Half-Time:

  • Definition: Time needed for plasma concentration to decrease by 50% after cessation of infusion.

  • Longer infusions result in greater drug accumulation in peripheral compartments, increasing elimination half-time.

    

Metabolism (Biotransformation)

• Definition: The process in which the liver synthesizes plasma proteins that bind to drugs, affecting their activity.

• Plasma Proteins:

  • Albumin: the most plentiful protein that’s negatively charged and binds acidic drugs.

  • It determines oncotic pressure and has a T1/2 of 3 weeks

  • Plasma concentration is increased by liver and renal disease, old age, malnuitrition, and pregnancy

  • alpha-1 acid glycoprotein and beta globulin (binds basic drugs).

    • Alpha-1 acid glycoprotein: A positive acute phase protein and its levels are influenced by inflammation and stress.

      

• Measuring Percent Change Formula:

  • $\text{Percent change} = \frac{\text{New value} - \text{Old value}}{\text{Old value}} \times 100$

• Alteration in protein binding: cardiopulmonary Bypass, ECMO, bilirubin, and thyroxin

• Factors Influencing rate Metabolism:

  • Blood flow to the metabolizing site.

  • Genetic factors and enzyme activity (inducers and inhibitors).

• Kinetics:

  • Zero Order Kinetics: Constant amount of drug metabolized per time (e.g., theophylline, heparin, Aspirin, Phenytoin, ETOH, and Warfrin).

    

  • First Order Kinetics: A fraction of drug metabolized per time (e.g, most common used in clinical practice)

    • can convert to zero order if saturation occurs.

      

• Sites of Metabolism:

  • Primarily in the liver (smooth endoplasmic reticulum), but also in kidneys, plasma (Hoffman and hydrolysis), lungs, and intestines.

  • Purpose of metabolism is to change lipid-soluble, active compounds into water-soluble, inactive byproducts (waste)

    

• Metabolism Phases:

  • Phase I: Adjusts the compound for Phase II (modification)

    • Oxidation: removes electron

    • Reduction: adss electron

    • Hydrolysis: adds water to split it apart (e.g., esters)

  • Phase II: Involves conjugation to make molecules inactive and water-soluble for excretion.

    • Adds a highly polar, water-soluble substrate

      • glucuronic Acids, Glycine, Acetic acid, Sulfric acid, or a methyl group

      • Enterohepatic Circulation: excreted into the bile and it’s reactivated in the intestine which leads to reabsoprtion back into the systemic circulation (e.g., Warfarin and Diazepam).

  • Phase III: ATP-dependent carrier potein transportion of drugs across the cell membrane for elimination.

• 4 Key Metabolic Pathways:

  • Pseudocholinesterase: Drugs include succinylcholine, Mivacurium, and ester local anesthetics (cocaine also involves hepatic.

  • Nonspecific Esterases: Includes remifentanil, Esmolol (RBC esterases), Atracurium (also invloves hoffman), Clevidipine, Etomidate (also involves hepatic), and remimazolam.

  • Alkaline Phosphatase: Engages fospropofol (prodrug).

  • Hoffman Elimination: Affected by pH and temperature (e.g., atracurium and cisatracurium).

    

• Important Enzyme Systems:

  • Located in the smooth endoplasmic reticulum of the hepatocytes.

  • Cytochrome P450 System (CYP): CYP3A4 handles 50% of anesthetics.

  • Enzyme Inducers: Increase drug clearance (e.g., ethanol, rifampin, barbiturates, St. John’s Wort) - may require higher doses.

  • Enzyme Inhibitors: Decrease drug clearance (e.g., grapefruit juice, erythromycin, ciprofloxacin, and SSRIs) - may lower dose requirements.

    

Hepatic Clearance

• Definition: The rate at which drugs are cleared from the liver is influenced by blood flow and the hepatic extraction ratio.

• Extraction Ratio:

  • Formula: $\text{Extraction Ratio} = \frac{\text{Arterial concentration} - \text{Venous concentration}}{\text{Arterial concentration}}$

• Effects: Extraction ratio of 1 means 100% drug removal.

• Ratios >0.7 (high extraction) means clearance is dependent on liver blood flow (e.g., fentanyl, morphine, ketamine, and propofol)

• Ratios <0.3 (low extraction) are dependent on liver extracting drug from blood (e.g., Rocuronium, diazepam, and methadone)

  

Renal Excretion

• Definition: The elimination of drugs from the body through kidney excretion.

• Mechanisms:

  • Unbound, small drugs pass freely from plasma to glomerular filtrate.

  • Unionized drugs are reabsorbed in the renal tubules; ionized drugs remain excreted based on urinary pH.

  • Renal elimination of drugs depends on urinary pH and polarity

• Transport Systems:

  • Organic Anion Transporters for drugs like furosemide, thiazide, and pencillin

  • Organic Cation Transporters for drugs like morphine, meperidine, and dopamine

  • These proteins are located in the proximal renal tubules and secrete both acidic and basic compounds.

  • Metabolites may convert back to parent drugs (example: lorazepam).