Pharmacokinetics Lesson 1: Volume of Distribution

Pharmacokinetics

• The volume of distribution (Vd) describes the relationship between the administered dose of a drug and the resulting plasma concentration.
• Vd is a theoretical measure of how a drug distributes throughout the body, assuming instantaneous distribution and no metabolism or elimination.
• A drug with a Vd that exceeds total body water (> 0.6 L/kg or > 42 L) is assumed to be lipophilic and requires a higher dose to achieve a given plasma concentration (e.g., Propofol).
• A drug with a Vd that is less than total body water (< 0.6 L/kg or < 42 L) is assumed to be hydrophilic and requires a lower dose to achieve a given plasma concentration (e.g., NMB).

Ionization

• Ionization is the process where a molecule gains a positive or negative charge, affecting its ability to pass through cell membranes.
• Weak acids or bases ionize in water, and the degree of ionization depends on the pH of the solution and the pKa of the drug.
• pKa is a constant property of a molecule, while pH is a changeable property of a solution.

Solubility and Pharmacologic Effects

• Ionized molecules are lipophobic and hydrophilic, while non-ionized molecules are lipophilic and hydrophobic.
• Ionized molecules have reduced pharmacologic activity, are more likely to undergo hepatic biotransformation, and are less likely to be eliminated by the kidneys.
• Non-ionized molecules have increased pharmacologic activity, are less likely to undergo hepatic biotransformation, and are more likely to be eliminated by the kidneys.

Plasma Protein Binding

• Only when a drug is released from plasma protein binding can it travel elsewhere in the body.
• The extent of plasma protein binding affects the intensity and duration of drug effect.
• Albumin is the most plentiful plasma protein and primary determinant of plasma oncotic pressure.
• α1-Acid Glycoprotein and Beta-Globulin also bind basic drugs.

Metabolism

• Phase 1 reactions prepare the molecule for a phase 2 reaction, including oxidation, reduction, and hydrolysis.
• Phase 2 reactions conjugate an endogenous, highly polar, water-soluble substrate to the molecule, inactivating the drug and readying it for elimination.
• Phase 3 reactions involve ATP-dependent carrier proteins that transport a drug across a cell membrane.
• Enterohepatic circulation occurs when conjugated compounds are excreted in the bile, reactivated in the intestine, and reabsorbed into the systemic circulation (e.g., Valium and warfarin).

Pharmacodynamics

• Pharmacodynamics explains the effect of drugs on the body.
• The biophase, or effect site, is the specific area of the body where the drug engages its receptor.

Dose-Response Curve

• The dose-response curve illustrates the relationship between the drug dose and its clinical effects.
• Efficacy is the ability of a drug to elicit a given clinical effect.
• Potency is the dose required to achieve a given clinical effect (ED50 and ED90 are measures of potency).
• A left-shifted dose-response curve indicates higher potency and a lower required dose to achieve ED50.
• A right-shifted dose-response curve indicates lower receptor affinity and higher dose required for ED50.

Agonists and Antagonists

• A full agonist instructs the receptor to produce its maximal response.
• A partial agonist is only capable of partially activating a cellular response.
• An antagonist binds to a receptor and prevents an agonist from binding to it.
• Inverse agonist binds to the receptor and causes an opposite effect to that of a full agonist.

Types of Antagonism

• Competitive antagonism is reversible and shifts the dose-response curve for the agonist to the right.
• Noncompetitive antagonism is not reversible and shifts the dose-response curve for the agonist downwards.

Drug Interactions

• Synergism: The effects of two drugs given at the same time are greater than the sum of their individual effects.
• Addition: The effect of two drugs given at the same time are added together.
• Potentiation: The effect of one drug is enhanced by a drug that has no effect on its own.
• Antagonism: The simultaneous administration of one drug negates the effects of the other.

ED50, LD50, and TD50

• ED50 is the dose that produces the expected clinical response in 50% of the population.
• LD50 is the dose that produces death in 50% of the population.
• TD50 is the dose that produces toxicity in 50% of the population.
• Therapeutic index is the ratio between the TD50 and the ED50, a measure of drug safety.

Chirality

• Chirality is the tetrahedral bonding of carbon (carbon binding to 4 different atoms).
• Enantiomers are chiral molecules that are non-superimposable mirror images of each other.
• Receptors that are stereospecific may respond differently to different enantiomers.
• Racemic mixture contains two enantiomers in equal amounts.