Pharmacokinetics for Nursing Pharmacology: Introduction

Nursing Pharmacology Chapter 2: General Principles: Pharmacokinetics

Table of Contents
Introduction to Pharmacokinetics Absorption Fick's Law Drug Absorption (Short Video) Routes of Administration First-Pass Effect Transdermal Administration Rectal Adminstration Parenteral Administration Pharmacokinetics First-Pass Effect First-Pass Elimination Extraction Ratios, Routes of Administration, and the First-Pass Effect Pulmonary Effects Volume of Distribution Factors Affecting Volume of Distribution Clearance Short Video on Clearance Renal clearance: clearance of unchanged drug and metabolites Other Factors Affecting Renal Clearance Factors affecting hepatic clearance Changes in Intrinsic Clearance Social Factors Diet Age Genetic Factors Capacity-limited elimination Half-life Short Video on Half-Life Drug Accumulation Bioavailablity Extent of Absorption Placental Transfer Redistribution Drug-Plasma Protein Binding Renal Clearance Kidney Other sites	Drug Metabolism Short Video on Drug Metabolism and Nursing Practice Introduction Phase I and Phase II Reaction Overview: Phase I characteristics Phase II characteristics Definition of Conjugates Principal organs for biotransformation Sequence I Sequence II Bioavailability Microsomal Mixed Function Oxidase System and Phase I Reactions The Reaction Cytochrome P450 Enzyme Induction Phase II Reactions Toxicities Acetaminophen (Tylenol) example Individual Variation in Drug Responses Genetic Factors in Biotransformation Effects of Age on Drug Responses Drug-Drug Interactions

"Introduction to Pharmacokinetics"

learnpkpd: Introduction to Pharmacokinetics https://www.youtube.com/watch?v=mp93nPUzHqM . PK/PD Associates Home Site: http://learnpkpd.com/ and https://www.youtube.com/user/learnpkpd .

Absorption

Some Factors Influencing Absorption and Bioavailability

Permeation:
- Passive diffusion (aqueous or lipid environment): most common
- Active transport: important for some drugs, particularly larger molecules.

I. Aqueous diffusion
- Within large aqueous components (e.g.,interstitial space, cytosol)
- Across epithelial membrane tight junctions
- Across endothelial blood vessel lining
  - Through aqueous pores: allows diffusion of molecules with molecular weights up to 20,000 -- 30,000.
- Driving force: drug concentration gradient (described by Fick's Law ).
  - The driving force represents a tendency for molecules to move in the direction of higher concentration to lower concentration in accord with random molecular motion.
    - A traditional way of thinking about this is to imagine a fluid-filled container which is two sections divided by an imaginary plane.
    - The solution on one side is more concentrated in terms of some dissolved substance that is the solution on the other side of the boundary plane.
  - Recall that the molecules move randomly, suggesting that sometimes a molecule initially in the "low concentration" section can move to the "high concentration" section.
    - However, on balance. It is more likely that based on probability molecules will tend to move from the higher concentrations side to the lower concentrations side.
    - Suppose that initially there are 2,000 molecules on side A and 1,000 molecules on side B.
    - After a while we look again and find that there now are 1750 molecules on side A and 1250 molecules on side B-- a new ratio is been established, but the process continues until the ratio is approximately 1:1.

Fick's Law
Fick's Law describes passive movement molecules down its concentration gradient. Flux (J) (molecules per unit time) = (C₁ - C₂) · (Area ·Permeability coefficient) / Thickness Where C₁ is the higher concentration and C₂is the lower concentration Area = area across which diffusion occurs Permeability coefficient: drug mobility in the diffusion path For lipid diffusion, lipid: aqueous partition coefficient -- major determinant of drug mobility Partition coefficient reflects how easily the drug enters the lipid phase from the aqueous medium. Thickness: length of the diffusion path
Katzung, B. G. Basic Principles-Introduction , in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 5.

Plasma protein-bound drugs cannot permeate through aqueous pores
Charged drugs will be influenced by electric field potentials {membrane potentials, important in renal, trans-tubular transport}

II. Lipid diffusion
- Most important barrier for drug permeation due to:
  - Many lipid barriers separating body compartments
- Lipid: aqueous drug partition coefficients described the ease with which a drug moves between aqueous and lipid environments
- Ionization state of the drug is an important factor: charged drugs diffuse-through lipid environments with difficulty.
  - pH and the drug pKa, important in determining the ionization state, will influence significantly transport (ratios of lipid-to aqueous-soluble forms for weak acids and bases described by the Henderson-Hasselbalch equation.
    - Uncharged form: lipid-soluble
    - Charged form: aqueous-soluble, relatively lipid-insoluble (does not pass biological membranes easily)

Henderson-Hasselbalch equation

General Form: log (protonated)/(unprotonated) = pK_a - pH

For Acids: pKa = pH + log (concentration [HA] unionized)/concentration [A^-]
- note that if [A^-] = [HA] then pKa = pH + log (1) or (since log(1) = 0), pK_a = pH

For Bases: pK_a = pH + log (concentration [BH⁺] ionized)/concentration [B]
- note that if [B] = [BH⁺] then pK_a = pH + log (1) or (since log(1) = 0), pK_a = pH

The lower the pH relative to the pK_a the greater fraction of protonated drug is found. Recall that the protonated form of an acid is uncharged (neutral); however, protonated form of a base will be charged.
As a result, a weak acid at acid pH will be more lipid-soluble because it is uncharged and uncharged molecules move more readily through a lipid (nonpolar) environment, like the some membrane, than charged molecules
Similarly, a weak base at alkaline pH will be more lipid-soluble because at alkaline pH a proton will dissociate from molecule leaving it uncharged and again free to move through lipid membrane structures

Lipid diffusion depends on adequate lipid solubility
- Drug ionization reduces a drug's ability to cross a lipid bilayer.

Drugs that are weak acids or bases

A weak acid is a neutral molecule that dissociates into an anion (negatively charged) and a proton (a hydrogen ion, H⁺).
- Example:
  - C₈H₇O₂COOH ⇄ C₈H₇O₂COO^- + H⁺
  - Neutral aspirin (C₈H₇O₂COOH) in equilibrium with aspirin anion (C₈H₇O₂COO^- ) and a proton (H⁺ )
  - A weak acid in its protonated form, having combined with a proton (H⁺ ) is electrically neutral and therefore more lipid-soluble
A weak base is a neutral molecule that can form a cation (positively charged) by combining with a proton.
- Example:
  - C₁₂H₁₁CIN₃NH₃⁺ ⇄ C₁₂H₁₁CIN₃NH₂ + H⁺
  - Pyrimethamine cation (C₁₂H₁₁CIN₃NH₃⁺) in equilibrium with neutral pyrimethamine (C₁₂H₁₁CIN₃NH₂) and a proton (H⁺ )
  - A weak base after accepting a proton (H⁺ ) is now in a protonated form which is positively electrically charged and thus less lipid-soluble

Weak acids	pK_a	Weak bases	pK_a
Phenobarbital (Luminal)	7.1	Cocaine	8.5
Pentobarbital (Nembutal)	8.1	Ephedrine	9.6
Acetaminophen	9.5	Chlordiazepoxide (Librium)	4.6
Aspirin	3.5	Morphine	7.9

III. Special Carriers
- Peptides, amino acids, glucose are examples of molecules then enter cells through special carrier mechanisms.
- Carriers:
  - Active transport describes an energy requiring process which is saturable, meaning that transport is probably against the concentration gradient and involves a specific number of carriers, hence the process must be saturable when all carrier sites are filled.
  - Facilitated diffusion, while not requiring "energy" is also saturable (limited number of carrier sites)
  - Saturable (unlike passive diffusion) because of limited number of carrier sites--once those sites are filled, transport rates cannot be increased.
  - A property of carrier systems is that process is subject to inhibition by other small molecules.

IV. Endocytosis and exocytosis

Endocytosis: Entry into cells by very large substances (e.g., iron vitamin B₁₂ -- each complexed with its binding protein -- movement across intestinal wall into the blood)
Neurotransmitter release at the synapse is an example of exocytosis:
- Following neuronal electrical activation of nerve endings, two steps may be initiated:
  1. Storage vesicles containing neurotransmitter fuse with cell membranes followed by release or diffusion of contents into the extracellular region.

Endocytosis and Exocytosis

Endocytosis and Exocytosis (cecamgmacz, https://www.youtube.com/watch?v=DuDmvlbpjHQ .)

Summary

Figure Developed by Dr. Steve Downing, University of Minnesota

Extent of Absorption

Incomplete absorption following oral drug administration is common:
- For example -- only 70% of a digoxin dose reaches systemic circulation. Factors:
  - Poor GI tract absorption
  - Digoxin (Lanoxin, Lanoxicaps) --- metabolism by gastrointestinal flora
Very hydrophilic drugs - not be well absorbed --cannot cross cell membrane lipid component
Excessively lipid-soluble (hydrophobic) drugs may not be soluble enough to cross a water layer near the cell membrane.

Ion Trapping

Kidney:
- Nearly all drugs filtered at the glomerulus:
  - Most drugs in a lipid-soluble form will be reabsorbed by passive diffusion.
  - To increase excretion: change the urinary pH to favor the charged form of the drug since charged form cannot be readily reabsorbed (they cannot readily pass through biological membranes)
    - Weak acids: excreted faster in alkaline pH (anion form favored)
    - Weak bases: excreted faster in acidic pH (cation form favored)
Other sites:
- Body fluids where pH differences from blood pH favor trapping or reabsorption:
  - Stomach contents
  - Small intestine
  - Breast milk
  - Aqueous humor (eye)
  - Vaginal secretions
  - Prostatic secretions

Ion Trapping: Placental transfer of basic drugs
Placental transfer of basic drugs from mother to fetus: local anesthetics. Fetal pH is lower than maternal pH. Lipid-soluble, nonionized local anesthetic crosses the placenta converted to poorly lipid-soluble ionized drug. Drug gradient is maintained for continual transfer of local anesthetic from maternal circulation to fetal circulation. In fetal distress, acidosis contributes to local anesthetic accumulation.

Weak bases amines

N + 1 carbon (R) and 2 hydrogens: primary amine (reversible protonation)
N + 2 carbons (R) and 1 hydrogen: secondary amine (reversible protonation)
N + 3 carbons (R): tertiary amine (reversible protonation)
N + 4 carbons (R): quaternary amine (permanently positively charged)

References
Katzung, B. G. Basic Principles-Introduction , in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 1-33 Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.