General Principles of Pharmacology: Pharmacokinetics

Table of Contents
Absorption Fick's Law Extent of absorption Ion trapping Routes of Administration Oral administration Transdermal adminstration Rectal administration Parenteral administration Bioavailability First-pass Effect First-pass elimination Extraction ratios Pulmonary Effects Pharmacokinetics Volume of Distribution Clearance Renal clearance: clearance of unchanged drug and metabolites Other ractors affecting renal clearance Factors affecting hepatic clearance Capacity-limited elimination Half-life Drug accumulation Bioavailablity Extent of absorption First-pass elimination Rate of absorption Extraction ratios Pharmacokinetic equations Placental Transfer Redistribution Drug-Plasma Protein Binding Renal_Clearance	Drug Metabolism Introduction Phase I and phase II reaction overview: Phase I characteristics Phase II characteristics Conjugates Principal Organs for Biotransformation Sequence I Sequence II Bioavailability Microsomal mixed function oxidase system and phase I reactions The reaction Favoprotein--NADPH cytochrome P450 reductase Cytochrome P450: -- terminal oxidase P450 enzyme induction P450 enzyme inhibition Human cytochrome P450 Phase II reactions Toxicities Individual variation in drug responses Genetic factors in biotransformation Effects of age on drug responses Drug-Drug Interactions Pharmacokinetics and some IV Anesthetics Agents Barbiturates Thiopental Benzodiazepines Ketamine and Etomidate Propofol Opioids Membrane Bilayer Structure

Pharmacokinetics

**Pharmacokinetics**

Attribution: Saffarzadeh A What is Pharmacokineticshttps://www.youtube.com/watch?v=CMRZqdrkCZw (8/2012) Saffarzadeh Youtube Channel: https://www.youtube.com/channel/UCh93eqkE5oje6973bZXqM8A

Absorption

Some Factors Influencing Absorption and Bioavailability

**"Absorption Overview"**

Attribution: Saffarzadeh A Drug Absorption Overview https://www.youtube.com/watch?v=eya9jR3v7i8 . (8/2012) Areo Saffarzadeh Youtube Channel: https://www.youtube.com/channel/UCh93eqkE5oje6973bZXqM8A

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

I. Aqueous diffusion

Acqueous diffusion may occur:
- 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 is the 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, a ratio of 2:1.
    - 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 (1750/1250 or 1.4 to 1), 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

**Lipophilic and Hydrophilic Drugs**

Attribution: AMBOSS: Medical Knowledge Distilled Pharmacokinetics-Part 2: Lipophilici and Hydrophilic Drugs AMBOSS: Medical Knowledge Distilled Youtube Channel: https://www.youtube.com/channel/UC8xEQrU6VhJU6pDZd-GkJWg

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.
  - The pH and drug pKa determine the ratio of lipid-to aqueous-soluble forms for weak acids and bases as 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) = pKa-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 cell membrane, compared to 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 thus free to move through lipid membrane structures

Lipid diffusion depends on adequate lipid solubility
- Drug ionization (charged form) 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). For example:
- C₈H₇O₂COOH ⇄ C₈H₇O₂COO^- + H⁺
- Neutral aspirin (C₈H₇O₂COOH) in equilibrium with aspirin anion (C₈H₇O₂COO^- ) and a proton (H⁺ )
- Weak acid: protonated form -- neutral, more lipid-soluble
Weak base: 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⁺ )
- Weak base: protonated form which is charged and therefore less lipid-soluble.
Examples:

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 finite 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 the process is subject to inhibition by other small molecules.
IV. Endocytosis and exocytosis:
- Entry into cells by very large substances (e.g., iron vitamin B₁₂, complexed with its binding protein moves across intestinal wall into the blood.
- Neurotransmitter system examples for exocytosis:
  - Following neuronal electrical activation of nerve endings, two steps may be initiated:
    1. Storage vesicles containing neurotransmitter fuse with cell membranes followed by
    2. Release or diffusion of contents into the extracellular region.
Summary
- Figure Developed by Dr. Steve Downing, University of Minnesota

**References**
Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17. Dolin, S. J. "Drugs and pharmacology" in Total Intravenous Anesthesia, pp. 13-35 (Nicholas L. Padfield, ed), Butterworth Heinemann, Oxford, 2000


Figure Developed by Dr. Steve Downing, University of Minnesota