Pharmacokinetics General Principles Lecture, Slide 2

Pharmacokinetics: General Principles-Lecture I, slide 2

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Figure Developed by Dr. Steve Downing, University of Minnesota, illustrating the many membrane barriers even within a single cell.

Absorption
- Fick's Law
Routes of Administration
First-Pass Effect
Pulmonary Effects
Pharmacokinetics
- Volume of distribution
- Clearance
  - Renal clearance: clearance of unchanged drug and metabolites
    - Other Factors Affecting Renal Clearance
  - Factors Affecting Hepatic Clearance
  - Capacity-Limited Elimination
  - Half-life
  - Drug Accumulation
- Bioavailablity
  - Extent of Absorption
  - First-Pass Elimination
  - Rate of Aborption
- 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
  - flavoprotein--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

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.

Many drugs are weak acids or weak bases
A weak acid is a neutral molecule that dissociates into an anion (negatively charged) and a proton (a hydrogen ion) 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 -- charged, 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 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 process is subject to inhibition by other small molecules.

Figure Developed by Dr. Steve Downing, University of Minnesota

IV. Endocytosis and exocytosis:
- 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 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

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)
      - example: urinary alkalinization to facilitate excretion of barbiturates in management of overdosage/poisonings
    - 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: Anesthesia correlation: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 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 charged)

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.