Physicochemical Properties in Relation to Biological Action

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Physicochemical Properties in Relation to
Biological Action

• Ch. 1 Pharmacokinetics
• Three As
• Absorption
• Availability (bio) Time to target
• Administration
• Distribution
• Excretion Time available
• Drug transfer across membranes
• Metabolism

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Drug Distribution
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Bioavailability

• Bioavailability is related to Absorption
• Fraction of drug that gets to its target
• Routes
• Oral Ingestion (P.O.)
• Sublingual
• Rectal
• Parenteral
• Intravenous (I.V.)
• Subcutaneous (S.C.)
• Intramuscular (I.M.)
• Intraarterial (I.A.)
• Intrathecal (I.T.)
• Pulmonary
• Topical
• Mucous Membranes
• Skin
• Eye

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Drug Distribution

• Follows Administration ? Absorption
• Interstitial Intercellular fluids
• Rate of delivery and distribution
• Cardiac output
• Regional blood flow
• Tissue volume
• Phase I
• Liver, kidney, brain get most (well-perfused)
• Muscle, viscera, fat ? SLOWER
• Phase II
• Minutes ? hours before tissue at equilibrium with
  blood
• Determined by partitioning (more mass in Phase
  II)
• Factors
• Lipid solubility
• Binding to plasma proteins

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Distribution cont

• Plasma Proteins
• In bloodstream drug ? protein (Albumin)
• Affinity Availability ? Rate of delivery
• Tissues
• As much as 1000x
• Affinity Receptor types
• Redistribution
• Termination ? metabolism excretion
• Ex Lipid soluble anesthetics
• High blood flow to the brain ? high brain
  concentration FAST!
• CNS CSF
• Dependent on ability to cross tight junctions
  (BBB)
• Requires I.T. injection of many agents
• Placental Transfer
• Factors Lipid solubility, plasma binding, degree
  of ionization

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Excretion

• Drugs eliminated
• Unchanged
• As metabolites
• Elimination more efficient for polar molecules
• Lipid soluble ? more polar ? excretion
• Renal decrease 1 per year in adulthood!
• Glomerular filtration (MW lt 40,000)
• Tubular secretion
• Passive tubular reabsorption
• Biliary Fecal
• Enterohepatic recycling ? prolong drug effects
• Other Routes
• Sweat, saliva, tears, skin, hair, breast milk,
  exhalation
• Not significant! (Forensic utility!)

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Common Administration Routes
Absorption Pattern
Limitation Precautions
Special Utility
Route
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Drug Distribution
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Cell Membranes

• Lipid bilayer noncovalent
• Phospho-, glycolipids, cholesterol
• Most water permeable
• Passive diffusion most drugs
• Osmotic/hydrostatic pressure
• Embedded Proteins Drug targets!
• Receptors external stimuli
• Ion channels gates
• Transporters active transport
• Signaling pathways

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Membranes Fluid Mosaic Model
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Fluid Mosaic Model - 4 Mechanisms

• Passive diffusion
• Most drugs!
• Function of the lipid solubility of the drug
  (partition coefficient)
• Drug moves from highest to lowest conc.
• Unionized species of the drug only!
• This is a first order process!
• Rate Drug

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Fluid Mosaic Model cont

• Carrier Mediated or Active Absorption
• Few drugs and nutrients absorbed this way
• Structural similarities between drug and natural
  substrate
• Differences with passive transport
• Transport is against the concentration gradient
• Saturable at high drug concentrations-limited
  number of carriers to shuttle the drug across the
  membrane
• Molecular specificity leads to competition
  between drug and natural substrate ? decreased
  drug transport
• Requires energy
• Highest affinity transported more rapidly

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Fluid Mosaic Model cont

• Convective absorption
• Small molecules (lt 4A radius)
• Travel through pores - sieving effect
• Saturable
• Ion pair absorption
• Equivalent to phase transfer that occurs with
  quaternary ammonium cations and an anion

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Acid/Base Properties

• Human body is 70-75 water
• 55 L per 160 lb (55 kg) individual
• Average drug molecule 200 g/mole
• 20 mg of drug would yield a 2 mM solution
• Dealing with DILUTE solutions
• Brönsted Lowry best describes this
• Acid H donor, Base H acceptor
• Drugs acids, bases, or both (Amphoteric)
• Physiologic pH 7.4

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Daily Wisdom
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Conjugate Acid - Base

• For an acid (ex. R-COOH)
• HA H A-
• For a base (ex. R-NH2)
• BH H B

Conjugate Acid Conjugate base
R-NH3 R-NH2
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Conjugate Acid - Base
Dopamine - Neurotransmitter

• Questions
• Conjugate acid or base?
• Where is the chemical form found?
• Where is the drug best absorbed? Why?

• Conjugate Acid
• Stomach

• Conjugate Base
• Small Intestine

3. Basic drugs are best absorbed in the Small
Intestine!
RATE!!!
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Conjugate Acid/Base Pairs
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pH Effects on Absorption
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Drug Transfer Acidic Drugs
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Drug Transfer Acidic Drugs
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Drug Transfer Basic Drugs
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Drug Transfer Basic Drugs
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Ionization vs. pH

• Henderson-Hasselbach equationpH pKa log
  (conjugate base/acid)
• Example What is the ratio of pseudoephedrine to
  pseudoephedrine HCl (pKa 9.9) in the small
  intestine at pH 8.0?8.0 9.9 log
  (pseudoephedrine/HCl salt)log
  (pseudoephedrine/HCl salt) -9.9 8.0
  -1.9 (pseudoephedrine/HCl salt) 0.0126
• 13 pseudoephedrine per 1000 pseudoephedrine HCl

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Ionized vs. pH

• For HA acids
• ionization 100/(1 10(pKa pH))
• For BH acids ionization 100/(1 10(pH
  pKa))

Example Percentage ionized pseudoephedrine HCl
(pKa 9.9) in the small intestine at pH
8.0? ionization 100/(1 10(8.0 9.9))
ionization 100/(1 0.0126) ionization
100/1.0126 ionization 98.76
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pH Effects on Absorption
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Lipid Solubility Partition Coefficient

• n-octanol / water partition coefficient
• Drug n-octanol / Drug water

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Factors that determine solubility

• Dipole Moments Ex Dichlorobenzene
• A dipole moment (m Debyes) results from the
  UNEQUAL sharing of electrons two atoms.

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Dipoles cont

• In general molecules that possess permanent
  dipole moments are called polar molecules
• The overall polarity of a molecule is the
  summation of the all the dipole vectors within a
  molecule.
• It is rare in a complex molecule like a drug that
  a plane of symmetry exists such that all dipoles
  effectively cancel each other out.

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Ans. (a) gt (c) gt (b) (d)
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Polarizability

• Induced Polarity Polarizability
• Adjacent molecules induce a functional group in
  a molecule to develop a dipole.
• Ex Distortion of Benzene p-electron cloud by
  interaction with a DMF molecule.
• Total Polarity Polarizability Dipole moment

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Other influences on polarity

• Intermolecular Forces
• Dipole Dipole interactions
• Dipole Induced Dipole interactions
• Induced Induced dipole interactions (London
  Forces)
• Ion Dipole dipole interactions
• Ion Induced Dipole interactions
• Hydrogen bonds - 2 to 8 kcal/mole
• 1 - 3 collectively as Van derWaals forces and
  4-5 afford 1-10 kcal/mole

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Hydrogen Bonding
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Hydrogen Bonding

• Affect physical chemical drug properties
• Determine strength of drug protein interaction
• Influences bioavailability
• Acidic drug Albumin
• Basic drug a1-acid glycoprotein
• Adsorption vs. Absorption

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Parameters to predict activity

• Hammetts s constant Useful for determining the
  effect of meta and para substituents in aromatic
  compounds a measure of resonance versus
  inductive effects
• Tafts steric parameters - Es
• Chartons steric parameters v
• Verloops multidimensional steric parameters
• Molar refractivity MR
• One of the most popular methods
• Involves a molecules refractive index, molecular
  weight and density
• Essentially a measure of a molecules bulk and
  electronic character

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Problems

• QSAR or Quantitative Structure Activity
  Relationships
• Only a predictive tool
• Often inaccurate
• Methods often do NOT directly predict
  biological/pharmacological activity
• Structural parameters only!
• Computer graphics allow 3-D structural predictions

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