RDM Cumulative Final Notes
Functional Groups
- Acidic nitrogens: imides, sulphonamides
- Neutral: pyrrole, imidazole
- Halogens: improve lipid solubility and chemical/metabolic stability
- Amides: stable to hydrolysis
- Lactam rings: susceptible to hydrolysis
- Ester: susceptible to hydrolysis
- Quarternary ammonium salt: neutral
- Imides: resonance stability
- Xanthine: acidic and based nitrogens
Drug Distribution
- Drug size: 200g/mol/nm
- Solubility cut off: >3g/mL
- Implications of drug molecules: size (nm-penetrating barriers, target binding, solubility),
electronegativity (polar/non-polar functional groups solubility), shape/geometry (target
site fit)
- Ion-dipole: polar bonds-ionized functional group
- Dipole-dipole: polar bonds in both mcs
- Induced dipole-dipole: tight packing of non-polar bonds
- Intermolecular forces govern equilibrium
- In vitro chemical stability: oxidation, hydrolysis
- Solubility is an equilibrium- to dissolve drug:
i. Drug water bonding > drug drug bonding (in solid)
ii. Drug water bonding > water water bonding (in solvent)
- Depends on intrinsic solubility of unionized drug in water (ie ability of fx groups to bond w
water which depends on strength of intermc forces)
- Empirical solubility msmt disadvs: only considers polar group contributions, doesn’t
include all fx groups, doesn’t consider both hydrophobic/hydrophilic groups
- Drug salt (PD effects unaffected): improves water solubility, in vitro chem stability, drug
liberation
Organic or inorganic
- Each functional group acts independently w own pKa
- Drug distribution: drug equilibration between blood, extravascular fluids/tissue
Reversible transfer of drug from one location to another (quant by Vd)
- Extent of drug movement depends on stability of drug-prot complexes in blood v drug-
tissue complexes
Dependent on properties of extravascular fluids/tissues and physicochem
drug properties
- Vd proxy for: how stable complexes are, where drug goes in body
i. Low: in blood, protein complexes more stable
ii. High: in tissues, tissue complexes more stable
- Factors influencing Vd: perfusion of tissues, endothelial capillary cell structure,
extent/strength of drug binding in plasma/tissues, physicochem drug properties
, - Drug movement bw blood/tissues depends on leaky microcirculation: cts capps (GIT),
fenestrated capps (kidney), discts capps (liver) – BBB the exception
Mcs <=6000g/mol pass freely, <2000g/mol free drug
- Drug binders: non specific binding impacted by drug structure, size, shape, ionization
extent, stereochem manifests itself in Vd
HSA: acidic, neutral drugs
Alpha1AGP: basic drugs
Drug Stereochemistry
- Enantiomers: asymm optical isomers each enantiomer considered a separate drug
i. Eutomer: intended PD response (3 points contact)
ii. Distomer: no/same/unintended response (2 points contact)
iii. 2n optical isomers, n=chiral centers
- Racemic mixture: contains equal amount of enantiomers
- Diastereomers: 2 or more chiral centers, optical isomers, not mirror images
- Any ADME involving binding to target-must consider stereo chem
Absorption
- Amount of intact drug reaching systemic circ
- Amount of drug absorbed= F(dose)
- Factors influencing F: incomplete liberation from dosage form, chemical instability in GI,
interactions, drug efflux, first pass metabolism, insufficient time for absorption, drug
physicochem
- Fick’s Law
i. P: partition coefficient (structural contribution)
ii. A: SA (membrane contribution)
iii. H: thickness (membrane contribution)
iv. D: diffusion coefficient (size contribution)
- Finding predominant forms predicts ionization/solubility/absorption
pH=pKa equal amounts of acid/base
pH<pKa drug in acidic environment
pH>pKa drug in basic environment
Drug Metabolism
- elimination: irrev removal of drug from body (excretion + metabolism)
- excretion: removal of unchanged drug
- metabolism: removal of changed drug (via kidney, liver metabolism)
- excretion occurs renally (via nephron) and hepatically (via biliary system)
- metabolism in liver via hepatocytes and host of metab enzymes
- route of excretion/metabolism pathways depend on drug physicochem: size, structure,
solubility, logP
<500 g/mol excreted renally
>500 g/mol exreted hepatically
- Liver: detox, inactivation, solubilization, elimination
Via phase I/II reactions with functional groups metabolites
Increases drug polarity, decreases log P, increases water solubility
Extent of metabolism governed by logP
Functional Groups
- Acidic nitrogens: imides, sulphonamides
- Neutral: pyrrole, imidazole
- Halogens: improve lipid solubility and chemical/metabolic stability
- Amides: stable to hydrolysis
- Lactam rings: susceptible to hydrolysis
- Ester: susceptible to hydrolysis
- Quarternary ammonium salt: neutral
- Imides: resonance stability
- Xanthine: acidic and based nitrogens
Drug Distribution
- Drug size: 200g/mol/nm
- Solubility cut off: >3g/mL
- Implications of drug molecules: size (nm-penetrating barriers, target binding, solubility),
electronegativity (polar/non-polar functional groups solubility), shape/geometry (target
site fit)
- Ion-dipole: polar bonds-ionized functional group
- Dipole-dipole: polar bonds in both mcs
- Induced dipole-dipole: tight packing of non-polar bonds
- Intermolecular forces govern equilibrium
- In vitro chemical stability: oxidation, hydrolysis
- Solubility is an equilibrium- to dissolve drug:
i. Drug water bonding > drug drug bonding (in solid)
ii. Drug water bonding > water water bonding (in solvent)
- Depends on intrinsic solubility of unionized drug in water (ie ability of fx groups to bond w
water which depends on strength of intermc forces)
- Empirical solubility msmt disadvs: only considers polar group contributions, doesn’t
include all fx groups, doesn’t consider both hydrophobic/hydrophilic groups
- Drug salt (PD effects unaffected): improves water solubility, in vitro chem stability, drug
liberation
Organic or inorganic
- Each functional group acts independently w own pKa
- Drug distribution: drug equilibration between blood, extravascular fluids/tissue
Reversible transfer of drug from one location to another (quant by Vd)
- Extent of drug movement depends on stability of drug-prot complexes in blood v drug-
tissue complexes
Dependent on properties of extravascular fluids/tissues and physicochem
drug properties
- Vd proxy for: how stable complexes are, where drug goes in body
i. Low: in blood, protein complexes more stable
ii. High: in tissues, tissue complexes more stable
- Factors influencing Vd: perfusion of tissues, endothelial capillary cell structure,
extent/strength of drug binding in plasma/tissues, physicochem drug properties
, - Drug movement bw blood/tissues depends on leaky microcirculation: cts capps (GIT),
fenestrated capps (kidney), discts capps (liver) – BBB the exception
Mcs <=6000g/mol pass freely, <2000g/mol free drug
- Drug binders: non specific binding impacted by drug structure, size, shape, ionization
extent, stereochem manifests itself in Vd
HSA: acidic, neutral drugs
Alpha1AGP: basic drugs
Drug Stereochemistry
- Enantiomers: asymm optical isomers each enantiomer considered a separate drug
i. Eutomer: intended PD response (3 points contact)
ii. Distomer: no/same/unintended response (2 points contact)
iii. 2n optical isomers, n=chiral centers
- Racemic mixture: contains equal amount of enantiomers
- Diastereomers: 2 or more chiral centers, optical isomers, not mirror images
- Any ADME involving binding to target-must consider stereo chem
Absorption
- Amount of intact drug reaching systemic circ
- Amount of drug absorbed= F(dose)
- Factors influencing F: incomplete liberation from dosage form, chemical instability in GI,
interactions, drug efflux, first pass metabolism, insufficient time for absorption, drug
physicochem
- Fick’s Law
i. P: partition coefficient (structural contribution)
ii. A: SA (membrane contribution)
iii. H: thickness (membrane contribution)
iv. D: diffusion coefficient (size contribution)
- Finding predominant forms predicts ionization/solubility/absorption
pH=pKa equal amounts of acid/base
pH<pKa drug in acidic environment
pH>pKa drug in basic environment
Drug Metabolism
- elimination: irrev removal of drug from body (excretion + metabolism)
- excretion: removal of unchanged drug
- metabolism: removal of changed drug (via kidney, liver metabolism)
- excretion occurs renally (via nephron) and hepatically (via biliary system)
- metabolism in liver via hepatocytes and host of metab enzymes
- route of excretion/metabolism pathways depend on drug physicochem: size, structure,
solubility, logP
<500 g/mol excreted renally
>500 g/mol exreted hepatically
- Liver: detox, inactivation, solubilization, elimination
Via phase I/II reactions with functional groups metabolites
Increases drug polarity, decreases log P, increases water solubility
Extent of metabolism governed by logP
