Pang concepts

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lawlzcakes
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Pang concepts
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2013-10-27 12:04:51
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  1. Factors that affect permeability
    • Drug lipophilicity (log P)
    • 􀁹 Drug size – molecular weight/size
    • 􀁹 Drug charge (degree of ionization) – pKa(pH partition hypothesis)
    • 􀁹 Polar surface area
    • 􀁹 Drug Stability
    • 􀁹 Nature of the membrane
    • 􀁹 Nature of the medium on either side
    • 􀁹 Drug-Protein (transporter) interactions
  2. Lipophilicity of R groups
    amino acid < urea < amide < hydroxyl < ester < carbonyl < ether
  3. Christopher Lipinski’s Rule of Five
    • Molecular Weight < 500
    • • log P < 5
    • • Hydrogen bonding < 5
    • • Hydrogen bonding donors (NH or OH) < 5
    • • Hydrogen bonding acceptor (N or O) < 10
  4. Predictors of Drug Absorption
    • 1. Good water – lipid solubility
    • 2. Not much ionized
    • 3. Stable in acidic medium
    • 4. Presence of carriers (transporters) for absorption
    • 5. Lack of efflux transporters / metabolism
  5. Increase GI motility
    • Metoclopramide
    • Alkali
    • Stress
    • Liquids
    • Hyperthyroidism
  6. Decrease GI motility
    • Food
    • Anticholinergics (Atropine, propantheline)
    • Narcotics (meperidine, morphine)
    • Acids
    • Surgery
    • Viscosity
    • Ulcers, hypothyroidism
    • Exercise
  7. Effect of Delayed Gastric Emptyingon Various Drugs

    Drugs that are unstable(labile drugs)
    Drugs that are poorlysoluble
    Drugs transported bycarriers
    Drugs that exhibit goodwater/lipid solubility
    Extent decreases for unstable, increases for poorly soluble, increase carrier, and no change to last one
  8. Rate Limiting Step (RLS)
    • Unstirred water level: for very lipophilic drugs
    • • Membrane: for very water soluble drugs and drugsabsorbed via transporters
    • • Blood flow: for drugs with good water and lipid solubility
  9. Factors Governing Rate & Extent ofDrug Distribution
    • 1. Vascular binding and tissue binding – extent
    • 2. Blood flow to tissues – rate
    • 3. Presence of barriers: blood brain barrier (BBB),cerebrospinal fluid barrier (CSF), placentalbarrier
    • 4. Presence of transporters for influx and efflux
  10. Forces for Reversible Drug Bindingto Proteins
    • 1. Ionic
    • 2. Hydrophobic
    • 3. Dipole-dipole
    • 4. Van der Waals – induced dipole dipole
  11. Importance of Protein Binding
    • Influence unbound drug (activity / toxicity,distribution and removal)
    • • Fluctuation in drug concentration within therapeuticrange
    • • Explain stereoselective disposition of drugs
    • • Drug-drug interactions
  12. What molecules get distributed?
    • Lipophilic, unionized, stable, appropriate molecular weight
    • Permeate membrane well, substrate of influx transportersand not efflux transporters
  13. What drug properties are important for high extent of distribution?
    • Lipophilic, unionized, stable, appropriate molecular weight
    • Permeate membrane well, substrate of influx transportersand not efflux transporters
    • low plasma protein binding and good tissue binding
  14. Bile acid is made from
    Cholesterol
  15. Importance of Biliary Excretion
    • 1. Enterohepatic circulation (EHC) of bile acids for digestion(reclaimed by ASBT in intestine, NTCP-BSEP in liver)
    • 2. Formation of micelles: with fatty acids, cholesterol, lecithin,and monoglycerides due to surfactant properties
    • 3. Excretion of bile acids (toxic if too much) for emulsificationof fat; and bilirubin glucuronides (toxic if too much)
    • 4. Route of drug and metabolite excretion
    • 5. Enterohepatic circulation (EHC) of drugs – leads toincreased duration of drugs
  16. Importance of Hepatobiliary Transport
    • Transporters: design carrier (bile acid-cisplatin)
    • 􀁹 Site of liver toxicity: bilirubin or bile acidaccumulation
    • 􀁹 Drug-drug interactions
    • 􀁹 Transporter deficiency and associated diseases◦ MRP2 deficiency: Dubin Johnson syndrome◦ BSEP deficiency: progressive familial intrahepaticcholestasis, type 1 (PFIC1)◦ progressive familial intrahepatic cholestasis type 2(PFIC2) mutation in BSEP
    • 􀁹 Polymorphism: single nucleotide polymorphism (SNP)changes transporter function
  17. Estimation of GFR: Ideal Marker Traits?
    • 1. Filtered freely
    • 2. Totally unbound
    • 3. Biologically inert
    • 4. Not secreted nor reabsorbed
    • 5. Easily measured in plasma and urine
  18. GFR markers?
    • Endogenous: Blood Urea Nitrogen, creatinine
    • Exogenous: Inulin
  19. Passive reabsorption (renal) is dependent on:
    • 1. Lipophilic, nonionic species
    • 2. pHurine and pKa (%non-ionic)
    • 3. Urine flow rate (changes transit time in renaltubules)
  20. Significance of Renal Excretion
    • 1. Mechanism of drug / metabolite removal
    • 2. Site of action of some drugs, e.g. Furosemide
    • 3. Site of drug-drug interactions• therapeutic or desired (probenecid + pencillin)• toxic or adverse (cimetidine and procainamide)
    • 4. Site of toxicity, e.g. aminoglycoside –accumulate in cells

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