introduction

• philosophy of pharmacology

  • to understand how drugs work on the basis of how they modulate biochemical, physiology and pathological pathways
  • organize and integrate your knowledge on the basis of such pathways
• philosophy of medicinal chemistry

  • discipline concerning the relationships btwn chemical structures of drugs and their biological activity
  • (1) drug name and category
  • (2) chemical structure features
  • (3) medicinal chemistry
  • (4) pharmaceutical properties
  • (5) therapeutic applications
  • building up knowledge of drugs / rationalized memorization (going down)
  • drug search or development / purpose driven learning (going up)
• from drug name/category to chemical structure features

  • numbers - none: nor; one: mono; two: di; three: tri; four: tetra ... etc.
  • elements - C: carb, car; H: hydro; O: o, ox; N; am, az (N in a ring), im (often means N w/ unsaturation); S: sulf, thi; Cl: chlor, lor ... etc.
  • chemical groups - methyl: meth; ethyl: eth; propyl: pro; phenyl: ph, f, p; alcohol: ol; ketone: one; amide: ide, am ... etc.
• from drug name/category to chemical structure features (cont.)

  • drug families: tetracyclines; cephalosporins; penicillins ... etc.
  • the names may reflect structural features or the source of production
  • drugs in same family share key common structural features and pharmaceutical properties
  • different drugs in same family also have unique properties and hence more specific therapeutic applications (tools in a tool box)
  • usually the names of the drug, especially the generic names, give valuable information on their structural features
• from chemical structural features to pharmaceutical properties (continued)

  • the chemical structure of a drug molecule affects its LADME process
  • the chemical sturcture of the drug affects its binding to the molecular target
  • ionic interaction, H bonding, hydrophobic interactions, etc.
  • the chemical structure of the drug affects its chemical stability and its degradation by enzymes of microorganisms
  • the chemical structure of the drug affects its safety/toxicities
• from pharmaceutical properties to therapeutics (eg, antimicrobial agents)

  1. suitable for route of administrations? (eg. oral vs. IV)
  2. sufficient plasma half-life?
  3. sufficient distribution to site of infection? (eg, GI vs. CNS)
  4. sufficient penetration into the microorganism cells? (eg, G+ vs. G-)
  5. sufficient affinity to the molecular drug target of the specific microorganism?
  6. ability to overcome the resistance by the specific microorganism? (eg, beta-lactamase(s) of the specific organism)
  7. tolerable adverse effects?
  8. danger of inducting further resistance? (the ladder protocol)
• antibiotics - the redefined definition in contemporary medicine

  • a substance that meets the following conditions

  1. it is a product of metabolism of synthetic product as a structural analogue of a naturally occurring antibiotic;
  2. it antagonizes the growth of survival of one or more species of microorganisms;
  3. it is effective in low concentrations
• antibiotics - qualitative description of the antibiotic effects

  • bactericidal: able to kill the invading microorganism
  • bacteriostatic: able to inhibit the growth of microorganisms
  • the immune system of the host is needed to eventually clear the microorgansims
• antibiotics - quantitative descriptors for the antibiotic effects in vitro

  • minimum inhibitory concentration (MIC): lowest concentration (highest dilution) of the antimicrobial drug that will stop all growth of a specific microorganism for a period of 18 - 24 hr
  • test is done in vitro
  • a low value of these concentrations indicates a high potency of the antibiotics to the microorganism
  • bacterial growth may be inhibited following exposure to an antibiotic even after the drug concentration has fallen below the MIC
  • known as the postantibiotic effect (PAE)
• PK and PD concerns of antimicrobial agents in clinic

  • time-dependent killing (T > MIC)
  • concentration-dependent killing (Cmax/MIC)
  • time-dependent, concentration-enhanced killing (AUC/MIC)
  • post-antibiotic effect
• chemotherapy: definition in contemporary medicine

  • chemotherapy means the killing (eradication) of unwanted (invasive) species without causing major harm to the host
  • unwanted, invasive species include:
  • microorganisms - bacteria, fungus, virus, parasites; exogenous and often have quite different cytology and biochemistry than the host (humans)
  • different types of cancers; endogenous and more similar to the host; cancer chemotherapy is the least effective chemotherapy
• selective toxicity

  • chemotherapy means the killing (eradication) of an unwanted (invasive) species without causing major harm to the host
  • selective toxicity (ie, high toxicity to the invading organism while having low toxicity to the host) is the key to the effectiveness of any chemotherapeutic agent. BUT HOW??
• major mechanisms of selective toxicity

  • selective distribution of the drug to the site of infection (eg, selective membrane permeability, transporters, intracellular drug ionization, etc; eg, drug gets trapped in cell)
  • a biochemical pathway/enzyme is often lacking in the host, but vital to the invading species
  • biochemical pathways/enzymes exist in both species, but have substantially different topography and hence different affinity to the drug (eg, enzymes have different amino acid sequences, cofactors, etc.)
• resistance

  • the loss of activity (potency) of a drug (antimicrobial agent in this case) against a microbial species
  • this involves a natural selection process
  • microbial load at the time of treatment is often > 10^10 cells
  • some of the cells have, or will acquire, altered biochemical features during the course of treatment that results in a more resistant cell line
  • causes by gene mutation and transfer of the mutated gene (plasmid, etc.)
• major types of microbial resistance

  • decreased influx of the drug to its target, usually d/t the changes in transporters or channel
  • eg, mutations on porins
  • increased efflux of the drug - efflux pump activation, etc.
  • expression of bacterial enzyems that inactivate the drug
  • mutations/modification of the target protein, which lower its affinity to the drug
  • over-production of the substrate of the bacterial enzyme to overcome its competitive inhibition by the drug
• less common microbial resistance

  • establishment of an alternative biochemical pathway to bypass the inhibition by the drug
• strategies to overcome resistance:

  1. avoid misuse of antimicrobial agents
  2. development of new antibiotics
  3. combination therapy
  4. "ladder" protocols to treat infections
• strategies to overcome resistance (cont.)

  3. combination therapy

  • rationale: if the probability of resistance against one drug is 10^-7 and to a second drug is 10^-6, then the probability of one microorganism cell being resistant to both drug is 10^-7 * 10^-6 = 10^-13
  • assumption: no cross resistance (the 2 drugs work by different mechanisms and are of different types of chemical structures)
  • other potential benefits of combination therapy: enhancement of potency against a specific infection, empirical therapy of severe infection of unknown cause polymicrobial infections
• quinolones

  • general structure:
  • common quinolones in clinic
  • ciprofloxacin (ciproxin)
  • levofloxacin (levaquin)
  • moxifloxacin (avelox)
  • delafloxacin (baxedela)
  • structural features: 1-N; 2,3-double bond; 3-carboxylate; 4-ketone; aromatic ring A
  • drug targets: DNA gyrase (mainly gram negative) and topoisomerase IV (mainly gram positive)

  
• mechanism of action of quinolones

  • blocks DNA coiling and uncoiling
  • causes DNA chain breaks
  • blocks DNA synthesis
  • however, premature chelation w/ metal ions such as Mg2+ in antacids will precipitate and inactivate the drug
• basis of selective toxicity

  • selective binding to bacterial DNA gyrase/topoisomerase IV than the human counter part, topoisomerase II
• mechanism of resistance to quinolones

  • point mutation of DNA gyrase or topoisomerase IV to a form that resists binding of the quinolones
  • plasmid transfer of qnrA gene
  • a serious concern in that it would lead to rapid horizontal transfer of quinolone resistance
  • decreased accumulation; decrease absorption and/or increased efflux
• common structure features of the more potent and broad-spectrum second-generation quinolones: (feature for 2nd generation quinolones)

  • 6-fluoro substitute
  • 7-piperizine-like structure w/ a basic amine
  • 1-alkyl or 1-aryl substitutes
• carries most of the structure features of the second-generation quinolones: (delafloxacin)

  • 6-fluoro substitute
  • 7-subsititute is polar but not basic so the whole molecules is weakly acidic
  • better activity in acidic tissues such in complicated skin infection
  • 1-alkyl or 1-aryl substitutes is large and polar for better binding and thus higher potency
  • 8-Cl makes the molecule more stable
• summary of SAR of quinolones

  • quinolone nucleus (1,4-dihydro-4-oxo-3-pyridine-carboxylic acid) is required for activity
  • 1-alkyl, 1-aryl substitutions increases activity
  • substitution at 2-position decreases activity
  • 6-fluoro substitution increases activity and extends spectrum of activity
• summary of SAR of quinolones (cont.)

  • 7-amine-containing substitutions extend spectrum of activity (more effective against G- bacteria), partly d/t better penetration through the porins
  • 7-polar but non-basic substituents favors activity in acidic tissues
  • 8-halo substitutions stabilizes molecules in solution but increase risk of phototoxicity; 5- or 8- aza or methoxy groups minimize risk of phototoxicity
• acid-base chemistry of 2nd gen quinolones

  • pI ~ 0.5 * (pKa1 + pKa2) = 7.4
  • at which there is the highest percentage of the drug in its zwitter ion form (QH +/-_ and at which the solubility of the drug is the lowest

  
• issues related to the solubility of the 2nd gen quinolones

  • 2nd gen fluoroquinolone in the zwitter ion form has low water solubility
  • at high doses, 2nd gen fluoroquinolones tend to cause crystalluria if the urine is more alkaline than usual (~6) and reaches pHs close to the pI of the quinolone
  • quinolone chelates w/ multivalent metals have very low solubility
  • co-administration of quinolones w/ antacids will precipitate quinolones w/ Mg2+ or Ca2+ in the GI lumen and severely decrease their oral bioavailability
  • Mg2+ in urin also contributes the risk of crystalluria