module 1-PHAR

• Organic medicinals


  Study of pharmaceutical chemistry focused on discovering, synthesis and design of bioactive molecules
• Pharmacodynamics


  Study of how drugs interact with its target (enzymes: proteins, lipids; receptors: nucleic acids)
• Enzymes as drug targets

  • Active site inhibitors
  • Allosteric site inhibitors
  • Uncompetitive inhibitor
• Reversible inhibitors


  Drug is designed similar to endogenous substrate which competes to active site
• Irreversible inhibitors


  Drug that forms a covalent bond to an amino acid residue in active site; permanent
• Allosteric site inhibitors


  Drug that binds to a site other than where endogenous ligand binds; will cause induced fit of active site
• Uncompetitive inhibitor


  Drug binds to enzyme-substrate complex
• Receptors as drug targets

  • Agonist
  • Antagonist
  • Partial agonist
  • Inverse agonist
• Agonist


  Drug designed similar to an endogenous ligand
• Allosteric modulators


  Indirect agonist effects - drug binds to site other than where ligand normally binds
• Antagonist


  Drug that binds to receptor but does not activate
• Partial agonist


  Drug similar to an agonist but does not elicit full response
• Inverse agonist


  Drug that binds to receptor; does not activate receptor; prevents endogenous ligand from binding
• Constitutional activity


  Activity of a receptor even in the absence of endogenous ligand
• Desensitization


  When agonist is bound to its receptor for a long period of time; shape of receptor is altered even if occupied
• Sensitization


  When antagonist is bound to its receptor for a long period of time
• Tolerance


  Situation where increased doses of a drug are required over time to achieve same effect; due to increased number of receptor
• Dependence


  Related to body's ability to adapt to presence of a drug; withdrawal symptoms occur as result of abnormal levels of target receptor
• Nucleic acids as drug targets

  • Intercalating agents
  • Topoisomerase poisons
  • Alkylating agents
  • Chain cutters
  • Chain terminators
• Intercalating agents


  Contain a planar, heteroatomic rings that slips in between DNA base pairs; interrupt DNA replication and transcription
• Topoisomerase poisons


  Drugs stabilize normally cleavable complex between topoisomerase and DNA
• Alkylating agents


  Electrophilic agents that form bonds to nucleophiles found in DNA
• Chain cutters


  Drugs that cut DNA and prevent DNA ligase from repairing damage
• Chain terminators


  Drugs that terminate DNA chain
• Pharmacokinetics


  Study of journey of drug in body; ADME
• Absorption


  • Drug must be sufficiently polar to dissolve in aqueous environment but must be sufficiently lipophilic to cross cell membrane
  • Ionization affects absorption
• Henderson-Hasselbach equation


  Equation that describes the relationship between pH, pKa, and the ratio of ionized to unionized drug
• Distribution


  Transfer of drug from blood to cell or interstitium; affected by plasma protein binding
• Metabolism


  Biotransformation; modification of drug to more polar and more excretable; formation of metabolites
• Phase I metabolism


  • Functionalization reactions; addition of functional group = more polar
  • Hydrolysis reactions
  • Oxidation reactions
  • Reduction reactions
• Phase II metabolism


  Conjugation reactions; addition of small, polar endogenous molecules to parent drug or phase I metabolites
• Excretion


  Renal excretion; biliary excretion; sweat, tears, saliva
• Catecholamines


  Catechol ring + alkylamine chain
• Dopamine


  First synthesized catecholamine
• Catecholamine biosynthesis


  Catecholamine biosynthesis steps
• Catecholamine metabolism


  MAO - deamination; COMT - methylation of one of -OH groups of catechol ring
• Structure-activity relationship of catecholamines

  • 3 binding groups: OH groups, aromatic ring, ionizable N
  • Modifications: attachment of bulky groups at N-atom increases β activity, loss of α activity; methyl substituents at α carbon increase α2 activity
• Adrenergic agonists


  • General agonists
  • Beta-2 agonists
• General agonists


  • Ephedrine
  • Pseudoephedrine
• Group shift strategy


  Replacement of m-OH group with hydroxymethyline; more resistant to COMT