1. Basics

• Pharmacology

  The study of the interaction between drugs and living organisms
• Pharmacology

  • Fundamental to anesthetic delivery
  • Combination of several drugs with specific goals in analgesia, sedation and muscle relaxation
• Drug


  Exogenous chemical substances used to alter a physiological system
• Drug discovery

  • Historically often derived from plant extracts used without validation
  • Not single compounds but mixtures of compounds
  • 19th century advances in chemistry allowed fractionation of crude extracts
  • Individual compounds that are pharmacologically active developed
  • Purification and determination of naturally occurring hormones
• Receptor concept


  • Specificity of drugs to a disease has been known since at least 17th century
  • Receptor term coined in 1900 by Ehrlich
  • Used to explain specificity of antibacterial action of antibodies
  • Drugs interacted with a "receptive substance" that is essential for the physiologic action of the drug
• Receptive substance

  Drugs interacted with a 'receptive substance' that is essential for the initiation of the physiological actions of the drug
• Receptors


  • Macromolecular protein on the cell membrane or within the cytoplasm or cell nucleus that bind to specific factors and initiate a cellular response
  • These factors can be the drugs we give, Neurotransmiters, hormones, or other substances
• Drug-receptor interactions

  • Most effects are reversible
  • Ending when drug concentration and occupation of receptor sites diminish
  • They can be irreversible
• Dissociation constant (KD)


  • Reflects the propensity of the drug-receptor complex to break down
  • Affinity is the inverse of KD
  • Propensity of the drug to form a complex
• Affinity


  Propensity of the drug to form a complex with the receptor
• Potency


  • Concentration of drug needed to produce a defined effect
  • A highly potent drug evokes a larger response at low concentration
• ED50 or EC50

  • The smaller the EC50 the less drug is required to produce the same effect
  • EC50 is commonly used to measure potency
• Efficacy


  • Refers to the maximum response achievable from a drug (Emax)
  • Reflects the ability of the agonist to activate a receptor
• Agonist


  • A drug that activates a receptor via binding to it
  • Full agonist = high affinity
  • Partial = low affinity
  • Inverse = negative efficacy
• Antagonist


  • Drug that binds to the receptor without activating it, and prevents an agonist from stimulating the receptor
  • Competitive antagonist = bind to agonist sites
  • Non-competitive antagonist = bind to sites other than the agonist sites
• Irreversible antagonist


  Binds directly to agonist making it unable to bind
• Indirect antagonist


  • Occurs without receptor binding
  • Example: Protamine to inactivate heparin preventing activation of antithrombin
• Tachyphylaxis


  • Rapidly (hours) diminishing responses to repeated drug doses
  • Rapid tolerance
  • Due to receptor desensitization
• ED50


  • The dose producing a therapeutic effect in 50% of the population
  • Similar to MAC in VA
• TD50


  Toxic dose in 50% of population
• LD50


  Lethal dose in 50% of population
• Therapeutic index


  Helps us develop a therapeutic index
• Receptor families


  • G-protein-coupled receptors (GPCRs)
  • Ligand-gated ion channel
• Drug-receptor interactions


  • Drugs will bind to a target receptor to exert its effects
  • The strength of these reversible interactions is known as its binding affinity
• Receptors


  Many receptors display stereoselectivity and may have a higher affinity for a more potent, more efficacious, and less toxic enantiomer
• Pharmacokinetics


  • Study of absorption, distribution, metabolism, and excretion of an administered drug and it's metabolites
  • What the body does to the drug
• Pharmacokinetics


  • Major elements include: Absorption, Distribution, Metabolism, Excretion
  • Compartmental model
• Plasma concentration curve


  • Distribution Phase = Initial rapid decrease in concentration
  • Elimination Phase = Slower decline in concentration
• Absorption


  • When a drug is given it takes time to establish an effect
  • Bioavailability (BA) describes the fraction of an administered dose of drug that reaches the systemic circulation
• Effect-site equilibration


  The delay between dosing and onset reflects the time necessary for the circulation to deliver the drug to its site of action
• Distribution


  • Vessel-rich group receives higher concentration of initial dose
  • Then it redistributes to muscle, fat, VPG
  • Tissue uptake of drug dependent on blood flow to tissue
  • Some drugs build up in the tissue and have a delay in transferring the drug out and back into circulation
• Blood-brain barrier


  The limited permeability of brain capillaries determine the absorptive characteristics of drugs into the central nervous system
• BA


  Must be considered when calculating drug dosages
• Elderly tend to have a lower CO (β-Blockers or decreased EF) thus longer circulation time and delay of onset
• Distribution


  • Vessel-rich group receives higher concentration of initial dose
  • Then it redistributes to muscle, fat, VPG
  • Tissue uptake of drug dependent on blood flow to tissue
  • Concentration gradient determines rate and direction of transfer between blood and tissue
• Distribution (cont'd)


  • Some drugs build up in the tissue and have a delay in transferring the drug out and back into circulation
  • Reservoir effect
  • Sevoflurane in Obese
  • Second dose effect
  • Greater effect then initial dose
• Blood-brain barrier


  • The limited permeability of brain capillaries determine the absorptive capacity of drug into the CNS
  • Non-ionized lipid soluble = Good
  • Ionized water-soluble = Bad
• Ionization


  • Most drugs are weak acids or bases that exist as both ionized and non-ionized molecules
  • Non-ionized: lipid soluble, active
  • Ionized: water soluble, inactive
• Metabolism


  • Active drug to inactive
  • Active drug to active metabolite
  • Inactive prodrug to activated metabolite
  • Drug to toxic metabolite
• Metabolism


  • A majority of biotransformation takes place in the liver via Phase 1 or 2 reactions
  • Phase 1 rxn: Uncover a functional group and tend to increase polarity
  • Phase 2 rxn: Link the drug to a highly polar molecule and thus very water-soluble, ready to be eliminated