Midterm 1

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Midterm 1
2015-09-26 09:21:26

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  1. pharmacodynamics vs pharmokinetics
    • pharmacodynamics - action of drugs on body
    • pharmokinetics - action of body on drugs
  2. What is the significance of charge on drug-receptor interactions?
    Three types of bonds
    • weak bonds b/w drug and receptor are more selective b/c it requires more precise fit if an interaction is to occur
    • covalent - very strong, irreversible usually
    • electrostatic - more common, a bit weaker than ^, many drugs, includes electrostatic, H, van der Waals
    • hydrophobic - usually weak, important with lipid interactions and highly lipid soluble drugs, many drugs
  3. 5 methods of signal transduction
    • 1. Lipid-soluble drug binds intracellular receptor
    • 2. Transmembrane enzyme e.g. insulin activates receptor TK
    • 3. Transmembrane non-enzyme e.g. cytokine receptors are activated by IL and allows mobile enzymes to bind to the receptor
    • 4. Drugs binds to open/block ion channel
    • 5. GPCRs
  4. potency
    • affinity + efficacy (ability to activate receptor and generate response)
    • defined by EC50 half max effective concentration --> compare this to give relative potency
    • *low potency is a concern if the dose given is too large
  5. How is tolerance built?
    • Synthesis of new receptors decreases
    • internalization of receptors in cell
    • phosphorylation to make the receptor inaccessible
  6. A rapid (acute) form of tolerance is called
  7. passive flux across membranes is driven by
    • solubility of drug (lipid-water partition coefficient)
    • drug concentration gradient across membrane
    • surface area of membrane
  8. what is ion trapping?
    • drug accumulates on side of cell membrane where degree of ionization is highest
    • basic drugs accumulate in acidic fluids while acidic drugs accumulate in basic fluids
  9. carrier-mediated transport is for
    • molecules too large to diffuse
    • molecules that are not lipid soluble
    • carriers are saturable, selective, inhibitable
    • active and facilitated
  10. pharmokinetics is divided into
    • Absorption
    • Distribution
    • Metabolism
    • Excretion
  11. What can reduce bioavailability?
    • precipitation of drug at injection site (SC,IM); unavailable for absorption
    • unable to be absorbed by GI tract -> physicochemical property of drug, reverse transport protein causing efflux of drug
    • first pass elimination
  12. Advantages of oral administration of drug (3)
    • economical
    • convenient
    • usually safer than injection
  13. Disadvantages of oral administration of drug (6)
    • absorption may be erratic
    • enteric coating protects some drugs against acids
    • px compliance problems
    • not for unconscious pxs
    • emesis and GI irritation possible
    • first pass elimination effect possible
  14. Subcutaneous injection advantages
    • suitable for solid pellets 
    • suitable for insoluble suspensions
    • easier to administer than IV
  15. Subcutaneous injection disadvantages
    • absorption slower than IV route - can be erratic depending blood flow to site
    • not suitable for large volumes
    • pain and/or necrosis with irritating solutions e.g. Doxorubicin
    • if drugs get extravascular --> phlebitis
  16. Advantages of IM
    • absorption is typically rapid for drugs in aqueous solution; oily suspensions will form depot
    • safe, easier than IV
  17. Disadvantages of IM injection
    Local pain and swelling with irritating solutions
  18. Advantages of IV
    • route of choice for emergency administration of drugs
    • large volumes can be given this route
    • bioavailability is complete; dose delivery is controlled
    • route with most rapid onset of action
    • irritating solutions given by this route
    • by passes "first pass elimination"
  19. Disadvantages of IV
    • must inject many solutions slowly
    • not for oily suspensions
    • adverse rxns can occur due to higher blood levels achieved rapidly compared to other routes
  20. Advantages of Topical Administration
    • drug delivered locally
    • can achieve very high concentration
  21. Disadvantages of Topical Administration
    • may be absorbed systemically
    • may not remain at desired site
  22. Advantages of transdermal
    • absorption enhanced by abraded, denuded or burned skin
    • controlled release e.g. nicotine and fentanyl patches --> prolonged duration of action
    • by passes "first pass elimination" effects
  23. Disadvantages of transdermal
    therapeutic blood levels are slow to achieve; delay onset of action
  24. biotransformation of drugs entails two phase
    • phase 1 functionalization reactions - inactivate drug by introducing functional (chemically reactive) groups --> oxidation, reduction and hydrolysis, introduce/remove fxnl groups (in hepatocyte ER)
    • Phase 2 increases water solubility to enhance excretion by kidney while deactivating phase I metabolites, conjugation rxns e.g. glucuronidation, sulfation, methylation, acetylation, glutathione
  25. four key parameters govern drug disposition (PK)
    • bioavailability
    • volume of distribution
    • clearance
    • elimination half life
  26. How is dosing rate calculated?
    Clearance x target drug concentration
  27. t1/2
    t1/2 = Vd and CL
  28. What is Vd
    it is a proportionality constant between the amount of drug in the body and the concentration of drug in the blood
  29. What type of drugs have small to intermediate Vd values? high Vd values?
    • a) water soluble drugs that tend to remain in ECF (plasma space, interstitial fluid, not intracellular fluids)
    • b) lipid soluble drugs, bind extensively to tissue sites outside the plasma space
  30. How is loading dose calculated
    Vd x TC = loading dose
  31. NSAID toxicity
    • Type A Dose Dependent ADR
    • pharmacological toxicity "receptor mediated"
    • cyclooxygenase enzymes become blocked, leads to decr prostaglandins --> decr pain and inflammation, decr GI mucosal protection--> GI ulceration
  32. intrinsic toxicity (Type A)
    • bioactivation often needed
    • determined by chemical properties of the drug
    • site of toxicity depends on accumulation of drug in susceptible cells (which binds non-specific targets e.g. DNA, proteins and disrupts cell fxn), localization of enzymes needed for metabolism
  33. Doxorubicin toxicity
    dose dependent cardiomyopathy (heart failure) following production of free radicals in the myocardium
  34. aminoglycoside toxicity
    • Type A - intrinsic toxicity
    • the parent molecule does not act on intended receptors
    • renal tubule toxicity following accumulation in the urine
  35. Most common type "B" ADR
    • immunologic toxicity
    • drugs often act as haptens and bind to larger endogenous molecules to induce and immune response
    • e.g. Type I-IV immune reactions possible b/c penicillin binds to protein
  36. idiosyncratic toxicity
    • bioactivation often needed
    • determined by the chemical properties of the drug
    • drug becomes bioactivated into a toxic form
    • e.g. chloramphenicol or felbamate --> aplastic anemia