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Pharm-kinetics

  1. How do Drugs molecules move through the body?
    ►Bulk flow: Via the vascular, lymphatic and spinal fluids

    ►Diffusion: Areas of high concentration to areas of low concentration
  2. What are 3 ways drugs transfer across biological membranes?
    • -Passive diffusion
    • -Carrier transport
    • -Pinocytosis- plasma membrane buds off and creates vesicle
  3. describe passive diffusion
    • Drugs transported down their concentration gradient
    • ►Law of mass action
    • ►Non-saturable
    • Lipid-soluble drugs pass directly across plasma membrane.
    • Some ionic drugs can move through protein channels in the membrane
  4. ATP-binding cassette (ABC) transporters:
    • ►"Primary active transporters”
    • ►Use energy from ATP hydrolysis
    • ►Can pump molecules against their concentration gradient
    • ►Saturable
    • ►Exhibit varying substrate selectivity
    • ►ex: P-glycoprotein
  5. Solute linked carriers:
    • ►Some use energy of passively diffusing solutes to pump drugs against their concentration gradients
    • ►“Secondary active transport”
    • ►e.g. organic cation/anions transporters ►Some facilitate diffusion of drugs down concentration gradient (no energy required)►“facilitated transport”
  6. Drug effectiveness in part dependent on:
    • ►affinity for target receptor (agonist or antagonist)
    • ►And possibly efficacy at target receptor (agonist)
    • ►drug’s ability to get to target receptor from site of administration
  7. To be absorbed and distributed to target tissue, drug must first:
    • ►be released from its formula
    • ►be water soluble (Either in the free form, or through binding to water-soluble plasma proteins)
  8. Drug formulation: give examples of solids, semi-solids, polymers, and liquids?
    • Solids
    • ►Tablets
    • ►Capsules
    • ►Powders
    • ►Suppositories

    • Semi-solids
    • ►Ointments
    • ►Creams
    • ►Pastes

    • Liquids
    • ►Suspensions
    • ►Solutions

    • Polymers
    • ►Transdermal patches
    • ►Drug-eluting stents
  9. what is drug chemistry and what does it depend on?
    Determines solubility in biological fluids and ability to penetrate biological membranes.

    Depends on:

    Size and shape

    • Ionization state and charge
    • ►Many drugs are weak acids or weak bases
    • ►Exist in both ionized and unionized states depending on pH

    • Lipid-water partition coefficient
    • ►The higher the coefficient the more easily the drug will pass across biological membranes
  10. The relative concentrations of the ionized and unionized forms of a weak acid are given by what equilibrium?
    • HA <-> H+ + A-
    • HA= nonionized drug
    • H+= proton
    • A-= ionized drug
  11. For a weak acid in a basic solution, which way does the equilibrium moves in favor of?
    ionization (rightwards)

    HA <-> H+ + A-

    • HA= nonionized drug
    • H+= proton
    • A-= ionized drug
  12. For a weak acid in an acidic solution, which way does the equilibrium move in favor of?
    the non-ionized form (leftwards)

    HA <-> H+ + A-

    • HA= nonionized drug
    • H+= proton
    • A-= ionized drug
  13. What is a drug pKa?
    the pH at which 50% of a weak acid drug is ionized
  14. What is the Henderson-Hasselbalch equation?
    the concentration ratio of the ionized and nonionized forms of a weak acid drug

    Log [HA]/[A-] = pKa- pH
  15. The relative concentrations of the ionized and unionized forms of a weak base at equilibrium are given by:
    • BH+ <-> B + H+
    • BH+ = ionized drug
    • B = nonionized drug
    • H+ = proton
  16. For a weak base in an acidic solution, which way does the equilibrium moves in favor of?
    of ionization (leftwards)

    BH+ <-> B + H+

    • BH+ = ionized drug
    • B = nonionized drug
    • H+ = proton
  17. For a weak base in a basic solution, which way does the equilibrium move in favor of?
    the non-ionized form (rightwards)

    BH+ <-> B + H+

    • BH+ = ionized drug
    • B = nonionized drug
    • H+ = proton
  18. In a solution of given pH, the concentration ratio of ionized and nonionized forms of a weak base drug is given by:
    Log [BH+]/ [B]= pKa- pH
  19. what is pH trapping?
    • since pH is not the same in all body compartment, the level of drug ionization depends on where the drug is.
    • pKa of morphine is 7.9 (weak base) so it gets trapped in the stomach (pH=2).
    • highly acidic pH causes ionization of weak base.
    • [BH+)/[B]= pKa- pH= 5.9
  20. How can acid-base chemistry affect elimination of a drug?
    forced diuresis- changing urine pH in order to speed elimination of drugs

    Na2CO3 will increase urine pH
  21. what is drug absorption?
    refers to drug transport from site of administration to the bloodstream
  22. what is bioavailability (F)?
    amount of drug in the bloodstream/ amount of drug administered.
  23. what is first-pass (pre-systemic) metabolism?

    orally admin drugs absorbed from intestine into_______?

    Pass thru _____ prior to entering systemic circulation.

    First-pass metabolism substantial for which drugs?
    Fraction of administered drug metabolized between administration site and systemic circulation.

    hepatic portal  system

    liver

    aspirin, morphine, & ethanol
  24. Bioavailabilty is affected by:
    • -diseased states
    • -drug interactions
    • -genetic factors
    • -route of administration
  25. routes of administration:
    • oral or rectal (gut)
    • percutaneous (skin)
    • intravenous (plasma)
    • intramuscular (muscle)
    • intrathecal (CSF)
    • inhalation (lung)
  26. 2 categories of the route of admin?
    • Enteral - involves GI absorption
    • -oral
    • -rectal (suppository)
    • -sublingual

    • Parenteral- no GI absorption
    • -intravenous
    • -intramuscular
    • -intrathecal
    • -subcutaneous
    • -topical
    • -inhalation
  27. Drug distribution between compartments influenced by:
    • ►Permeability between compartments
    • ►Binding to compartments
    • ►pH partition
    • ►Fat:water partition
  28. Where is the initial drug distribution?
    • ►Cardiac output and regional blood flow
    • ►Drugs reach brain, lungs, kidney, liver first (high blood flow)
  29. drug redistribution:
    • Drug accumulates in organs and tissue with binding affinity for drug
    • ►Includes the specific high affinity target receptors…
    • ►But also non-specific low affinity sites
  30. Volume of distribution:
    ►Apparent volume (l) in which drug is dissolved to produce known plasma concentration

    Vd= dose/ [drug] plasma

    12 mg/ (6 mg/5L)= 10 L
  31. Vd is influenced by:
    • Plasma protein binding
    • ►Serum albumin, glycoproteins, steroid binding proteins
    • ►Can markedly affect free [Drug]Plasma

    • Tissue binding
    • ►Drugs can be sequestered tissue protein and fat
    • ►Drug stored in tissue can be released back into circulation as plasma concentration falls
  32. 2 processes involved in drug elimination:
    • Biotransformation
    • ►Anabolic or catabolic alteration of the drug’s structure

    • Excretion
    • ►Removal of drug or drug metabolite from the blood plasma
  33. Are drugs lipophilic or hydrophilic? why?
    • Many drugs are lipophilic
    • ►Because this facilitates absorption across biological membranes

    • ►… but excretion apparatus favors elimination of hydrophilic molecules
    • ►Because these are readily soluble in urine

    Therefore… Lipophilic drugs have to be made hydrophilic
  34. 2 processes for drug elimination:
    • Phase I – catabolic (break down)
    • ►Activate “prodrugs” – e.g. codeine
    • ►Generate reactive species for Phase 2 reaction
    • Phase II – anabolic (putting together)
    • ►“Conjugation” of water soluble chemical group to assist elimination

    some drugs can be excreted after phase 1 metabolism
  35. what are the phase I rxns?
    • -oxidation (cytochrome P450, 80% of oxidations)
    •         CYP3A4- 30% of hepatic CYP, metabolizes most drugs
    •         non-CYP pathways: monoamine oxidase, OH- dehydrogenase
    • -reductions (cytochrome P450 reductase)
    • -hydrolysis
    •         ex. esterases; carboxylesterases, acetylcholinesterase
  36. what are the phase II rxns?
    • Conjugation reactions
    • ►Of parent drug…
    • ►…or Phase I metabolite

    ex: acetaminophen

    • Addition of polar chemical group
    • e.g. Glucuronide, Glutathione, Acetate, Sulfate 

    increase water solubility                    increase elimination
  37. Excretion pathways include:
    • ►Kidneys
    • ►Bile
    • ►Sweat
    • ►Expiration
    • ►Breast milk

    drugs have to be water soluble to get out
  38. Kidneys filter approx. how many liters/day of plasma?
    180
  39. 3 processes for renal excretion:
    • ►Glomerular filtration
    • ►Tubular secretion
    • ►Tubular reabsorption
  40. Glomerular filtration involves what type of diffusion?

    Glomerular filtration rate and renal blood flow determine:

    Eliminates:
    • -passive diffusion
    • - rate of drug clearance
    • - freely dissolved small molecules
  41. Tubular secretion involves:

    its ideal for:
    ►Involves active transport (ABCs, SLCs etc)►Ideal for removing protein-bound drug that escapes filtration
  42. Tubular reabsorption:
    ►Ionized drugs concentrated in distal tubule ►e.g. digoxin

    • ►Depending on urine pH, some drug may become de-ionized…
    • ►… and reabsorbed
    • ►e.g. aspirin
  43. what is the challenge of clinical pharmacokinetics?
    Challenge: Producing a [Drug]Plasma that is therapeutic, not toxic
  44. what is the therapeutic window?
    range of drug dosage within therapeutic range but outside of toxic range
  45. (kinetics of elimination)
    Drugs elimination dictated by what two possible time-dependent patterns?
    • First order kinetics
    • ►Most of the time
    • ►exponential decay. ex: if 50% drug eliminated per hr, then in 1 hr:
    •        100 mg/ml-> 50 mg/ml
    •        500 mg/ml-> 250 mg/ml
    •      Higher [], greater change in 1 hr


    • Zero order kinetics
    • ►When an elimination step is saturated
  46. what is Kel?
    elimination rate constant

     Kel= slope= change conc/ change time
  47. T 1/2=
    T 1/2= Ln2/Kel

    How long it takes a [] to drop by ½. How slow the drug is being eliminated

    • ►Longer the T1/2, slower the elimination
    • ►4-5 half-times required to eliminate 95% of drug
    • ►Important for designing repeated administration regimens
  48. first order drug elimination: plasma clearance-
    • Rate at which a given volume of plasma is cleared of all drug
    • e.g. ml/min

    • clearance: Vd x Kel
    •  
    • Allows calculation of rate of drug administration required to maintain therapeutic plasma concentration
  49. continuous administration: IV administration

    dosage rate=
    clearance x steady state [drug] plasma

    • ►Drug can be introduced at constant rate to offset elimination
    • ►Rate of administration must exceed T1/2 of elimination for [Drug]Plasma to be elevated
    • ►Takes ~4-5 half-lives to reach steady state plasma concentration
  50. continuous administration: non-IV administration
    dosage rate=
    clearance x steady state [drug] plasma / bioavailability

    • ►Drug can be introduced at constant rate to offset elimination
    • ►Rate of administration must exceed T1/2 of elimination for [Drug]Plasma to be elevated
    • ►Takes ~4-5 half-lives to reach steady state plasma concentration
  51. Repeated clearance
    Avg. [Drug] plasma = dose x bioavailability/ dosage interval x clearance 

    • More commonly used ►e.g. oral tablets
    • ►Consecutive administration of fixed doses produces plateau in [Drug]Plasma
    • ►Both dose interval and dose can be modified to alter plasma concentration

    For tablet drugs: Need to measure the time in btwn the tablets, don’t have as much control over the [],so you need to figure how often to administer
  52. Loading dose:
    = desired [drug] plasma x Vd

    When you want to get to a plasma [] quickly. General anesthesia: propofol (IV adminster), and then after use isoflurane (inhaled substance.

    • ►Necessary when rapid increase in [Drug]Plasma to therapeutic levels is required
    • ►Usually IV to reduce time and circumvent bioavailability limitations
    • ►Subsequent smaller “maintenance” doses administered to maintain desired [Drug]Plasma
Author
merazar15
ID
192871
Card Set
Pharm-kinetics
Description
Exam 1
Updated

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