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581 - Pharmacology I > Exam 2 - Distribution, Clearance, Dosage, & Receptors > Flashcards

Exam 2 - Distribution, Clearance, Dosage, & Receptors Flashcards

1
Q

Drug distribution happens via

A
  • bloodstream

- immediately after administration

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2
Q

Factors that affect distribution

A
  • CO
  • Capillary permeability
  • Protein binding
  • Lipophilicity
  • Tissue volume
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3
Q

CO and distribution

A
  • Higher flow -> more drug [ ]
    • heart, brain, kidneys, liver, muscles
  • Low flow organs
    • adipose tissue, skin
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4
Q

Capillary permeability

A
  • depends on how exposed to slit junctions
    • openings in basement membrane
    • brain has tight slits…need lipophilic to get through
    • hydrophilic need slit junctions to get through
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5
Q

Protein binding and distribution

A
  • reversible protein binding sequesters drug in plasma
  • can’t diffuse
  • slows transfer
  • drug bound to protein…can’t bind to active site
  • Example: albumin…acts as drug reservoir
    • free drug is eliminated…albumin bound saved as store
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6
Q

Tissue protein binding

A
  • higher [ ] of drug in tissue than in blood
    • due to lipids, proteins, nuclei acid binding
    • due to active transportation of drug
  • drug sequestered in tissues
    • prolong drug action
    • cause local toxicity
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7
Q

Volume of distribution

A
  • Volume required to contain entire drug in body at same [ ] measured in plasma
  • Vd (L) = amount in body (mg) / [plasma drug] (mg/L)
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8
Q

Total body H2O volume

A
  • 60% of weight
  • 40% is intracellular
  • 20% is extracellular
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9
Q

Plasma compartment

A
  • 4% of body weight
  • high MW drugs
  • lots of proteins
  • low Vd drugs are in plasma (intravascular)
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10
Q

Extracellular fluid compartment

A
  • 20% body weight
  • low MW drugs
  • hydrophilic drugs
  • high Vd drugs in interstitial fluid (extracellular) (outside plasma)
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11
Q

Calculating Vd

A
  • know equation and units
  • be ready to index Vd to determine where drug is
  • high Vd = intracellular or low [plasma]
  • low Vd = intravascular or high [plasma]
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12
Q

Vd and drug half-life

A
  • high Vd increases half-life

- drug more bound to tissues

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13
Q

How many half lives until drug is gone

A
  • 4th or 5th
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14
Q

3 major elimination routes

A
  • hepatic metabolism
  • biliary metabolism
  • urinary metabolism
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15
Q

1st order kinetics

A
  • most drugs eliminated with this….95%
  • constant fraction in given unit of time
  • drug half life is used to measure clearance
  • constant proportion used (constant half life) (i.e. 50%)
  • rate of elimination proportional to [plasma]
  • exponential decay curve
  • dependent on initial [drug]
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16
Q

Clearance equation

A

CL = (0.639 x Vd) / half life

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17
Q

Zero order kinetics

A
  • [plasma] -> no change in rate of metabolism
  • constant rate (i.e. 2 mg/hr)
  • only 5% of drugs
  • rate of elimination independent of [ ] (saturated process)
  • elimination decreases at higher drug [ ]
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18
Q

Drug metabolism

A
  • break down into water soluble metabolites
    • aids in excretion
  • occurs by chemical rxns
  • Liver is big player
    • cytochrome P450
    • induced or inhibited
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19
Q

Phase I Biotransformation of drug

A
  • lipophilic drugs into more water soluble
    • OH or NH2 groups added
  • Reduction / oxidation / hydrolysis
  • metabolites can often sometimes still be too lipophillic
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20
Q

Phase II Biotransformation of drug

A
  • conjugation reactions
    • links acid to phase I metabolite
  • even more water soluble compound
  • therapeutically inactive after phase II
  • excreted
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21
Q

Inducers of Cytochrome P450

A
  • increases biotransformation in liver
  • drops [drug plasma]
  • i.e. Antibiotics, sedatives, anti-seizure
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22
Q

Inhibitors of Cytochrome P450

A
  • adverse side effects
  • decreases elimination and makes drug last longer
  • lead to toxicity
  • i.e. Ulcers / kidney stones
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23
Q

Renal clearence

A
  • most important route of elimination
  • glomerular filtration / secretion / absorption

Excretion = filtration + secretion - reabsorption

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24
Q

Continuous infusion regimen

A
  • rate of drug entry is constant
  • [drug plasma] increases until steady state

Steady state: elimination rate = administration rate (Css)

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25
Q

Relationship between infusion rate and Css?

A
  • directly proportional (infusion x2…Css x2)
  • time it takes to reach Css is the same
  • Css and clearance are inversely related
    • low elimination -> high Css (liver/renal disease)
    • high elimination -> low Css (diarrhea/high metabolism)
26
Q

Length of time to reach Css?

A
  • equal to half life
  • 50% of Css after one half life
  • 75% after two
  • 87.5% after 3….and so on
  • Will reach Css between 4-5 half lives
27
Q

Fixed dose/time regimen

A
  • more convenient than continuous infusion

- results in fluctuating levels of drug

28
Q

IV fixed time regimens

A
  • given at intervals shorter than 5 half lives
    • some drug from 1st dose remains at 2nd dose
    • some drug from 2nd dose remains at 3rd dose…so on
29
Q

Oral fixed dose regimen

A
  • Css is influenced by rate of absorption and elimination
30
Q

Optimal dose

A
  • maintain [drug plasma] in therapeutic window

- window = safe range between [min therapeutic] and [min toxic]

31
Q

Two ways of optimizing dose

A
  • loading dose

- maintenance dose

32
Q

Loading dose

A
  • achieve rapid desired plasma levels of drug
  • single or series of doses
  • drugs w/ long half lives (long time to reach Css)
    • so we need to reach it quicker
  • followed by maintenance dose
33
Q

Loading dose IV equation

A

LD = Vd x Css

34
Q

Maintenance dose equation

A
  • maintain [plasma drug] in window

MD = CL x Css

35
Q

When to adjust dosage

A
  • decrease renal/hepatic blood flow
    • heart failure / hemorrhage
  • renal/hepatic disease
  • children (renal function immature)
  • elderly (GFR decreases)
  • increased hepatic flow
36
Q

Drug approval process

A
  • Investigation New Drug Application (IND)
    • preclinical data / proposal for trials / to FDA
  • Clinical trials (info for NDA)
    • Phase 1: dose-response relationship
      On small # of healthy volunteers (20-100)
    • Phase 2: on moderate # w/ disease (100-200)
      Controls included / single or double blind / check efficacy
    • Phase 3: on high # (1000-5000)
      Placebo/positive controls
      Double blind / further eval of toxic / compare studies
    • if successful:NDA to FDA…if approved…marketed and into phase 4
      -Phase 4: post marketing surveillance / not as regulated
37
Q

Pharmacodynamics

A

Actions of drug on body

38
Q

Drug

A
  • any substance that brings about change in biology through chemical actions
  • need right: size/charge/shape (chiral) / atomic composition
  • want selective binding (smaller less selective)
39
Q

3 types of electrical charges

A
  • covalent (strong)
  • electrostatic (most common)
  • hydrophobic (weak but good for lipid solubles)
  • drugs that bind through weak bonds are more selective
40
Q

Racemic mixtures

A
  • majority of drugs available w/ 2 diff isomers
  • R and S
  • one may be active and one may not be
41
Q

Receptors

A
  • binds to drug AND produces response
  • mostly proteins
  • needs to be selective
  • need to have pharmacological response
    • albumin binds drugs but not receptor (inert binding)
42
Q

Drug-receptor complex

A
  • cells have many types of receptors
  • specific to agonist and have unique response
  • response depends on # of complexes
  • Not all drugs exert effect through receptors (tums)
  • R = inactive
  • R* = active
  • reversible equilibrium usually favors inactive
    • shifts to R* when agonist binds
43
Q

Ligand gated ion channels

A
  • binding site is extracellular
  • opens for few ms
  • ions move in or out
  • i.e. Ach / cholinergic / nicotinic receptors
44
Q

G-protein coupled receptors

A
  • aka serpentine receptors
  • longest lasting
  • agonist binds receptor -> activates G protein -> GTP binds -> activate enzyme
45
Q

Enzyme linked receptors

A
  • molecular switches
  • multiplication of initial signal
  • lasts minutes to hours
  • i.e. Insulin receptors
46
Q

Intracellular receptors

A
  • ligand must diffuse into cell
  • targets transcription factors in nucleus
  • lasts hours to days BUT takes at least 30 min to work
  • i.e. Steroids
47
Q

Two important features of signal transduction

A
  • amplify signals

- protect cell from excessive stimulation

48
Q

Signal amplification

A
  • G protein and enzyme linked receptors
  • amplify intensity AND duration
  • ligand binding short….effect keeps happening
  • we do have spare receptors
    • only fraction needed to make max response
49
Q

Protection from excessive stimulation

A
  • desensitization (fast)
    • diminished effect
  • down regulation (slow)
    • receptors degraded / recycled
  • refractory period (in ion channels)
50
Q

Potency curve

A
  • amount of drug needed to produce given magnitude
  • EC50: [ ] producing 50% of max effect
  • potency difference overcome by giving more drug
51
Q

Efficacy curve

A
  • magnitude of response a drug causes when it binds
  • depends on: # of drug-receptor complexes formed
    Intrinsic activity of drug
  • efficacy more clinically useful than potency
  • want a drug that gets us to target level
52
Q

Law of mass action and drug-receptor interactions

A
  • drug and receptor combine reversibly
  • occupancy of drug to receptor proportional to dose AND # of free receptors
  • response proportional to fraction of occupied sites
  • plateaus due to limited # of receptors
53
Q

Full agonist

A
  • max bio response
  • mimics endogenous ligand (same Emax)
  • intrinsic activity = 1
54
Q

Partial agonist

A
  • cannot make same Emax

- affinity can be >,

55
Q

Inverse agonist

A
  • Stabilizes receptors in inactive state to prevent activation
  • opposite effect of agonist
  • Intrinsic activity = 0
56
Q

Antagonist

A
  • bind to receptor w/ high affinity
  • intrinsic activity = 0
  • blockers
57
Q

Competitive antagonism

A
  • block site
  • over some with more agonist
  • same Emax…..increased EC50 (shifts right)
  • i.e. Beta blocker (propranolol)
58
Q

Non-competitive antagonism

A
  • irreversible (covalently binds to receptor site)
  • allosteric ( binds to other site and changes shape)
  • decreased Emax….same EC50
  • no shift of curve….just drop
59
Q

Functional antagonism

A
  • drug acts at a different receptor to initiate response opposite to that of agonist
60
Q

Chemical antagonism

A
  • drug binds to agonist itself to counter effects
61
Q

Quintal-dose response relationship

A
  • relationship between drug dose and proportion of population that have a response
  • helps find therapeutic window
62
Q

Therapeutic Index

A

TI = TD50 / ED50

TD = toxic dose
ED = effective dose
LD50 = lethal dose
  • Higher TI is safer
  • Low TI (<2) used only for serious disease

581 - Pharmacology I (6 decks)

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