Exam 2 - Distribution, Clearance, Dosage, & Receptors Flashcards
1
Q
Drug distribution happens via
A
- bloodstream
- immediately after administration
2
Q
Factors that affect distribution
A
- CO
- Capillary permeability
- Protein binding
- Lipophilicity
- Tissue volume
3
Q
CO and distribution
A
- Higher flow -> more drug [ ]
- heart, brain, kidneys, liver, muscles
- Low flow organs
- adipose tissue, skin
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
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
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
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)
8
Q
Total body H2O volume
A
- 60% of weight
- 40% is intracellular
- 20% is extracellular
9
Q
Plasma compartment
A
- 4% of body weight
- high MW drugs
- lots of proteins
- low Vd drugs are in plasma (intravascular)
10
Q
Extracellular fluid compartment
A
- 20% body weight
- low MW drugs
- hydrophilic drugs
- high Vd drugs in interstitial fluid (extracellular) (outside plasma)
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]
12
Q
Vd and drug half-life
A
- high Vd increases half-life
- drug more bound to tissues
13
Q
How many half lives until drug is gone
A
- 4th or 5th
14
Q
3 major elimination routes
A
- hepatic metabolism
- biliary metabolism
- urinary metabolism
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]
16
Q
Clearance equation
A
CL = (0.639 x Vd) / half life
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 [ ]
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
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
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
21
Q
Inducers of Cytochrome P450
A
- increases biotransformation in liver
- drops [drug plasma]
- i.e. Antibiotics, sedatives, anti-seizure
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
23
Q
Renal clearence
A
- most important route of elimination
- glomerular filtration / secretion / absorption
Excretion = filtration + secretion - reabsorption
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)
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
- Phase 1: dose-response relationship
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
