Exam 2 - Distribution, Clearance, Dosage, & Receptors Flashcards
(62 cards)
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
Relationship between infusion rate and Css?
- 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
Length of time to reach Css?
- 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
Fixed dose/time regimen
- more convenient than continuous infusion
| - results in fluctuating levels of drug
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IV fixed time regimens
- 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
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Oral fixed dose regimen
- Css is influenced by rate of absorption and elimination
30
Optimal dose
- maintain [drug plasma] in therapeutic window
| - window = safe range between [min therapeutic] and [min toxic]
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Two ways of optimizing dose
- loading dose
| - maintenance dose
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Loading dose
- 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
Loading dose IV equation
LD = Vd x Css
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Maintenance dose equation
- maintain [plasma drug] in window
MD = CL x Css
35
When to adjust dosage
- decrease renal/hepatic blood flow
- heart failure / hemorrhage
- renal/hepatic disease
- children (renal function immature)
- elderly (GFR decreases)
- increased hepatic flow
36
Drug approval process
- 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
Pharmacodynamics
Actions of drug on body
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Drug
- 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)
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3 types of electrical charges
- covalent (strong)
- electrostatic (most common)
- hydrophobic (weak but good for lipid solubles)
- drugs that bind through weak bonds are more selective
40
Racemic mixtures
- majority of drugs available w/ 2 diff isomers
- R and S
- one may be active and one may not be
41
Receptors
- 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)
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Drug-receptor complex
- 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
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Ligand gated ion channels
- binding site is extracellular
- opens for few ms
- ions move in or out
- i.e. Ach / cholinergic / nicotinic receptors
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G-protein coupled receptors
- aka serpentine receptors
- longest lasting
- agonist binds receptor -> activates G protein -> GTP binds -> activate enzyme
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Enzyme linked receptors
- molecular switches
- multiplication of initial signal
- lasts minutes to hours
- i.e. Insulin receptors
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Intracellular receptors
- 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
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Two important features of signal transduction
- amplify signals
| - protect cell from excessive stimulation
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Signal amplification
- 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
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Protection from excessive stimulation
- desensitization (fast)
- diminished effect
- down regulation (slow)
- receptors degraded / recycled
- refractory period (in ion channels)
50
Potency curve
- amount of drug needed to produce given magnitude
- EC50: [ ] producing 50% of max effect
- potency difference overcome by giving more drug
51
Efficacy curve
- 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
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Law of mass action and drug-receptor interactions
- 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
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Full agonist
- max bio response
- mimics endogenous ligand (same Emax)
- intrinsic activity = 1
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Partial agonist
- cannot make same Emax
| - affinity can be >,
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Inverse agonist
- Stabilizes receptors in inactive state to prevent activation
- opposite effect of agonist
- Intrinsic activity = 0
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Antagonist
- bind to receptor w/ high affinity
- intrinsic activity = 0
- blockers
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Competitive antagonism
- block site
- over some with more agonist
- same Emax.....increased EC50 (shifts right)
- i.e. Beta blocker (propranolol)
58
Non-competitive antagonism
- irreversible (covalently binds to receptor site)
- allosteric ( binds to other site and changes shape)
- decreased Emax....same EC50
- no shift of curve....just drop
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Functional antagonism
- drug acts at a different receptor to initiate response opposite to that of agonist
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Chemical antagonism
- drug binds to agonist itself to counter effects
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Quintal-dose response relationship
- relationship between drug dose and proportion of population that have a response
- helps find therapeutic window
62
Therapeutic Index
TI = TD50 / ED50
```
TD = toxic dose
ED = effective dose
LD50 = lethal dose
```
- Higher TI is safer
- Low TI (<2) used only for serious disease
