Pharmacokinetics: Drug-Specific Application Flashcards
A free drug enters the systemic circulation how?
and can be eliminated how?
absorption
metabolism or excretion
Equation for bioavailability?
Amount of drug reaching systemic circulation / quantity of drug administered
In linear/first order kinetics how is drug eliminated?
Serum concentration changes are proportional to drug dosing changes
Constant proportion of drug is eliminated
In nonlinear/zero order kinetics how is drug eliminated?
Constant amount of drug is eliminated
What does therapeutic drug monitoring allow us to do?
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Optimize clinical response
Avoid toxicity
Assess patient compliance
What is a peak?
Maximum drug concentration (Cmax)
When do we measure peaks?
and why?
Measured 30 – 60 min after end of infusion (allows time for tissue distribution)
What is a trough?
Minimum drug concentration (Cmin)
When do we measure troughs?
Measured immediately (
What is Phenytoin (Dilantin®):?
Anticonvulsant in central nervous system (CNS) for treatment and prevention of seizure
What is Phenytoin (Dilantin®) mehanism of action?
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- Na+ channel antagonist
- Slows Na+ channel recovery from inactivated state to resting/closed state
- Stabilizes neuronal membranes which decreases seizure activity
What is the bioavailability of phenytoin?
90-100%
In phenytoin time to peak increases with what?
ex?
larger doses
400 mg, 800 mg, and 1600 mg ER caps peak at 8, 13, 30 hours, respectively
What are the distributions characteristics of phenytoin?
Its lipid soluable
and highly protein bound (lower in neonates and infants than adults)
What is the half life of phenytoin?
oral: 22 hrs but highly variable
IV: 10-15 hrs
When is the steady state reached of phenytoin?
4-6 half lives
How is phenytoin cleared?
Capacity limited hepatic metabolism
NOT BY THE KIDNEYS
What kind of kinetics does phenytoin follow?
Michaelis-Menten kinetics
-Zero order when concentration >4 mg/L in adults, higher in younger and older populations
What are the risks with loading doses in phenytoin?
2
What happens when you give the max dose quicker than slower?
Bradycardia
Hypotension
associated with rapid infusion of either oral or IV product
-If you give it quicker (max dose) you will most likely have these side effects than over a longer period of time
What are the benefits of a maintenance dose of phenytoin in children?
2
Minimizes plasma concentration fluctuations and gastrointestinal disturbances
Whats the therapeutic range of phenytoin?
10-20mg/L
50% respind at 10mg/L
Phenytoin side effects?
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- Nystagmus
- CNS depression
- Commonly includes ataxia and impaired motor function
What serum phenytoin concentration would you aim for?
15 mg/L
When do we give maintence doses for phenytoin?
At the trough (at the minimum drug concentration)
Phenytoin is a strong inducer of CYP enzymes. What does this effect?
It makes the enzyme more active (work more) thus breaking down more drug = less drug in your blood
If you have hepatic disease and you are taking phenytoin what are the effects?
2
- If you have hepatic disease if you don’t have the enzymes working then you more have an inhibitory effect. There’s going to be more drug in your system that isn’t being broken down
- Phenytoin wont be eliminated with hepatic disease = toxic effects and no elimination of drugs.
Can you still give someone with hepatic disease phenytoin?
Depending on how severe the hepatic disease is you could still give a reduced dose but if its severe you cant give it.
If you have renal failure and you are taking phenytoin what are the effects?
Renal failure doesn’t really matter because its not cleared by the kidneys
Why does phenytoin have the potential for many drug interactions?
highly protein bound and a strong inducer of CYP enzymes
How is phenytoin metabolized?
Saturable metabolism
Michaelis-Menten
Where do we want its serum concentrations to be and would we want to monitor it closely or do we not need to?
10 – 20 mg/L
NEED to monitor sreum concentrations
-low therapuetic index
What kind of medications are Gentamicin/Tobramycin?
Aminoglycoside antibiotics
What is the mechanism of action for Gentamicin/Tobramycin?
It binds to a ribosomal subunitand disrupts bacteral protein synthesis
What are the primary dosage forms for Gentamicin/Tobramycin?
injection
Absorption of Gentamicin/Tobramycin?
poor orally
100% for IV/IM
Distribution characteristics of Gentamicin/Tobramycin?
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- highly hydrophilic and located primarily in the extracellular fluid
- High concentration in renal cortex
- Poor CNS penetration
- Vd- higher in younger ages
- Protein binding low
Who has a higher Vd?
Phenytoin or Gentamicin/Tobramycin?
phenytoin
Why do Gentamicin/Tobramycin have poor CNS penetration?
its hydrophilic (water soluble)
Why does Gentamicin/Tobramycin have a higher Vd in children and neonates?
children are composed of more water and Gentamicin/Tobramycin are hydrophilic
How is Gentamicin/Tobramycin metabolized?
It isnt. Its completely dependant on kidney function/GFR
How is Gentamicin/Tobramycin excreted?
Through normal renal function
90-95% is eliminated in 24 hours
What does MIC stand for?
minimum inhibitory concentration
-how much antibiotic is required to inhibit growth in a test tube
What does AUC stand for?
area under the curve (amount of drug given)
Bactericidal activity dependents on what in Gentamicin/Tobramycin?
drug concentration
In Gentamicin/Tobramycin what correlates with efficacy?
peak concentration/ MIC
How do we usually dose Gentamicin/Tobramycin?
Larger doses, longer intervals
What are nomograms based on and what are they used to dose?
Dosing based on weight and adjustments based on a chart.
Used to dose Aminoglycosides (Gentamicin/Tobramycin)
What does the Baysian model of doing based on?
2
Computer model of normal population parameters
Dosing/adjustments based on clinical circumstances
What do the peaks in Gentamicin/Tobramycin correlate with?
Correlate with efficacy
Not typically drawn with extended interval dosing
Why do we look at troughs for Gentamicin/Tobramycin?
To monitor toxicity (so that we see how how they are eliminating it and if we can give the next dose)
What is Ototoxicity?
toxicity to the ear
What are the symptoms of Ototoxicty?
Vestibular & cochlear damage
Hearing loss, tinnitus, loss of balance/ataxia
What is the pathology related to of Ototoxicity?
2
related to sustained high concetrations Gent and Tob
Its irreversible
What is Nephrotoxicity?
toxicity to the kidneys
What are the symptoms of Nephrotoxicity?
3
Acute kidney injury due to acute tubular necrosis
This can occur with usual dosing
Is reversible
What are some risk factors for nephrotoxicity?
- prolonged duration of therapy, 2. advanced age,
- sepsis/decreased renal perfusion,
- other nephrotoxic drugs
When do we monitor/draw for troughs?
Immediately prior to the next dose
When do we monitor/draw for peaks?
30 minutes following the end of infusion (after 4-5 half-lives)
When do we only monitor for Gentamicin/Tobramycin?
Drug monitoring only done for IM or IV
What are Gentamicin/Tobramycin’s distribution characteristics?
Hydrophilic (low Vd)
What is Gentamicin/Tobramycin’s elimination characteristics directly related to?
GFR
What is Gentamicin/Tobramycin’s efficacy related to?
Cmax (peak)/MIC ratio
And what are the different dosing options for gent/tobo?
Extended interval dosing
Traditional dosing
How do we monitor serum concentrations for gent/tobo?
Troughs (routinely)
Peaks (traditional dosing, individualized dosing)
What kind of drug is vancomycin?
Glycopeptide antibiotic
What is vanco’s mechanism of action?
Binds to bacterial cell to cause cell lysis
What kind of infections is it reserved for?
Resistant ones
MRSA
Best form of dosage for vanco?
injection
Vanco distribution characteristics?
2
Widely distributed in tissues except for the CNS
Moderate protein binding at 50%
How is vanco metabolized?
its not
What is vancos half life?
5-11 hours with adults. much longer with renal impairment
How is vanco excreted?
IV: Through urine (80-90% unchanged drug)
Orally through the feces
What is oral vanco only used for?
C. Diff
What is the bactericidal activity of vancomycin dependent on?
Time
What does efficacy correlate with in vancomycin?
AUC (amount of drug) /MIC (how much it takes to inhibit growth in a test tube)
What is vancomycin’s interval dosing based on?
renal function (creatinine clearance)
What do we monitor to ensure efficacy in vancomycin?
troughs
Do we monitor peaks in Vanco?
no,
No definitive relationship between peak/trough concentrations and toxicity/response
What is Redman’s syndrome related to in vanco and what does it cause?
related to infusion rate
causes hypotension
and Erythematous rash
What is ototoxicty related to in vanco and what does it cause?
Its proportional to amount of drug given & duration of therapy
causes are tinnitus and vertigo
Vanco can also causes nephrotoxicity
Acute kidney injury
What do we measure for drug monitoring in vanco?
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Troughs
Immediately prior to next dose
which we want to give about 4-5 half lives after the initial doses and dosage changes
We rarely monitor for peaks
When is the only time we monitor Vanco?
when its given via injection
Elimination in vanco is directly related to what?
GFR
What is efficacy related to in vanco?
AUC/MIC
How do we monitor serum concentrations in vanco?
troughs
What kind of drug is warfarin?
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Anticoagulant
Vitamin K antagonist
What is warfarin mechanism of action?2
inhibits vitamin K enzymes in liver and decreases syntheis of clotting factors
What is the primary dosage form in warfarin?
oral tablets
What are warfarin’s absorption characteristics?
rapid and complete
What is warfarins distribution characteristics?
High Vd
High protein binding affinity 99%
How is warfarin metabolized?
Hepatically metabolized by CYP enzymes
What is warfarins half life?
40 hrs (large range of 20-60 hrs)
How is warfarin excreted?
Through the urine (92% metabolites)
Can warfarin be taken during pregnancy?
No!
Category X drug
How do we monitor warfarin?
The time in seconds it takes to form a clot or prothrombin times
Why must be overlap another anticoagulant with warfarin for the first 5 days?
Because decreased protein C and S initally make the patient hypercoaguable (abnoramally increased tendency to blood clot)
Warfarin is CYP mediated. If CYP is induced what will happen? What if it is inhibited?
induced= less warfarin in the body inhibited= more warfarin in the body
Warfarin is vitamin K mediated. What are the considerations we have to deal with?
Should not eat excessive amounts of green leafy vegetables. We would have to tailor the dose of warfarin to fit their diet and make sure they are consistant with their eating habits
Why is hitting the therapeutic range so important in warfarin?
Because the side effects for too much or too little warfarin are on opposite side of the spectrum. With too little you get clotting and with too much you get excessive bleeding
How long does it take for warfarin to reach a steady state?
5 days
Why does warfarin capable of having a lot of drug interactions?
3
CYP-mediated
Protein binding
Vitamin K containing drugs/foods
How does phenytoin affect warfarin?
decreases serum concentration of warfarin
IT IS NOT GIVEN SPECIFICALLY TO INDUE OTHER DRUGS
What would happen if hepatic failure occurred in a patient that kept taking phenytoin?
build up of drug
could reach toxic levels
Vancomycin:
Efficacy?
bactericidal activity?
When does the optimal response occur?
Efficacy: trough
AUC/MIC
Time-dependent bactericidal activity:
i.e. it’s the time that the serum concentration remain above the MIC
The optimal response occurs when the time of the drug remain above the MIC >50% of the dosing interval
Aminoglycoside:
Efficacy?
Bactericidal activity?
When does the optimal response occur?
Why do we measure the troughs in Aminoglycoside?
Efficacy: peak
Peak/MIC
Concentration-dependent bactericidal activity
The optimal response occurs when the concentrations are >10x the MIC
toxicity
