Clinical Pharmacokinetics: Individualizing Therapy Flashcards
What are the main principles are associated with every pharmacological agent?
Absorption, Distribution, Metabolism, Elimination (ADME)
How are starting doses for drugs requiring therapeutic drug monitoring determined? How are adjustments made?
Population Pharmacokinetic (PK) provide the basis for “usual” dose
18-64 year olds, healthy, clinical trials to determine “usual dose”
These principles provide a basis for “usual” doses but deviations occur within patients.
Starting dose for drugs requiring TDM are designed based on population
pharmacokinetics. Adjustments are made utilizing patient specific pharmacokinetic
parameters calculated from patient specific drug levels.
Define absorption, bioavailability.
Absorption = How the drug gets into the body from the site of administration
Bioavailablity (F): the fraction of administered drug that reaches systemic circulation unchanged.
(Intravenous: F = 100%)
Where in the GI tract are most drugs absorbed? What are the implications for drugs administered via tube feed?
Most drugs are absorbed in stomach or first part of duodenum
Tube feeds – where is the tip of the feeding tube located?
Jejunal tube (hint: not great for enteral absorption)
solutions and suspensions in stomach or early small intestine
in jejunum cannot have suspensions; only solutions
Should sustained release/controlled release drugs be crushed?
Do not crush sustained release/controlled release drugs
sometimes formulations can be dissolved in water
How does the bioavailability of enteral routes, non enteral routes, intramuscular, topical, transdermal, and subcutaneous routes compare?
Which avoid first pass metabolism?
enteral (oral) F less than 100%
parenteral is 100% bioavailable
intramuscular is less than 100% F
topical, transdermal, subcutaneous: less than 100% F
parenteral, intramuscular, topical, transdermal, subcutaneous avoid first pass effect
Six months after a spinal surgery, a 24 year old graduate student was prescribed the fentanyl transfermal patch to treat his severe, chronic pain in order to provide a continuous, around-the-clock opioid analgesic for needed for an extended period of time. It’s November and he is a big Notre Dame fan and attends all the games, often getting so excited that he forgets to wear a proper coat. Today he checked the weather and looked at the wrong city and so headed out in a t-shirt. Soon he feels a the pain in his back worsen. The patch is dry, fully attached. Why doesn’t it seem to be working?
Skin temperature will affect absorption
warm skin-vasodilation, absorption may be greater
vasoconstriction (more impaired absorption)
What are the units for volume of distribution? Define this term.
L/kg
Theoretical fluid volume needed to maintain the total absorbed drug amount in the
plasma.
What do Ca levels in the blood indicate?
Reported Ca levels measure bound calcium (80% Ca is bound to albumin)
-normal levels are 8.5-9.3
if albumin is low this could falsely depress Ca levels; so if you gave this patient more Ca, run risk of causing hypercalcemia …
Ionized calcium measures ‘non bound’ calcium
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How must Vd change in cases of low or high protein binding?
low protein binding -
generally large Vd
High protein binding- Vd may be challenged
albumin used as clinical marker
How migh inflamed meninges affect the BBB?
Inflamed meninges: increased spaces, possibly better penetration
Noninflamed meninges: tight web, minimal penetration
What kind of medications cross the BBB easier?
How can you improve absorption in this case?
Medications with decreased protein binding cross BBB easier
Maximize dosing or consider alternate routes of administration (i.e.
intraventricular)
Define metabolism.
Where does this process primarily take place?
What can cause some alterations in metabolism?
How a medication is broken down to less active, more water soluble by-products
Primary site: liver
Phase I
Reduction, oxidation, hydrolysis with CypP450 systems
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4
Phase II (Conjugation)
Glucuronidation, Acetylation, Sulfation (GAS)
Alterations in metabolism:
Disease state(s)
Medication competition or effects
Define elimination. Where are most drugs eliminated?
Affects half life (t ½)
Most drugs undergo renal elimination (about 95%)
Fecal / biliary less common – no dose adjustment needed at all
Discuss dose adjustments for renal, fecal, or bilary elimination.
Anticipate dose adjustments with deviations from ‘normal’ for renally eliminated drugs!
Fecal / biliary less common – no dose adjustment needed at all
A patient’s creatinine clearance has diminished. What should you consider when prescribing a drug dose?
Renal function deteriorates with age
Creatinine (Cr) also comes from muscle
-May overestimate renal function if using actual Cr level if less than 1 for elderly or cachectic patients
A patient is on hemodialysis. What should you consider regarding his/her medications?
hemodialysis/hemofiltration may filter out drugs
Hydrophilic drugs
Small molecular weight (particle size)
What are the PK variations that should be considered in neonates?
immature skin, increased skin hydration, increased absorption of topical products
increased ECF, increased Vd of H2O soluble drugs
metabolic pathways mature at different times
immature GFR, tubular secretion and reabsorption
What are some PK variations that should be considered in the elderly?
skin thinning - increased absorption of topical products
increased adipose tissue –increased Vd of fat soluble drugs
decreased ECF - decreased Vd of H2O soluble drugs
Age related changes in renal function (decreased GFR)
Why might you prescribe a loading dose?
Loading Dose (LD) may be given to help achieve an immediate therapeutic response.
Levels approximate those seen at steady state (SS).
How does a loading dose affect the time to reach steady state?
SS NOT reached faster —4 -6 half-lives still needed.
How are dose and half life related to steady state?
SS is dependent only on half life (t ½).
PK parameters must remain stable for patient truly to be at steady state.
At what plasma concentration are dose adjustments most accurate?
Dose adjustments are most accurate when made at SS.
Why is being at SS important?
Minimizes potential for over/under dose adjustment.
Ensures maximum and stable
distribution.
Safe and potentially cost effective dose adjustments.
What if the PK parameters keep changing?
still get levels and have to be careful about prolonged scheduled dose bc parameters still changing
Dose adjustment is only as good as level assessment. What are important questions to keep in mind when monitoring therapeutic dose?
When was the dose actually given?
When was the level actually drawn?
From where was it drawn?
If a patient is fluid overloaded, how would the Vd compare with population estimates?
fluid overloaded so her Vd would be expected to be larger than population estimates.
A patient is fluid overloaded at present leading to an even larger Vd.
How will this affect peak?
How can the dose be changed?
What if renal function worsened?
peak will be lower
can increase mg amount and keep same interval
if renal function worsened can lengthen interval
If a patient is on a platelet thinner and aspirin, what type of interactions could occur?
(both will work to thin blood) could increase risk of bleeding
How will St. John’s Wort affect Tacrolimus?
(revs up c450 system and increases metabolism of drugs
How does drinking grapefruit juice on Simvastatin affect the drug’s metabolism?
g-juice could be inhibitor of cp450 system
What is the Disulfiram effect?
Disulfiram + white wine (inhibits alcohol dehydrogenase; feel sick when drink)
The breakdown of alcohol is impeded via inhibition of the enzyme acetaldehyde dehydrogenase resulting in increased acetaldehyde concentration and symptoms of nausea and vomiting
Describe the following pharmacodynamic interaction:
Warfarin + spinach
a. Warfarin inhibits vitamin K dependent clotting factors
b. Spinach has vitamin K
c. End result is decreased anticoagulant effect
Describe the following pharmacodynamic interaction:
Warfarin + spinach
a. Warfarin inhibits vitamin K dependent clotting factors
b. Spinach has vitamin K
c. End result is decreased anticoagulant effect
Describe the following pharmacodynamic interaction:
Methylprednisolone and glucose control
Steroids can increase blood sugar
Ritonavir is a CYP450 inhibitor.
If given with lopinavir (HIV protease inhibitor), how will concentrations of the drugs be affected? Should dose be adjusted? What about frequency of administration.
lopinavir levels will increase
dose should be decreased
cleared less so frequency of administration should be reduced
