Module 6 - Drug Level Monitoring Flashcards
List 5 indications for drug monitoring
- Therapeutic confirmation
- Dose optimization
- Suspected toxicity
- Assess for inefficacy
- Non-adherence vs. treatment failure
What are some ideal drug characteristics?
- Clinically necessary
- Drug level = clinical outcome
- Established assays
- Risk of toxicity high/narrow TI
- Unpredictable dose-response
What is the therapeutic index?
window between therapeutic effects and toxic effects
List advantages of population PK
- Provides a “best guess” based on majority of population
- Standardized dosing nomograms, easily available for clinical use
List disadvantages of population PK
- Genetic variability
- “Compartmental” PK
- Not very generalizable (very sick individuals)
List advantages of patient-specific PK
- specific to patient
- individualized therapy
List disadvantages of patient-specific PK
- time-consuming
- requires special knowledge
- intensive monitoring
Describe the elderly
- Decreased organ function
- Decreased Vd (increased adipose tissue, decreased muscle mass)
- Absorption (decreased GI motility, increased pH, decreased blood flow)
Describe infants
- Underdeveloped liver enzymes (decreased metabolism)
- Underdeveloped renal clearance
- Gastric acidity (12 years)
- Infants increase TBV
Describe males
- Larger body size
- Increased muscle mass (increased sCr)
- Lower % body fat
- Higher CYP 1A2, 2D6, and CYP 2E1 activity, higher p-glycoprotein activity
- Faster renal and hepatic clearance
Describe females
- Smaller body size
- Decreased muscle mass (decreased sCr)
- Higher % body fat
- Higher CYP 3A activity, lower p-glycoprotein activity
- Slower renal and hepatic clearance
Describe ethnicity
PK characteristics most likely to result in ethnic differences
- Gut or hepatic first-pass effects
- High plasma protein binding
- Hepatic metabolism as major route of elimination
List examples of ethnic differences regarding drugs
- Rosuvastatin: Asians require lower doses
- Carbamazepine: Han Chinese higher risk of SJS and TENS
- Warfarin: African Americans require higher doses, Asians require lower doses than caucasians
- Tacrolimus: Black patients require higher doses than caucasians
How does pregnancy affect absorption?
- Morning sickness (n/v)
- GI motility reduced
How does pregnancy affect distribution?
- Increased Vd (TBW increases by 8L)
- Decreased plasma albumin (dilution)
How does pregnancy affect metabolism?
-CYP enzymes induced by hormones
How does pregnancy affect excretion?
-Higher cardiac output, higher renal blood flow (GFR increases by 50%), higher clearance
How does obesity affect the body?
- renal clearance increased
- lipophilic drugs = higher Vd
- hydrophilic drugs = ? Vd
How does being really skinny affect the body?
-muscle wasting, low body weight, low body fat (Vd altered)
How does renal disease affect the body?
- Bioavailability may be increased or decreased
- Vd increased
- Protein binding decreased
How does hepatic disease affect the body?
- Decreases metabolism
- Phase 1 > Phase 2
- Cirrhosis»_space; chronic hepatitis
What are the clinical uses for ahminoglycosides (gentamicin/tobramycin) ?
- Concentration-dependent, bactericidal antibiotic with gram-negative coverage (including Pseudomonas)
- Used conservatively due to potential for serious adverse effects (ototoxicity/nephrotoxicity)
- Usually used in an inpatient setting (IV)
Describe absorption of aminoglycosides
Oral: poor absorption
IM: rapid absorption (peak within 30-120 mins)
IV: 30-60 min infusion, slow bolus or continuous infusion (peak 30 mins after infusion)
Describe the distribution of aminoglycosides
Vd = 0.2 - 0.3 L/kg (ECF), significantly affected by volume status
Vd = 0.35 - 0.4 L/kg in the critically ill
protein binding = 10%
Describe the metabolism of aminoglycosides
unchanged; no major metabolites
Describe the excretion of aminoglycosides
- t1/2 = 2-3 hours
- kidney, unchanges
- fe = 85-95%, directly related to renal function
What is the equation we use for half life of aminoglycoside?
Dettli equation
*if CrCl is known
Who is allowed high dose ahminoglycosides?
only for patients with good renal function (>60 mL/min)
Can high dose ahminoglycosides be used as mono therapy?
no
Describe the monitoring for aminoglycosides
- Obtain levels pre-3rd dose (traditional), pre 2nd dose (high dose)
- Peak: 30 mins post infusion
- Trough: 30 mins prior to next dose
- Watch sCr, urea and urine output at least 2-3x/week
2 toxicities associated with aminoglycosides
- ototoxicity
- nephrotoxicity
Describe ototoxicity caused by aminoglycosides
- Overt, 2-10% of patients, 43% subclinical; onset > 5 days
- Audiometry (hearing test) if treatment is > 72 hours
Describe nephrotoxicity caused by aminoglycosides
- Onset 6-10 days
- Proximal tubule reabsorption, can bind to renal membranes and cause acute tubular necrosis
- Labs will show: increased sCr, decreased eGFR, increased urea and impaired urinary concentrating ability
What are the goals of aminoglycoside therapy?
- keep levels within range
- shortest possible treatment duration
- once daily dosing (if good renal function)
What are some clinical uses of vancomycin?
- Antibiotic with slow bactericidal activity against GP, including MRSA, alternative to pens/cephs in severe allergy
- Used in inpatient or outpatient IV therapy
- Used orally against C. dif infection
What is the best predictor of clinical efficacy for vancomycin?
AUC/MIC = 400 (up to 600 for MRSA)
Describe absorption of vanco
- Oral < 10%
- Intraperitoneal 54-65% (peak approx 6 hours)
- IM erratic absorption
- IV (peak after completion of infusion)
Describe distribution of vanco
Vd = 0.4-1.0 L/kg fu = 50%
Metabolism of vanco
very small amount of liver metabolism
Excretion of vanco
t1/2 = 6-8 hours with normal renal function
IV = 80-90% urine (as unchanged drug)
Oral: primarily feces
What equation can be used for finding half life of vancomycin if CrCl is known?
Matzke
Describe the monitoring of vancomycin
- Obtain levels pre-3rd dose (assess Css)
- Peak: 1-2 hours post infusion (distribution)
- Trough: 15-30 mins prior to next dose
- Repeat weekly (stable patients) or as needed for unstable patients
Describe the consequences of toxic levels of vanco
Nephrotoxicity (controversial)
- “mississippi mud” - problems with fermentation methods
- now 95% pure, drastically reduced nephrotoxicity
- Not nephro or ototoxic unless combined with aminoglycosides
- Suggested risk factors: trough > 20 mg/L, concomitant treatment with nephrotoxic agents, prolonged therapy (>7 days) and ICU stay
Goals of vancomycin?
hit hard and fast (optimize therapy)
Clinical uses of phenobarb
- Management of seizures
- Sedative/hypnotic (withdrawal management-unlabeled use)
metabolism of phenobarb
hepatic; inactive metabolites
phenobarbital is an INDUCER
excretion of phenobarb
long half life (5 days in adults, 2.5 days in children)
35-50% fu in urine
remainder eliminated in feces
What equation do we use for phenobarb?
WAGNER !!!
Css target for phenobarb?
15-30 mg/L
Describe drug level monitoring for phenobarb
- Bc of the very long half life, it will take 3 weeks to reach Css
- Can measure 1 hour after IV load or in 5-7 days if PO
- If sub-therapeutic, can consider a loading dose to get patient to Css
- Monitor levels at same time of day (consistency)
What are some other lab monitoring parameters for phenobarb?
sCr: Reduce dose in renal impairment
LFT’s: caution in hepatic impairment
CBC: can cause agranulocytosis, thrombocytopenia, megaloblastic anemia
What are some consequences of toxic levels of phenobarb?
CNS side effects
35-80mg/L = sedation and ataxia
> 65 mg/L = stupor and coma
Clinical uses of phenytoin?
- Management of seizures
- Trigeminal neuralgia
- Seizure prophylaxis after neurosurgery
What kinetics does phenytoin follow?
Michaelis-Menten dose-dependent kinetics
Phenytoin acts as an _____
inducer (important for drug interactions
Can you do ratio dose adjustments for phenytoin?
NO WAY
use orbit plot!!
Phenytoin may need corrections for what two things?
- uremia
- hypoalbuminemia
How will phenytoin be adjusted for hypoalbuminemia?
- Less albumin = less protein binding = more free drug
- Adjusted will be higher than measured
How will phenytoin be adjusted for uremia +/- hypoalbuminemia ?
- Urea binds to albumin and displaces phenytoin (more free drug)
- Adjusted will be higher than measured
What are some drug level monitoring timelines for phenytoin?
- Very long half life (may take 3 weeks to reach Css)
- Draw first level: 1hr after IV load or 24h after PO load
- Second level: 2-3 days after starting
What are some other lab monitoring parameters for phenytoin?
CBC: leukopenia, agranulocytosis, thrombocytopenia, granulocytopenia
LFTs: hepatitis, acute hepatic failure
Albumin: critical illness, renal/hepatic disease (decrease albumin = increased free drug)
What are some consequences of toxic levels of phenytoin?
nystagmus, taxis, nystagmus, diminished mental capacity, involuntary muscle movements, seizures, death
What is valproic acid used for?
- Management of seizures
- Mood stabilizer
- Migraine prophylaxis
metabolism of VPA
primarily hepatic
VPA acts as an ______
inhibitor
____ VPA concentration and dose relationship is linear
free
Describe drug level monitoring timeline of VPA
- draw first level within 5 days of starting therapy
- if t1/2 = 10 hour then Css at 50 hours (approx 2-3 days)
What are other lab monitoring parameters for VPA
LFTs: baseline and frequently during first 6 months (small risk of hepatic failure with genetic disease)
CBC: platelets at baseline and then periodically due to thrombocytopenia
Consequences of toxic levels of VPA
sedation, lethargy, ataxia
cerebral edema, coma, bone marrow, depression
What is carbamazepine used for?
- management of seizures
- trigeminal neuralgia
- mood stabilizer
- neuropathic pain
Describe the metabolism of carbamazepine
hepatic with active metabolite
Carbamazepine can have ___________ (induces it’s own metabolism) which is complete 3-5 weeks after initiation
autoinduction
Describe the drug level monitoring timeline of carbamazepine
- Autoinduction: complete by 6-7 weeks (including 2-3 weeks for initial dose titration)
- Takes 2-3 weeks for new Css to occur if dose adjustments are made or interacting drugs are added or adjusted
Describe some other lab monitoring parameters for carbamazepine
- electrolytes (hyponatremia)
- sCr and urea: renal failure
- CBC and differential: DRESS syndrome, bone marrow depression
- TSH
- LFTs
- pregnancy test (teratogenic)
What are some consequences of carbamazepine?
ataxia, sedation, n/v, decreased consciousness, hallucinations, belligerence, abnormal movements, seizures and coma
What are some clinical uses of lithium?
- Mood stabilizer
- Unlabeled: augmentation of antidepressants, PTSD, conduct disorder in children, cluster headaches
Describe the metabolism of lithium
not metabolized
The formula:
Cl(Li) = 0.288 (CrCl)
is for _______ patients
non-manic
The formula:
Cl(Li) = 0.432 (CrCl)
is for _______ patients
manic
What is the conversion between mmol and mg of lithium?
8.12 mmol = 300 mg
Can you do linear dose adjustments for lithium?
Yes
How do ACEi interact with Li ?
ACEi decrease renal blood flow, reduces aldosterone, both causing increased Na+ and Li+ reabsorption
How do NSAIDs interact with Li ?
NSAIDs decrease renal blood flow (PG inhibition), increase Na+ and Li reabsorption
How does dehydration interact with Li ?
increase Li reabsorption
How does HYPOnatremia interact with Li ?
increase Li reabsorption
How does HYPERnatremia interact with Li ?
decrease Li reabsorption
How do thiazides affect Li ?
Promote Na and H20 loss in distal tubule causing increased Na and Li reabsorption in proximal tubule
How does caffeine/theophylline osmotic diuretics affect Li ?
increase Li excretion
What is the acute mania target for lithium?
0.8-1.2 mmol/L
What is the maintenance target for lithium?
0.6-0.8 mmol/L
Describe the drug level monitoring timeline for lithium
- Initiation of therapy: draw level in 2-3 days (for safety reasons) - Css at 5 days
- Once Css achieved, every 1-2 weeks until stable, then every 6-12 months if disease is well-controlled
- Draw level ideally 12 hours after the last dose
What are some consequences of toxic levels of lithium?
fine tremors, GI upset, muscle weakness, fatigue, polyuria, polydipsia, coarse tremors, slurred speech, confusion, delirium and vomiting, seizures, coma, death
What are some other lab monitoring parameters for lithium?
- electrolytes
- renal function
- thyroid function
- pregnancy test
- fasting glucose
- fasting lipid panel
- prolactin
- CBC
What is the bottom line for immunosuppressant drug monitoring?
Don’t meddle with these drugs unless you have a very good reason to or have a specialized practise
What are some clinical uses for cyclosporine?
- Transplant rejection prophylaxis
- Immunomodulatory therapy (levels not monitored)
Describe the metabolism of cyclosporine
Hepatic via CYP 3A4 (drug interactions). Forms at least 25 metabolites, the most active ones having only 10-20% immunosuppressive activity. Extensive first pass effect with oral administration
Does cyclosporine follow proportional kinetics?
yes
concentration of cyclosporine at ___h post dose is ideal
2
What does C2h correlate with?
AUC which clinically correlates with organ rejection rates
Describe the drug level monitoring timeline of cyclosporine
Initially: every 1-2 days (even if Css is not reached), Css is at 2-5 days depending on half life, then q3-5 days
Maintenance: monthly
Ideally 2h post dose (C2 level) or prior to next dose (trough)
Target levels based on type of transplant and transplant protocol
What are some consequences of cyclosporine toxic levels?
nephrotoxicity, neurotoxicity, hypertension, hyperlipidemia, hirsutism, gingival hyperplasia
What are some other lab monitoring parameters of cyclosporine?
- Electrolytes and uric acid: hyperkalemia, hyperuricemia, hypomagnesemia
- CBC: infections (immunosuppressive), leukopenia, thrombocytopenia, anemia
- Renal (sCr, urea): structural kidney damage
- LFTs: hepatotoxicity, hepatitis
- Lipid panel: low cholesterol can increase cyclosporine levels, hyperlipidemia (TGs)
What are some clinical uses for tacrolimus?
- Transplant rejection prophylaxis (kidney, liver, heart)
- Rheumatoid arthritis that is not responsive to DMARD therapy
Prograf = _____ release
immediate
Advagraf = ______ release
extended
Metabolism of tacrolimus
- extensive CYP 3A4 metabolism (drug interactions)
- 8 metabolites
- equipotent to parent drug
What are some factors affecting tacrolimus blood concentrations?
- genetics
- age, disease, race, diet
- pre-existing factors
- blood concentration
- clinical status
- transplanted organ and time after transplant
- concomitant therapy (drug interactions)
What do targets of tacrolimus levels depend on?
- type of solid-organ transplant (heart, kidney, liver)
- with or without induction therapy
- concomitant immunosuppressive therapies
- time post-transplant
What are some other lab monitoring parameters for tacrolimus?
- electrolytes and glucose
- CBC: anemia, leukopenia, thrombocytopenia
- renal: nephrotoxicity
- hepatic (LFTs): abnormal liver enzymes
Clinical uses of sirolimus
- Labelled: Transplant rejection prophylaxis (kidney)
- Unlabeled: heart transplant, HSCT, other cancers
metabolism of sirolimus?
hepatic; extensive CYP 3A4 metabolism (drug interactions)
What do the target sirolimus levels depend on?
- Type of solid-organ transplant (heart, kidney)
- Concomitant immunosuppressive therapies (CsA, MMF +/- steroids)
- Time post-transplant
Sirolimus:
Css may take >___ days to occur
10
What are some other lab monitoring parameters?
- electrolytes
- CBCs: anemia, leukopenia, thrombocytopenia
- renal, urine: proteinuria, nephrotoxicity
- lipid profile: increase TG 50%, increase cholesterol 45%
- hepatic (LFTs)
What are some clinical uses of mycophenolate?
-Transplant rejection prophylaxis (kidney, liver, heart)
Reliable AUC can be determined with as little as 3 blood samples for mycophenolate; when are these samples taken?
- Trough level before next dose (C1)
- 30 minutes after dose (C2)
- 120 minutes after dose (C3)
When does mycophenolate reach steady state?
3 days
What is the most important lab monitoring parameter?
CBC: weekly for 1st month, twice monthly for month 2-3 then monthly thereafter
What are clinical uses of methotrexate?
Low doses: rheumatoid arthritis, psoriasis (usually not monitored)
High doses: cancer (leukaemia’s, breast, head and neck, lung, osteosarcoma)
Others: ectopic pregnancy, Crohn’s disease, bladder cancer
Describe the metabolism of methotrexate
Partially metabolized by intestinal flora, polyglutamtes formed inside cells are equipotent to methotrexate and elicit effects
Methotrexate monitoring levels is important for ___ _____ _____ protocols for monitoring risk of toxicity
high dose chemo
______ rescue dosing is based on methotrexate levels
Leucovorin
What are some consequences of methotrexate toxicity?
- hematological
- GI
- hepatic
- renal
- respiratory
What do we need to monitor for methotrexate?
Baseline, then Q2-4 weeks x 3 months, then Q3 months:
CBC
sCR, urea
LFTs
Baseline, then annually:
chest radiograph
What is digoxin used for?
- Heart failure (inotropy)
- Arrhythmias; supra ventricular tachycardia (chronotropy)
metabolism of digoxin?
majority: stomach or by intestinal bacteria
Digoxin presents as a ___ compartment model
2
*takes time to distribute to target tissues
When should we take digoxin levels?
- at least 6 hours after dose
- ideally 12 hours after last dose
Digoxin equations:
Cl = 1.303 (Crcl) + 20
Who is it for?
moderate to severe heart failure (Class 3 or 4)
Digoxin equations:
Cl = 1.303 (Crcl) + 40
Who is it for?
without heart failure
List some factors that affect digoxin volume of distribution and clearance
- CHF
- eGFR
- Obese
- Thyroid
- Physical activity
- Age
What are the clinical uses?
Airway diseases (add-on therapy for severe, chronic asthma, last-line for COPD, neonatal apnea but caffeine is preferred)
Metabolism of theophylline
- 85-90% hepatic
- metabolized to active metabolites
Describe drug level monitoring timeline for theophylline
- Initial: 30 minutes after IV loading dose, one half-life after starting continuous infusion
- Oral: 2 days to Css
Consequences of toxic levels theophylline
vomiting, diarrhea, irritability, insomnia, tachycardia, hypotension, arrthymias, seizures, brain damage, death
