27/28 - Therapeutic Drug Monitoring & Clinical Toxicology Flashcards
Why and When do we measure drug levels?
Monitored on Clinical Grounds
rather than blood levels (except for phenytoin)
Blood levels are monitored to AVOID TOXICITY
Also, Drug Abuse
When are steady state concentrations reached?
in interpreting drug levels
generally reached after 5 Half Lives
When is sampling done?
in interpreting drug levels
Timing of sampling is important, it is done:
JUST BEFORE ADMIN of NEXT DOSE
unless TOXICITY is suspected
Interpreting Drug Levels
Timing is especially important for drugs with
NARROW WINDOWS
Therpeutic Range = Gap between Toxic & Ineffective
Css MAX - Css Min
What are the Four big reasons for
- *Therapeutic Drug Monitoring**
- *TDM**
TDM does NOT involve all drugs
only for those that have:
Low Therapeutic Index / Narrow Range
Symptoms of OVERDOSE, resembling those of the disease
Poor record of Compliance
Considerable variation in ADME
Very important in TDM
Record ALL PERTINENT DATA when doing TDM
Use a sepecific / standardized form, and record the following:
- *Dosage** / Route
- *Time** of last draw + last dose
Serum or Plasma concentration
Peak or Trough
OTHER DRUGS + their dosage regimens
6 Clinical Settings requiring TDM
In addition to the BIG 4:
LACK of therapeutic effect
&
Drug used as a PROPHYLACTIC
Big 4:
- *Compliance** / Toxicity
- *Drug Interaction +** multidrug therapy
- *Physiological state –> ADME**
Clinical settings that require STAT ASSAYS
need ASAP
Suspected DRUG OVERDOSE
Drug optimization in CRITICALLY-ILL patient
UNKNOWN MEDICATION (comotose patient)
LEUCOVORIN rescue therapy
used with high-dose methotrexate
Quantitative or Qualitative Assays for TDM?
QUANTITATIVE
to measure drug levels
Immunoassays + Chromatography
Qualitative assays MAY be used
in toxicology, but do NOT provide good info on DRUG LEVELS
TLC / Spot Tests
Common Drug Classes for TDM
Anticonvulsants
Cardiovascular Agents
Antibiotics
BronchoDilators
AntiDepressants
Antineoplastics
Why is Phenobarbital chosen for TDM?
Anticonvulsants
Orally, absorbed SLOWLY, peak occurs late
40-60% bound to plasma protein
HIGH Half-Life = 60-120 hours
NARROW WINDOW, without _SEDATION_
CYP450 INDUCER of ITSELF + Other Drugs
less active drug, may need to INCREASE dose
DRUG INTERACTIONS w/ ACIDIC drugs
valproic acid / salicylic acid
Why is Phenytoin chosen for TDM?
Anticonvulsant
- *Narrow Therapeutic Window**
- incompletely absorbed / slow absorption*
Excretion pathway is easily saturated,
does NOT show FIRST ORDER ELIMINATION
- *EXTENSIVELY Metablized** @ low doses
- -> HPPH, excreted as glucorinide conjugate
High Half Life, varies in adults vs children
90-95% protein bound
Drug Interactions of PHENYTOIN
anticonvulsant
Several DI’s through:
Enzyme Action
INDUCTION by barbiturates / carbamazepine
decreases phenytoin levels
DISPLACEMENT
acidic drugs displace phenytoin from protein -> result VARIES
( sulfonamides / salicylic+valproic acid / phenylbutazone )
Methods of ANALYSIS for
Anticonvulsants
Phenytoin / Phenobarbital / Valproic Acid
EMIT** or **FPIA
most common, homogenous immunoassay
HPLC
might be good, may need derivatization
GLC
for valproic acid, due to Volatility
GLC / FID were some of the first tests
Which Cardiovascular Agents are used for TDM?
DIGOXIN
digitalis, antiarrhythmic agent
used to INCREASE cardiac constrictions / reduce afib+flutter
Quinidine / Verapamil / Propranolol
Why is DIGOXIN used for TDM?
Cardiovascular Agent
THE PROTOTYPE FOR TDM
Low Therapeutic Index
Difficult to distinguish toxic symptoms of Overdose
Toxic Symptoms = Same as Sx of underlying disease
Variable Absorption
typically, blood sample is @8 hours after oral dose
FIRST ORDER Elimination Kinetics
Half life VARIES from 18-70 hours
Digoxin Drug Interactions / Complications
TDM - Cardiovascular Agent
Concomitant admin of Quinidine –> Decrease digoxin clearance
INCREASE in Digoxin levels
Decreased Digoxin GI ABSORPTION
due to diet / GI motility / spur
DIGOXIN
Methods of ANALYSIS
Homogenous Immunoassays
EMIT + FPIA
possibly some sensitivity/accuracy issues
typically monoclonal antibodies (little to no cross reactivity)
but may have difficulty in _distinguishing amoung metabolites_
Radioimmunoassay = RIA, used in the past
- NO GOOD CHROMOPHORE*
- so not well suited for HPLC* detection
- Not Volatile*
- so GC/GLC is nto a good option*
Which Antibiotics are monitored by TDM?
- *Aminoglycosides**:
- *GENTAMICIN** / amikacin / kanamycin
Chloramphenicol / Sulfonamides / Vancomycin
Need to Maintain HIGH dose to KILL bacteria
without _damaging the host_
Why is Gentamicin used for TDM?
Aminoglycosides
Low Therapeutic Index
need dose to KILL bacteria, but not to hurt patient
Very Polar -> poorly absorbed by GUT
need to be given by IV / IM route
- *MAINLY Renal Excretion**
- not significantly metabolized*
- Half Life INCREASES** as *_renal function decreases_
Low Protein Binding
Antibiotics
Methods of ANALYSIS
- *Homogenous Immunoassays**
- *EMIT + FPIA**
not GC/GLC, lack volitilaty
not HPLC, no chromophore
Bioassays
sensitive enough, but not as accurate. also take 24-48 hours
What BRONCHODILATORS are monitored by TDM?
THEOPHYLLINE
Inhibits PDE4, act on cell surface receptors for Adenosine –> AC
Relaxes smooth muscle
Reduces cytokine release by inflammatory cells
Beta-Adrenergic Agonists
Corticosteroids / Epinephrine / Caffeine / aminophilline
Very useful for asthma,
but cardiac + CNS ADR’s are dangerous
(HT / Arrythmias / tremors)
Why is THEOPHYLLINE monitored by TDM?
VERY NARROW Therapeutic Window
small dose -> DRASTICLY elevate blood concentration
Cardiac Arrhythmias / Seizures = HIGH MORTALITY
- *Clearance is HIGHLY dependent on PHYSIOLOGY**
- *CHF** reduces clearance –> toxicity
- *Children / Smokers** reduces clearance as well, not as much
FOOD slows peak down
Certain drugs reduce clearance
Erythromycin / troleandomycin / fluvoxamine / cimetidine
THEOPHYLLINE
Methods of ANALYSIS
Samples: Serum / Plasma
- *IMMUNOASSAYS**
- *RIA + EMIT + FPIA**
- but there is some cross-reactivity* with adenosine + caffeine
- *Chromatography**
- *GLC + HPLC**
- Soluble + Good Chromophore** (even if not volatile)*
What ANTIDEPRESSANTS / ANTIPSYCHOTICS are monitored by TDM?
TRICYCLICS
Imiprimane / Amitriptyline / Nortriptyline / desimpramine
act on the reuptake of NR + Serotonin
autonomic effects (DRYING)
blurred vision / constipation / hypoTension
Sedation / cardiac stimulation
Serotonin-Release Inhibitors
buproprion / fluoxetine / sertraline / trazadone
Lithium / Clozapine / Olanzapine
Why are TRICYCLICS monitored by TDM?
NONCOMPLIANCE
is an issue due to autonomic side effects:
Sedation / Tremor / Insomnia / Drying effects
Depressed patients are likely to OVERDOSE
highly hazardous -> typically unresponsive patients
- *Drug Interactions**
- *SSRI’s** are inhibitors of CYP450 2D6
Cyclic Antidepressants
Methods of ANALYSIS
Many Tricyclics –> converted into Active metabolites
need to quantitate active + parent compound
Gas Chromatography-Mass Spectrometry (GC-MS)
Preferred, does not have limitations of NPD or ECD
Gas Chromatography
NPD (nitrogen-phosphorous) + ECD (electron capture)
Immunoassays
NOT used due to nonspecificity, SIMILAR chemical features
What ANTINEOPLASTICS are monitored by TDM?
prevent / halt development of a TUMOR
METHOTREXATE
inhibits DHFR (dihydrofolate reductase)
lowers the rate of pyrimidine synthesis + inhibits DNA synthesis
Causes unwanted cytotoxic SIDEFFECTS:
myelosupression / GI mucositis / hepatic cirrhosis
Is Displaced / “rescued” by Leucovorin (Folate analog)
Why is METHOTREXATE monitored by TDM?
MTX
HIGH-DOSE MTX is monitored to determine when to initiate
LEUCOVORIN RESCUE
(24 / 48 / 72 hours after a SINGLE dose of MTX)
low doses are POORLY absorbed –> need HIGHER DOSES
MTX is a nonspecific cytotoxin
–> will inhibit growth of OWN CELLS
- *Renal Elimination**
- is NOT extensively metabolized*
What is LEUCOVORIN?
Folate analog that is a synthetic substrate for DHFR
It can “rescue” host cells if
MTX causes unwanted cytotoxic effects
(myelosupression / GI mucositis / hepatic Cirrhosis)
DISPLACES METHOTREXATE
(Dihydrofolate Reductase)
What special considerations do we have to also consider for METHOTREXATE?
Elimination is primarily by RENAL ROUTE
ALKALINE** **URINE is CRITICAL
pKa of MTX = 5.5,
if the pH drops (acidic) then…
MTX will PRECIPITATE
(want to keep the urine BASIC)
What is Clinical Toxicology LIMITED TO?
CT
CT is limited to only CERTAIN CLASSES of drugs:
Those that are Readily Available:
involved in accidental poisoning of children = aspirin/APAP
Those with High Abuse Potential:
sedatives / hypnotics / narcotics / stimulants / hallucinogens
Those taken for Suicidal / Homicidal Intent:
sedative hypnotics / tranquilizers / pesticides
What is the FIRST STEP of Clinical Toxicology?
CLINICAL EVALUATION of the CT case,
typically is an unconcious patient so we LACK drug history
After the results of the evaluations, we will
Direct a SAMPLE to one of several SCREENING MEHODS
Considerations for the TESTS needed for CT
QUICK TESTS
Need turn around time of <24 hours to be of any use
unless monitoring effectiveness of treatment is helpful
LOCAL Conditions
knowing community conditions / prescribing trends / poison control center records can help select the right agents
Common Tests
Obvious toxic agents like:
Ethanol / Analgesics / Sedatives / Tranquilizers
What are SPOT TESTS?
Simple & Rapid
with little or NO instrumentation required
usually involves reactions that give a colored result
QUALITATIVE, not quantitative
Spot Tests tend to give FALSE Positives –> need to be followed up by a MORE SPECIFIC METHOD
need a DIRECT comparison to standards
should use both + & - controls
How is ACETAMINOPHEN tested in CT?
and what indicates its presence?
- *SPOT TEST**
- not detected in some TLC tests & poor properties for GC (unless derivatized)*
hydrolize -> p-aminophenol -> o-cresol + ammonium hyroxide
= indophenol = BLUE
How is SALICYLATE tested in CT?
and what indicates it’s presence?
SPOT TEST
not detected by TLC / variable GC response
React with TRINDER’s REAGENT (contains iron)
= VIOLET-Colored derivative
Diflunisal + Labetalol produce a False Positive
What are used as a DEFINITIVE END TEST in CT?
Quantitative / Semi-Quantitative Methods
MASS SPECTROSCOPY is the MOST definitive
Immunoassays
ALSO definitive but they have many False Positives
TLC / GC / HPLC
TLC
Positives and Negatives of this TEST in Clinical Toxicology
Sample Source: Urine / serum / gastric contents
Positives:
requires NO special instrumentation / Simple & inexpensive
can be used for a Wide Range of Compounds
easy to inculde standards for comparison = Parallel Development
Negatives:
Detection range is WIDE = Not Very Sensitive
many False Positives
GC (Gas Chromatography)
Positives and Negatives of this TEST in Clinical Toxicology
needs a Volitile Compound
- Negatives:*
- NOT good with Reactive or POLAR* compounds
Positives:
applicable to a Broad range of drugs
relatively RAPID, QUANTITATIVE results
can resolve Closely-related species, no derivatation needed
has several types of sensitive detectors = FID / EC / NPD / MS
HPLC
Positives and Negatives of this TEST in Clinical Toxicology
Positives:
can analyze POLAR compounds (morphine)without derivatization
also adv in detecting compounds with REACTIVE groups
(advantages > GC)
Good for HIGH MW compounds, that lack volitility
various detectors = UV-Vis absorption / fluorimetric / ELSD
Mass Spec still the best for detection
- Negatives:*
- not good for volitile compounds*
MS = Mass Spectrometry
Positives and Negatives of this TEST in Clinical Toxicology
After “ordinary” HPLC/GC –> GC-MS** or **HPLC-MS
used as a second CONFIRMATORY test
Positives:
HIGHLY SENSITIVE, robust method for identification
unique “fingerprint” identification + computerized searching
Negatives:
requires special instrumentation + expensive
Ethanol + Methanol Intoxication
What is the preferred ANALYTICAL METHOD in
Clinical Toxicology?
GAS CHROMATOGRAPHY = GC
can readily distinguish amoung the various alcohols
(no issues with VOLATILITY)
Ethanol > methanol > Isopropyl Alcohol
in order of MOST common
Salicylate Toxicity
What is the preferred ANALYTICAL METHOD in
Clinical Toxicology?
Simplest = SCREENING TESTS:
- *Ferric Chloride** Urine test –> Violet
- possible interference with labetalol + diflunasal*
Drop of Urine or Serum –> Phenitix Dipstix = BROWN color
used in PKU diagnosis
MORE SOPHISTICATED = HPLC analysis
to determine quantitatively the LEVELS of salicylate
Salicylate Toxicity
+ Symptoms
ASA –> rapidly hydrolyzed to Salicylic Acid
can BLOCK the TCA cycle
+
stimulate the CNS –> HYPERventilation + Respiratory ALKALosis
Nausea** / **Tinnitus** / **Ataxia
HIGH dose can lead to
Renal / Cardiac COLLAPSE** / **COMA or DEATH
Acetaminophen Toxicity
What is the preferred ANALYTICAL METHOD in
Clinical Toxicology?
SCREENING TEST: –> BLUE indophenol compound
may pick up the APAP overdose, but to follow the SEVERE cases:
GLC** or **HPLC
APAP shows poor GC properties
needs to bederivatized for volatility
Since OVERDOSE SYMPTOMS subside within 24 hours:
we can use liver function tests = AST
(still elevated 4-6 hours AFTER ingestion)
Acetaminophen Toxicity
- either ACUTE overdose or CHRONIC use*:
- *severe TOXICITY** from minor metabolites
this is INSIDIOUS because they may APPEAR TO RECOVER
but they can _SUBSEQUENTLY DIE of HEPATIC FAILURE_
the symptoms of overdose subside within 24 hours
–> test AST, still ELEVATED after 4-6 days
Amphetamines
What is the preferred ANALYTICAL METHOD in
Clinical Toxicology?
Initially: Standard Screening Tests
for further analysis / quantitation
IMMUNOASSAY** or **GLC w/ electron capture detection
need to be derivatized for volatility
Acute toxicity symptoms:
agitation / hyperthermia / convulsions / coma
respiratory + cardiac Failure –> DEATH
Barbiturates = Phenobarbital
What is the preferred ANALYTICAL METHOD in
Clinical Toxicology?
Need to FIRST determine if it is a SHORT or LONG acting BARB:
done by UV-SPECtroscopy under specific pH conditions
then quantitated & ID’d by:
GLC** w/ **Nitrogen-Phosphorus detector
Barbiturate / Benzodiazepine OVERDOSE
Phenobarbital / Midazolam + Alprazolam
BARBS are the LEADING drugs taken in OD cases
Both are Sedative Hypnotics often used for Suicides
typically in the presence of ALCOHOL
synergism with the alcohol –> fatality
BenZoDiazepines (-azolam)
What is the preferred ANALYTICAL METHOD in
Clinical Toxicology?
SCREENING TESTS
used to pick up this CLASS of drugs
they are Extensively metabolized + have ACTIVE Metabolites
excreted in the serum or urine under BASIC conditions
to form organic solvents –> dissolved with methanol to be
DIRECTLY injected into the
HPLC
Opiates / Opiods
What is the preferred ANALYTICAL METHOD in
Clinical Toxicology?
URINE sample
IMMUNOASSAYS
very sensitive! but beware of POPPY SEEDS (positive result)
need to be CONFIRMED by GC / MS
need to first hydrolyze the samples to remove glucoronic moieties
Symptoms of Opioid/Opiate OVERDOSE
Respiratory Depression
hypoTension
N/V
PIN POINT PUPILS
COMA
Fluoride OVERDOSE
one of 2 halides
NaF** is found in **RodentiCIDES** & **InsectiCIDES
which can be ingested ACCIDENTALLY by children
or
used for SUICIDAL / HOMOCIDAL intent
corrosive on contact with STOMACH acid
also can REPLACE HYDROGEN in the TCA Cycle / ATP
Bromide OVERDOSE
1 of two halides
Bromides are SEDATIVES and are sometimes taken for
SUICIDAL INTENT
Fluoride is often ACCIDENTALLY ingested, from insecticides or rodenticides
FLUORIDE (1 of 2 halides)
What is the preferred ANALYTICAL METHOD in
Clinical Toxicology?
Treat samples to produce fluoride ion, allows it to be quantified with:
FLUORIDE SELECTIVE ION ELECTRODE
BROMIDE (1 of 2 halides)
What is the preferred ANALYTICAL METHOD in
Clinical Toxicology?
Toxicity occurs under ACIDIC conditions
- *Bromide ION** will form:
- *BROWN-COLORED GOLD-BROMIDE**
which can be quantitated @ 400nm
SPECTROCOPICALLY
Carbon Monoxide POISONING
other TOXIC agents
RED
LIPS / FINGERNAILS
typically just FATAL, cant be treated. too QUICK
Cyanide Poisoning
other toxic agents
- *BLUE**
- *lips / fingernails**
typically just FATAL, cant be treated. too QUICK
3 minutes of death w/o oxygen
Organophosphotase Pesticide TOXICITY
or other cholinesterase inhibitors
type of cholinesterase inhibitor
attacks the NERVES –> paralysis + foaming @ the mouth
test is too complicated
MOST SERIOUS ACUTE POISON
Halogenated Insecticides = DDT, TOXICITY
Pesticides
determined by:
GLC** w/ **Electron-Capture Detector
Usually a CHRONIC problem
unlike organophosphate pesticides which are ACUTE & serious poisons
METALS
What is the preferred ANALYTICAL METHOD in
Clinical Toxicology?
quantitative method for analysis
ATOMIC ABSORPTION SPECTROSCOPY = AAS
of the blood or urine
typically requires a CHELATING AGENT to complex w/ the metal ion
excreted through the _KIDNEYS_
METAL TOXICITY
that are CHRONIC toxic agents
Heavy Metals / Lead / Cadmium / MERCURY
+
Arsenic / Antimony / Bismuth
all have Variable Symptoms & toxicity is hard to diagnose
they often react with SULFUR
which is used in many reactions in the body:
collapse DI-SULFIDE bridges
or
REPLACE metal Cofactors
IRON OVERDOSE
METALS
Due to it’s availability in ORAL form:
Ferrous Sulfate/Gluconate/Fumarate
PRENATAL VITAMINS
Ingestions >30mg/kg = FATAL
AAS test w/ chelating agent
