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BioMedChem M3 > 27/28 - Therapeutic Drug Monitoring & Clinical Toxicology > Flashcards

27/28 - Therapeutic Drug Monitoring & Clinical Toxicology Flashcards

1
Q

Why and When do we measure drug levels?

A

Monitored on Clinical Grounds
rather than blood levels (except for phenytoin)
Blood levels are monitored to AVOID TOXICITY

Also, Drug Abuse

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2
Q

When are steady state concentrations reached?

in interpreting drug levels

A

generally reached after 5 Half Lives

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3
Q

When is sampling done?

in interpreting drug levels

A

Timing of sampling is important, it is done:
JUST BEFORE ADMIN of NEXT DOSE

unless TOXICITY is suspected

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4
Q

Interpreting Drug Levels

A

Timing is especially important for drugs with
NARROW WINDOWS

Therpeutic Range = Gap between Toxic & Ineffective
Css MAX - Css Min

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5
Q

What are the Four big reasons for

  • *Therapeutic Drug Monitoring**
  • *TDM**
A

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​

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6
Q

Very important in TDM

Record ALL PERTINENT DATA when doing TDM

A

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

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7
Q

6 Clinical Settings requiring TDM

A

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**
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8
Q

Clinical settings that require STAT ASSAYS

need ASAP

A

Suspected DRUG OVERDOSE

Drug optimization in CRITICALLY-ILL patient

UNKNOWN MEDICATION (comotose patient)

LEUCOVORIN rescue therapy
used with high-dose methotrexate

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9
Q

Quantitative or Qualitative Assays for TDM?

A

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

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10
Q

Common Drug Classes for TDM

A

Anticonvulsants

Cardiovascular Agents

Antibiotics

BronchoDilators

AntiDepressants

Antineoplastics

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11
Q

Why is Phenobarbital chosen for TDM?

Anticonvulsants

A

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

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12
Q

Why is Phenytoin chosen for TDM?

Anticonvulsant

A
  • *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

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13
Q

Drug Interactions of PHENYTOIN

anticonvulsant

A

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 )

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14
Q

Methods of ANALYSIS for

Anticonvulsants

Phenytoin / Phenobarbital / Valproic Acid

A

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

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15
Q

Which Cardiovascular Agents are used for TDM?

A

DIGOXIN
digitalis, antiarrhythmic agent
used to INCREASE cardiac constrictions / reduce afib+flutter

Quinidine / Verapamil / Propranolol

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16
Q

Why is DIGOXIN used for TDM?

Cardiovascular Agent

A

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

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17
Q

Digoxin Drug Interactions / Complications

TDM - Cardiovascular Agent

A

Concomitant admin of Quinidine –> Decrease digoxin clearance
INCREASE in Digoxin levels

Decreased Digoxin GI ABSORPTION
due to diet / GI motility / spur

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18
Q

DIGOXIN

Methods of ANALYSIS

A

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*
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19
Q

Which Antibiotics are monitored by TDM?

A
  • *Aminoglycosides**:
  • *GENTAMICIN** / amikacin / kanamycin

Chloramphenicol / Sulfonamides / Vancomycin

Need to Maintain HIGH dose to KILL bacteria
without _damaging the host_

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20
Q

Why is Gentamicin used for TDM?

Aminoglycosides

A

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

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21
Q

Antibiotics

Methods of ANALYSIS

A
  • *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

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22
Q

What BRONCHODILATORS are monitored by TDM?

A

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)

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23
Q

Why is THEOPHYLLINE monitored by TDM?

A

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

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24
Q

THEOPHYLLINE

Methods of ANALYSIS

A

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)*
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25
Q

What ANTIDEPRESSANTS / ANTIPSYCHOTICS are monitored by TDM?

A

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

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26
Q

Why are TRICYCLICS monitored by TDM?

A

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
27
Q

Cyclic Antidepressants

Methods of ANALYSIS

A

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

28
Q

What ANTINEOPLASTICS are monitored by TDM?

A

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)

29
Q

Why is METHOTREXATE monitored by TDM?

MTX

A

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*
30
Q

What is LEUCOVORIN?

A

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)

31
Q

What special considerations do we have to also consider for METHOTREXATE?

A

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)

32
Q

What is Clinical Toxicology LIMITED TO?

CT

A

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

33
Q

What is the FIRST STEP of Clinical Toxicology?

A

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

34
Q

Considerations for the TESTS needed for CT

A

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

35
Q

What are SPOT TESTS?

A

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

36
Q

How is ACETAMINOPHEN tested in CT?

and what indicates its presence?

A
  • *SPOT TEST**
  • not detected in some TLC tests & poor properties for GC (unless derivatized)*

hydrolize -> p-aminophenol -> o-cresol + ammonium hyroxide

= indophenol = BLUE

37
Q

How is SALICYLATE tested in CT?

and what indicates it’s presence?

A

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

38
Q

What are used as a DEFINITIVE END TEST in CT?

A

Quantitative / Semi-Quantitative Methods

MASS SPECTROSCOPY is the MOST definitive

Immunoassays
ALSO definitive but they have many False Positives

TLC / GC / HPLC

39
Q

TLC

Positives and Negatives of this TEST in Clinical Toxicology

A

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

40
Q

GC (Gas Chromatography)

Positives and Negatives of this TEST in Clinical Toxicology

A

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

41
Q

HPLC

Positives and Negatives of this TEST in Clinical Toxicology

A

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*
42
Q

MS = Mass Spectrometry

Positives and Negatives of this TEST in Clinical Toxicology

A

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

43
Q

Ethanol + Methanol Intoxication

What is the preferred ANALYTICAL METHOD in
Clinical Toxicology?

A

GAS CHROMATOGRAPHY = GC
can readily distinguish amoung the various alcohols
(no issues with VOLATILITY)

Ethanol > methanol > Isopropyl Alcohol

in order of MOST common

44
Q

Salicylate Toxicity

What is the preferred ANALYTICAL METHOD in
​Clinical Toxicology?

A

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

45
Q

Salicylate Toxicity

+ Symptoms

A

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

46
Q

Acetaminophen Toxicity

What is the preferred ANALYTICAL METHOD in
​Clinical Toxicology?

A

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)

47
Q

Acetaminophen Toxicity

A
  • 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

48
Q

Amphetamines

What is the preferred ANALYTICAL METHOD in
​Clinical Toxicology?

A

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

49
Q

Barbiturates = Phenobarbital

What is the preferred ANALYTICAL METHOD in
​Clinical Toxicology?

A

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

50
Q

Barbiturate / Benzodiazepine OVERDOSE

Phenobarbital / Midazolam + Alprazolam

A

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

51
Q

BenZoDiazepines (-azolam)

What is the preferred ANALYTICAL METHOD in
​Clinical Toxicology?

A

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

52
Q

Opiates / Opiods

What is the preferred ANALYTICAL METHOD in
​Clinical Toxicology?

A

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

53
Q

Symptoms of Opioid/Opiate OVERDOSE

A

Respiratory Depression

hypoTension

N/V

PIN POINT PUPILS

COMA

54
Q

Fluoride OVERDOSE

one of 2 halides

A

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

55
Q

Bromide OVERDOSE

1 of two halides

A

Bromides are SEDATIVES and are sometimes taken for
SUICIDAL INTENT

Fluoride is often ACCIDENTALLY ingested, from insecticides or rodenticides

56
Q

FLUORIDE (1 of 2 halides)

What is the preferred ANALYTICAL METHOD in
​Clinical Toxicology?

A

Treat samples to produce fluoride ion, allows it to be quantified with:

FLUORIDE SELECTIVE ION ELECTRODE

57
Q

BROMIDE (1 of 2 halides)

What is the preferred ANALYTICAL METHOD in
​Clinical Toxicology?

A

Toxicity occurs under ACIDIC conditions

  • *Bromide ION** will form:
  • *BROWN-COLORED GOLD-BROMIDE**

which can be quantitated @ 400nm

SPECTROCOPICALLY

58
Q

Carbon Monoxide POISONING

other TOXIC agents

A

RED
LIPS / FINGERNAILS

typically just FATAL, cant be treated. too QUICK

59
Q

Cyanide Poisoning

other toxic agents

A
  • *BLUE**
  • *lips / fingernails**

​typically just FATAL, cant be treated. too QUICK

3 minutes of death w/o oxygen

60
Q

Organophosphotase Pesticide TOXICITY

or other cholinesterase inhibitors

A

type of cholinesterase inhibitor

attacks the NERVES –> paralysis + foaming @ the mouth
test is too complicated

MOST SERIOUS ACUTE POISON

61
Q

Halogenated Insecticides = DDT, TOXICITY

Pesticides

A

determined by:
GLC** w/ **Electron-Capture Detector

Usually a CHRONIC problem
unlike organophosphate pesticides which are ACUTE & serious poisons

62
Q

METALS

What is the preferred ANALYTICAL METHOD in
​Clinical Toxicology?

A

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_

63
Q

METAL TOXICITY

that are CHRONIC toxic agents

A

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

64
Q

IRON OVERDOSE

METALS

A

Due to it’s availability in ORAL form:

Ferrous Sulfate/Gluconate/Fumarate

PRENATAL VITAMINS

Ingestions >30mg/kg = FATAL

AAS test w/ chelating agent

BioMedChem M3 (8 decks)

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