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

27/28 - Therapeutic Drug Monitoring & Clinical Toxicology Flashcards

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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
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 / *hypo*Tension Sedation / **cardiac stimulation** **_Serotonin-Release Inhibitors_** buproprion / fluoxetine / sertraline / trazadone **Lithium / Clozapine** / Olanzapine
26
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**
27
**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) + **EC****D** (electron capture) ***_Immunoassays_*** NOT used due to ***_nonspecificity_***, SIMILAR chemical features
28
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)
29
Why is **METHOTREXATE** monitored by **TDM?** ## Footnote **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*
30
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)
31
**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**)
32
What is **Clinical Toxicology** **LIMITED TO?** ## Footnote **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
33
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**
34
**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**
35
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**
36
**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_**
37
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_***
38
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**
39
**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_***
40
**GC** (Gas Chromatography) ## Footnote **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**
41
**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 absorptio****n** / fluorimetric / ELSD **Mass Spec** still the best for detection * _Negatives:_* * not good for _volitile compounds_*
42
**MS** = Mass Spectrometry ## Footnote **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_***
43
**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
44
**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
45
**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_**
46
**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 be***derivatized for volatility** *Since OVERDOSE SYMPTOMS subside within 24 hours:* we can use **liver function tests = _AST_** (still elevated **4-6 hours AFTER ingestion)**
47
**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
48
**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**
49
**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-SPEC_**troscopy under specific pH conditions then **quantitated** & **ID'**d by: **_GLC**_ w/ _**Nitrogen-Phosphorus detector_**
50
**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**
51
**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_**
52
**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*
53
**Symptoms of Opioid/Opiate OVERDOSE**
**Respiratory Depression** ***hypoTension*** **N/V** **_PIN POINT PUPILS_** **COMA**
54
**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**
55
**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*
56
**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_**
57
**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_**
58
**Carbon Monoxide POISONING** other TOXIC agents
**_RED LIPS / FINGERNAILS_** *typically just FATAL, cant be treated. too QUICK*
59
**Cyanide Poisoning** other toxic agents
* *_BLUE_** * *lips / fingernails** ​typically just FATAL, cant be treated. too QUICK 3 minutes of death w/o oxygen
60
**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_**
61
**Halogenated Insecticides = DDT, TOXICITY** **Pesticides**
determined by: **_GLC**_ w/ _**Electron-Capture Detector_** Usually a **CHRONIC problem** *unlike organophosphate pesticides which are ACUTE & serious poisons*
62
**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_***
63
**METAL TOXICITY** ## Footnote **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**
64
**_IRON_** **OVERDOSE** ## Footnote **METALS**
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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