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Clinical Chemistry > Toxicology/Therapeutic Drug Monitoring > Flashcards

Toxicology/Therapeutic Drug Monitoring Flashcards

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1
Q

Testing Methodology

A
  • Immunoassay
  • Thin-Layer Chromotography
  • HPLC
  • Gas Chromotography-Mass Spectrophotometry
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2
Q

Specimen Collection in Therapeutic Drug Monitoring

A

Steady State must be reached before monitoring can begin, which takes around 5 1/2 half lives

Usually drawn during a trough state

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3
Q

Therapeutic Drug Monitoring Testing Methods

A

Immunoassays, HPLC and GC (measure parent drug and metabolites)

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4
Q

Therapeutic Drug Metabolism

A

Most metabolized in Liver and excreted in urine, meaning kidney and liver diseases affect drug levels

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5
Q

Aminoglycosides

A
  • Inhibit protein synthesis, treat severe gram-neg bacterial infections
  • Need to be monitored because they can cause kidney and hearing damage
  • Administered via IV/IM due to poor GI absorption
  • Poor tissue distribution
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6
Q

Antiarrhythmias/Cardioactive Drugs

A
  • Digoxin
  • Quinidine
  • Procainamide
  • Disopyramide
  • Lidocaine
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7
Q

Digoxin

A
  • When K+ is low or Mg+ is high, therapeutic levels can be toxic; overdoses can be treated with Digibind (antibody)
  • Cardioactive inotropic for Congestive Heart Failure acts by inhibiting Na/K ATPase pump, decreasing intracellular K and increasing intracellular Ca giving improved Cardiac Contractions
  • Metabolism: Need monitoring because absorption varies
  • Measure Cp 8 hr after dose, due to slow tissue absorption
  • Range: 0.8-20ng/mL
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8
Q

Quinidine

A

If the patient is already taking digoxin, the levels with this drug will increase

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9
Q

Procainamide

A
  • Antiarrhythmic
  • Block K outflow
  • Major Active Metabolite, NAPA
  • Slow and Fast Acetylators
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10
Q

Why do we monitor Drug Concentrations?

A
  • Patient Compliance
  • Dosage Adjustment
  • Toxicity from Drug interactions
  • Optimize Single Drug Therapy prior to introducing Multi-drug Therapy
  • Confirm steady concentration while other drugs are added
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11
Q

Drug Concentration Dynamics depend on:

A
  • Administration method
  • Metabolic pathways
  • Drug half-life
  • Patient age/health
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12
Q

Drug administration routes

A
  • IV
  • IM
  • Ointments/Topical
  • Orally
  • Buccal
  • Sublingual
  • Subcutaneous
  • Inhaled
  • Transdermal
  • Intrathecal
  • Enteral
  • Parenteral
  • Rectally
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13
Q

Buccal

A

Cheek, mouth

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14
Q

Intrathecal

A

Within spinal cord

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15
Q

Enteral

A

Through intestines

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16
Q

Parenteral

A

Any route other than enteral

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17
Q

Absorption

A

Usually through GI at steady rate

Liquids are absorbed more rapidly

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18
Q

Absorption in Circulation

A

Oscillate between maximum and minimum levels in blood, as the drug is distributed, absorbed, and eliminated.

Dependent on drugs pKa and pH

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19
Q

Free vs Bound Drugs

A

Free drugs interact with target sites and produce a response, and are best monitored by therapeutic and toxic effect

Other drugs or endogenous substances can compete for binding sites

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20
Q

Drug Metabolism

A

Biotransformation of parent drug to metabolite

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21
Q

Prodrugs

A

Parent compounds that must be metabolized to active form

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22
Q

Active Metabolites

A

Formed from parent drug and required measurement of prodrug and metabolite

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23
Q

First Pass Metabolism

A

90% of oral drugs absorbed in GI must go through Liver before entering circulation

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24
Q

Drug binding to protein

A

Most drugs circulate bound to plasma proteins

  • Acidic drugs, bind to albumin
  • Basic drugs, bind to alpha1-acid glycoprotein (AAG)
  • Some can bind to both

Only free drug may interact with target sites and produce a response

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25
Q

Drug Metabolism in Body

A

Primarily in Liver and Kidney

Liver damage will slow metabolization

Kidney damage will excrete drugs more slowly

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26
Q

Drug metabolite activity in the body

A

Usually more water-soluble to be excreted by Kidney

Less active/toxic than parent compounds

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27
Q

Drug distribution in body

A

After travelling in blood, it can stay within bloodstream and enter extravascular fluids or migrate into tissues/organs

Two-compartment distribution may be between

  1. Plasma and Liver
  2. Plasma and Bone
  3. Plasma and Muscle
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28
Q

Drug Equilibrium Post-distribution

A

Plasma and Active metabolites are measured by total drug concen.

Total may differ between central and peripheral areas

Free drugs will have the same concentration whether at action site or another location

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29
Q

Elimination

A

Half-life, time required to reduce blood level by half

Mainly eliminated via:

  • Hepatic: altered to metabolites and make them water-soluble
  • Renal filtration: conjugated drugs excreted in urine or bile
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30
Q

Factors affecting drug function

A
  • Lipemia
  • Low albumin
  • Uremia
  • Other hydrophobic drugs
  • CHF
  • Liver Disease
  • Kidney Disease
  • GI malabsorption
  • Age
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31
Q

Effect of Age on Drug Function

A
  • Newborn, increased from immature Liver and slow metabolism
  • Children, decreased from fast metabolism
  • Elderly, increased from slow metabolism/elimination and drug/drug elimination
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32
Q

Steady State Drug Levels

A

Levels after single dose, from peak through trough

Minor drug level fluctuations, oscillation within a range

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33
Q

Dose Response Curve

A
  • Timed intervals, to keep level from dropping below a concen. that has therapeutic benefits but is not toxic
  • Loading Dose, helps to rapidly approach steady state
  • Trough Levels, lowest level reached before next dose
  • Peak Concentration, highest concen. reached after dosage within therapeutic range
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34
Q

First-Order Kinetics (Theraputic Drugs)

A

Rate of change in drug concen is dependent on initial concentration

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35
Q

Zero-Order Kinetics (Theraputic Drugs)

A

Rate of change in drug concen is independent of initial concen, as a constant amount is eliminated over time

36
Q

Vd Calculation

A

Concen. Of Drug in Body/Concen. Of Drug in Plasma

37
Q

Amounts of Water Distribution in Body

A

Total Body Water, 42L

Intracellular, 28L

Extracellular, 14L

  1. Interstitial, 10L
  2. Plasma, 4L, levels correlate with effectiveness/toxicity and mark drug concen at receptor

Extent of Distribution

  1. Plasma, 5
  2. Extracellular, 5-20
  3. Total Body fluids, 20-40
  4. Deep Tissues, >40
38
Q

Volume of Distribution based on Drug Type

A

High in Extravascular Tissues, lipid soluble drugs

Low in plasma, water soluble drugs, neuromuscular agents

39
Q

Creatinine Clearance Ranges

A

Female: 72-110mL/min

Male: 94-140mL/min

Impaired clearance

  • Slight: 52-63mL/min
  • Mild: 42-52mL/min
40
Q

Renal Clearance

A

Ionization of drugs can change secretion

Unionized/Lipid Soluble drugs are reabsorbed from renal tubules before excretion

Aspirin is cleared more quickly the more alkaline urine pH is

41
Q

Concentration Plasma (Cp) correlations

A

Correlation with TI and Toxicity

Correlation with Therapeutic Efficacy

Lack of correlation with dose administered

42
Q

When to Draw a Blood Sample

A
  • Baseline levels for dosage adjustment
  • Change in dosing schedule
  • Cp check during Chronic Therapy
  • Onset of Intercurrent Illness
  • Change in metabolic status
43
Q

Blood Draw Timing

A

Draw right before next dose if trough level is needed, 1 hour after administration for peak in oral doses, 30min if IV

44
Q

Conditions where TDM is measured

A

Seizures

Cardiac Drugs

Analgesics

Antibiotics

45
Q

Bromide

A

Used for Epilepsy Treatment

Therapeutic vs Toxic Levels:

  • Therapeutic 20mmol/L
  • Accumulates to toxic levels due to half life of 15 days

Effects of Toxicity: Psychotic reactions

Level Testing: Colormetric gold chloride test on serum

46
Q

Aspirin (salicylate)

A

Used as an Analgesic, antipyretic, anti-inflammatory

Can cause acid-base imbalance, respiratory alkalosis and metabolic acidosis

May cause bleeding by platelet interference, assoc. with Reye syndrome in youth

Detected via colormetric method, GC

47
Q

Theophylline Target Concen., Clearance, Dosing Interval/Rate, Distribution

A

Target concentration, 10mg/L

Clearance, 2.8L/Hr/70kg

Dosing Interval/Rate, 12hr

Volume Distribution, 35L/70kg

48
Q

Dosing Rate Calculation

A

Clearance (Target Concentration) = Dosing Rate

49
Q

Phenobarbitol

A
  • Treat epilepsy/Gran Mal seizures
  • Increases Cl flux at GABA receptors
  • Oral administration, slow absorbing with long half-life
  • Metabolized in Liver and filtered by Kidney
  • 20% Cp increase can be seen
50
Q

Primidone

A

Treats Tonic-clonic seizures, prodrug of phenobarbital (Inactive form (proform) that is quickly converted)

Must Measure parent and Metabolite

51
Q

Phenytoin

A
  • Treats temporal lobe epilepsy
  • Modulates Sodium channels
  • Via IM or IV
  • Require dose adjustments
52
Q

Lidocaine

A
  • Ventricular thachycardia/fibrillation
  • Metabolized in Liver by MEGX, which increases toxic effect; both Lidocaine and MEGX levels must be measured
  • Levels 4-8ug/mL show CNS depression, >8ug/mL show seizures and severe hypotension
  • Draw 25 min after administration
53
Q

Vancomycin

A
  • Glycopeptode, G(+) or (-)
  • Administered via IV for poor GI absorption
  • Ototoxic, damage to cranial nerves
  • CDP-1 degradation product in storage solution,can be Ab cross-reactive
  • “red-man syndrome” extremity flushing
54
Q

Methotrexate

A
  • Folic Acid antagonist, blocks synthesis of DNA (targets neoplastic cells)
  • Administered by IV, eliminated by Kidney filtration
  • Calculate leukovorin dose based on MTX, then monitor daily
  • Leukovorin offsets Methotrexate cytotoxicity in normal cells
55
Q

Cyclosporin

A
  • Immunosuppressent in transplants, stops cytokine production
  • Oral administration and elimination dependent on Liver metabolism
  • 2/3 drug bound to cells
  • Whole blood levels correlate best with immunosuppression
56
Q

Lithium

A
  • Treats Bipolar disorders
  • Inhibits pathways and lower overactive circuits
  • Oral administration
  • Complete distribution into body water, no protein binding, no metabolism
  • Excreted through kidney
  • Substitutes Na for action potentials
  • Variable effect on NT levels
  • Toxicity correlates with Cp
57
Q

Acetaminophen

A
  • Analgesic without anti-inflammatory action
  • Can cause rapid toxic liver injury, elimination dependent on Liver metabolization
  • Detected by immunoassays and HPLC
  • Liver toxicity treated by NAC oral administration
58
Q

Prontosil

A
  • Antimicrobial
  • Inactive in vitro, active in vivo
  • Turns patient’s skin red
59
Q

Sulfonamide

A

Antimicrobial

60
Q

Sub-disciplines of Toxicology

A

Forensics, legal investigations

Environmental Pollution

Emergency accidents and Drug Abuse

Therapeutic drug monitoring

61
Q

Toxicity Rating Chart

A

Super Toxic, 15g/kg

62
Q

Therapeutic Index Calculation

A

TI = Lethal Dose 50% Pop./Effective Dose 50% Pop.

Larger TI, safer drug

63
Q

Dose-Response Relationship

A

Increase in toxic response as the dose is increased

64
Q

Barbiturates

A

Categorized by Short/Intermediate/Long Acting

Treat overdose by treating respiratory depression by opening airway and supporting ventilation, cardiac problems

65
Q

Narcotics

A

Heroin, morphine, codeine, and synthetic compounds

CNS effects

66
Q

Pesticides

A

Heavy metals - organic compounds

Mainly Organophosphates which affect Nervous System by inhibiting acetyl-cholinesterase

Detected by assessing enzyme activity of erythrocyte acetylcholinesterase

67
Q

Carbon Monoxide Poisoning

A

Effect on Respiration, binds to hemoglobin and doesn’t allow Oxygen to attach

Colormetric/GC Detection

Treatment: oxygen and remove source of carbon monoxide

68
Q

Arsenic

A

Testing Methods, atomic absorbtion

Arsenic avg. exposure levels, 5ug/L

Effects of arsenic and cellular targets, bind to thiol groups in proteins in mitochondria

Mees’ Lines, lines in fingernails indicating exposure to arsenic (concentrations)

69
Q

Lead

A

Causes of exposure: ingestion, inhalation, and touch

Distribution in Body/Storage: Found in red cells and bones (with decades long half life and slow-releases into circulation)

Effects on cells/body systems:

  • Binds to proteins and inhibits enzymes and heme synthesis
  • Inhibits ion transport and excretion in kidney o Blocks Uric Acid excretion and causes “Saturnine Gout”
  • “Lead Colic” contraction of intestines, cardiovascular changes, CNS effects
70
Q

Toxicity Samples

A

Blood: contains only small amounts of toxins

Gastric Lavage ; large amounts of unmetabolized drug, but does not indicate how much was absorbed

Urine: concentrated and large volume of drug metabolites

71
Q

Analytical Methods

A

Gas Chromatography, sample vaporization

Thin Layer Chromatography, has a low sensitivity for drug conformation

Mass Spectroscopy, detects compounds that have been fragmented into charged molecules

72
Q

LD 50

A

Advantages, rapid, early worker hazard approx., widely available

Disadvantages, lethality not acute effects, animal testing, no info on chronic toxicity, extrapolation from animals to humans

73
Q

Adverse reactions

A

Allergic, immune mediated

Idiosyncratic, genetic abnormality

74
Q

Cytochrome P450 Enzymes

A

Enzymes involved in absorption/binding of drugs

75
Q

Genetic Polymorphisms

A

EM, extensive metabolism in normal pop.

PM, poor metabolism with drug accumulates

UEM, ultra-extensive metabolism with low drug levels and high metabolic rate

76
Q

Chelating Therapy

A

Treatment of lead poisoning with substances that can complex with lead and can be excreted

77
Q

ALA (Alpha aminolevulinic acid)

A

Detectable in urine and blood

78
Q

Alternative Sources of Lead Exposure

A

Herbal Medicines

Earthenware pots used for food storage

Leaded glass food containers

79
Q

Effects of Lead Poisoning

A

ALA accumulates in urine due to ALAD inhibition

Ferrochelatase: blocks insertion of iron into heme, protoporphyrins accumulate

80
Q

Lead Poisoning Nervous System Signs

A

Reduced IQ, impaired hand-eye coordination, poor sensory/motor nerve conduction, “Wrist Drop” radial nerve is sensitive to lead, encephalopathy

81
Q

Lead Detection

A

Whole blood added to reagent

Lead is released from blood components

Lead in solution is plated onto thin-film electrode

Plated lead is removed by stripping current, amount of lead is directly proportional to current released

82
Q

Treatment

A

Therapeutic Healers: EDTA and DMSA

Remove lead from soft tissue and bone by forming LMW complexes that are cleared by renal system and monitored in urine

83
Q

Valproic Acid

A

Seizure control

Oral administration. 93% protein bound in circulation before being metabolized in liver

84
Q

Carbamazepine

A

Seizure control

Oral adminstration, 70-80% proetin bound in circulation

85
Q

Tricyclic Antidepressants

A

For depression, insomnia, extreme apathy

Orally administered, but slow absorbtion in GI

Metabolized in liver

Some have metabolites that are active

86
Q

Tacrolimus

A

Immunosuppressant used to prevent organ rejection, much stronger than Cyclosporin

87
Q

Sirolimus

A

Immunosuppressant given to prevent transplant rejection

Oral administration with peak levels in 2 hrs

Theraputic range 4-12ng/mL

Clinical Chemistry (38 decks)

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