Toxicology/Therapeutic Drug Monitoring Flashcards Preview

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Flashcards in Toxicology/Therapeutic Drug Monitoring Deck (87):
1

Testing Methodology

  • Immunoassay
  • Thin-Layer Chromotography
  • HPLC
  • Gas Chromotography-Mass Spectrophotometry

2

Specimen Collection in Therapeutic Drug Monitoring

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

Usually drawn during a trough state

3

Therapeutic Drug Monitoring Testing Methods

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

4

Therapeutic Drug Metabolism

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

5

Aminoglycosides

  • 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

6

Antiarrhythmias/Cardioactive Drugs

  • Digoxin
  • Quinidine
  • Procainamide
  • Disopyramide
  • Lidocaine

7

Digoxin

  • 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 

8

Quinidine

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

9

Procainamide

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

10

Why do we monitor Drug Concentrations?

  • 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

11

Drug Concentration Dynamics depend on:

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

12

Drug administration routes

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

13

Buccal

Cheek, mouth

14

Intrathecal

Within spinal cord

15

Enteral

Through intestines

16

Parenteral

Any route other than enteral

17

Absorption

Usually through GI at steady rate

Liquids are absorbed more rapidly

18

Absorption in Circulation

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

Dependent on drugs pKa and pH

19

Free vs Bound Drugs

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

20

Drug Metabolism

Biotransformation of parent drug to metabolite

21

Prodrugs

Parent compounds that must be metabolized to active form

22

Active Metabolites

Formed from parent drug and required measurement of prodrug and metabolite

23

First Pass Metabolism

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

24

Drug binding to protein

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

25

Drug Metabolism in Body

Primarily in Liver and Kidney

Liver damage will slow metabolization

Kidney damage will excrete drugs more slowly

26

Drug metabolite activity in the body

Usually more water-soluble to be excreted by Kidney

Less active/toxic than parent compounds

27

Drug distribution in body

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

28

Drug Equilibrium Post-distribution

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

29

Elimination

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

30

Factors affecting drug function

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

31

Effect of Age on Drug Function

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

32

Steady State Drug Levels

Levels after single dose, from peak through trough

Minor drug level fluctuations, oscillation within a range

33

Dose Response Curve

  • 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

34

First-Order Kinetics (Theraputic Drugs)

Rate of change in drug concen is dependent on initial concentration

35

Zero-Order Kinetics (Theraputic Drugs)

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

36

Vd Calculation

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

37

Amounts of Water Distribution in Body

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

Volume of Distribution based on Drug Type

High in Extravascular Tissues, lipid soluble drugs

Low in plasma, water soluble drugs, neuromuscular agents

39

Creatinine Clearance Ranges

Female: 72-110mL/min

Male: 94-140mL/min

Impaired clearance

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

40

Renal Clearance

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

Concentration Plasma (Cp) correlations

Correlation with TI and Toxicity

Correlation with Therapeutic Efficacy

Lack of correlation with dose administered

42

When to Draw a Blood Sample

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

43

Blood Draw Timing

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

44

Conditions where TDM is measured

Seizures

Cardiac Drugs

Analgesics

Antibiotics

45

Bromide

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

Aspirin (salicylate)

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

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

Target concentration, 10mg/L

Clearance, 2.8L/Hr/70kg

Dosing Interval/Rate, 12hr

Volume Distribution, 35L/70kg

48

Dosing Rate Calculation

Clearance (Target Concentration) = Dosing Rate

49

Phenobarbitol

  • 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

Primidone

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

Must Measure parent and Metabolite

51

Phenytoin

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

52

Lidocaine

  • 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

Vancomycin

  • 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

Methotrexate

  • 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

Cyclosporin

  • 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

Lithium

  • 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

Acetaminophen

  • 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

Prontosil

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

59

Sulfonamide

Antimicrobial

60

Sub-disciplines of Toxicology

Forensics, legal investigations

Environmental Pollution

Emergency accidents and Drug Abuse

Therapeutic drug monitoring

61

Toxicity Rating Chart

Super Toxic, 15g/kg

62

Therapeutic Index Calculation

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

Larger TI, safer drug

63

Dose-Response Relationship

Increase in toxic response as the dose is increased

64

Barbiturates

Categorized by Short/Intermediate/Long Acting

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

65

Narcotics

Heroin, morphine, codeine, and synthetic compounds

CNS effects

66

Pesticides

Heavy metals - organic compounds

Mainly Organophosphates which affect Nervous System by inhibiting acetyl-cholinesterase

Detected by assessing enzyme activity of erythrocyte acetylcholinesterase

67

Carbon Monoxide Poisoning

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

Arsenic

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

Lead

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

Toxicity Samples

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

Analytical Methods

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

LD 50

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

Adverse reactions

Allergic, immune mediated

Idiosyncratic, genetic abnormality

74

Cytochrome P450 Enzymes

Enzymes involved in absorption/binding of drugs

75

Genetic Polymorphisms

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

Chelating Therapy

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

77

ALA (Alpha aminolevulinic acid)

Detectable in urine and blood

78

Alternative Sources of Lead Exposure

Herbal Medicines

Earthenware pots used for food storage

Leaded glass food containers

79

Effects of Lead Poisoning

ALA accumulates in urine due to ALAD inhibition

Ferrochelatase: blocks insertion of iron into heme, protoporphyrins accumulate

80

Lead Poisoning Nervous System Signs

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

81

Lead Detection

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

Treatment

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

Valproic Acid

Seizure control

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

84

Carbamazepine

Seizure control

Oral adminstration, 70-80% proetin bound in circulation

85

Tricyclic Antidepressants

For depression, insomnia, extreme apathy

Orally administered, but slow absorbtion in GI

Metabolized in liver

Some have metabolites that are active

86

Tacrolimus

Immunosuppressant used to prevent organ rejection, much stronger than Cyclosporin

87

Sirolimus

Immunosuppressant given to prevent transplant rejection

Oral administration with peak levels in 2 hrs

Theraputic range 4-12ng/mL