Toxicology/Therapeutic Drug Monitoring Flashcards
Testing Methodology
- Immunoassay
- Thin-Layer Chromotography
- HPLC
- Gas Chromotography-Mass Spectrophotometry
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
Therapeutic Drug Monitoring Testing Methods
Immunoassays, HPLC and GC (measure parent drug and metabolites)
Therapeutic Drug Metabolism
Most metabolized in Liver and excreted in urine, meaning kidney and liver diseases affect drug levels
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
Antiarrhythmias/Cardioactive Drugs
- Digoxin
- Quinidine
- Procainamide
- Disopyramide
- Lidocaine
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
Quinidine
If the patient is already taking digoxin, the levels with this drug will increase
Procainamide
- Antiarrhythmic
- Block K outflow
- Major Active Metabolite, NAPA
- Slow and Fast Acetylators
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
Drug Concentration Dynamics depend on:
- Administration method
- Metabolic pathways
- Drug half-life
- Patient age/health
Drug administration routes
- IV
- IM
- Ointments/Topical
- Orally
- Buccal
- Sublingual
- Subcutaneous
- Inhaled
- Transdermal
- Intrathecal
- Enteral
- Parenteral
- Rectally
Buccal
Cheek, mouth
Intrathecal
Within spinal cord
Enteral
Through intestines
Parenteral
Any route other than enteral
Absorption
Usually through GI at steady rate
Liquids are absorbed more rapidly
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
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
Drug Metabolism
Biotransformation of parent drug to metabolite
Prodrugs
Parent compounds that must be metabolized to active form
Active Metabolites
Formed from parent drug and required measurement of prodrug and metabolite
First Pass Metabolism
90% of oral drugs absorbed in GI must go through Liver before entering circulation
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
Drug Metabolism in Body
Primarily in Liver and Kidney
Liver damage will slow metabolization
Kidney damage will excrete drugs more slowly
Drug metabolite activity in the body
Usually more water-soluble to be excreted by Kidney
Less active/toxic than parent compounds
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
- Plasma and Liver
- Plasma and Bone
- Plasma and Muscle
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
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
Factors affecting drug function
- Lipemia
- Low albumin
- Uremia
- Other hydrophobic drugs
- CHF
- Liver Disease
- Kidney Disease
- GI malabsorption
- Age
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
Steady State Drug Levels
Levels after single dose, from peak through trough
Minor drug level fluctuations, oscillation within a range
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
First-Order Kinetics (Theraputic Drugs)
Rate of change in drug concen is dependent on initial concentration
Zero-Order Kinetics (Theraputic Drugs)
Rate of change in drug concen is independent of initial concen, as a constant amount is eliminated over time
Vd Calculation
Concen. Of Drug in Body/Concen. Of Drug in Plasma
Amounts of Water Distribution in Body
Total Body Water, 42L
Intracellular, 28L
Extracellular, 14L
- Interstitial, 10L
- Plasma, 4L, levels correlate with effectiveness/toxicity and mark drug concen at receptor
Extent of Distribution
- Plasma, 5
- Extracellular, 5-20
- Total Body fluids, 20-40
- Deep Tissues, >40
Volume of Distribution based on Drug Type
High in Extravascular Tissues, lipid soluble drugs
Low in plasma, water soluble drugs, neuromuscular agents
Creatinine Clearance Ranges
Female: 72-110mL/min
Male: 94-140mL/min
Impaired clearance
- Slight: 52-63mL/min
- Mild: 42-52mL/min
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
Concentration Plasma (Cp) correlations
Correlation with TI and Toxicity
Correlation with Therapeutic Efficacy
Lack of correlation with dose administered
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
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
Conditions where TDM is measured
Seizures
Cardiac Drugs
Analgesics
Antibiotics
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
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
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
Dosing Rate Calculation
Clearance (Target Concentration) = Dosing Rate
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
Primidone
Treats Tonic-clonic seizures, prodrug of phenobarbital (Inactive form (proform) that is quickly converted)
Must Measure parent and Metabolite
Phenytoin
- Treats temporal lobe epilepsy
- Modulates Sodium channels
- Via IM or IV
- Require dose adjustments
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
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
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
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
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
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
Prontosil
- Antimicrobial
- Inactive in vitro, active in vivo
- Turns patient’s skin red
Sulfonamide
Antimicrobial
Sub-disciplines of Toxicology
Forensics, legal investigations
Environmental Pollution
Emergency accidents and Drug Abuse
Therapeutic drug monitoring
Toxicity Rating Chart
Super Toxic, 15g/kg
Therapeutic Index Calculation
TI = Lethal Dose 50% Pop./Effective Dose 50% Pop.
Larger TI, safer drug
Dose-Response Relationship
Increase in toxic response as the dose is increased
Barbiturates
Categorized by Short/Intermediate/Long Acting
Treat overdose by treating respiratory depression by opening airway and supporting ventilation, cardiac problems
Narcotics
Heroin, morphine, codeine, and synthetic compounds
CNS effects
Pesticides
Heavy metals - organic compounds
Mainly Organophosphates which affect Nervous System by inhibiting acetyl-cholinesterase
Detected by assessing enzyme activity of erythrocyte acetylcholinesterase
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
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)
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
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
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
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
Adverse reactions
Allergic, immune mediated
Idiosyncratic, genetic abnormality
Cytochrome P450 Enzymes
Enzymes involved in absorption/binding of drugs
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
Chelating Therapy
Treatment of lead poisoning with substances that can complex with lead and can be excreted
ALA (Alpha aminolevulinic acid)
Detectable in urine and blood
Alternative Sources of Lead Exposure
Herbal Medicines
Earthenware pots used for food storage
Leaded glass food containers
Effects of Lead Poisoning
ALA accumulates in urine due to ALAD inhibition
Ferrochelatase: blocks insertion of iron into heme, protoporphyrins accumulate
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
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
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
Valproic Acid
Seizure control
Oral administration. 93% protein bound in circulation before being metabolized in liver
Carbamazepine
Seizure control
Oral adminstration, 70-80% proetin bound in circulation
Tricyclic Antidepressants
For depression, insomnia, extreme apathy
Orally administered, but slow absorbtion in GI
Metabolized in liver
Some have metabolites that are active
Tacrolimus
Immunosuppressant used to prevent organ rejection, much stronger than Cyclosporin
Sirolimus
Immunosuppressant given to prevent transplant rejection
Oral administration with peak levels in 2 hrs
Theraputic range 4-12ng/mL
