TOXICOLOGY and THERAPEUTIC  A chemical/cmpd used to selectively perturb 6. Environmental T.

= evaluation of environmental
specific functions of the tissues in an chemical pollutants and their impact on human
DRUG MONITORING organism health.
TOXICOLOGY  NOT ALL CHEMICALS ARE DRUGS MAJOR FACTORS THAT INFLUENCE
DEFINITION OF TERMS  What makes a particular chemical a TOXICITY:
A. Toxicology DRUG::  Route of Administration
 study of poisonous subs, their axns on living
o Has selectivity as to its site of  Duration and Frequency of Exposure
organism, their detection by laboratory/other
action/target  Dose or Concentration
methods & measures taken to counteract their
o Has reversibility in its axn
biologic effects
o Promotes prodxn of a SPECTRUM UNDESIRED EFFECTS:
 the study of the adverse effects of xenobiotics in
beneficial/therapeutic effect 1. Allergic rxn
humans.
G. Major Disciplines of Toxicology o Type I Hypersensitivity Rxn
 Special field of clinical chemistry because of the 1. Mechanistic T. = elucidates the cellular, molecular o Type II Antibody-Mediated Cytotoxic
Qualitative and Quantitative methodologies & biochemical effects of xenobiotics within the Hypersenstivity
applied context of a dose–response relationship between o Type III Immune Complex-Mediated
 Includes ROUTINE SCREENING AND the xenobiotic and the adverse effect. This provides Hypersensitivity
CONFIRMATORY TESTING a basis for rational therapy design and the o Type IV Delayed-type Hypersensitivity
B. Xenobiotics development of tests to assess the degree of 2. Idiosyncratic rxn
 chemicals and drugs that are not normally found exposure in individuals. 3. Immediate vs. delayed toxicity
or produced in the body. 2. Descriptive T.= uses the results from animal 4. Reversible vs. irreversible toxicity
 Exogenous agents that may have an adverse effect experiments to predict what level of exposure will 5. Local vs. systemic toxicity
on a living organism. cause harm in humans (risk assessment) 6. Acute vs. Chronic toxicity
 often used to describe environmental chemicals or 3. Regulatory T.= interpretation of the combined
drug exposures (antibiotics, antidepressants, etc) data of Mechanistic and Descriptive T. to establish DOSE-RESPONSE RELATIONSHIP
C. Poisons standards that define the level of exposure that will “The dose makes the poison.” -Paracelsus 
 agents that have an adverse effect on a biological not pose a risk to public health or safety. A. INDIVIDUAL DOSE-RESPONSE
system. a. Government agencies that RELATIONSHIP
 more often used when describing animal, plant, handles Regulatory  Response of an individual organism to
mineral, or gas poisons. Toxicology: varying doses of a chemical
o Venom from poisonous animals, i. Food and Drug Administration (FDA)  Changing health effects based on the
poisons from poisonous plants, chemical ii. Environmental Protection Agency (EPA) change in xenobiotic exposure levels
poisonings iii. Occupational Safety and Health B. QUANTAL DOSE-RESPONSE
D. Toxins Administration (OSHA) RELATIONSHIP
 Substances that are biologically synthesized iv. Consumer Product Safety Commission  Change in health effects of a defined
either in living cells or in microorganisms. v. Department of Transportation population based on changes in the
o Clostridium botulinum- Botulinum toxin 4. Forensic T. = primarily concerned with the exposure to xenobiotics
o Hemotoxins medicolegal consequences of exposure to
o Mycotoxins chemicals or drug, and establishing and validating  LD50 = the dose that would predict death response
E. Toxicant/Toxic the analytic performance of the methods used to in 50% of the population
 this applies to a substance not produced within generate evidence in legal situations.  TD50 = the dose that would be predicted to
a living cell or microorganism 5. Clinical T.= the study of interrelationships produce a toxic response in 50% population
o Environmental chemicals between xenobiotics and disease states. This area  ED50= the dose that would predict
emphasizes not only diagnostic testing but also therapeutic/effective response in 50% of the
F. Drugs therapeutic intervention. population

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  TI= the ratio of TD50 / ED50
o Drugs with a large therapeutic index
have few toxic adverse effects when the
dose of the drug is in the therapeutic
range.
o THE LARGER THE RATIO, THE
GREATER THE RELATIVE OF
SAFETY
TOXICOKINETICS
DRUG DISPOSITION: Administration, Distribution,
Metabolism, Elimiation
-selection of specimen
- timing of specimen(relative to the time of exposure)
Pre-analytical variables:
a. elimination patterns
b. analyte stability
c. specimen collection procedures
ADMINISTRATION
 Inhalation
 Oral administration
 Intravenous
 Subcutaneous
 Intramuscular
DISTRIBUTION
- Blood is the vehicle of the drug
Factors Affecting Distribution:
-pH
- degree of plasma protein binding
ALBUMIN- major CHON for circulatory transport of the
drugs to cells
 Protein-bound drug: Pharmacologically
INACTIVE
o † serum alpha-1-acid glycoprotein
during acute phase rxn = † binding of
drugs, such as:
 Propranolol
 Quinidine
 chlorpromazine
 cocaine
 benzodiazepines
o Changes in serum-binding proteins may
occur during:
 Inflammation
 Malignancies
 Pregnancy
 Hepatic dss
 Nephrotic syndrome
 Malnutrition
 Acid-Base distubances
 Free-form drug: Pharmacologically ACTIVE
o toxic adverse effects (high free fraction)
o therapeutic benefit (low free fraction).
BIOTRANSFORMATION (aka METABOLISM)
Major site of metabolism: Liver
Secondary sites: Kidneys, Lungs, Skin, Brain, GIT
DEPENDENT factors of GIT absorption:
- formulation of drug
- transport mechanism
-passive diffusion
FIRST-PASS METABOLISM
- this is when certain drugs are subject to hepatic
uptake, metabolism and inactivation in the liver
Phase I
- Reactions metabolize lipophilic drugs to more
polar forms
(reactive
intermediates)
- thru Oxidation, Reduction, Hydroxylation,
Deamination,
Dealkylation, with monooxygenase
-Cytochrome P-450 system takes part
Phase II
- Conjugation of drugs with cmpds
- Water soluble products
FIRST-ORDER KINETICS – rate of metabolism is
dependent on the concentration of the substrate
- As drug dose/conc. † , rate of metabolism †
ZERO-ORDER KINETICS- constant amount of drug is
metabolized per unit of time, regardless of the increase of
drug dose
ANALYSIS OF TOXIC AGENTS
PRE-ANALYTICAL VARIABLES
 Elimination Patterns
 Analyte Stability
 Specimen Collection Procedures
Important Factor: TIMING OF SPECIMEN
COLLECTION
SPECIMEN OF CHOICE: Heparinized
plasma
Others:
- Whole Blood/Serum
o EDTA, CITRATE,OXALATE (avoid
using these ) = Ca – binding ACs add a
variety of anions & cations that may
interfere w/ analysis or cause a drug to
distribute differently bet cells & plasma
o Use ”trace element-free” collection tubes
(Royal blue top= most elements; Tan=
Lead)
- Midstream-catch Urine (24-hr collection)
o represent the net load of the drug over a
long period whereas the blood sample
provides only a guide picture of the drug
level at specific time for drug of abuse
o Random urine specimen is used for
screening only
o Concentrated acids are used to preserve
urine specimens
- Hair & Nails
o sample for arsenic (As) heavy metal det.
o conc of As is higher in the hair & nail
than in any other tiss cuz the metal is
strongly attracted to keratin that forms
hair & nails
- Saliva, Sweat, Mammary milk, Breath
Detectability of substances of abuse in urine (single use)
Amphetamines 48 hrs
Barbiturates 42 hrs
Benzodiazepine 3days
Coccaine 2-3 days
Marijuana 3 days (L. smoker)
21-27 days (H. smoker)
Morphine 48 hrs
Phencyclidine 3 days (casual use)
8 days (heavy use)
Kaori Sembrano ’17 || 2
Screen testing  Identify when the drug is above or below a BIOAVAILABILITY
-rapid, simple, qualitative routine procedure therapeutic range - The unchanged fraction of the administered dose
-good analytic sensitivity, poor specificity as it enters systemic circulation and eventually
-positive results must subject to confirmatory testing, COMMON INDICATORS OF TDM: reaches its site of action
regardless the pleas of the client (wawa is them)  Identify non-compliance STEADY STATE
- IMMUNOASSAYS are commonly used  Preventing the consequences of overdosing or - When the rate of drug input is equal to the rate of
underdosing drug elimination
EXAMPLES OF IMMUNOASSAYS (the ff are mostly  Maximizing the therapeutic effect - is reached when a time of 4 to 5 times the half-life
used in TDM Testing also):  Optimizing a dosing regimen based on drug- for a drug after regular dosing is started.
1. EMIT (Enzyme-Multiplied Immunoassay) drug interactions (pharmacogenomics) or a
2. FPIA (Fluorescence polarization change in the patients physiologic state (they GUIDELINES FOR SAMPLING TIME
immunoassay) may unpredictably affect circulating drug - Establish serum drug concentration (SDC) @
3. ELISA (Enzyme-Linked Immunosorbent concentrations) steady state
Assay)  Hepatic and Renal Change - Ensure complete absorption and distribution
4. HPLC (High Powered Liquid - Reasons for TDM:
Chromatography) BASIS OF TDM: o Aminoglycosides only:
5. RIA (Radioactive Immunoassay)  Administration  Suspect toxicity= Peak and
 Rate of absorption Trough SDC
Confirmatory testing  Distribution of drug w/in the body  Suspect system failure and
- specific,Quantitative method  Rate of elimination non-compliance= Peak SDC
- Thin-layer chromatography: is a relatively simple, o All except aminoglycosides:
inexpensive method of detecting various drugs and other  Suspect toxicity= Peak SDC
organic compounds PHARMACODYNAMICS  Suspect system failure and
- Gas Chromatography-Mass Spectrophotometry: - concerns with the actions of the non-compliance= Trough
reference method for detection of Organic Cmpds for chemical on the organism’s biologic SDC
Qualitative and Quantitative determintations system
- Inductively Coupled Plasma-Mass Spectrophotometry
(ICP-MS) or Atomic Absorption (AA) – Inorganic cmpd II. ABSORPTION
determination I. ADMINISTRATION Factors of the bioavailability of orally administered drugs:
 Dissociation from its administered form
ROUTES OF ADMINISTRATION:  Solubility in GIT fluids
1. Intranvenous adm. (IV)  Diffusion across GI membranes
THERAPEUTIC DRUG MONITORING 2. Intramuscular adm. (IM)
(TDM) 3. Subcutaneous adm. - most drugs are absorbed by passive diffusion from the GIT
4. Transcutaneous adm. to the bloodstream
- involves the coordinated effort of several health 5. Inhalation - weak acids are efficiently absorbed in the stomach
professionals to measure and monitor circulating 6. Suppository -weak bases are absorbed in the intestines
drug levels primarily in serum, plasma, or whole 7. Oral adm.
blood Factors that affect the absorption rates in GIT:
- establish appropriate dose regimen STANDARD DOSAGE - Intestinal motility
- aids in dosing adjustment - Statistically derived from observations in a - pH
healthy population
- Inflammation
CRITICAL ROLES IN ACHIEVING SAFE AND -
- Presence of food or other drugs
EFFECTIVE PATIENT DRUG THERAPY: Examples Of Factors That Influence Drug Levels And
 Timing of Specimen Efficacy:
Drugs that can affect absorption:
 Measurement of Drug Levels  Pxn’s Age and Gender
 Genetics - Cholestyramine
 Reporting of Data - Antacids
PURPOSE OF TDM:  Recent Food consumption
 Prescription of Drugs - Morphine (slows down gut motility)
 Ensure that a given drug dosage is within a -
range that produces maximal therapeutic  Self-administered OTC drugs Sucralfate
 Naturopathic Agents - Anti-ulcer medications
benefit
- Kaolin
Kaori Sembrano ’17 || 3
III. DRUG DISTRIBUTION
- Free-fraction Drugs are subject to diffusion out of
the vasculature into the interstitial and
intracellular spaces of tissues
- Dependent on the lipid solubility of the blood
- Highly hydrophobic drugs can easily traverse
cellular membranes and partition into lipid
compartments
- Drugs that ARE POLAR BUT UN-IONIZED,
cannot sequester lipid compartments
Volume of Distribution (Vd)
- index is used to describe the distribution
characteristics of a drug
- Large Vd values = Drugs that are hydrophobic can
have due to partitioning into hydrophilic
compartments.
- small Vd value= Substances that are ionized or are
primarily bound in plasma due to sequestration in
the vasculature
Vd = D/C
Where:
D= Intravascular injected dose ; C= Concentration in Plasma
 Free and Protein-bound drugs (see toxicology
page hehe… same ra siya)
 Free drug measurements should be considered for
drugs that are highly protein bound and for which
clinical signs are inconsistent with total drug
concentrations.
IV. METABOLISM
- Hepatic Portal System (“First-pass” metabolism)
o a phenomenon of drug metabolism in
the liver whereby the concentration of a
drug is greatly the bioavailability of the
drug. before it reaches the systemic
circulation
o influenced/alter hepatic metabolism
 by genetics
 Fatty/cirrhosis liver (reduces
the capacity to metabolize
drugs)
o examined by Pharmacogenomics
- BIOTRANSFORMATION:
o An enzymatic/metabolic process of
generating a therapeutically active drug
- HALF-LIFE
o The time it takes for the serum drug
concentration to decrease by half.
- HEPATIC MIXED-FUNCTION OXIDASE
PATHWAY / SYSTEM (MFO)
o Is a nonspecific system that allows
many different endogenous and
exogenous substances to go through this
series of reactions
o responsible for a large portion of drug
metabolism
o Involves taking hydrophobic substances
and, through a series of enzymatic
reactions, converting them into water-
soluble substances
o These products are then either
transported into the bile or released into
the general circulation for elimination
by renal filtration
PHASE I
-
produce reactive intermediates
PHASE II
- reactions conjugate functional groups to these
reactive sites, the products of which are water-
soluble
- Fxnal groups usually conjugated with the reactive
intermediates:
o Glutathione
o Glycine
o Phosphate
o Sulfate
- In an OVERDOSE, MFO system will be
overwhelmed and be inefficient in metabolizing
durgs
- Accumulation of Phase I occurs during the
depletion of conjugating groups of the drugs in
Phase II.
- Induction of MFO system results in :
o accelerated clearance
o regimen
shorter Half-life
V. DRUG ELIMINATION
- Plasma-free fraction of a parent drug or its
metabolites is subject to GLOMERULAR
FILTRATION
- The elimination rate of FREE-fraction drugs
have a a DIRECT RELATIONSHIP to the
glomerular filtration rate
- ™ glomerular filtration rate = † serum drug half-
life and concentration
- Hepatic metabolism or Renal Filtration are the two
common ways in eliminating most drugs
Important factors in establishing an effective and safe
dosage regimen:
 Information regarding elimination rate
 Estimating the circulating concentration of
drug after a given time
FIRST-ORDER PROCESS
- Aka EXPONENTIAL RATE OF LOSS
- Akaka FIRST ORDER KINETICS 
- Independent of clearance mechanism
- The rate of change of the drug concentration over
time (ΔC/ΔT ) VARIES continuously in relation
to the concentration of the drug (C).
ΔC/ΔT = -kC
k= elimination constant / rate of elimination
= simple proportionality factor that describes the
percentage change per unit of time
- Curvilinear
kT
CT = C0e-
o Useful form of the elimination equation
PHARMACOKINETICS
- The activity of a drug in the body as influenced by
ADME
- Assists in establishing or modifying a dosage
- Rate of elimination (k) can be determined
AFTER drug distribution is complete
- Concentrations rise when the rate of absorption
exceeds distribution and elimination.
- The concentration declines as the rate of
elimination and distribution exceeds
absorption.
Kaori Sembrano ’17 || 4
PEAK SERUM DRUG CONCENTRATION: separator collection tubes (FAILURE ANTIBIOTICS
- the highest concentration of a drug in TO FOLLOW= FALSE VALUES) 1. Aminoglycosides
the patient's bloodstream. o EDTA, Oxalate and Citrate= calcium- 2. Vancomycin
TROUGH SERUM DRUG CONCENTRATION: binding anticoagulants add a variety of
- the lowest concentration in the patient's
anions and cations that may interfere FIRST GENERATION ANTI-EPILEPTIC DRUGS
bloodstream
with analysis or cause a drug to (PPVC- EFGL-LOTTZ)
 DOSAGE REGIMEN- schedule of doses of a distribute differently between cells and 1. Phenobarbital
therapeutic agent per unit of time plasma. 2. Phenytoin
- the time between doses (e.g., every 6 3. Valproic Acid
hours) 4. Carbamazepine
- the time when the dose(s) are to be PHARMACOGENETIC PROFILING 5. Ethosuximide
given (e.g., at 8 a.m. and 4 p.m. daily) (aka PHARMACOGENOMICS)
6. Felbamate
- the amount of a medicine to be given
- Use to predict drug-drug interactions 7. Gabapentoin
at each specific time
o MULTIPLE-DOSE REGIMEN - As an indicator if the drug will provide any 8. Levetericetam
- The goal is to achieve a trough and therapeutic (or toxic) effect 9. Lamotrigine
peak in the therapeutic range and  Responders: pxn benefiting from the therapeutic 10. Oxcarbazepine
ensure that the peak is not in the toxic and desired effects of drugs 11. Topiramate
range.  Non-responders: pxns who do not demonstrate a 12. Tiagabine
- 5-7 doses are usually required before beneficial or desired effect form the initiation of a 13. Zonisamide
a steady-state oscillation is achieved dosing regimen
- By the end of the seventh dose, the
 CYP-450 ANTIPSYCHOTIC DRUGS
amount of drug administered in a
single dose is equal to the amount o Prominent gene families within the (CLOT)
eliminated during the dosage period. MFO system that affect drug 1. Clozapine
metabolism 2. Lithium
MINIMUM EFFECTIVE CONCENTRATION (MEC) o Doses of drug depends on the patient’s 3. Olanzapine
- lowest concentration of drug in the blood that will produce CYP-450 profile;
4. Tricyclic Antidepressants (TCA)
the desired/therapeutic response  If CYP-450 profile have a
gene that metabolizes drug
slowly, it would be given IMMUNOSUPPRESIVE DRUGS
MINIMUM TOXIC CONCENTRATION (MTC) lower doses of drug to avoid (My STaC)
- lowest concentration of drug in the blood that will produce toxic serum concentrations. 1. Mycophenolic acid
an adverse/toxic response (and vice versa) 2. Sirolimus
o Most common enzymes linked to 3. Tacrolimus
SAMPLE COLLECTION differences in degrees of drug
4. Cyclosporin
 Timing of Specimen Collection – most important metabolism:
indicator in TDM  CYP-2D6
 CYP-2C9 ANTINEOPLASTIC DRUG
o trough concentrations- drawn right before
the next dose  CYP-3A4 1. Methotrexate
o peak concentrations - drawn 1 hour after
an orally administered dose
o EXCEPTION TO THIS RULE IS CARDIOACTIVE DRUGS
DIGOXIN (absorbed slowly; may require (DD-QP)
several hours before peak drug levels can be 1. Digoxin
evaluated) 2. Disopyramide
3. Quinidine
- Specimen of Choice: SERUM or PLASMA 4. Procainamide
o certain drugs have a tendency to be
absorbed into the gel of certain serum
Kaori Sembrano ’17 || 5