THERAPEUTIC DRUG MONITORING

 Involves analysis, assessment and evaluation of circulating

concentrations of drugs in serum, plasma or whole blood
 It allows for the safe use of drugs that would otherwise be potentially
toxic
 TDM ensures that given drug produces maximal therapeutic benefit and
minimal side effects; to achieve a constant serum level of the drug that
will be therapeutic
 Half-life determines the time to reach the steady-state or average
concentration
 Only the free fraction of the drugs can interact with the site of action
and results in a biologic response
 MIXED FUNCTION OXIDASE SYSTEM- Biochemical pathway responsible for the
greatest portion of drug metabolism

Indications

o There is small difference between therapeutic and toxic dose

o Helps monitoring patients compliance

Routes of administration
o Intravenous route-100% bioavailability
o Orally-Administered drug should achieved 0.7 bioavailability
fraction
o Intramuscular
o Subcutaneous and transcutaneous
o Inhalation
o Suppository
Five pharmacological parameters
Liberation Drug  Release
Absorption Drug  Blood (most: by passive diffusion)
Distribution Drug  Tissues
Metabolism Drug  Chemical modification
Excretion Drug  metabolites  excreted

Absorption
o

Distribution
o
Excretion
o
Causes of drug toxicity:
-elevated concentration of free drug
-abnormal response to drug after administration
-the presence of active drug metabolism

TERMINOLOGIST
  Bioavailable fraction (f)-is the fraction of the dose that reaches the
blood
 Vd of a drug-represents the dilution of the drug after it has been
distributed in the body
 First-pass hepatic metabolism-Drugs that are transported to the Liver
decreased bioavailability before it reaches general circulation
 First order elimination-linear relationship between the amount of drug
eliminated per hour and the blood level of drug
 Half life- time required to reduce drug level to half of its initial
value
 Pharmacodynamics-relationship between drug concentration at the target
site and response of the tissues
 Pharmacokinetics-mathematical expression of relationship between drug
dose and drug blood level
 Pharmacogenomics-Study of genes that affect the performance of a drug in
an individual
 Therapeutic index-ratio between the minimum toxic and maximum
therapeutic serum concentration
 Therapeutic range- difference between highest and lowest dosages
 Trough concentration-the lowest concentration of a drug obtained in the
dosing interval(Drawn immediately (or 30 mins) before the next dose)
 Peak concentration- highest concentration of a drug obtained in the
dosing interval( Drawn one hour after an orally administered dose
(except digoxin))

CLASSIFICATION OF CARDIOACTIVE DRUGS

 Class I-Rapid Na+ channel blockers (Procainamide, Lidocaine, Quinidine)
 Class II-Beta receptor blockers (Propanolol)
 Class III-K+ channel blockers (Amiodarone)
 Class IV-Ca2+ channel blockers (Verapamil)
Cardioactive Drugs
Digoxin -cardiac glycoside, treatment of atrial atrial
arrhythmia and CHF
-elimination: renal filtration of pplasma free form
-half life: 38 hrs
Lidocaine -corrects ventricular arrhythmias for treatment of
(Xylocaine) myocardial infarction
-used as local anesthetic
-elimination: hepatic metabolism
-toxic effect: CHF and heart block
-1’ product of hepatic metabolism: MEGX
(monoethylglycinexylidide)
Quinidine -natural occurring drug for treatment of arrhythmia
-elimination: hepatic metabolism
-toxic effect: cinchonism, blood dyscrasia and
hepatitis
-Common formulations: Quinidine sulfate and
Quinidine gluconate
Procainamide -used to treat ventricular arrhythmia
(Pronestyl) -GIT absorption is rapit and complete
-Hepatic metabolite: NAPA (N-acetylprocainamide)
-Toxic effect: reversible lupus-like syndrome
Disopyramide -Substitute for quinidine
-Anticholinergic effects
 Elimination: renal filtration
Propanolol -beta receptor blocking drug
-Tx: angina pectoris; thyrotoxicosis
Amiodarone -blocks potassium channel in cardiac muscle
(Cordarone) -use for treatment ventricular arrhythmias
-Iodine-containing drug
Verapamil -Treatment: angina, hypertension, supraventricular
arrhythmias
Antibiotics
Aminoglycosides -gentamicin, tobramycin, amikacin, kanamycin,
neomycin,streptomicin
-used for treatment of gram negative bacterial
infections, not given to out patients
-may damage 8th cranial nerve
-requires trough and peak measurement
-Tx: Nephrotoxic and ototoxic
Vancomycin -glycopeptide effective against gram-positive cocci
and bacilli
-only trough levels are monitored
Toxic effects:
“______________________”
Nephrotoxic and ototoxic
Chloramphenicol -distributes to all tissues, and concentrates in the
CSF
Antiepileptic Drugs
Phenobarbital -long acting barbituratees that controls grandmal
clonic seizure and focal epileptic
-used to treat withdrawal symptoms in infants
-Long acting barbiturate
-treats congenital hyperbilirubinemia-
Enhances bilirubin metabolism
-Inactive proform: Primidone
-elimination: hepatic metabolism
Phenytoin -controls seizure
(Dilantin) -not used for petit mal and atomic seizure
-Injectable proform: fosphenytoin
-elimination: hepatic pathway
Valproic acid -used to treat petit mal, atomic seizure and grandma
(Depakene) -highly protein bound
-elimination: hepatic metabolism
Carbamazepine -tricyclic compound related to imipramine
(Tegretol) -treats grand mal seizure accompanied by pain
Ethosuximide -Drug of choice for controlling petit mal seizure
(Zarontin)
Gabapentin -Similar to neurotransmitter GABA
(Neurontin) -administration orally, unbound to protein
Others Topiramate, Lamotrigine (Lamictal)(both for
(Antiepileptic) __________)Felbamate
Psychoactive Drugs
Lithium -treatment for bipolar disorders (Manic depression)
-inhibits thyroid hormone synthesis and release
-inhibits iodine uptake
-inhibits ADH
-elimination: renal filtration
Tricyclic -treatment of depression, insomnia, extreme apathy,
antidepressantas (TCA) and loss of libido
 -example:Imipramine, Amitriptyline, Doxepin
Nortriptyline, Tradazone
-major metabolite: desipramine
Fluoxetine (Prozac) -blocks the reuptake of serotonin in central
serotonergic pathways
-treatment for Obsessive-compulsive disorders
Bronchodilator
Theophylline -methylated xanthine class
-relaxes bronchial smooth muscle
-Tx: Asthma and other COPD
Immunosuppressive drugs
Cyclosporine -inhibits cellular immune response by blocking
___________
-prevents allogenic organ
transplant(________________)
Tacrolimus -100x more powerful than cyclosporine
(Prograf/FK-506) -elevate levels obrserved in cholestasis
Other -rapamycin(sirolimus), mycophenolate mofetil,
immunosuppressive drug leflunomide,
Anti-inflammatory and Analgesic Drugs
Salicylates/Aspirin -commonly used analgesic, antipyretic and anti-
(Acetylsalicylic acid) inflammatory drug
-has anticoagulant property
-function: decreases thromboxane and prostaglandin
formation
-Antiplatelet (inhibits ___________)
-Method: Trinder assay
Acetaminophen -inhibitor of prostaglandin metabolism
(Tylenol) -Hepatotoxic
Ibuprofen -analgesic and anti-inflammatory action
-Lower risk of toxicity than salicylates and
acetaminophen
Neuroleptics (Antipsychotic major tranquilizers)
Neuroleptics -Block the action of dopamine and serotonin
-treatment for acute Schizophrenia
2 classes:
-Phenothiazines (chlorpromazine)
-Butyrophenones (haloperidol)
Examples:
-Risperdal
-Olonzapine (Zyprexa)
-Quetiapine (Seroquel)
-Aripiprazole (Abilify)

METHODS FOR TDM

 Specimen of choice: serum, plasma

 Whole blood is required for_________________ and _________________
 Timing of collection is single most important factor for TDM
 No changes occurred in __________ and _______ when blood is collected in
SST
 TDM samples should not be collected in tube with serum separator gel for
some drugs are absorbed by the gel
SPECIMEN CONSIDERATION

COLORIMETRY
 Acetaminophen in urine is detected by boiling to form p-amphenol
which reacts in o-cresol to form ________________
 Trinder assays for salicylates using ferric nitrate forming (+)
colored complex
IMMMUNOASSAY METHOD
 Provides rapid analysis for urine and blood sample
 Uses antibody specifically reactive in some drugs
o Enzyme mediated Immunologic Technique
o Fluorescence polarization immunoassay (FPIA)
CHROMATOGRAPIC
o THIN LAYER CHROMATOGRAPHY
o HIGH PERFORMANCE LIQUID CHROMATOGRAPHY
o GAS CHROMATOGRAPHY MAS SPECTROMETRY-gold standard