Therapeutic Drug Monitoring

Topic: Photosynthesis

Key Vocabulary:

Therapeutic Drug Monitoring

  • Involves analysis, assessment, and evaluation of circulating concentrations of drugs

  • Quantitative procedure performed for drugs with narrow therapeutic index

  • Ensures the minimal and maximal therapeutic benefit of different drugs

Indications of Therapeutic Drug Monitoring (unprohibited drug that needs to be monitored)

  • Consequences of overdosing and underdosing

    • Vitamin C - overdose (more than 1000 mg); can cause kidney stones

  • Difference between therapeutic and toxic dose (excess of required dose)

  • Relationship between circulating concentration and therapeutic and toxic effect

  • Effects of physiologic state to circulating drug concentrations

  • Drug interaction

  • Monitoring patient compliance

Routes of Administration

  • Intravenous (IV)

    • vein

  • Oral

    • intake

  • Intramuscular (IM)

    • muscles; for antibiotics and hormones

  • Subcutaneous

    • skin test; allergy, insulin

  • Inhalation

    • asthma/ anesthesia

  • Suppository

    • rectum, vagina, urethra

  • Transcutaneous

    • transdermal; patches

Parameters that Determine Serum Drug Concentration

  • Liberation- refers to the release of the drug

    • Immediate - effect with no delay; epinephrine and anti-histamine

    • Delayed - not immediate effect; delayed by 1 hour usually; tablets

    • Extended - over an extended period of time; anesthesia, early diagnosis

  • Absorption- the transport of drug from the site of administration to the blood

  • Distribution- refers to the delivery of the drug to the tissues

  • Metabolism- the process of chemical modification of the drug by cells

  • Excretion- the process by which the drug and its metabolites are excreted from the body

Causes of Drug Toxicity

  • Elevated Concentration of free drug

    • Prodrugs - medications that turn into an active form once they enter the body. Prodrugs help improve a medication's effectiveness. They may also be designed to avoid certain side effects or toxicities.

  • Abnormal response to drug after administration

  • Presence of active drug metabolite

Different Classifications of Therapeutic Drugs

1. Cardioactive Drugs

2. Antibiotics

3. Anti-epileptic

4. Psychoactive

5. Bronchodilators

6. Immunosuppressive

7. Antineoplastic

8. Antiinflammatory/Analgesics

9. Neuroleptics (antipsychotic)

Cardioactive Drugs

- Digoxin

- Lidocaine (Xylocaine)

- Quinidine

- Procainamide (Pronestyl)

- Disopyramide

- Propranolol

- Amiodarone (Cordarone)

- Verapamil

Classifications of Cardioactive Drugs

  • Class I– rapid sodium channel blockers

    • Quinidine, procainamide, lidocaine

  • Class II– beta receptor blockers

    • propranolol

  • Class III– potassium channel blocker

    • amiodarone

  • Class IV– calcium channel blocker

    • verapamil

Digoxin

  • Treatment for atrial arrhythmia and congestive heart failure (CHF)

  • It’s therapeutic actions and toxicities can be influenced by serum electrolytes

  • Hypomagnesemia, hypokalemia, hypocalcemia increased sensitivity to digoxin

  • HalfLife: 38 hours

Lidocaine (Xylocaine)

  • It is used to correct ventricular arrhythmia for treatment of acute myocardial infarction

  • It is administered by continuous IV infusion after loading dose

  • Used as local anesthetic

Quinidine

  • It is naturally occurring drug for the treatment of arrhythmia

  • It is almost 85% protein-bound

Procainamide (Pronestyl)

  • It is used to treat ventricular arrhythmia

  • 20% protein-bound

  • Common route: Oral

  • Hepatic Metabolite: N-acetyl procainamide (NAPA)

Disopyramide

  • It is used to treat cardiac arrhythmias; used as a substitute for quinidine

  • Administered orally

  • It has anticholinergic effects- dry mouth and constipation (> 4.5 ug/mL)

Propranolol

  • It is a beta-receptor-blocking drug

  • It is used in the treatment of angina pectoris, hypertension, and coronary artery disease

  • Treatment of thyrotoxicosis

Amiodarone (Cordarone)

  • It blocks potassium channels in the cardiac muscle

  • It is an iodine-containing drug which can cause hyperthyroidism or hypothyroidism

Verapamil

  • It is used for treatment of angina, hypertension, and supraventricular arrhythmias

Antibiotics

- Aminoglycosides

  • Gentamicin, Tobramycin, Amikacin, Kanamycin, Neomycin and Streptomycin

- Vancomycin

- Chloramphenicol

Aminoglycosides

(Gentamicin, Tobramycin, Amikacin, Kanamycin, Neomycin, and Streptomycin)

  • used for treatment of Gram-negative bacterial infections, not given to outpatients

  • It has poor oral absorption; administered by IV infusion/ IM

  • Toxic effects: “Red Man syndrome”, nephrotoxicity, ototoxicity

Vancomycin

  • effective against Gram-positive cocci and bacilli

  • toxic side effects occur in the therapeutic range (5-10 ug/mL)

Chloramphenicol

  • Distributes to all tissues, and it concentrates in the CSF

  • 50% is protein-bound; rapidly absorbed in the GIT

Anti-epileptic Drugs

- Phenobarbital

- Phenytoin (Dilantin)

- Valproic Acid (Depakene)

- Carbamazepine (Tegretol)

- Ethosuximide (Zarontin)

- Gabapentin (Neurontin)

Phenobarbital

  • most common

  • Controls grand mal tonic-clonic seizure

  • Used for treating -withdrawal symptoms in infants- mothers are addicted to opiate or barbiturate

  • Inactive proform: Primidone (mysoline)

Phenytoin (Dilantin)

  • It is a short-term prophylactic agent in brain injury

  • It controls seizures (tonic-clonic, simple partial seizures)

Valproic Acid (Depakene)

  • one of the most common also

  • It is used for treatment of petit mal ( absence seizure), atomic, and grand mal seizures

  • It is highly protein-bound (93%)

  • therapeutic level: 50-100 ug/mL

Carbamazepine (Tegretol)

  • one of the most common also

  • It is tricyclic compound related to imipramine (TCA)

  • It is effective for grand mal seizures and for treating seizures accompanied by pain

  • It has antineuralgic action, and 70-80% is protein bound

Ethosuximide (Zarontin)

  • It is the drug of choice for controlling petit mal (absence seizure)

Gabapentin (Neurontin)

  • It is chemically similar to neurotransmitter gamma aminobutyric acid (GABA)

  • It is used for partial seizures and as an adjunctive therapy

Psychoactive Drugs

- Lithium

- Tricyclic Antidepressants

- Fluoxetine

Lithium

  • It is used for treatment of manic-depressive illness (bipolar disorders)

  • It is the drug of choice for the prevention of chronic cluster headache

  • It inhibits thyroid hormone synthesis and release; inhibits iodine uptake causing hypothyroidism

Tricyclic Antidepressants (TCAs)

  • They are used for the treatment of depression, insomnia, extreme apathy, and loss of libido

  • Major metabolite: Desipramine

Fluoxetine (Prozac)

  • It blocks the re-uptake of serotonin in central serotonergic pathways

  • It is also used for the treatment of obsessive-compulsive disorders

Bronchodilator

Theophylline

  • belongs to the methylated xanthine class

  • Used for relaxation of bronchial smooth muscle

  • Used for treatment of asthma and chronic obstructive pulmonary disease

  • Administration: IV then orally; 50% is protein-bound

  • Can cross the placenta and maybe teratogenic in pregnant females

Immunosuppressive Drugs (transplant center; graft versus host client)

- Cyclosporine

- Tacrolimus (prograf)

- Rapamycin (sirolimus)

Cyclosporine

  • It inhibits the cellular immune response by blocking production of interleukin-2

  • It is used to prevent rejection of allogenic organ transplants

  • It is utilized for suppression of acute-graft-versus-host disease (GVHD)

Tacrolimus (Prograf/ FK-506)

  • It is 100x more powerful than cyclosporine

Rapamycin (Sirolimus)

  • Similar to tacrolimus; major side effects are lipid abnormalities and thrombocytopenia

Antineoplastic Drugs

- Methotrexate

- Busulfan

Methotrexate

  • Inhibits DNA synthesis in all cells, blocking dihydrofolate reductase

  • Leucovorin is used to reverse the action of methotrexate known as the “leucovorin rescue”

Busulfan

  • alkylating agent used to treat leukemias and lymphomas prior to bone marrow transplantation

  • overdosage may cause hepatic occlusive disease

Anti-inflammatory/ Analgesics

- Salicylates/Aspirin

- Acetaminophen (Tylenol/Paracetamol)

- Ibuprofen

Salicylates/ Aspirin (Acetylsalicylic Acid)

  • Commonly used analgesic, antipyretic, and anti-inflammatory drug

  • It is a direct stimulator of the respiratory system and an inhibitor of the Kreb’s cycle

  • Anticoagulant property (antiplatelet activity) by inhibiting the action of cyclooxygenase

Acetaminophen (Tylenol)

  • or paracetamol

  • commonly used as an analgesic and antipyretic drug

  • overdosage leads to hepatoxicity

Ibuprofen (Alaxan daw)

  • It has an analgesic and anti-inflammatory action

  • It has lower risk of toxicities than salicylates and acetaminophen

Neuroleptics (Antipsychotic Major Tranquilizers)

  • Antipsychotic

  • Blocks the action of dopamine (causes enhanced/ exaggerated emotions/feelings of people) and serotonin in the limbic system

  • Used for treatment of acute schizophrenia

Sample Consideration based on Timing of Collection

  • Trough Concentration

    • Reflects the lowest level of drug in the blood

    • Sample drawn immediately before the next dose

  • Peak Concentration

    • Best specimen for initial investigation of therapeutic drug toxicity

    • Sample is drawn one hour after an orally administered doses

    • IV drugs, peak levels are determined after the infusion is completed

    • Increasing the dose rate may result in peak drug levels in the toxic range

Sample Considerations in TDM

  • Specimen of Choice: Serum or Plasma

  • Whole blood EDTA: for cyclosporine and tacrolimus assay

  • TDM samples should not be collected in tubes with gel separators (absorbance of certain drugs can cause false low result); only serum tubes without gel separators must be used

  • Measurement should only be done after steady state has been achieved

  • Measurements for TDM are mostly homogenous assays

  • Timing of sample collection is the single most important factor in TDM

Terminologies

  • Bioavailable Fraction

  • Vd of a drug

  • First– pass hepatic metabolism

  • First– order elimination

  • Half–life

  • PeakConcentration

  • Pharmacodynamics

  • Pharmacogenomics

  • Pharmacokinetics

  • Therapeutic Index

  • Therapeutic Range

  • Trough Concentration