CLINICAL CHEMISTRY 2

Flashcards for Clinical Chemistry 2 - Therapeutic Drug Monitoring and Toxicology

Analysis, assessment, and evaluation of circulating concentrations of drugs in serum, plasma or whole blood. It is qualitative and allows for the safe and effective use of drugs with a narrow therapeutic index, ensuring maximal therapeutic benefit and minimal side effects.

Therapeutic Drug Monitoring (TDM)

Determines the time to reach the steady-state or average concentration of a drug in the body.

Half-life (drug)

The biochemical pathway responsible for the greatest portion of drug metabolism.

Mixed Function Oxidase (MFO) system

Warfarin, Aminoglycoside, Lithium, Amphotericin B, Carbamazepines, Phenobarbital, Phenytoin, Vancomycin, Theophylline, Digoxin

Narrow Therapeutic Drugs

The consequence of overdosing and underdosing are serious; small difference between therapeutic and toxic dose; poor relationship between the dose of drug and circulating concentrations but a good correlation between circulating concentrations and therapeutic and toxic effects; change in patient’s physiologic state; a drug interaction is or may be occurring; helps in monitoring patient compliance.

Indications for TDM

A convenient method that can effectively deliver most drugs to its site of action.

Circulatory system (Route of Administration)

Is the most immediate route with constant distribution and elimination rates and is associated with 100% bioavailability.

IV route administration

Drug should achieve 0.7 bioavailability fraction.

Oral administration

Liberation, Absorption, Distribution, Metabolism, Excretion.

Pharmacokinetics

Release of the drug.

LIBERATION

Transport of drug from the site of administration to the blood.

ABSORPTION

Delivery of the drug to the tissues.

DISTRIBUTION

Process of chemical modifications of the drug by cells.

METABOLISM

Process by which the drug and its metabolites are excreted from the body.

EXCRETION

For a drug to achieve therapeutic dose, it must be at the proper concentration at its site of action.

Therapeutic Dose Requirement

Most drugs are absorbed by passive diffusion and must be in a hydrophobic/nonionized state; liquid solutions are rapidly absorbed.

Passive Diffusion

Where drugs absorbed by the intestine enters. All the blood from the GIT is routed through the liver before it enters into the general circulation.

Hepatic Portal System

Weak acid is absorbed in the stomach and weak bases in the intestine.

Absorption based on pH

Changes in intestinal movement, pH inflammation, presence of food or another drugs

Factors affecting absorption

Locations where the drugs are effective are in the body tissues, not generally in the blood.

Drug effectiveness

The relationship between tissue & blood levels.

Distribution space

Indicates that much of the drugs moves into the tissues than stays in the circulation.

Large distribution space

Dependent upon not only on the type of drug itself, but also on a patient’s capacity to metabolize and excrete it.

Rate of drug clearance

Conversion of a parent drug to its metabolites occurs in the liver.

Drug Metabolism Location

Uncharged in the urine, excreted as metabolites, some drugs enter the enterohepatic circulation and excreted in stool

How all drugs are excreted

Elevated concentration of drugs, Abnormal response to drugs after administration, The presence of active drug metabolites.

Causes of Drug Toxicity

Fraction of the dose that reaches the blood.

Bioavailable fraction (f)

Represents the dilution of the drug after it has been distributed in the body; used to estimate the peak drug blood level expected after a loading dose is given; the principal determinant of the dose.

Vd of a drug

Drugs that are transported to the liver lost a fraction of its bioavailability before the drug reaches the general circulation.

First-pass hepatic metabolism

Represents a linear relationship between the amount of drug eliminated per hour and the blood level of a drug.

First order elimination

The time reduces a drug level to half of its initial value.

Half-life (t1/2)

Highest concentration of a drug obtained in the dosing interval.

Peak concentration

The relationship between the drug concentration at the target site and response of the tissues.

Pharmacodynamics

The study of genes that affect the performance of the drug in an individual.

Pharmacogenomics

The mathematical expression of the relationship between drug dose and drug blood level.

Pharmacokinetics

The ratio between the minimum toxic and maximum therapeutic serum concentration.

Therapeutic index

The difference between highest to lowest effective dosages.

Therapeutic range

Lowest concentration of a drug obtained in the dosing interval.

Trough concentration

Used for treatment of arrhythmias and congestive heart failure (CHF)

Cardioactive drugs

Rapid sodium channel blockers, divided into Class Ia, Ib, Ic.

Class I (Anti-arrhythmic drugs)

Prolong angina pectoris, for atrial & ventricular arrhythmias, for post-myocardial infarction. Drugs: Procainamide, Quinidine, Nisopyramide

Class Ia (Anti-arrhythmic drugs)

Shorten angina pectoris, for ventricular arrhythmias, for post-myocardial infarction. Drugs: Lidocaine, Phenytoin, Digoxin, Mexilenne, Tocainide

Class Ib (Anti-arrhythmic drugs)

No effect, for refractory arrhythmia, MOST arrythmogenic. Drugs: Flucainide, Propafenone

Class Ic (Anti-arrhythmic drugs)

Beta-blockers / beta-receptor blockers, ends with “olol”, acts in phase 4. Drugs: Propanolol, Atenolol, Metoprolol, Esmolol

Class II (Anti-arrhythmic drugs)

Potassium (K) channel blockers, acts on phase 3, prolongation of angina pectoris duration. Drugs: Amiodarone, Sotalol, Ibutilide, Dofetilide

Class III (Anti-arrhythmic drugs)

Calcium (Ca) channel blocker. 2 Types: Dihydropyridine (Amlodipine) & Nondihydropyridine (Verapamil & Diltiazem)

Class IV (Anti-arrhythmic drugs)

Cardiac glycoside for treatment of ATRIAL arrhythmia or CHF. Inhibits membrane Na-K-ATPase. Therapeutic level: 0.5-2 ng/mL Toxic level: >2 ng/mL

Digoxin

To correct VENTRICULAR arrhythmia, for treatment of acute myocardial infraction, used as a LOCAL ANESTHETIC. Therapeutic level: 1.5-4.0 ug/mL Toxicity level: >4.0 ug/mL

Lidocaine

A naturally occurring drug for the treatment of arrhythmia. Therapeutic level: 2.3-5ug/mL Toxicity level: >5ug/mL

Quinidine

Used to treat ventricular arrhythmia. Therapeutic level: 4-5ug/mL Toxicity level: >12ug/mL

Procainamide

Used to treat cardiac arrhythmias. Therapeutic level: 3-5ug/mL Toxicity level: 10ug/mL

Disopyramide

Beta-blocker suppresses the conversion of T4 → T3. Used in the treatment of angina pectoris, hypertension, coronary artery disease, thyrotoxicosis. Therapeutic range: 50-100 ug/mL

Propanolol

Blocks potassium channels in the cardiac muscle. Use for treatment of ventricular arrhythmias. Therapeutic level: 1.0-2.5ug/mL Toxicity level: >2.5 ug/mL

Amiodarone

For treatment of angina, hypertension and supraventricular arrhythmias. Therapeutic range: 80-400ng/mL

Verapamil

Typically used for treatment of gram negative bacterial infections but may cause damage to the 8th cranial nerve at toxic levels (hearing loss).

Aminoglycosides

A glycopeptide effective against Gram-positive cocci & bacilli only. Typically trough levels are monitored to ensure serum drug concentration is within therapeutic range.

Vancomycin

Distributes to all tissues, concentrates in the CSF. Toxicity level >25 ug/mL

Chloramphenicol

Long acting barbiturate that controls grand mal tonic-clonic seizure and focal epileptic seizure. Therapeutic level: Phenobarbital = 20- 40 µg/ml; Primidone = 5- 12 µg/ml

Phenobarbital

Short term prophylactic agent in brain injury/decreases sodium and calcium influx into hyperexcitable neurons. Therapeutic range: 10- 20 µg/ml

Phenytoin

Used for treatment of petit mal (absence seizure), atomic seizure and grand mal. Therapeutic level: 50-100 µg/ml

Valproic Acid

Is a tricyclic compound related to imipramine effective for grand mal seizures. Therapeutic level: 4-16 µg/ml

Carbamazepine

Drug of choice for controlling petit mal (absence seizure). Therapeutic level: 40-100 µg/ml

Ethosuximide

Chemically similar to neurotransmitter gamma aminobutyric acid (GABA). Therapeutic level: 2-15 ug/ml

Gabapentin

Used for treatment of manic-depressive illness (bipolar disorders). Therapeutic range: 0.8-1.2 mmol/L; Toxicity level: 1.2-2 mmol/L

Lithium

Used for treatment of depression, insomnia, extreme apathy, & loss of libido. Therapeutic level: 100-300ng/mL

Tricyclic Antidepressants (TCAs)

Blocks the re-uptake of serotonin in central serotonergic pathways. Therapeutic level: 90-300ng/mL

Fluoxetine

Belongs to the methylated xanthine class specific to the relaxation of bronchial smooth muscle. Therapeutic level: 10-20 ug/mL

Theophylline

Used to prevent rejection of allogenic organ transplants. Specimen of choice: Whole blood (with lysis of RBC to yield the total amount)

Cyclosporine

100x more powerful than cyclosporine. Specimen of choice: Whole blood

Tacrolimus

Inhibits lymphocyte proliferation; for treatment of rheumatoid arthritis.

Leflunomide

An effective therapy for a variety of neoplastic conditions and also an immunosuppressive agent. Toxic level: 0.01 µmol/L

Methotrexate

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

Busulfan

Commonly used analgesic, antipyretic and anti- inflammatory drug Therapeutic level: 5 mg/dl; Toxic level: >30 mg/dl

Salicylates/Aspirin

Is an inhibitor of prostaglandin metabolism commonly used as analgesic and antipyretic drug. Therapeutic level: 25 μg/ml; Toxic level: >50 μg/ml

Acetaminophen

Has analgesic and anti-inflammatory actions, has a lower risk of toxicities than salicylates and acetaminophen. Therapeutic level: 10-50 μg/ml; Toxic level: >100 μg/ml

Ibuprofen

Blocks the action of dopamine and serotonin in the limbic system. Used in the treatment of acute schizophrenia. Two Types: Classical/Typical & Atypical

Neuroleptics (Antipsychotic/major tranquilizers)

Serum, plasma, or whole blood EDTA (for cyclosporine & tacrolimus)

Specimen of choice for TDM

Drawn immediately (or 30 min) before the next dose. Reflects the lowest level of drug in the blood. Affected by drug clearance rate.

Trough Concentrations

Drawn 1 hour after an orally administered dose (except digoxin). The BEST specimen for initial investigation of therapeutic drug toxicity.

Peak Concentrations

Acetaminophen in urine - detected by boiling → p- amphenol + o-cresol = indophenol blue; salicylate + ferric nitrate = (+) colored complex

COLORIMETRY

Provides rapid analyses of blood & urine samples. Sensitive & specific methods. Uses antibody specifically reactive with a particular drug.

IMMUNOASSAY

Amount of enzyme activity is directly proportional to the amount of drugs present in the sample.

Enzyme-Mediated Immunologic Technique (EMIT)

Binding of the marker drug to antibody can be quantitated by the angle at which emissions occur. The drug is attached to a fluorescent label or fluorophore.

Fluorescent Polarization Immunoassay (FPIA)

Thin Layer Chromatography (TLC), High Performance Liquid Chromatography (HPLC), Gas Chromatography-Mass Spectrometry (GC-MS).

CHROMATOGRAPHIC Methods

Best specimen: urine. Uses serum, urine, or gastric fluid for analysis. Qualitatively identifies drugs by means of Rf values. Extraction of drugs is pH dependent.

Thin Layer Chromatography (TLC)

Highly quantitative procedure. Ideal for separation of tricyclic antidepressants & its metabolites.

High Performance Liquid Chromatography (HPLC)

The GOLD STANDARD. Used for quantitation of many drugs. Drugs must be volatile in form or can be chemically derivatized into volatile form.

Gas Chromatography-Mass Spectrometry (GC-MS)

Is reached when drug in the next dose is sufficient only to replace the day eliminated since the last dose. Can be measured after 5 drug half-lives because blood levels will have reached 97% of steady state

Steady-state drug level

The study of substances toxic to the body

Toxicology

A process requires that the substance cross cellular barriers

Passive diffusion of toxins

Diarrhea, Bleeding, Malabsorption of nutrients

GIT Toxic effects

CBC, Serum electrolytes, BUN, Glucose, Urinalysis, Blood gas

Tests to determine in drug overdosed

Alcohol, Acetaminophen, Salicylate, Abuse substance, Carbon monoxide

Common substances causing ACUTE toxicity

Ingestion, Inhalation, Transdermal absorption

Routes of exposure to toxins

Single, short-term exposure to a substance

Acute toxicity

Repeated exposure for extended period of time

Chronic toxicity

Is the dose that would be predicted to produce a toxic response in 50% of the population

TD50

Is the dose that would predict death in 50% of the population

LD50

Is the dose that would be predicted to be effective or have a therapeutic benefit in 50% of the population

ED50

Ethanol, Methanol, Isopropanol, Ethylene glycol

Types of Alcohol