Therapeutic Drug Monitoring

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Clinical Chemistry
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1

ensure that dose produces maximal therapeutic benefit with minimal toxic side effects

main purpose of therapeutic drug monitoring

2

standard dose

dosage that provides therapeutic effect based on stats from healthy people

3

identify non-compliance and optimize dosing regimen

two smaller purposes of therapeutic drug monitoring

4

GI absorption, distribution throughout body (biological response), circulating free drug (protein binding), and elimination, renal excretion, metabolism (production of metabolites)

4 factors that affect oral drugs

5

pharmacokinetics

quantitative study of drug disposition in the body-mathematical relationships used to predict dosage adjustments

6

pharmacodynamics

study of the biochemical and physiological effects of drugs and their mechanism of action

7

therapeutic range

relationship between desired clinical effect and concentration in the plasma

8

half-life

time required for the serum concentration of a drug to decline by 50%

9

steady state

drug input and output are equal

10

5 half-lives

usual timing to reach steady state

11

peak concentration

highest concentration reached after dosage

12

trough concentraiton

lowest concentration reached after dosage

13

drug absorption

dependent on drug's dissociation from dosing form, solubility in GI fluids, and diffusion across GI membranes into blood stream

14

bioavailability

fraction of drug absorbed into systemic circulation calculated by comparing IV and oral doses; depends on size, solubility, and ionization

15

passive diffusion

concentration on one side of the membrane if higher than the other; 95% of all drug absorption

16

active transport

drug binds to carrier molecules and uses energy to go into blood stream

17

facilitated transport

same as active, but follows concentration gradient

18

drug distribution

free vs bound (to albumin); active when free-able to cross cellular membranes and interact with receptors

19

acidic drugs

drugs that primarily bind to albumin

20

basic drugs

drugs that primarily bind to globulins

21

uremia

condition that causes increased levels of free drugs due to binding sites being taken up by hemoglobin

22

drug metabolism (biotransformation)

breakdown of drugs into polar metabolites; substances absorbed from the intestine enter the hepatic portal system before entering general circulation; important in efficacy since it is how the drug is generated into the active metabolite

23

first-pass metabolism

process occurring within the liver-hepatic uptake and metabolism during passage

24

hepatic mixed-function oxidase (MFO) system

biochemical pathway responsible for a large portion of drug metabolism

25

phase I biotransformation

chemical structure of drug is modified through oxidation, reduction, or hydrolysis in the liver

26

phase II biotransformation

intermediate is conjugated in the liver-soluble compound is formed

27

enzyme activity/inhibition, drug interactions, disease states, and GI motility

four factors affecting drug metabolism and biotransformation

28

drug elimination (excretion)

drugs removed through hepatic metabolism, renal filtration, or combination of both

29

kidney

major elimination route; glomerular filtration, tubular secretion and reabsorption

30

creatinine clearance

an effective monitor of drug clearance; gent, tobra, amikacin, dig, vanc, and cyclosporine

31

first order elimination equation

...

32

accurate specimen collection timing

single most important factor in steady state levels

33

responders

patients benefitting from therapeutic and desired effects of drug

34

nonresponders

patients not benefitting from the therapeutic and desired effects of drug

35

therapeutic effectiveness

attributed to interindividual variation in genetic polymorphisms of drug metabolism pathways

36

cytochrome P-450

gene group family that affects drug metabolism, family of enzymes within MFO system

37

cardioactive drugs

glycosides and antiarrhythmics

38

digoxin (Lanoxin)

cardiac glycoside used to treat CHF by inhibiting membrane Na-K-ATPase; absorbed by GI motility, eliminated by renal filtration; half life 38 hours; immunoassay

39

Quinidine

cardiac arrhythmia treatment; GI absorbed, hepatic metabolized; half-life 6-8 hours; immunoassay

40

Procainamide

cardiac arrhythmia treatment; GI absorption; renal and hepatic elimination; 4 hour half-life; immunoassay

41

Disopyramide

cardiac arrhythmia treatment; GI absorption, hepatic metabolism elimination; half life 7 hours; immunoassay

42

aminoglycosides

treat gram-negative bacterial infections that are resistant to other less-toxic antibiotics; gent, tobra, amikacin, and kanamycin; most serious effects are nephrotoxicity and ototoxicity; IV or IM only-not for outpatients

43

Vancomycin

glycopeptide antibiotic effective against gram-positive cocci and bacilli infections; IV infusion; toxicities include red man syndrome, nephrotoxicity and ototoxicity

44

red man syndrome

flushing of extremities; sign of vanco toxicity

45

Phenobarbital and primidone

slow-acting barbituate that effectively controls several types of seizures

46

primidone

inactive form of phenobarbital; rapidly absorbed in GI tract and converted to phenobarbital; preferred when steady-state kinetics need to be established quickly

47

Phenytoin and Fosphenytoin

commonly used treatment for seizure disorders; used as short-term prophylactic agent in brain injury to prevent loss of functional tissue

48

fosphenytoin

injectable proform of phenytoin that is rapidly metabolized (75 minutes) to form the parent drug

49

Valproic acid or valproate

used as a monotherapy for treatment of petit mal and absence seizures

50

Carbamazepine

treatment for various seizure disorders; less frequently used due to toxic affects-rash, leukopenia, nausea, vertigo, febrile reactions

51

Ethosuximide

used to control petit mal seizures; toxicity: nausea, vomiting, anorexia, dizziness, and lethargy

52

Felbamate

treatment for severe epilepsy; oral administration-GI absorption; known for toxicity; primarily indicated in severe epilepsies such as Lennox-Gastaut syndrome (children) and refractory epilepsy (adults)

53

Gabapentin

may be indicated as monotherapy or in conjunction with other antiepileptic drugs in patients suffering from complex partial seizures with or without generalized seizures

54

Lamotrigine, Levetiracetam, Topiramate, and Zonisamide

treat patients with partial and generalized seizures (4)

55

Oxcarbazepine

a pro-drug that is almost immediately metabolized to licarbazepine; indicated for monotherapy of partial seizures and secondarily generalized tonic-clonic seizures

56

Tiagabine

used in treatment of partial seizures; Adverse central nervous system (CNS) side effects: confusion, difficulty in speaking clearly (stuttering), mild sedation, and a tingling sensation in the body’s extremities, or paresthesia, especially in the hands and fingers

57

lithium

psychoactive drug orally administered to treat manic depression

58

Tricyclic antidepressants

a class of drugs used to treat depression, insomnia, extreme apathy, and loss of libido

59

Clozapine

an atypical antipsychotic used to treat otherwise treatment-refractory schizophrenia

60

Olanzapine

a thienobenzodiazepine derivative that effectively treats schizophrenia, acute manic episodes, and recurrence of bipolar disorders

61

cyclosporine

primary clinical use is suppression of graft-vs-host rejection of heterotopic transplanted organs

62

tacrolimus

immunosuppressive 100 times more potent than cyclosporine

63

sirolimus

an antifungal agent with immunosuppressive activity; FDA approved for patients receiving kidney transplants

64

mycophenolic acid

a lymphocyte proliferation inhibitor; used most commonly as supplemental therapy with cyclosporine and tacrolimus in renal transplant patients

65

methotrexate

antineoplastic; one of few which TDM offers benefit to therapeutic regimen; inhibits DNA synthesis in all cell

66

leucovorin

reverses effects of methotrexate at certain point so normal cells can divide and replicate

67

theophylline

bronchodilator used in treatment of respiratory disorders such as asthma and stable COPD for those that cannot use inhaler or with nocturnal symptoms; effects include insomnia, tachycardia, seizures, arrhythmias, cardiorespiratory arrest