21) Therapeutic drug monitoring Flashcards
4 parts of pharmacokinetics
Absorption
Distribution
Metabolism/Biotransformation
Excretion
Drugs are absorbed from the gastrointestinal tract by either ——– or ———-.
passive diffusion
active transport
how does pH affect drug absorption
A drug that is uncharged tends to pass through membranes more readily than a charged drug.
Indicates the fractional extent to which a dose of drug reaches its site of action.
bioavailability
Metabolism or biliary excretion may occur before it reaches the systemic circulation.
first-pass effect
PO disadvantages
Limited absorption because of solubility, vomiting, destruction by digestive enzymes, and low gastric pH that may inactivate the drug
counteract disadvantages of PO administration
controlled-release drugs
how can first-pass effect work on parenteral meds?
- Partitioning into the lipids located in liver tissue
- Filtration
- Elimination as a volatile substance
aqueous solutions or specialized depot preparations in ethylene glycol or peanut oil
IM meds
50% of the drug absorbed will bypass the liver; avoids first-pass effect
rectal meds
topical anesthetics
Tetracaine and lidocaine
applied to eye to induce vomiting
atropine
Initially, most of the drug goes to the…
Then, to…
liver, kidneys, brain, and other well-perfused organs
muscles, skin, fat, and viscera
tissue distribution of a drug depends on…
- Partitioning of drug between blood and the particular tissue
- Lipid solubility
- pH gradients between intracellular and extracellular fluid
2 forms of drug circulating
bound and unbound
albumin alpha 1-acid glycoprotein
plasma protein that binds drugs
how does hypoalbuminemia affect drug levels?
protein binding is reduced, ↑ free drug level
Metabolism of a drug into more hydrophilic metabolites is essential for…
- Elimination of these compounds from the body
- Cessation of their biological activity
Reactions generate more polar, inactive metabolites that are readily excreted from the body.
biotransformation of drugs
2 types of biotransformation
Phase I (functionalization)
Phase II (conjugation)
phase I biotransformation reactions
Hydrolysis
Reduction
Oxidation
may be rapidly excreted into the urine, or they can react with endogenous compounds to form highly water-soluble conjugates
Products of phase I reactions
phase II biotranformation reactions
Leads to formation of covalent linkage between a functional group on the parent compound with an endogenously derived:
Glucuronic acid
Sulfate
Glutathione
Amino acid
Or acetate group
concentration of drug < MM constant
1st order kinetics
rate of drug metabolism is directly proportional to the concentration of free drug
concentration of drug > MM constant
zero-order kinetics
rate of metabolism remains constant over time
drugs that lead to zero order kinetics
aspirin
ethanol
Enzymes involved in biotransformation are found mainly in the ——-
liver
biotransformation phases location
Phase I: Endoplasmic reticulum
Phase II: Cytosol
Major enzyme system that metabolizes drugs
cytochrome P450 (CYP) monooxygenase system
most important organs for excretion of drugs and their metabolites
kidneys
——- compounds are more efficiently excreted than ——- ones.
polar
nonpolar
Measure of the body’s efficiency in eliminating drugs
Clearance (CL)
clearance (CL)
amount of renal plasma flow multiplied by the extraction ratio
extraction ratio
C2/C1
a function of clearance (mL/ min) times plasma drug concentration (mg/mL)
Excretion rate (mg/min)
Sum of the clearances from the various body organs that metabolize and eliminate drugs
total body clearance
CLtotal =
CL hepatic + CL renal + CL pulmonary + CL other
Clearance of a drug indicates…
the volume of biological fluid from which a drug would have to be completely removed to account for elimination
Measure of the apparent space the body has available to contain the drug
volume of distribution
volume of distribution (Vd) =
D/C
units: L
C = plasma conc; D = total drug in body
Takes —— half-lives to achieve steady state
5-7
A parameter that changes as a function of both clearance and volume of distribution
elimination half-life
elimination half-life =
0.693(Vd/CL)
conditions that alter half-life of drug
- Decreased renal blood flow
- Addition of a second drug that may displace the first drug from its carrier protein
- Decrease in metabolism because of hepatic insufficiency
Point when the total amount of drug in a human does not change over multiple loading dose intervals.
steady state
dosing rate (mg/min) =
CL(mL/min) x Css (mg/mL)
Css = the concentration at steady state
MEC
MTC
minimum effective conc.
minimim toxic conc.
between them –> therapeutic range
C maxss
minimum steady-state conc
Fraction of drug dose reaching the systemic circulation following administration by any route.
bioavailability
used to maintain the steady-state concentration of the drug associated within the therapeutic window
maintenance dose
Usually results in the attainment of target drug concentration in a shorter period of time
loading dose
Occurs more frequently in long-term treatments of diseases antihypertensive, antiretroviral, and anticonvulsant drugs
pt non-compliance
Fundamental action(s) of drugs
pharmacodynamics
The formation of a ——– leads to a biologic response or effect.
drug-receptor complex
The probability that a drug molecule will interact with its receptor to form the drug-receptor complex
drug affinity
The measurement of biological effectiveness of a drug-receptor complex
intrinsic affinity
Least amount of drug required to produce the maximum effect
potency
Measure of a drug’s ability to produce the desired therapeutic effect
efficacy
drug-induced complications
Drug allergies, blood dyscrasias, hepatotoxicity and nephrotoxicity, teratogenic effects, behavioral toxicity, drug dependence, and drug addictions
specimen of choice for the majority of therapeutic drugs measured in the clinical laboratory
serum
plasma is also OK
gel tubes are not preferred
WB can be used to measure…
Cyclosporine & Tacrolimus
Amikacin, Gentamicin, and Tobramycin
aminoglycosides antibiotics
Tissue concentrations are low, although high concentrations are found in the renal cortex and in the endolymph and perilymph of the inner ear
aminoglycosides
Broad spectrum against GN including most strains of Serratia, Proteus, and Pseudomonas aeruginosa
Amikacin
Active against nearly all strains of Klebsiella, Enterobacter, and Escherichia coli that are usually resistant to gentamicin and tobramycin
Amikacin
Often administered in combination with penicillin to treat serious gram-negative microbial infections
Gentamicin
Superior for treatment of P. aeruginosa
tobramycin
Shows poor activity in combination with penicillin against many strains of Enterococci
tobramycin
Most strains of Enterococcus faecium are highly resistant to…
tobramycin
Treatment of severe infections caused by gram-positive bacteria in patients who cannot receive or who have failed to respond to penicillin and cephalosporins
vancomycin
Minimally removed by hemodialysis or peritoneal dialysis, but substantially removed by hemofiltration
vancomycin
Ototoxicity and nephrotoxicity are the most serious adverse effects of parenteral ———– therapy.
vancomycin
Hyaline or granular casts in urine
vancomycin toxicity
combination of drugs often used to treat seizure
Phenobarbital and phenytoin
May be used to assist patients who are in the process of drug withdrawal from persistent use of barbiturate or non-barbiturate hypnotics
phenobarbital
Severe tiredness/dizziness
Inability to wake up
Very slow breathing rate
phenobarbital toxicity
Not recommended for the solo treatment of pure absence (petit mal) seizures because it may increase the frequency
phenytoin
5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH)
metabolite of phenytoin
valproic acid
antiepileptic
used for migraine headaches, with or without aura
Divalproex sodium
(valproic acid)
Effects of the drug may be related in part to increased brain concentrations of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA)
valproic acid
Drowsiness
Coma
Irregular/slow heartbeat
valproic acid toxicity
carbamazepine
antiepileptic
Used both as an anticonvulsant and for the relief of pain associated with trigeminal neuralgia (tic douloureux)
carbamazepine
other uses of carbamazepine
- Used in the symptomatic management of the acute phase of schizophrenia
- Used for management of aggression or uncontrolled rage outbursts or loss of control (dyscontrol)
- Used for alcohol withdrawal syndrome
- Used to relieve neurogenic pain
- Used for antidiuretic effects in the management of neurohypophyseal diabetes insipidus
Slowed breathing, loss of consciousness, muscle twitching, uncontrolled movements, and very fast heartbeat
carbamazepine toxicity
Generally considered the drug of choice in the management of absence seizures
ethosuximide
ethosuxamide
antiepileptic
primidone
antiepileptic
Structural analog of phenobarbital
primidone
Used mainly in the prophylactic management of partial seizures with complex symptomatology (psychomotor seizures)
primidone
Slowly excreted in urine as phenylethylmalonamide (PEMA), phenobarbital, and p-hydroxy phenobarbital
primidone
false positive phenobarbital result
pt also on primidone
topiramate
antiepileptic
Enhances postsynaptic gamma-aminobutyric acid (GABA-receptor) currents and also limits activation of the AMPA-kainite-subtypes(s) of glutamate receptor
topiramate
dizziness, headache, diplopia, nausea, somnolence, and skin rash
topiramate toxicity
Lamotrigine
antiepileptic
- Partial seizures in adults and children
- Primary generalized tonic-clonic seizures
- Myoclonic seizures of juvenile myoclonic epilepsy
Levetiracetam (Keppra)
Levetiracetam (Keppra)
antiepileptic
decreased hematocrit and RBC count, decreased neutrophil count, somnolence, asthenia, and dizziness
Levetiracetam (Keppra) toxicity
———– contains a sugar or monosaccharide moiety within its structure. This is not true of most anti-epileptic drugs.
Topiramate
methotrexate
antineoplastic
Antifolate, or folic acid analog, that inhibits dihydrofolate reductase
methotrexate
management of lymphoblastic leukemia in children
leukemic meningitis in children & adults
methotrexate
Intrathecal(spinal cord) administration is used for treatment or prophylaxis
methotrexate
Resistant if used alone for uterine choriocarcinoma and testicular choriocarcinomas
methotrexate
High affinity for dihydrofolate reductase and prevents the formation of tetrahydrofolate
methotrexate
main methotrexate toxicity
renal failure
Leucovorin
used to counteract methotrexate
Alopecia, dermatitis, interstitial pneumonitis, nephrotoxicity, defective oogenesis or spermatogenesis, and teratogenesis
methotrexate toxicity
lithium
antipsychotic
very narrow therapeutic window
lithium
important tube consideration for drug level
lithium – no lithium heparin tube
- Inhaled glucocorticoids
- ß-adrenergic receptor agonists
- Leukotriene-modifying drugs
used to tx asthma
Theophylline
bronchodilator
cardiac glycoside
digoxin
Indirect actions on the cardiovascular system through the influence on the autonomic nervous system
digoxin
Spironolactone (synthetic steroid- diuretic)
causes false positive digoxin
hyper/hypokalemia
digoxin toxicity
lidocaine
cardioactive drug
anesthetic
- For acute treatment of ventricular arrhythmias that occur following myocardial infarction
- During cardiac manipulative procedures such as cardiac surgery or cardiac catheterization
lidocaine
Class I (membrane-stabilizing) antiarrhythmic agent
lidocaine
procainamide
cardioactive drug
anesthetic
major metabolite is N-acetyl procainamide (NAPA)
procainamide
Major hepatic metabolism pathway is conjugation by N-acetyl transferase to form N-acetylprocainamide (NAPA)
procainamide
——- is 70% as effective as Procainamide but stays in the circulation longer
NAPA
quinidine
cardioactive drug
antimalarial
Alkaloid obtained from the bark of the cinchona tree
quinidine
quinidine contraindications
- Long QT syndrome
- glucose-6-phosphate dehydrogenase deficiency
- Myasthenia gravis
- Optic neuritis
- If you have taken quinine in the past and it caused a blood cell disorder or severe bleeding
As of April 2019, ———– is the new CDC recommended treatment for malaria
artesunate
Prevents arrhythmias, atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia
quinidine
- Calcineurin inhibitors
- Glucocorticoids
- Antiproliferative and antimetabolic compounds
immunosuppressants used after transplants
cyclosporine
immunosuppressive
It is lipophilic and strongly hydrophobic, it must be made soluble for clinical administration
cyclosporine
Trough whole blood levels are usually used to measure in lab (EDTA or Heparin)
cyclosporine
blood level alone should not be deciding factor for changes in treatment
cyclosporine
Used to prevent the rejection of liver and renal allografts
tacrolimus
tacrolimus
immunosuppressive
Macrolide of fungal origin
Shown to be 10-100 times more potent than cyclosporine
tacrolimus
In the T-cell cytoplasm, binds to a specific binding protein called immunophilin
tacrolimus
Used as prophylaxis and a therapy for steroid refractory acute and chronic graft-versus-host disease in hematopoietic stem cell transplant recipients
sirolimus
sirolimus
immunosuppressive
used for select dermatological disorders and management of uveoretinitis (inflammation of the uvea and retina of the eye)
sirolimus
Pulmonary toxicity, lower effectiveness of the immune system, decreased glucose tolerance, and insensitivity to insulin
sirolimus toxicity
