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Avert toxicity
Optimize dose/therapeutic response
Detect changes in pharmacokinetics
Monitor compliance
Therapeutic Index
Toxicity
Toxic
Therapeutic range
Sub-therapeutic
Therapeutic Index
High therapeutic index
NSAIDs
Aspirin
Tylenol
Ibuprofen
Sedative/hypnotics
Benzodiazepines
Most antibiotics
Beta-blockers
Some antibiotics
Gent/Vanco/Amikacin
Digoxin
Immunosuppressives
Introduction to Pharmacokinetics
What are pharmacokinetics?
The study of the absorption, distribution, and
elimination of drugs
Pharmacodynamics is the study of drug effects
Absorption
Ka
Kd
Blood
Ke
Elimination
K-d
Tissue
Drug absorption
Route
Oral
Intravenous
Intramuscular/subcutaneous
Dermal
Inhaled/intranasal
Slow/sustained release
minutes
hours
First-pass metabolism
Absorption
ka
kd
Blood
Tissue
k-d
ke
Elimination
Distribution () phase
Once drug is absorbed into the blood, it begins to
distribute to tissues
The amount of drug that partitions into tissues
depends on . . .
Lipophilicity
Protein binding
kd
Tissue
k-d
Low tissue
concentration
kd << k-d
Vd is low
If kd = 0, Vd = 0.07 L/Kg (lower limit)
Vd (L/Kg)
Amikacin
Gentamycin/Tobramycin
Phenytoin
Primidone
Theophylline
Valproic Acid
Ethanol
0.05 0.70
0.07-0.70
0.70
0.60
0.50
0.20
0.53
kd
Tissue
k-d
High tissue
concentration
kd >> k-d
Vd is high
For highly lipophilic drugs, Vd may be 100 L/Kg
Vd (L/Kg)
Digoxin
500 600
Carbamazepine
0.8 1.9
Lidocaine
130
Procainamide
2.4
Propranolol
Quinidine
200 300
3.0
Interpreting Vd
Drugs with low Vd are contained mostly in
the plasma, because . . .
They are highly water soluble (plasma water
content is higher than tissues), or
They are highly protein bound (which prevents
them from freely diffusing into tissues
Example of Vd calculation
5.0 mg
0.07 mg
70 g / L
1.0 L
L
70 Kg
Kg
Example of Vd calculation
15 g 0.5 L
55 Kg 412.5 g
L
Kg
Time
Absorption
ka
kd
Blood
ke
Elimination
k-d
Tissue
Elimination () phase
Hepatic function
Renal function
Urine pH
Genetic factors
Other drugs
Pharmacokinetics
Peak plasma concentration
t1/2
Time
dose
Trough
Time
TDM methods
HPLC
RIA
FPIA
EMIT
CEDIA
Chromatography
Separation of components based on their. . .
Solubility in mobile and stationary phases
Terminology:
Gas/liquid
Liquid/liquid
Ion exchange
Partition
Chromatographic separations
Mobile Phase
Stationary Phase
Chromatographic separations
Detector signal
Chromatographic separations
A
B
Time
HPLC Detectors
Detector
Sensitivity
Specificity
Cost
UV/Vis
Moderate
Low
Low
Fluorescence
Moderate
Moderate
Moderate
Refractive index
Low
Low
Low
Electrochemical
High
Moderate
Moderate
Moderate
High
High
Mass spectrometer
Radioimmunoassay
Fluorescence Polarization Immunoassay
Enzyme-Multiplied Immunoassay Technique
Cloned Enzyme Donor Immunoassay
Theophylline
Bronchodilator
Therapeutic range: 5 - 20 g/mL
Neonates metabolize theophylline to caffeine
Vd = 0.5 L/Kg
Toxic at > 20 g/mL
Nausea, vomiting, diarrhea, stomach pain, headache,
insomnia, tachycardia
Seizures, cardiac arrhythmia at > 35 g/mL
Gentamycin/Tobramycin
Wide-spectrum aminoglycoside antibiotics
Vd = 0.2 L/Kg
Therapeutic
4 - 10 g/mL (peak); 0.5 - 1.5 g/mL (trough)
Toxic: 12 - 15 g/mL
Ototoxicity
Nephrotoxicity
Digoxin
Improves cardiac output in CHF patients
Vd = 500 - 600 L/Kg
Highly bound to tissues
What does this say about small changes in plasma
digoxin concentration?
Procainamide
Antiarrhythmic
Active metabolite is NAPA
N-acetyltransferase
Fast vs. slow acetylators
Vd = 2.4 L/Kg
Therapeutic: 4 - 10 g/mL
Toxicity: Heart block, n/v, diaphoresis, malaise at
Procainamide + NAPA > 30 g/mL
Carbamazepine
Anticonvulsant, and for Rx of TGN
Active in tonic-clonic (grand mal) sz
Phenobarbital
Anticonvulsant (metabolite of Primidone)
Long-acting barbiturate (t1/2 = 2 - 4 days)
Vd = 1.0 L/Kg
Therapeutic range: 15 - 40 g/mL
Toxic symptoms at > 60 g/mL
Drug interactions (induction of hepatic
microsomal enzymes)
Phenytoin
Nystagmus
Blurred vision
Ataxia
Drowsiness/Coma
Valproic acid
Broad spectrum anticonvulsant, but mostly
used for absence (petit mal) seizures
Vd = 0.2 L/Kg
Therapeutic range: 50 - 100 g/mL (trough)
Hepatotoxic