Kinetics Flashcards
ALTERATIONS IN ADME
*MAIN CAUSES INCLUDE
(4)
*AGE
*GENETIC FACTORS
*END-ORGAN DAMAGE
*DRUG INTERACTIONS
TYPES OF VARIABILITY
(3)
- PHARMACOKINETIC
- PHARMACODYNAMIC
- IDIOSYNCRATIC
IDIOSYNCRATIC
(3)
- OCCUR IN A SMALL MINORITY OF PATIENTS
- SOMETIMES WITH LOW OR NORMAL DOSES
- POORLY UNDERSTOOD
PHARMACODYNAMIC INTERACTION
*INTERACTION BETWEEN 2 OR
MORE DRUGS THAT LEADS TO
(2)
- ACCENTUATION/SYNERGISM
- ATTENUATION/ANTAGONISM
DON’T DIRECTLY INVOLVE
ABSORPTION, DISTRIBUTION,
METABOLISM, OR EXCRETION
PHARMACOKINETIC INTERACTION
* INTERACTION THAT CHANGES THE BASIC
KINETIC PROPERTIES
* ABSORPTION
* DISTRIBUTION
* METABOLISM
* ELIMINATION
- EXAMPLE: WARFARIN + SULFAMETHOXAZOLE
SKIPPED
RED FLAG DRUGS
∙Warfarin
∙Digoxin
∙TCAs (amitriptyline, doxepin, nortriptyline, desipramine)
∙Phenytoin
∙Carbamazepine
∙Lithium
∙Methotrexate / cyclosporine / tacrolimus
∙HIV medications – protease inhibitors (indinavir, nelfinavir,
ritonavir, saquinavir)
∙Rifampin
SKIPPED
CAUTION
(8)
Aminoglycosides
Fluoroquinolones
Tetracyclines
Macrolides
Magnesium
Beta blockers
Procainamide
Neuromuscular blockers*
THE UP SIDE – DENTAL DRUGS
(3)
Primarily single-dose or short term Tx
Large margin of safety
Extensive history of use
*PHARMACOKINETICS
*WHAT THE BODY DOES TO THE
DRUG
*PHARMACODYNAMICS
*WHAT THE DRUG DOES TO THE
BODY
HOW WE USE KINETICS
* IMPORTANT IN
DRUG DEVELOPMENT AND CLINICAL
TESTING, NEEDED TO DETERMINE OPTIMAL DOSE
KINETICS
IMPORTANT IN THE CLINICAL SETTING
(5)
- TOXICOLOGY
- THERAPEUTIC MONITORING (CLINICAL EFFECT, LABS)
- DRUG INTERACTIONS
- DOSE ADJUSTMENTS
- EFFECT OF ILLNESS, ORGAN DYSFUNCTION
KINETICS
* TIME COURSE OF DRUG CONCENTRATION
DEPENDS ON
ADME
KINETICS FOCUSES ON CONCENTRATIONS
OF DRUG IN PLASMA
* CAN USE KINETICS TO CALCULATE
PRECISE
DOSES TO ACHIEVE A PRECISE
CONCENTRATION
PLASMA CONCENTRATION = CP
* GOAL IS TO GET CP WITHIN A
THERAPEUTIC
WINDOW IN ORDER TO ELICIT APPROPRIATE
RESPONSE WITHOUT CAUSING TOXICITY
MTC VS MEC
- MINIMUM TOXIC CONCENTRATION
- MINIMUM EFFECTIVE CONCENTRATION
- CLEARANCE – DETERMINES THE
MAINTENANCE DOSE-RATE
- VOLUME OF DISTRIBUTION (VD) – DETERMINES THE
LOADING DOSE
- HALF-LIFE – DETERMINES THE TIME TO
STEADY STATE AND DOSING INTERVAL
KINETICS
* PARAMETERS FOR A DRUG ARE
DETERMINED BY USING
IV INJECTION OR
INFUSION SINCE IV = 100%
BIOAVAILABILITY
* CL, VD, AND T½ ARE THEN DERIVED FROM
A TIME/CONCENTRATION CURVE
CLEARANCE
(2)
CLEARANCE
* VOLUME OF PLASMA CLEARED OF DRUG PER
UNIT TIME
* INDEX OF HOW WELL A DRUG IS REMOVED
IRREVERSIBLY FROM THE CIRCULATION
INDEX OF HOW WELL A DRUG IS REMOVED
IRREVERSIBLY FROM THE CIRCULATION
* DETERMINES THE DOSE-RATE (DOSE/UNIT TIME)
REQUIRED TO
MAINTAIN A CP
- CREATININE CLEARANCE =
WAY TO
CORRELATE
140 – AGE / SCR
ZERO ORDER KINETICS
* RATE OF ABSORPTION
/ELIMINATION DOESN’T
DEPEND ON THE
DRUG
CONCENTRATION
RATE LIMITED PROCESS
- FIXED NUMBER OF
ENZYMES, CARRIER, OR
ACTIVE TRANSPORT
PROTEINS; SATURATION
OCCURS
HALF LIFE (T ½ )
— OVER TIME
DECREASES
ZERO ORDER KINETICS
ex (6)
- PHENYTOIN
- WARFARIN
- HEPARIN
- ETHANOL
- ASPIRIN (HIGH DOSE)
- THEOPHYLLINE
FIRST ORDER KINETICS
* THE DECLINE IN CP IS NOT CONSTANT WITH
TIME, BUT VARIES WITH —
* THE HALF LIFE (T ½ )
* CONCENTRATION DECREASES BY —% PER
EACH T ½
* MAJORITY OF DRUGS FOLLOW
CONCENTRATION
STAYS THE SAME
50
FIRST ORDER
ELIMINATION
- RATE OF ABSORPTION OR ELIMINATION
CAN BE EXPRESSED - T ½ - TIME REQUIRED FOR —% ABSORPTION
OR ELIMINATION - RATE CONSTANT (KE) –
50
FRACTION ELIMINATED
PER UNIT TIME
CLEARANCE
* INDEX OF HOW WELL A DRUG IS REMOVED
IRREVERSIBLY FROM THE CIRCULATION
* DETERMINES THE
DOSE-RATE REQUIRED
TO MAINTAIN A Cp
TO MAINTAIN STEADY STATE (CPSS), ,
ADMINISTRATION RATE MUST EQUAL
RATE
OF ELIMINATION
CL = KE X VD
STEADY STATE / PLATEAU
EFFECT
- WHEN REPEATED DOSES OF A DRUG ARE GIVEN IN
SHORT ENOUGH INTERVALS AND ELIMINATION IS 1ST
ORDER, THE CP WILL EVENTUALLY REACH STEADY
STATE
DURING IV INFUSION, DRUG LEVEL INCREASES
EXPONENTIALLY IN A WAY EQUIVALENT TO THE
DRUG’S T1/2E
* 1 HALF LIFE = –% OF FINAL CONCENTRATION
* 2 HALF LIVES = –% OF FINAL CONCENTRATION
* 3 HALF LIVES = –% OF FINAL CONCENTRATION, ETC.
50
75
87.5
VOLUME OF DISTRIBUTION (VD)
- VOLUME INTO WHICH A DRUG APPEARS
TO BE DISTRIBUTED WITH A
CONCENTRATION EQUAL TO THAT OF
PLASMA - TELLS YOU WHERE THE DRUG DISTRIBUTES
TO REACH A TARGET CP, YOU HAVE TO
“FILL UP THE TANK”, I.E., V
IMPORTANT EQUATION: VD
VD = F X DOSE / CP0
VD = F X DOSE / CP0
* REMEMBER: BIOAVAILABILITY (F) FOR IV
DRUGS EQUALS
* NOTE: VD CAN FAR EXCEED THE
* DRUGS WITH SMALL VD TEND TO BE
1 (100%)
ACTUAL
BODY VOLUME, E.G., DIGOXIN VD = 500L
POLAR AND WATER SOLUBLE
HALF LIFE (T1/2)
- TIME FOR THE DRUG CONCENTRATION TO
HALVE
HALF LIFE (T1/2)
PROVIDES AN INDEX OF
(3)
- TIME COURSE OF DRUG ELIMINATION
- TIME COURSE OF DRUG ACCUMULATION
- CHOICE OF DRUG INTERVAL
TAKES APPROXIMATELY — HALF-LIVES FOR
A DRUG TO EITHER REACH STEADY STATE
(CPSS) OR BE ELIMINATED FROM THE BODY
5
STEADY STATE KINETICS
- POINT AT WHICH THE AMOUNT ABSORBED EQUALS
AMOUNT ELIMINATED PER UNIT TIME
CSS = KA / (VD X KE)
WHERE: CSS = STEADY STATE CONCENTRATION
KA = ABSORPTION RATE CONSTANT
VD = VOLUME OF DISTRIBUTION
KE = ELIMINATION RATE CONSTANT
NOTE: KA = VD X KE X CSS
FOR CONTINUOUS INFUSION, KA =
DOSE/TIME, E.G.,
MG/HOUR
