Pharmacokinetics: clinical Flashcards
What determines plasma concentration of drug and target site concentration
Dynamic interactions among drug ADME
Fundamental tenet of clinical pharmacokinetics is a
relationship exists between a drugs pharmacological effects and concentration of drug in blood or plasma
Four key parameters govern drug disposition (PK) and dosage regimens
-Bioavailability (%F)……..previously discussed
-Volume of distribution (Vd)…….previously discussed
-Clearance………previously discussed
-Elimination half-life (t1/2 )
Eliminatory drug processes are usually __________ processes
First-order; a constant fraction of the drug in the blood (body) is eliminated per unit time
How many half-lives is drug considered essentially eliminated from blood
4-5 half-lives
Elimination half-life
Time required for blood drug concentrations to decrease by 50%
True of false: Half-life depends on dose or blood drug concentration
False: does NOT depend on dose or blood drug concentration
MEC
minimum effective concentration
What happens if duration is prolonged above MEC for desired effect by increasing dose
May produce peak concentration that yields adverse effects
Prolonged eddicacy is usually achieved by
administering multiple small doses of drug maintaining drug concentration above MEC for desired effects
Do drugs with short half-lives accumulate
Do not unless administered frequently
Drug given after every half life: when is steady state reached
Drug accumulation is greater when drug given every half life; plateau or steady state is reached
after ~5 half lives ie. drug input equals drug eliminated
Elimination half-life provides clinicians with information regarding
frequency of drug administration needed to maintain blood drug levels in the therapeutic range
Elimination half-life equation
t1/2 = (0.693 x Vd)/CL
The goal of most dosing regimens is to
Maintain plasma drug
level in the therapeutic range for the duration of therapy
Dosing regimens consist of the following:
- Dose (amount of drug given in mg)
- Route of administration
- Frequency of administration eg q12 hrs
- Duration of therapy eg. 3 days
Loading doses can be used to
Achieve target therapeutic drug levels quickly
Dose loading equation
DoseLoading = Vd x Csteady state / %F
Maintenance doses are given to
maintain drug levels in the target therapeutic range
Maintenance dose equation
Dosemain = CL x Csteady state / %F
Factors (physiologic, disease and drug factors) will have effects predominately on elimination t1/2 through changes in……..
-Volume of distribution
-Clearance
Alteration to PKs can result clinically in adverse drug effects
-achieving too high drug levels in the blood and toxicity
-failure to achieve adequate drug levels in the blood and subtherapeutic failure
What factors decrease volume of distribution (either increase or decrease) and how this affects half-life
Aging: decrease distribution (decrease muscle mass) –> decrease half-life
Obesity: Increase distribution (increase adipose mass) –> increase half-life
Pathologic fluid: increase distribution –> increase half-life
What factors affect clearance and how does this affect half-life
Cytochrome P450 induction (increase metabolism) –> decrease half-life
Cytochrome P450 inhibition (decrease metabolism) –> increase half-life
Cardiac failure (decrease clearance) –> increase half-life
Hepatic failure (decreased clearance) –> increase half-life
Renal failure (decreased clearance) –> increase half-life
Drug interaction
change in the magnitude or duration of a pharmacologic effect of a drug due to the presence of another drug, food or environment factor
Incidence of drug interactions…
-Increases with number of drugs given ie polypharmacy
-Increases with duration of use
Pharmaceutical interactions occur
Before the drug is absorbed by the patient
-Usually when combined in same syringe or IV fluids
-Can also occur in the GI tract lumen
-Affects total dose available for absorption if given orally, or for injection if given by the IV route
Result of alterations in physicochemical properties of the affected drug
-Drug-drug interactions most common….aka drug incompatabilities
-Less commonly drug-environment or drug-diet interactions
Most drug interactions of clinical significance are due to changes in
Drug pharmacokinetics
Absorption interacions
- stomach pH
- GI motility
- P-glycoprotein (MDR-efflux pump), and GI CYP450’s
Distribution interactions
- Plasma protein binding or tissue protein binding displacement
- Changes in tissue blood flow
Metabolism interactions
- Metabolizing enzymes (CYP450); phase I MFOs; inhibition and induction
Excretion interactions
- Urine pH
- Tubular secretion
- Renal blood flow
Induction or inhibition is usually not planned resulting in
an adverse drug effect
Occasionally inhibition can be planned resulting in
desired therapeutic effect
Induction of P450 enzymes produces ________ primarily through _______
increase in the expression of the enzyme, primarily thru increased gene transcription (mRNA)
Consequences of induction include
Increased metabolism of the inducing drug
How long does induction take to be realized clinically
Usually days or weeks
The clinical significance of induction
is a reduced elimination half life and decreased blood drug levels necessitating increased dosage adjustments to accommodate the induction effect
Clinical significance of inhibition relative to induction
Opposite; necessitating
decreasing dosage to accommodate the inhibition effect
Onset of inhibition effects on other co-administered drugs PKs is
Must faster than occurs with induction
