Principles of Pharmacokinetics and Autonomic Pharmacology- 7&8 Flashcards
Pharmacokinetics
the study of how an organism handles a drug (ADME). Entails use of the mathematical models to predict the time course for drug actions and the duration of drug retention in the body. Provides a framework to understand different drug treatment regimens.
Clinical pharmacokinetics
based on the fundamental concept that “… a relationship exists between the pharmacological effects of a drug and the concentration of drug in some accessible compartment (blood).”
In most cases, the plasma concentration-time relationship is out of phase with the effect (response)-time relationship.
Target outcome of pharmacokinetics
the ultimate goal is the identify a dosing regimen that is safe, effective, and devoid of unintended consequences such as violative residues (food animals) or contributes to drug resistance (antibiotics).
Pharmacokinetic models
Several features: complex enough to yield useful info, simple enough to understand and calculate.
Drawbacks: requires assumptions, limits the accuracy of info that is generated.
Key PK properties
bioavailability (F), volume of distribution (Vd), clearance (Q), elimination half-life (T1/2).
Volume of distribution (Vd)
an apparent volume with actual anatomical correlate. Vd can be bigger than the animal’s body.
Practical aspects: the volume within the body that would be necessary in order to account for the initial concentration of drug in plasma following a given dose of drug. Units of volume or volume per unit body weight. Provides no real clue about where the drug goes.
Plasma Drug Concentration
= drug dose (mg)/ volume of distribution
Concentration (C)
=Dose/Volume of distribution
Volume of distribution (Vd) calculation
= total body drug dose/plasma concentration
Interpreting Vd
low Vd means limited distribution. IV will remain in the bloodstream. High Vd means it is widely distributed.
K1= rate of drug movement from blood to tissue.
K-1= rate of drug movement from tissue to blood.
When K1>k-1 than Vd is very large.
What can change Vd?
Body fat index- With a small Vd obesity leads to OD. With a large Vd obesity leads to reduced plasma concentration.
Disorders that lead to poor tissue perfusion (CHF)- edema accumulation.
Reduction in plasma proteins (liver disease)- increase Vd for drugs that bind strongly to plasma proteins (NSAIDS).
Zero Order Kinetics
drug is eliminated at a constant rate. Fixed amount of drug is eliminiated per unit time. Rate of drug elimination is unrelated to the drug concentration. Potentially dangerous.
NOT REALISTIC. DON’T USE THIS MODEL
First order kinetics
Drugs is eliminated at an exponential rate. Fixed fraction of drug is eliminated per unit time. Rate of drug elimination is proportional to the drug concentration. Much safer since elimination is appropriate for the total body burden of drug. Can convert to zero-order kinetics if the elimination process becomes saturated.
Linear plot- first order kinetics
drug concentration decreases exponentially over time. Rate of disease (slope) is proportional to concentration at that point in time.
Semi-log plot- first order kinetics
used most often for reporting date. Serves to linearize the concentration vs time relationship. Slope of the line equals the rate of drug elimination.
Half-life (T1/2)
time required to eliminate one half of the drug present in plasma. Has simple units of time (mine, hr, day), is a constant for drugs that obey first order kinetics.
Inversely proportional to the elimination rate constant (Ke). Ke= 0.693/T1/2
Single dose regimens
dose, volume of distribution and peak (initial) plasma drug concentration and interrelated. By knowing two you can know the third. Dose must account for drug bioavailability. Vd= dose/Cpo.
For first-order elimination, plasma drug half-life is a constant. Can be sued to perdict how long it will take drug to fall to a certain level. Predicts drug level in blood, but NOT necessarily for it in the tissues.
Reasons for prolonged drug treatment
drug therapy controls symptoms, but does not cure the underlying disease- NSAID therapy, antiepileptic therapy. The drug cures the disease, but therapeutic success requires prolonged exposure to drug- antibiotic therapy, antifungal therapy.
Multi-dose treatment regimens.
goal is to achieve and maintain an effective drug level without causing harm to the animal. Drug dose regimens are determined by drug companies or researchers for each target species. The time required to achieve steady-state drug concentrations in plasma depends solely on the half-life of the drug.
It requires approximately five half lives of sustained drug administration in order to achieve stead state.
Steady-state
plasma drug concentrations do not mean that drug concentration is unchanging… it still fluctuates, but in a consistent way.
Takes roughly 5 drug half-lives to achieve study state.
Peak (Cpmax)ss and through (Cpmin)ss drug concentrations are determined by the drug dose as well as the dosing freuency
Cpmax^ss
peak steady state. Is calculated in a manner similar to estimating Cpmax from a single dose.
Cpmaxss= (dose x F x R)/ Vd.
R= accumulation factor.
Peak to Trough
the ratio of peak to trough concentrations is also a function of dose interval relative to half life. When dose interval equals T1/2, Cpmin is one half of Cpmax. At an interval of twice T1/2, Cpmin is 1/4th of Cpmax.
Factors that alter steady state
slow absorption reduces both peak and through drug levels relative to IV administration- PO administration is usually slowest- meals, slow release formulations.
Irregular doses- lolz that every 8 hours happens.
Renal Insufficiency
if you have to use a drug cleared by the kidney, it is usually necessary to alter the dosing regimen.
Two approaches: interval extension or dose reduction.
Common methods for altering dosing regimens
Individualized regimen- based on actual drug levels in the patient (TDM-expensive).
Creatinine clearance- compared to normal urinary levels.
