JUSTICE HAS BEEN SERVED

JUSTICE HAS BEEN SERVED 

KINETICS OF ELIMINATION

Granny: No printer, just fax!

We should be more pro-active or we’ll see more of such sad fates of honest people.

Pharmacokinetics Overview

(Absorption and distribution of drugs)

The study of the time course of drugs and their metabolites in the body (what the body does to the drug) consisting of:

administration

absorption

distribution

metabolism

excretion

Administration

Enteral (passes through intestine)

oral (mouth)

buccal/sublingual (applied in cheek/under tongue)

Gastrosomy (surgical opening through the abdomen into the stomach)

Topical (applied directly)

Nasal

Rectal

Ophthalmic (eyes)

Parentral (injection)

Intravenous (into veins)

intramuscular (into muscles)

intradermal (within layers of skin)

subcutaneous (under the skin)

Drug molecules move around the body either through bulk flow (bloodstream, lymphatics or cerebrospinal fluid) or diffusion (molecule by molecule over short distances)

Absorption 

Passage of drug from its site of administration into plasma - important for all routes except intravenous injection.

Injection

IV = fastest route of administration

bolus injection = very high concentration of drug

rate limiting factors = diffusion through tissues and removal by local blood flow

Drugs need to pass through membranes (cell membranes, epithelial barriers, vascular endothelium, blood-brain barrier, placenta barrier etc) via

passive diffusion through lipids

carrier-mediated

passage through membrane pores/ion channels

pinocytosis (ingestion into a cell by the budding of small vesicles from the cell membrane)

Diffusion through lipid

non-polar molecules can dissolve freely in membrane lipids

the rate is determined by the permeability coefficient (P)(solubility in the membrane and diffusibility) and the concentration difference across the membrane

pH and Ionisation

Many drugs are weak acids or weak bases

exist in unionised or ionised forms

pH = balance between the two forms

ionised forms have low lipid solubility

uncharged however the drug is usually lipid soluble

ionisation affects:

rate of drug permeation through membranes

steady state distribution of drug molecules between aqueous compartments if pH difference exists between them

Therefore:

urinary acidification accelerates the excretion of weak bases and slows that of weak acids

alkalisation has opposite effect

increasing plasma pH causes weak acids to be extracted from CNS into plasma

Reducing plasma pH causes weakly acidic drugs to become concentrated in CNS, increasing neurotoxicity

Bioavailibility

Bioavailibility (F) indicates the fraction of an orally administered dose that reaches systemic circulation intact, taking into account both absorption and local metabolic degradation

determined by comparison between oral and IV absorption

affected by:

drug preparation

variation in enzyme activity of gut

gastric pH

intestinal motility

Volume of Distribution

Vd is defined as the volume of fluid required to contain the total amount, Q, of drug in the body at the same concentration as that present in the plasma, Cp

determined by relative strength of binding between drug and tissue compared with drug and plasma proteins

tight binding to tissue but not plasma –> drug appears to be dissolved in large volume –> large Vd (eg chloropromazine)

tight binding to plasma –> V can be very close to blood volume –> low Vd (eg warfarin)

PHARMACOKINETICS CALCULATIONS

Single-Dose: •Vd = Dose/Co •t1/2 = 0.7 x Vd/Cl

Multiple-Dose, Infusions: •Ko = Cl x Css •LD = Vd x Cp/f •MD = Cl x Css x dosing interval/f

Vd: volume of distribution Co: plasma [ ] at zero time Cp: plasma [ ] t1/2: half life Cl: clearance = free fraction x GFR Ko: infusion rate Css: steady state [ ] LD: loading dose MD: maintaining dose f: bioavailability