Clinical Pharmacokinetics | Mind Map

Overview

With most drugs a relationship exists between a pharmacologic or toxic effect of a drug and the concentration of drug in the blood.

In most cases the concentration of the drug in the blood will be related to its concentration at the site of action.

Pharmacokinetics provide quantitative relationship between the dose of the drug and its effectiveness with the aid of measurements of drug concentrations in various biologic fluids.

The main aim of plasma pharmacokinetics in patient care is to

Obtain the right Effect,

At the right Time,

For the right Duration

With minimal risk of toxicity.

This can be achieved by optimizing and adjusting dosage regimens.

Therapeutic Drug Monitoring (TDM)

What is TMD

TDM-It means the follow up of the drug concentration in the blood during drug therapy.

How to achive it

Optimum treatment with many drugs depends on achieving a plasma concentration that lies between two specific limits

A minimum effective concentration

A maximum safe concentration.

When TDM is Useful

(TDM) has proved useful in the following conditions

Drugs with low therapeutic index where the therapeutic dose is close to the toxic dose

e.g., Cardiac glycosides, antidysrhythmic drugs, antiepileptic drugs, lithium, aminoglycoside antibiotics, anticancer drugs, immunosupressants

Failure of therapeutic response at a dose that is expected to be effective as in patient non-compliance and incomplete drug absorption

In case of multiple drug therapy with the possible occurrence of drug interactions

In presence of organ disease as hepatic or renal disease that adversely affect the pharmacokinetic processes

To diagnose drug toxicity

When TDM is not Useful?

For some drugs whose dose can be correlated with an easily measured effect as with

e.g antihypertensives (blood pressure measurements), oral anticoagulants (prothrombin time) and hypoglycemics (blood sugar), plasma drug concentration is not worth measuring.

For other drugs that act irreversibly as MAO inhibitors, some anticholinesterases and cytotoxic drugs, their effect persists after the drug has left the plasmaand in such cases plasma concentration may have no correlation with effect.

"hit and run drugs"

For drugs that have more than one action depending on the dose used

e.g., nortriptyline in small dose inhibits the amine pump and in large dose produces alpha adrenergic blockade

Volume of distribution (Vd)

What is Vd

It is the apparent volume that would be required to contain all of the drug in the body at the same concentration as in plasma assuming the body acts as a single homogenous compartment for the drug

The volume of distribution is determined by

a-Extent of ionization.

b-Degree of lipid solubility.

c-Degree of binding to plasma proteins.

d-Degree of binding to tissue proteins

Utility of Vd Estimates

To calculate the loading dose

The dose required to quickly reach a specific plasma drug concentration level with a single IV administration

Unit: mg

EX: 20 mg IV of Atropine

In case of some drugs e.g., digoxin it is necessary to achieve therapeutic levels within hours instead of days to get a rapid response and so we have to give a loading dose (LD)

LD = Vd x Css ........................... (1) LD = loading dose Vd = volume of distribution Css = plasma steady state concentrations where the rate of administration equals the rate of elimination.

To estimate plasma clearance (CL)

CL = Vd x Kel .............................. where Kel = elimination rate constant = 0.693/t1/ So equation (2) can be rewritten CL = Vd x 0.693/t1/2 ..........................

To predict the maintenance Dosing rate

The dose required for regular administration to maintain a target plasma level

Unit: mg/time

EX: 250 mg/8hrs of Ampicillin

which occur with repetitive dosing from the kinetic behavior of a single dose

Css = F.D / Vd. Kel . t .............................. Css = steady state concentration F = bioavailability D = dose Kel = elimination rate constant = 0.693/t1/2 t= dose interval From equations (2) and (4) we can substitute Vd Kel by CL and equation (4) can be written as follows Css = F.D / CL .t ..................................

Clinical Relevance of Vd

When a drug is extensively distributed outside blood i.e. high Vd it is not easily removed from the body by hemodialysis

e.g., 95% of Digoxin

When a drug is extensively distributed outside blood i.e. high Vd , it provides a reservoir from which the blood is continuously replenished between doses and so fluctuations in blood concentrations are minimal.

Pharmacokinetic Variables

The four pharmacokinetic parameters that are of importance are

Bioavailability,

Bioavailability is the fraction of the dose given (F) that reaches the systemic circulation; it has a value between 0 and 1.

Low oral bioavailability denotes

Poor absorption

Enhanced first pass metabolism

It refers to the metabolism of a drug that occurs in any part from the gut lumen to the systemic circulation

Clearance

Overview

Clearance of most drugs is usually constant over the range of concentrations encountered clinically.

This means that elimination is not saturated and the rate of elimination of a drug is directly proportional to its concentration in plasma.

Elimination of most drugs follows First order kinetics where a constant fraction of the drug is eliminated per unit time.

If mechanisms of elimination of a given drug become saturated, the kinetics become Zero order where a constant amount of drug is eliminated per unit time.

Under such a circumstance, clearance becomes variable

First order, zero order and non-linear elimination kinetics

First order elimination kinetics: a constant fraction (proportion, percentage) of drug is eliminated per unit time

Elimination of most drugs follows first order kinetics where a constant fraction (proportion, percentage) of the drug is eliminated per unit time (concentration dependent)

First order kinetics is a concentration-dependent process (i.e. the higher the concentration, the faster the clearance)

Gentamicin as a model of first-order elimination kinetics

Zero order elimination kinetics: a constant amount (certain milligrams) of drug is eliminated per unit time.

Ethyl alcohol as a model of zero-order elimination kinetics

zero order elimination rate is independent of concentration but saturated enzyme can be seen

Non-linear elimination kinetics

Phenytoin as a model of nonlinear elimination kinetics

A drug at low concentration is cleared by first-order kinetics

and at high concentrations by zero order kinetics

Volume of distribution

Half life

It is the time required for the plasma concentration to fall to one half its original value.

As a rule, steady state condition when drug is administered at regular intervals is where the Rate of administration equals to the rate of elimination.

This is attained in 5 half-lives.

Once the drug is stopped elimination is usually complete after 5 half- lives.

It can be determined graphically from the plot of log concentration versus time.

The half - life of a drug has an important role in the selection of dosage interval for maintenance therapy

Two situations illustrate this

1- If the dosage interval is much longer than t1/2, the drug is effectively eliminated before the next dose and each dose represents a new single dose.

2- If the dosage interval is much shorter than t1/2, a true steady state is achieved with very minimal fluctuations in plasma levels. These are determined largely by clearance