HALF LIFE

Pharmacokinetics

Half-Life and k
Half-life is the time taken for the drug concentration to fall to half its original value The elimination rate constant (k) is the fraction of drug in the body which is removed per unit time.

Drug Half-Life

Half-Life
C = Co e - kt C/Co = 0.50 for half of the original amount 0.50 = e k t

ln 0.50 = -k t -0.693 = -k t
t 1/2 = 0.693 / k

Drug Elimination

C KC t dC KC dt Kt C t C 0e

Use of t and kel data

If drug has short duration of action, design drug with larger t and smaller kel If drug too toxic, design drug with smaller t and larger kel

Drug Concentration
C1

Exponential decay
C2

dC/dt C = -k.C

Time

Log Concn.
C0
C0/2 t1/2 t1/2 t1/2

Time
Time to eliminate ~ 4 t1/2

Integrating:

Cp2 = Cp1

-kt .e

Logarithmic transform:
lnC2= lnC1 - kt

logC2 = logC1 - kt/2.303

Elimination Half-Life:
t1/2 = ln2/k

t1/2 = 0.693/k

Steady-State
Steady-state occurs after a drug has been given for approximately five elimination half-lives. At steady-state the rate of drug administration equals the rate of elimination and plasma concentration - time curves found after each dose should be approximately superimposable.

Accumulation to Steady State 100 mg given every half-life

175 150 100 87.5 94 97 100 187.5

194

200

75
50

C
Cpav

t
Four half lives to reach steady state

What is Steady State (SS) ? Why is it important ?

Rate in = Rate Out
Reached in 4 5 half-lives (linear kinetics) Important when interpreting drug concentrations in time-dependent manner or assessing clinical response

Drug Effectiveness
Dose-response (DR) curve: Depicts the relation between drug dose and magnitude of drug effect Drugs can have more than one effect Drugs vary in effectiveness
Different sites of action Different affinities for receptors

The effectiveness of a drug is considered relative to its safety (therapeutic index)

Therapeutic Index
Therapeutic index = toxic dose/effective dose
This is a measure of a drugs safety
A large number = a wide margin of safety A small number = a small margin of safety

Acute vs Steady State

Liver P450 systems

Liver enzymes inactivate some drug molecules
First pass effect (induces enzyme activity)

P450 activity is genetically determined:

Some persons lack such activity leads to higher drug plasma levels (adverse actions) Some persons have high levels leads to lower plasma levels (and reduced drug action)

Other drugs can interact with the P450 systems

Either induce activity (apparent tolerance) Inactivate an enzyme system

Drug Metabolism and pK

How are [drug] measured?

Invasive: blood, spinal fluid, biopsy Noninvasive: urine, feces, breath, saliva
Most analytical methods designed for plasma analysis C-14, H-3

Therapeutic Window
Useful range of concentration over which a drug is therapeutically beneficial. Therapeutic window may vary from patient to patient Drugs with narrow therapeutic windows require smaller and more frequent doses or a different method of administration Drugs with slow elimination rates may rapidly accumulate to toxic levels.can choose to give one large initial dose, following only with small doses

Shape different for IV injection