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

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

• ln 0.50 = -k t ½ • -0.693 = -k t ½
• t 1/2 = 0.693 / k

Drug Elimination

C  KC t dC  KC dt  Kt C t  C 0e

Use of t ½ and kel data
• If drug has short duration of action, design drug with larger t ½ and smaller kel • If drug too toxic, design drug with smaller t ½ and larger kel

Drug Concentration

Exponential decay

dC/dt  C = -k.C


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

Time to eliminate ~ 4 t1/2


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 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 …




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 drug’s 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

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