Vol. of Distribution, Half Life (Dr. Imran Ashraf)

VOLUME OF DISTRIBUTION (Vd)
&
HALF LIFE (t1/2)
Dr. M IMRAN ASHRAF

Associate Professor
MBBS. M.Phil. PhD(S).
DRUG DISTRIBUTION
• Distribution is defined as
the reversible transfer of
drugs between body fluid
compartments
Total body fluid (42 liters) in a 70 Kg adult
28 L 14 L
10 L 4L
Plasma compartment
PLASMA
VOLUME
4L
Which type of drugs will remain
in the plasma compartment?
Plasma compartment
Very high molecular weight drugs, or

drugs that bind to plasma proteins
excessively
Example: heparin 4L (3-5)
Which type of drugs will be distributed to extracellular
compartment?
• Drugs with low lipid solubility &

Low molecular weight
• These drugs cannot easily enter the cells because of

their low lipid solubility, and they do not traverse
the blood-brain and placental barrier freely
Extracellular fluid
Drugs that have a low molecular weight

but are hydrophilic (water soluble molecules ) ---
Atracuronium 11 L (8-15)
Gentamicin, Aminoglycoside
INTRACELULLAR FLUID
Lipophilic small
molecule
Diffusion to
intracelullar fluid
Ethanol 38 L (34-41)
Apparent Volume of distribution
(Vd)
It is the hypothetical volume
of body fluid into which a drug is
uniformly distributed
Vd =
amount of drug in the body
plasma concentration
Vd is expressed as in units of volume

Is it is possible to have
Vd higher than total
body water?
Vd higher than total body water
Drug that binds strongly to tissues.
Vd higher than total body water.

Fentanyl: 280 L
Propofol: 560 L
Digoxin : 385 L
Drugs with Vd greater than total body volume
• Morphine, TCA, Haloperidol
• Will dialysis remove these drugs

in case of overdose?
• No.
– Such drugs are not efficiently removed from the
body by haemodialysis, which is therefore
unhelpful in managing overdose with such drugs
Features of Vd
• The higher the Vd,

the lower the plasma
concentration and
vice versa.
High Vd
• A very high Vd value may indicate that

the drug is extensively bound to the
tissue sites
• An exceptional large Vd indicate
considerable sequestration of the drug
in some organ or the compartment
Low Vd
Very high molecular weight drugs, or

drugs that bind to plasma proteins
excessively
Example: heparin 4L (3-5)
Effects of Vd on other parameters
• Loading dose of a drug

• Half life of a drug ---- t1/2
& Duration of action
• Drug interaction
Large Vd & loading dose of a drug
• Drugs with large Vd need a

loading dose to achieve the
desired plasma concentration
• Additional dose needed = Vd (C2 – C1)
• LD = Vd x TC
Effect of a large Vd on t1/2 life of a drug
• A very large Vd indicate that most

of the drug is in the extraplasmic
space and is unavailable to
excretory organs. --- the longer
is half life and the duration of
action of the drug
Drug displacement, Vd & drug interaction
• A very low Vd value indicate extensive plasma

protein binding of the drug.
• Displacement of drug from albumin --- ↑in the
“free” drug
• If the therapeutic index of the drug is small. An ↑ in
free drug concentration may lead to
– ↑ therapeutic effects
– ↑ toxic effects
• Tolubutamide (95% bound) displaced by a
sulphonamide
The Vd may be influenced by
• Age, sex, weight, & disease processes –

edema, ascities
• Vd is altered by diseases --- For drugs
that are normally bound to plasma
protein
– Liver disease – ↓ protein synthesis
– Kidney disease – ↑ urinary protein loss
Determinats of Vd
• 1. Physiological space available

• 2. Affinity of drug to tissues
• 3. Plasma protein binding
• 4. Blood flow
SIGNIFICANCE
1. Helps in calculating the loading dose
LD = Vd x TC
2. Helps in calculating Plasma Half life

T ½ = 0.7 x Vd
CL
3. Drugs having large Vd have prolonged duration of
action
HALF LIFE (t1/2)
Half life of a drug (t1/2)
• The time taken for plasma

concentration of a drug to be
reduced to half of its original
value (in the therapeutic range)
during elimination
PLASMA HALF LIFE
It is the time taken by the drug to reduce its plasma
concentration or the amount of drug in the body by
50% during elimination ,
Or
50 % rise during constant infusions.
t1/2 = 0.7 x Vd
CL
It indicates time required to attain 50% of steady
state or to decay 50% from steady state.
t1/2 of drugs eliminated by
first-order kinetics
• t1/2 of a drug does not depend on

the size of administered dose
t1/2 = 0.7 Vd / CL
[The natural logrithium of 2 = 0.693
(approx --- 0.7)]
Vd =
amount of drug in the body
plasma concentration

t1/2 =0.7 Vd / CL
(The natural log of 2 = 0.693(approx
--- 0.7)
DECLINE IN PLASMA CONCENTRATION
1 x t1/2 plasma concentration falls 50%
2 x t1/2 25%
3 x t1/2 12.5%
4 x t1/2 6.25%
5 x t1/2 3.125%
Plasma Half Life
100
100
75
Half life
50
25
1 2 3 4 5 6 8
Factors Affecting Plasma ½ life
1. Factors affecting CL and Vd independently will

change t ½.
if both CL and Vd are altered there may not be
change in t½ e.g. Digoxin in chronic renal failure and
Lidocaine in chronic heart failure.
2. Diseases of organ of metabolism / excretion---

hepatic and renal disease (prolonged t½)
3. ADDITION OF 2ND DRUG
1- Enzyme inducers ----- ↓ plasma t½

2- Enzyme inhibitors ----- ↑plasma t½
3- Active metabolites ↑ half t½
4-Enterohepatic recirculation ↑ t½
5- ↓ hepatic Blood flow --- ↑ t½
6- Plasma protein binding-- ↑ t½
Clinical Significance of plasma half life
Interval between dosage
Duration of action
Drugs having short plasma half life:
Succinylcholine – 2 minutes
Aspirin – 15 minutes
Hydralazine – 1 hour
Drugs having long plasma half life:
Chloroquine – 214 hours
Digitoxin – 161 hours
Phenobarbital – 98 hours
MCQ 1
A drug , given as a 100mg single dose, results in a peak
plasma concentration of 20μg/ml. the apparent
volume of distribution is (assume a rapid distribution
and negligible elimination prior to measuring the
peak plasma level.)
a) 0.5 L
b) 1L
c) 2L
d) 5L
e) 10L
SEQs SEQs
1) What is plasma half life? Give its clinical significance

2) Define Half life? Describe its relation with the
loading dose
3) Define volume of distribution and enumerate its
clinical importance .
4) Define volume of distribution & Enumerate the
determining factors of Vd
STEADY STATE
CONCENTRATION
STEADY STATE CONCENTRATION
“ In pharmacokinetics, the condition in which the

average total amount of drug does not change over
multiple dosing cycles (i.e., the condition in which rate
of elimination equals the rate of drug administration)” is
called SSC
Steady state conc.= F x Dose

Cl x T
Steady state conc. = F x Dose
Cl x T
F = fractional bioavailability of dose
( in percentage)
D = Dose in mg/70 kg
Cl = clearance from systemic circulation
(in L/hr/70 Kg)
T = dose interval ( in hours)
When a drug is given at a constant rate
(continuous or repeated administration) time to reach steady
state SSC depends on t ½ and for all practical purpose after 5 x
t ½ periods the amount of drug in the body is constant and
plasma concentration is at a plateau.
Time to reach steady state
With the passage of each half life the plasma
concentration rises by half the difference between
current concentration and the ultimate steady state
100%.
1 x t1/2 (100/2) 50%
2 x t1/2 (50+100/2 = 150/2 ) 75%
3 x t1/2 (75+100/2 = 175/ 2) 87.5%
4 x t1/2 (87.5+100/2 = 187.5/2 ) 93.75%
5 x t1/2 (93.75+100/2 = 193.75/2 ) 96.87%
Medications obeying first order kinetics reach steady state
conc. in 4 – 5 half lives, & in some books it is 3 – 4
half lives
DOSAGE
REGIMENS
1. Maintenance Dose
2. Loading dose
MAINTENANCE DOSE
MAINTENANCE DOSE
“Drugs are administered in such a way as to maintain
a steady state of drug in the body,ie.just enough
drug is given in each dose to replace the drug
eliminated since the preceding dose.”
At steady state , the dosing rate must equal the rate of

elimination .
Dosing rate ss= rate of elimination
=CL x TC
TC= target concentration
CL= clearance
• If drug is given by oral route then
Dosing rate oral = dosing rate
F oral
F = Bioavailability
• If intermittent doses are given

Maintenance dose = Dosing rate x Dosing interval
LOADING DOSE
LOADING DOSE
A loading dose is initial higher dose of a drug that

may be given at the beginning of course, to achieve
earlier effect rapidly, in an individual whose body
does not contain the drug – Loading dose is followed
by maintenance dose
Loading dose LD= Vd x TC

Loading dose is given for a drug who has long plasma
half life i.e digoxin, Chloroquine.
Loading dose
LD= Vd x TC
As Vd is directly proportional to half life
So loading dose is also directly proportional to

half life
PLEASE OFFER
• SURAH FATIHA (01 TIME)

• SURAH IKHLAS (03 TIMES)
FOR MY MOTHER
JAZAKALLAH
THANK YOU

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VOLUME OF DISTRIBUTION (Vd)

Dr. M IMRAN ASHRAF

Very high molecular weight drugs, or

• Drugs with low lipid solubility &

• These drugs cannot easily enter the cells because of

Drugs that have a low molecular weight

Vd is expressed as in units of volume

Vd higher than total body water.

• Will dialysis remove these drugs

• The higher the Vd,

• A very high Vd value may indicate that

Very high molecular weight drugs, or

• Loading dose of a drug

• Drugs with large Vd need a

• A very large Vd indicate that most

• A very low Vd value indicate extensive plasma

• Age, sex, weight, & disease processes –

• 1. Physiological space available

2. Helps in calculating Plasma Half life

• The time taken for plasma

• t1/2 of a drug does not depend on

Vd is expressed as in units of volume

1. Factors affecting CL and Vd independently will

2. Diseases of organ of metabolism / excretion---

1- Enzyme inducers ----- ↓ plasma t½

Interval between dosage

1) What is plasma half life? Give its clinical significance

“ In pharmacokinetics, the condition in which the

Steady state conc.= F x Dose

At steady state , the dosing rate must equal the rate of

• If intermittent doses are given

A loading dose is initial higher dose of a drug that

Loading dose LD= Vd x TC

As Vd is directly proportional to half life

So loading dose is also directly proportional to

• SURAH FATIHA (01 TIME)

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