PROBLEM

• A known epileptic patient, in a

unconscious state was brought to ER with
complains of repetitive ,continuous jerky
movements of limbs with froth in the
mouth…..

• Diagnosis: Status epilepticus

 Solution/ drug therapy
Diazepam
• Which Drug?

• What dose ? What rate? 10mg, 2mg/minute

• Which route?
IV
• How frequently ?

• When is he going to be alright ? 12th hourly

• Do I have to reduce the dose If I am using this drug along with another

drug?
• In clinical practice, a drug should be

able to reach its intended site of

action after administration by some

convenient route.
• In only a few situations it is possible to

directly apply a drug to its target tissue,

e.g. by topical application of a cream on

skin or mucous membrane.

• Most often, a drug is administered into one body

compartment, eg, the gut, and must move to its

site of action in another compartment, eg, the

brain. This requires that the drug be

absorbed into the blood from its site of

administration and distributed to its site of

action,
• Finally, after bringing about its effect, a drug

should be metabolised and eliminated

at a reasonable rate by the body.
• To reach its site of action in another

compartment, drug has to cross through

the various barriers (Cell membrane ) that

separate these compartments

 What Happens After Drug Administration?

Drug at site
of administration
1. Absorption

Drug in plasma 2. Distribution

Drug/metabolites
in tissues

3. Metabolism
Drug/metabolites 4. Elimination
in urine, feces, bile
• Absorption
• Distribution
• Metabolism
• Elimination /Excretion

•A
•D
•M
•E
We are now talking about …

Pharmacokinetics
 Pharmacokinetics
• Pharmacokinetics is the quantitative study

of drug movement in, through and out of

the body
 Why Pharmacokinetics?

• To determine
– The route of administration

– Dose

– Onset of action of drug

– Duration of action

– How frequently to administer the drug

 Drug Absorption… How does the drug get
into blood stream ?

• Absorption… is the transfer of a drug from its

site of administration to the blood stream.
• For IV administered drug absorption is
complete
• In order to reach their site of action, a drug
has to pass through several membranes
 How drugs will pass through the membrane?
1. Passive diffusion:
• Concentration gradient across membrane is the driving force
for movement of drug molecule across the membrane
• Small size, water soluble drug molecule penetrate through
aqueous channels or paracellular spaces …Filtration …few
drugs do this
• Lipid soluble drugs readily pass through membrane by
dissolving in membrane ….many drugs do this
2. Active Transport:
• Movement occurs against the concentration gradient and
needs energy like ATP
 Lipid Bilayer

Outside of Cell Inside of Cell

Passive diffusion
of a water soluble
drug through
aqueous channel
Passive diffusion of a Lipid soluble drug by dissolving in
membrane

Outside of Cell Lipid Bilayer Inside of Cell

Lipid
Lipid insoluble
insoluble drug
drug

Lipid
Lipid Soluble
Soluble drug
drug
 Active
Active Drug
Drug transport
transport

Outside of Cell Lipid Bilayer Inside of Cell

Active
Active Drug
Drug transport
transport

ATP ADP
 How does most of the drugs pass through the
membrane ?

• Answer is ….By dissolving in membrane

• For this , drug has to be lipid soluble

• Are all drugs lipid soluble ? ..No… No..

• However many drugs are lipid soluble

• Some are lipid insoluble (they are water soluble)

• Lipid solubility is a big issue in

pharmacology….remember this
 Factors that affect absorption
• The particle size – Smaller is better

• concentration gradient

• Surface area and vascularity (blood supply) of that area

• Lipid solubility / Water solubility

• Nature of the drug…acidic or basic?

• The pH levels on either side of cell membrane

• pKa of the drug

 Lipid / Water solubility

• The more lipophilic, better absorbed, the better

a molecule can cross membranes, especially
the blood- brain barrier (and placental barrier)

• The more hydrophilic, the more a drug is

sequestered in the blood supply. It is less likely
to enter the brain .. Not absorbed in gut. Rather
fit for excretion
 Lipid / Water solubility
Once in solution, drugs exist as a mixture of two
interchangeable forms

1. Water-soluble is the ionized (polar) or electrically

charged form…Cannot cross membrane .. Eg.
Antihelminth drugs bc they have to stay in the
intestines for action

2. Lipid-soluble is the non ionized, or uncharged

form….Can cross membrane
 What is ionization ?

A drug molecule carrying an electrical

charge is said to be Ionized

An uncharged molecule is said to be

Unionized
 Membranes and Absorption

Hydrophilic
Lipid Bilayer
Hydrophilic
Heads
Heads Hydrophobic
Hydrophobic
Tails
Tails
Small, H2O, urea,
uncharged Swoosh!
CO2, O2, N2

Large, Glucose DENIED!

uncharged Sucrose
Small
charged H+, Na+, K+,
ions Ca2+ , Cl-, DENIED!
HCO3-
 Concept of ionization…continued

most drugs are either weak acid or a weak base

and when dissolved in body fluids, some or all
of a drugs molecules become
ionized/unionized

HA H+ + A-

BH+ B + H+
Ionization in neutral environment

Acids
Acids Release/Donate H
Release/Donate H ++

Ionized
Ionized
HA H+ + A- form
form
Bases
Bases Bind/Accept H
Bind/Accept H ++

H+ + B- HB Non-
Non-
ionized
ionized
form
form
 Concept of ionization…continued

• What percentage is ionized /unionized

determined by following factors :

1.Whether the drug was an acid or a base

2. Whether it is dissolved in an acid or base

medium (Stomach or intestine ?) i.e pH

3. And also the pKa of the drug

Environmental pH and Ionization

If
If we
we put
put an
an acidic
acidic drug
drug in
in an
an
environment
environment with a lot of H (low
with a lot of H ++
(low pH)
pH)
what
what will
will this
this equilibrium
equilibrium do?
do?

HA
HA
HA H+ + A-
HA
HA

⇑ System
H fromat
H from
Non-ionized
⇑ System
++
Non-ionized at Equilibrium
acid
form
acid
formenvironment
predominates!
Equilibrium
environment
predominates!
Role of pH on ionization of a Weak Acid

• As pH decreases, a weak acid will become more and

more unionized ,lipid soluble and better absorbed

• As pH increases, a weak acid will become more and

more ionized ,lipid insoluble and will not be

absorbed. Also becomes more water soluble and

better excreted
 Role of pH in ionization of a Weak base

• As pH increases, a weak base will become more and

more unionized ,lipid soluble and better absorbed

• As pH decreases, a weak base will become more and

more ionized ,lipid insoluble, and will not be absorbed.

Also becomes more water soluble and better excreted .

 A real live, actual clinical
question...

Aspirin
Aspirin (analgesic,
(analgesic, antianti inflammatory,
inflammatory,
anti
anti pyrexia)
pyrexia) isis anan acidic
acidic drug.
drug. In
In the
the
stomach
stomach will
will itit exist
exist mostly
mostly inin ionized
ionized
or
or non-ionized
non-ionized form?form? Non
Non ionized
ionized

NON-IONIZED
Why?
Why? Bc
Bc stomach
stomach isis acidic
acidic
 How will this affect aspirin absorption?

Lipid Bilayer

Ionized
Ionizedform
form
(charged)
(charged)
A-

Un
UnIonized
Ionizedform
form
(uncharged)
(uncharged)
HA HA
 Moral of the story...

Acidic drugs are best Absorbed

from Acidic environments

Basic drugs are absorbed best in

Basic environments
 So...
To ⇑⇑ absorption
To absorption of of an
an acidic
acidic drug…
drug…
acidify
acidify the
the environment
environment

To ⇓⇓ absorption
To absorption of
of an
an acidic
acidic drug…
drug…
alkalanize
alkalanize the
the environment...
environment...

This concept is very important in treatment of

a drug poisoning
 pKa
• pKa is equivalent to the pH at which 50% drug

is ionized and 50% is unionized….remember this

point

• pKa Is the negative logarithm of acidic

disassociation constant of the weak electrolyte

% of Unionized form

100%

75%

50%

25%

0%
1 2 3 4 6 8 9 10 11
12 13 14

pH of the medium
pKa
 Henderson-Hasselbalch equation
• The ratio of lipid-soluble form to water-
soluble form for a weak acid or weak base is
expressed by the Henderson-Hasselbalch
equation

log (Protonated form) = pKa - pH

(Unprotonated form)
 Application of ionization principle

• An application of this principle is in the manipulation of

drug excretion by the kidney. Almost all drugs are

filtered at the glomerulus. If a drug is in a lipid-soluble

form during its passage down the renal tubule, a

significant fraction will be reabsorbed by simple

passive diffusion.
• If the goal is to accelerate excretion of the drug, it is
important to prevent its reabsorption from the
tubule. This can often be accomplished by adjusting
urine pH to make certain that most of the drug is in
the ionized state, the drug will be "trapped" in the
urine. Thus, weak acids are usually excreted faster
in alkaline urine; weak bases are usually excreted
faster in acidic urine
 Another question is …..only in
case of poisoning
• How do you acidify/alkalinize the urine?

• Acidification of urine (in basic drug poisoning)

– Give Ammonium chloride or Vitamin C or

Canberry juice

• Alkalinization of urine (in acidic drug poisoning)

– Give Sodium bicarbonate or Acetazolamide

Clinical implications
Weakly acidic drugs phenobarbitone
ionise more in alkaline pH
Weakly basic drugs atropine,
chloroquine ionise more in acidic pH
So, in acidic drug poisoning –
enhance excretion by alkalanising
the urine (NaHCo3)
So, in basic drug poisoning –
enhance excretion by acidifying the
urine (ammonium chloride)