Pharmacokinetic

Overview
The intensity of the
drug's effect, and the
duration of the drug
action are controlled by
four fundamental
pathways of drug
movement and
modification in the body.

Figure: Schematic representation of

drug absorption, distribution,
metabolism and elimination.
First, drug absorption from the site of administration
permits entry of the therapeutic agent (either directly or
indirectly) into plasma (input). Absorption is defined as
the passage of a drug from its site of administration
into the plasma.
Second, the drug may then reversibly leave the blood
stream and distribute into the interstitial and
intracellular fluids (distribution).
Third, the drug may be metabolized by the liver,
kidney, or other tissues.
Finally, the drug and its metabolites are excreted from
the body (output) in urine, bile, or feces.
Routes of drug administration
The route of administration is determined primarily
- by the properties of the drug (such as water or lipid
solubility, ionization, etc.) and
- by the therapeutic objectives (for example, the
desirability of a rapid onset of action or the need for
long-term administration or restriction to a local site).

The route of administration (ROA) that is chosen may

have a profound effect upon the speed and efficiency
with which the drug acts.
The main routes of drug administration are:
Enteral: oral, sublingual,
rectal

Parenteral: intravascular
(intravenous), intramuscular,
subcutaneous

Other: inhalation, intranasal,

intrathecal (in CSF), topical,
transdermal

Figure: Commonly used routes of drug

administration.
Enteral routes:
Drug placed directly in the GI tract:
Oral- swallowing
Sublingual- placed under the tongue
Rectum- absorption through the rectum
Oral
Giving a drug by mouth is the most common route of
administration but it is also the most variable, and
requires the most complicated pathway to the tissues.
Little absorption occurs until the drug enters the small
intestine.
Drug absorption from the intestine:
The drug absorbed by passive transport mechanism in
intestine at a rate determined by the ionization and
lipid solubility of the drug molecules.
Strong bases of pKa 10 or higher are poorly absorbed,
as are strong acids of pKa less than 3, because they
are fully ionized.
Figure: Absorption of drugs from the intestine, as a function of pKa,
for acids and bases.
Weak acids and bases are well absorbed; strong acids and bases
are poorly absorbed.
There are a few instances where intestinal absorption
depends on carrier-mediated transport mechanism
rather than simple lipid diffusion.
For example levodopa, iron, calcium (task).
Advantages:
Convenient- can be self-administered, pain free, easy
to take
Absorption- takes place along the whole length of the
GI tract
Cheap- compared to most other parenteral routes
Disadvantages:
- Unpleasant taste of some drugs
- Irritation to gastric mucosa - nausea and vomiting
- Destruction of drugs by gastric acid and digestive
juices
- Sometimes inefficient- only part of the drug may be
absorbed
- Effect too slow for emergencies
- First-pass effect - drugs absorbed orally are initially
transported to the liver via the portal vein
- Unable to use in unconscious patient or who have
had GI surgery
Most of the drug is absorbed in the small intestine,
Why?
1. Small intestine has a much larger surface area for
absorption (~200 m2) as compared to the stomach
(~1-3 m2).
2. Drug spends more time in the small intestine (~4
hrs) than the stomach (~0.5-1 hrs).
Food in the stomach can decrease absorption
- Food may delays gastric emptying time so that drugs
may destroyed by acid.
- Interactions between drug and food particles.
- Exception: propranolol- due to  blood flow.
First-pass effect
When a drug is absorbed across the GI tract, it enters
the portal circulation before entering the systemic
circulation.
A drug can be metabolized in the gut wall or even in
the portal blood, but most commonly it is the liver that
is responsible for metabolism before the drug reaches
the systemic circulation (plasma). In addition, the liver
can excrete the drug into the bile (fluid secreted by
liver).
Any of these sites can contribute to this reduction in
bioavailability, and the overall process is known as
first-pass effect or first-pass elimination.
 Portal circulation

Figure: First-pass effect

The greater the first-pass effect, the less the agent will
reach the systemic circulation when the agent is
administered orally. (imp)
Lidocaine (anesthetic agent) is a drug with a first-pass
effect that is so great that oral administration is not
practical.
In the case of propranolol, a significant portion of the
orally administered dose is metabolized through a first-
pass effect.
More than 90% of nitroglycerin is cleared during a
single passage through the liver.
Therefore, a much larger oral dose is required to
achieve the same therapeutic response as that
obtained from a dose administered intravenously.
Sublingual/Buccal
Placement under the tongue allows the drug to diffuse
into the capillary network and therefore to enter the
systemic circulation directly.
When only small amounts of drugs are required to gain
access to the blood, the sublingual route may be very
satisfactory.
For example, nitroglycerin in angina pectoris.

Because the stomach is bypassed, acid-liability and

gut-permeability is not important.
Drugs are absorbed from the mouth straight into the
systemic circulation without entering the portal system
and so escape first-pass metabolism by the liver.
Advantages Drug’s property:
-rapid absorption - Non-polar
- Lipid soluble
-drug stability
-avoid first-pass effect
Disadvantages
-inconvenient
-small doses
-unpleasant taste of some drugs

Rectal
50% of the drainage of the rectal region bypasses the
portal circulation; thus the biotransformation of drugs
by the liver is minimized.
- Devoid of destruction of the drug by intestinal
enzymes or by low pH in the stomach
- Unconscious patients (postoperative) and children
- If patient is nauseous or vomiting
- Absorption may vary
- Good for drugs affecting the bowel such as laxatives
- Irritating drugs contraindicated
- Can be used for both local effects and systemic
effects
Parenteral routes:
Parenteral administration is used for drugs that are
poorly absorbed from the gastrointestinal (GI) tract,
and for agents such as insulin that are unstable in the
GI tract.
Parenteral administration is also used for treatment of
unconscious patients and under circumstances that
require a rapid onset of action.
The three major parenteral routes are
- Intravascular (intravenous or intra-arterial)
- Intramuscular
- Subcutaneous
Intravascular:
Intravenous (IV) injection is the most common
parenteral route. For drugs that are not absorbed
orally, there is often no other choice.
- Rapid onset of action because the drug is injected
directly into the bloodstream
- Useful in emergencies and in patients that are
unconscious
- The drug avoids the GI tract and first-pass
metabolism by the liver
- Smaller doses generally are required than the other
routes but cost is high
Greater risk of adverse effects as:
a. High concentration attained rapidly
b. That are injected cannot be recalled by
strategies such as emesis or binding to activated
charcoal
c. Risk of embolism (obstruction of blood vessel)
d. May introduce bacteria through contamination,
induce hemolysis
e. Pain at application site
f. No self administration facility

Capillary: brings the blood into intimate relationship with the tissue cell
Artery Arterioles Capillary VenulesVeins
Intra-artery
Similar properties, advantages and disadvantages of
intravascular route. Intra-artery route is specially used
when high drug concentration in specific tissue is
required than other tissue:
- diagnostic purpose and
- for chemotherapy

Intramuscular
Drugs administered intramuscularly can be aqueous
solutions or specialized depot preparations- often a
suspension of drug in a non-aqueous vehicle, such as
ethylene glycol or peanut oil.
Absorption of drugs in aqueous solution is fast,
whereas that from depot preparations is slow. Drug
passes through capillary walls to enter the blood
stream.

- Pain at injection sites for certain drugs

- This parenteral route may be used when an
immediate effect is not required but a prompt effect is
desirable
- Absorption from an intramuscular depot is more
predictable and uniform than from a subcutaneous site
Subcutaneous
Drug is injected beneath the skin and permeates
capillary walls to enter blood stream.
Absorption from the site of injection is dependent on
local blood flow. Concurrent administration of
vasoconstrictor will slow absorption.

For example, minute amount of epinephrine is

sometime used in combination with a drug to restrict
its area of action. Epinephrine acts as a local
vasoconstrictor and decreases removal of a drug,
such as lidocaine (local anesthetic), from the site of
administration.
Examples of drugs given by this route are insulin and
sodium heparin, neither of which is absorbed orally,
and both of which should be absorbed slowly over
many hours.

Inhalation
Inhalation provides the rapid delivery of a drug across
the large surface area of the mucous membranes of
the respiratory tract and pulmonary epithelium,
producing an effect almost as rapidly as by
intravenous injection.
This route of administration is used for drugs that are
gases and volatile agents (for example, some
anesthetics), or those that can be dispersed in an
aerosol.
The route is particularly effective and convenient for
patients with respiratory complaints (for example,
asthma or chronic obstructive pulmonary disease) as
drug is delivered directly to the site of action and
systemic side effects are minimized.
Topical
Topical application is used when a local effect of the
drug is desired.
Used for most dermatologic and ophthalmologic
preparations.
Clotrimazole is applied as a cream to the skin in the
treatment of dermatophytosis.
Atropine is instilled directly into the eye to dilate the
pupil and permit measurement of refractive errors.

Intra-articular
Injected into bone joints
Intrathecal/lntraventricular
It is sometimes necessary to introduce drugs directly
into the cerebrospinal fluid (CSF): some anesthetics.

Transdermal
This route of administration achieves systemic effects
by application of drugs to the skin, usually via a
transdermal patch.
The rate of absorption can vary markedly depending
upon the physical characteristics of the skin at the site
of application. Small lipid soluble molecule.
This route is most often used for the sustained delivery
of drugs, such as the antianginal drug, nitroglycerin.
 INTRODUCTION TO
PHARMACOKINETICS
ADME

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 LEARNING OBJECTIVES
• At the end of this session participants
should be able to:
– Describe ADME
– Explain the importance of ADME in Research,
clinical settings, industries and drug
development

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Pharmacokinetics of drugs
(ADME)
What the body does to the drug
 Absorption
 Distribution
 Metabolism
 Excretion of drugs
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 Importance of PK studies

- Therapeutic drug monitoring (TDM)

- Establish safety and efficacy in BA/BE studies

- Establishment of dosage regimen

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• Extra vascular route of administration is
the most preferred one

• Absorption is the prerequisite for

pharmacological effects

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Delays or drug loss during absorption
(i) Contribute to variability in drug
response
(ii) Contributes to failure of drug
therapy

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Is the passage of drug molecule through
cell membranes from the site of
administration to the systemic circulation

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Selective permeability

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Mechanisms of drug absorption

1. Simple diffusion
2. Active transport.
3. Facilitated diffusion.
4. Pinocytosis (Endocytosis).

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Drug transport across
membrane

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water soluble drug (ionized or polar) is readily
absorbed via aqueous channels or pores in cell
membrane.

Lipid soluble drug (nonionized or non polar) is

readily absorbed via cell membrane itself.

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Characteristics
 common.
 Occurs along concentration gradient
 Non selective
 Not saturable
 Requires no energy
 No carrier is needed
 Depends on lipid solubility
 Depends on pka of drug - pH of
medium
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PKa of the drug
pH at which half of the substance is
ionized & half is unionized.
pH of the medium
Affects ionization of drugs.
– Weak acids  best absorbed in
stomach.
– Weak bases  best absorbed in
intestine.

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 Figure 2-2 Application of pH trapping to renal drug
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4/15/2016 Transfer across membranes
elimination.
Occurs against concentration gradient.
Requires carrier and energy.
Specific
Saturable.

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Active Transport

1. Symport substance is transported in the same

direction as the “driver” ion (Na+)

Examples:
outside

Na+ AA Na+ gluc Na+ 2 HCO3-

inside
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2. anti-porters substance is transported in the opposite
direction as the “driver” ion (Na+)

Examples:
outside

Na+ Na+ Na+/HCO3-

Ca2+ H+ Cl-/H+
inside 54
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 Occurs along concentration
gradient.
 Requires carriers
 Selective.
 Saturable.
 No energy is required.

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Endocytosis: uptake of membrane-bound
particles.
Exocytosis: expulsion of membrane-bound
particles.
High molecular weight drugs or
Highly lipid insoluble drugs

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Dosage forms:
Tablets and capsules, rate of disintegration
and dissolution is limiting factor in their
absorption.
After dissolution, smaller the particle size,
more efficient will be absorption

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Influence of dosage forms

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Influence of P-glycoprotein and first
pass effect
Intestinal motility (Transit Time)
• Diarrhea reduce absorption
Drug interactions
Food
• slow gastric emptying
• generally slow absorption
• Tetracycline, aspirin, penicillin V

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Enterohepatic absorption
• Enterohepatic recirculation is the process by
which biliary excreted drug is reabsorbed
in the intestine and transport back to the
liver instead of being removed from the body.
• This can result in a lagging secondary
absorption process and increases in drug
exposure.
• Examples:Chloramphenicol, aspirin,
paracetamol, diazepam, lorazepam,
morphine, metronidazole.
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Enterohepatic absorption

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Route of Administration Determines
Bioavailability (AUC)

Administration
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 PK-PD relationship

Typical plasma concentration time profile showing

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pharmacokinetic and
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 AUC calculation: Model independent
Calculation of AUC Trapezoidal Rule

From: Rowland M, Tozer TN. Clinical Pharmacokinetics. p 470.

Calculate the area for each part of the parts 1,2,3,4,5 and 6 (until the last
observed concentration) using trapezoidal rule
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 Clinical importance of the concept
of bioavailability
Help clinician to choose the best route for
drug administration depending on clinical
situation E.g.
Patient factors – generalized edema,
unconsciousness
Rapid onset of action (Emergency basis)

Used in bioavailability and bioequivalence

studies
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Therapeutic significance
of AUC

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PLASMA DRUG CONCENTRATION-
TIME PROFILE
 Group work
 Plasma samples from a Time Concentration
(hr) (ng/mL)
patient were collected after 0.25 2.85
an oral bolus dose of 10 mg 0.50 5.43
of a new benzodiazepine, 0.75 7.75
using the given data below, 1.00 9.84
2.00 16.20
plot them in the provided
4.00 22.15
semilog graph and 6.00 23.01
calculate the following:- 10.00 19.09
(i) Elimination half-life, 14.00 13.90
Cmax, Tmax and AUC 20.00 7.97

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NEW SESSION

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 Drug Distribution
• Refers to the reversible transfer of a drug
between systemic circulation and the extra
vascular fluids and tissues of the body (for
example, fat, muscle, and brain tissue).

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 Drug Distribution
• Once in the bloodstream, a drug is distributed throughout the body
• Very little of the drug is in contact with receptors at any given time
• Most of the drug is in areas remote from the site of action (of
interest), such as
– Plasma binding sites
– Muscle tissue
– Adipose tissue (fat)
– Liver
– Kidneys

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• In pharmacokinetics, drug distribution is
described by the parameter the apparent
volume of distribution (Vd).

• The extent to which a drug distributes

affects the half-life of the drug and the
fluctuation of the concentration at steady
state.
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• The volume of distribution (Vd) is defined as
the volume of fluid in which a drug would
need to be dissolved to have the same
concentration as it does in plasma.

• The Vd does not represent the volume in a

particular body fluid compartment instead, it
is an apparent volume that represents the
relationship between the dose of a drug and
the resulting plasma concentration of the
drug.
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VOLUME OF DISTRIBUTION

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 The Extent of Distribution and Vd in a 70 kg
Normal Man

% Body
Vd Extent of Distribution
Weight
(L)
5 7 Only in plasma
5-20 7-28 In extracellular fluids
20-40 28-56 In total body fluids.
In deep tissues; bound to
>40 >56
peripheral tissues
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 Factors affecting Vd

• Pregnancy-Increase in TBW-increase Vd for

hydrophilic drug also increase in fatty tissue

increases Vd for lipophilic drug

• Disease eg liver reduced plasma protein less

protein binding hence higher Vd

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 2.PROTEIN BINDING
• Refers to phenomenon of complex formation btn drug and a

protein

• Common proteins include blood and extravascular tissue

proteins

• A bound drug is neither metabolized nor excreted nor Pd

active

• PD action is a result of free drug conc at the site of action

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 Cont…

• PB is a results of weak chemical bonds such as H-

bonds ,van der waal forces hence reversible

• Irreversible protein binding is very rare and result

in carcinogenicity and tissue toxicities eg covalent

bond btn PCM-metabolites and hepatocytes

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 Cont….
• Binding of drug falls into 2 classes:
1) Blood
a) Plasma proteins.
b) Blood cells.
2) Extra vascular tissue proteins, fats, bones, etc.

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 BINDING TO BLOOD
COMPONENTS
1.Plasma Protein-drug binding.
•The binding of drugs to plasma proteins is
reversible. The extent or order of binding of
drug to plasma proteins is:

•Albumin ›ὰ -Acid glycoprotein ›Lipoproteins

1

›Globulins

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 A)BINDING OF DRUG TO HUMAN SERUM
ALBUMIN.
It is the most abundant plasma protein (59%), having M.W. of 65,000 with large drug

binding capacity. Endogenous compounds & Large variety of all types of drugs

4 diff. sites on HSA for drug binding

- Site I: warfarin & azapropazone binding site

- Site II: diazepam binding site

- Site III: digitoxin binding site

1
- Site IV: tamoxifen binding site 0
1

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B) BINDING OF DRUG TO ὰ1-ACID
GLYCOPROTEIN
• It has a M.W. 44,000 and plasma conc.

range of 0.04 to 0.1 g%. It binds to no. of

basic drugs like imipramine, lidocaine,

propranolol, quinidine.

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 C.BINDING OF DRUG TO
LIPOPROTEINS
• Lipoproteins are amphiphilic in nature. It contains

combination of lipid & apoproteins

• The lipophilic lipid consist of triglycerides & cholesteryl

esters and hydrophilic apoprotein consists of free cholesterol

&proteins

• They includes chylomicrons, VLDL, LDL and HDL

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 D) BINDING OF DRUG TO
GLOBULINS
• ἀ1-globulin:- (transcortin) corticosteroid binding globulin-
Prednisolo,dexamethasone toxicity

• ἀ2-globulin:- (ceruloplasmin) it binds vita. A, D, E, K & cupric ions

• ᵝ1-globulin:- (transferrin) it binds to ferrous ions

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 DRUG BINDING TO BLOOD
CELLS (RBC)
• RBC has the following components where drug
binds
a) Haemoglobin: It has a M.W. of 64,500 Dal. -
phenytoin, pentobarbital
b) Carbonic anhydrase: Carbonic anhydrase inhibitors drugs
like acetazolamide & chlorthalidone.
c) Cell membrane: Imipramine & chlorpromazine bind to
this component

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 DRUG BINDING TO
EXTRAVASCULAR TISSUE
• Tissue binding is more significant than PP binding

• Tissue may act as storage site for drug

• Binding depends on lipophilicity & structural features of

the drug, perfusion rate, pH differences etc

• The order of binding is Liver ›Kidney › Lung › Muscles

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 Cont..
• Liver-Halogenated Hydrocarbons and PCM-Hepatotoxicity

• Lungs- Imipramine, CPZ and antihistamine

• Kidney (metallothionin proteins)- Lead, mercury and cadmium-

nephrotoxicity

• Skin-Chloroquine and Phenothiazines i.e bond with melanin-

• Eye- Chroloquine and phenothiazines -Retinopathy

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Drug toxicities due to tissue
binding

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 Clinical implications of plasma
protein
1. Highly plasma protein bound drugs does not cross membranes so
largely restricted to vascular compartments (smaller Vd).

2. Temporary storage of the drug which is not available for any action.

3. High degree of protein binding generally makes the drug long acting

4. Plasma concentrations of the drug refer to bound as well as free drug.

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 Cont…
5. One drug can bind to many sites on the albuminmolecule. Conversely, more than one drug
can bind to the same site.

6. Displacement reactions- (Drug interactions)

– Salicylates displace sulfonylureas & methotrexate.

– Indomethacin, phenytoin displace warfarin.

– Sulfonamides and vit K displace bilirubin(kernicterus in neonates) .

7. In hypoalbuminemia, reduced binding leads to high concentrations of free drug e.g.

phenytoin and furosemide.

8. Other diseases: e.g. phenytoin and pethidine binding is reduced in uraemia;

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Drugs highly bound to plasma proteins

• To albumin • To α1 acid glycoprotein

• Barbiturates • β-blockers
• Benzodiazepines • Bupivacaine
• NSAIDs • Lidocaine
• Valproic acid • Disopyramide ,
• Phenytoin • Imipramine
• Penicillins • Methadone
• Sulfonamides • Prazosin
• Tetracyclines • Quinidine
• Warfarin • Verapamil

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 Clinical implications of volume of distribution

• It helps in estimating the total amount of drug

at any time

amount of drug = Vd X plasma conc of drug at

certain time

• Vd is important to determine the loading dose

Loading dose = Vd X desired concentration
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• May determine the effectiveness of
dialysis
• Example in accidental drug overdose
dialysis may not be very useful for drugs
with large Vd e.g digoxin, imipramine

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• Thank you!

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