1.introduction to pharmacology

Presented by: Prof.Mirza
Anwar Baig
1
Chapter :3Chapter :3
Introduction to PharmacologyIntroduction to Pharmacology
Presented by: Prof.Mirza Anwar BaigPresented by: Prof.Mirza Anwar Baig
Anjuman-I-Islam's Kalsekar Technical CampusAnjuman-I-Islam's Kalsekar Technical Campus
School of Pharmacy,New Pavel,NaviSchool of Pharmacy,New Pavel,Navi
Mumbai,MaharashtraMumbai,Maharashtra
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Contents:
1. Important terms
2. Drug nomenclature
3. Routes of drug adminsterations
4. Pharmacokinetics (ADME)

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At the end of topic you should be able
to....
Compare advantage and disadvantages of routes
of drug administration.
Explain the essential characteristics of drug for
proper absorption & excretion.
Summarize the role of distribution and metabolism
in drug actions.

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1.Pharmacology:
• Science of drugs (Greek:Pharmacon--drug; logos-discourse
in). In a broad sense, it deals with interaction of
exogenously adminstered chemical molecules (drugs) with
living systems.
• It encompasses all aspects of Pharmacodynamics
knowledge about drugs, but most importantly- What the
drug does to the body.
• those that are relevant to effective and safe use for This
includes physiological and biochemical medicinal purposes.
The two main divisions of pharmacology are:
• Pharmacodynamics: knowledge about drugs, but most
importantly - What the drug does to the body.
• Pharmacokinetics (Greek: Kinesis-movement):- What the
body does to the drug.

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2. Drug (French: Drogue -a dry herb)
"Drug is any substance or product that is used or is
intended to be used to modify or explore physiological
systems or pathological states for the benefit of the
recipient."
3. Pharmacotherapeutics:
• It is the application of pharmacological information
together with knowledge of the disease for its
prevention,mitigation or cure.
• Selection of the most appropriate drug, dosage and
duration of treatment taking into account the specific
features of a patient are a part of pharmacotherapeutics.

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4.Clinical pharmacology:
It is the scientific study of drugs in man.
It includes pharmacodynamic and pharmacokinetic
investigation in healthy volunteers and in patients;
evaluation of efficacy and safety of drugs and
comparative trials with other forms of treatment;
surveillance of patterns of drug use, adverse effects etc.
5. Chemotherapy:
It is the treatment of systemic infection/malignancy
with specific drugs that have selective toxicity for
the infecting organism malignant cell with no/minimal
effects on the host cells

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6.Toxicology:
It is the study of poisonous effect of drugs and other
chemicals (household, environmental pollutant,
industrial, agricultural, homicidal) with emphasis on
detection, prevention and treatment of poisonings.
It also includes the study of adverse effects of drugs,
since the same substance can be a drug or a poison,
depending on the dose.

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DRUG NOMENCLATURE
Three categories of names:
(a) Chemical name:
It describes the substance chemically, e.g.1-(lsopropylamino)-
3-(1-naphthyloxy) propan-2-ol for propranolol.
This is cumbersome and not suitable for use in prescribing.
A code name, e.g. RO 15-1788 (later named flumazenil) may
be assigned by he manufacturer for convenience and
simplicity before an approved name is coined.
b) Brand name –
Original drug which is defended by patent and may be
produced during patent term only by this pharmaceutical
firm
c) Generic name–
When term of patent is discontinued the drug may be
produced by different pharmaceutical companies under new
product (trade) names but at the basis of original active
substance (similar quantity, route of administration etc.)

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ESSENTIAL DRUGS (MEDICINES) CONCEPT
The WHO has defined Essential Drugs (medicines) as
"those that satisfy the priority healthcare needs of the
population.
They are selected with due regard to public health
relevance, evidence on efficacy and safety, and
comparative cost effective.
Essential medicines are intended to be available within
the context of functioning health systems at all times and
in adequate amounts, in appropriate dosage forms, with
assured quality and adequate information, and at a
affordable price.
For optimum utilization of resources, governments
(especially in developing countries) should concentrate on
well tested,cheaper,safe and efficacious drugs by
identifying them as Essential medicines.

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WHO criteria for the selection of an
essential medicine.
a) Adequate data on its efficacy and safety should be available from clinical
studies.
b) It should be available in a form in which quality, including bioavailability,
and stability on storage can be assured.
c) Its choice should depend upon pattern of prevalent diseases; availability of
facilities and trained personnel; financial resources; genetic, demographic
and enviromental factors.
d) In case of two or more similar medicines, choice should be made on the
basis of their relative efficacy, safety, quality, price and availability, by
comparative pharmacokinetic properties and local facilities for
manufacture and storage.
f) Most essential medicines should be single compounds. Fixed ratio
combination products should be included only when dosage of each
ingradient meets the requirements of a defined population group, and
when the combination has a proven advantage in therapeutic effect, safety,
adherence or in decreasing the emergence of drug resistance.

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(g) Selection of essential medicines should be a continuous process which
should take into account the changing priorities for public health
action, epidemiological conditions as well as availability of better
medicines/ formulations and progress in pharmacological knowledge.
(h) Recently, it has been emphasized to select essential medicines
based on rationally developed treatment guidelines.
Ø First Model List of Essential Drugs along with their dosage forms
and strengths in 1977 by WHO which could be adopted after
suitable modifications according to local needs.
Ø India produced its National Essential Drugs List in 1996 and has
revised it in 2003 with the title "National List of Essential
Medicines". This includes 354 medicines which are considered to be
adequate to meet the priority healthcare needs of the general
population of the country.
Ø Adoption of the essential medicines list for procurement and supply
of medicines, especially in the public sector healthcare system, has
resulted in improved availability of medicines, cost saving and more
rational use of drugs.

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Orphan Drugs
• These are drugs or biological products for diagnosis/treatment/
prevention of a rare disease or condition, or a more common
disease (endemic only in resource poor countries) for which
there is no reasonable expectation that the cost of developing
and marketing it will be recovered from the sales of that drug.
• The list includes:
Sodium nitrite, fomepizole, liposomal amphotericin 8, ancrod,
rifabutin, succimer, somatropin, digoxin immune Fab (digoxin
antibody), liothyronine (T3) and many more.
• Though these drugs may be life saving for some patients, they
are commercially difficult to obtain.
• Governments in developed countries offer tax benefits and other
incentives to pharmaceutical companies for developing and
marketing orphan drugs (e.g. Orphan Drug Act in USA).

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Route of drug adminsteration
Definition:
A route of administration is the path by
which a drug, fluid, poison or other
substance is brought into contact with the
body.

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Classification
Routes of administration can broadly be divided into:
1. Topical:
Drugs are applied topically to the skin or mucous membranes,
mainly for local action.
2. Oral:
used for systemic (non-local) effect, substance is given via the
digestive tract.
3. Parenteral:
A drug administered parenterally is one injected via a hollow
needle into the body at various sites and to varying depth.
4. Rectal: Drugs given through the rectum by suppositories or
enema.
5. Inhalation: The lungs provide an excellent surface for
absorption when the drug is delivered in gaseous, aerosol or
ultrafine solid particle form

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ROUTES OF DRUG ADMINISTRATION
Mostly common considerations are:
1. Physical and chemical properties of the drug
- Solid/liquid/ gas
– Solubility and stability
– PH and irritancy
2. Site of desired action - localized and aprochable
3. Rate and extent of absorption of the drug from different
routes.
4. Effect of digestive juices and first pass metabolism of the
drug.
5. Rapidity with which the response is desired (eg.routine
treatment or emergency).
6. Accuracy of dosage required (i.v. and inhalation).
7. Condition of the patient (unconscious, vomiting) etc.

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Local route
• These routes can only be used for localized lesions at
accessible sites and for drugs whose systemic
absorption from these sites is minimal or absent.
• Thus, high concentrations are attained at the desired
site without exposing the rest of the body.
• Systemic side effects or toxicity are consequently
absent or minimal.
• The same can serve as systemic route of
administration, e.g. glyceryl trinitrate (GTN) applied
on the skin as ointment or transdermal patch.

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A.Topical route
This refers to external application of the drug to the
surface for localized action.
It is often more convenient as well as encouraging to the
patient.
Drugs can be efficiently delivered to the localized lesions
on skin, oropharyngeal/nasal mucosa, eyes, ear canal, anal
canal or vagina.
The dosage forms are lotion, ointment, cream,powder,
paints, drops, spray, lozengens, suppositories or pesseries.
Nonabsorbable drugs given orally (sucralfate,
vancomycin), inhalation of drugs for action on bronchi
(salbutamol, cromolyn sodium) and irrigating
solutions/jellys (povidone iodine,lidocaine) applied to
urethra

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1- Topical route:
I Skin
A-Dermal – cream, ointment (local action)
B- Transdermal- absorption of drug through skin (i.e systemic
action)
I. stable blood levels(controlled drug delivery system)
II. No first pass metabolism
III. Drug must be potent or patch becomes too large
II Mucosal membranes
• eye drops (onto the conjunctiva)
• ear drops
• intranasal route (into the nose)

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2- Oral route:
- By swallowing.
- It is intended for systemic effects
resulting from drug absorption
through the various epithelia and
mucosa of the gastrointestinal tract.

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Advantages:
1- Convenient - portable, no pain, easy to take.
2- Cheap - no need to sterilize, compact, multi-dose bottles,
automated machines produce tablets in large quantities.
3- Variety - tablets, capsules, suspensions, mixtures .
Disadvantages:
1- Sometimes inefficient - low solubility drugs may suffer
poor availability e.g. Griseofulvin
2- First-pass effect - drugs absorbed orally are transported to
the general circulation via the liver. Thus drugs which are
extensively metabolized will be metabolized in the liver
during absorption. e.g. propranolol

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First pass effect:
First pass effect

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1. The first pass effect is the term used for the hepatic metabolism
of a pharmacological agent when it is absorbed from the gut
and delivered to the liver via the portal circulation.
2. The greater the first pass effect, the lower the bioavailability of
the drug(the rate and extent of the drug reaching systemic
circulation).
3. Food and G-I motility can affect drug absorption.Often patient
instructions include a direction to take with food or take on an
empty stomach.
4. Absorption is slower with food(milk and milk products) for
tetracyclines and penicillins, etc. However, for propranolol
bioavailability is higher after food, and for griseofulvin
absorption is higher after a fatty meal.
First pass effect (Cont.):

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5. Sometimes may have adverse reactions – e.g.
Antibiotics may kill normal gut flora and
allow overgrowth of fungal varieties. Thus,
antifungal agent may be included with an
antibiotic.
6. Not suitable for unconscious patient - Patient
must be able to swallow solid dosage forms.
Liquids may be given by tube.
7.May cause irritation to gastric mucosa, nausea
and vomiting.
8.Effect too slow for emergencies.

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3- Buccal/Sublingual route:
• Some drugs are taken as smaller tablets
which are held in the mouth (buccal tablet)
or under the tongue (sublingual tablet).
• Buccal tablets are often harder tablets [4 hour
disintegration time], designed to dissolve
slowly.
• E.g Nitroglycerin, as a softer sublingual
tablet [2 min disintegration time], may be
used for the rapid relief of angina.

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Advantages
1- Avoid hepatic first pass - The liver is by-
passed thus there is no loss of drug by first pass
effect for buccal administration. Bioavailability is
higher.
2- Rapid absorption - Because of the good blood
supply to the area, absorption is usually quite
rapid.
3- Drug stability - pH in mouth relatively neutral
(gf. stomach - acidic). Thus a drug may be more
stable.
3- Buccal/Sublingual route (Cont.)

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Disadvantages
1- Holding the dose in the mouth is
inconvenient.
2- Small doses only can be
accommodated easily.
3- Buccal/Sublingual route (Cont.)

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4- Parenteral route:

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A- Intravascular (IV, IA):
- placing a drug directly into blood stream.
-May be - Intravenous (into a vein) or - intraarterial (into
an artery).
Advantages
1- precise, accurate and immediate onset of action, 100%
bioavailability.
Disadvantages
1- risk of embolism.
2- high concentrations attained rapidly leading to greater
risk of adverse effects.
4- Parenteral route (Cont.)

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4- Parenteral route (Cont)
B-Intramuscular :(into the skeletal muscle).
Advantages
1- suitable for injection of drug in aqueous solution
(rapid action) and drug in suspension or emulsion
(sustained release).
Disadvantages
1- Pain at injection sites for certain drugs.

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C- Subcutaneous (under the skin), e.g. insulin.
D- Intradermal, (into the skin itself) is used for skin
testing some allergens.
E- Intrathecal (into the spinal canal) is most commonly
used for spinal anesthesia .
F- Intraperitoneal, (infusion or injection into the
peritoneum) e.g. peritoneal dialysis in case of renal
insuffeciency.
4- Parenteral route (Cont)

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5-Rectal route:
Most commonly by suppository or enema.
Advantages
1- By-pass liver - Some of the veins draining the rectum lead
directly to the general circulation, thus by-passing the liver.
Reduced first-pass effect.
2- Useful - This route may be most useful for patients unable to
take drugs orally (unconscious patients) or with younger children.
- if patient is nauseous or vomiting

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Disadvantages
1- Erratic absorption - Absorption
is often incomplete and erratic.
2- Not well accepted.
5- Rectal route (Cont.)

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6- Inhalation route:
- Used for gaseous and volatile agents and aerosols.
- solids and liquids are excluded if larger than 20 micron. the
particles impact in the mouth and throat. Smaller than 0.5
micron , they aren't retained.
Advantages
A- Large surface area
B- thin membranes separate alveoli from
circulation
C- high blood flow
- As result of that a rapid onset of action due
to rapid access to circulation.

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Disadvantages
1- Most addictive route of administration because it
hits the brain so quickly.
2- Difficulties in regulating the exact amount of
dosage.
3- Sometimes patient having difficulties in giving
themselves a drug by inhaler.
6- Inhalation route (Cont.)

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Comparisons:

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Comparisons:

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Pharmacokinetics
Pharmacokinetics refers to what the
body does to a drug & phar-
macodynamics describes what the
drug does to the body.
• Four pharmacokinetic properties
determine the onset, intensity,and the
duration of drug action
• Absorption:
• Distribution:
• Metabolism:
• Elimination:
Using knowledge of pharmacokinetic
parameters, clinicians can design
optimal drug regimens, including the
route of administration, the dose,the
frequency, and the duration of
treatment.

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Drug absorption:

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B.Factors influencing absorption:
1.Effect of pH on drug absorption:
2. Blood flow to the absorption site:
3. Total surface area available for absorption:
4. Contact time at the absorption surface:
5. Expression of P-glycoprotein:

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1.Effect of pH on drug absorption:
5. Expression of P-glycoprotein:

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Bioavailability
• Bioavailability is the rate and
extent to which an administered
drug reaches the systemic
circulation.
• For example, if 100 mg of a drug
is administered orally and 70 mg
is absorbed unchanged, the bio-
availability is 0.7 or 70%.
• Determining bioavailability is
important for calculating drug
dosages for nonintravenous
routes of administration.
Determination of bioavailability:

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2.Factors that influence bioavailability:
a.First-pass hepatic
metabolism:
b.Solubility of the drug:
c.Chemical instability:
d.Nature of the drug
formulation:

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a. First-pass hepatic metabolism :
What is FPHM:
When a drug is absorbed from the GI tract, it enters the portal
circulation before entering the systemic circulation.
If the drug is rapidly metabolized in the liver or gut wall during
this initial passage, the amount of unchanged drug entering
the systemic circulation is decreased. This is referred to as
first-pass hepatic metabolism.
First-pass metabolism by the intestine or liver limits the
efficacy of many oral medications.
For example:
More than 90% of nitroglycerin is cleared during
first-pass metabolism. Hence, it is primarily administered
via the sublingual or transdermal route.
Drugs with high first-pass metabolism should be given in doses
sufficient to ensure that enough active drug reaches the
desired site of action.

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Examples:
a. Nitroglycerin pacth b. First pass effect

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b.Solubility of the drug:
• Very hydrophilic drugs are poorly absorbed because of their
inability to cross lipid-rich cell mem-branes.
• Paradoxically, drugs that are extremely lipophilic are
also poorly absorbed, because they are totally insoluble in
aqueous body fluids and, therefore, cannot gain access to
the surface of cells.
• For a drug to be readily absorbed, it must be largely
lipophilic, yet have some solubility in aqueous solutions.
• This is one reason why many drugs are either weak acids or
weak bases.
c.Chemical instability:
Some drugs, such as penicillin G, are unstable in the pH of the
gastric contents. Others, such as insulin, are destroyed in the
GI tract by degradative enzymes.

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d.Nature of the drug formulation:
Drug absorption may be altered by factors unrelated to the
chemistry of the drug.
For example,
Particle size
Salt form
Crystal polymorphism
Enteric coatings,
Presence of excipients (such as binders and dispersing agents)
can influence the ease of dissolution and,therefore, alter the
rate of absorption.

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D.Bioequivalence
Two drug formulations are bioequivalent if they show
comparable bioavailability and similar times to achieve peak blood
concentrations.
Clinical effectiveness often depends on both the maximum
serum drug con-centration and the time required (after
administration) to reach peak concentration
E.Therapeutic equivalence
Two drug formulations are therapeutically equivalent if they are
pharmaceutically equivalent (that is, they have the same dosage
form, contain the same active ingredient, and use the same route
of administration) with similar clinical and safety profiles.
Therefore, two drugs that are bioequivalent may not be
therapeutically equivalent.

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IV. DRUG DISTRIBUTION
• Drug distribution is the process by which a drug reversibly
leaves the bloodstream and enters the interstitium
(extracellular fluid) and the tissues.
• For drugs administered IV, absorption is not a factor, and the
initial phase (from immediately after administration through
the rapid fall in concentration) represents the distribution
phase, during which the drug rapidly leaves the circulation and
enters the tissues.
• The distribution of a drug from the plasma to the interstitium
depends on cardiac output and local blood flow, capillary
permeability, the tissue volume,the degree of binding of the
drug to plasma and tissue proteins, and the relative
lipophilicity of the drug.

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Factors affecting distribution:
A. Blood flow
B. Capillary permeability
C. Binding of drugs to plasma proteins
and tissues
D. Lipophilicity
E. Volume of distribution

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A. Blood flow
1. The rate of blood flow to the tissue capillaries varies
widely.
2. For instance, blood flow to the “ vessel-rich organs ”
(brain, liver, and kidney) is greater than that to the
skeletal muscles. Adipose tissue, skin, and viscera have
still lower rates of blood flow.
3. Propofol has short duration of hypnosis produced by an
IV bolus.
4. High blood flow, together with high lipophilicity of
propofol, permits rapid distribution into the CNS and
produces anesthesia.
5. A subsequent slower distribution to skel-etal muscle
and adipose tissue lowers the plasma concentration so
that the drug diffuses out of the CNS, down the
concentration gradient, and consciousness is regained.

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B.Capillary permeability
• Capillary permeability is determined by capillary structure
and by the chemical nature of the drug.
1. LIVER AND SPLEEN:
• A significant portion of the basement membrane is
exposed due to large,discontinuous capillaries through
which large plasma proteins can pass.
2. BRAIN:
The capillary structure is continuous, and there are no
slit junctions.
• These closely jux-taposed cells form tight junctions that
constitute the blood–brain barrier.
• For example, a specific transporter carries levodopa into the brain.
By contrast, lipid-soluble drugs readily penetrate the CNS because
they dissolve in the endothelial cell membrane.
• Ionized or polar drugs generally fail to enter the CNS because they
cannot pass through the endothelial cells that have no slit junctions.

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C.Lipophilicity
1. The chemical nature of a drug strongly influences its
ability to cross cell membranes.
2. Lipophilic drugs readily move across most biologic
membranes.
3. These drugs dissolve in the lipid membranes and
penetrate the entire cell surface.
4. The major factor influencing the distribution of lipophilic
drugs is blood flow to the area.
5. In contrast, hydrophilic drugs do not readily penetrate cell
membranes and must pass through slit junctions.

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D.Volume of distribution
The apparent volume of distribution, Vd , is defined
as the fluid volume that is required to contain the
entire drug in the body at the same concentration
measured in the plasma.
Vd = Amount of drug in to the body
(C0)
Plasma concentration at time zero (C0).
Although Vd has no physiologic or physical basis, it
can be useful to compare the distribution of a drug
with the volumes of the water compartments in the
body.

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1. Distribution into the water compartments in
the body:
• Once a drug enters the body, it has the potential to
distribute into any one of the three functionally distinct
compartments of body water or to become sequestered in
a cellular site.
a. Plasma compartment:
If a drug has a high molecular weight or is extensively
protein bound, it is too large to pass through the slit
junctions of the capillaries and, thus, is effectively
trapped within the plasma (vascular) compartment.
As a result, it has a low Vd that approximates the
plasma volume or about 4 L in a 70-kg individual.
Heparin shows this type of distribution.

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b. Extracellular fluid:
• Drug with low molecular weight but is hydrophilic, it can
pass through the endothelial slit junctions of the
capillaries into the interstitial fluid.
• Hydrophilic drugs cannot move across the lipid
membranes of cells to enter the intracellular fluid.
• Therefore, these drugs distribute into a volume that is the
sum of the plasma volume and the interstitial fluid, which
together constitute the extracellular fluid (about 20% of
body weight or 14 L in a 70-kg individual).
• Example:Aminoglycoside antibiotics
c. Total body water:
Drug with LMW and is lipophilic, it can move into the
interstitium through the slit junctions and also pass
through the cell membranes into the intracellular fluid.
These drugs distribute into a volume of about 60% of
body weight or about 42 L in a 70-kg individual.

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2.Apparent volume of distribution:
1. A drug rarely associates exclusively with only one of the
water compartments of the body.
2. Instead, the vast majority of drugs distribute into several
compartments, often avidly binding cellular components,
such as lipids (abundant in adipocytes and cell
membranes), proteins (abundant in plasma and cells),
and nucleic acids (abundant in cell nuclei).
3. Therefore, the volume into which drugs distribute is
called the apparent volume of distribution (Vd ).
4. Vd is a useful pharmacokinetic parameter for calculating
the loading dose of a drug.

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3.Determination of Vd :
• The fact that drug clearance is usually a
first-order process allows calculation of
Vd . First order means that a constant
fraction of the drug is eliminated per
unit of time.
• This process can be most easily analyzed
by plotting the log of the plasma drug
concentration (Cp ) versus time.
• The concentration of drug in the plasma
can be extrapolated back to time zero
(the time of IV bolus) on the Y axis to
determine C0 , which is the
concentration of drug that would have
been achieved if the distribution phase
had occurred instantly.
• This allows calculation of Vd as
Vd= Dose
----------
Co

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V. DRUG CLEARANCE THROUGH
METABOLISM
Once a drug enters the body, the process of elimination begins.
The three major routes of elimination are hepatic metabolism,
biliary elimination,and urinary elimination.
Together, these elimination processes decrease the plasma
concentration exponentially.
That is, a constant fraction of the drug present is eliminated in
a given unit of time.
Most drugs are eliminated according to first-order kinetics,
although some,such as aspirin in high doses, are eliminated
according to zero-order or nonlinear kinetics.
Metabolism leads to production of products with
increased polarity, which allows the drug to be eliminated.

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• Clearance(CL) estimates the amount
of drug cleared from the body per
unit of time.
• Total CL is a composite estimate
reflecting all mechanisms of drug
elimination and is calculated as
follows:
CL = 0 . 693 × Vd / t 1/2

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Kinetics of metabolism:
1.First-order kinetics:
The metabolic transformation of drugs is catalyzed by enzymes,
and most of the reactions obey Michaelis-Menten kinetics.
V max [ C ]
v = Rate of drug metabolism = ------------------------
K m + [ C ]
In most clinical situations, the concentration of the drug, [C], is
much less than the Michaelis constant, K m , and the Michaelis-
Menten equation reduces to
v = Rate of drug metabolism = V max [ C ]
K m
This means that a constant fraction of drug is metabolized per
unit of time (that is, with each half-life,the concentration
decreases by 50%). First-order kinetics is also referred to as linear
kinetics.

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2.Zero-order kinetics:
• With a few drugs, such as aspirin, ethanol,and phenytoin,
the doses are very large. Therefore, [C] is much
greater than Km , and the velocity equation becomes
V max [ C ]
v = Rate of drug metabolism = [ C ] = V max
• The enzyme is saturated by a high free drug concentration,
and the rate of metabolism remains constant over time.
This is called zero-order kinetics (also called nonlinear
kinetics).
• A constant amount of drug is metabolized per unit of time.
The rate of elimination is constant and does not depend on
the drug concentration.

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B.Reactions of drug metabolism
The kidney cannot efficiently eliminate lipophilic drugs that
readily cross cell membranes and are reabsorbed in the distal
convoluted tubules.
Therefore, lipid-soluble agents are first metabolized into more
polar (hydrophilic) substances in the liver via two general sets
of reactions, called phase I and phase II.

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1.Phase I:
• Phase I reactions convert lipophilic drugs into more polar
molecules by introducing or unmasking a polar functional
group,such as –OH or –NH 2 .
• Phase I reactions usually involve reduction, oxidation, or
hydrolysis.
• Phase I metabolism may increase,decrease, or have no effect
on pharmacologic activity.
• a.Phase I reactions utilizing the P450 system:
• Most frequently involved reactions in drug metabolism are
catalyzed by the cytochrome P450
• The P450 system is important for the metabolism of many
endogenous compounds (such as ste-roids, lipids) and for the
biotransformation of exogenous substances (xenobiotics).
• Cytochrome P450, designated as CYP,is a superfamily of
heme-containing isozymes that are located in most cells, but
primarily in the liver and GI tract.

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[1] Nomenclature: The family name is indicated by the Arabic
number that follows CYP, and the capital letter designates
the subfamily, for example, CYP3A. A second
number indicates the specific isozyme, as in CYP3A4.
[2] Specificity:
Different P450 isoforms present.
Have the capacity to modify a large number of structurally
diverse substrates.
An individual drug may be a substrate for more than one
isozyme.
Four isozymes are CYP3A4/5,CYP2D6, CYP2C8/9, and
CYP1A2.
Most of the CYP3A4 are found in intestinal mucosa,
accounting for first-pass metabolism of drugs such as
chlorpromazine and clonazepam.

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66
[3] Genetic variability:
P450 enzymes exhibit considerable genetic variability among
individuals and racial groups.
Variations in P450 activity may alter drug efficacy and the
risk of adverse events.
CYP2D6, in particular, has been shown to exhibit genetic
polymorphism.
CYP2D6 mutations result in very low capacities to metabolize
substrates.
No benefit from the opioid analgesic codeine due to lack the
CYP2D6 enzyme that activates the drug.
Clopidogrel (prodrug) in poor CYP2C19 metabolizers have a
higher incidence of cardiovascular events.
Although CYP3A4 exhibits a greater than 10 fold variability
between individuals, no polymorphisms have been identified so
far for this P450 isozyme.

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[4] Inducers:
• The CYP450-dependent enzymes are an important target for
pharmacokinetic drug interactions through inducing the CYP
iszymes.
• Certain drugs (phenobarbital, rifampin, and carbamazepine)
increasing the synthesis of one or more CYP isozymes. results
in loss of pharmacological effect of drugs which are
metabolized by these CYP isozymes.
• Rifampin significantly decreases the plasma concentrations of
HIV pro- tease inhibitors, thereby diminishing their ability to
suppress HIV replication.
• St. John’s wort is a widely used herbal product and is a potent
CYP3A4 inducer.
• Many drug interactions have been reported with concomitant
use of St. John’s wort.

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[5] Inhibitors:
An important source of drug interactions that lead to serious
adverse events.
Inhibition of drugs metabolism is through competition for the
same isozyme.
Omeprazole is a potent inhibitor of three of the CYP isozymes
responsible for warfarin metabolism.
If the two drugs are taken together, plasma concentrations of
warfarin increase, which leads to greater anticoagulant effect
and increased risk of bleeding.
More important CYP inhibitors are erythromycin,ketoconazole,
and ritonavir, because they each inhibit several CYP isozymes.
Grapefruit juice inhibits CYP3A4 and leads to higher levels
and/or greater potential for toxic effects with drugs, such as
nifedipine, clarithromycin, and simvastatin, that are metabolized
by this system.

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b.Phase I reactions not involving the
P450 system:
These include
Amine oxidation (catecholamines or histamine)
Alcohol dehydrogenation (ethanol oxidation)
Esterases (metabolism of aspirin in the liver)
Hydrolysis (procaine).

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2.Phase II:(conjugation reactions)
• Polar metabolite of drugs can be excreted by the kidneys.
• Lipophillic metabolite (after phase I
metabolism) ,subsequent conjugation reaction with an
endogenous substrate, such as glucuronic acid, sulfuric acid,
acetic acid, or an amino acid, results in polar, usually more
water-soluble compounds that are often therapeutically
inactive.
• A notable exception is morphine-6-glucuronide, which is
more potent than morphine.
• Glucuronidation is the most common and the most
important conjugation reaction.
• Drugs already possessing an –OH, –NH 2 , or –COOH group
may enter phase II directly and become conjugated
• The highly polar drug conjugates are then excreted by the
kidney or in bile.

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VI. DRUG CLEARANCE BY THE KIDNEY
Polar drugs are eliminated easily from the body.
Number of routes are available for elimination, the most
important being elimination through the kidney into the
urine.
Patients with renal dysfunction may be unable to excrete
drugs and are at risk for drug accumulation and adverse
effects.
Elimination of drugs via the kidneys into urine involves the
processes
– Glomerular filtration,
– Active tubular secretion
– Passive tubular reabsorption.

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1.Glomerular filtration:
Free drug (not bound to albumin) flows through the
capillary slits into the Bowman space as part of the
glomerular filtrate.
The glomerular filtration rate (GFR) is normally about 125
mL/min but may diminish significantly in renal disease.
Lipid solubility and pH do not influence the passage of
drugs into the glomerular filtrate.
However, variations in GFR and protein binding of drugs do
affect this process.

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73
2. Proximal tubular secretion:
Drugs that were not transferred into the glomerular filtrate
leave the glomeruli through efferent arterioles,(network)
Two energy-requiring active transport systems take part in
secretion of drugs: one for
a. For anions (deprotonated forms of weak acids)
b. For cations (protonated forms of weak bases).
Each of these transport systems shows low specificity and
can transport many compounds.
Thus, competition between drugs for these carriers can
occur within each transport system.
Premature infants and neonates have an incompletely
developed tubular secretory mechanism and, thus, may
retain certain drugs in the glomerular filtrate.

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3.Distal tubular reabsorption:
As a drug moves toward the distal convoluted tubule, its
concentration increases and exceeds that of the perivascular
space.
The uncharged drug may diffuse out of the nephric lumen,
back into the systemic circulation.
Manipulating the urine pH to increase the fraction of ionized
drug in the lumen may be done to minimize the amount of
back diffusion and increase the clearance of an undesirable
drug.
As a general rule, weak acids can be eliminated by
alkalinization of the urine,whereas elimination of weak bases
may be increased by acidification of the urine. This process is
called “ion trapping.”
For example,a patient presenting with phenobarbital (weak
acid) overdose can be given bicarbonate, which alkalinizes
the urine and keeps the drug ionized, thereby decreasing its
reabsorption.

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4.Role of drug metabolism:
Most drugs are lipid soluble and, without chemical
modification, would diffuse from the tubular lumen to
perivascular space (why) due to concentration gradient
between the drug concentration in the filtrate and
perivascular space.
To minimize this reabsorption, drugs are modified primarily
in the liver into more polar substances via phase I and
phase II reactions.
The polar or ionized conjugates are unable to back diffuse
out of the kidney lumen.

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Summery Drug elimation:

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77
VII. CLEARANCE BY OTHER ROUTES
Drug clearance may also occur via the intestines, bile, lungs,
and breast,milk etc.
Drugs that are not absorbed after oral administration or drugs
that are secreted directly into the intestines or into bile are
eliminated in the feces.
The lungs are primarily involved in the elimination of anesthetic
gases (for example, isoflurane).
Elimination of drugs in breast milk may expose the breast-
feeding infant to medications and/or metabolites being taken by
the mother and is a potential source of undesirable side effects
to the infant.
Excretion of most drugs into sweat, saliva, tears,hair, and skin
occurs only to a small extent.
Total body clearance and drug half-life are important measures
of drug clearance that are used to optimize drug therapy and
minimize toxicity.

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A.Total body clearance:
The total body (systemic) clearance, CL total , is the sum of
all clearances from the drug-metabolizing and drug-
eliminating organs.
The kidney is often the major organ of elimination. The liver
also contributes to drug clearance through metabolism
and/or excretion into the bile.
Total clearance is calculated using the following equation:
CL total = CL hepatic + CL renal + CL pulmonary + CL other
where CL hepatic + CL renal are typically the most
important.

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B.Clinical situations resulting in
changes in drug half-life
• Adjustment in dosage is required when a patient has an
abnormality.
Increase in drug half-life include in case of
1) diminished renal or hepatic blood flow
2) decreased ability to eliminate drug from plasma
3) decreased metabolism,
These patients may require a decrease in dosage or less
frequent dosing intervals.
In contrast, the half-life of a drug may be
1) decreased by increased hepatic blood flow
2)decreased protein binding, or increased metabolism.
This may necessitate higher doses or more frequent dosing
intervals.

1.introduction to pharmacology

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