FOR BACHELOR OF PHARMACY STUDENTS

By Tasisa Ketema (MSc, B.Pharm)

August, 2022
INTRODUCTION
What is Pharmacology?
 Derived from Greek “pharmakon [drug], logos
[Science ].
 Pharmacology is the science of drugs dealing
with FATE and ACTION [pharmacokinetics and
pharmacodynamics] of drugs.
 Pharmacology studies the effects of drugs and
how they exert their effects.

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 What are drugs?
 No definition of drugs yet offered is entirely
satisfactory.
 However it can be defined as “chemicals that
can alter functions of living organisms at small
concentration” are all drugs
 For medical case these drugs are intended for:
treatment, diagnosis, prevention and control
of diseases
 Despite all these facts drugs cause
toxicity ’iatrogenic disease’, Outcomes are
therefore separate from definition of drugs
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Branches of pharmacology
 Pharmacology is a vast science having major
sub-divisions:
 Pharmacodynamics
It is a branch of pharmacology that deals with the
mechanism of action and drug effects
In general it deals with action of drug on the body
[what the drug do on the body].
 Pharmacokinetics
Quantitative study of the relation among drug dose,
concentration and magnitude of effect.
It deals with the action of body on the drug
[what the body do on the drug].
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 Pharmacology do also have other sub-division,
based on different criteria, for example:
1.The organ system of primary concern
 Neuropharmacolgy, Cardiovascular pharmacology,
Renal pharmacology, Chemotherapy etc
2.Techniques used
Biochemical pharmacology, Molecular
pharmacology, Behavioral pharmacology etc
3.Purpose or application to which the
knowledge is used:
Clinical pharmacology, Pharmacogenomics,
Toxicology, Agricultural pharmacology

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Pharmacology related fields
 Pharmacy: the science of drug preparation
and monitoring of proper utilization
 Pharmacotherapeutics: the science of drug
use in the treatment of disease
 Pharmacology lays its foundations on the
principles of: biochemistry, physiology,
molecular biology, chemistry, biophysics,
pathology, etc
 Pharmacology is not concerned primarily for
what the drug is used but with what actions it
has and what fate it encounters in the body.
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HISTORY OF PHARMACOLOGY
 Primitives undoubtedly recognized the beneficial
or toxic effects of many plant and animal
products
– Herbal Remedies
– Arrow Poisons [d-tubocurarine]
– Mood altering plants [Opium ,nicotine,
hashish]
 Ancient
– Preservative substances (Egyptian Mummification)
– 100 A.D. = 600 substances listed in the Roman
“Materia Medica” (the science of drug preparation
and the medical use of drugs)
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 Medieval period
– Plants and herbs are classified
– Relationship of dose to toxicity is recognized
– Use of poisons for homicide prevalent
 17th and 18th Century
– Increased knowledge of drugs and shared
with world as increase in world travel
continued
– Widely accepted by physicians

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 Synthetic organic chemistry was born in 1828,
when Friedrich Wohler synthesized urea from
inorganic substances
 In the early 19th century, physiologists
performed many pharmacologic studies.
François Magendie studied the action of nux
vomica on dogs, and showed that the spinal cord
was the site of its convulsant action.
Claude Bernard discovered that the arrow poison
curare acts at the neuromuscular junction to
interrupt the stimulation of muscle by nerve
impulses.
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In 1847, Rudolf Buchheim was appointed
professor of pharmacology at the University of
Dorpat in Estonia
• Buchheim built a laboratory at his own
expense in the basement of his home (turning
the purely descriptive and empirical study of
medicines into an experimental science)
• In 1872, he became professor of pharmacology
at the University of Strasburg, receiving
generous government support in the form of a
magnificent institute of pharmacology

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 In 1869, Schmiedeberg showed that muscarine
evoked the same effect on the heart as electrical
stimulation of the vagus nerve
• In 1878, he published a classic text, Outline of
Pharmacology, and in 1885, he introduced
urethane as a hypnotic.
• He was largely responsible for the preeminence of
the German pharmaceutical industry up to World
War II.

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 In the United States, the first chair in pharmacology
was established at the University of Michigan in 1890
under John Jacob Abel, an American who had trained
under Schmiedeberg
• In 1893, Abel went to Johns Hopkins University in
Baltimore, where he had a long and brilliant career
• His major accomplishments include the isolation of
epinephrine from adrenal gland extracts (1897–1898),
isolation of histamine from pituitary extract (1919),
and preparation of pure crystalline insulin (1926).
• His student Reid Hunt discovered acetylcholine in
adrenal extracts in 1906.
• Today, there is a pharmacology department in every
college of medicine or pharmacy.
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 In general in 19th Century
– The beginning of the modern science of
pharmacology
– Problems with
 Dose – effect relationship
 Processes involved in absorption/excretion
 Localization of the site of action of a drug
 Specific mechanisms of drug action
 Relation between chemical makeup &
biologic activity of substances were
recognized

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Sources of Drugs
Plants
Microorganisms
Animals
Chemical synthesis
Biotechnology
Semi-synthetic: heroin, oxacilin, fludrocortison

 Currently majority of the drugs used in

therapeutics are from synthetic source

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1-Plant sources
Various parts of plants may be used as sources of
drugs e.g. Leaves of belladonna for atropine, Bark
of cinchona for quinine and quinidine.
2-Animal sources
Insulin from pancreas of different animals e.g.
cattle or pig
3-Mineral sources
e.g. Magnessium sulphate and iodine
4-Microrganism:
Fungi and bacteria isolated from soil are
important sources of antibiotics e.g.pencillin
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5-Synthetic drugs:
Many drugs are produced in the laboratory
e.g. Sulphonamide, barbiturates, aspirin
6-Biotechnology:
Human insulin and growth hormone have
successfully been produced by genetic
engineering

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 DRUG NOMENCLATURE

 Many names are given to drugs often confusing.

 It is therefore necessary to know drug
nomenclature.
 The following is the drug name system
1) Chemical/Molecular/Scientific name:
 It depicts the chemical/molecular structure of the
drug
 e.g. N-acetyl-p-amino-phenol (Paracetamol)

N-acetyl-p-amino-phenol
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2) Non-Proprietary/Generic/Approved Name:
It is the official medical name of the drug. Removes
confusion of giving several names to the same drug
regardless of who manufactures them e.g:
paracetamol (Britain English) or Acetamenophen
(American English)
3) Proprietary/Trade/Brand Name: These are
names given to the drug by the manufacturing
and marketing company. In most cases one
drug could have so many trade/brand names
e.g paracetamol has many trade names. Like:
Pacimol, Tylenol, Paramol, Panadol, Capol etc.

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4) Code Name

 The name assigned for the drug before

approved.
 Eg, RO 15-1788
 Which is later named Flumazenil.

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 Routes of drug administration

 There are three types of classification:

I. Routes of administration can be:
 Enteral routes: administration through the
alimentary tract (oral, sublingual, and rectal
route)
 Parenteral routes: administration through
other sites, non alimentary (injections,
inhalation)
 Topical route: local application of drugs on
the skin and mucus membrane

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Classification of routes…
II. Routes of administration can be divided also
 Intravascular route: the drug is placed directly
in to the blood stream (I.V).
 Extravascular route: the drug reaches the
blood stream via absorption from site of
administration e.g. oral, rectal, I.M, S.C…)

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Classification of routes…

III. Routes of administration can be divided

also in to:
 Those for local action
 Those for systemic action

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1. Systemic routes of
administration

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 1.1. Oral ingestion
 Administration of drugs through the mouth
 Administered for systemic effects.
 It is the most common method of drug
administration
 Advantages:
 Safe, most convenient and economic
 Often painless
 Untoward effect, if any, appears slowly
 Reverse of dose management is easily done (how?)

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1.1. Oral …
 Disadvantages:
 Slow onset of action (why?)
 Not suitable for Unpalatable drugs
 Not suitable for uncooperative /unconscious/
vomiting patients, unable to swallow
 Not suitable for Irritant drugs and drugs which are
poorly absorbed, metabolized extensively in the gut
by gut flora and liver (first-pass metabolism).

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1.1. Oral …
 Not suitable for acid sensitive drugs (e.g. penicillin G
preparations) and for drugs which may be inactivated
by gastric enzymes (e.g. insulin).
 Drug-food interactions may lead to formation of
unabsorbable complexes
 Presence of food in stomach delays gastric emptying
and delays the onset of action
 Dosage forms: liquids and solids (tablets and capsules)

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1.2. Parenteral route
 Par = beyond and enteral = intestine
 Drug directly introduced into tissue fluids or blood
without having to cross the intestinal mucosa.
 Routes include
 Intravenous (iv)
 Intramuscular (im) Most common
 Subcutaneous (sc)
 Other parenteral routes include
 Intraarterial
 Intrathecal Less common
 Intraarticular
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 1.2. Parenteral cont.…..
 Advantages:
 Action faster (hence valuable in emergencies)
 Employed in
unconscious/uncooperative/vomiting patients
 Interference of food or digestive juice and first
pass effect is bypassed to a certain extent.
 Disadvantages:
 Preparation is expensive
 Need of assistance during administration
 Dosage forms: liquid preparations
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 A. Intravenous administration

 Drug injected as a bolus or infused slowly

over hours in one of the superficial veins
 Only aqueous solutions can be injected
 Advantages:
Suitable during emergency conditions; rapid onset
of action
Large volume of the drug can be administered
Too irritant drugs are to be administered
(insensitivity and rapid dilution)
Consciousness and cooperation is not necessary
Bioavailability is 100%, why? 29
 Intravenous…
 Disadvantages:
Difficulty of administration, painful
Once administered, it can not be taken out.
More chance of thrombophlebitis, air embolism,
hemolysis
Needs strict sterility (Possible spread of disease)
Velocity reaction due to rapid injection e.g.
theophyline
Sever anaphylactoid or hypersensitivity reactions in
allergic patients
Not economic for the patient (expensive)
Not suitable for suspensions, oily and alcoholic
solutions
No local action 30
B. Intramuscular administration
 Drug is injected in one of the large skeletal muscles:
deltoid, triceps, gluteus maximus, rectus femoris etc.
 Muscle is less richly supplied with sensory nerves and
(mild-moderate irritants can be applied) and is more
vascular (absorption is faster)
 Both soluble & insoluble drugs (suspension, oily
preparations) can be administered.
 Care not to inject in nerves (severe pain and paresis)
or vessels (serious toxic effect)
 Massage, heat and exercise increases absorption

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C. Subcutaneous administration

 The drug is deposited in the loose subcutaneous

tissue
 Is richly supplied by nerves (unsuitable for irritant
drug administration) & less vascularized (slow
absorption)
 Self injection is simple
 Oily solution or aqueous suspensions can be injected
for prolonged action

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1.3. Sublingual administration

 Tablets are placed under the tongue to be

dissolved in saliva.
 Drugs are absorbed directly in to systemic
circulation.
 E.g. nitroglycerine, clonidine, isoprenaline and
methyl testestrone

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1.3. Sublingual …
 Advantages:
Rapid onset of action
Self administration possible
First pass effect bypassed
Unwanted side effects can be avoided to some extent
(excess drug can be expelled)
 Disadvantages:
Irritant, water soluble and distasteful drug can not be
administered
Frequent use may cause ulceration locally
Excessive salivation my lead to swallowing of the
drug and advantage of sublingual is lost
Not suitable for children
Dosage forms: tablets 34
1.4. Rectal administration
 Drugs are inserted into the rectal route as
suppositories or enema for systemic and local
effect.
 Advantages:
cooperation and consciousness is not necessary
Irritant and unpleasant drugs can be administered
The effect of digestive enzymes is avoided
50% bypass the first pass effect
Suitable for vomiting, unable to swallow patients

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1.4. Rectal…
 Disadvantage:-
 It is inconvenient and embarrassing
Absorption is slower, irregular and often
unpredictable
Many drugs can cause irritation to the mucosa
 Dosage forms given rectally:
Suppositories
Enemas
Evacuation enema- to evacuate bowel before
procedure
Retention enema-insert drug to act locally or
systemically 36
1.5. Pulmonary administration
 Suitable for aerosol, gas and volatile liquid drugs.
 Drug is administered by inhalation with the inspired
air either through the nose or mouth in to the lung.
 Rapid absorption due to large surface area, rich
blood supply, rapid circulation
 Advantage: Rapid absorption, avoidance of hepatic
first pass effect, used for both local and systemic
application
 Disadvantage: Poor ability to regulate the dose and
irritation of the pulmonary mucosa

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38
2. Topical administration

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 Application could be on mucous
membranes, skin or the eye.
 Mucous membranes
 Drugs are applied on the mucous membranes
of the conjunctiva, nasopharynx, oropharynx,
vagina and colon usually for their local effects.
 Absorption through mucous membranes occur
readily to cause systemic effects

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 Skin
 Absorption is proportional to the surface area and
lipid solubility of the drug.
 Conditions that increase cutaneous blood flow
enhance absorption.
 Systemic absorption from skin is sometimes a reason
of toxicity.
 Eye
 Ophthalmic preparations are meant for their local
action
 Systemic absorption that results from drainage
through the nasolacrimal canal is usually undesirable
 Very little is lost through drainage; hence, systemic
side effects are minimized.
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42
 Factors governing choice of route of
administration
 Physical and chemical properties of the drug
(solid/liquid/semisolid/gaseous/lipid
solubility/stability/PH/irritancy)
 Site of desired action (localized or generalized)
 Rate and extent of absorption from different routes
 Effect of gastric acidity, digestive juices and first pass
effect
 Rapidity with which the response is desired
 Accuracy of dosage required (I.V and inhalation can
provide fine tuning)

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Factors governing choice…

 Condition of the patient (unconsciousness, vomiting,

presence of contraindication for certain routes,
severity of disease, emergency condition…)
 The available dosage form in the market
 Economic condition of the patient( injections need
syringes and an assistant, some dosage forms are
expensive)
 Personal factors (e.g. preference )

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Pharmacokinetics

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 Pharmacokinetics
 Pharmacokinetics deals with absorption, distribution,
metabolism and excretion of drugs.
 Pharmacokinetics describes what the body does to the
drug.
 To produce its characteristic effects, a drug must be
present in appropriate concentration at its site of
action.
 Concentration at the site of action depends on
absorption, distribution, binding or localization in
tissues, biotransformation, and excretion.
 All the pharmacokinetic processes involve passage of
drug through membranes.
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47
 THE MOVEMENT OF DRUG MOLECULES
ACROSS CELL BARRIERS
 Drug to be absorbed, it must be able to cross the
biological membrane.
 Cell membrane is semipermeable bilipid layer through
which some molecules pass freely, some others pass
with difficulty and few can not pass.
 The cell membrane consists of lipid and intermingled
protein in the ratio 1:1.
One part is hydrophilic and other part is
hydrophobic.

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 THE MOVEMENT Cont ….
 Protein in the membrane is arranged randomly as
peripheral protein and integral protein.
– The peripheral protein acts:
• To provide membrane integrity
• As enzyme
• As receptor
• As pores for filtration of water soluble drugs
• As carrier

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50
THE MOVEMENT…
 Processes of drug transfer across membrane:
 Generally two types:
A. Passive transport
– Simple diffusion
– Filtration
B. Specialized transport
– Facilitated diffusion
– Active transport
– Endocytosis
– Ion pair transport

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Passive transport
 Simple diffusion:
Slow, commonest process of drug transport
passage of lipid soluble, uncharged drugs through
membrane
Across concentration gradient.
Carrier and energy independent.

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 Passive…
 Factors that affect simple diffusion:
Lipid solubility
Pka of the drug
Concentration
Surface area
PH of absorption site (media)
 Filtration:
Means passage of water soluble, ion and some non
polar molecules of low molecular weight through
the pores of the membrane.

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 PH and pharmacokinetics
 Most drugs are weak electrolytes, either weak acids or
weak bases and their ionization depends on the PH:
– Acids are ionized (lipid insoluble) in basic media
– Bases are ionized in acidic media
– Pka is the PH at which a drug is 50% ionized and 50%
unionized
• Unionized drugs are better absorbed while ionized ones
are not from stomach, intestine or other routes

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 PH and pharmacokinetics
 Drug elimination via the kidney: urine PH (4.5-7.5)
– for weak acids re-absorption will occur in acidic urine
and eliminated in basic urine
– For weak bases re-absorption occurs in basic urine
and eliminated in acidic urine
• Drug distribution in to/across milk and placenta:
– Milk and placenta have acidic PH of 7.0 in relation to
plasma PH 7.4. thus bases tend to concentrate in the
compartments, b/c they become ionized on the acidic
side and effectively trapped (called ion trapping).

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Specialized transport
1. Facilitated diffusion:
 quick process than passive transport
 Carrier dependent
 Across concentration gradient
 No need of energy
 Shows Saturability and selectivity
Saturability-when binding sites of the carrier is
completely occupied.
Selectivity-selection of drugs with specific chemical
structure by the carrier
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Specialized …
2. Active transport:
– Very quick process
– Energy and carrier dependent
– Against concentration gradient
– Shows selectivity and saturability
3. Endocytosis: engulfment of large molecules by the
cell membrane and release them intra-cellulary
– Pinocytosis (fluid phase endocytosis)
– Phagocytosis (adsorptive phase endocytosis)
4. Ion-pair transport: highly ionized cpds form neutral
ion pair complex. This complex penetrates the
membrane by simple diffusion.
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1. Absorption
 Absorption is the movement of a drug from its site of
administration in to the central compartment (blood)
and the extent to which this occurs
 Except when given intravenously, the drug has to
cross biological membrane
 Numerous factors can affect the movement of drugs
across biological membrane

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Factors that affect absorption
I. Aqueous solubility
II. Concentration
III. Surface area of absorption
IV. Vascularity of absorption surface
V. Route of drug administration
Aqueous solubility
 Absorption first requires dissolution of tablets or
capsules
 For poorly water soluble drugs (Aspirin,
Griseofulvin) rate of dissolution governs rate of
absorption
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Concentration
 Absorption is higher from higher concentration of
drug
Surface area of absorption
 Greater surface area helps in absorption
Vascularity of absorption surface
• Good circulation facilitates absorption
Route of drug administration
• Affects drug absorption, because each route has its
own peculiarities.

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 Bioavailability

 Refers to the rate and extent of absorption of a drug

 Bioavailability: fraction of administered drug (F) that
reaches the systemic circulation in unchanged form
 The area under the blood concentration time-curve
is a common measure of the extent of bioavailability

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 BA = AUC Oral X100%
AUC Injected IV

Cp A
C B

AUC= shows extent of absorption or amount of the

drug inter to the blood
Cp= Plasma concentration
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NB
 Formulation B is more slowly absorbed than
formulation A, and ultimately both are absorbed to
the same extent (area under the curve is the same),
B may not produce therapeutic effect
 C is absorbed to less extent-low bioavailability, rate
of absorption of A is same as C.

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Eg; A(100mg) B(30mg)+A(70mg)
F= 70/100=70%
 Bioavailability of drug “A” is 70%, which is the
amount that reaches systemic circulation in
unchanged form.
 Bioavailability is expressed in percentage
 Bioavailability is 100% for drugs given IV.
Factors affecting bioavailability
Extent of absorption
First pass effect

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Bioequivalence
 Pharmaceutical equivalents- pharmaceutically
equivalents could have;
Same active ingredients
Identical in strength or concentration
Dosage form, and
Route of administration
 Bioequivalent
 Two pharmaceutically equivalent drug products are
considered to be bioequivalent when the rate and
extents of bioavailability of the active ingredient in
the two products are not significantly different under
suitable test conditions. 65
 Therapeutic equivalence
Two products which are bioequivalent may not be
therapeutically equivalent.
Two products are said to be therapeutically
equivalent when they have comparable efficacy
and safety.

66
 Difference in BA are due to variation in;
 Disintegration
 Dissolution
 Rate of disintegration depends;
Manufacturing process
Nature of additives
 Rate of dissolution depends on;
Inherent solubility
Particle size

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 BA variation assumes practical significance for drugs
with low safety margin eg. Digoxin
 It may also be responsible for success or failure of an
antimicrobial regimen

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 2. Drug Distribution

 Process by which a drug reversibly leaves the blood

stream & enters the interstitial and/or cells of the
tissues.
 Factors affecting drug distribution
1. Lipid solubility, Ionization, Blood flow, Barriers,
Tissue uptake
2. Plasma and tissue protein binding
Albumin[acidic drugs]
-glycoprotein [basic drugs]

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 Movement of drugs proceed until an equilibrium is
established between unbound drug in plasma and
tissues.
 Subsequently there is a parallel decline in both due
to elimination

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 Volume of Distribution (Vd)

 Presuming that the body has single homogenous

compartment with volume V in to which drugs
get immediately and uniformly distributed.

Vd = Amount of drug in the body

C
 An apparent volume --- “the volume that would
accommodate all the drug in the body, if the
concentration through out is the same as plasma”
71
 E.g, if 25mg of a drug is administered and the plasma
concentration is 1mg/L. find Vd ?
Vd = 25mg
1mg/L
Vd = 25L
 Lipid insoluble drugs couldn’t inter cells ------ Vd
approximates extracellular fluid volume.
 Drugs extensively bound to plasma proteins have low
Vd.
 Drugs sequestered in other tissues may have Vd much
more than total body water or even body mass.

72
 Incase of poisoning, drugs with large volume of
distribution are not easily removed by hemodialysis.
Factors governing volume of distribution
• Lipid-water partition coefficient of the drug
Increase in partition coefficient will increase lipid
solubility that results in large Vd
 Pka value of the drug
Polar drugs remain in the blood-- low Vd
 Degree of plasma protein binding
Increased plasma protein binding end up with low Vd

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 Fat: lean body mass ratio
 Disease like CHF, uremia, cirrhosis
CHF decrease blood flow to tissues--- low Vd
Cirrhosis decrease plasma proteins that decrease
binding of drug in plasma------high Vd
Uremia increases plasma proteins ---low Vd

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 Phase of drug distribution
A) Rapid phase- most of the drugs initially distributed
to the highly perfused organs such as heart, brain,
kidneys and liver
B) The slow phase- involves distribution of drugs to
larger fraction of body mass as muscle, skin and fat.
C) Selective distribution- chloroquine is selectively
distributed and accumulated in liver, tetracycline in
bone, thiopental and other general anesthetics
accumulated in brain tissues.

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D) Redistribution- inhalation initially get
distributed to organs with high blood flow e.g,
brain, heart, kidney, etc and later, less vascular
but more bulky tissues such as muscle and fat
takes up the drug.
 Redistribution results in termination of drug
action e.g, thiopental
Thiopental site of action is brain but its
redistribution to adipose tissue terminates its
anesthetic effect.
 But all drugs do not show termination of action
up on redistribution 76
Plasma protein binding

 Most drugs posses physicochemical affinity for

plasma proteins
 Acidic drugs generally binds to plasma albumin
and basic drugs to α-acid glycoprotein
 The clinical significance implication of plasma
protein binding:
Highly plasma protein bound drugs are largely
restricted to the vascular compartments and tend
to have low Vd.

77
 The bound fraction is not available for action---
however, its an equilibrium with the free drug in
plasma and dissociates when the concentration of
the later is reduced due to elimination
 High degree of protein binding generally makes the
drug long acting, because bound fraction is not
available for metabolism or excretion.
 High protein bound drugs are not removed by
haemodialysis and needs special techniques for
treatment of poisoning.

78
Drugs bound to plasma protein

To albumin To α-acid glycoprotein

Barbiturate β-blockers
Benzodiazepines Bupivacaine
NSAIDs Lidocaine
Valproic acid Disopyramide
 Phenytoin Imipramine
Sulfonamides Quinidine
Tolbutamide Verapamil
Warfarin
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 One drug can bind to many site on albumin molecule
 Conversely more than one drug can bind to the same
site on albumin.
 This can give rise to displacement interactions among
drugs bound to the same site on albumin
 Drugs bound with higher affinity will displace that
bound with low affinity.
 Displaced drug will be free and increase the
percentage of free drug in our body and leads to
toxicity.

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 Some clinically important displacement
interactions are:
Phenylbutazone and salicylate displaces
tolbutamide
Indometacin, phenylbutazone displace warfarin
Sulfonamides and vitamin k displaces bilirubin
Salicylates displace methotrixate
NB:
 Acidic drugs do not displace basic drugs
 Two highly bound drugs do not displace each other

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Penetration in to brain and CSF
 The distribution of drugs in to the CNS is unique.
 One reason for this is that the brain capillary
endothelial cells has continuous tight junction (BBB),
therefore drug penetration in to the brain depends on
trans cellular rather than paracellular transport.
 The lipid solubility of the non ionized and unbound
species of a drug is therefore an important
determinant of its uptake by the brain --- the more
liphophilic the drug is, the more likely it cross the BBB.
 Inflammation such as meningitis increase the gap
between cellular spaces and allows drugs to cross in to
the brain unlike the usual.
82
Passage across placenta
 Placental membranes are lipoidal and allow
free passage of liphophilic drugs, while
restricting hydrophilic drugs.
 The fetal plasma is slightly more acidic than
that of the mother (PH 7.0 to 7.2 versus 7.4),
so that ion trapping of basic drugs can occur

83
3. Biotransformation/Metabolism

 Chemical alteration of drug structure - w/c may

result in ;
 inactivation
activation (prodrug) of the drug.
Activation from another active drug
 Protects the body from ingested toxins
 Most hydrophilic drugs excreted in unchanged
form
 Main site of biotransformation
– Liver, intestine, plasma, lungs
84
 Reaction can be classified;
1. Phase I rxn (non synthetic rxn)
Metabolite may be active or inactive
2. Phase II rxn (synthetic/conjugation rxn)
Metabolite is mostly inactive

85
Phase I Rxn
 Introduce or expose a functional group on the
parent compound
 Generally result in the loss of pharmacological
activity
 Sometimes it results in retention or
enhancement of activity
 Convert pro drugs to active metabolites by
hydrolysis of an ester or amide linkage
 Pro drugs are designed to maximize the
amount of active species that reaches its site
of action. 86
 Products of phase I reaction if not rapidly
excreted, it can inter in to phase II reaction.
Types of phase I reactions
 Oxidation- the most important drug
metabolizing reactions
Carried out by the group of monooxygenases in the
liver.
 Reduction- this reaction is the converse of
oxidation reaction and CYP-450 enzymes
working in opposite direction
Drugs primarily reduced are chloralhydrate,
chloramphenicol and halothane
87
 Hydrolysis- this is cleavage of drug molecule by
taking up water
Similarly amides and poly pepetides are cleaved by
amidases and peptidases.
Occurs in liver, intestine, plasma and other tissues
Eg, choline esters, procaine, lidocaine,
procainamide, pethidine and oxytocin
 Cyclization- this is formation of ring structure
from straight chain compound. Eg, proguanil
 Decyclization- this is the opening up of ring
structure of the cyclic drug molecule. Eg,
barbiturates, phenytoin
88
Phase II (synthetic rxn)

 Involves conjugation of the drug or its phase I

metabolite with an endogenous substance
such as glucorunic acid, sulfate, glutathione,
amino acids, acetate etc.
 Which is generally derived from carbohydrate
or amino acids
 The end product is generally inactive highly
polar organic acid which can be easily
excreted with urine.
Eg, active conjugate is morphine-6-glucuronide
89
Site of biotransformation
 Enzymes system responsible for
biotransformation are available in liver.
 Other site includes, GIT, kidney and lung
Phase I metabolizing enzymes are found in
Endoplasmic Reticulum
Major phase I enzymes includes---CYP 3A4/5
(50%), CYP 2D6 (20%) and CYP 2C8/9
Phase II metabolizing enzymes are found in Cytosol
Major phase II enzymes includes--- glucuronyl
transferase, sulfotransferases, N-acetyl
transferase
90
 The drug metabolizing enzymes are divided in
to two types:
Microsomal
Non microsomal
Microsomal
 The monooxygenase, CYP450, glucuronyl transferase
are microsomal enzymes
 Catalyze most of the oxidations, reductions, hydrolysis
and glucuronide conjugation
 Microsomal enzymes are inducible by drugs, diet and
other agents.

91
Non microsomal
 Present in the cytoplasm and mitochondria of
hepatic cells as well as in other tissues
including plasma.
 The flavo protein oxidases, estrases, amidases
and conjugases are non microsomal
 Catalyze some oxidations and reductions,
many hydrolytic reactions and all conjugations
except glucuronidation are
 Non-microsomal enzymes are not inducible

92
Enzyme Induction
 Induce the transcription microsomal enzymes
especially CYP-450 and glucuronyl transferase
 Induction results in:
Acceleration of substrate metabolism
Decrease the action of the inducer and the co-
administered drugs
 Enzyme inducers:
Barbiturates, Rifampicin, Carbamazepine,
Tobacco smoke, Griseofulvin, DDT,
Phenylbutazone, Chloralhydrate, Pollutants and
androgens 93
Consequence of enzyme induction
 Decrease intensity and/or duration of action
 Increase of drug toxicity-hepatotoxicity of
paracetamol by its reactive metabolite (N-
acetylbenzoaminoquinone) occurs at lower dose
in patients receiving enzyme inducer
 Tolerance
 Acute intermittent phorpyria
 Interfere with dose adjustment of an other drug
prescribed on regular base. Eg, with oral
anticoagulant
94
Possible use of enzyme induction
 Congenital non hemolytic jaundice:
Phenobarbitone cause rapid clearance of
jaundice.
 Cushing’s syndrome(steroid hormone
produced by adrenal cortex)
 phenytoin may reduce manifestations.
 Chronic poisonings
 Liver disease

95
Enzyme Inhibition
 Occurs when the drug is metabolized by similar
enzymes.
 Clinically significant inhibition of drug metabolism
occurs in drugs having affinity for the same
isoenzyme and metabolized by saturation kinetics.
 Inhibition of drugs metabolism occurs in a dose
related manner.
 Can precipitate toxicity of the object drug
 Imidazole-containing drugs bind tightly to the P450
heme iron and effectively reduce metabolism.

96
 Macrolide antibiotics metabolite complexes
with the cytochrome heme-iron of CYP3A and
render it catalytically inactive.
 Because enzyme inhibition occurs by direct
effect on the enzyme, it has a fast time course
(within hours) compared to enzyme induction.
 Metabolism of drugs with high hepatic
extraction is dependent on liver blood flow.
 Propranolol reduces rate of lignocaine
metabolism by decreasing hepatic blood flow

97
 Enzyme Inhibitors

Chloramphenicol Cimetidine
Clarithromycin Ciprofloxacin
Omeprazole Allopurinol
Metronidazole Ketoconazole
Erythromycin Grape fruit juice
Estrogens Progestrone

98
Factors affecting drug metabolism

1. Genetic variation
May result in:
 Luck of metabolizing activity
 Reduction in metabolizing activity
 Enhanced in metabolizing activity
 Individualizing drug therapy may be
important for drug with narrow
therapeutic index.
99
Example:
 Genetic polymorphism of debrisoquin 4-
hydroxylation by CYP2D6 in a caucasian
population
 Isoniazide-(N-acetyl transferase)
Fast acetylater
Slow acetylator –neurotoxicity
 Premaquine (Glu-6-p-dehydrogenase)-
hemolytic anemia
 Sucinylcholine (pseudocholinestrase)- apnea
100
2. Drug interaction
 Enzyme induction and inhibition
 Competition for endogenous substrates for
conjugation
3. Smocking
 Smoking leads in to enzyme induction
4. Sex
 Females metabolizes at slower rate
 Males metabolizes at higher rate

101
5. Age
 Extreme age usually susceptible to drug
toxicity due to non developed or impaired
activity of microsomal enzymes
6. Heavy metal poisoning
 Impair enzyme activity
7. Disease
 Liver, kidney and liver disease etc.

102
 4. Excretion

 Transportation of unaltered or altered drug out

of the body.
 Drugs and their metabolite excreted in:
A) Urine: the most important channel for
excretion of most drugs
B) Faces: apart from the un absorbable fraction,
most of the drugs present in faces is derived
from bile
C) Exhaled air: gasses and volatiles are eliminated
by lung irrespective of their lipid solubility
103
D) Saliva and sweat: this are of minor importance
for excretion
As saliva swallowed the drug meets the same
fate as orally swallowed.
E) Milk: the excretion of drug in milk is not
important for the mother, but the suckling
infant inadvertently receives the drug.
 Drugs inter breast milk by passive diffusion
 Milk has a lower PH (7.0) than plasma, basic
drugs are some what more concentrated in
plasma.
104
Renal excretion
 Excretion of water soluble drugs and
metabolites three process:
Glomerular filtration
Passive tubular reabsorption
Active tubular secretion
 Renal function is not constant
 In neonates, renal function is low but mature
rapidly
 During adulthood, there is a slow decline in
renal function
105
A) Glomerular Filtration

 Glomerular filtration capillaries have pores

larger than all non protein bound drug
(whether lipid soluble or insoluble) presented
to glomerulus is filtered.
 Thus GF of a drugs depends on its;
1. Plasma protein binding
2. Renal blood flow.

106
B) Tubular Reabsorption
 This depend on lipid solubility and ionization
of the drug at the urinary PH.
 Lipid soluble drugs filtered at glomeruls back
diffuse in the tubules, because 99% of
glomerular filtrate is reabsorbed.
 Non lipid soluble and ionized drugs unable to
do so.
 Thus the rate of excretion for such drugs eg,
aminoglycosides, tubocurarine, parallels with
glomerular filtration rate.
107
Reabsorption depends on PH
 Weak bases ionize more and less
reabsorbed in acidic urine.
 Weak acids ionize more and less reabsorbed
in alkaline urine
 Excretion of drugs can be hastened by
alkalinization and acidification of the urine.

108
C) Tubular Secretion
 Active transfer of organic acids and bases by
two separate non specific mechanisms which
operates in the proximal tubules.
I. Organic acid transport - for penicillin,
probenecid, uric acid, salisylate, sulfinprazone,
nitrofurantoin, methotrixate, drug glucuronide
II. Organic base transport – for thiazides, quinine,
procaineamide, choline, cimetidine, amiloride,
etc.
 Inherent both transport process are
bidirectional
109
Drug interactions:
 Probenicid decrease excretion of
nitrofurantoin, penicillin and methotrixate
 Sulfinprazone inhibit excretion of
tolbutamide
 Quinidine decrease renal and biliary
clearance of digoxin.

110