DEFINITION OF PHARMACOLOGY;

DRUGS; CLASSIFICATION AND NAMING

Dr. Yousef Al-saraireh

Associate Professor
Faculty of Medicine
1
 CONTENTS

 DEFINATION AND DIVISIONS

 DRUG SOURCES

 DRUG CLASSIFICATION

 DRUG NAMES

 DOSE FORMS OF DRUGS

2
 DEFINITION AND DIVISIONS
 PHARMACOLOGY : It is the science that deals with
interaction of drugs with living systems.

Drugs : These are chemical substances that shows

biological activity (treatment or sometimes diagnosis).

 Divisions of Pharmacology:

1. Pharmacodynamics :

(What the drug does to the body)

 This deals with the action of drugs on living tissues ,

namely the type or quality of action, its quantitative 3
aspect , as well as the mechanism of action .
 Adverse effects and safety of drugs on body tissues or
systems are also included

 The main organ or tissue on which the drug acts , and for
which it is used therapeutically, is called the target
organ or tissue of drug action

2. Pharmacokinetics :

(What the body does to drug)

 This includes administration and absorption of drugs,

their distribution inside body, and their elimination by
metabolism or excretion

4
 OTHER TOPICS LINKED WITH PHARMACOLOGY
1. Pharmacotherapeutics: It is concerned with the proper
use of drugs in treatment of disease in man

2. Clinical Pharmacology: This includes :-

A. Drug pharmacology
B. Clinical evaluation of drugs in treating disease
in man. This is done by :
a. Clinical trials b. Surveillance studies

3.Chemotherapy : It is used to imply the use of drugs to

inhibit growth or kill either :
a. Microbes (i.e. anti-microbial agents)
b. Cancer cells ( Cyto-toxic anti-cancer drugs) 5
4. Pharmacy : It is the science and profession that is
concerned with the preparation, storage, dispensing, and
proper utilization of drug products

5. Toxicology : It is the science that deals with the

harmful effects of chemicals (including drugs) .

6
 DRUG SOURCES
These may be either :-

I. Synthetic sources : common at present

- these drugs are prepared by the labs or factories of the
pharmaceutical industry. Nowadays, computers
greatly assist in discovery of new drugs

II. Semi-synthetic drugs :

- these are obtained from natural sources, but are
modified by pharmaceutical industry in order to
improve their physical or chemical properties or
pharmacological activity. 7
III. Natural sources : These are less used now . They
may be either :
1. Organic :
A. Plants : Any part of the plant (stem, leaves, flowers,
seeds, roots) may be used to extract active ingredients for
drugs; same plant may contain more than one active
principle. All of this is dealt with in PHARMACOGNOSY

Examples of drugs from plants are : alkaloids, steroids,

some vitamins, tannins, volatile oils, gums

Note :
Alkaloids are small organic molecules containing
nitrogen . e.g. atropine, morphine, caffeine, theophylline,
quinine
8
B. Animals : these may include either proteins , oils,
enzymes from exocrine glands, hormones, vaccines and
anti-sera, and some vitamins

C. Microbes : like fungi, and sometimes bacteria which are

sources of antibiotics

2. Non-Organic sources :
- metals : Platinum, Zinc
- non-metals : Sodium chloride , magnesium sulfate

9
Rational drug design:

 This implies the ability to predict the chemical structure

of drug molecule on basis of 3-dimensional structure of
its receptor, employing at present suitable computer
programs. Only few drugs in clinical use at present
were developed in this rational way.

 Most drugs were in the past developed through random

testing of chemicals , or modified molecules of known
drugs that are known to have some pharmacological
effect.

However, as more becomes known about

detailed structure of receptors, rational drug
design with the aid of computers would become 10
more feasible
 DRUG CLASSIFICATION
There is no fixed rule; classification is usually done
according to their :

1. Therapeutic use : e.g. anti-hypertensive drugs ;

anti-microbial drugs ; anaesthetics; hypoglycemic drugs;
anticoagulants;

2. Type of pharmacological action :

This should be precise. e.g. local or general
anaesthetics; vasodilators; anticoagulants OR
according to molecular or cellular site of action in
target cells e.g. enzyme inhibitors, receptor blockers ,
ion channel blockers, inhibitors of transporters,
antimicobials acting on cell wall, DNA, or ribosomes 11
3. Physiological systems on which they act : Drugs
acting on cardio-vascular system; drugs acting on GIT or
CNS or respiratory system
4. Chemical nature or Source :
Common chemical groups or structures can be used to
classify drugs that have similarity in their
pharmacological profile e.g. benzodiazepines, steroids.

For drugs derived from nature, both the plant species or

genus and drug chemistry are included e.g. belladona
alkaloids from atropa belladona , digitalis glycosides
from Digitalis leaves .

12
 DRUG NAMES
1. Chemical name :
 Because of its complexity , the chemical structure is not
usually used to name drugs.
 However, sometimes a shorthand name based on a simple
chemical structure is employed e.g. acetylsalisylic acid
(aspirin) , acetaminophen (parectamol)

13
2. Generic (non-proprietory ) name :
 This is a unique name that is given by official
pharmaceutical bodies;
 It is present in pharmacopeas (BP or USP) .
 It is the approved scientific name, and must be used in
scientific publications as well as in prescriptions esp. in
hospitals .
 Its use makes it easier for pharmacist to choose from
many available brands of same drug.
 Only few drugs show more than one generic name :
Noradrenaline & adrenaline in UK but are named Nor-
epinephrine and epinephrine, respectively, in USA &
WHO; salbutamol in UK while albuterol in USA

 Generic names of drugs in a classified group may

have common endings e.g. – olol for beta-
adrenoceptor blockers; -caine for local anaesthetic drugs.
These endings may give a hint about the drug 14
pharmacotherapeutic action
3. Commercial or trade or brand or proprietory name:
 This name is given by the specific pharmaceutical
company synthesizing and marketing the drug.
 Examples: Diclofenac Na (Voltaren, Inflaban, Diclogesic)
 A single drug can have many brand names (this may be
confusing) due to its manufacture and marketing by many
pharmaceutical companies.

15
 DOSE FORMS OF DRUGS
 It is the physical form of drug product that is suitable for
administration to man. It contains specified dose or
amount of drug in a specified quantity or unit of the
formulation.

 Types of drug dose forms:

1. Oral
2. Inhalational
3. Parenteral
4. Topical
5. Suppository

16
1. Oral dose forms: It includes the following
A. Pill: Tablets and capsules
B. Liquid: Syrup or suspension
C. Powder
D. Herbal plants: seeds, leaves etc..
E. Pastes
2. Inhalational:
A. Aerosol
B. Inhaler
C. Vaporizer (Solutions)
3. Parenteral:
A. Intradermal (ID) B. Intramuscular (IM)
C. Intraperitoneal (IP) D. Intravenous (IV)
17
E. Subcutanous (SC) F. Intrathecal (IT)
4. Topical:
A. Cream, gel, ointment, lotion
B. Eye drops ( ophthalmic)
C. Ear drops (otic)
D. Skin patch (transdermal)

5. Suppository:
A. Vaginal
B. Rectal

18
THANKS

19
 PRINCIPLES OF
PHARMACODYNAMICS

Dr. Yousef Al-saraireh

Assistant Professor
Faculty of Medicine
1
 CONTENTS

 MECHANISMS OF DRUG ACTION

 TYPES OF LIGAND-RECEPTOR INTERACTIONS

 TYPES OF DRUG-RECEPTOR BONDING

 CLASSIFCATION OF RECEPTORS

2
 MECHANISMS OF DRUG ACTION
 Drugs can act through:
1. Physical action:
Drug can produce a therapeutic response because of
it’s physical properties. e.g: Mannitol as diuretic
because it increase osmalerity, Radio-isotopes : emit
ionizing radiation
2. Simple chemical reaction:
Drug may act through a chemical reaction. e.g: Gastric
antacids work by neutralizing the stomach acidity
with a base, Chelating agents that bind heavy metals
in body.
3. Receptors:
A receptor is a specialized target macromolecule
mostly protein, present on the cell surface or
intracellular, that binds a drug and mediates it’s
pharmacological actions. 3
Receptors can either be enzymes,
nucleic acids or structural proteins to
which drugs may interact.
 A molecule that binds to a receptor
is called a ligand, and can be
a peptide or another small molecule
like a neurotransmitter, hormone, or
drug.
 Ligand binding changes
the conformation (three-dimensional
shape) of the receptor molecule. This
alters the shape at a different part of
the protein, changing the interaction
of the receptor molecule with
associated biochemicals, leading in
turn to a cellular response mediated
by the associated biochemical
pathway. 4
TYPES OF LIGAND-RECEPTOR INTERACTIONS

Agonist Hormone
e.g. important
Antagonist
binds β2 receptor in lung → control heart beat
therapy bronchial relaxation
in asthma
binds β2 receptor in heart muscle →
increased heart rate
5
TYPES OF LIGAND-RECEPTOR INTERACTIONS
Not every ligand that binds to a receptor also activates the
receptor. The following classes of ligands exist:
1. (Full) agonists are able to activate the receptor and
result in a maximal biological response. The
natural endogenous ligand with greatest efficacy for a
given receptor is by definition a full agonist (100%
efficacy).
2. Partial agonists do not activate receptors thoroughly,
causing responses which are partial compared to those of
full agonists (efficacy between 0 and 100%).
3. Antagonists bind to receptors but do not activate them.
This results in receptor blockage, inhibiting the binding of
agonists and inverse agonists.
4. Inverse agonists reduce the activity of receptors by 6
inhibiting their constitutive activity (negative efficacy).
 TYPES OF DRUG-RECEPTOR BONDING
Drugs interact with receptors by means of chemical forces
or bonds. These are of three major types:

1. Covalent: It is very strong and in many cases not

reversible under biologic conditions. Thus, the duration of
drug action is frequently, but not necessarily, prolonged
(irreversible)

2. Electrostatic: is much more common than covalent

bonding in drug-receptor interactions. These vary from
relatively strong linkages between permanently charged
ionic molecules to weaker hydrogen bonds and very weak
induced dipole interactions such as van der Waals forces.
Electrostatic bonds are weaker than covalent bonds. 7
(reversible)
3. Hydrophobic: are usually quite weak and are probably
important in the interactions of highly lipid-soluble drugs
with the lipids of cell membranes and perhaps in the
interaction of drugs with the internal walls of receptor
"pockets.“

 Drugs which bind through weak bonds to their receptors

are generally more selective than drugs which bind
through very strong bonds.

 This is because weak bonds require a very precise fit of

the drug to its receptor if an interaction is to occur

8
 DURATION OF DRUG ACTION
Termination of drug action at the receptor level results from
one of several processes:
1. The effect lasts only as long as the drug occupies the
receptor, so that dissociation of drug from the receptor
automatically terminates the effect.
2. The action may persist after the drug has dissociated,
because, for example, some coupling molecule is still
present in activated form.
3. Drugs that bind covalently to the receptor, the effect may
persist until the drug-receptor complex is destroyed and
new receptors are synthesized.
4. Many receptor-effector systems incorporate
desensitization mechanisms for preventing excessive
activation when agonist molecules continue to be present 9

for long periods

 CLASSIFCATION OF RECEPTORS
This is based on the type of the transduction mechanism that
these receptors activate when stimulated by their agonists:

1. Transmembrane ligand-gated
ion channels: These receptors are
present in the walls of ion channels in
cell membranes. When activated by
their specific agonist, they open these
ion channels & lead to movement of
ions across cell membrane.

These mediate diverse functions,

including neurotransmission, cardiac
conduction, and muscle contraction.
10
Examples :
1. Nicotinic receptors for acetylcholine (Ach.) : when
stimulated, they open receptor-operated Na+ channels,
and thus increase influx of sodium ions across
membranes of neurons or NMJ(neuromuscular junction)
in skeletal muscle and therefore activation of contraction
in muscle.
2. γ-aminobutyric acid (GABA) receptors:
Benzodiazepines enhance the stimulation of the GABA
receptor by GABA, resulting in increased chloride influx
and hyperpolarization of the respective cell.

11
2. Transmembrane G protein–coupled receptors:

 When these receptors are stimulated by their specific

agonists, they will activate a regulatory G-protein in cell
membrane which in turn change activity of membrane
enzymes ( either adenyl cyclase or phospholipase C )
leading to a change in intracellular level of a second
messenger like cAMP (cyclic adenosine monophosphate),
or IP3 (inositol triphosphate), respectively, and this
would lead to cell response.

 Examples : e.g. Receptors for transmitters :

Stimulation of muscarinic receptors (M1 and M3) for
Ach will activate G and leads to increase intracellular
level of IP3 & DAG

12
 13

guanosine triphosphate (GTP), guanosine diphosphate (GDP)

3. Enzyme-linked receptors:

 These membrane receptors have an extra-cellular site

that binds to specific agonists and an intra-cytoplasmic
domain which contains tyrosine and other amino acids.

 Binding to specific agonist and activation of these

receptors usually lead to phosphorylation of
tyrosine in intra-cellular domain which then
acquires kinase activity and leads to activation of
intracellular substrates or enzymes that finally leads to
cell response.

 Examples:
Receptors for insulin,
Receptors for growth factors like EGF or PDGF,
Receptors for immune cytokines 14
15
4. Intracellular receptors:

 These receptors are located in cytoplasm (e.g. steroid

receptors) or nucleus (receptors for thyroid hormones or
vitamin D3) .

 The specific agonist must cross cell membrane to inside of

cell, binds and activates these receptors, which will then
bind to DNA gene response elements in nucleus and lead to
change in gene transcription , and thus synthesis of new
proteins

16
17
THANKS

18
 PHARMACODYNAMICS II

Dr. Yousef Al-saraireh

Associate Professor
Faculty of Medicine
1
 RELATION BETWEEN DRUG DOSE & CLINICAL
RESPONSE
In order to make rational therapeutic decisions, the
prescriber must understand how drug-receptor
interactions underlie
1. The relations between dose and response in
patients

2. The nature and causes of variation in

pharmacologic responsiveness

3. The clinical implications of selectivity of drug

action. 2
1. The relations between dose and response in patients

These relations are exhibited as following:

A. Graded dose–response relationships ( individual):

The response is a graded effect, meaning that the response is

continuous and gradual

B. Quantal dose–response relationships (population)

describes an all-or-no response

3
 A. GRADED DOSE–RESPONSE RELATIONSHIPS
➢The magnitude of the drug effect depends on the drug concentration at
the receptor site, which in turn is determined by the dose of drug
administered and by factors characteristic of the drug pharmacokinetic
profile, such as rate of absorption, distribution, and metabolism.

➢As the concentration of a drug increases, the magnitude of its

pharmacologic effect also increases.

➢Plotting the magnitude of the response against increasing doses of a drug

produces a graph, the graded dose–response curve, that has the general
shape described as a rectangular hyperbola.

➢ Two important properties of drugs, can be determined by graded dose–

response curves which are

1. Potency
4
2. Efficacy
 1. POTENCY:
A measure of the amount of drug
necessary to produce an effect of a
given magnitude.

➢ The concentration of drug

producing an effect that is 50
percent of the maximum is used to
determine potency and is
commonly designated as the EC50
➢ Drug A is more potent than Drug
B, because a lesser amount of
Drug A is needed when compared
to Drug B to obtain 50-percent
effect. 5
➢ Potency is affected by:
1. Receptor concentration or density in tissue,
2. Efficiency of stimulus-response coupling mechanism in
tissue
3. Affinity: describes the strength of the interaction (binding)
between a ligand and its receptor
4. Efficacy

➢ Potent drugs are those which elicit a response by binding

to a critical number of a particular receptor type at low
concentrations (high affinity) compared with other drugs
acting on the same system and having lower affinity and
thus requiring more drug to bind to the same number of
receptors
6
 2. EFFICACY
It is the ability of a drug to elicit a response when it
interacts with a receptor.
➢Efficacy is dependent on:

1. Number of drug–receptor complexes formed

2. the efficiency of the coupling of receptor
activation to cellular responses.

➢ Maximal efficacy (Emax) of a drug assumes that

all receptors are occupied by the drug, and no
increase in response will be observed if more drugs
are added

➢The height of maximal response is used to

measure maximal efficacy of agonist drug, and to
compare efficacy of similar acting agonists

7
 EFFECT OF DRUG CONCENTRATION ON
RECEPTOR BINDING
The quantitative relationship between drug concentration
and receptor occupancy is expressed as follows:
Drug + Receptor ←→ Drug–receptor complex → Biologic effect

➢ As the concentration of free drug increases, the ratio of

the concentrations of bound receptors to total receptors
approaches unity

8
➢ the relationship between the percentage of bound receptors and the
drug concentration:

[D] = the concentration of free drug,

[DR] = the concentration of bound drug,
[Rt] = the total concentration of receptors and is equal to the sum of the
concentrations of unbound (free)receptors and bound receptors,
Kd = the equilibrium dissociation constant for the drug from the receptor.

➢ The value of Kd is used to determine the affinity of a drug for its

receptor.

Affinity describes the strength of the interaction (binding) between a

ligand and its receptor.
➢ The higher the Kd value, the weaker the interaction and the lower the
9

affinity.
 ANTAGONISTS
➢ They are of 3 main types :
1. Chemical antagonist :
This combines with agonist and inactivates it away from
tissues or receptors
Examples:
a. Alkaline antacids neutralize HCl in stomach of peptic
ulcer patients;
b. protamine (basic) neutralizes the anti-coagulant heparin
(acidic) in plasma ;
c. chelating agents bind with higher affinity to heavy
metals (e.g. lead, mercury, arsenic ) in plasma and tissues,
preventing their tissue toxicity
10
2. Physiological antagonist :

➢This is actually an agonist on the same tissue but

produces opposite effect to that of the specific agonist; it
acts by mechanisms or receptors that are different
from those of the specific agonist .

➢Physiological antagonists quickly reverse the action of

the specific agonist on the same tissue.

Examples:

Adrenaline, given IM, is a quick acting physiologic

antagonist to histamine (that is released from mast cells or
basophils) in anaphylactic shock; it is a life-saving drug in
this condition
11
3. Pharmacological antagonist :

Pharmacological receptor antagonists have affinity for the

receptors but have no intrinsic activity or efficacy

There are three main types :

A. Competitive reversible antagonist :

This antagonist , because of similarity in its chemical
structure to agonist, competes with agonist for binding to
its specific receptors in tissue, and thus decreases or
prevents binding of agonist and its effect on tissue.

The antagonist molecules bind to the agonist

receptors with reversible ionic bonds, so that it can
be displaced competitively from receptors by
increasing the concentration or dose of agonist ,
and thus response of tissue to agonist is restored. 12
 agonist (A) and antagonist (I)

➢ The DR curve of agonist is shifted to the right, and the

maximal response can be restored by increasing dose of
agonist. The more is the concentration of antagonist, the
greater is this shift of DR curve of agonist to the right.
Examples:
➢ atropine is a competitive reversible antagonist to Ach at
muscarinic receptors;
➢ Beta-blockers are competitive antagonists to adrenaline13
at beta –adrenergic receptors.
➢The affinity of competitive antagonist KI to its receptors is
calculated from :

C*/C = 1 + [I] / KI
where C* is concentration of agonist that restores response
in presence of antagonist concentration [I], and C is agonist
concentration giving this response in absence of antagonist.

B. Non-competitive antagonist :

There are two subtypes:

1. Irreversible antagonist :

Here, the antagonist molecules either bind to agonist

receptors by strong irreversible covalent bonds or
dissociate very slowly from the receptors, so that the effect
of antagonist can not be overcome fully by increasing 14
concentration of agonist.
➢ The dose response curve of agonist is shifted slightly
to the right , but the maximal height or response of
curve is depressed and can NOT be restored by
increasing the dose of agonist . This is due to decrease
in number of receptors remaining available to bind to
agonist.

➢ The more is the concentration of antagonist, the 15

more is depression of maximal response
2. Allosteric antagonism :
Here, the antagonist binds to allosteric site on receptor
that is different from the site that binds agonist molecules,
leading to change in receptor binding or affinity to agonist
with subsequent antagonism.
The dose response curve of antagonist is similar to that of
irreversible non-competitive antagonist.

Note : Allosteric enhancement : with some receptors, a

drug can bind to another allosteric site on agonist receptor
leading to increase in binding of agonist to its receptor and
thus allosteric enhancement of agonist effect . e.g. Binding of
benzodiazepines to GABA-A receptors can enhance the
depressant GABA effect on brain neurons.

16
17
 C. Uncompetitive antagonism :
Here antagonist bind to a receptor different from that of
agonist, and is located more distally in the effector
mechanism so that the effect of agonist is blocked as well
as that of other agonists that produce similar effect by
acting on a different receptor. The dose-response curve is
similar to that of irreversible non-competitive antagonist.

A + RA Depolarization → Increases free

calcium
B + RU
Y
Uncompetitive antagonist
X
Competitive antagonist
18

Contraction
 RECEPTOR REGULATION
1. Receptor up-regulation :
This means increase in number and/or affinity of specific
receptors ( receptor supersensitivity).
It may occur with :
A. Prolonged use of receptor antagonist : here,
there is lack of binding of receptor to agonist for long
period of time

B. Disease : e.g. hyperthyroidism : here excess

thyroxine hormone in blood stimulate proliferation of
beta-adrenergic receptors in heart which increases risk of
cardiac arrhythmia from adrenaline or use of beta-
adrenoceptor agonists .

19
B. Receptor down-regulation (Receptor tolerance):
This means a decrease in number and/or affinity of
available specific receptors due to their prolonged
occupation by agonist .

➢ It occurs with continued use (for days or weeks) of

receptor agonist , and is evident as decrease in response
to agonist .
➢ In order to restore the intensity of response, the dose of
agonist must be increased.

Tachyphylaxis : it is a rapidly developing tolerance

➢ It is not due to receptor downregulation

➢ It is associated with repeated use of large doses

of direct receptor agonist, usually at short dose intervals ,

20
OR with continuous IV infusion of agonist.
➢ It may be due to :
1. Desensitization of receptors :
Change in the receptor: where the agonist-induced
changes in receptor conformation result in receptor
phosphorylation, which diminishes the ability of the
receptor to interact with G proteins
2. Depletion of intra-cellular stores of transmitter
e.g. depletion of noradrenaline stores in vesicles inside
sympathetic nerve ending resulting from repeated use of
indirect sympathomimetic amphetamine

➢ In order to restore the response, the agonist drug

must be stopped for short time to allow for
recovery of receptors or stores of transmitter. 21
2. INDIVIDUALS USUALLY SHOW VARIATION IN
INTENSITY OF RESPONSE TO DRUGS DUE TO :

1. Variation in concentration of drug that reaches

the tissue receptors : due to pharmacokinetic factors
2. Abnormality in receptor number or function :
either genetically-determined or acquired due to up-
regulation or down-regulation
3. Post-receptor defect inside cells :
This is an important cause of response variation

4. Variation in Concentration of an Endogenous

Receptor Ligand
contributes greatly to variability in responses to
pharmacologic antagonists. 22
THANKS

23
 PHARMACODYNAMICS III

Dr. Yousef Al-saraireh

Associate Professor
Faculty of Medicine
1
B. QUANTAL DOSE–RESPONSE RELATIONSHIPS

the influence of the magnitude of the dose on the proportion

of a population that responds.
 These responses are known as quantal responses,
because, for any individual, the effect either occurs or it
does not.

The desired response is either :

A. Specified in amount or magnitude :

e.g. increase in heart rate of 20 beats/min by a drug that
stimulates heart.
If the recorded response in any individual shows this
amount or more, then this is regarded as positive
response; otherwise, the response is negative 2
 B. All-or-none response :
e.g. death; prevention of epileptic seizures; prevention of
cardiac arrhythmias

 For most drugs, the doses required to produce a specified

quantal effect in individuals are lognormally distributed; ie,
a frequency distribution of such responses plotted against
the log of the dose produces a gaussian normal curve of
variation

Determines minimum dose at which

each patient responded with the
desired outcome. The results have
been plotted as a histogram, and fit
with a gaussian curve. μ = mean
response; σ = standard deviation.
3
 When these responses are summated, the resulting
cumulative frequency distribution constitutes a quantal
dose-effect curve of the proportion or percentage of
individuals who exhibit the effect plotted as a function of
log dose

Example:

at 5mg/L, 2% respond, and

7mg/L 3% respond, then at
5mg/L plot 2%, at 7mg/L
plot 2+3 = 5% etc.)

4
 The quantal dose-effect curve is often characterized by:
1. median effective dose (ED50): the dose at which 50%
of individuals exhibit the specified quantal effect.

2. median toxic dose (TD50): the dose required to

produce a particular toxic effect in 50% of Animals.

3. Median lethal dose (LD50): the dose required to

produce a death in 50% of Animals.

5
 SUMMATION AND POTENTIATION
Two common types of “agonistic” drug interactions are :
1. Summation: When two drugs with similar mechanisms
are given together, they typically produce additive
effects.
2. Potentiation or synergism : if the effect of two drugs
exceeds the sum of their individual effects.
Potentiation requires that the drugs act
at different receptors or effector systems.

Example of potentiation would be the

increase in beneficial effects noted in the
treatment of AIDS by combination
therapy with AZT (a nucleoside analog
that inhibits HIV reverse transcriptase)
and a protease inhibitor (protease activity
is important for viral replication). 6
 PREDICTION OF DRUG SAFETY IN MAN
 This may be obtained from knowledge of Therapeutic
Index (TI) of drug.

the ratio of the dose that produces toxicity to the dose that
produces a clinically desired or effective response in a
population of individuals

TI = TD50 / ED50
where :
TD50 = the drug dose that produces a toxic effect in half the population
ED50 = the drug dose that produces a therapeutic effect in half the
population.

7
 A larger value indicates a wide margin between doses that
are effective and doses that are toxic.
 TI is determined by measuring the frequency of desired
response, and toxic response, at various doses of drug.

 In humans, the therapeutic index of a drug is determined

using drug trials and accumulated clinical experience.
These usually reveal a range of effective doses and a
different (sometimes overlapping) range of toxic doses.

 The concentration range over which a drug produces its

therapeutic effect is known as its therapeutic window

8
 when the therapeutic index is low,
it is possible to have a range of
concentrations where the effective
and toxic responses overlap
Agents with a low therapeutic
index are those drugs for which
bioavailability critically alters the
therapeutic effects

When therapeutic index is large, it

is safe and common to give doses in
excess (often about ten-fold excess) of
that which is minimally required to
achieve a desired response. In this
case, bioavailability does not
critically alter the therapeutic 9
effects.
 SPECIFICITY VS. SELECTIVITY
 Specificity : If a drug has one effect, and only one effect
on all biological systems it possesses the property of
specificity.
 In experience, the vast majority of drugs are selective
rather than specific. This is the case because most drugs
will act on more than one receptor site once they reach an
appropriately high concentration.

 Example: yohimbine a drug used

therapeutically as an α2-adrenoceptor blocker
but which also blocks 5-HT receptors, α1-
adrenoceptors, Na channels, monoamine
oxidase, and cholinesterase at higher
concentrations. An illustration of the
therapeutic window for selective blockade of
α2-adrenoceptors by yohimbine is shown in
Figure . 10
 ADVERSE EFFECTS OF DRUGS
These are unwanted and/or harmful effects
I. Predictable or dose-related or type A effects :
A. Side effects : These occur at therapeutic doses of a
drug. They are usually minor, and decrease or disappear
on reducing dose or sometimes with continued use of drug

B. Toxic effects : These are due to large toxic doses .

They are usually serious, and need stopping drug use,
and sometimes supportive treatment to save life. They
may be :
1. Functional e.g. respiratory depression OR
2. Structural : causing tissue damage e.g.
damage to liver or kidney or heart or nerves 11
II. Unpredictable or Type B reactions :
A. Allergy : This is due to activation of immune
mechanisms by drug. Drug acts as hapten to
induce formation of antibodies by plasma cells or to
sensitize T-lymphocytes .
Usually, allergic reactions have no dose-response
relation ; they are of 4 main types :

Type 1 : Immediate type ; it is the commonest type ;

it is mediated by IgE antibodies that bind to
membrane of mast cells in tissues or basophils in
blood.
After re-exposure and binding to their specific antigen,
they trigger release of histamine and other mediators
from granules of these cells.

This causes urticaria or , in severe cases , anaphylactic

shock which is a life threatening emergency
12
Type 2 : Cyto-toxic reaction :
mediated by either IgM antibodies in plasma or IgG
antibodies that causes tissue damage by fixing
complement and activating complement cascade
e.g. hemolysis ; liver or kidney damage .

Type 3 : Immune complex mediated reaction :

Circulating immune complexes form between antigen
and IgG antibodies which become deposited in capillaries
of skin , joints , and kidney. Clinical features occur after
many days of exposure to drug e.g. serum sickness

Type 4 : Delayed cell-mediated reactions :

These are due to activation of sensitized T lymphocytes
which release their cytokines and attract macrophages to
site that also release tissue damaging cytokines
13
B. Idiosyncrasy :
abnormal drug reactions due usually to genetic
factors affecting tissue enzymes or receptors.
Examples:
a. Hemolysis by sulfonamides or the antimalarial drug
primaquin in patients with genetic deficiency of the
enzyme glucose-6-phosphate dehydrogenase (G-6-PD) in
their RBC

b. Resistance to vitamin D or to the oral anti-coagulant

warfarin

14
III. Special toxicity including
1. Genotoxicity leading to Mutagenicity :
Alkylating agents

2. Teratogenicity :
Congenital disorder : drugs taken in pregnancy

3. Carcinogenicity : may take about 2 years .

- may be related to mutagenicity but less than
is the case with teratogenicity

4. Reproductive toxicity recording pregnancy

rate, number of live or stillbirths, & postnatal growth

15
IV . Others

1. Delayed toxicity : occurs sometime after

stopping drug use e.g. idiosyncratic
aplastic anemia due to chloramphenicol

2. Chronic toxicity : occurs with prolonged use

of drug e.g. Cushing syndrome from
long-term use of steroids

3. Dependence : occurs with prolonged use

of CNS depressants e.g. alcohol ; opioids like morphine
16
Adverse effects may be caused by :

1. Over-extension of same mechanism of action on

same target tissue : e.g. sedative-hypnotics;
anticoagulants ; beta-adrenoceptor blockers
2. Effect on same receptor type but in another
tissue :
e.g. anti-muscarinic drugs ; beta-blockers
3. Effect on different receptor or by different
mechanism on target or other tissues

The following groups are more susceptible to adverse

drug reactions : foetus during pregnancy; elderly ;
patients receiving many drugs (polypharmacy); patients
with pre-existing disease ; patients with genetic enzyme
defects in liver (poor oxidizers or slow acetylators) or
tissues 17
THANKS

18
Pharmacokinetics (I)

Dr Mohammed Al-sbou
Professor of Clinical Pharmacology
Department of Pharmacology
Faculty of Medicine, Mutah University

1 1
 The goal of drug therapy is to prevent,
cure, or control diseases
 To achieve this goal, adequate drug doses
must be delivered to the target tissues so
that therapeutic yet nontoxic levels are
obtained

2
 Pharmacokinetics (PK)

 Greek: Phrmaco= drug

Kinein = to move

 Definition PK: examines movement of a

drug over time through body

3 3
 Pathways of drug movement: (ADME)
 Absorption
 Distribution
 Metabolism,
 Elimination

4
Clinicians must recognize that:
 Speed of onset of drug action

 Intensity of drug’s effect

 Duration of drug action are controlled

by four fundamental pathways (ADME)

5
 Knowledge of these four processes
(ADME) influences clinician’s decision of:
 Route of administration for drug

 Amount and frequency of each dose, and

the dosing intervals

6
 Pathways of PK

 Absorption:
- Is transfer of a drug from its site of
administration to bloodstream
 Distribution:

- Drug leaves bloodstream and distributes

into interstitial & intracellular fluids

7 7
 Metabolism:
- By liver, kidney, or other tissue
 Elimination:

- Removal of drug & its metabolites from

body in urine, bile, or feces

8
 Absorption

 Rate & efficiency of absorption depend

on route of administration
 Routes of drug administration:
 Enteral: (by mouth) oral, subligual
 Parenteral: intravenous (IV),
intramuscular (IM), subcutaneous (Sc)
 Others: inhalation, intranasal, intrathecal,
topical, rectal
9 9
Routes of drug administration:
 IV absorption is complete
(total dose of drug reaches systemic
circulation)
 Drug delivery by other routes may result

in partial absorption and, thus, lower

bioavailability

11
 For example, oral route requires that a
drug dissolve in GI fluid and then pen-
etrate epithelial cells of intestinal mucosa,
disease states or presence of food may
affect this process

12
 Absorption

A. Transport of drug from GI tract:

- Depending on chemical properties
- Drugs may be absorbed from GI tract
by either passive diffusion or active
transport

13 13
 1. Passive diffusion:

- Drug move from high concentration to

one of lower concentration
- The vast majority of drugs gain access to
body by this mechanism
- Lipid-soluble drugs: readily move
across biological membranes due to their
solubility in membrane bilayers

14
 Water-soluble drugs: penetrate cell
membrane through aqueous channels or
pores
 Other drugs enter cell through specialised
transmembrane carrier proteins (large
molecules)

15 15
 2. Active transport:

- Involves specific carrier proteins

- Is energy-dependent & is driven by
hydrolysis of ATP
- Moving drugs against concentration
gradient

17 17
 3. Endocytosis & exocytosis

- Endocytosis involves engulfment of a

drug molecule by cell membrane
- For example, vitamin B12 is transported
across gut wall by endocytosis

18
 Exocytosis is reverse of endocytosis and
is used by cells to secrete many
substances
 Certain neurotransmitters (Norepinephrine)
are stored in membrane-vesicles in nerve
terminal & are released by exocytosis

19
20
B. Effect of pH on drug absorption:
- Most drugs are either weak acids or weak
bases
- Uncharged drugs passes through
membranes readily

21 21
 Physical factors influencing absorption:

 Blood flow to absorption site

 Total surface area available for abs

 Contact time at abs surface

(in severe diarrhea, drug is not well absorbed)

 Presence of food in stomach: dilutes drug &

slow gastric emptying & delay abs in small

intestine

22 22
 Bioavailability

 Is fraction of administered drug that

reaches systemic circulation in a chemically
unchanged form
 Bioavailability is determined by comparing
plasma levels of drug after particular route
of administration with plasma drug levels
after IV injection

23 23
 Bioavailability for drugs delivered IV is
100%
 When drug is given orally, only part of
the administered dose appears in
plasma, bioavailability is less 100%

24 24
 Bioavailability= AUC orally *100
AUC IV

25
 If 100 mg of drug are administered orally,
70 mg are absorbed unchanged,
bioavailability 70%

26
 Area under the curve (AUC): by
plotting plasma concentration of drug
versus time
 Bioavailability of orally administered drug
is ratio of AUC for oral admin compared
with AUC for IV injection

27
Determination of bioavailability
Factors influencing bioavailability

A- First-pass hepatic metabolism:

- When drug is absorbed across GI tract, it
enters portal circulation before entering
systemic circulation
- If drug is rapidly metabolised by liver,
amount of unchanged drug that enters
systemic circulation is decreased

29 29
 Propranolol, lidocaine undergo
significant metabolism during passage
through liver

30
First-pass metabolism occurs with orally
administered drugs
B- Solubility of drug:
- Hydrophilic drugs are poorly absorbed
because of their inability to cross lipid-rich
cell membrane

32
C- Chemical instability:
 Benzylpenicillin (Penicillin G) unstable

in pH of stomach, is given IV
 Phenoxymethylpenicillin (Penicillin V)

is used orally, it is acid-stable & is not

destroyed by gastric acid
 Insulin destroyed by enzymes in GI tract,

is given IV
33
 Bioequivalence:

 Two related drugs are bioequivalent if

they show comparable bioavailability &
similar times to achieve peak blood
concentrations

34 34
Pharmacokinetics (II)

Dr Mohammed Alsbou
Professor of Clinical Pharmacology
Department of Pharmacology
Faculty of Medicine, Mutah University

1 1
 Drug Distribution

 Is the process by which a drug leaves

blood stream & enters interstitium
(extracelullar fluids) and/or cells of the
tissues

2 2
 Drug distribution depends on:

 Blood flow to tissue capillaries

 Capillary permeability
 Degree of binding to plasma & tissue
proteins
 Drug distribution depends on:

 Blood flow to tissue capillaries:

o Blood flow to tissue capillaries vary
o blood flow to brain, liver & kidney is higher
than that to skeletal muscles & adipose tissue
 Capillary permeability is determined by:
 Drug structure: Hydrophobic drugs, which

have no net charge, readily move across

biologic membranes. They dissolve in lipid
membranes and, therefore
 hydrophilic drugs, which have a positive or

negative charge, do not readily penetrate cell

membranes, and therefore, must go through
slit junctions
 Capillary structure: (brain continuous, liver
discontinuous)
Cross-section of liver and brain capillaries
 Blood-Brain Barrier (BBB)

- To enter brain, drug must pass through

endothelial cells of capillaries of CNS or activelly
transported (specific transporters)
- Lipid-soluble drugs readily penetrate into CNS
because they can dissolve in membrane of
endothelial cells
- Ionised or polar drugs fail to enter CNS
because they are unable to pass through
endothelial cells of CNS
8 8
The BBB is created by the tight apposition of endothelial cells lining
blood vessels in brain, forming a barrier between circulation and
brain parenchyma (e.g. astrocytes, microglia)
 Binding of drugs to plasma protein

 Plasma albumin is major drug-binding protein

- Bound drugs are pharmacologically inactive
- Only free drug (unbound drug) can act on
target sites in tissues (active)
- As concentration of free drug decreases due to
elimination (metabolism, excretion), bond drug
dissociate from protein
- Hypoalbumunemia may alter level of free
drug
10 10
 Drug Metabolism

 Drugs are eliminated by biotransformation

and/or excretion into urine or bile
 Metabolism transform lipophilic drugs
into more polar products
 Liver is major site of drug metabolism
 Other sites kidney, intestines

11 11
 Some drugs are administered as inactive
compound (pro-drug) & must be
metabolised to their active forms
 Kinetics of metabolism

 First-order kinetics:
- Metabolism is catalyzed by enzymes
- At low doses, drug metabolism is first
order – rate of metabolism is directly
proportional to drug dose

13 13
 Kinetics of metabolism

 Zero-order kinetics:
- At high doses, drug metabolism is zero
order (no-Linear) that is constant &
independent of drug dose (because the
enzyme is saturated by high free-drug
concentration)
Effect of drug dose on rate of
metabolism
 Reactions of metabolism

 Kidney cannot eliminate lipophilic drugs

that readily cross cell membranes and
reabsorbed in distal tubules
 Lipid-soluble drugs must be metabolised
in liver using two reactions called:
 Phase I

 Phase II

16 16
 Phase I

 Converts lipophilic molecules into more

polar molecule by introducing or
unmasking polar functional group such
as –OH or –NH2
 Phase I reactions are catalsyed by
cytochrome P450 system (also called
microsomal mixed function oxidase)
 Cytochrome P450 system

 Designated as CYP
 Is composed of many families of heme-
containing isozymes that are located in
most cells primarily in liver & GI tract
 There are many different genes & many
different enzymes known as P450
isoforms

18 18
 Most isoforms involved in metabolism
of drugs are:
 CYP3A4= (60% of drugs)

 CYP2D6= (25% of drugs)

 CYP2C9= (15% of drugs)

 CYP2C19= (15% of drugs)

 Genetic Variability

 These enzymes exhibit genetic

variability, which has implication for
individual dosing regimens, determining
responsiveness & risk of adverse drug
reactions

20 20
 CYP 450 inducers

 Certain drugs phenobarbital, rifampin,

carbamazepine increase synthesis of CYP
enzymes
 Thus increase metabolism of drugs
metabolised by these CYP enzymes,
decrease plasma concentration & decrease
therapeutic effect

21 21
 CYP 450 inhibitors

 Inhibition of CYP isozymes can lead to serious

adverse events
 Important CYP inhibitors are erythromycin,
ketoconalzole, omeprazole
 Omeprazole is a potent inhibitor of three of CYP
isozymes responsible for warfarin metabolism
 If two drugs are taken together, plasma
concentrations of warfarin increase, which leads
to increase risk of hemorrhage and other serious
bleeding reactions 22 22
 Natural substances such as grapefruit juice
may inhibit drug metabolism
 Grapefruit juice inhibits CYP3A4 and, thus,

drugs such as amlodipine & clarithromycin,

which are metabolized by this system, have
greater amounts in systemic circulation—
leading to higher blood levels & potential to
increase therapeutic and/or toxic effects of
drugs
 Phase II

 This phase consists of conjugation reactions

 If the metabolite from Phase I metabolism is
sufficiently polar, it can be excreted by
kidneys
 However, many Phase I metabolites are too
lipophilic to be retained in kidney tubules
 A 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 most often
therapeutically inactive
 Phase II

 Glucuronidation is the most common and

important conjugation reaction
 Drugs possessing –OH, HN2, COOH group
may enter phase II directly & become
conjugated without phase I

26 26
Biotransformation of drugs
Pharmacokinetics (III)

Dr mohammed Alsbou
Professor of Clinical Pharmacology
Department of Pharmacology
Faculty of Medicine, Mutah University

1
 Drug elimination

 Removal of drug from body occurs via a

number of routes
 The most important being through kidney
into the urine
 Other routes include the bile, intestine,
lung, or milk in nursing mothers

2
 A. Renal elimination of a drug

1. Glomerular filtration
2. Proximal tubular secretion (active
secretion)
3. Distal tubular reabsorption (passive
reabsorption)
4. Effect of drug metabolism on
reabsorption in distal tubule
3
 A. Renal elimination of a drug

1. Glomerular filtration:
 Drugs enter kidney through renal arteries

 Free drug (not bound to albumin) flows

into Bowman’s space as part of the

glomerular filtrate

4
 2. Proximal tubular secretion
(active secretion):

 Drugs that were not transferred into

glomerular filtrate
 Secretion occurs in proximal tubules by
active transport systems
 Competition between drugs for these
carriers can occur within each transport
system

5
 3. Distal tubular reabsorption
(passive reabsorption):

 As drug moves toward distal tubule, its

concentration increases & exceeds that of
perivascular space
 Lipid-soluble drug, uncharged drug, may
diffuse out of kindney’s lumen, back into
systemic circulation (back-diffusion)

6
Drug elimination by kidney

7
 Effect of drug metabolism on reabsorption
in distal tubule

 Most drugs are lipid soluble & would diffuse

out of kidney’s lumen when drug
concentration in filtrate becomes greater
than that in perivascular space
 To minimize this reabsorption, drugs are
modified primarily in liver into more ionized
or polar substances by phase I & II
reactions
8
Effect of drug metabolism on
reabsorption in distal tubule

9
 Manipulating pH of urine

 Manipulating pH of urine to increase

ionized form of drug in lumen may be used
to minimize amount of back-diffusion
 Hence, increase clearance of an
undesirable drug

10
 As a general rule, weak acids can be
eliminated by alkalinization of urine
 Whereas elimination of weak bases may
be increased by acidification of urine

11
 Examples

 A patient presenting with phenobarbital

(weak acid) overdose can be given
bicarbonate, which alkalinizes urine and
keeps drug ionized,
 Thereby decreasing its reabsorption

12
 Examples

 If overdose is with a weak base, such as

cocaine,
 Acidification of urine with NH4Cl leads
to increase in its clearance

13
 Plasma clearance is expressed as
volume of plasma from which a drug is
removed in a given time (mL/min)

14
 Extraction ratio:
 The drugs enter kidneys at concentration
C1 and exit kidneys at concentration C2
The extraction ratio = C2/C1

15
 Half-life (t1⁄2) of drug: is the time
required for drug concentration to change
by fifty percent

16
 Total body clearance:
 CL total or CLt, is the sum of clearances
from various organs
CL total = CL hepatic + CL renal + CL pulmonary + CL other

17
 When a patient has an abnormality that
alters half-life of a drug, adjustment in
dosage is required

18
 Half-life of drug is increased by:

- Diminished renal plasma flow or hepatic

blood (cardiogenic shock, heart failure,
hemorrhage)
- Decreased extraction ratio—in renal disease
- Decreased metabolism— when another drug
inhibits its biotransformation or in hepatic
insufficiency, as with cirrhosis

19
 Half-life of a drug may decrease by:

- Increased hepatic blood flow

- Increased metabolism

20
 KINETICS OF CONTINUOUS
ADMINISTRATION

 PK describes time-dependent changes of

plasma drug concentration and total amount
of drug in body, following drug’s
administration by various routes:
A. IV infusion
B. Oral fixed-dose/fixed-time interval
regimens (e.g one tablet every 4 hours)

21
 A. Kinetics of IV infusion
 Rate of drug exit from body increases
proportionately as plasma
concentration increases, and at every
point in time, it is proportional to plasma
concentration of drug

22
 1. Steady-state drug levels in
blood:

 Following initiation of IV infusion, plasma

concentration of drug rises until rate of
drug eliminated precisely balances rate of
administration
 A steady-state is achieved in which
plasma concentration of drug remains
constant

23
 Rate of drug elimination from body = (CLt)(C)
 CLt = total body clearance

 C = plasma concentration of drug

24
 2. Influence of rate of drug
infusion on steady state:

 Steady-state plasma concentration occurs

when rate of drug elimination is equal to
rate of administration

25
 At steady state,
input (rate of infusion) equals
output (rate of elimination)

26
 Css = Ro/keVd = Ro/CLt
 Css = steady-state concentration
 Ro = infusion rate (mg/min)
 Ke =first-order elimination rate
 Vd = volume of distribution
 Because ke, CLt & Vd are constant for most
drugs showing first-order kinetics, Css is
directly proportional to Ro
27
 If infusion rate is doubled, plasma
concentration achieved at the steady
state is doubled

28
 Effect of infusion rate on
steady-state concentration
of drug in plasma

29
 3. Time required to reach
steady-state drug concentration:

 Concentration of drug rises from zero at

start of infusion to its ultimate steady-state
level (Css)

30
 a. Exponential approach to
steady state:

 50% of steady state concentration of drug

is achieved in the (First t1/2)
 Waiting another half-life (Second t1/2)
allows drug concentration to approach 75%
of Css
 90% of steady state concentration of drug
is achieved in the Third t1/2
 A drug will reach steady-state in about
Four half-lives 31
Rate of attainment of steady-state
concentration of drug in plasma

32
 b. Rate of drug decline when
infusion is stopped:

 When infusion is stopped, plasma

concentration of a drug declines (washes
out) to zero with same time course
observed in approaching steady state

33
 c. Loading dose:

 A delay in achieving desired plasma levels

of drug may be clinically unacceptable
 Therefore, a “loading dose” of drug can
be injected as a single dose to achieve
desired plasma level rapidly
 Followed by an infusion to maintain steady
state (maintenance dose)

34
 B. Kinetics of fixed-dose/fixed-
time-interval regimens

 Administration of a drug by fixed doses

(e.g. one tablet every 4 hrs) rather than by
continuous infusion is more convenient
 However, fixed doses, given at fixed-time
intervals, result in time-dependent
fluctuations in circulating level of drug

35
1. Single IV injection:
 Circulating level of drug

decreases exponentially
with time

36
2. Multiple IV injections:
 When a drug is given repeatedly at regular

intervals, the plasma concentration increases

until a steady state is reached

37
 3. Orally administered drugs:

 Plasma concentration
of orally administered
drugs is influenced by
both the rate of
absorption and the
rate of drug
elimination

38
 Plasma Site of
Dosage Effects
Concen. Action

Pharmacokinetics Pharmacodynamics
 12
Plasma Concentration

10 TOXIC RANGE

6 THERAPEUTIC RANGE

2 SUB-THERAPEUTIC

0
0 1 2 3 4 5 6 7 8 9
Dose
 DISPOSITION OF DRUGS

The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York:
McGraw-Hill, 1996).
 LOCUS OF ACTION TISSUE
“RECEPTORS” RESERVOIRS
Bound Free Free Bound

ABSORPTION Free Drug EXCRETION

SYSTEMIC
Bound Drug CIRCULATION

BIOTRANSFORMATION
 Plasma concentration vs. time profile of a
single dose of a drug ingested orally

14
Plasma Concentration

12
10
8
6
4
2
0
0 5 10 15 20
TIME (hours)
 12
Plasma Concentration

10 TOXIC RANGE

6 THERAPEUTIC RANGE

2 SUB-THERAPEUTIC

0
0 1 2 3 4 5 6 7 8 9
Dose
 LOCUS OF ACTION TISSUE
“RECEPTORS” RESERVOIRS
Bound Free Free Bound

ABSORPTION Free Drug EXCRETION

SYSTEMIC
Bound Drug CIRCULATION

BIOTRANSFORMATION
 Bioavailability

Definition: the fraction of the administered

dose reaching the systemic circulation
for i.v.: 100%
for non i.v.: ranges from 0 to 100%

e.g. lidocaine bioavailability 35% due to

destruction in gastric acid and liver metabolism

First Pass Effect

 Bioavailability
Destroyed Not Destroyed Destroyed
in gut absorbed by gut wall by liver

to
Dose systemic
circulation
 PRINCIPLE

For drugs taken by routes other than the

i.v. route, the extent of absorption and the
bioavailability must be understood in
order to determine what dose will induce
the desired therapeutic effect. It will also
explain why the same dose may cause a
therapeutic effect by one route but a toxic
or no effect by another.
 PRINCIPLE

Drugs appear to distribute in the body as if it

were a single compartment. The magnitude of
the drug’s distribution is given by the apparent
volume of distribution (Vd).

Vd = Amount of drug in body ÷ Concentration in Plasma

(Apparent) Volume of Distribution:

Volume into which a drug appears to distribute with
a concentration equal to its plasma concentration
 Examples of apparent Vd’s for
some drugs
Drug L/Kg L/70 kg
Sulfisoxazole 0.16 11.2
Phenytoin 0.63 44.1
Phenobarbital 0.55 38.5
Diazepam 2.4 168
Digoxin 7 490
 Elimination
of drugs from the body

M KIDNEY LIVER
A
J filtration metabolism
O secretion secretion
R (reabsorption)

M LUNGS OTHERS
I
N exhalation mother's milk
O sweat, saliva etc.
R
 Elimination by the Kidney
• Excretion - major
1) glomerular filtration
glomerular structure, size constraints,
protein binding

2) tubular reabsorption/secretion
- acidification/alkalinization,
- active transport, competitive/saturable,
organic acids/bases
- protein binding

• Metabolism - minor
 Elimination by the Liver
• Metabolism - major
1) Phase I and II reactions

2) Function: change a lipid soluble to more

water soluble molecule to excrete in kidney

3) Possibility of active metabolites with

same or different properties as parent
molecule

• Biliary Secretion – active transport, 4 categories

The enterohepatic shunt
Drug Liver

Bile Bile formation

duct
Biotransformation;
Hydrolysis by glucuronide
beta glucuronidase
gall bladder produced

Portal circulation

Gut
 12
Plasma Concentration

10 TOXIC RANGE

6 THERAPEUTIC RANGE

2 SUB-THERAPEUTIC

0
0 1 2 3 4 5 6 7 8 9
Dose
 Influence of Variations in Relative Rates of
Absorption and Elimination on Plasma
Concentration of an Orally Administered Drug

14 Ka/Ke=10
Plasma concentration

12 Ka/Ke=1

10
Ka/Ke=0.1
8 Ka/Ke=0.01
6
4
2
0
0 5 10 15 20

TIME (hours)
 Elimination

• Zero order: constant rate of elimination

irrespective of plasma concentration.

• First order: rate of elimination proportional to

plasma concentration. Constant Fraction of drug
eliminated per unit time.

Rate of elimination ∝ Amount

Rate of elimination = K x Amount
 Zero Order Elimination
Pharmacokinetics of Ethanol
• Ethanol is distributed in total body water.
• Mild intoxication at 1 mg/ml in plasma.
• How much should be ingested to reach it?
Answer: 42 g or 56 ml of pure ethanol (VdxC)
Or 120 ml of a strong alcoholic drink like whiskey
• Ethanol has a constant elimination rate = 10 ml/h
• To maintain mild intoxication, at what rate must
ethanol be taken now?
at 10 ml/h of pure ethanol, or 20 ml/h of drink.
Rarely Done DRUNKENNES Coma Death
 First Order Elimination
dA/dt ∝A DA/dt = – k•A

14 DC/dt = – k•C
Plasma concentration

12 Ct = C0 . e – Kel •t
10 lnCt = lnC0 – Kel • t
8 logCt = logC0 – Kel •t
6 2.3
4 y = b – a.x
2
0
0 5 10 15 20

TIME (hours)
 Plasma Concentration 10000

First Order Elimination

1000

100

10

1
0 1 2 3 4 5 6
Time
logCt = logC0 - Kel . t
2.303
 Plasma Concentration Profile
after a Single I.V. Injection

10000
Distribution and Elimination
Plasma Concentration

Elimination only
1000
C0
100

10

Distribution equilibrium
1
0 1 2 3 4 5 6

Time
 lnCt = lnCo – Kel.t

Vd = Dose/C0

When t = 0, C = C0, i.e., the concentration at

time zero when distribution is complete and
elimination has not started yet. Use this value
and the dose to calculate Vd.
 lnCt = lnC0 – Kel.t

t1/2 = 0.693/Kel

When Ct = ½ C0, then Kel.t = 0.693. This is the

time for the plasma concentration to reach half
the original, i.e., the half-life of elimination.
 PRINCIPLE

Elimination of drugs from the

body usually follows first order
kinetics with a characteristic
half-life (t1/2) and fractional rate
constant (Kel).
 First Order Elimination
• Clearance: volume of plasma cleared of drug
per unit time.
Clearance = Rate of elimination ÷ plasma conc.
• Half-life of elimination: time for plasma conc.
to decrease by half.
Useful in estimating:
- time to reach steady state concentration.
- time for plasma concentration to fall after
dosing is stopped.
 BLOOD OUT
CA CV

I
N

Blood Flow = Q

ELIMINATED
Rate of Elimination = QCA – QCV = Q(CA-CV)
SIMILARLY FOR
Liver Clearance = Q(CA-CV)/CA = Q x EF OTHER ORGANS
•
Renal Clearance = Ux•V/Px

Total Body Clearance = CLliver + CLkidney + CLlungs + CLx

 Rate of elimination = Kel x Amount in body
Rate of elimination = CL x Plasma Concentration

Therefore,
Kel x Amount = CL x Concentration

Kel = CL/Vd

0.693/t1/2 = CL/Vd

t1/2 = 0.693 x Vd/CL

 PRINCIPLE
The half-life of elimination of a drug (and
its residence in the body) depends on its
clearance and its volume of distribution

t1/2 is proportional to Vd
t1/2 is inversely proportional to CL

t1/2 = 0.693 x Vd/CL

 Multiple dosing
• On continuous steady administration of a drug,
plasma concentration will rise fast at first then more
slowly and reach a plateau, where:
rate of administration = rate of elimination
ie. steady state is reached.
• Therefore, at steady state:
Dose (Rate of Administration) = clearance x plasma conc.
Or
If you aim at a target plasma level and you know the
clearance, you can calculate the dose required.
Constant Rate of Administration (i.v.)
 Single dose –
Loading dose
7

6
Plasma Concentration

Therapeutic
5 level

3
Repeated doses –
2
Maintenance dose
1

0
0 5 10 15 20 25 30

Time
The time to reach steady
state is ~4 t1/2’s

Concentration due to
repeated doses

Concentration due to a single dose

 Pharmacokinetic parameters
Get equation of regression line; from it get Kel, C0 , and AUC

• Volume of distribution Vd = DOSE / C0

• Plasma clearance Cl = Kel .Vd

• plasma half-life t1/2 = 0.693 / Kel

• Bioavailability (AUC)x / (AUC)iv

 dC/dt = CL x C

dC = CL x C x dt

But C x dt = small area under the curve. For total

amount eliminated (which is the total given, or the
dose, if i.v.), add all the small areas = AUC.
Dose = CL x AUC and Dose x F = CL x AUC
 Bioavailability = (AUC)o
70 (AUC)iv

60
Plasma concentration

50 i.v. route

40
30 oral route

20

10

0
0 2 4 6 8 10
Time (hours)
 Variability in Pharmacokinetics

60
Concentration (mg/L)

50
Plasma Drug

40

30

20

10

0
0 5 10 15
Daily Dose (mg/kg)
 PRINCIPLE

The absorption, distribution and

elimination of a drug are qualitatively
similar in all individuals. However, for
several reasons, the quantitative aspects
may differ considerably. Each person
must be considered individually and
doses adjusted accordingly.
 RATIONAL USE OF DRUGS
AND MEDICATION ERRORS

Dr. Yousef Al-saraireh

Assistant Professor
Chairman of pharmacology department
1
Faculty of Medicine
 CONTENTS

 RATIONAL USE OF DRUGS

 MEDICATION ERRORS

2
 RATIONAL USE OF DRUGS
Rational use of drugs: "patients receive medications
appropriate to their clinical needs, in doses that meet
their own individual requirements, for an adequate
period of time, and at the lowest cost to them and their
community".

3
 MEASURES TO ENSURE RATIONAL USE
OF DRUGS
The WHO advice several measures to ensure
rational use of drugs that include development of:
 National committee on drug use

 National list of essential drugs

 Use of clinical guidelines: by physicians as in

treating hypertension & asthma
 Some regulations and measures

4
 IRRATIONAL USE OF DRUGS
Include:
 Poly-pharmacy (use of too many drugs)

 Poor compliance (non-adherence to instructions of

therapy)
 Misuse or inappropriate use of antimicrobials

 Over-use of injections

 Failure to prescribe in accordance with clinical

guidelines
 Inappropriate self-medication

5
 SELECTION OF DRUGS
Choice of effective drugs should be based on:
1.Efficacy

2. Cost: affordable by patient and community

3. Chosen from Essential Drugs: These are

effective drugs that are commonly used in
community, and must always be available

6
 MEDICATION ERRORS

Definition:
any preventable event that may cause or lead to
inappropriate medication use or patient harm while the
medication is in the control of the health care professional,
patient, or consumer ...
 Such events are related to professional practice, health
care products, procedures, and systems,
 including prescribing; order communication; product
labeling, packaging, and nomenclature; compounding;
dispensing; distribution; administration; education;
monitoring; and use.
7
 What kinds of errors are most common?

the most common error involving medications was related to:

1. Administration of an improper dose of medicine,
accounting for 41 % of fatal medication errors.

2. Giving the wrong drug and using the wrong route of

administration each accounted for 16% of the errors.

Almost half of the fatal medication errors occurred in people

over the age of 60.

Older people may be at greatest risk for medication errors

because they often take multiple prescription medications.

8
 Causes of medication errors:
1. Poor communication between health care providers
2. Poor communication between providers and their patients
3. Sound-alike medication names and medical abbreviations
4. Errors when prescribing, transcribing, dispensing, and
administering medications
5. Errors related to patient monitoring of the effects of
medications
6. Potential or actual confusion regarding look-alike drug or
vaccine names, and packaging similarities
7. Misuse or malfunction of medication-related tools (e.g.,
syringes, needles), equipment (e.g., tubing, infusion pumps),
and technology (e.g.,
barcode scanning).
9
 Examples

1. A physician ordered a 260-milligram preparation of

Taxol for a patient, but the pharmacist prepared 260
milligrams of Taxotere instead

2. One patient died because 20 units of insulin was

abbreviated as "20 U" but the"U" was mistaken for a
"zero." As a result, a dose of 200 units of insulin was
accidentally injected.

3. A patient developed a fatal hemorrhage when given

another patient's prescription for the blood thinner
warfarin.

10
 Medication errors may stem from:
1. poor communication,

2. misinterpreted handwriting,

3. drug name confusion,

4.lack of employee knowledge, and

5.lack of patient understanding about a

drug's directions.
11
Poor handwriting

12
Poor handwriting

13
DRUG NAME CONFUSION

14
DRUG NAME CONFUSION

15
 MEDICATION ERROR PREVENTION

1. Patient communication
2. Intraprofessional communication
3. Education and training
4. Reporting
5. Electronic prescribing

16
THANKS

17
DRUGS USED DURING PREGNANCY
& LACTATION
 PREGNANCY PHYSIOLOGY AND ITS EFFECTS ON PHARMACOKINETICS

Absorption
1. Gastrointestinal motility is decreased but there appears to be no major
affect in drug absorption except that reduced gastric emptying delays the
appearance in the plasma of orally administered drugs, especially during
labor.
2. Absorption from an intramuscular site is likely to be efficient because tissue
perfusion is increased due to vasodilatation.
 DISTRIBUTION:
1. Total body water increases by up to 8 Litres, creating a larger space
within which water soluble drugs may distribute.
2. As a result of haemodilution, plasma albumin (normal 33-55 g/1)
declines by some 10 g/1. Thus there is scope for increased free
concentration of drugs that bind to albumin.
3. Unbound drug, is free to distribute, metabolized and excreted; e.g. the
free (and pharmacologically active) concentration of phenytoin is
unaltered, although the total plasma concentration is reduced.
METABOLISM
• Hepatic metabolism increases, but not the blood flow to liver.

• So, increased clearance of drugs such as phenytoin and theophylline

(elimination rate depends on liver enzyme activity)

• Drugs that are so rapidly metabolized that their elimination rate

depends on their delivery to the liver, i.e. on hepatic blood flow, have

unaltered clearance, e.g. pethidine.

 ELIMINATION:
• Renal plasma flow almost doubles

• So there is rapid loss of drugs that are excreted by kidney

• e.g. amoxycillin, dose of which should be doubled for systemic infections

(but not for urinary tract infections as penicillins are highly concentrated

in urine).
 PLACENTAL TRANSFER OF DRUGS
1. The placenta is not a perfect barrier to drugs and chemicals
administered to mother.
2. Thalidomide tragedy, showed that placenta was capable of
transferring drugs ingested by mother to fetus, with potential for
great harm.
3. On other hand, placental transfer of drugs administered to mother
has been used to treat fetal arrhythmias, congestive heart failure, &
other conditions.
 FACTORS AFFECTING PLACENTAL DRUG TRANSFER &
FETAL TISSUE
(1) Physicochemical properties of drug

(2) Rate at which drug crosses placenta & amount of drug reaching the fetus

(3) Duration of exposure to drug

(4) Distribution characteristics in different fetal tissues

(5) Stage of placental & fetal development at time of exposure to the drug

(6) Effects of drugs used in combination

A teratogen is a chemical substance that can
induce a malformation during development.
TERATOGENESIS
PRINCIPLES OF TERATOLOGY
 Teratogens act with specificity. A teratogen produces a specific abnormality or
constellation of abnormalities. Eg. thalidomide produces phocomelia, and valproic
acid produces neural tube defects.

 Teratogens demonstrate a dose-effect relationship.

 Teratogens must reach the developing conceptus in sufficient amounts to cause

their effects.

 The effect that a teratogenic agent has on a developing fetus depends upon the
stage during development when the fetus is exposed.
MECHANISMS OF TERATOGENESIS

 Genetic interference, gene mutation, chromosomal breakage,

interference with cellular function, enzyme inhibition, and altered
membrane characteristics.

 The response of the developing embryo to these insults is failure of

cell–cell interaction crucial for development, interference with cell
migration, or mechanical cellular disruption.
EXAMPLES
PRESCRIBING IN PREGNANCY
•minimize prescribing;
•use ‘tried and tested’ drugs whenever possible in preference to new agents;
• use the smallest effective dose;
• remember that the fetus is most sensitive in the first trimester;
• consider pregnancy in all women of childbearing potential;
• discuss the potential risks of taking or withholding therapy with the patient;
• seek guidance on the use of drugs in pregnancy in the British National
Formulary, Drug Information Services, National Teratology Information
Service (NTIS);
• warn the patient about the risks of smoking, alcohol, over-the-counter drugs
and drugs of abuse.
DRUG USE DURING LACTATION

 Most drugs administered to lactating women are detectable in breast milk.

Fortunately, the concentration of drugs achieved in breast milk is usually low.
 Infant would receive in a day is substantially less than what would be considered a
“therapeutic dose.”
 If the nursing mother must take medications and the drug is a relatively safe one,
she should optimally take it 30–60 minutes after nursing and 3–4 hours before the
next feeding.
 Caution: Sedative-Hypnotics, Lithium Tetracyclines
THANK YOU
Pharmacovigilance & Adverse
Drug Reactions

Dr Mohammed Al-Sbou (MD, MSc, PhD)

Professor of Clinical Pharmacology
Faculty of Medicine, Mutah University

1
‘First of all be sure you
do no harm’

Hippocrates (460-370 BC)

2
 Pharmacovigilance (PV)
 The root of
pharmacovigilance:
Pharmaco (Greek)= Drug
Vigilance (Latin)= to keep
awake or alert

3
 Pharmacovigilance (PV)
 PV is concerned
with detection,
assessment &
prevention of
adverse reactions
to drugs (ADRs) or
any drug-related
problems

4
 Drug-Related Problems
 Lack of efficacy
 Medication errors
 Drug misuse and abuse
 Overdose
 Quality issues:
 Manufacturing defects

 Contamination

 Counterfeit products

5
 Why Pharmacovigilance?

 Because information collected during

pre-marketing phase are incomplete
with regard to possible ADR
 Tests in animals are insufficiently
predictive of human safety
 Why Pharmacovigilance?
 In clinical trials:
- Patients are limited in number
- Conditions of use differ from those in
clinical practice
- Duration of trials is limited

7
 Why Pharmacovigilance?
 Information about rare adverse reactions,
chronic toxicity, use in special groups
(children, elderly or pregnant women) or
drug interactions is often incomplete or not
available

Post-marketing surveillance by
companies is therefore essential
9
 Definition of ADR
 An ADR is defined according to definition
of WHO “any response to a drug which is
noxious, unintended & that occurs at
doses used in man for prophylaxis,
diagnosis, or therapy of diseases’’

10
 Epidemiology of ADRs
 ADRs represent a significant cause of
morbidity & mortality
 Many ADRs are mild, sometimes serious
& can cause death
 U.S, ADRs caused 100 000 deaths per
year, 4th & 6th leading cause of death
 About 50% of ADRs are preventable

11
 Importance of ADRs
 Prolong length of stay in hospitals
 Increase costs of patient care
(£600 million NHS in UK)
 Commonest cause of drug withdrawal
from market (recall):
 ARBs (Valsartan, Losartan, Irbesartan) 2019
 Reductil (Sibutramine) 2010
 Valdecoxib (Bextra) 2005
 Rofecoxib (Vioxx) 2004
12
 Classification of ADRs
 Classification of Rawlins & Thompson
Type A reactions
- Augmentation of known pharmacological effect of drug
- Predictable
- Dose related
- e.g. warfarin causing bleeding

Type B reactions
- Bizarre (idiosyncratic)
- Not dose dependent
- Unpredictable
- e.g. carbamazepine-induced skin rash
13
Warfarin-induced calf haematoma

14
Carbamazepine-induced Stevens
Johnson Syndrome (SJS)

15
 ADRs according frequency are divided into
very common, common, rare, very rare
 ADRs divided according to severity into
mild, moderate, severe

16
 ADRs is considered serious if:
1. Causes death of patient
2. Life-threatening
3. Prolong inpatient hospitalisation
4. Causes significant or persist disability
5. Congenital abnormality

17
Risk Factors Predisposing to ADRs

 Age
 Long duration of treatment
 Polypharmacy
 Liver, kidney diseases

18
 Causes of ADRs
1. Patient
2. Drug
3. Prescriber
4. Environmental factors

19
 Causes of ADRs
1. The patient:
- Age (over 60)
- Genetic factors (e.g. polymorphisms
in CYP450)
- Previous history of ADR
- Hepatic or renal diseases

20
 Causes of ADRs
2. The drug
- Narrow therapeutic index, e.g. warfarin,
digoxin
- Antimicrobials have a tendency to cause
allergy & may lead to type B reactions
- Ingredients of a formulation, e.g.
colouring, flavouring

21
 Causes of ADRs
3. The prescriber:
- A drug is used for an inappropriately
long time
- At a critical phase in pregnancy
- Given with other drugs (drug-drug
interactions)

4. Environmental factors:
- Diet, smoking, alcohol

22
Drugs Most Commonly Causing ADRs

 Warfarin  Anticancer drugs

 Diuretics  Immunomodulators
 Digoxin  Analgesics
 Antibacterials  Biological &
 Steroids biosimilars
 Antihypertensives

23
Burden of Adverse Drug Reactions

Admission

In patients

A&E

Primary
care

24
Burden of Adverse Drug Reactions

Admission
(Inter J of Cl Phar & Ther,1998, 36(9):478-482)

In patients

(J Med J, 2010; 44(4);442-446)

25
26
 6.5% (n=1224) of admissions are due to ADRs
 Seven 800-bed hospitals are occupied by ADR
patients
 Death in 0.15% - equivalent to 5700 deaths per
year
 Cost NHS £600 million per annum

27
 16of 200 patients (8%) suffered from one
or more ADRs
 50% of ADRs were avoidable

 Onepatient died during admission and his

death was contributed to an ADR

28
29
Number of ADR Reports / Drug Class
Number of ADR Reports / System Organ Class
 Why report suspected ADRs?
 Documentation of ADRs in patients’
records is often poor
 Physicians fear that reporting of ADR may
put them at risk
 Under-reporting is common phenomenon

32
 Methods of Reporting ADRs
- Spontaneous reporting:
‘Yellow Card system’

33
 Reporting Methods

1- Spontaneous reporting: (Voluntary)

- Doctors, nurses & pharmacists are supplied
with forms to record suspected ADRs
- Regional PV centers at hospitals
- Reporting ADRs to National
Pharmacovigilance Centre
- In UK & jordan this is called ‘Yellow Card
system’
34
Online ADRs reporting form

35
36
37
International Collaboration
 WHO International Drug Monitoring
programme, 86 member nations have
systems to record & report ADRs
 Member countries send their report to
Uppsala Monitoring Centre (Sweden)
where they are entered into WHO Database

38
- WHO database (vigibase) include 15
million case reports

39
 MedWatch is FDA
reporting system
in U.S. for adverse
effects of drugs

40
 Jordan Food & Drug
Administration (JFDA)

Jordan Pharmacovigilance Centre

41
 Pharmacovigilance Center for South
Jordan/ Alkarak Governmental Hospital

42
43
44
Pharmacogenetics
Dr. Mohammed Al-Sbou
Professor of Clinical Pharmacology
Faculty of Medicine-Mutah Uni

1
 The human genome project has led to an
explosion of genetic information that is freely
available to identify polymorphisms that may
determine drug response

2
 Advances in molecular genetics and
genotyping technologies during the last two
decades have led to identification of many
polymorphisms in phase I and phase II drug
metabolising enzymes, drug targets, and in
drug transporters

3
Individual Variation in Response to Drugs
 How individuals in a population are expected
to respond to a fixed dose of drug?
 Inter-individual variability:

- Some show less than usual response

- Most show usual response
- Others show more than usual response

4
Factors Determine Response to Drugs

Environmental
(Age, sex, race, concomitant diseases, diet,
smoking, alcohol)
 Genetic (polymorphisms drug metabolising
enzymes, receptors, drug targets)

6
Pharmacogenetics/Pharmacogenomics
 Pharmacogenetics: is study of variation in
drug response due to heredity & is used in
relation to genes determining drug
metabolism
 Pharmacogenomics is a more general term; it
refers to research area that comprises all genes
in the human genome that may determine
drug response

7
 Benefits of
Pharmacogenetics/Pharmacogenomics
 The concept “The right medicine to the right
patient” is the basis of pharmacogenetics
(personalised or individualised medicine)
 Ultimate goals are to improve clinical
therapeutic outcome by:
- Increasing drug efficacy
- Increasing safety of drugs e.g. reducing
incidence of ADRs

8
Personalised or Individualised Medicine

9
Pharmacogenomic approach to personalized medicine.
Drug therapy is chosen for each patient based on their
particular genetic profile

10
Polymorphisms can occur in any gene that
encode:
- Drug metabolising enzymes
- Drug transporters
- Drug targets and receptors

11
 Genetic polymorphisms of drug
metabolising enzyme genes
 The majority of phase I and phase II drug
metabolising enzymes are polymorphic
 The cytochrome P450 (CYP) enzymes are the
most important group of phase I enzymes
 Polymorphisms in cytochrome P450 genes can
cause enzyme products with abolished or
reduced or increased enzyme activity

12
 Cytochrome P450 enzymes
 All genes that encode for families 1-3 are
polymorphic & their capacity to metabolise
drugs depends on the functional importance
and frequency of variant alleles

13
 CYP450 Enzymes
 CYP2D6
 CYP2C9
 CYP2C19

14
 CYP2D6
 CYP2D6 contributes to metabolism of large of
medications about 25% of all drugs, including:
 Antidepressants (TCAs, SSRIs)

 Antiarrythmics

 Analgesics

15
 CYP2D6 Phenotypes
- Poor metabolisers( PM): lack functional enzyme
- Intermediate metabolisers (IM): carry two
alleles that cause reduce activity
- Extensive metabolisers ( EM): have two normal
alleles
- Ultra-rapid metabolisers (UM): multiple gene
copies

16
 Poor metabolisers can experience adverse
effects when treated with standard dose
 Ultra-rapid metabolisers require high doses
of drugs

17
 Depression
- Tricyclic antidepressants are metabolised by
CYP2D6
 Disposition of nortriptyline is related to
number of active CYP2D6 alleles and
 Dose required to obtain same plasma drug
concentrations varies between subjects with
different CYP2D6 phenotypes

20
 Ultra-rapid metabolisers needed a 10-fold
larger dose of nortriptyline than poor
metabolisers to achieve the same plasma
concentration
 Ultra-rapid metabolisers require 500 mg of
doses compared to 50 mg in poor metabolisers

21
 Genetic polymorphisms of CYP2D6 gene may
be associated with ADRs and clinical response
to antidepressants
 30% of patients with ADRs to antidepressants
were PMs
 High incidence of UMs among non-responders
(20%)

22
 CYP2C9
 CYP2C9 metabolises a wide range of drugs
 Including drugs with narrow therapeutic indices
such as:
 Warfarin

 Phenytoin

 Non-steroidal anti-inflammatory drugs

(NSAIDs) including ibuprofen, diclofenac
and celecoxib

23
 Warfarin and Bleeding
 Warfarin is one of the most widely prescribed
oral anticoagulant drugs
 It is used for:
 Prophylaxis and treatment of venous
thromboemolism
 Treatment of deep vein thrombosis (DVT)

 Atrial fibrillation (AF)

 In patients with prosthetic heart valves

24
 Warfarin and Bleeding
 The main complication of warfarin therapy is
haemorrhage
 Genetic polymorphisms in CYP2C9 gives rise to
variants with altered enzymes activity
 Two allelic variants CYP2C9*2 (Arg144Cys) and
CYP2C9*3 (Ile359Leu) show 12% and 5% of
enzyme activity of the wild type CYP2C9*1 allele,
respectively, and are associated with decreased
warfarin dose requirements & increased risk
of bleeding
25
 Peptic Ulcer
- Proton pump inhibitors (PPIs) are used for treatment
of gastric acid related diseases such as peptic ulcers,
gastro-esophageal reflux disease (GERD) & in
combination with antibiotics (amoxicillin &
clarithromycin) for eradication of Helicobacter
pylori (Hp)
- CYP2C19 metabolises several PPIs including
omeprazole and lanzoprazole
- Plasma concentrations of omeprazole, depend on
patient’s CYP2C19 phenotype

26
 AmpliChip CYP450 Array
 The AmpliChip CYP450
Test provides comprehensive
detection of gene variations
including deletions and
duplications for the
CYP2D6 and CYP2C19
genes

27
 Genetic Polymorphisms of Drug
Metabolising Enzyme Genes

 With respect to phase II enzymes, the most

important polymorphisms occur in N -
acetyltransferase-2 (NAT-2) and thiopurine
methyltransferase (TPMT)
 NAT-2 is involved in the metabolism of
isoniazid and sulphamethoxazole

28
 Acetylation
- Most individuals are either rapid or slow
acetylators, but proportion varies between races
- The percentage of slow acetylators:
 90% in North African

 50% in Caucasian

 10% in Asian populations

29
 Thiopurine S-methyltransferase (TPMT)

 TPMT catalyzes methylation of thiopurine

drugs such as 6-mercaptopurine & azathioprine
 These drugs are commonly used in treatment of
acute lymphoblastic leukaemia (ALL),
autoimmune diseases, inflammatory bowel
diseases, in organ & tissue transplantation
 Clinical testing for TPMT genetic polymorphisms
is available

30
 It has been shown that:
- 90% of population exhibit high TPMT activity
- 10% show intermediate activity
- 0.3% have low or absent enzyme activity

31
Genetic Polymorphisms in Drug Transporters

 Transporters are membrane proteins that play

crucial role in absorption, distribution &
elimination of drugs
 Genetic polymorphisms can occur in transport
proteins & may contribute to inter-individual
variation in drug response
 MDR1 (multi-drug resistant) P-glycoprotein-
Digoxin
 Serotonin transporter-antidepressant response

32
 Genetic Polymorphisms in Drug targets
and Receptors
 Drug target genes including those coding for
receptors, ion channels and specific enzymes are
subject to genetic polymorphisms
 B2-adrenergic receptor: B2 agonist (salbutamol)
 Angiotensin converting enzyme (ACE):
ACE inhibitors (lisinopril)
 Vitamin K epoxide reductase complex
(VKORC): Warfarin

33
 Practical Points
 Genetic is an important factor responsible for
failure to therapy & occurrence of adverse drug
reactions
 The goal of PGx is to maximize efficacy &
minimize toxicity, based on individual’s genetic
composition
 Individual variation in response to drug (some may
benefit, other fail to respond to treatment,
others may develop adverse effects)
34
Drug Therapy In Pediatric & Geriatric
Age Groups
Objectives

a. Discuss the principles of prescribing in pediatric and geriatric age groups.

b. Discuss the pharmacokinetic and pharmacodynamics differences in pediatric, geriatric and adult age

groups.

c. Describe how the efficacies of drugs vary according to age.

d. Describe different pediatric dosage forms & compliance in children.

e. Discuss important adverse drug reactions occurring in geriatric & pediatric age groups.
What is different from normal adult prescribing?

Children cannot be regarded as miniature adults in

terms of drug response, due to differences in body

constitution, drug absorption and elimination, and

sensitivity to adverse reactions.

Pediatric Group – Pharmacokinetics
Absorption:

o Gastro-intestinal absorption is slower in infancy, but absorption from intra-

muscular injection is faster.

o Infant skin is thin and percutaneous absorption can cause systemic toxicity

Distribution:

o Lower volume of distribution of fat-soluble drugs (e.g. diazepam) in infants.

o Plasma protein binding of drugs is reduced in neonates.

o Blood–brain barrier is more permeable in neonates and young children,

leading to an increased risk of CNS adverse effects.
Metabolism:

o At birth, the hepatic microsomal enzyme system is relatively immature.

o Drugs administered to the mother can induce neonatal enzyme activity

(e.g. barbiturates).

Excretion:

o All renal mechanisms (filtration, secretion and reabsorption) are reduced in

neonates.

o Subsequently, during toddlerhood, it exceeds adult values, often

necessitating larger doses per kilogram. E.g. the dose per kilogram of
digoxin is much higher in toddlers than in adults
PHARMACODYNAMICS

 Apparently paradoxical effects of some drugs (e.g. hyperkinesia with

phenobarbitone, sedation of hyperactive children with amphetamine)
are as yet unexplained.

 Augmented responses to warfarin in prepubertal patients occur at

similar plasma concentrations as in adults, implying a
pharmacodynamic mechanism.
PEDIATRIC DRUG DOSAGE

 Most drugs approved for use in children have recommended pediatric doses,
generally stated as milligrams per kilogram.

 Calculations of pediatric dosage:

o Surface area based (Young’s formula): Dose = 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 ×

𝐴𝐴𝐴𝐴𝐴𝐴(𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦𝑦)
𝐴𝐴𝐴𝐴𝐴𝐴+12

o Body weight based (Clark’s rule): Dose = 𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 ×

𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊 (𝑘𝑘𝑘𝑘)
70
 ADVERSE EFFECTS
• With a few notable exceptions, drugs in children generally have a similar adverse
effect profile to those in adults.

Some specific ADR examples are;

• chronic corticosteroid use, including high-dose inhaled corticosteroids, to inhibit

growth
• Tetracyclines are deposited in growing bone and teeth, causing staining and
occasionally dental hypoplasia
• Fluoroquinolone antibacterial drugs may damage growing cartilage
• Dystonias with metoclopramide occur more frequently in children and young
adults than in older adults
• Valproate hepatotoxicity is increased in young children
 PEDIATRIC DOSAGE FORMS & COMPLIANCE
 Children under the age of five years may have difficulty in swallowing even small tablets, and
hence oral preparations which taste pleasant are often necessary to improve compliance. (Elixirs
& Suspensions)
 Pressurized aerosols (e.g. salbutamol inhaler) in children over the age of ten years, as
coordinated deep inspiration is required. Nebulizers may be used.
 Children find intravenous infusions uncomfortable and restrictive. Rectal administration is a
convenient alternative (e.g. metronidazole to treat anaerobic infections). Rectal diazepam is
particularly valuable in the treatment of status epilepticus. Rectal administration should also be
considered if the child is vomiting.
Rules of prescribing for Pediatric populations

 Calculate the doses for prescribed drugs based on weight of the patients.

 Ensure proper instructions to the care giver, including when the child vomits the given
medication after consumption.

 Ensure that all medicines are strictly out of reach of children at all times.

 Avoid prolonged treatment with drugs that have delayed complications (Steroids).

 Use antibiotics sparingly and only when required.

 Medications affecting the CNS need to be extensively reviewed and routinely monitored
to ensure minimal growth disturbances.
Older patients are not slowed
down adults!!!!
Geraitric Group - Pharmacokinetics

 Absorption: Little evidence of any major alteration in drug absorption with

age. However, conditions associated with age may alter rate at which some
drugs are absorbed. (Diabetic gastroparaesis, laxative abuse)

 Distribution: Elderly have reduced lean body mass, reduced body water.

 Metabolism: Capacity of liver to metabolize drugs does not appear to

decline consistently with age for all drugs.

 Elimination: Kidney is major organ for clearance of drugs from body, age-
related decline of renal functional capacity is important.
Pharmacodynamics
• Geriatric patients believed to be much more "sensitive" to action of many
drugs, implying a change in pharmacodynamic interaction of drugs with their
receptors. BUT, most of these are a result of changing Pharmacokinetics!
Rules of prescribing for the elderly

o Think about the necessity for o Take a careful drug history.

drugs.
o Avoid drugs with negligible or
doubtful benefits.
o Think about the dose.
o Think about drug formulation.
o Use fixed combinations of drugs
rarely.
o Check Compliance.
o Think before adding a new drug to
the regimen.

o Assume any new symptoms may o Stopping is as important as Starting.

be due to drug side-effects.
Geriatric Prescribing - ADRs
Most frequent drug classes causing
ADRs and Age ADRs

o Incidence of ADR increases with age o Cardiovascular active agents

o Elderly receive more medicines
o Analgesics (opioid mainly)
o Incidence of ADR increases the more
o Antibiotics
prescribed medicines taken

o For patients aged>50 yrs o Hypoglycemic agents

o ADR rates – 5% for 1 or 2 medicines o Psychotropic agents
o Increased to 20% when >5 medicines
o Anticoagulants
THANK YOU
 Management of Drug
Poisoning
/
Mutah Faculty of Medicine

14/11/2021 1
14/11/2021 2
 Eric Doglas

14/11/2021 3
 Drug Poisoning

14/11/2021 4
14/11/2021 5
14/11/2021 6
 Causes of death in drug
poisoning
 CNS depression: Narcotics, sedative-hypnotics
 CVS toxicity: Digitalis, Cocaine

 Cellular hypoxia: Cyanide and CO

 Convulsions: Cocaine

 Organ system damage: Paracetamol

 Accidents

14/11/2021 7
 ABCD of Poisoning treatment

 A: Airway
 B: Breathing

 C: Circulation

 D: Dextrose

14/11/2021 8
 Prevention of further absorption of
the poison:
 Remove patient from the toxic environment
 Measures of decontamination:

 Removing toxins from:

Skin
GIT:
Emesis (not in petrolium nor in corrosive poisoning)
Gastric lavage
Activated charcoal

14/11/2021 9
 Principles of treatment of poisoning
 ABCD of poisoning treatment
A: Airway, B: Breathing, C: Circulation, D:
Dextrose
 Diagnosis;history, exam, investigations
 Prevention of absorption of the poison:
Skin, GIT (Emesis, G lavage, Activated Charcoal)
 Specific
antidote
 Enhancing elimination of toxins by:
Haemodialysis or alteration of urinary pH
14/11/2021 10
 Activated charcoal
 Reduces drug absorption
 Better than emesis or gastric lavage

 Safer, easier, adsorb toxic substances

 Binds to and inactivates many drugs

 Does not bind iron, lithium, corrosive acids

and alkali
 Given early within one hour of poisoning

14/11/2021 11
 Specific antidote

 Paracetamol Acetylcysteine
 Iron Desferoxamine
 Digitalis Digoxin antibodies
 Benzodiazepines Flumazenil
 Opioids Naloxone
 OPI (CE inhibitors) Pralidoxime

14/11/2021 12
Enhancing Elimination of Toxins
 Haemodialysis:
Aspirin, Lithium, Carbamazepine

 Urinary pH alteration:
Urine alkalinazation: aspirin
Urine acidification: amphetamines

14/11/2021 13
 Examples of Common Poisoning

14/11/2021 14
 Paracetamol (Acetaminophen)
 Most common suicide drug
 Ingestion of 7 g total (adults) is toxic

 A highly toxic metabolite (NABQI) is

produced in the liver leading to depletion of
the protective hepatic glutathione
 Patient is asymptomatic initially

 After 24–36 hours, hepato-renal failure and

even death may occur
14/11/2021 15
 Paracetamol poisoning

 Early treatment (within 8 hrs) is important

 N-acetylcysteine IV or methionine orally to
increase hepatic glutathione

14/11/2021 16
Pharmacokinetics of Paracetamol
 The highly toxic metabolite is N-acetyl-p-benzo
quinonimine (NABQI) conjugates with glutathione
 In overdose toxicity:
 Excess NABQI
 Glutathione depletion
 Then NABQI oxidizes thiol group of enzymes
 Leading to cell death
 Resulting in hepatic & renal tubular cell damage

14/11/2021 17
 Paracetamol (Acetaminophen)
 Serum level > 200 mg/L after 4 hours of
ingestion suggests a risk for liver injury

 Acetylcysteine acts as a glutathione

substitute, binding the toxic metabolite

 Should be started within 8–10 hours if

possible
14/11/2021 18
 Anti-muscarinic agents
(Atropine-like drugs)

 Hot, dry, flushed skin

 Blurred vision

 Delirium

 Tachycardia, mydriasis

 Treatment is supportive

14/11/2021 19
 Aspirin (Salicylate)
 Ingestionof > 200 mg/kg
 Hyperventilation, respiratory alkalosis,
metabolic acidosis
 Hyperthermia

 Convulsions, coma

 CV collapse

14/11/2021 20
 Aspirin (Salicylate)
 General supportive care
 Gastric lavage

 Activated charcoal

 IV fluid

 IV sod bicarbonate: renal elimination

 Severe poisoning: Haemodialysis

14/11/2021 21
 Organophosphorous insecticide
poisoning
 Cholinergic crisis
Muscarinic & Nicotinic stimulation
 Pinpoint pupil, sweating, diarrhoea
 Urination, defecation

 Hypotension, bradycardia

 Treatment:
Atropine (anti-muscarinic)
Pralidoxime (enzyme reactivator)
14/11/2021 22
 Other poisoning
 Iron:
Childhood poisoning; bleeding
Desferoxamine

 Opioids:
Drugs of abuse
CNS & respiratory depression
Naloxone IV

14/11/2021 23
 Other poisoning
 Carbon monoxide (CO):
 Colorless, odorless gas
 Results from incomplete combustion
 Forming carboxyhaemoglobin
 Interfering with carrying of oxygen
 Leading to hypoxia

 Cyanide poisoning:
 Syncope, convulsions, coma
 Treatment: Cyanide antidote kit consists of:
 Nitrites: induce methemoglobinemia
 Thiosulfate: converts cyanide to thiocyanate

14/11/2021 24
 New Drugs: Their
Development & Evaluation
Dr. Mohammed Al-sbou
Professor in Clinical Pharmacology
Faculty of Medicine, Mutah University

1
 New Drug Development
 Idea or hypothesis
 Design & synthesis of substances
 Studies on tissues & animal (preclinical studies)
 Studies on man (clinical studies)
 Official license (registration & market
authorization)
 Post-marketing studies

2
 Aims of Therapeutic Evaluation
 To assess efficacy, safety & quality of new
drugs
 To expand indications for the use of current
drugs
 To protect public health

3
 Drug Development
 Drugs are chemical substances useful in
prevention & diagnosis & treatment of diseases
 The process of drug development may be
abandoned at any stage including after
marketing (safety, inadequate efficacy)

4
 Drug Development
 New drug development is enormously expensive
 Cost of development of a new chemical entity
from synthesis to market US $ 500 million
 The process may take 10-15 years

5
 Origin of Drugs
 Natural sources:
 Plant origin like morphine, digoxin, atropine

 Micoorganisms as fungi & bacteria synthesizing

antibiotics
 Animal origin like hormones (insulin), heparin

 Mineral origin like iron, calcium

6
 Origin of Drugs
 Synthetic when synthesized chemically in
laboratories
 These represent majority of drugs, as they are
easily manufactured & cheaper like aspirin,
paracetamol & propranolol

7
 Medicines
 Medicines are drugs formulated in a suitable
way for administration & use by patients
 Medicines consist of the active drug
combined with excipients that give it shape,
size, stability & other criteria as starch, Arabic
gum & many other substances

8
 Therapeutic Investigation
 There are three questions to be answered during
drug development:
1. Does the drug work?
2. Is it safe?
3. What is the dose?

9
 Phases of Drug Development
1. Pre-clinical studies in animals
2. Clinical studies in human

10
1. Pre-clinical studies in animals including:
A. General pharmacology studies:
 Pharmacokinetic studies
 Pharmacodynamic studies
 Dose, preparation & routes of
administration

11
 1. Pre-clinical Studies in Animals including:
B. Toxicological studies
 Acute toxicity
 Special toxicity studies:
 Reproductive system

 Mutagenesis (mutation production)

 Oncogenesis (malignancy)

 Teratogenicity (harmful effects on

foetus)

12
 2. Clinical Studies in Human
 These are carried out in
humans in clinical trials
centers & in hospitals
under supervision of qualified
investigators
 These include:

13
 2. Clinical studies in human
 Phase 1 studies
 Phase 2 studies
 Phase 3 studies
 Phase 4 studies

14
 Phase 1 Studies
(Human pharmacology)
 These are performed on a limited number of
healthy volunteers (20-50 subjects)
The aims of these trials are:
 Study of the general pharmacology of drug

 Pharmacokinetics (ADME)

 Pharmacodynamics (biological effect)

 Tolerability, efficacy & safety (associated

adverse effects)
15
 Phase 2 Studies
(Therapeutic exploration)
 These are carried out on a limited number of
patients (50-300) to:
 General pharmacology of drug in patients
 Pharmacokinetics
 Pharmacodynamics
 Establish safety of drugs
 Assess potential therapeutic effects,
comparison with placebo
16
 Phase 3 Studies
(Therapeutic confirmation)
 Randomized control trials
 These include multi-centre comparative
studies on a large number of patients (250-
1000) to establish therapeutic efficacy & safety,
comparison with existing drugs
 Short term efficacy & safety

17
 Phase 4 studies
(Therapeutic use)
 These include post-marketing surveillance
(post-authorization studies) (2000- 10,000) to
look for possible long term effects of drugs
 Long term efficacy & safety

18
Phases of Drug Development

19
20 20
 Clinical Trials

 Clinical trials are carefully and ethically

designed controlled experiments performed
on human beings to evaluate certain aspects of
drug studies

21
 Aims of clinical trials
 Whether treatment is of value
 Magnitude of that value compared with other
remedies
 Type of patients in whom it is of value
 Best method of applying treatment (how often,
dosage of drug)
 Disadvantages & dangers of treatment

22
Fundamental to any clinical trial are:
 An hypothesis
 Definition of primary endpoints
 Method of analysis
 A protocol

23
Other factors when designing a trial:

 Characteristics of patients
 Size of trial
 Duration
 Method of monitoring
 Use of interim analyses

24
Subjects included in the studies are either:
 Healthy normal volunteers or
 Patients

25
Patients excluded from clinical trials include:

 Children
 Pregnant women
 Mentally ill patients

26
 Techniques to avoid bias
 Randomization:
- Introducing element of chance into selection &
allocation of subjects to treatments
 Blinding

27
 Criteria of clinical trials (CCT)

 Objective: should be clear & limited to one aim

 Careful design: A protocol should be prepared
that shows design of the CCT prepared by clinical
pharmacologist, physician & statistician
 Crossover design: when each subject is
randomized to a sequence of two or more
treatment, and he acts as his own control for
treatment comparisons

28
 Criteria of clinical trials
 Clinical trials may be of non-crossover design
recruiting different subjects as a control group
 Balanced regarding sex, age, weight & disease state
 Double-blind technique when neither investigator
nor subject knows about treatments they are
receiving. This technique is important to:
 Eliminate investigator bias
 Eliminate patients or subject bias
 Allow the use of placebo

29
 Single-blind technique is described when
investigator knows but patient does not
know treatment given to him
 Control group is used who will receive either
placebo or a standard therapy
 Statistical analysis should be planned initially
including the proper tests used

30
 The use of placebo
 It is a pharmacologically inert substance
identical in all aspects to the active treatment
indistinguishable from it
It is intended to:
 Eliminate observer or investigator bias
 Detect non-pharmacological effects of drugs
(placebo effects)
 A control for statistical comparison

31
 Conditions that do not require use of
placebo
 Therapeutic studies as it is unethical to
deprive patients of treatments. A standard
therapy is chosen instead of placebo
 When the active compound can be identified
e.g. a vasodilator, alkaptonuria (nitisinone)
 Dose-finding studies
 Pharmacokinetic studies

32
Ethical Considerations in Clinical Trials
 Declaration of Helsinki
 The declaration of Helsinki (1964, 1975) sought to
clarify the ethical principles governing clinical
research involving human subjects emphasizing
informed consent & proper scientific research
design. It is the mission of doctor to safeguard
health of people. The doctor’s knowledge &
conscience are dedicated to the fulfillment of this
mission
33
 Recommendations are essential as a
guide to doctors in clinical research:

 Risks & benefits must be carefully assessed

 Nature, purpose & possible hazards must be
explained to subjects by doctor

34
 Recommendations are essential as a
guide to doctors in clinical research:

 Informed written consent must be obtained

 Subjects must be free to withdraw from clinical
trial anytime
 The investigators should discontinue research, if in
their judgment it may if continued be harmful to
subjects

35
 DevelopAKUre

 4 years international multicenter

clinical trials, funded by European
commission (FP7) - € 6 million
 12 European partners & Jordan
(Faculty of medicine-mutah university)
 3 trial sites: UK (Liverpool), France
(Paris) & Slovakia (Piestany)
 Aims: to study the potential
effectiveness & safety of nitisinone in
treating alkaptonuria (AKU)
 37
SONIA 2 (Suitability of Nitisinone in AKU )

o 140 patients
o Patients were from Spain,
France, Belgium, Italy,
Netherlands, Germany,
Slovakia & Jordan
o 19 Jordanian patients
National Institute for
Rheumatic diseases,
Slovakia
 38
Procedures

• Bloods: • Urine: • Yearly:

• HGA, tyrosine, • HGA, tyrosine, • Abdominal ultrasound,
nitisinone nitisinone Audiometry
• Bone/muscle/cartilage • Bone & cartilage • ECG, Echocardiogram
markers markers
• Bone density scan
• Biochemistry profiles, • Metabolomics (Dexa)
metabolomics
• Isotope scintigraphic
• Genetics scan
• Acute phase reactants, • Medical Photographs
cytokines
 www.ClinicalTrials.gov

39
Autonomic Nervous System
Lecture-5 :Topics
 Functions of ANS
 Effect of Sympathetic &
Parasympathetic stimulation
 Overall difference between 2 divisions
of ANS
Learning Objectives
 Effects of sympathetic and
parasympathetic neurotransmitters on
target organs and tissues.
Sympathetic Effects

 Fight, Fright or flight response

 Release of Neurotransmitters (NT)-
Norepinephrine (NT) from
postganglionic fibers
Epinephrine (NT) from adrenal medulla
Sympathetic Effects

 Mass activation prepares for intense

activity
Heart rate (HR) increases
Bronchioles dilate
Blood [glucose] increases
Sympathetic Effects

 GI motility decreases
 Contraction of sphincters
 Relaxation of
Detrusor muscle
Ciliary muscle
 Mydriasis
Parasympathetic Effects
 Normally not activated as a whole
Stimulation of separate parasympathetic
nerves.
 Release ACh as NT
 Relaxing effects-
Decreases HR.
Dilates visceral blood vessels.
Increases digestive activity.
Parasympathetic Effects

 Bronchonstriction
 GI motility increases
 Relaxation of sphincters
 Contraction of
Detrusor muscle
Ciliary muscle
 Miosis
Adrenergic and Cholinergic Synaptic
Transmission

 ACh is NT for all preganglionic

Sympathetic fibers
Parasympathetic fibers
 Transmission at these synapses is termed
cholinergic
 All preganglionic fibers terminate in
autonomic ganglia
Adrenergic and Cholinergic Synaptic
Transmission

• ACh is NT released by -
Most postganglionic parasympathetic
fibers
Some postganglionic sympathetic
fibers
• Postganglionic autonomic fibers
innervate the target tissue
Adrenergic and Cholinergic Synaptic
Transmission
Adrenergic Synaptic Transmission
(continued)

 Transmission at these synapses is called

adrenergic:
Norepinephrine
released by most postganglionic sympathetic
nerve fibers.
Epinephrine,
released by the adrenal medulla
 Collectively called Catecholamines
Responses to Adrenergic Stimulation

 Beta adrenergic receptors:

Produce their effects by stimulating
production of cAMP
NE binds to receptor
G-protein dissociates.
Responses to Adrenergic Stimulation

• Depending upon tissue, either α subunit or

βγ−complex produces the effects
• Alpha subunit-
Activates adenylate cyclase
 Producing cAMP
cAMP activates protein kinase
Opening ion channels
Responses to Adrenergic Stimulation
(continued)

 Alpha1 adrenergic receptors:

Produce their effects by the production
of Ca2+
Epi binds to receptor
Ca2+ binds to calmodulin
Calmodulin activates protein kinase,
modifying enzyme action
Responses to Adrenergic Stimulation
(continued)

 Alpha2 adrenergic receptors:

1. Located on Presynaptic terminal
 Decreases release of NE.
 Negative feedback control.
2. Located on postsynaptic membrane.
 When activated, produces
vasoconstriction
Responses to Adrenergic Stimulation
(continued)

 Has both excitatory and inhibitory

effects.
 Responses due to different membrane
receptor proteins.
α1 : constricts visceral smooth muscles.
α2 : contraction of smooth muscle.
β1 : increases HR and force of contraction.
β2 : relaxes bronchial smooth muscles.
β3: adipose tissue, function unknown
Responses to Cholinergic
Stimulation

 Cholinergic fibers-.
Release ACh as NT
All somatic motor neurons,
 All preganglionic neurons
 Most postganglionic parasympathetic
neurons
 Some postganglionic sympathetic neurons
Responses to Cholinergic
Stimulation (continued)

• Somatic motor  Excitatory

neurons
• All preganglionic  Excitatory
autonomic
neurons
• Postganglionic
axons  Excitatory or
 Inhibitory
Responses to Cholinergic
Stimulation (continued)

.
 Muscarinic receptors
Ach binds to receptor
Requires the mediation of G-proteins
βγ-complex affects-
 Opening a channel or
 Closing a channel or
Activating enzymes
Responses to Cholinergic
Stimulation (continued)

 Nicotinic receptors (ligand -gated)

ACh binds to 2 nicotinic receptor
binding sites.
Causes ion channel to open within the
receptor protein.
Opens a Na+ channel.
 Always excitatory
Responses to Cholinergic
Stimulation(continued)
Other Autonomic NTs

 Certain nonadrenergic, noncholinergic

postganglionic autonomic axons produce
their effects through other NTs
ATP
NO
Organs With Dual Innervations

 Dual innervations
 Innervations by both
Sympathetic fibers
Parasympathetic fibers
 Most visceral organs receive dual innervations
 Effects of dual innervations
Antagonistic
Complementary
Cooperative
Organs With Dual Innervations
 Antagonistic :
◦ Sympathetic and parasympathetic fibers innervate the
same cells.
 Actions counteract each other.
 Heart rate.
 Complementary:
◦ Sympathetic and parasympathetic stimulation
produces similar effects.
 Salivary gland secretion.
 Cooperative:
◦ Sympathetic and parasympathetic stimulation produce
different effects that work together to produce
desired effect.
 Micturition.
Organs Without Dual Innervations

 Regulation achieved by increasing or decreasing

firing rate.
 Organ receive only sympathetic innervations-
Adrenal medulla
Arrector pili muscle
Sweat glands
Most blood vessels.
Applied
Horner’s syndrome
 Characterized by-
Constriction of the pupil
Enophthalmos
Drooping of eye lid
Anhydrosis on affected side of face
 Occurs due to-
Damage of stellate ganglia
Paralysis of Cervical Sympathetic nerve trunk
Horner’s syndrome
Drugs acting on autonomic ganglia
Increases activity Decreases activity
• Direct effect • Ganglion blockers-
Acetylcholine Hexamethonium
Nicotine (Low doses) Macamylmamine
• Indirect effect Pentolinum
(ACE inhibitors) Trymethaphan
Physostigmine
Neostgmine
Parathion
DFP
Drugs acting on Postganglionic sympathetic
nerve endings
Increases activity Decreases activity
• Release NE (TEA)  Block NE Synthesis
Tyramine Metyrosine
 Ephedrine  Block Storage
 Amphetamine Reserpine
Guanethidine
 Prevent Release
Bretylium
 False transmitters
 Methyldopa
Drugs acting on Muscarinic receptors

Increases activity Decreases activity

 Acetylcholine Atropine
scopolamine
Drugs acting on Beta adrenergic receptor

Increases activity  Decreases activity

 β stimulators  β blockers
Isoproterenol Propranolol
• β2stimulators Metaprolol
Salbutamol  β1 blockers
Terbutaline
Atenolol
 β2 blockers
Butoxamine
Drugs acting on Alpha adrenergic receptors

Increases activity Decreases activity

(α1 stimulators) (α blockers)
 Methoxamine Phenoxybenzamine
 Phenylepinephrine Phentolamine
Prazocin (α1 blockers)
Yohimbine (α2blockers)
Autonomic Nervous System
Parasympathomimetic drugs
Parasympatholytics
Sympathomimetics
Sympatholytics
 Sympathetic Parasympathetic
Anatomy:
2 From 1st thoracic to 3rd lumber -Cranial: (III,VII,IX&X)
1- Origin segments -Sacral: (S2,3,4)
2- Ganglia Close to spinal cord Near or embedded in organs
3- Preganglionic Short Long
4- Postganglionic Long Short
5- Innervation: Sympathetic only Parasympathetic only
• Most organs • Dilator pupillae muscle • Constrictor pupillae
receive dual nerve [DPM]. muscle [CPM]
supply except: • Erector pili M.
• Sweat glands
• Adrenal medulla.
• Ventricles •Blood vessels
Physiology: Blood vessels & sweat glands. All organs except blood
• Tone vessels& sweat gland.
3
Autonomic Nervous System

The autonomic nervous system(ANS) is concerned primarily with

visceral functions such as cardiac output, blood flow to various organs,
and digestion, which are necessary for life.

The autonomic nervous system has two divisions:

sympathetic & parasympathetic.
 Sympathetic Parasympathetic
• Actions
4 They are antagonistic except for atrial conduction and salivation
[both ]
• Cardiovascular: all cardiac properties. all cardiac properties.
- Heart
- Blood vessels -VC of skin &mucous membrane Not innervated
blood vessels.
-VD of coronary & skeletal blood
vessels
-Blood pressure Increased Decreased
• Eye Active mydriasis [++DPM] 1-Miosis[+++CPM]
2- Accommodation for near
vision
3- IOP
• Bronchi Bronchodilation Bronchoconstriction
 5 Sympathetic Parasympathetic
• GIT & Urinary Relax wall& contract sphincters Contract wall& contract
tract sphincters
• Genital Ejaculation in male Erection in male
Relaxation of uterus in female

• Exocrine glands:
- Salivary Thick & viscid Watery
- Sweat Increase No effect
Neurotransmitters
• Ganglia Ach Ach
• Postganglionic Norepinephrine(NE) except in Ach
sweat glands Ach is released
 Sympathetic Parasympathetic
• Synthesis
6 1. Phenylalanine tyrosine (by - Choline is transported
hydroxylase) into cholinergic neurons
2. Tyrosine DOPA (by tyrosine by carrier system
hydroxylase)
3. DOPA dopamine (by dopa - Choline is acetylated to
decarboxylase) Ach by choline acetyl-
4. Dopamine is actively transported into transferase in presence of
synaptic vesicles by carrier system acetyl CoA
5. Finally, NE is formed by hydroxylation
of dopamine (via dopamine B-
hydroxylase)
* In the adrenal medulla & some CNS
tracts, epinephrine(adrenaline) is formed via
methylation of NE by phenyl ethanolamine
N-methyl-transferase [PENMT]
Release of transmitters:
Arrival
7 of impulse to the nerve ending.
Opening of voltage-activated Ca2+ channel calcium influx into nerve ending.
Fusion of vesicles with membrane of the nerve ending and exocytosis of the transmitter.
Fate of NE & epinephrine:
8 A] Reuptake:
1- Neuronal reuptake [uptake I], 65-70% :
• Active reuptake by neuronal membrane monoamine transporter (MAT).
• Inhibited by cocaine, tricyclic antidepressants (TCAs) and guanethedine &
guandril.
2- Vesicular reuptake [uptake III]:
• Follows uptake I to protect NE from monoamine oxidase [MOA].
• Inhibited by reserpine.
3- Tissue reuptake [uptake II], 7-13%:
• NE is taken by the target tissue where it is inactivated by MAO(in the
mitochondria)& catechol orthomethyltransferase [COMT]in cyroplasm.
• Inhibited by corticosteroids
B] Metabolism (15%):
9 • MAO in mitochondria of nerve endings and tissues.

• COMT in cytoplasm of tissues but not in nerves.

• End product of NE & epinephrine in urine is vanilmandelic acid [VMA]

• Normal level of VMA is 2-6mg/24hrs. VMA more than 50mg/24hrs

indicates pheochromocytoma.
C] Excretion in urine unchanged (5%)
Fate of ACh: Metabolism by cholinesterase [2types]
10
True cholinesterase Pseudo-cholinesterase
Sites Cholinergic structures, RBSs and Contract wall& contract
CNS. sphincters

Specificity ACh , Methacholine Non specific- destroys Ach,

procaine and
succinylcholine.

Regeneration In 3 month In 3 weeks

11
 Autonomic Receptors
12 Cholinergic receptors: Cholinergic receptors are classified into:
A. Nicotinic receptors: They are directly coupled to Na+ channels and mediate
fast excitatory synaptic transmission at:
1. The neuromuscular junction.
2. Autonomic ganglia.
3. Adrenal medulla.
4. Various sites in CNS
B. Muscarinic receptors: They are G-protein-coupled receptors causing :
 Activation of phospholipase C (hence formation of IP3 and DAG) [M1,3,5].
 Inhibition of adenylyl cyclase decrease in cAMP, activation of potassium
channels or inhibition of calcium channels [M2,4].
 M1 M2 M3
13
Sites - CNS - CNS & presynaptic - CNS
- Ganglia - Heart (mainly of - Smooth muscles
atria) & secretory
glands
Selective blocker Pirenzepine Gallamine

o M4 and M5 receptors present mainly in the CNS.

o All muscarinic receptors are activated by acetylcholine and blocked by
atropine.
Adrenergic receptors:
14
α1 (Gg) α2 (Gi) β1 (Gs) β2 (Gs) β3 (Gs)

• VC(skin& • Inhibits • Increase all • VD(coronary • Lipolysis

mucous NE, Ach cardiac &skeletal
membranes) release properties muscle)
• Mydriasis • Decreases • renin • Bronchodilation
• tone of renin& release • Glycogenolysis
urinary insulin • Increases insulin
bladder secretion secretion
sphincter • Relaxes wall of
uterus
• Hypokalemia
&tremors
 Autonomic drugs
15
1. Parasympathomimetics.
2. Parasympatholytics.
3. Sympathimetics.
4. Sympatholytic.
5. Ganglion stimulants & ganglion blockers.
Parasympathomimetics [Cholinomimetic drugs]
Acetylcholine (ACh) receptor stimulants and cholinesterase inhibitors together
comprise a large group of drugs that mimic Ach (cholinomimetics or
parasympathomimetics).
Cholinoceptor stimulants: they are either:
I-Direct-acting cholinomimetic agents bind to and activate muscarinic and/or
nicotinic receptors: 1- Choline esters:
*Ach * Methacholine * Carbachol * Bethanechol
2- Cholinomimetic alkaloids: * Pilocarpine

16
II-Indirect-acting agents inhibit cholinesterases increase the endogenous
Ach in synaptic clefts and neuroeffector junction stimulate cholinoceptors.
The are classified into:

Reversible
 Physostigmine & neostigmine.
 Neostigmine substitutes:
(edrophonium,
pyridostigmine, ambenonium,
benzpyrinium and demecarium)
Irreversible
 Organophosphorus compounds:
- Echothiophate -Isoflurophate
- Ware gases e.g. sarin &soman.
- Thiophosphate insecticides e.g.
parathion &malathion.
 I-Direct Cholinomimetics
17 (1) Choline esters

They are poorly absorbed and poorly distributed into CNS (they are hydrophilic).

Choline Susceptibility to Muscarinic Nicotinic Selectivity

Ester cholinesterase action action
Acetylcholine True and pseudo +++ +++ No selectivity
Methacholine True only ++++ None Heart
Carbachol Non ++ +++ Eye,GIT,urinary
Bethanechol Non ++ None GIT,urinary
Pharmacological actions:

18
Eye:
Muscarinic (M3)
1) Contraction of constrictor pupillae muscle resulting in miosis.
2) Contraction of the ciliary muscle.
 As a result of 1&2 the iris is pulled away from the angel of the anterior chamber,
and the trabecular meshwork at the base of the ciliary muscle is opened. Both
effects facilitate aqueous humor outflow into the canal of Schlemm, and I.O.P .
3) Accommodation for near vision.
Nicotinic: Lid twitches due to activation of nicotinic receptors in the eye lid
muscles.
When applied to eye, carbachol miosis& lid twitches ( muscarinic and
nicotinic).
Cardiovascular System

19
1) Vasodilation: Stimulation of M3 production of NO (endothelium –
derived relaxing factor), which diffuses to smooth muscles cells of blood
vessels cGMP VD.
2) Bradycardia & delay AV conduction are due to stimulation of M2

 Experimental IV injection of a small dose of Ach hypotension.

 If large doses of Ach are injected after atropine [muscarinic blocker]
hypertension, due to stimulation of adrenal medulla and autonomic gaglia [
nicotinic action of Ach] release catecholamines into the circulation and
at postganglionic sympathetic nerve ending reversal of action of Ach on
blood pressure.
 Atropine can reverse the hypotensive action of parasympathomimetics
20
having both nicotinic and muscarinic actions [Ach, carbachol&
anticholinesterase], but only abolish the hypotensive effect of drugs having
only muscarinic actions [ Methacholine & Pilocarpine]

The effect of intravenous

injection of Ach on the blood
pressure
Gastrointestinal and Urinary Tracts (M2,3) : Stimulation of the wall (M3) and
relaxation the sphincters (M2).
21
Respiratory System:
• Bronchospasm
• Increase bronchial secretion
This combination of effects can cause symptoms, especially in individuals with
asthma.
Exocrine Glands (M3 ) :
• Stimulate secretion of all glands [ sweat, lacrimal, salivary, nasopharyngeal glands,
gastric, pancreatic and intestinal].
Neuromuscular Junction (Nm ) :
• Activation of Nm receptors results in Na influx and depolarization of skeletal
muscle with muscle contraction. High concentration of Ach results in persistent
depolarization muscle weakness and paralysis.
Clinical uses:
22
Bethanechol is very occasionally used in post operative urinary retention and
paralytic ileus.

• It acts mainly on M3 receptors and has little effect on the heart.

Ach, Carbachol & methacholine are used as experimental tools.

Side effects:

• Flushing , sweating, abdominal cramps, bronchospasm, headache, and salivation .

• Toxic reactions to these drugs are treated with atropine.

• Epinephrine can be used in severe cardiovascular or bronchoconstrictor responses.

Contraindications:
23 1- Bronchial asthma [ bronchospasm].
2- Angina pectoris [ BP so decrease coronary flow].
3- Hyperthyroidism [ AF can occur].
4- Peptic ulcer [++ gastric secretion].
5- Hypotension [ cause vasodilation].
2) Cholinomimetic alkaloids (Pilocarpine)
• Alkaloid from leaves of Pilocarpus Jaborandi
• Tertiary amine so:
 well absorbed from most sites of administration.
• Crosses BBB ( avoided in Parkinsonism) Not metabolized by Ch.E long
duration. • Excreted in urine.
• Has muscarinic action, but no nicotinic actions(its hypotensive effect is abolished
by atropine)
• Has a specific action on :
• 24 * Eye [ no lid twitches].
* Secretions [ salivary & sweat].
Clinical uses:
1. Glaucoma.
2. Counteracts action of mydriatics after fundus examination.
3. To cut recent adhesion between iris and lens [ alternatively with mydriatics]
4. Promotes hair growth [ blood flow to hair follicle].
5. Sialagogue in xerostomia.
 II-Indirect Cholinomimetics
25 [Cholinesterase Inhibitors or Anticholinesterases]
They are classified into:
Reversible Irreversible
Binding to Ch.E. Loose Firm
Activity of Ch.E. Enzymes can regain activity Enzymes cannot regain activity
Duration of action Short Long( till synthesis of new
enzymes)
Examples Physostigmine, neostigmine Organophosphorus compounds
and neostigmine substitutes
According to the binding with Ch.E. enzymes:
26 1- Bind reversible by electrostatic bond with anionic site Edrophonium

2- Bind reversibly with both anionic & esteratic sites

Physostigmine, neostigmine.

3- Phosphorylation of the esteratic site Organophosphorus compounds

 (1) Reversible cholinesterase Inhibitors
27
Physostigmine neostigmine
Source & Natural plant alkaloid Synthetic
chemistry Tertiary amine Quaternary ammonium compound
Absorption & Complete oral absorption Partial oral absorption .
distribution Passes BBB Cannot pass BBB
Metabolism Both are metabolized by cholinesterase
Actions 1-Muscarinic (eye): Miosis, 1-Muscarinic (mainly GIT&
accommodation for near vision, urinary tract)
IOP, lid twithches,
lacrimation] 2- Nicotinic Muscle
2- Nicotinic Muscle twitches (direct & Indirect
twitches (Indirect action only)
action)
3- CNS: Stimulation
3- CNS: no action
(convulsions in high doses)
Clinical uses:
28 Physostigmine :
A) Eye drops:

1- Glaucoma.

2- Counteracts action of mydriatics after fundus examination.

3- To cut recent adhesion between iris and lens [alternatively with mydriatics].

B) Alzheimer dementia but newer drugs are better.

C) Atropine toxicity: It antagonizes central and peripheral action but not preferred due
to CNS toxicity
Neostigmine :
29 1- Reversal of paralysis induced by non-depolarizing neuromuscular
blockers during surgical operations.
2- Postoperative retention of urine (Catheterization is better alternative).
3- Postoperative paralytic ileus.
4- Myasthenia gravis.
5- Antidote to atropine toxicity.
6- Glaucoma.
Toxicity:
30 Muscarinic : Bradycardia, hypotension, bronchospasm, miosis, vomiting,
diarrhea and secretions.
Nicotinic : muscle twitches.
CNS: (with physostigmine only)
 Convulsions & collapse
 Coma
 Death from RC depression
Treatment of toxicity:
1- Stomach wash.
2- Oxygen and artificial respiration.
3- Atropine.
4- Anticonvulsant in case of seizures.
 Edrophonium Pyridostigmine Benzpyrinium Demecarium
Ambenonium
31

Selectivity Skeletal muscle Skeletal muscle GIT & Urinary Eye

tract
Uses 1- Diagnosis of Treatment of 1- Postoperative • Glaucoma
myasthenia gravis myasthenia gravis urine retention
improves ( longer duration 2- Postoperative
2- Treatment of than neostigmine paralytic ileus
myasthenia crisis & more specific)
3- Differentiation
between myasthenia
crisis & cholinergic
crisis:
 Myasthenia crisis
improves
 Cholinergic crisis
worsens
 32
Myasthenia gravis
Muscle weakness and increased fatigability resulting from a failure of
neuromuscular transmission due to formation antibodies against motor end plate
loss of nicotinic receptors.
Diagnosis: Edrophonium IV or neostigmine SC + Atropine [ to block unwanted
muscarinic actions] improvement.

Treatment :
1- Neostigmine or Pyridostigmine + Atropine.
2- Adjuvant treatment : ephedrine or caffeine (potentiates neostigmine & facilitate
NM transmission
3- Others : to decrease antibodies
 Steroids (e.g. prednisolone) or immunosuppressant drugs e.g. azathioprine.
 Plasmapharesis to wash antibodies.
 Thymectomy.
 33
Drugs contraindicated in myasthenia gravis:
1-Skeletal muscle relaxants. 2- Aminoglycosides 3- β-blockers.
N.B.
• Myasthenia crisis: severe muscle weakness due to under treatment with
anticholinesterase drugs Edrophonium produces muscle improvement.
• Cholinergic crisis: severe muscle weakness due to over treatment with
anticholinesterase drugs [ sustained depolarization] Edrophonium
produces more weakness.
 Alzheimer's disease
34
Alzheimer's disease (AD) is a common age-related dementia.
The main pathological features of AD comprise amyloid plaques & loss of neurons
(particularly cholinergic neurons of the basal forebrain).
Drugs approved for the treatment of AD:
1- Cholinesterase inhibitors:
 Tacrine is a drug with anticholinesterase activity, has been used for the
treatment of mild to moderate Alzheimer's disease but hepatotoxic.
 Donepezil, galantamine, and rivastigmine are newer, more selective and lack
the hepatotoxic effect of tacrine.
2- Memantine [NMDA receptor antagonist] inhibiting glutamate-induced
excitotoxicity and neuronal damage. The drug improves cognitive function in
moderate-to-severe AD.
 (2) Irreversible cholinesterase Inhibitors

35
 Echothiophate &Isoflurophate eye drops for glaucoma.
 Ware gases [e.g. sarin & soman].
 Thiophosphate insecticides [e.g. Parathion & Malathion]
Pharmacokinetics:
All organophosphates (except for echothiophate) are well absorbed from the skin,
lung, gut, and conjunctiva and distributed to all parts of the body, including CNS.
The thiophosphate insecticides (parathion & malathion) are prodrugs. They are
rapidly activated in insects and vertebrates. Malathion (not parathion)is rapidly
metabolized by other pathways to inactive products in birds and mammals but
not in insects (considered to be relatively safe).

N.B. Fish cannot detoxify malathion

Pharmacodynamics:
36  They cause irreversible inhibition of cholinesterase by formation of
covalent bond with its esteratic site.
 At first loose then non-competitive block [ aged enzyme].
 Accumulation of huge amount of Ach over-activation of cholinoceptors
at NM junction and at autonomic and central nervous system.
 Their actions ended by resynthesis of new cholinesterases.

Organophosphorus poisoning
Causes :
1- Occupational inhalation or contamination of skin, clothes and food with
insecticides.
2- Suicidal.
3- Wars.
 Clinical manifestations:
37 • Muscarinic : Salivation, miosis, sweating, vomiting, colic, bradycardia and
bronchospasm.
• Nicotinic : Muscle fasciculation then muscle weakness and paralysis.
• CNS : Confusion, convulsions the CNS depression.
• Cause of death : Respiratory failure.
Treatment:
1.Remove contaminated clothes and wash the skin by soap or NaHCO3.
2.Aspiration of secretion and artificial respiration.
3.Gastric lavage.
4.Atropine 1 mg IV every 10 minutes till full atropinization [dryness of mouth, mydriasis
and tachycardia]. The patient is kept full atropinized for 24 hrs.
 5. Cholinesterase reactivators [ oximes]:
Pralidoxime (PAM): [30mg/kg bolus dose then 8mg/kg/hr IV infusion until
38
clinical improvement] can break the bond between organophosphates and the
enzyme, so the enzyme becomes free and hydrolyzes Ach at the receptors.
Diacetylmonoxime (DAM): like pralidoxime but can cross BBB and reactivate
central cholinesterase.
6. Diazepam for convulsions, and artificial ventilation for respiratory failure.
Note:
o Early after intoxication and formation of organophosphate-enzyme complex
spontaneous reactivation of the enzyme can occurs that can be hastened by oximes.
o Within a few hours, the organophosphate-enzyme complex loses one alkyl group renders it
no longer susceptible to reactivation ageing. So cholinesterase reactivators should be
administered as early as possible.
 Parasympatholytics
[Muscarinic Antagonists or Antimuscarinics]
39
Muscarinic receptors blockers are competitive antagonists.
1. Natural belladonna alkaloids [ atropine and hyoscine]
2. Synthetic atropine substitutes.
Atropine
- Natural belladonna alkaloids .
- Tertiary amine.
Pharmacokinetics :
• Well absorbed from all sites except intact skin.
• Passes BBB.
• Metabolized in liver.
• Excreted in urine [1/3 unchanged], enhanced by acidification of urine.
Pharmacodynamics :
40 A. Antimuscarinic actions:

1) Inhibition of secretions [ all secretion except milk, bile and urine]:

 Salivary secretion dry mouth.
 Lacrimal secretion.
 Sweat dry skin [ atropine fever].
 Gastric secretion is only slightly reduced.
 Mucociliary clearance in the bronchi is inhibited, so that residual secretions tend to
accumulate in the lungs. Ipratropium lacks this effect.
2) Cardiovascular system:
41  Tachycardia is most pronounced in young people, in whom vagal tone at
rest is highest; it is often absent in the elderly.
 If injected slowly IV paradoxical bradycardia followed by tachycardia
This, possibly, is due to:
Earlier M2 inhibition (relieves the inhibitory effect on Ach release) Ach release.
Central action [stimulation of CIC].
 Blood vessels are unaffected at therapeutic doses.
Toxic doses atropine flush ( actual cause is unclear, but it may be due to
compensatory VD in blush area to increase heat loss to compensate inhibition of
sweat).
 Blood pressure is unaffected.
 Atropine reverses hypotension of Ach, carbachol n& neostigmine [M&N].
 It abolishes hypotension of methacholine, bethanechol & pilocarpine [M].
3) eye:
42 • Passive mydriasis.
• Paralysis of accommodation( cycloplegia), so that near vision is impaired.
• IOP dangerous in patients suffering from narrow-angle glaucoma.
4) Gastrointestinal tract:
• Relaxes wall [ antispasmodic ] and constricts sphincters.
• Inhibits secretion constipation.
5) Urinary tract:
• Relaxes wall and constrict sphincters of the bladder.
• Relaxes ureter.
6) Respiration :
43 • Bronchodilation and reduced secretions [viscid and difficult to expel].

B. Effects on the CNS:

It has both stimulant and depressant actions (mainly stimulant).
• Stimulates RC ( respiratory center)& CIC (cardiac inhibitory center).

• Mild restlessness; higher doses cause agitation, hallucination, mania, convulsions

followed by CNS depression.

• Inhibit basal ganglia and vomiting center.

 Clinical uses:
1) Preanesthetic medication: (Atropine is usually used, but hyoscine is
44 preferred in thyrotoxicosis as it causes less tachycardia).
• Reduces secretions.
• ++ RC.
• Bronchodialatation .
• Counteracts excess vagal tone & bradycardia induced by general
anesthetics
2) CVS: heart block due to digitalis, infraction, verapamil, or β-blockers.
3) Organophosphorus poisoning [ atropine is life-saving].
4) GIT: In colic, peptic ulcer and antiemetic[ in motion sickness, hyoscine is
used]
5) CNS: Parkinson`s disease.
6) Respiration: not preferred in bronchial asthma (inhibits mucociliary
movement and bronchial secretion becomes viscid and difficult to expel).
7) Eye : mydriatic in children & in iritis ( alternatively with miotics to prevent
adhesions).
45
• Accurate measurement of refractive error in uncooperative patients e.g.
young children, requires ciliary muscle paralysis. For adults and older
children, the shorter acting drugs are preferred.

• α-adrenoceptor stimulant drugs e.g. phenylephrine, produce a short-

lasting mydriasis that is usually sufficient for funuscopic examination. So,
atropine & its substitutes are preserved for cases when cycloplegia or long
duration is needed
Atropine toxicity:
• Dry mouth and hot, dry and flushed skin.
46
• Mydriasis, blurred vision and IOP.
• Tachycardia.
• Urine retention especially in patients with benign prostatic hyperplasia.
• Body temperature is frequently elevated. Unfortunately, children,
especially infants, are very sensitive to the hyperthermic effects of
atropine.
• Agitation, delirium, convulsions followed by coma and depression of RC
[cause of death]
Treatment:
• Gastric lavage with tannic acid.
• Artificial respiration with oxygen.
• Cold fomentation.
• Diazepam.
• Neostigmine 1mg SC [antidote]- physostigmine is dangerous.
 Contraindications:
1. Narrow angle glaucoma.
47
2. Patients with benign prostatic hyperplasia (BPH).
3. Angina and arrhythmia.
4. Constipation and ileus.
Atropine substitutes
1) Antisecretory antispasmodics:
a- Atropine methyl nitrate to relax pylorus in hypertrophic pyloric stenosis.
b- Hyoscine N-butyl bromide to relax spasm of GIT and urinary tract.
c- Propantheline and oxyphenonium to relax spasm of GIT.
d- Pirenzepine &telenzepine in peptic ulcer [ selective M1 blockers, reduce
gastric secretion]

2) Antiasthmatic: (Ipratropium & tiotropium) given by inhalation with little

effect on secretion & ciliary movement.
 48
Drugs having atropine-like action:
1.Atropine substitutes.
2.Tricyclic antidepressants.
3.Pethidine.
4.Some:
 Antipsychotics [ typical group]
 Antithistaminics [first generation]
 Antiarrhythmics [ quinidine and disopyramide]
3) For urinary incontinence: Oxybutynin, emepronium and tolterodine (M3-
selective).
49

4) Antiparkinsonian: Benztropine and benzhexol.

5) Mydriatics:

Atropine Homatropine Tropicamide& Cyclopentolate

Duration 7-10 days 24hrs 6hrs
Cycloplegia +++ ++ +
Uses  Iritis  Fundus examination
 Measurement of  Measurement of refractive errors
refractive errors
in children
 CHOLINERGIC ANTAGONISTS

Dr. Yousef Al-saraireh

Associate Professor
Pharmacology Department
1
Faculty of Medicine
 CONTENTS

 DEFINATION AND TYPES

 ANTIMUSCARINIC AGENTS

 ADVERSE EFFECTS OF ANTIMUSCARINIC

AGENTS

 GANGLIONIC BLOCKERS

 NEUROMUSCULAR BLOCKERS
2
 DEFINATION AND TYPES
 Cholinergic antagonists (cholinergic
blockers, or anticholinergic drugs) bind
to cholinoceptors, but they do not trigger
the usual receptor-mediated
intracellular effects.
Types:
A. Antimuscarinic agents: selectively
block muscarinic receptors of the
parasympathetic nerves
B. Ganglionic blockers: block nicotinic
receptors of the sympathetic and
parasympathetic ganglia
C. Neuromuscular-blockers: interfere
with transmission of efferent impulses 3

to skeletal muscles.
4
 A. ANTIMUSCARINIC AGENTS:
1. Atropine:
 It is obtained from a plant called
belladonna alkaloid. It binds
competitively and prevents Ach from
binding to muscarinic receptors.

A. Actions and therapeutic uses:

a. Eye:

Topical atropine causes mydriasis (dilation of the pupil),

unresponsiveness to light, and cycloplegia (inability to focus
for near vision)

 It is used in eye examinations 5

b. Gastrointestinal (GI):
 Atropine and scopolamine reduce motility of GIT and therefore
these drugs are used as antispasmodic.
c. Urinary system:
 Atropine-like drugs are used to reduce hypermotility states of the
urinary bladder. It is used in enuresis (involuntary voiding of
urine) among children
d. Cardiovascular:
 Atropine blocks vagus nerve

 Increasing heart rate

 Useful in bradycardia after acute Myocardial infraction

e. Secretions:
 Atropine blocks the salivary glands (producing dry mouth),

Sweat and lacrimal glands

f. Respiratory:
 It is used as an antisecretory agent to block secretions in the 6
upper and lower respiratory tracts prior to surgery.
2. Scopolamine:
 It is used for prevention of motion sickness

3. Ipratropium and tiotropium:

 The route of administration is inhalational

 ipratropium and tiotropium are approved bronchodilators

for maintenance treatment of bronchospasm associated
with chronic obstructive pulmonary disease (COPD), both
chronic bronchitis and emphysema.

4. Tropicamide and cyclopentolate:

 These agents are used as ophthalmic solutions for
mydriasis and cycloplegia.
 Their duration of action is shorter than that of atropine.
Tropicamide produces mydriasis for 6 hours, and
7

cyclopentolate for 24 hours.

ADVERSE EFFECTS

Tachycardia

8
 B. GANGLIONIC BLOCKERS:
 These specifically act on the nicotinic receptors of both
parasympathetic and sympathetic autonomic ganglia
 These drugs block the entire output of the autonomic
nervous system at the nicotinic receptor

1. Mecamylamine:
 It produces a competitive nicotinic blockade of the ganglia
and is primarily used to lower blood pressure in
emergency situations

9
 C. NEUROMUSCULAR BLOCKERS
 These drugs block cholinergic transmission between
motor nerve endings and the nicotinic receptors on the
neuromuscular endplate of skeletal muscle
 These neuromuscular blockers are structural analougs of
ACh, and they act either as
a. Antagonists :Nondepolarizing (competitive) blockers
b. Agonists (depolarizing type)
at the receptors on the endplate of the NMJ.

 They are given during surgery to produce muscle

relaxation
 All neuromuscular-blocking agents are injected
intravenously because their uptake via oral absorption 10

is minimal
NONDEPOLARIZING (COMPETITIVE) BLOCKERS
 These drugs interact with the
nicotinic receptors to prevent
the binding of Ach. Thus, these
drugs prevent depolarization of
the muscle cell membrane and
inhibit muscular contraction.

 These blockers are used as adjuvant drugs in anaesthesia

during surgery to relax skeletal muscle. They are also used
to facilitate orthopaedic surgery

 Pancuronium , Atracurium , cisatracurium.

Action can be overcome by administration of

cholinesterase inhibitors as neostigmine, pyridostigmine, 11
and edrophonium.
 DEPOLARIZING AGENTS
 Succinylcholine is the only depolarizing
muscle relaxant in use today.
 It works by depolarizing the plasma
membrane of the muscle fiber, similar
to the action of ACh. However, these
agents are more resistant to
degradation by AChE, and can thus
more persistently depolarize the muscle
fibers and thus cause flaccid paralysis.
Uses
 It is useful when rapid endotracheal
intubation is required during the
induction of anesthesia
 It is also used during electroconvulsive 12

shock treatment
THANKS

13
Adrenergic Drugs

Dr. Mohammed Al-Sbou

Professor in Clinical Pharmacology
Pharmacology Department
Faculty of Medicine, Mutah University

1
 Sympathomimetics
(Adrenergic Agonists)
 Agents that mimic actions of sympathetic
system & stimulate adrenergic receptors
(adrenoceptors)
 Adrenergic neurons release norepinephrine
as primary neurotransmitter

2
Classification of Sympathomimetics

 Direct-acting:
 Selective: salbutamol (B2), dobutamine (B1)
 Non-selective: adrenaline, noradrenaline (B &
alpha receptors)
 Indirect-acting
 Releasing agents (amphetamine)
 Uptake inhibitors (cocaine, tricyclic
antidepressants TCAs)
 MAO Inhibitors
 Mixed-acting (ephedrine, pseudoephedrine)
3
 Actions of sympothomimetics

 These are mediated through stimulation of

alpha, beta & dopaminergic adrenoceptors

5
 Sympathomimetics
They are also classified into:
 Catecholamines: (adrenaline, NA,
dopamine, dobutamine, isoprenaline)
 Non-catecholamines:
(synthetic alpha-agonists & beta-
agonists, e.g. phenylephrine, ephedrine,
amphetamine)

6
 PK of Sympathomimetics
 Catecholamines
 Parenteral
 Rapid onset of action, brief duration of
action (have short t ½)
 Enzymatic metabolism by MAO & COMT
 Poor penetration into CNS

7
 PK of Sympathomimetics
 Non-catecholamines
 Oral & parenteral
 Slower onset & longer duration of action
 Less enzymatic degradation
 More central effects (CNS effects)

8
Locations & Functions of adrenoceptors

 -adrenoceptors: 1 & 2

 -adrenoceptors: 2 subtypes of -receptors

 Dopamine receptors: 4 subtypes

9
 1-Adrenoceptors
 Vascular smooth M Vasoconstriction
 Radial M. of iris Mydriasis
 Bladder sphincter Contraction
 Intestine sphincter Contraction
 Male sex organs Ejaculation
 Inhibits entry of K into cells Hyperkalemia
 Increase peripheral vascular resistance
(PVR)

10
 2-adrenoceptors
 Presynaptic Inhibits NA release

11
 Alpha-stimulants
 Pressor agents:
- Phenylephrine
 Mucosal decongestants:
- Pseudoephedrine, Oxymetazoline
 Alpha 2-agonists:
- Clonidine & alpha-methyldopa

12
 Alpha-stimulants
1- Pressor agents
 These are non-catecholamines that
increase peripheral vascular resistance
(PVR) & arterial blood pressure (both
SBP & DBP)
 They reduce renal blood flow (RBF) &
splanchnic blood flow due to 1-
vasoconstriction

13
 Phenylephrine

 Is a direct acting, synthetic adrenergic drug

 It has predominantly direct 1-agonist effect,
a vasoconstrictor & It is used as:
 Pressor agent
 Nasal decongestant agent (vasoconstriction)
 Mydriatic agent (ophthalmic solutions)
 Vasoconstrictor agent with local anesthetics
(LA)

14
 2. Mucosal decongestants:
Pseudoephedrine, Oxymetazoline
 Oxymetazoline (Otrivin)
 Useful in allergic rhinitis,
common cold & sinusitis
 Oxymetazoline is used in
Ophthalmic drops for
relief of redness of eye
associated with swimming,
colds or contact lens

15
 2. Mucosal decongestants:
Pseudoephedrine, Oxymetazoline

 Avoid:
 Prolonged use (rebound congestion)
 In hypertensive patients
 Children below 2 years of age
 Alpha 2-agonists
(Clonidine & methyldopa)
 Centrally acting antihypertensive drugs:
clonidine & methyldopa (Aldomet)
 These act centrally to produce inhibition of
sympathetic vasomotor centers, decreasing
sympathetic outflow to the periphery
 Methyldopa is used in hypertension during
pregnancy
 They are rarely used because of risk of
rebound hypertension on withdrawal of
therapy 17
 Beta-adrenoceptors (receptors)
Two subgroups 1, 2
1-adrenoceptors:
 Heart Increase HR, contractility &
conductivity
 Kidneys Increase renin release

18
 2-adrenoceptors
 Bronchi Bronchodilatation
 Bladder wall Relaxation
 Skeletal M. arterioles Vasodilatation
 Glycogenolysis Increase blood glucose
 Gluconeogenesis Increase blood glucose
 Uterus Relaxation
 Enhances entry of K into cells Hypokalemia

19
Adrenergic Drugs

Dr. Mohammed Al-Sbou

Professor in Clinical Pharmacology
Pharmacology Department
Faculty of Medicine, Mutah University

1
 Beta-adrenoceptors (receptors)
Two subgroups 1, 2
1-adrenoceptors:
 Heart Increase HR, contractility &
conductivity
 Kidneys Increase renin release

18
 2-adrenoceptors
 Bronchi Bronchodilatation
 Bladder wall Relaxation
 Skeletal M. arterioles Vasodilatation
 Glycogenolysis Increase blood glucose
 Gluconeogenesis Increase blood glucose
 Uterus Relaxation
 Enhances entry of K into cells Hypokalemia

19
 -Stimulants
1. Selective 2 agonists:
Salbutamol (Albuterol) (Ventolin)
 non-catecholamine
 can be given by inhalation, orally &
injection
 Short acting bronchodilator
 Its t ½ is about 4 hours
 Has a rapid onset of action (acute
asthmatic attacks)
20
 1. Selective 2 agonists:

It is used in treatment of:

 Acute bronchial asthma attacks
 Premature labour or threatened abortion
 Adverse effects:
Tremor, tachycardia & hypokalemia,
hyperglycemia
 Salmeterol & Formoterol
 is a long acting bronchodilator similar to
salbutamol with longer t ½ (12 hr)
 Have a delay onset of action
 It is useful in prophylaxis of bronchial
asthma
 Not useful for acute attacks
 Not recommended as monotherapy &
highly efficacious when combine with
corticosteroid
22
 2. Selective 1-agonist

Dobutamine
- Is a synthetic, direct acting catecholamine
- Inotropic sympathomimetic
- is used in congestive heart failure (CHF) to
increase cardiac output
- Inotropic support after cardiac surgery
- Septic and cardiogenic shock

23
 3. Non-selective -stimulants:
Isoprenaline (Isoproterenol)
 A synthetic, direct acting drug
 It is a catecholamine with non-selective
1 & 2 agonistic activities
 It increases SBP & HR (1 effect) &
decreases DBP (2 effect)
 It is rarely used to increase heart rate in
heart block & to stimulate heart in
cardiac arrest

24
 Mixed Alpha & Beta agonists

Adrenaline (Epinephrine)
 It is an endogenous catecholamine
synthesized in adrenal medulla &
certain areas in brain
 Commonly used therapy (drug of
choice in emergency situations)

25
 Pharmacodynamic effects
 On blood vessels:
Response differs according to site of vessels:
- Skin, mucous membrane & viscera
arterioles contain 1 receptors & show
vasoconstriction
- Skeletal muscle vessels contain mainly 2-
receptors that show vasodilatation

26
 Pharmacodynamic effects

- Veins contain 1 vasoconstrictors

 Heart shows +ve inotropic
+ve chronotropic effects

27
 Effect on blood pressure:
- Small doses of adrenaline given by Sc or
i.m will increase SBP (1 effect on heart)
& decrease DBP (2 vasodilatation of
skeletal BV) ( effect predominate)
- Giving adrenaline in large doses or by IV
administration will increase both SBP &
DBP (predominant 1 effect)

28
 Iris(mydriasis), bronchi (bronchodilatation)
 Sphincters of gut & bladder show
contraction, while walls of gut & bladder show
relaxation
 Metabolic effects: adrenaline increases
blood glucose

29
 Adrenaline (Epinephrine)

Pharmacokinetics:
 Has rapid onset & brief duration of action
 Is given Iv, Sc, by inhalation or topically
to the eye
 Therapeutic uses
 Cardiac arrest (cardiopulmonary resuscitation-
CPR)
 Severe allergic reactions (anaphylactic shock &
angioedema):
 Physiological antagonist to histamine & stabilizer of mast
cells
 Vasoconstrictor with LA
 Chronic open angle glaucoma (topically):
vasoconstriction; reduces aqueous humor production &
IOP
31
 Adverse effects
 CNS disturbances: Headache, tremor,
anxiety
 High doses may increase BP, precipitate
cerebral haemorrhage, cardiac
arrythmias

32
 Noradrenaline (Norepinephrine)

 It has alpha agonist, 1-agonist & weak

2 agonist effects
 It increases both SBP & DBP (potent 1
effect)
 It is mainly used to treat shock as a
vasoconstrictor

33
 Dopamine
 It is an alpha, beta & dopaminergic agonist
 Increases renal blood flow due to D1
vasodilatory effect on renal circulation
 At low dose, activates B1 receptors on heart,
increases cardiac output, heart rate & BP
 At very high doses, activates alpha
receptors, causes vasoconstriction
 Is the drug of choice for shock (cardiogenic &
septic) and is given by continuous infusion to
improve renal blood flow

34
Indirect-acting sympathomimetics
Amphetamines
 Are important because can be misused as
a central psychostimulants that improve
mood & alertness
 Acts by releasing endogenous NA from
adrenergic neurons after being taken up
into neurons

35
 Amphetamines
 Its effects include increase alertness &
improved mood & decreased fatigability
 It has also central anorectic effects
(depress appetite) due to its action in
hypothalamic feeding center

36
 Amphetamines
 Paradoxically, it produces sedation in
children
 Peripheral effects include increase in BP
& arrhythmias
 It produces emotional dependence
Therapeutic uses of amphetamines

 Narcolepsy (excessive abnormal sleep in

adults- daytime )
 Attention deficit hyperkinetic disorder
(ADHD) in children (abnormal
pathological hyperactivity):
amphetamines improve attention, reduce
hyperkinesia)

38
 Adverse effects
 CNS: insomnia, irritability, dizziness,
tremor
 CVS: Palpitations, cardiac arrhythmias, HTN,
angina pain
 Emotional dependence
 Psychosis (Schizophrenia-like with
hallucinations & delusions)
 Anorexia

39
 Direct & indirect sympathomimetics
Ephedrine
 Mixed-action drugs induce release of NA
from pre-synaptic terminals and they
activate adrenergic receptor on
postsynaptic membrane
 Non-catecholamine

40
 Ephedrine
 It is non-selective agonist, stimulate
both alpha & beta receptors & its effects
are similar to that of adrenaline
 Ephedrine raises systolic & diastolic
blood pressure by vasoconstriction &
cardiac stimulation
 It causes bronchodilation
 Is give orally
 Therapeutic uses
 Bronchial asthma
 Mydriatic agent & nasal mucosal
decongestant
 Pressor agent in chronic orthostatic
hypotension
 Heart block to increase heart rate

42
 ADRENERGIC ANTAGONISTS

Dr. Yousef Al-saraireh

Associate Professor
Pharmacology Department
1
Faculty of Medicine
 CONTENTS
➢ DEFINATION AND TYPES
➢ PHARMACOLOGICAL ACTIONS OF ALPHA BLOCKERS
➢ THERAPEUTIC USES OF ALPHA BLOCKERS
➢ ADVERSE EFFECTS OF ALPHA BLOCKERS
➢ INDIVIDUAL ALPHA BLOCKERS
➢ BETA – BLOCKERS
➢ PHARMACOKINETICS OF BETA BLOCKERS
➢ PHARMACODYNAMICS OF BETA BLOCKERS
➢ THERAPEUTIC USES OF BETA BLOCKERS
➢ ADVERSE EFFECTS OF BETA BLOCKERS
➢ CONTRAINDICATIONS OF -BLOCKERS 2
➢ INDIVIDUAL BETA-BLOCKERS
 DEFINATION AND TYPES
➢ These drugs occupy & block
adrenergic receptors in competition
with NA & adrenaline. They are of
two classes:
1. Alpha – blockers
2. Beta – blockers

1. Alpha – blockers: these are

divided to
A. Selective -blockers (block
either 1 or  2 receptors)
B. Non-selective -blockers (block
both 1 &  2 receptors) 3
1. PHARMACOLOGICAL ACTIONS OF ALPHA BLOCKERS
1. CVS:
Blockade of 1 vasoconstrictor receptors produces
vasodilatation & decrease in arterial blood pressure.
This is associated with stimulation of the heart rate.

2. Eye:
Blockade of 1 receptors in the radial muscle of the iris
leads to miosis.

3.Headache, nasal congestion (vasodilatation of the

cranial & nasal vessels)

4
 THERAPEUTIC USES

1. Hypertension
2. Hypertensive crisis
3. Pheochromocytoma hypertension
4. Benign prostatic hypertrophy to relax
bladder sphincter muscle & reduces urine
retention
5. Peripheral vascular disease e.g. Raynaud’s
syndrome (spasm of the upper limb blood
vessels on exposure to cold weather).

5
 ADVERSE EFFECTS

1. Postural hypotension
2. Tachycardia (more with nonselective alpha-
blockers)
3. Failure of ejaculation.
4. Headache, sedation, nasal congestion

6
 INDIVIDUAL ALPHA BLOCKERS
1. Doxazosin: selective -1 blocker suitable for once daily
administration in hypertension & benign prostatic
hypertrophy (BPH).

2. Phenoxybenzamine: irreversible nonselective oral long

acting -blocker useful in treatment of
phaeochromocytoma (tumour of the adrenal medulla
secreting excessive adrenaline & NA causing
hypertension).

3.Phentolamine: nonselective reversible injectable -

blocker useful in hypertensive crisis associated with
high catecholamine levels in blood as in
phaeochromocytoma. 7
 2. BETA – BLOCKERS

1. Cardioselective -Blockers: (atenolol, metoprolol).

2. Non-selective -Blockers: 1 & 2-receptors
(propranolol)
3. Mixed  &  blocker (Labetalol)

➢ These agents block beta-effects of adrenaline & NA.

Cardioselective -blockers have higher affinity to cardiac
1- than for 2-receptors. Non-selective -blockers block 1
& 2-receptors.

8
 PHARMACOKINETICS OF BETA BLOCKERS
➢ Most beta-blockers can be given orally once daily or more.

➢ Lipid-soluble compounds (e.g. propranolol):

 Cross blood brain barrier (BBB) into the CNS
 Produce more central effects than the water soluble
agents.
 Highly metabolized in the liver
 Safe in renal impairment

➢ Water-soluble drugs (e.g. atenolol):

 Excreted unchanged in urine
 Have longer t ½ & accumulate in renal disease 9
 Should be avoided in renal impairment
 PHARMACODYNAMICS OF BETA BLOCKERS

1. CVS: These agents decrease heart rate, myocardial

contractility, cardiac output & O2 consumption. They
decrease renin release by kidneys.

2. Bronchi: producing bronchoconstriction & may

precipitate in asthmatic attack.

3. Eye: producing a reduction in intraocular pressure (IOP)

10
 THERAPEUTIC USES OF BETA BLOCKERS
1.CVS indications:
 Essential hypertension
 Angina pectoris: Beta-blockers are cardioprotective by reducing
cardiac work & myocardial O2 demand.
 Acute myocardial infarction (AMI) to reduce infarction size & to
prevent new infarction.
 Arrhythmias like ectopic beats & tachycardia
2. Glaucoma: timolol eye drops reduces production of
aqueous humour & the high IOP
3. Hyperthyroidism to reduce manifestations of
sympathetic over-activity in the disease.
5. CNS indications:
 Migraine prophylaxis
 Chronic anxiety to control excessive sympathetic manifestations of
anxiety 11
ADVERSE EFFECTS OF BETA BLOCKERS

1. Bradycardia
2. Bronchospasm & precipitation of asthmatic attack
3. Cold extremities due to peripheral vasoconstriction
4. Nightmares with lipid soluble agents

Sudden withdrawal of -blockers should be

avoided.

12
CONTRAINDICATIONS OF -BLOCKERS

1. Asthma
2. Heart block
3. Severe heart failure (although small doses of
selective beta-blockers were found to be useful
in mild heart failure)
4. Late pregnancy

13
 INDIVIDUAL BETA-BLOCKERS:
1. Atenolol (selective)
2. Propranolol ((nonselective)
3. Timolol (nonselective)
4. Metoprolol (selective)
5. Pindolol (nonselective)

14
THANKS

15
ANTIMICROBIAL AGENTS
⚫ Classification
⚫ Resistance
⚫ Cross resistance
⚫ Prevention of drug resistance
MASKING of an INFECTION

⚫ Short course treats one infection

⚫ Another infection is masked initially
⚫ Does not manifest
⚫ Manifests later in severe form
 Example
⚫ Short course streptomycin for trivial
respiratory infection
⚫ Tuberculosis masked
Hypersenstivity reactions
⚫ macropapular rash
⚫ urticarial rash
⚫ fever
⚫ bronchospasm
⚫ vasculitis
⚫ serum sickness
⚫ exfoliative dermatitis
⚫ Stevens-Johnson syndrome
⚫ anaphylaxis
Drugs that cause Hypersenstivity
reactions
Penicillins
Cephalosporins
Sulphonamides.
⚫ Local Irritancy
⚫ Systemic toxicity
High therapeutic index
Lower therapeutic index
Very low therapeutic index
Local Irritancy
⚫ Gastric irritation
⚫ Pain & abcess at site of i.m inj.
⚫ Thrombophlebitis i.v
Systemic toxicity
⚫ High therapeutic index – safely

⚫ Lower therapeutic index –

doses indivisualized & toxicity watched
Aminoglycosides
Tetracyclines
Chloramphenicol
⚫ Very low therapeutic index
⚫ used in conditions, no available
alternative
Vancomycin
Amphotericin B
Nutritional deficiency

⚫ Prolonged use alter intestinal flora

⚫ Intestinal flora synthesizes vitamin B
complex & Vit K
⚫ Utilized by man.
⚫ Vitamin Deficiency
Superinfections

⚫ Appearance of bacteriological &

clinical evidence of a new infection
during the chemotherapy of a primary
one.
(common & dangerous)
Microorganisms resp. for new infection :

Enterobacteriaceae
Psuedomonas
Candida & other Fungi
WHY?????

⚫ Alteration in the normal microbial

population of the
intestinal,
upper respiratory
& genitourinary tracts.
⚫ Removal of inhibitory influence of the
normal flora
⚫ Normal flora contributes to host defence -
antibacterial substances, bacteriocins
which inhibit pathogenic microorganisms.
⚫ Pathogen has to compete with the normal flora
for essential nutrients
⚫ Lack of competition may allow even
nonpathogenic component of flora to
predominate & invade
⚫ More complete the suppression of body flora,
greater the chances of developing
superinfections.
⚫ Common with Broad spectrum/extended
spectrum antibiotics
Tetracyclines, Chloramphenicol
⚫ Low with penicillins
⚫ Incidence inc. with prolonged administration
⚫ Pathogen selective agents i.e.

Narrow spectrum
Duration short
Selection of antimicrobial agent

Judicious selection requires

⚫ Clinical judgement &
⚫ Detailed knowledge of Pharmacological
properties of the antibiotic
⚫ As well as microbiological factors i.e.
potential infecting microorganisms
⚫ Emperical therapy
⚫ Definitive therapy
⚫ Prophylactic or preventive
therapy
Emperical therapy
⚫ Infecting microorganism is unidentified
⚫ Antibiotic must cover all the likely
pathogens. Combination therapy/Single
broad spectrum agent is employed
⚫ Requires knowledge of infecting
microorganisms
⚫ Clinical picture suggests the likely
microorganism
 Definitive therapy
⚫ Culture sensitivity is done
⚫ Once the infecting microorganism is
identified Definitive antimicrobial therapy
is instituted
⚫ Narrow spectrum
Prophylactic therapy
⚫ Preventing the setting of an infection
⚫ Suppressing contacted infection before it
becomes clinically manifest
⚫ Prophylaxis against specific infections
Tuberculosis INH (susceptible contacts of open
cases)
⚫ Prevention of infection in high risk situations

Eg: immunocompromised host, surgical prophylaxis,

catheterization, dental extraction,
Factors affecting Antimicrobial Therapy

Depends on

⚫Pharmacokinetic factors
⚫Host factors
Pharmacokinetic factors

⚫ Site of infection, Infection in CSF-BBB

⚫ Concentration - site of infection
Minimal drug concentration achieved at the infected site (should
be approximately equal to the MIC for the infecting organism)
Concentration should inhibit microorganisms,
simultaneously it should be below the level toxic to
human beings.
⚫ Route of administration
⚫ Plasma protein binding
Factors affecting Antimicrobial Therapy

⚫ Dose & dosing frequency

Constant antibacterial activity,
rather than peaks & trough.
⚫ Mechanism of drug metabolism
Renal failure: dose reduction
Aminoglycosides vancomycin Flucytosine
liver failure:
Erythromycin Metronidazole Chloramphenicol
Factors affecting Antimicrobial Therapy

⚫ Host Defences
Immunity intact - Bacteriostatic Agents
Impaired immunity - Bactericidal Agents
Factors affecting Antimicrobial Therapy

⚫ Local factors
Pus, pH, anaerobic conditions,
⚫ Age
⚫ Genetic factors
⚫ Pregnancy & lactation
⚫ Drug allergy
Therapy with combined AMA’s
Justified
⚫ Broaden the spectrum
For emperical therapy
Treatment of polymicrobial (mixed)
infections
⚫ To enhance antimicrobial activity i.e.
synergism for a specific infection
⚫ To reduce severity or incidence of adverse
effects.
⚫ To prevent emergence of resistance
Therapy with combined AMA’s

⚫ For emperical therapy

⚫ Bacterial diagnosis not known
⚫ Gram +ve, Gram –ve, Anaerobic
⚫ Till culture senstivity report

⚫ Treatment of polymicrobial (mixed)

infections
⚫ Bronchiectasis, UTI, Peritonitis,
Abcesses, bed sores.
⚫ Aerobic + anaerobic organisms both
Therapy with combined AMA’s

⚫ 2/more AMA have to be used to cover

the pathogens.
⚫ Drugs chosen : C/S, Bacteriological
diagnosis, Senstivity pattern,
⚫ Clindamycin /metronidazole for
anaerobes
⚫ Single agent.
Therapy with combined AMA’s

To achieve synergism:
When two antimicrobials of different
classes are used together
Their can be synergism (supra-additive)
additive
antagonism
⚫Two bacteriostatic agents: Additive
eg. combination of tetracyclines,
chloramphenicol, erythromycin
Exception, Sulphonamide + Trimethoprim
Supraadditive / synergism
⚫ Two bactericidal agents:

Additive if organism is sensitive to both

eg. Penicillin + streptomycin
Carbenicillin + gentamycin
Rifampin + isoniazid
⚫ Combination of bacteriostatic with
bactericidal agents: Synergistic /
Antagonistic
⚫ If organism sensitive to cidal drug-
response to the combination is equal to the
static drug given alone
⚫ Apparent antagonism
⚫ Cidal drugs act on rapidly multiplying bacteria.
⚫ Static drug retards multiplication
⚫ If the organism has low senstivity to the
cidal drug – synergism may be seen.
⚫ Wherever possible, synergistic
combinations may be used to treat
infections that are normally difficult to
cure.
Therapy with combined AMA’s

To reduce severity or incidence of

adverse effects.
⚫ Possible if combination is synergistic so
that doses can be reduced
⚫ Needed with AMA’s with low safety margin,
which when used alone in effective doses
produce unacceptable toxicity e.g.
⚫ Amphotericin B + Rifampin / minocycline
⚫ Amphotericin B + flucytosine
⚫ To prevent emergence of resistance
⚫ If the incidence of resistant mutants of a
bacillus infecting an individual for drug P
is 10-5 and for drug Q is 10-7, then only
one out of 1012 bacilli will be resistant to
both.
⚫ Chances of relapse will be less
⚫ Chronic infections needing prolonged
therapy eg: Tb, Leprosy, H.pylori, HIV
etc.
Therapy with combined AMA’s

Disadvantages
⚫ Risk of toxicity
⚫ Multiple drug resistance
⚫ Increased cost
⚫ Antagonism of antibacterial effect if
bacteriostatic & bactericidal agents
are given concurrently.
Antibiotic misuse
⚫ Treatment of untreatable infections
⚫ Viral : measles, mumps, self-limiting.
⚫ Improper dosage
⚫ Wrong frequency, excessive/sub-therapeutic
⚫ Inappropriate reliance on chemotherapy
alone
⚫ Abcesses, necrotic tissue/foreign body,
⚫ Pneumonia, empyema
⚫ Surgical drainage + AMA
⚫ Lack of adequate bacteriological
information.
⚫ Lack of adequate bacteriological
information.

⚫ Bacterial cultures, Gram stains too infrequent

⚫ Drug prescription based on habit

⚫ Dosage employed routine rather than indivisualized :

Microbiological information
Clinical situation
⚫ Improper selection of drug
⚫ dose
⚫ route

⚫ or duration of treatment

⚫ Treatment begun too late

⚫ Poor host defence
Failure of chemotherapy

⚫ Failure to take adjuvant measures, pus

drainage of empyma, abcesses etc
⚫ Treatment of untreatable infections
⚫ Presence of dormant or altered
organisms
Thank u
 Beta-Lactam Antibiotics
& Other Cell Wall
Synthesis Inhibitors

12/21/2021 Haitham Alwali 1

Penicillins and cephalosporins are the major
antibiotics that inhibit bacterial cell wall
synthesis.
They are called beta-lactams because of the
unusual 4-member ring that is common to all
their members.
The beta-lactams include some of the most
effective, widely used, and well-tolerated
agents available for the treatment of microbial
infections.

12/21/2021 Haitham Alwali 2

Alexander Fleming

12/21/2021 Haitham Alwali 3

12/21/2021 Haitham Alwali 4
12/21/2021 Haitham Alwali 5
❖ Classification PENICILLINS
All penicillins are derivatives
of 6-aminopenicillanic acid
and contain a beta-lactam
ring structure that is
essential for antibacterial
activity.
Penicillin subclasses have
additional chemical
substituents that confer
differences in antimicrobial
activity, susceptibility to acid
and enzymatic hydrolysis,
and biodisposition.
12/21/2021 Haitham Alwali 6
❖ Pharmacokinetics
a. Routes of administration:
1-The combination of ampicillin with sulbactam,
ticarcillin with clavulanic acid, and piperacillin
with tazobactam,
and the antistaphylococcal penicillins nafcillin and
oxacillin must be administered intravenously (IV)
or intramuscularly
(IM).
Penicillin V, amoxicillin, and dicloxacillin are
available only as oral preparations. Others are
effective by the oral, IV, or IM routes

12/21/2021 Haitham Alwali 7

2- Depot forms:
Procaine penicillin G and benzathine penicillin G
are administered IM and serve as depot forms. They
are slowly absorbed into the circulation and persist
at low levels over a long time period.
b. Absorption: Most of the penicillins are
incompletely absorbed after oral administration, and
they reach the intestine in sufficient amounts to
affect the composition of the intestinal flora.
Food decreases the absorption of all the
penicillinase-resistant penicillins because as gastric
emptying time increases, the drugs are destroyed by
stomach acid. Therefore, they should be taken on an
empty stomach.
12/21/2021 Haitham Alwali 8
C- Distribution:. All the penicillins distribute well &
cross the placental barrier, but none have been
shown to have teratogenic effects. However,
penetration into bone or (CSF) is insufficient for
therapy unless these sites are inflamed.
D-Excretion: The primary route of excretion is by
glomerular filtration. Patients with impaired renal
function must have dosage regimens adjusted.
Nafcillin and oxacillin are metabolized in the liver
Probenecid inhibits the secretion of penicillins by
competing for active tubular secretion via the
organic acid transporter and, thus, can increase
blood levels.

12/21/2021 Haitham Alwali 9

 ❖ Mechanisms of Action and Resistance
Beta-lactam antibiotics are bactericidal drugs. They
act to inhibit cell wall synthesis by the following
steps:
(1) Binding of the drug to specific enzymes
(penicillin-binding proteins [PBPs]) located in
the bacterial cytoplasmic membrane;
(2) inhibition of the transpeptidation reaction that
cross-links the linear peptidoglycan chain
constituents of the cell wall; and
(3) activation of autolytic enzymes that cause
lesions in the bacterial cell wall.

12/21/2021 Haitham Alwali 10

12/21/2021 Haitham Alwali 11
mechanism of bacterial resistance:
➢ The formation of beta-lactamases (penicillinases)
by most staphylococci and many gram-negative organisms.
✓ Inhibitors of these bacterial enzymes (eg, clavulanic acid,
sulbactam, tazobactam) are often used in combination
with penicillins to prevent their inactivation.
➢ Structural change in target PBPs is responsible for
methicillin resistance in staphylococci and for resistance
to penicillin G in pneumococci (eg, PRSP, penicillin
resistant Streptococcus pneumoniae) and enterococci.
➢ In some gram-negative rods (eg, Pseudomonas
aeruginosa), changes in the porin structures in the outer
cell wall membrane may contribute to resistance by
impeding
12/21/2021
access of penicillins to PBPs.
Haitham Alwali 12
❖Clinical Uses
1. Narrow-spectrum penicillinase-susceptible agents—
Penicillin G is the prototype of a subclass of penicillins.
Clinical uses include therapy of infections caused
by common streptococci, meningococci, gram-positive
bacilli, and spirochetes.
Many strains of pneumococci (penicillin-resistant S.
pneumoniae [PRSP] strains). Staphylococcus aureus and
Neisseria gonorrhoeae are resistant via production of beta-
lactamases.
penicillin G remains the drug of choice for syphilis. Activity
against enterococci is enhanced by coadministration of
aminoglycosides. Penicillin V is an oral drug used mainly in
oropharyngeal
12/21/2021
infections. Haitham Alwali 13
2. Very-narrow-spectrum penicillinase-resistant
drugs—
This subclass of penicillins includes methicillin (the
prototype, but rarely used owing to its nephrotoxic
potential), nafcillin, and oxacillin.

Their primary use is in the treatment of known or

suspected staphylococcal infections. Methicillin-
resistant (MR) staphylococci (S. aureus [MRSA] and S.
epidermidis [MRSE]) are resistant to all penicillins and
are often resistant to multiple antimicrobial
drugs.
12/21/2021 Haitham Alwali 14
3. Wider-spectrum penicillinase-susceptible drugs
a. Ampicillin and amoxicillin—has a wider spectrum of
antibacterial activity than penicillin G. Their
clinical uses include indications similar to penicillin G
as well as infections resulting from enterococci, Listeria
monocytogenes,
Escherichia coli, Proteus mirabilis, Haemophilus
influenzae, and Moraxella catarrhalis, although
resistant strains occur.
When used in combination with inhibitors of
penicillinases (eg, clavulanic acid), their antibacterial
activity is often enhanced. In enterococcal and listerial
infections, ampicillin is synergistic with
aminoglycosides.

12/21/2021 Haitham Alwali 15

b. Piperacillin and ticarcillin—
These drugs have activity against several gram-
negative rods, including Pseudomonas,
Enterobacter, and in some cases Klebsiella species.
Most drugs in this subgroup have synergistic
actions with aminoglycosides against such
organisms.
Piperacillin and ticarcillin are susceptible
to penicillinases and are often used in combination
with penicillinase inhibitors (eg, tazobactam and
clavulanic acid) to enhance their activity.
12/21/2021 Haitham Alwali 16
E. Toxicity
1. Allergy—Allergic reactions include urticaria, severe
pruritus, fever, joint swelling, hemolytic anemia, nephritis,
and anaphylaxis.
Methicillin causes interstitial nephritis, and nafcillin is
associated with neutropenia.
Complete cross-allergenicity between different penicillins
should be assumed.
2. Gastrointestinal disturbances— Nausea and diarrhea
may occur with oral penicillins, especially with ampicillin.
Gastrointestinal upsets may be caused by direct irritation
or by overgrowth of gram-positive organisms or yeasts.

12/21/2021 Haitham Alwali 17

 Beta-Lactam Antibiotics
& Other Cell Wall
Synthesis Inhibitors

12/23/2021 Haitham Alwali 1

 CEPHALOSPORINS
The cephalosporins are β-lactam antibiotics
that are closely related both structurally and
functionally to the penicillins.
Most cephalosporins are produced
semisynthetically by the chemical attachment
of side chains to 7-aminocephalosporanic acid.
Cephalosporins have the same mode of action
as penicillins, and they are affected by the
same resistance mechanisms.
However, they tend to be more resistant than
the penicillins to certain β-lactamases.

12/23/2021 Haitham Alwali 2

Pharmacokinetics
Several cephalosporins are available for oral use, but
most are administered parenterally.
Cephalosporins with side chains may undergo hepatic
metabolism, but the major elimination mechanism
for drugs in this class is renal excretion via active
tubular secretion.
Cefoperazone and ceftriaxone are excreted mainly in
the bile.
Most first- and second-generation cephalosporins do
not enter the cerebrospinal fluid even when the
meninges are inflamed.

12/23/2021 Haitham Alwali 3

Mechanisms of Action and Resistance
Cephalosporins bind to PBPs on bacterial cell membranes to
inhibit bacterial cell wall synthesis by mechanisms similar to
those of the penicillins. Cephalosporins are bactericidal
against susceptible
organisms.
Cephalosporins less susceptible to penicillinases produced
by staphylococci, but many bacteria are resistant through
the production of other betalactamases that can inactivate
cephalosporins.
Resistance can also result from decreases in membrane
permeability to cephalosporins and from changes in PBPs.
Methicillin-resistant staphylococci are also resistant to
cephalosporins.

12/23/2021 Haitham Alwali 4

• Clinical Uses
1. First-generation drugs—Cefazolin (parenteral)
and cephalexin (oral) are examples of this
subgroup.
They are active against gram-positive cocci,
including staphylococci and common streptococci.
Many strains of E coli and K pneumoniae are also
sensitive.
• Clinical uses include treatment of infections
caused by these organisms and surgical
prophylaxis in selected conditions.
12/23/2021 Haitham Alwali 5
2. Second-generation
have slightly less activity against gram-positive
organisms than the first-generation drugs but have
an extended gram-negative coverage.
Marked differences in activity occur among the
drugs in this subgroup. Examples of clinical uses
include infections caused by the anaerobe
Bacteroides fragilis (cefotetan, cefoxitin) and sinus,
ear, and respiratory infections caused by H
influenzae or M catarrhalis (cefamandole,
cefuroxime, cefaclor).

12/23/2021 Haitham Alwali 6

3. Third-generation drugs:
(eg, ceftazidime, cefoperazone, cefotaxime)
include increased activity against gram-negative organisms
resistant to other beta-lactam drugs and ability to penetrate
the blood-brain barrier (except cefoperazone and cefixime).
• Most are active against Providencia, Serratia marcescens,
and beta-lactamase producing
strains of H influenzae and Neisseria
▪ Ceftriaxone and cefotaxime are currently the
most active cephalosporins against penicillin-resistant
pneumococci (PRSP strains)
▪ Also have activity against Pseudomonas (cefoperazone,
ceftazidime) and B fragilis (ceftizoxime)
▪ Ceftriaxone (parenteral) and cefixime (oral), currently
drugs of choice in gonorrhea.

12/23/2021 Haitham Alwali 7

4. Fourth-generation drugs—
• Cefepime is more resistant to beta-lactamases
produced by gram-negative organisms, including
Enterobacter, Haemophilus, Neisseria, and some
penicillin resistant pneumococci.
• Cefepime combines the gram-positive activity of
first-generation agents with the wider gram-
negative
spectrum of third-generation cephalosporins.
• Ceftaroline has activity in infections caused by
methicillin-resistant staphylococci.
12/23/2021 Haitham Alwali 8
Toxicity
1. Allergy—Cephalosporins cause a range of allergic
reactions from skin rashes to anaphylactic shock. These
reactions occur less frequently with cephalosporins
than with penicillins.
Complete cross-hypersensitivity between different
cephalosporins should be assumed. Cross-reactivity
between penicillins and cephalosporins
is incomplete (5–10%).
2- Cephalosporins may cause pain at intramuscular
injection sites and phlebitis after I.V administration.
They may increase the nephrotoxicity of
aminoglycosides when the two are administered
together.

12/23/2021 Haitham Alwali 9

OTHER BETA-LACTAM DRUGS:
A. Aztreonam
• Aztreonam is a monobactam that is resistant to
beta-lactamases produced by certain gram-negative
rods, including Klebsiella, Pseudomonas, and
Serratia. The drug has no activity against gram
positive bacteria or anaerobes.
• Aztreonam is administered intravenously and is
eliminated via renal tubular secretion. Its half-life is
prolonged in renal failure.
• Adverse effects include gastrointestinal upset with
possible superinfection, vertigo and headache, and
rarely hepatotoxicity.

12/23/2021 Haitham Alwali 10

B. Imipenem, Doripenem, Meropenem, and
Ertapenem:
• These drugs are carbapenems (chemically
different from penicillins but retaining the
beta-lactam ring structure)
• They have wide activity against gram-positive
cocci (including some penicillin-resistant
pneumococci), gram-negative rods, and
anaerobes.
• For pseudomonal infections, they are often
used in combination with an aminoglycoside.
• MRSA strains of staphylococci are resistant.

12/23/2021 Haitham Alwali 11

• Imipenem is rapidly inactivated by renal
dehydropeptidase-I and is administered in fixed
combination with cilastatin, an inhibitor of this
enzyme. Cilastatin increases the plasma half life
of imipenem and inhibits the formation of
potentially nephrotoxic metabolite.
• Adverse effects of imipenem-cilastatin include
gastrointestinal distress, skin rash, and, at very
high plasma levels, CNS toxicity (confusion,
encephalopathy, seizures).
• There is partial cross allergenicity with the
penicillins.
12/23/2021 Haitham Alwali 12
C. Beta-Lactamase Inhibitors
Clavulanic acid, sulbactam, and tazobactam are
used in fixed combinations with certain
hydrolyzable penicillins.
• They are most active against plasmid-encoded
beta-lactamases such as those produced
by gonococci, streptococci, E coli, and H influenzae.
• They are not good inhibitors of inducible
chromosomal beta-lactamases
formed by Enterobacter, Pseudomonas, and
Serratia.

12/23/2021 Haitham Alwali 13

OTHER CELL WALL OR MEMBRANE-ACTIVE
AGENTS:
A. Vancomycin
• Vancomycin is a bactericidal glycoprotein that
binds to the d-Ala-d-Ala terminal of the nascent
peptidoglycan pentapeptide side chain and
inhibits transglycosylation. This action prevents
elongation of the peptidoglycan chain and
interferes with crosslinking.
• Resistance in strains of enterocci (vancomycin-
resistant enterococci [VRE]) and staphylococci
(vancomycin-resistant S aureus [VRSA]) involves
a decreased affinity of vancomycin for the
binding site

12/23/2021 Haitham Alwali 14

Vancomycin has a narrow spectrum of activity
and is used for serious infections caused by drug-
resistant gram-positive organisms, including
methicillin-resistant staphylococci (MRSA)
and in combination with ceftriaxone for
treatment of (PRSP). Vancomycin is for treatment
of infections caused by Clostridium difficile.
❑Toxic effects of vancomycin include chills, fever,
phlebitis, ototoxicity, and nephrotoxicity. Rapid
intravenous infusion may cause diffuse flushing
(“red man syndrome”) from histamine release.
12/23/2021 Haitham Alwali 15
B. Fosfomycin
Fosfomycin is an antimetabolite inhibitor of
cytosolic enolpyruvate transferase. This action
prevents the formation of N-acetylmuramic
acid, an essential precursor molecule for
peptidoglycan chain formation.
Fosfomycin is excreted by the kidney, with
urinary levels exceeding the minimal inhibitory
concentrations (MICs) for many urinary tract
pathogens.

12/23/2021 Haitham Alwali 16

C. Bacitracin
Bacitracin is a peptide antibiotic that interferes with a
late stage in cell wall synthesis in gram-positive
organisms.
Because of its marked nephrotoxicity, the drug is limited
to topical use.
E. Daptomycin
Daptomycin is a novel cyclic lipopeptide with spectrum
similar to vancomycin but active against vancomycin-
resistant strains of enterococci and staphylococci.
The drug is eliminated via the kidney. Creatine
phosphokinase should be monitored since daptomycin
may cause myopathy.

12/23/2021 Haitham Alwali 17

Inhibitors of Bacterial
Protein Synthesis
Dr. mohammed Alsbou
Professor in Clinical Pharmacology
Faculty of Medicine

1
1. Aminoglycosides
2. Tetracyclines
3. Macrolides
4. Clindamycin
5. Chloramphenicol
6. Linezolid
7. Glycylcylines: Tigecycline

2
 Aminoglycosides (AG)
➢ Mechanism of action:
➢ These are bactericidal antibiotics that
inhibit bacterial protein synthesis by an
action on ribosome 30S resulting in
abnormal proteins & killing of bacteria
➢ They are effective against aerobic
bacteria only (their entry into bacteria is
oxygen-dependent)

3
➢ Aminoglycoside antibiotics had been
mainstays for treatment of serious
infections due to aerobic gram -ve bacilli
➢ Because their use is associated with
serious toxicities, they have been replaced
to by safer antibiotics, such as:
▪ 3ed & 4th generation cephalosporins
▪ Fluoroquinolones
▪ Carbapenems

4
➢ Gentamicin
➢ Amikacin
➢ Tobramycin
➢ Streptomycin
➢ Spectinomycin
➢ Neomycin
➢ Framycetin

5
Mechanisms of Bacterial resistance

➢ Enzymes formation (about 9 enzymes

are isolated; transferred by plasmids)
➢ Decrease uptake of drugs
➢ Anaerobic bacteria infections

6
Therapeutic Uses & Spectrum of Activity

➢ AG are active against aerobic Gram –ve

bacilli & also are active against
staphylococci
AG are indicated in the following conditions:
➢ Serious Gram –ve bacillary infections like
UTI, septicemia & pelvic infections caused
by E.coli, Proteus, Klebsiella &
Pseudomonas aeruginosa

7
➢ Some serious Gram +ve infections like bacterial
endocarditis (combined with penicillin G or
vancomycin)
➢ Streptomycin (Tuberculosis)
➢ Topical therapy including:
⚫ Eye, ear & skin infections (using topical

neomycin, gentamicin & framycetin)

⚫ Prepare bowel prior surgery (oral neomycin)

8
 Pharmacokinetics
➢ AG are water-soluble agents that are poorly
absorbed from GIT
➢ Therefore, they should be given parenterally
or topically
➢ AG are eliminated by kidneys by glomerular
filtration with no significant metabolism
➢ Accumulation occurs in renal cortex,
endolymph & perilymph of inner ear

9
Aminoglycosides & renal disease
➢ In renal impairment, AG t ½ increases &
therefore, intervals between doses should be
increased or daily doses should be reduced
➢ Doses can be obtained from tables according to
patient’s weight & renal function
➢ The following formula helps to calculate daily dose
in renal disease:
Dose (mg/day) = Daily dose/creatinine = 300 /
creatinine

10
Aminoglycosides & renal disease
➢ Blood levels have also to be checked e.g.
twice weekly
➢ Single daily dose administration of AG is
recommended nowadays rather than 2-3
doses daily to reduce risk of ototoxicity
& nephrotoxicity

11
 Adverse effects
➢ These are more in elderly, in renal & liver
diseases & with prolonged therapy
➢ Adverse effects are dose-related
(therapy should not exceed 7 days)
➢ Monitor plasma levels

12
 Adverse effects
➢ Nephrotoxicity:
➢ AG may accumulate in proximal tubular cells
➢ Kidney damage ranging from mild,
reversible renal impairment to severe,
acute tubular necrosis, which can be
irreversible
➢ being highest with kanamycin & least with
streptomycin

13
 Adverse effects
➢ Ototoxicity:
▪ Irreversible in the form of vestibular damage (
patients presented with vertigo) or cochlear
damage ( presented with deafness & tinnitus) or
both. AG ear drops may also produce ototoxicity
➢ Neurotoxicity: AG may reduce acetylcholine
release & may produce neuromuscular blockade
& muscle weakness
➢ Others like allergic reactions, fever & blood
disorders

14
Contraindications & precautions of AG

➢ Pregnancy as AG may cause ototoxicity

in newborn
➢ Allergy
➢ Avoid AG in:
⚫ Myasthenia Gravis
⚫ Prolonged use (more than one week)

15
 Drug interactions with AG:
➢ Loop diuretics (frusemide, bumetanide):
increase ototoxicity & nephrotoxicity of AG
➢ β-LA (penicillins & CSs): potentiate their
antibacterial activity
➢ Neuro-muscular blockers: potentiation
of effect

16
 Gentamicin
➢ Itis mainly used in serious aerobic Gram
–ve infections (E. coli, Proteus, Klebsiella
& Pseudomonas) & some Gram +ve
infections (endocarditis)
➢ can also be used topically in eye, ear &
skin infections
➢ In septicemia, it is combined with a
penicillin & metronidazole

17
 Tetracyclines

➢ Tetracycline, Doxycycline, Minocycline,

Demeclocycline
➢ These broad spectrum (gram +ve, -ve
bacteria), bacteristatic antibiotics contain
4 rings in their structure
➢ They inhibit bacterial protein synthesis
by binding to bacterial ribosome 30S

18
 Pharmacokinetics
➢ Tetracyclines are usually given orally
➢ Their absorption from GIT is impaired by
antacids, iron & by food particularly calcium-
containing food like milk. Therefore, they are
better taken on empty stomach
➢ Unabsorbed fraction alters bacterial flora &
causes diarrhea
➢ They are distributed throughout body but have
poor entry into CSF (except minocycline)
➢ They cross placenta and are excreted in milk

19
➢ Tetracyclines are eliminated mainly
unchanged in urine and should be
avoided in renal disease
➢ Doxycycline & minocycline are excreted
only in bile & are therefore, safe in renal
disease
➢ Tetracyclines bind to calcium of teeth &
bones

20
 Therapeutic uses
➢ Brucellosis
➢ Cholera
➢ Mycoplasma pneumonia
➢ Chlamydia infections like pelvic inflammatory disease,
urethritis, trachoma, psittacosis
➢ Syphilis
➢ Chronic bronchitis exacerbations
➢ Acne (inhibit Corynobacterium acnes bacteria)

21
 Contraindications
➢ Pregnancy
➢ Breast feeding women
➢ Renal disease because they accumulate in
renal disease (except doxycycline &
minocycline)
➢ Children because of yellow discoloration
of teeth

22
Tetracycline-Induced Discoloration of Teeth

23
 Adverse effects
➢ GI: Epigastric pain or discomfort, nausea,
vomiting, diarrhea or even antibiotic-associated
colitis
➢ Sore throat, black hairy tongue & dysphagia
➢ Photosensitivity, burn, rash & blue gray
discolouration (with minocycline)
➢ Yellow discolouration & hypoplasia of teeth
in children
➢ Renal impairment

24
 Macrolides

➢ Erythromycin, Clarithromycin &

Azithromycin
➢ These are bacteriostatic agents that
inhibit protein synthesis by acting on
ribosome 50S

25
 Pharmacokinetcis
➢ Route of administration is usually orally
➢ They are well absorbed & widely
distributed in tissues but do not cross
BBB into the CSF
➢ Elimination is in bile through liver

26
 Therapeutic uses
➢ Alternative to penicillin in presence of
penicillin allergy
➢ Mycoplasma pneumonia (called atypical
pneumonia)
➢ Helicobacter infections like gastro-enteritis
➢ Chlamydia infections
➢ Diphtheria
➢ Whooping cough (pertussis)
➢ Legionnaire’s disease (characterized by
respiratory, GIT & CNS manifestations)

27
 Contraindications
➢ Liver disease

Adverse effects:
➢ GI upset
➢ Liver damage (cholestatic jaundice)
➢ Inhibition of hepatic drug metabolism

28
 Erythromycin
(Erythrocin)
➢ Effective against gram +ve organisms
➢ Antibacterial spectrum is similar to that of
penicillin
➢ It is used in patients allergic to penicillin

29
 Clarithromycin (Klacid)
➢ It acts like erythromycin & with similar spectrum
of activity mainly against Gram +ve organisms
& also against H. influenzae
➢ It is rapidly & better absorbed than erythromycin
and produces less GIT upset
➢ It is used in respiratory tract infections & soft
tissue infections
➢ It is useful in peptic ulcer therapy to eradicate
Helicobacter pylori with other anti-ulcer drugs

30
 Azithromycin
(Zithromax)
➢ It is active against many Gram -ve organisms
like H. influenzae & N. gonorrhoea & against
chlamydia but less effective than erythromycin
against Gram +ve organisms
➢ It is useful to treat respiratory TI (mycoplasma
pneumonia), soft tissue infections & sexually
transmitted chlamydial disease
➢ Long half-life (40 hrs)
➢ Orally or intravenous infusion
31
 Clindamycin (Dalacin)

➢ It is a bacteriostatic agent that acts by

inhibiting bacterial protein synthesis
➢ It has similar spectrum of activity to
erythromycin, penicillin & anaerobes
➢ It is well absorbed after oral administration

32
 Therapeutic uses
➢ Anaerobic infections like in abdomen,
teeth (dental infections), pelvis & septic
abortion
➢ Osteomyelitis (infection of bone caused
by staphylococci) because of good bone
penetration & good anti-staph activity
➢ In serious Gram +ve infections

33
 Adverse effects
➢ Diarrhoea, antibiotic-associated colitis,
allergy & liver dysfunction

34
 Chloramphenicol
➢ It is a bacteriostatic agent, but sometimes,
may be bactericidal (H.influenzae, strep
pneumonia)
➢ It has a broad spectrum of activity against
Gram +ve & Gram –ve bacteria & anaerobes
➢ Because of its serious adverse effects, it has
limited uses mainly in serious infections

35
 Pharmacokinetics

➢ The drug can be given orally or

parenterally
➢ It is widely distributed in tissues & crosses
BBB into the CSF
➢ It is metabolized in liver and its excretion is
in urine (smaller doses in liver disease)

36
 Therapeutic uses
➢ Salmonellosis
➢ H. influenza meningitis
➢ Meningococcal meningitis in penicillin
allergic patients
➢ Anaerobic infection in CNS
➢ Topically in ocular infections (bacterial
conjunctivitis)

37
 Adverse effects
➢ Bone marrow depression includes:
⚫ Reversible dose-dependent depression (anemia)
⚫ Idiosyncratic irreversible depression (aplastic anemia)
➢ Gray baby syndrome (cyanosis, hypotension,
death) because of inability of newborn liver to
metabolize drug efficiently resulting in its
accumulation & toxicity
➢ Optic & peripheral neuritis
➢ Inhibition of hepatic metabolism of drugs like
warfarin & phenytoin

38
 Contraindications

➢ Latepregnancy
➢ Newborn babies (risk of grey baby
syndrome)
➢ Breast feeding women

39
 Linezolid
➢ Itsmain clinical use in resistant gram-
positive organisms such as:
- Methicillin- and vancomycin-resistant
staphylococcus aureas
- Vancomycin- resistant Enterococcus
- Penicillin– resistant streptococci
➢ Oral & iv administration
➢ Adverse effects: nausea, diarrhea,
headache, rash, thrombocytopenia
40
 Glyclycyclines
➢ Tigecyline
➢ Structure similar to tetracylines
➢ Has extended broad spectrum activity against:
➢ Multidrug–resistant gram +ve:
➢ - methicillin-resistant staphylococci, multi-drug
resistant streptococci, vancomycin-resistant
enterococci
➢ Extended- spectrum B-lactamase producing gram –
ve
➢ Acinetobacter baumanii
➢ Anaerobic organisms
41
➢ Not active against Proteus & Pseudomonas
➢ Is indicated for:
- complicated skin & soft tissue infections
- complicated intra-abdominal infections
➢ Given iv infusion every 12 hrs
➢ Eliminated via biliary/fecal excretion
➢ No dose adjustment in renal impairment

42
➢ Adverse effects:
➢ Similar to tetracyclines
➢ Nausea & vomiting
➢ Photosensitivity
➢ Discoloration of teeth in children
➢ Contraindicated during pregnancy

43
Inhibitors of Metabolism & Inhibitors
of Nucleic Acid Function or
Synthesis

Dr. Mohammed Alsbou

Professor of Clinical Pharmacology
Faculty of Medicine

1
➢ Inhibitors of metabolism:
- Sulfonamides, trimethoprim
➢ Inhibitors of nucleic acid function or
synthesis:
- Fluoroquinolones

2
 Folic Acid Antagonists
➢ Sulpha drugs (sulphonamides),
Trimethoprim
➢ These are synthetic agents that inhibit folic
acid synthesis in bacteria, therefore,
leading to interference with nucleic acid
synthesis
➢ Interfere with ability of bacteria to divide

3
➢ Bacteria require folic acid, which is
synthesized in bacteria from para-amino-
benzoic acid (PABA)
➢ Sulpha drugs compete with PABA
preventing synthesis of folic acid in
bacteria

4
➢ Trimethoprim inhibits DHFR
(dihydrofolate reductase) enzyme which
converts folic acid into folinic acid
resulting in impaired synthesis of folinic
acid (an essential coenzyme in nucleic
acid synthesis) leading to antibacterial
effects

5
 Mechanism of action
DHFR
PABA Folic acid Folinic acid
(Dihydrofolate) (Tetrahydrofolate)

6
➢ Sulpha drugs & trimethoprim are
bacteriostatic when given alone
➢ However, their combination (co-
trimoxazole) inhibits above 2 steps resulting
in bactericidal effect

7
 Sulpha Drugs
➢ These agents were active against many
Gram +ve & Gram -ve bacteria & others
➢ At the present time, they are infrequently
used with limited indications because of
increased bacterial resistance
➢ Safer more effective agents have
replaced sulpha drugs
➢ The following sulpha are important:

8
 Sulpha Drugs
➢ Sulphadiazine
➢ Sulphadoxine
➢ Sulphacetamide
➢ Sulphamethoxazole
➢ Sulphasalazine

9
 Sulphadiazine
➢ Itis an oral well absorbed short acting
sulpha that crosses well BBB into CSF
➢ Useful in treatment of meningitis (with
penicillin)
➢ Useful in treatment of toxoplasmosis (with
pyrimethamine)
➢ Flamazine (silver sulphadiazine):
useful topically in prevention & treatment of
infections in burns, leg ulcers & pressure
sores
10
 Sulphadoxine
➢A long acting sulpha useful in treatment of
malaria (with pyrimethamine)
➢ Fansidar: sulphadoxine + pyrimethamine

Sulphacetamide
➢ It is useful topically for eye infections

11
 Sulphamethoxazole
➢ It is combined with trimethoprim
producing co-trimoxazole

12
 Sulphasalazine (salazopyrine)
➢ It is useful in chronic inflammatory bowel
disease (IBD) like ulcerative colitis &
Crohn’s disease
➢ It is used orally
➢ In colon, it is splitted by bacterial flora into
sulphapyridine & 5-aminosalicylic acid
which is the active part that produces anti-
inflammatory effect of the drug

13
➢ Sulpha drugs are metabolised in liver by
process of acetylation
➢ People are either rapid or slow
acetylators
➢ Slow acetylators accumulate drug & are
more prone to adverse effects
➢ The drug & its metabolites are excreted in
urine (excretion increases in alkaine urine)

14
 Contraindications
➢ Newborn babies because of risk of kernicterus
due to displacement of billirubin from binding
sites on plasma proteins & increased entry into
brain tissues through immature BBB leading to
mental retardation
➢ Late pregnancy due to possible passage to fetus
& risk of kernicterus
➢ Allergy
➢ G6-PD deficiency leading to hemolytic anemia

15
Kernicterus

16
 Adverse effects
➢ Crystalluria: Sulpha may precipitate in urine
leading to hematuria & even obstruction; can be
prevented by increasing water intake & urine
alkalinization
➢ Haemolytic anaemia in patient deficient of
G6-PD enzyme
➢ Kernicterus

17
 Adverse effects
➢ Hypersensitivityreactions (HSR):
fever, skin rashes, including severe
Stevens-Johnson syndrome (SJD) &
TEN (Toxic epidermal necrolysis)
(Erythema multiform; target lesions in skin
& mucous membrane)

18
Stevens- Johnson syndrome
(SJS)

19
 Trimethoprim
➢ This is a DHFR inhibitor that inhibits
conversion of folic acid into folinic acid
➢ It can be used alone or with
sulphamethoxazole (co-trimoxazole)
➢ It may be used in UTI, prostatitis & in
respiratory infections

20
➢ Prolonged therapy may produce blood
disorders (macrocytic anemia,
leucopenia & thrombocytopenia) due to
effect on folic acid pathway in cells

21
 Co-trimoxazole (Septrin)

➢ It consists of Sulphamethoxazole 400 mg

& trimethoprim 80 mg (ratio is 5:1)
Pharmacokinetics:
➢ It is usually used orally & sometimes IV in
serious infections
➢ It is well absorbed from GIT & its t½ is
about 10 hours (given twice daily)

22
 Therapeutic uses
➢ Respiratory TI: (pneumococci, haemophilus,
klebsiella infections, Pneumocystis carini
pneumonia in patients with AIDS)
➢ UTI (caused by E.coli, Proteus)
➢ Enteric fever (salmonellosis)
➢ Brucellosis
➢ Gonorrhoea

23
 Fluroquinolones
➢ First generation:
Nalidixic acid, used less today, Gram – ve
(narrow spectrum mainly in UTI)
➢ Second generation:
Gram –ve, Gram +ve, Atypical bacteria
(chlamydia, mycoplasma)
Ciprofloxacin, norfloxacin & ofloxacin

24
➢ Third generation:
Gram –ve, Gram +ve (streptococcus
pneumonia), Atypical bacteria (chlamydia,
mycoplasma)
Levofloxacin (Tavanic) (UTIs & respiratory
infections: acute sinusitis, chronic bronchitis,
community acquired & nonsocial pneumonia)
➢ Fourth generation:
Gram –ve, Gram +ve, Anaerobic
Moxifloxacin 25
➢ Mechanism of action:
➢ Acts by inhibiting DNA gyrase enzymes
(inhibit topoisomerases) in bacteria
leading to interference with DNA synthesis
& anti-bacterial effect

26
 Fluroquinolones
Nalidixic acid (Negram)
➢ Active against Gram –ve organisms
including E.coli, salmonella, shigella & H.
influenza
➢ This is useful in UTI (concentrated in urine)
but has limited systemic anti-bacterial
actions
➢ Its derivatives called fluroquinolones
(ciprofloxacin, norfloxacin & ofloxacin)
are 60 times more potent with systemic anti-
bacterial actions
27
 Ciprofloxacin

➢ Most frequently used

➢ This is a synthetic fluroquinolone which is
bactericidal agent with broad spectrum
anti-bacterial actions (mainly against
Gram –ve & moderate activity against
Gram +ve bacteria) & atypical pathogens

28
 Pharmacokinetics

➢ It is usually given orally twice daily

➢ It can be given IV
➢ It is well absorbed & widely distributed in
tissues with a half-life of about 3 hours
➢ The drug is partly metabolized and is
eliminated through kidneys (smaller
doses are used in renal impairment)

29
 Therapeutic uses
➢ UTI (prostatitis) even those caused by resistant
Gram –ve b. as Pseudomonas
➢ Traveler’s diarrhea (E.coli)
➢ Enteric fever (salmonellosis) & shigellosis
➢ Gonorrhoea
➢ Septicemia
➢ bone infections
➢ Chlamydia & Helicobacter infections
➢ Serious respiratory TI like that caused by H.
influenza & atypical pneumonia (mycoplasma,
chlamydia)
➢ Topically in some eye infections like that caused
by Pseudomonas 30
 Contraindications

➢ Pregnancy & lactation

➢ Children
➢ Epilepsy
➢ G6-PD deficiency

31
 Adverse effects
Usually well tolerated with few adverse reactions
which may include:
➢ GI: nausea, vomiting , diarrhea
➢ Arthralgia
➢ Allergy: rash, photosensitivity, anaphylaxis,
Stevens-Johnson syndrome
➢ CNS manifestations: (headache, hallucination &
convulsions).
➢ Tendon damage like rupture of Achilles tendon

32
 ANTI-PROTOZOAL DRUGS

Dr. Yousef Al-saraireh

Associate Professor
Faculty of Medicine
1
 CONTENTS
 CHEMOTHERAPY FOR MALARIA

 CHEMOTHERAPY FOR AMOEBIASIS

 CHEMOTHERAPY FOR GIARDIASIS

 CHEMOTHERAPY FOR LEISHMANIASIS

 CHEMOTHERAPY FOR TOXOPLASMOSIS

2
 Protozoa are a diverse group of mostly motile unicellular
eukaryotic organisms
1. Treatment of Malaria:
 Malaria is an acute infectious disease caused by four
species of the protozoal genus Plasmodium.
P falciparum, P vivax, P malariae, and P ovale

 P falciparum is the most dangerous species, causing an

acute, rapidly fulminating disease that is characterized by
persistent high fever, orthostatic hypotension, and
massive erythrocytosis .This infection can lead to capillary
obstruction and death if not treated.

 P malaria is common to many tropical regions, 3

4
 CLASSIFICATION OF ANTI-MALARIALS
Several classes of antimalarial drugs are available:
1. Tissue schizonticides (Exoerythrocytic): Drugs that
eliminate developing or dormant liver forms (Primaquine)
2. Blood schizonticides (erythrocytic): those that act on
erythrocytic parasites (Artemisinin, chloroquine,
quinine, mefloquine, pyrimethamine)
3. Gametocides: those that kill sexual stages and prevent
transmission to mosquitoes. (primaquine)
4. Radical cure: eliminate both hepatic and erythrocytic
stages. Primaquine
5. Causal prophylactic drugs: those capable of preventing
erythrocytic infection. Chloroquine and Pyrimethamine

5
 1. TISSUE SCHIZONTICIDES:
 Primaquine eradicates exoerythrocytic forms of recurring
malarias and has gametocidal action.
 Primaquine is the only agent that can lead to radical
cures of malarias,
Mechanism of action:
 It interferes with plasmodial mitochondria

Adverse effects
1.GI upset.
2.Jaundice.
3.Haemolytic anaemia (in patients with glucose-6-
phosphate dehydrogenase2 deficiency).

6
 2. BLOOD SCHIZONTICIDES:
1.Chloroquine :
 is the drug of choice in the treatment of erythrocytic
malaria
 It prevents ploymerization of heme to hemozoin leading to
lysis of parasite and red blood cells

7
Therapeutic uses:
1. Treatment & prophylaxis of malaria.
2. Hepatic amoebiasis
3. Others as in rheumatoid arthritis for its anti-
inflammatory actions.
Adverse effects:
1.GI upset.
2.Rashes & pruritis.
3.Pigmentation of skin & mucous membrane.
4.Deposition in cornea, iris & retina (retinopathy) causing
various ocular manifestations.
Precautions:
1.Should not be taken by patients with psoriasis because of
risk of exacerbation of the disease. 8
2.Regular ocular examination is needed during prolonged
therapy to detect early ocular complications.
2.Quinine:
Itinterferes with heme polymerization leading to death of
parasites
Cinchonism or quinism
Adverse effects
GI upset (nausea & vomiting).
Blood disorders (haemolysis and thrombocytopenia)
Allergic rashes
Cinchonism.
Hypotension, convulsion, respiratory depression and ventricular
tachycardia (following rapid IV).

3. Mefloquine
 Used for multi-resistant forms of P. falciparum, single,
produce cure
 Damage parasite membrane as quinine
9
4. Artemisinin
 For multi-resistant Falciparum malaria

 It acts by Production of free radicals

 It produces Neurotoxicity

5.Pyrimethamine
 It is a dihydofolate reductase inhibitor useful in the
prophylaxis of malaria and treatment of chloroquine-
resistant malaria.
 Prolonged use may lead to bone marrow depression &
therefore, blood counts are needed.
 Folate deficiency: Folinic acid is commonly administered
to protect against folate deficiency
10
 DRUG THERAPY OF AMOEBIASIS
 Amebiasis (amebic dysentery) is an infection intestinal
tract caused by Entamoeba histolytica.
 mild diarrhea to fulminating dysentery.

11
A.Mixed Ambicides (Luminal and systmic) :
1. Metronidazole (Flagyl)
 This is an anti-microbial agent that has an amoebicidal
activity against the vegetative form of the Entamoeba
histolytica.
Mechanism of action
Metronidazole acts by interference with DNA.
Therapeutic uses
 Acute amoebic dysentery.
 Hepatic amoebiasis & pulmonary amoebiasis.
 Anaerobic bacterial infections.
 Postoperative prophylaxis.
 Trichomoniasis: is primarily an infection of the urogenital
tract
 Giardiasis.
 Ulcertive gingivitis. 12

 Non-specific vaginitis.
 Adverse effects
1. Metallic taste in the mouth.
2. GI disturbances.
3. Headache
4. Allergy
 Metronidazole is contraindicated in the first trimester
of pregnancy.

2. Tinidazole:
 is a second-generation imidazole family that is similar to
metronidazole in spectrum of activity.
 Treatment of amebiasis, amebic liver abscess, giardiasis,
and trichomoniasis
 Tinidazole is as effective as metronidazole, with a shorter
13
course of treatment.
B. Luminal amebicides:
o A luminal agent should be administered for treatment of
the asymptomatic colonization state(carrier to disease).
1. Iodoquinol:
 is amebicidal against E. histolytica and is effective
against the luminal trophozoite and cyst forms.
 Side effects include rash and diarrhea

2. Paromomycin:
 Effective against the intestinal (luminal) forms of E.
histolytica.
 It exerts its antiamebic actions by reducing the population
of intestinal flora. Its direct amebicidal action is probably
due to the effects it has on cell membranes, causing
leakage.
14
 Adverse effects: diarrhea

.
C. Systemic amebicides:
 liver abscesses and intestinal wall infections
1. Chloroquine: is used in combination with metronidazole
to treat and prevent amebic liver abscesses
2. Emetine Hcl & dehydroemetine
 They are used in amoebiasis when there is intolerance to
metronidazole or when there is no response to it.
 They have low safety index & may cause cardiotoxicity.

 Dehydroemetine is less cumulative & less cardiotoxic.

Adverse effects
These agents are given as IM injection in hospital under close
supervision because of risk of toxicity.
 GI upset (nausea & vomiting).

 Allergy (rashes & urticuria).

 Cardiovascular effects like chest pain, tachycardia, hypotension

15
& ECG abnormalities.
 CHEMOTHERAPY FOR GIARDIASIS
 Giardia lamblia
 Although some infections are asymptomatic, severe
diarrhea can occur, which can be very serious in
immune-suppressed patients.

Treatment :
1. Metronidazole for 5 days.
Or
2. Tinidazole, which is equally effective as metronidazole
in the treatment of giardiasis but with a much shorter
course of therapy (2 grams given once).

16
CHEMOTHERAPY FOR LEISHMANIASIS
 There are three types of leishmaniasis:
cutaneous, mucocutaneous, and visceral.
 Pentavalent antimonials, such as sodium
stibogluconate, are the conventional therapy
used in the treatment of leishmaniasis.
1. Sodium stibogluconate
 Given daily by IV or IM injections or
topically in cutaneous lesions.

17
 CHEMOTHERAPY FOR TOXOPLASMOSIS
 Toxoplasma gondii, which is transmitted to humans when
they consume raw or inadequately cooked infected meat.
 An infected pregnant woman can transmit the organism to
her fetus.
Treatment:
 A combination of sulfadiazine and pyrimethamine.

 Folinic acid is commonly administered to protect against

folate deficiency

18
Anthelmintics

19
1. TREATMENT OF NEMATODES
 They cause infections of the intestine as well as the blood
and tissues (round worm)
A. Mebendazole:
 Mebendazole acts by inhibiting microtubule synthesis and
also by decreasing glucose uptake.
Therapeutic uses :
ascariasis, enterobiasis & ancylostomiasis.
Contraindications :
Pregnancy: it has been shown to be embryotoxic and
teratogenic in experimental animals
Children under 2 years of age.

20
2. TREATMENT OF CESTODES
o The cestodes, or “true tapeworms,” typically attach to
the host’s intestine
A. Albendazole:
o inhibits microtubule synthesis and glucose uptake

o It is used as alternative to mebendazole against intestinal

lumen nematodes; it is given as single oral daily dose.

o Its primary therapeutic application, however, is in the

treatment of cestodal infestations, such as cysticercosis
(caused by Taenia solium larvae or pork tape worm) and
hydatid disease

o Treatment of hydatid disease (3 months) has a risk of

hepatotoxicity and, rarely, agranulocytosis or pancytopenia
21
3. TREATMENT OF TREMATODES
o The trematodes (flukes) are leaf-shaped flatworms that
are generally characterized by the tissues they infect. For
example, they may be categorized as liver, lung,
intestinal, or blood flukes

A. Praziquantel:
 agent of choice for the treatment of all forms of
schistosomiasis .
 It increases permeability of the cell membrane to calcium,
causing contracture and paralysis of the parasite.

22
ANTIFUNGAL DRUGS
 CLASSIFICATION OF ANTIFUNGAL DRUGS
Drugs for systemic fungal infections
Polyene antibiotics
-Amphotericin B
Pyrimidine antimetabolites
-Flucytosine
Antifungal azoles
-Ketoconazole
-Fluconazole
-Itraconazole
Echinocandins
Caspofungin, micafungin, and anidulafungin
Drugs for superficial fungal infections
Systemic drugs
-Griseofulvin
-Iodide
Topical drugs
-Nystatin
-Haloprogin
-Tolnaftate
Targets of antifungal drugs
 PHARMACOLOGY OF AMPHOTERICIN B
Chemistry
-Amphotericin B is a polyene antibiotic (polyene:
containing many double bonds)
Mechanism of action
-Binding to ergosterol present in the membranes of
fungal cells

Formation of “pores” in the membrane

Leaking of small molecules (mainly K+) from the

cells

-The ultimate effect may be fungicidal or

fungistatic depending on the organism and on
drug concentration.
Model for Amphotericin B induced
Pore in Cell Membrane
Antifungal spectrum and resistance

-Antifungal spectrum includes:

• Histoplasma capsulatus
• Coccidioides immitis
• Paracoccidioidoides braziliensis
• Aspergillus fumigatus
• Blastomyces dermatitidis
• Cryptococcus neoformans
• Candida albicans
• Sporothrix schenckii
• Mucor and Rhizopus spp
• Resistance may occur but is very rare
Pharmacokinetics
-F(oral): < 1% (too irritant to be given IM)
-Distribution in all body tissues, except CNS and eye
(concentrations in CSF are <10% than in plasma; however
therapeutic concentrations in CNS can usually be
achieved with parenteral administration)
-Biotransformation: > 95%
-Renal excretion: < 5%
-Half life: » 14 days
Drug formulations and administration
-Formulations:
a) complex with deoxycholate
b) liposomal complex (adverse effects seem diminished)
-Administration:
IV infusion, intrathecal, topical, oral (to treat intestinal
mycoses)
 Adverse effects
(the therapeutic index of the drug is very narrow)
-Headache, arthralgias, nausea and vomiting fever
and chills, hyperpnea, shock-like fall in blood
pressure (they may appear during IV infusion
and may be reduced by concomitant
administration of antipyretics or meperidine)
-Malaise, weight loss
-Nephrotoxicity (azotemia , decreased GFR, renal
tubular acidosis, renal wasting of K+ and Mg++,).
It is common (up to 80% of patients) and may be
severe
-Normocytic anemia, likely due to decreased
production of erythropoietin (frequent)
-Thrombophlebitis
 Therapeutic uses
Amphotericin is the drug of choice for:
-Disseminated histoplasmosis
-Disseminated and meningeal coccidioidomycosis
-Disseminated and meningeal cryptococcosis
-Invasive aspergillosis
-Deep candidiasis
-Mucormycosis
Amphotericin is an alternative drug for:
-Blastomycosis
-Paracoccidioidomycosis
-Extracutaneous sporotrichosis
[Amphotericin is preferred when these mycoses
are rapidly progressive, occur in
immunocompromised host or involve the CNS]
 PHARMACOLOGY OF FLUCYTOSINE
Chemistry
-Flucytosine is a fluorinated pyrimidine
Mechanism of action
-The drug is accumulated in fungal cells by the action of a
membrane permease and is converted by a cytosine
deaminase to 5-fluorouracil (selectivity occurs because
mammalian cells do not accumulate and do not deaminate
flucytosine)

5-fluorouracil is metabolized to 5-fluorouridylic acid

which can be
a) incorporated into the RNA (this leads to a misreading of
the fungal genetic code)
b) further metabolized to 5-deoxyfluorouridylic acid, a
potent inhibitor of thymidylate synthase (this leads to a
blockade of fungal DNA synthesis)
-The ultimate effect may be fungicidal or fungistatic
depending on the organism and on drug concentration.
Action of flucytosine in fungi.

5-Flucytosine is transported into the fungal cell, where it is deaminated to 5-

fluorouracil (5-FU). The 5-FU is then converted to 5-fluorouracil-ribose
monophosphate (5-FUMP) and then is either converted to 5-FUTP and
incorporated into RNA or converted by ribonucleotide reductase to 5-FdUMP,
which is a potent inhibitor of thymidylate synthase.
Antifungal spectrum and resistance
-Antifungal spectrum includes Cryptococcus
neoformans, Candida albicans, Aspergillus
fumigatus, and several soil fungi which cause
chromomycosis.
-Resistance may arise rapidly during therapy
and is an important cause of therapeutic
failure when the drug is used alone.
Pharmacokinetics and administration
-F(oral): > 80%
-Distribution in all body tissues, including CNS
and the eye.
-Volume of distribution: » 42 L
-Renal excretion: » 99%
-Half-life: » 4 hours (in renal failure, half-life
may be as long as 200 hours)
Adverse effects
(toxicity is generally not pronounced)
-Anorexia, nausea and vomiting, diarrhea
-Severe ulcerative enterocolitis (rare)
-Skin rashes
-Headache, dizziness, confusion
-Reversible bone marrow depression (8-13%)(leukopenia,
thrombocytopenia)
-Liver dysfunction (5-10%)
-Alopecia, peripheral neuritis (rare)
[toxicity may be due to the conversion of flucytosine to 5-
fluorouracil by the intestinal flora of the host]
Therapeutic uses
-Deep candida infections, cryptococcal meningitidis
(always in combination with amphotericin B)
-Chromomycosis (effectiveness is limited)
Contraindications
-Pregnancy ( 5-fluorouracil is teratogenic)
 PHARMACOLOGY OF ANTIFUNGAL AZOLES
Chemistry
-Imidazole derivatives: ketoconazole, miconazole,
econazole, clotrimazole
-Triazole derivatives: itraconazole, fluconazole.
Mechanism of action
-Inhibition of sterol 14-alpha-demethylase, a
cytochrome P450-dependent enzyme (relative
selectivity occurs because the affinity for
mammalian P450 isozymes is less than that for the
fungal isozyme)

blockade of the synthesis of ergosterol in fungal

cell membranes
-The ultimate effect may be fungicidal or
fungistatic depending on the organism and on
Antifungal spectrum and resistance
-Antifungal spectrum includes:
Histoplasma capsulatus, Coccidioides immitis
Paracoccidioidoides braziliensis , Aspergillus fumigatus
Blastomyces dermatitidis, Cryptococcus neoformans
Candida albicans , Sporothrix schenckii
Dermatophytes (Microsporum, Epidermophyton,
Trichophyton, Malassezia furfur)
-Resistance can occur but is rare.
-Cross-resistance between azoles is a common finding.
Other effects
-Azoles may inhibit certain mammalian cytochrome P450
isozymes and therefore they may
1) inhibit the synthesis of androgens and of corticosteroids
2) potentiate the effects of several drugs including
cyclosporine, phenytoin, terfenadine, astemizole,
tolbutamide and warfarin.
Pharmacokinetics and administration
-F(oral): itraconazole » 55%, fluconazole >90%.
(acidity favors oral absorption of ketoconazole)
-Distribution in all body tissues. Penetration into CNS is
generally negligible, but good for fluconazole.
-Renal excretion: fluconazole » 75%, others < 1%
-Half-lives (hrs): ketoconazole » 8, itraconazole » 35
-Administration: oral, IV, topical
Adverse effects
-Anorexia, nausea and vomiting (they are dose-dependent
and patients receiving high doses may require
antiemetics)
-Gynecomastia, decreased libido, impotence, menstrual
irregularities (with ketoconazole, due to blockade of
adrenal steroid synthesis)
-Hepatitis (is rare, but can be fatal)
-Hypokalemia, hypertension (itraconazole)
Therapeutic uses
Azoles are first choice drugs for:
-Blastomycosis (ketoconazole)
-Paracoccidioidomycosis (ketoconazole)
-Chronic pulmonary histoplasmosis
-Meningeal coccidioidomycosis (fluconazole)
-Meningeal cryptococcosis (fluconazole)
-Cutaneous and deep candidiasis
Azoles are alternative drug for:
-Invasive aspergillosis
-Sporotrichosis
Topical azoles are used for:
-Dermatophytoses (not of hair and nails)
-Tinea versicolor
-Mucocutaneous candidiasis
Contraindications
-Systemic azoles are contraindicated in pregnancy (potential teratogenic
effects and endocrine toxicity for the fetus)
 PHARMACOLOGY OF GRISEOFULVIN
Chemistry
-Griseofulvin is a benzofuran derivative
-The drug is practically insoluble in water
Mechanism of action
-An active transport accumulates the drug in sensitive fungal
cells where

griseofulvin causes disruption of the mitotic spindle by

interacting with polymerized mycrotubules
-The ultimate effect is fungistatic
Antifungal spectrum and resistance
-Antifungal spectrum includes only Dermatophytes (Microsporum,
Epidermophyton, Trichophyton)
-The drug is ineffective against other fungi producing superficial
lesions (like Candida and Malassezia furfur) and those producing
deep mycoses.

-Resistance is uncommon. It seems to be due to a decrease of the

energy-dependent transport mechanism.
 Echinocandins
• Newest class of antifungal agents
• Intravenous
• inhibiting the synthesis of (1–3)-glucan
• Well tolerated
• Caspofungin
• Micafungin
• Anidulafungin
Pharmacokinetics and administration
-F(oral): » 50% (micronization of the drug and a
high-fat food favor oral absorption)
-Distribution is mainly in keratinized tissues where the drug is tightly
bound and where it can be detected 4-8 hours after oral administration.
Concentration in other tissues and body fluids is negligible.
-Elimination: mainly in the feces.
-Half-life (hrs): » 24 hours
-Administration: oral
Adverse effects
(incidence is quite low)
-Xerostomia, nausea and vomiting, diarrhea
-Headache (up to 15%), fatigue, blurred vision, vertigo, increased effects of
alcohol
-Hepatotoxicity (rare)
-Leukopenia, neutropenia
-Allergic reactions (urticaria, skin rashes, serum sickness, angioedema)
-Teratogenic effects in several animal species
Therapeutic uses
-Mycotic disease of the skin, hair and nails (long treatments are needed)
 TOPICAL ANTIFUNGAL DRUGS
Nystatin
-A polyene antibiotic useful only for local candidiasis.
-Administration: cutaneous, vaginal, oral.

Haloprogin
-The drug is fungicidal to various species of dermatophytes and
candida.
-Principal use: in tinea pedis (cure rate » 80% )
Tolnaftate
-The drug is effective against most dermatophytes and
Malassezia furfur but not against Candida
-In tinea pedis the cure rate is » 80%
Antifungal azoles
-Azoles are reported to cure dermatophyte infections in
60-100% of cases
-The cure rate of mucocutaneous candidiasis is > 80% and that
of tinea versicolor > 90%.
-Administration: cutaneous, vaginal.
-Cutaneous application rarely causes erythema, edema,
vescication, desquamation and urticaria
Antiviral Drugs
Dr. Mohammed Al-Sbou
Professor in Clinical Pharmacology
Faculty of Medicine, Mutah University

1
 Viral infections
• Viruses lack both cell wall & cell membrane
• Clinical symptoms of viral infection appear
late in course of disease, at time that most viral
particles have replicated
• Administration of antiviral drugs have limited
effectiveness
• Some antiviral are use as prophylaxis

2
3
4
Respiratory Virus Infections
• Antiviral drugs for influenza types A &
B and respiratory syncytial virus (RSV)
• Immunization against influenza A is
the preferred approach

5
 Antiviral drugs for Respiratory
Virus Infections
• Neuraminidase inhibitors:
oseltamivir & zanamivir
• Inhibitor of viral uncoating:
Amandatine
• Ribavarin

6
 1. Neuraminidase inhibitors

• At surface of influenza virus two glycoproteins:

hemagglutinin (HA)& neuraminidase (NA)
• Neuraminidase enzyme that is essential for release
of virus particles from surface of infected cell
• Neuraminidase can be inhibited by sialic acid
analogs:
• oseltamivir (Tamiflu) & Zanamivir (Relanza)

7
• These drugs prevent release of new
virions & their spread from cell to cell
• Oseltamivir & zanamivir are effective
against influenza types A & B

8
1. Neuraminidase inhibitors
• Neuraminidase inhibitors prevent infection if
administered prior exposure
• They are most effective for treatment of
influenza if given within few hours of onset of
symptoms
• When administered within first 24-48 hrs of
onset of infection, they have modest effect on
intensity & duration of symptoms

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1. Neuraminidase inhibitors

• They reduce risk of

complications in elderly &
in patients with chronic
diseases
• Oseltamivir is given orally
for 5 days
• Zanamivir is administered
either inhaled or intranasally
for 5 days

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1. Neuraminidase inhibitors

• Adverse effects:
• Oseltamivir: GI discomfort, nausea
• Zanamivir: irritation of respiratory
tract, bronchospasm, should be avoided
in patients with asthma, COPD

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 2. Inhibitor of Viral Uncoating
• Adamantine derivatives: Amandatine
• Effective only against influenza A
infections
• Treatment is useful for unvaccinated
individuals & during epidemics
• Amantadine is also effective in treatment
of some cases of Parkinson’s disease

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2. Inhibitor of Viral Uncoating

• drugs are well absorbed orally

• Adverse effects:
• Amantadine: CNS symptoms
o Minor neurological symptoms (insomnia,
dizziness, ataxia)
o Serious effects (hallucinations & seizures)
• should be avoided in pregnancy

13
 3. Ribavirin
• Effective against RNA & DNA viruses
• Is used in treating infant & children with
severe RSV infections
• Is indicated in chronic hepatitis C in
combination with interferon-alpha-2b
• Is given orally or I.V, aerosol
• Adverse effects:
- Transient anemia, elevated bilirubin,
teratogenic
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 Hepatic viral infections

• Hepatitis viruses identified A, B, C, D, E

• Hepatitis B & C are most common causes
of chronic hepatitis, cirrhosis,
hepatocellular carcinoma
• Therapy is currently available only for
B&C
• Chronic hepatitis B is treated with
interferon-α or lamivudine

15
 Hepatic viral infections

• Chronic hepatitis C respond to

interferon-α & ribavirin
• Hepatitis A is a common infection but not
chronic

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 Antiviral drugs for hepatic viral
infections:

• Interferon
• Lamivudine

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 1. Interferon
• A family of naturally occurring,
inducible glycoproteins that interfere
with ability of viruses to infect cells
• Three types interferon- α, β, γ

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• Pegylated” formulations has been
attached to either interferon-α-2a or
interferon-α-2b to increase size of
molecule
• The larger molecular size delays
absorption from injection site, increase
duration of action of drug & decreases its
clearance

19
Some approved indications for interferons

20
 Interferon
• Interferon is not active orally
• Is administered intralesionally, SC & I.V
• Adverse effects:
- Flu-like symptoms: fever, chills, myalgias, arthralgias
- Bone marrow suppression
- Neurotoxicity (severe fatigue, weight loss, thyroditis)
- Rarely CHF, hypersensitivity reactions (HSR)

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 2. Lamivudine

• Cytocine analog that inhibits both HBV

DNA polymerase & HIV reverse
transcriptase
• Is given orally

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 Herpesvirus infections
• Acyclovir, Ganciclovir, famciclovir,
penciclovir

• Two most important herpes viruses:

- Herpes simplex viruses type 1 & 2
(HSV-1 & HSV-2)

- Varecilla-zoster virus (VZV)

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 Herpesvirus infections
• Herpes simplex infections:
- Mouth, lips (cold sores) & eye
are associated with HSV-1,
- are treated with topical antiviral

- Genital infection is associated

with HSV-2,
- are treated with oral antiviral

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 Herpesvirus infections
• Varecilla-zoster virus:
- Chickenpox in healthy children
mild & antiviral drug is not required
- Chikenpox in adults is more severe,
required antiviral therapy

- In herpes zoster (shingles)

systemic antiviral treatment can
reduce severity, duration of pain &
reduce complications

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 1. Acyclovir (Zovirax)
• Is a prototypic antiherpetic agent
• The most common use of acyclovir is in
therapy for genital herpes infections
• Herpes simplex virus type 1 & 2 (HSV-1
& HSV-2), varecilla-zoster virus (VZV),
mediated infections are sensitive to
acyclovir
• Drug of choice in HSV encephalitis
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 1. Acyclovir

• Route of administrations:
I.V, orally or topical route

• Adverse effects:
- Topical: Local irritation
- Oral: headache, diarrhea,
nausea, vomiting
- I.V: renal dysfunction

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 AIDS
• Aquired immunodeficiency syndrome
• Is disease of human immune system
caused by HIV (Human immunodeficiency
virus)
• 33.2 million live with AIDS worldwide

28
29
 Treatment of AIDS
• A highly active regimen that uses combinations
of drugs to suppress replication of HIV & to
restore immunocompetency of host

30
 Treatment of AIDS
• Highly Active AntiRetroviral Therapy
(HAART)
1. Nucleoside & nucleotide reverse
transcriptase inhibitors (NRTIs)
2. Non-Nucleoside reverse transcriptase
inhibitors (NNRTIs)
3. Protease inhibitors (PIs)

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 Treatment of AIDS

• There is no cure for infection caused by

HIV
• A number of drugs slow disease
progression & increase life expectancy

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 Treatment of AIDS

• Current recommendation for primary

therapy two NRTIs with either a PI or a
NNRTI

33
 Nucleoside & nucleotide reverse
transcriptase inhibitors (NRTIs)

1. Zidovudine (AZT)
2. Didanosine
3. Abacavir

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 Non-Nucleoside reverse
transcriptase inhibitors (NNRTIs)

• Nevirapine

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 Protease inhibitors (PIs)
• Saquinivir
• Ritonavir
• Indinavir

36
 Protease inhibitors (PIs)

• Adverse effects:
- Lipodystrophy syndrome:
metabolic effects include fat
redistribution, insulin resistance &
dyslipidemia
- Fat redistribution after chronic use
including loss of fat from extremities &
its accumulation in abdomen & base of
neck (buffalo hump)

Buffalo hump
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