Professional Documents
Culture Documents
DRUG SOURCES
DRUG CLASSIFICATION
DRUG NAMES
2
DEFINITION AND DIVISIONS
PHARMACOLOGY : It is the science that deals with
interaction of drugs with living systems.
Divisions of Pharmacology:
1. Pharmacodynamics :
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 :
4
OTHER TOPICS LINKED WITH PHARMACOLOGY
1. Pharmacotherapeutics: It is concerned with the proper
use of drugs in treatment of disease in man
6
DRUG SOURCES
These may be either :-
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
2. Non-Organic sources :
- metals : Platinum, Zinc
- non-metals : Sodium chloride , magnesium sulfate
9
Rational drug design:
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
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.
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
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:
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
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.
11
2. Transmembrane G protein–coupled receptors:
12
13
Examples:
Receptors for insulin,
Receptors for growth factors like EGF or PDGF,
Receptors for immune cytokines 14
15
4. Intracellular receptors:
16
17
THANKS
18
PHARMACODYNAMICS II
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.
1. Potency
4
2. Efficacy
1. POTENCY:
A measure of the amount of drug
necessary to produce an effect of a
given magnitude.
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
8
➢ the relationship between the percentage of bound receptors and the
drug concentration:
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 :
Examples:
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 :
1. Irreversible antagonist :
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.
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
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 .
23
PHARMACODYNAMICS III
Example:
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.
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.
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.
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
14
III. Special toxicity including
1. Genotoxicity leading to Mutagenicity :
Alkylating agents
2. Teratogenicity :
Congenital disorder : drugs taken in pregnancy
15
IV . Others
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)
3 3
Pathways of drug movement: (ADME)
Absorption
Distribution
Metabolism,
Elimination
4
Clinicians must recognize that:
Speed of onset of drug action
5
Knowledge of these four processes
(ADME) influences clinician’s decision of:
Route of administration for drug
6
Pathways of PK
Absorption:
- Is transfer of a drug from its site of
administration to bloodstream
Distribution:
7 7
Metabolism:
- By liver, kidney, or other tissue
Elimination:
8
Absorption
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
13 13
1. Passive diffusion:
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:
17 17
3. Endocytosis & exocytosis
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:
22 22
Bioavailability
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
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 given IV
33
Bioequivalence:
34 34
Pharmacokinetics (II)
Dr Mohammed Alsbou
Professor of Clinical Pharmacology
Department of Pharmacology
Faculty of Medicine, Mutah University
1 1
Drug Distribution
2 2
Drug distribution depends on:
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
Phase II
16 16
Phase I
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)
20 20
CYP 450 inducers
21 21
CYP 450 inhibitors
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
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
4
2. Proximal tubular secretion
(active secretion):
5
3. Distal tubular reabsorption
(passive reabsorption):
6
Drug elimination by kidney
7
Effect of drug metabolism on reabsorption
in distal tubule
9
Manipulating pH of urine
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
12
Examples
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:
19
Half-life of a drug may decrease by:
20
KINETICS OF CONTINUOUS
ADMINISTRATION
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:
23
Rate of drug elimination from body = (CLt)(C)
CLt = total body clearance
24
2. Influence of rate of drug
infusion on steady state:
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:
30
a. Exponential approach to
steady state:
32
b. Rate of drug decline when
infusion is stopped:
33
c. Loading dose:
34
B. Kinetics of fixed-dose/fixed-
time-interval regimens
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
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
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
SYSTEMIC
Bound Drug CIRCULATION
BIOTRANSFORMATION
Bioavailability
to
Dose systemic
circulation
PRINCIPLE
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
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
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
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
t1/2 = 0.693/Kel
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
Therefore,
Kel x Amount = CL x Concentration
Kel = CL/Vd
0.693/t1/2 = CL/Vd
t1/2 is proportional to Vd
t1/2 is inversely proportional to CL
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
dC = CL x C x dt
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
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
4
IRRATIONAL USE OF DRUGS
Include:
Poly-pharmacy (use of too many drugs)
Over-use of injections
5
SELECTION OF DRUGS
Choice of effective drugs should be based on:
1.Efficacy
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?
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
10
Medication errors may stem from:
1. poor communication,
2. misinterpreted 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.
depends on their delivery to the liver, i.e. on hepatic blood flow, have
(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
(5) Stage of placental & fetal development at time of exposure to the drug
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
1
‘First of all be sure you
do no harm’
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?
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
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
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
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
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)
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:
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
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)
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
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
29
Thiopurine S-methyltransferase (TPMT)
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
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
b. Discuss the pharmacokinetic and pharmacodynamics differences in pediatric, geriatric and adult age
groups.
e. Discuss important adverse drug reactions occurring in geriatric & pediatric age groups.
What is different from normal adult prescribing?
o Infant skin is thin and percutaneous absorption can cause systemic toxicity
Distribution:
Excretion:
Most drugs approved for use in children have recommended pediatric doses,
generally stated as milligrams per kilogram.
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).
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
Distribution: Elderly have reduced lean body mass, reduced body water.
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
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
Convulsions: Cocaine
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:
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
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
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
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
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
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
Oncogenesis (malignancy)
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)
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
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)
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:
34
Recommendations are essential as a
guide to doctors in clinical research:
35
DevelopAKUre
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
39