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Pharmacology
Introduction
PHARMACOLOGY
Greek Word
Pharmacon
Drug
Logos
Science
• Pharmacology: the science that deals with
drugs.
• Drug: a substance that is used for prevention,
treatment & diagnosis.
Names
Drugs
Drug of
Names
Chemical name
• The drug’s chemical composition and molecular
structure… is the name by which the chemist
knows it.
Generic name (nonproprietary name, Official)
• Name given by international organization of drug
nomenclature & independent of the manufacture.
Trade name (proprietary name, brand name)
• The drug has a registered trademark; use
of the name restricted by the drug’s owner
(usually the manufacturer)
• Pharmacologic Principles: Drug Names
• Chemical Name : N-(4-Hydroxyphenyl)acetamide
• Generic Name: Acetaminophen.
Paracetamol.
• Trade Name: Panadol®
Revanin®
Pandarin®
Source of drugs
1. Plants: such as digitalis, vincristine.
2. Animals: insulin
1. Minerals: as iron, iodine and zinc
3. Microorganism: antibiotics
4. Synthetic and chemical substance: as sodium
bicarbonate.
5. Drugs produced by genetic engineering :
Human insulin, human growth hormone
Drug classification
•
•
•
•
Drugs may be classified by:
Their effect on particular Body system.
Their Therapeutic uses.
Their chemical structure.
• E.g: morphine can be classified as central
nervous system depressant, a narcotic or
opioid analgesic, & as an opiate( derived from
opium)
• Prescription & non prescription drugs
American consumers have 2 routes of access to
therapeutic drugs:
1.Over the counter (OTC) purchase of drugs that
do not require a prescription.
2. By prescription or order from a licensed
health care provider.
•
Using prescription drugs for non therapeutic
purposes by persons who are not authorized
to have the drugs or whom they are not
prescribed , is illegal.
Pharmacokinetic Processes
The study of what the body does to the drug:
“ADME” is key
Absorption
Distribution
Metabolism
Excretion
• What is the effect of the body on the drug?
Pharmacologic Principles
Pharmacodynamics
• The study of what the drug does to the body:
– The mechanism of drug actions in living tissues
Dosage
Plasma Site of
Concen. Action
Pharmacokinetics
Effects
Pharmacodynamics
• Routes of administration
• Selection of the best route of drug
administration depends on:
• Patient condition
• Drug property
Definition:
A route of administration is the path by which a
drug, fluid, poison or other substance is
brought into contact with the body.
CLASSIFICATION
Enteral
Oral
Sublingual
Rectal
Parenteral
Injections
Intravenous
Intramuscular
Subcutaneous
Intra-arterial
Intra-articular
Intrathecal
Intradermal
Others
LOCAL
•Skin topical
•Intranasal
•Ocular drops
•Mucosal-throat,
vagina, mouth,
ear
Inhalational
Transdermal
Enteral Routes
• Enteral - drug placed directly in the GI tract:
– sublingual - placed under the tongue
– oral - swallowing (p.o.)
– rectum - Absorption through the rectum
Oral Route
• Advantages: Convenient- portable
no pain
easy to take
Cheap – no sterilization
no expert.
Oral Routes
• Disadvantages: Variable bioavailability
Food can affect absorption
Local effect: taste,irritation
Unsuitable for Unconscious pts.
First pass effect
First pass effect
• Drugs absorbed orally are transported to liver
by Portal circulation before reach systemic
circulation, thus are extensively metabolized in
the Liver, this is known as first pass effect.
Swallowed
Drug
Digestive
system
Hepatic
portal
system
Liver
Rest of the
body
Dosage forms
Capsules, powders
Tablets
Syrup,
Suspension, elixirs
Tablets
Hard- gelatin capsule
Syrup
Soft- gelatin capsule
Sublingual Medication
Administration
Place the pill between the underside of the tongue
and the floor of the oral cavity.
Sublingual
• Advantages: No first pass effect
Rapid absorption and effect
• Disadvantages: Inconvenient
Small doses only.
Bitter tasting
can not give to unconscious patient.
Buccal/Sublingual route (Cont.)
Applicable dosage forms:
Tablets
Chewable tablets
3. Rectal
Drugs are administered rectally for their local or for
systemic effect
Advantages:
• Reduced first pass hepatic effect
• Useful if the drug induces vomiting when given
orally or if the patient is already vomiting
Disadvantages:
• Absorption is often incomplete
• Chance for local irritation
• Loss of dosage form by defecation
•
•
•
•
Applicable dosage forms:
Suppositories
Ointments
Solutions, usually employed as enemas
Prepackaged enema container
•
•
•
•
B. Parentral Route
A drug administered parentrally is one
injected via a hollow needle into the body at
various sites and to varying depth.
Parentral administration is used for drugs
that are:
Poorly absorbed from GIT
Unstable in the GIT
Parenteral Routes
– Intravascular (IV, IA)- placing a drug directly
into the blood stream
– Intramuscular (IM) - drug injected into skeletal
muscle
– Subcutaneous - Absorption of drugs from the
subcutaneous tissues.
Parenteral route
1. Intravenous (I.V.)
I.V. injection is the most common parentral route
Drugs may be given into peripheral vein over 1-2 min or
longer by infusion
Advantages:
• With I.V. administration the drug avoids the GIT, so
bypass the Liver
• Large volume can be given
• Used to treat acute cases as epileptic seizures,
cardiac arrhythmias
Disadvantages:
• Unlike drugs present in GIT, those that are injected
cannot be recalled by strategies such as emesis.
• Chance of infection
• More expensive.
• Require trained personnel for their proper
administration
Parenteral route (Cont)
B-Intramuscular : (into the skeletal muscle).
suitable for injection of drug in aqueous solution (rapid
action) and drug in suspension (sustained release).
Large volume can be given 1-5 ml
Should be given at an angle of 90˚
Disadvantages:
• Trained personnel required for injection
• Painful
• Absorption is sometimes erratic
3.Subcutaneous (S.C.)
• This involves administration of a dose into the fatty
layer just under the skin
• The needle is inserted at an angle of 45 ْ
Advantages:
• Can be given by the patient.
Disadvantages:
• Can be painful
• Irritant drugs can cause local tissue damage
• Intrathecal/intraventricular: It is sometimes
necessary to introduce drugs directly into the
cerebrospinal fluid. For example, amphotericin B
is used in treating cryptococcal meningitis
Intradermal
• Intradermal injections are delivered into
the dermis, or the skin layer underneath the
epidermis at angle 10-15˚. Mainly used for
testing sensitivity to drugs.
the position of needle for I.M, S.C, Intradermal injection
Ampules and Vials
Vials
Ampules
Others- Topical route:
Topical: Drugs are applied topically to the skin or
mucous membranes, mainly for local action.
I Skin
cream, ointment (local action)
Lotion, paste,gel
II Mucosal membranes
• eye drops (onto the conjunctiva)
• ear drops
• intranasal route (into the nose)
Others- Transdermal
Transdermal - absorption of drug through
skin (systemic action)
 stable blood levels
 no first pass metabolism.
Inhalation route:
- Used for gaseous and volatile agents and aerosols.
• Delivery of drugs across the large surface area of
mucous membranes of respiratory tract.
• Local effect – Bronchodilator
• Systemic effect – General anesthesia
• Advantages: - Rapid
- No first pass effect
• Disadvantages: - Irritation
- Some particles may be
precipitated in mouth or throat
Nebulizer
Inhaler
DRUG DOSAGE FORMS
Tablets
Capsule
Aerosol
Injection
Suspension
Infusion
Cream
Solution
Absorption
• The passage of drug from site of administration
(from out side) to the blood stream.
• To do so the drug has to pass through cell
membranes.
• Cell membranes are of lipid bilayer and pores.
• Most drugs are absorbed by “Passive diffusion”
or simple diffusion.
III. ABSORPTION OF DRUGS
• A. Transport of Drug
from the GIT
1. PASSIVE DIFFUSION
- The driving force for
passive absorption of
a drug is the
concentration
gradient
- Does not involve a
carrier
- Vast majority of drugs
gain access to the body
by this mechanism
Mechanisms of Passage Across Membranes
ACTIVE TRANSPORT
♦ requires carrier
♦ energy consuming
♦ against a concentration
gradient
♦ saturability
♦ selectivity
• Factors influencing absorption:
1. Effect of pH on Drug Absorption
• Most drugs are either weak acids or weak bases
which disassociate in the body fluid
• Diffusion of the non-ionized form of a weak acid
through a lipid membrane. B. Diffusion of the
nonionized form of a weak base through a lipid
membrane
.
Environmental pH and Ionization
If we put an acidic drug in an environment with a lot of H+ (low pH)
what will this equilibrium do?
HA
HA
HA
H+ + A-
Equilibrium
System
H+ fromatacid
environment
Non-ionized
form
predominates!
Acidic drugs are best absorbed from
acidic environments
Basic drugs are best absorbed from
basic environments
Factors influencing absorption:
2. Blood flow
3. Contact time at absorption site
4. Total surface area available for absorption
Bioavailability
Definition: the fraction of the administered
dose reaching the systemic circulation
unchanged
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
Factors that influence bioavailability:
• First-pass hepatic metabolism
• Solubility of the drug
• Chemical instability
• Drug Distribution
refers to the movement of a drug from the blood
to various tissues of the body and depend on:
1.Blood flow.
2. Capillary permeability
2. Capillary permeability
Membranes
• Special barriers to distribution
• Blood/Brain Barrier: This barrier provides a
protective environment for the brain. Speed of
transport across this barrier is limited by the lipid
solubility of the drug and its molecular weight…
• Placental Barrier: This barrier separates two
distinct human beings but is very permeable to
small molecular weight drugs.
Blood-Brain Barrier
The blood brain barrier consists of cell
tightly packed around the capillaries of
the CNS. What characteristics must a
drug possess to easily cross this
barrier?
Non-protein bound, non-ionized, and highly lipid soluble
Why?
3. Binding of drugs to proteins
•
D + plasma protein
[D-plasma protein] complex
Reversible binding to plasma proteins sequesters drugs
in a non-diffusible form & slows their transfer out
the vascular compartment
Plasma albumin is the major drug-binding protein & act
as a drug reservoir
LOCUS OF ACTION
“RECEPTORS”
Bound
Free
ABSORPTION
TISSUE
RESERVOIRS
Free
Bound
Free Drug
Bound Drug
SYSTEMIC
CIRCULATION
BIOTRANSFORMATION
EXCRETION
Volume of Distribution(Vd)
♦ It is the volume that would be
required to contain all the drug in
the body at the same concentration
as in the plasma
♦ drugs with large volume of distribution
will have a longer half-life and duration of
action
Elimination
of drugs from the body
M
A
J
O
R
KIDNEY
LIVER
filtration
secretion
metabolism
secretion
M
I
N
O
R
LUNGS
OTHERS
exhalation
mother's milk
sweat, saliva etc.
(reabsorption)
VII. DRUG METABOLISM
 Drugs are often
eliminated by
biotransformation and
or excretion into the
URINE OR BILE.
 LIVER – the MAJOR
SITE FOR DRUG
METABOLISM
• Renal elimination
of a drug
• Effect of drug
metabolism
On reabsorption in the
distal tubule.
Reactions of Drug Metabolism
 The kidney cannot
efficiently eliminate
lipophilic drugs ,
therefore lipid soluble
agents must 1st be
metabolized in the liver
using 2 general sets of
reactions
PHASE I
PHASE II
Phase I
• uses the P 450 system
Located within the
endoplasmic reticulum
of hepatocytes.
• Its function is to convert
lipophilic molecules into
more polar (H2Osoluble) molecules by
introducing a polar
• Phase I metabolism may
group as –OH2 –NH2
increase, decrease, or
• Hydrolysis
leave unaltered the
drug’s pharmacologic
• Oxidation
activity.
• Reduction
Phase II
• Consists of conjugation
reactions
• Uses substrates like
glucuronic acid, or an
amino acid
• Renders the
metabolites INACTIVE
and more water soluble
• The highly polar drug
conjugates may then be
excreted by the kidney
or bile
• Factors Affecting Drug Metabolism
• P450 activity is genetically determined:
– Some persons lack such activity  leads to higher drug
plasma levels (adverse actions)
– Some persons have high levels  leads to lower plasma
levels (and reduced drug action)
• Other drugs can interact with the P450 systems
– Either induce activity. e.g : rifampicin
– Inactivate an enzyme system. e.g: cimetidine
• Age, neonates and very old.
• Pathological factors – Liver diseases.
Question
• The addition of glucuronic acid to a drug:
A. Decreases its water solubility.
B. Usually leads to inactivation of the drug.
C. Is an example of a Phase I reaction.
D. Occurs at the same rate in adults and
newborns.
E. Involves cytochrome P450.
Elimination by the Kidney
• Excretion - major
1) glomerular filtration
2) tubular reabsorption/secretion
• Proximal tubular secretion
• Distal tubular reabsorption
Clearance
♦ the measure of the ability of the body to
eliminate the drug
♦ the sum of hepatic metabolism and renal
excretion
• The speed of elimination is the main factor in
deciding the duration of action of the drug & is
referred plasma half-life (t½) of the drug
T½: The time required to change the plasma
concentration of the drug by one half
Half- life (T½)
♦ often used to determine frequency of
administration
♦ determines the time to attain steady-state
concentration
• Factors influencing the dosage regime
• The blood level & therapeutic effectiveness
depend on the dose, distribution within the
body & speed of elimination.
• Rapidly excreted drugs with short t½ will
require frequent administration to maintain a
fairly constant concentration in the body
where as those that are eliminated slowly can
be given once or twice
• With repeated dosing, concentration in plasma
climbs until more or less steady state (SS) is
obtained.
• Steady-state occurs after a drug has been
given for approximately five elimination halflives.
Steady State
♦ the point where rate of drug availability
equals rate of elimination
♦ constant drug concentration
♦ point where expect maximum drug effect
♦ usually attained after 4-5 half lives
• To hasten achievement of SS & full therapeutic
effect with more slowly excreted drugs, a large
loading dose is given followed by smaller
maintenance doses
Single dose –
Loading dose
7
Plasma Concentration
6
Therapeutic
level
5
4
3
Repeated doses –
Maintenance dose
2
1
0
0
1.9 3.9 5.9 7.9 9.9 11.9 13.9 15.9 17.9 19.9 21.9 23.9
Time
Dose Response Relationships
• Loading dose
– Bolus of drug given initially to rapidly reach
therapeutic levels
• Maintenance dose
– Lower dose of drug given continuously or at
regular intervals to maintain therapeutic levels
• Pharmacodynamics
• The action of the drug on the body
• The drug interacts with a receptor:
• D+R
D – R complex  effect
• This reaction is reversible & in order to occur,
an affinity between the drug & receptor
Non-receptor Mechanisms
• Actions on Enzymes
– Drugs altering enzyme activity alter processes
catalyzed by the enzymes
– Examples
• Cholinesterase inhibitors
• Monoamine oxidase inhibitors
Non-receptor Mechanisms
• Changing Physical Properties
– E.g:Mannitol
– Changes osmotic balance across membranes
– Causes urine production (osmotic diuresis)
Non-receptor Mechanisms
• Changing Cell Membrane Permeability
– Lidocaine
• Blocks sodium channels
– Verapamil, nefedipine
• Block calcium channels
Non-receptor Mechanisms
• Combining With Other Chemicals
– Antacids
– Chelation of heavy metals.
• Replacement therapy as hormones&
vitamins
Non-receptor Mechanisms
• Anti-metabolites
– Enter biochemical reactions in place of normal
substrate “competitors”
– Result in biologically inactive product
– Examples
• Some anti-neoplastics
• Some anti-infectives
• Types of drugs:
• Agonist: a drug that interact with a receptor
followed by effect
• Antagonist: a drug that interact with a
receptor but with no effect
• Partial Agonist: a drug that bind to a receptor
followed by weak effect
PARTIAL AGONISTS - EFFICACY
Even though drugs may occupy the same # of receptors, the magnitude of
their effects may differ.
% Maximal Effect
1.0
0.8
0.6
0.4
0.2
0.0
0.01
0.10
1.00
[D]
10.00
(concentration units)
100.00
1000.00
Receptor Interactions
Lock and key mechanism
Agonist
Receptor
Agonist-Receptor
Interaction
Receptor Interactions
Competitive
Inhibition
Antagonist
Receptor
DENIED!
Antagonist-Receptor
Complex
Receptor Interactions
Non-competitive
Inhibition
Agonist
Antagonist
Receptor
DENIED!
‘Inhibited’-Receptor
• Dose – Response curve
Graded -dose response:
• Drugs A & B have the similar efficacy but they differ
in potency
• Efficacy: The maximal response produced by the
drug
• Potency: How much of the drug required to produce
a response
• More potent drug is capable to produce the desired
effect with smaller dose
• In the case of drug C it has lower efficacy than A & B
& lower potency
• Therapeutic Index
The ratio of the dose that produce toxicity to that
produce clinical response
Therapeutic index TD50/ED50
• TD50: The dose that cause toxicity in 50% of
individuals
• ED50: The dose that produce an effect in 50% of
individuals
The ratio must be large in order to be a safe drug