2. Definition
Pharmacodynamics
It is what the drug does to the body. It deals with
pharmacological actions of drugs
(therapeutic and toxic) and the mechanisms by
which these actions are performed.
3. Modes of Drug Action
• Modes of drug action:
• A- By acting on receptors:
• -In the most, drugs interact with macromolecules, most commonly
located in cell membrane and are called receptors.
• -Receptors are mainly protein in nature.
• Composition of protein (amino acids)
• makes the receptors flexible (less rigid) and allowing conformational
changes (by folding) to take place easily whenever required; also
structureof proteins is rich in functional groups (electrochemical
charges).
4. Key and Lock model
• Receptors act as regulatory molecules in the pathway of
tissue responsiveness to drugs.
• -
• Drugs were described to interact with these receptors in
a manner similar to the
• interaction between a lock and its key, but proteins make
receptors a flexible structure compared with the lock
which is a rigid (metal).
• -Interaction between the drug and the receptor is usually
reversible
5. Affinity
• Affinity is ability of the drug to bind its receptor. It is
required for the binding between the drug and its
receptor to take place i.e. the drug shape and size
should be
• complementary to the receptor to fit in; and also the drug
should have the appropriate
• functional groups which allow it to be attracted to the
receptor.
6. Key and lock model
RESPONSE
Response
Response
Receptor
Agonist
8. Types of bonds
• Types of bonds involved in drug-receptor interaction:
• Most drugs bind with receptors by precise
physicochemical and steric interactions
• which create some sort of bonding (chemical forces)
such as:
• A )Covalent bonds: This type of bond is strong, usually
irreversible under biological conditions, occurs rarely and
prolongs drug action.
R
9. Types of bonds
• b) Electrostatic bonds:
• This type of bond is more common and can be:
• -Strong (but weaker than covalent bond). Occurs
between permanently charged
• ionic molecules.
• -Weak e.g. hydrogen bonds.
• -Very weak e.g. vander Waals forces (type of dipole
interaction)
R
R
R
10. Types of bonds
c) Hydrophobic bonds:
- This type of bond is weak.
- It takes place between highly lipid soluble drugs and
lipids of the cell membrane.
11. • Selectivity:
• -Binding between the receptor and its ligand
(the binding drug) is characterized by
• selectivity.
• -In order to have a good "fit" to only one type
of receptor (specific), drug molecule
• has to be unique in shape and size (MWt >
100
spuorg lanoitcnuf gnivah dna ,)
• ehto ot gnidnib sti eziminim ot ,)segrahc(
12. Selectivity
• Selectivity:
• -Binding between the receptor and its ligand (the
binding drug) is characterized by
• selectivity.
• -In order to have a good "fit" to only one type of receptor
(specific), drug molecule
• has to be unique in shape and size (MWt > 100
dna ,)
spuorg lanoitcnuf gnivah
• .srotpecer rehto ot gnidnib sti eziminim ot ,)segrahc(
ni erar si yticificepS
• pharmacology but selectivity can exist.
13. Structure activity relationship
• Structure-activity relationship:
• -Drug molecular size, shape, functional groups
(electrochemical charges) determine its binding to the
receptor.
• -Minor changes in structure of the drug may have a profound
effect on its pharmacokinetics and pharmacological actions
(therapeutic and toxic).
• -By making changes in drug molecule, it is possible to
develop a congener with better therapeutic effect, less toxic
effect, better pharmacokinetic profile or more selectivity.
14. Stereisomerism chirality
• Stereoisomerism (chirality):
• Many of the clinically used drugs are chiral molecules
(exist as enantiomeric pairs( Mirror images isomers)) which
have different pharmacological activities and
physicochemical properties . Amphetamine different
effect depend on ratio of enantiomer
• Although, only one isomer of the drug can interact with
the targeted receptor, while the other(s) may be
responsible for the adverse effects, most of drugs are
still used as racemic mixture 50:50 enantiomers( mixture
of the beneficial and the harmful isomers.) Salbutamol
15. • Classification of receptors:
• 1
- On the bases of actions of their agonists and antagonists:
• -Muscarinic receptors:Antagonized by atropine and further
subtyped to M1 ,M 2
M ,
3
M ,
4 and M5 receptors.
• -
• Nicotinic receptors: Further subtyped to:
• N
1
yb dezinogatna si hcihw rotpecer )nN( trimethaphan.
• N
2
yb dezinogatna si hcihw rotpecer )mN( D-tubocurarine
16. Classification of receptors:
1- On the bases of actions of their agonists and
antagonists:
a) ACh-receptors:
- Muscarinic receptors: Antagonized by atropine and
further subtyped to M1,M2, M3, M4 and M5 receptors.
-
Nicotinic receptors: Further subtyped to:
N1 (Nn) receptor which is antagonized by trimethaphan.
N2 (Nm) receptor which is antagonized by tubocurarine
17. Receptors
b) Adrenergic receptors:-receptor: It is sutyped to:
1 Alpha receptor (subtyped to 1A , 1B receptors.)
2. Alpha receptor.
-B-receptor: It is sutyped to 1
2
3
receptors.
c) Histamine receptors: They are subtyped to H 1
,
H
2
H ,
3
H ,
4 receptors.
d) Others ……
..
18. • 2
- On bases of their function:
• Receptors can act as regulatory proteins e.g:.
• -Receptors for endogenous neurotransmitters,
autacoids, hormones and most of the therapeutically
used drugs.
• -Ion-channels.
• -Enzymes.
• -Transport proteins e.g. Na+ +K -ATPase
• -Structural proteins e.g. tubulin.
19. Receptor Ligand and Effector
• Receptors are
formed of:
• - Ligand (drug)
binding domain.
• - Effector domain.
Agonist
Response
Can be
G-protein
Agonist gated
channels
Enzymes
20. • 3.According to effector coupling/ signling mechanisms
• a) G-proteins coupled receptors:
• G-proteins (guanine nucleotide (GDP, GTP) binding regulatory
proteins) act as intermediates between the receptor and one of the
following:
• -Adenyl cyclase enzyme: In this case G-protein can be:
• sG
:
• -It acts as an intermediate between receptors, such as -
• adrenoceptors, D 1
-
H dna srotpecer
2
-
esalcyc lyneda dna ,srotpecer
.
• -It increases formation of cAMP from ATP.
• iG
:
• -It acts as an intermediate between receptors, such as, M 2
-
D dna srotpecer
2
-
esalcyc lyneda dna ,srotpecer
.
• -It reduces cAMP.
21. G protein coupled receptors
Agonist
B-receptors
D1 receptors
H2 receptors
ATP
cAMP
ATP
cAMP
Alpha receptor
M2 receptor
D2 receptor
Agonist
22. • Phospholipase C (PLC): In this case G-protein is
Gq which:
• Acts as an intermediate between receptors, such
as 1-receptors and M1-receptors, and PLC (in
cell membrane).
• It increases formation of IP3 (diffuses to
cytoplasm) and DAG from PIP2.
23. • - G-protein is heterotrimeric composed of 3 units
)α, β, γ(.
• - G-proteins (G) use a molecular mechanism
that involves binding to and separation
• from GDP and GTP, to amplify the transduced
biological signal. GDP and GTP
• bind α-subunit of the G-protein.
• - G-protein is inactive when it is bound to GDP
(G-GDP form) and it is active when
• it is bound to GTP (G-GTP form).
25. b) Receptors incorporate agonist-gated
ion channel in the same molecule:
-Receptor stimulation causes opening of the
channel e.g:.
gninepo sesuac rotpecer cinitocin fo noitalumitS
aN fo
+ channel with Na+influx.
27. • Binding of2 molecules of ACh WORKS ON ALPHAsubunits to sites
on -subunits conformational changes in the
receptor opening of Na+-channel (Na
influx) yrev decudorp si esnopseR.noitaziraloped
m ni( ylkciuqilliseconds.
•
• Another example is stimulation of GABA A-receptor
causes opening of
• chloride-channel lC fo xulfni htiw
-
noruen eht otni
hyperpolarization stabilization of the neuronal activity.
•
• Stimulation of 5HT 3
- receptors causes opening of
Na+-K+ channels.
28. c. Receptors in which enzymes are incorporated
• Insulin ,
• Epidermal growth factor (EGF),
• Platelet-derived growth factor(PDGF),
• Transforming growth factor- (TGF- ) and many other trophic
hormones act on receptors which are polypeptides consisting of an
• extracellular (hormone- or drug-binding domain) and a cytoplasmic
enzyme which can be a protein tyrosine-kinase (phosphorylates
certain proteins containing tyrosine residues). Glucose transporter
goes out to bring in glucose .
• - In case of atrial natriuretic peptides (ANP), the cytoplasmic enzyme
domain is guanylyl cyclase. Activation of ANP-receptor increases
production of cGMP from GTP.
29. Agonist eg insulin or
EGF
Active tyrosine Kinase
Extracellular
domain
Hydrophobic
Non covalent
binding
p
p
Incorporated
30. d. Cytokine receptors
• They closely resemble tyrosine kinase-linked
receptors, but in this case tyrosine kinase is
separate from the receptor and binds to it non
covalently.
• - They can be stimulated by heterogeneous
group of peptides e.g. GH, erythropoietin and
interferons.
32. e. Intracellular receptors
• -Some lipid soluble drugs can pass through cell
membrane and act on intracellular receptors
• e.g. corticosteroids, sex hormones, vit. D, thyroid
hormones (T3 4
& T
• -
• In the absence of the agonist, the receptor is
bound to hsp 90
)nietorp kcohs taeh(
• ,i.e. prevents the formation of the functionally
active transformations (
33. Intracellular receptors
• This causes translocation of the drug-receptor complex
• into the nucleus to bind specific DNA sequences (DNA
response elements) near the gene whose expression is
to be regulated, leading to synthesis of certain proteins
which are required for certain effects.
• - The response is produced after a lag period of about 30
minutes to several hours (delayed), because of the time
needed for new protein synthesis.
35. • Corticosteroids usually cause positive gene
expression (protein synthesis) e.g.
• synthesis of lipocortin which inhibits PLA2, but
incase of cyclooxygenase 2 (an
• enzyme which is important for production of PG
E2 in site of inflammation),
• corticosteroids cause negative gene expression
i.e. they reduce synthesis of COX-2
• and hence they reduce inflammation.
36. B- Blockade of ion channels:
Beside agonist-gated ion channels, drugs may act by
blocking ion channels to prevent passage of ions e.g.:
• Blockade of the voltage-gated Na+-channel by local
anaesthetics. eg Lidocaine
• Blockade of Ca2+-channel by calcium-channel
antagonists. Adalat, Nifedipine hypertension
C- Opening of ion channels:
e.g. minoxidil Antihypertensive opens K+-channels of
blood vessels mooth muscle, causing their relaxation.
39. E.Inhibition of active transport
• Tricyclic antidepressants Inhibits reuptake of NA
• Cocaine
• Hemicholinium inhibits choline uptake to cholinergic
neuronal terminal
• Digoxin heart failure increase Na inhibits Na K ATPase
• Omeprozole inhibits H K ATPase proton pump
irreversible
• Verapamil inhibits P-glycoprotein protein
40. • F- Other modes of drug action:
• Chemical neutralization:
• - Antacids + gastric acid in the stomach.
• - Protamine sulphate (positively charged)
+ heparin (negatively charged) in the
blood.
41. Chelation:
• Chelation:
• -EDTA (edetate calcium disodium ethylene diamine
tetraacetic acid) binds Ca 2
cniz ,dael ,+
.
• -BAL (British anti-Lewisite, also called dimercaprol)
binds lead. Penicillamine binds copper (accumulation of
copper in the body gives
• Wilson's disease with formation of Kiser-Flicher ring in
the cornea, it can be
• due to deficiency of copper transporter protein,
ceruloplasmin.)
• -Deferoxamine binds iron.
• -Cyclophosphamide binds DNA
42. • Adsorption:
• -Pectin and kaolin + water.
• -Activated charcoal + some drugs.
• lotinnam yb .g.e ytiralomso eniru dna doolb gnignahC
.
• eniru dna doolb fo Hp gnignahC
.
• e.g. sodium bicarbonate makes them alkaline,
• but Vit. C and ammonium chloride make them acidic.
• Incorporation in nucleic acids e.g. anticancer and
antiviral drugs.
•
• Binding tubulin e.g. colchicine.
43. • Formation of channels in cell wall e.g. nystatin
and amphotericin B.
• Monoclonal antibodies (biologics): e.g.
rituximab, abciximab (mabs).
•
• Oligonucleotides:
• These intracellular targets may provide the next
major advances in therapeutics .
44. Intracellular second messengers
They are intracellular regulatory molecules which have an
important role in transduction of the messages produced
by stimulation of receptors in order to give a
response (action )
.
They include: cAMP (cyclic 3
,'
5
enisoneda '
)etahpsohponom
:cAMP is synthesized from ATP as follows: Adenylyl
cyclase (AC) in cell membrane ATP cAMP
45. • Adenylyl cyclase (AC) can be stimulated:
• Directly: by e.g. cholera toxin, Bordetella
pertussis toxin whooping cough,
forskolin,fluoride. increased CAMP
•
• Indirectly: by formation of G-proteins
(Gs).
• - Adenylyl cyclase can be inhibited by Gi.
47. • Examples of receptors when stimulated form Gs
which stimulates adenyl cyclase to
• increase cAMP:
• 1, 2, 3-receptors.
• Dopamine D1-receptor (fenoldopam is an
agonist).
• Histamine H2-receptor.
• Glucagon receptor.
• Prostaglandins E- and I-receptors.
• ACTH, TSH, FSH.
48. • Examples of receptors when stimulated form Gi
which inhibits adenyl cyclase and
• reduces cAMP:
• 2-receptors (clonidine and alfa-
methyldopa are agonists).
• Dopamine D2-receptors (bromocriptine
is an agonist).
• M2-receptors (in the heart).
49. 2- Phosphoinositides (IP3 and DAG):
• - They are products of the hydrolysis of the
phosphatidyl inositol 4, 5-biphosphate
• (PIP2), a membrane phospholipid.
• - The hydrolysis is catalyzed by phospholipase C
which is stimulated by the formation of Gq
protein to produce inositol triphosphate (IP3) and
diacylglycerol (DAG) in cell membrane. IP3
diffuses to cytoplasm.
50.
51. • 3- Intracellular Ca2+:
• Elevation of intracellular Ca2+ can be obtained
by:
• a) Ca2+ influx through Ca2+-channels in cell
membrane which include:
• Voltage-sensitive Ca2+-channels which are
opened by depolarization.
52. • 4- cGMP (3',5' cyclic guanosine monophosphate):
• Guanylyl cyclase (GC)
• GTP cGMP
• Guanylyl cyclase (GC)
• GTP cGMP
• GC can be activated by:
• a) Nitric oxide (NO) (previously known as EDRF).
• - It is a gas of small molecule which can diffuse through
cell membrane.
• - Nitrates and sodium nitroprusside (both act through NO).
• - NO release can also be mediated by receptor stimulation
e.g. M3- and H1- Rs.
53.
54. Types of drug responses
• Types of drug responses
• - It is a measurable (quantitative) response e.g. muscle
contraction, BP and blood sugar.
• - Drug-receptor interaction, in this type of response,
follows the simple mass-action relationships (describes
the association between 2 molecules of a given affinity,
• D+R ↔ DR → response.
• Dose-response curve:
• - It is used to quantify agonist-receptor interaction.
55. TYPES OF DRUG RESPONSE
Maximal response
Hyperbolic
curve
ED50
Maximal Response
56. • The response to low doses of an agonist increases in
direct proportion to the increase of its dose, as doses
increase, however, the incremental rise in response
• diminishes to an extent at which no further increase in
response can be obtained (maximal response)
• e.g. contraction of intestinal smooth muscle after
addition of different doses of ACh.
57. Definitions:
• Definitions:
• - ED50: It is the dose which produces 50% of the
maximal response.
• - ED0: It is the highest dose which does not produce any
response.
• - ED100: It is the lowest dose which produces maximal
response.
• Transformation of the dose to log-dose changes the
hyperbolic curve to sigmoid curve
• which is semilinear (a linear middle portion from about
25% response to about 75%response).
59. • Advantages of the log-dose response curve:
• - Because the relation between X and Y is linear in the
middle portion of the curve,
• ED50 can be calculated easily and accurately.
• - Easier graphical comparison between the different
dose-response curves, because
• transforming doses to log doses expands the scale of
the dose axis at low doses
• where the response is rapidly changing and compresses
it at higher doses where
• the changes in response are slow
60. • The shape of the curve can give an idea about the
therapeutic index (TI) of the
• drug as follows:
• A drug with steep curve has low ED50 (more potent)
and may have low TI (less safe), because a little
increase in dose produces large increase in
• response.
• A drug with less steep curve (flat curve) has higher
ED50 (less potent) and may have high TI (more safe),
because larger doses are needed to increase the
• response.
61. Potency
• It relates amount (weight) of the drug to
the produced response.
• - An example: 5mg of drug A produce 50%
of the maximal response the tissue is
• capable of giving, 5mg of drug B produce
70% of the maximal response the tissue
• is capable of giving. In this case, drug B is
more potent than drug A and ED50 of
• drug B is less than ED50 of drug A.
• - Potency has no clinical significance.
63. Efficacy:
• Efficacy:
• - It is the ability of the drug to produce a
response of higher maximal level.
• - It is important clinically, because the
more efficacious drug has more maximal
• response i.e. better clinical effect.
64. B- Quantal response:
• - It is unmeasurable (qualitative) response i.e. there is
response or no response (all or none).
• - An example: prevention of convulsions and
arrhythmias; anaesthesia and death.
• - In this case, the dose-response curve can not be
plotted as incase of the graded response. LD50
• Therapeutic index (TI) = ----------
• LD50/ED50
66. Therapeutic index (TI):
• - It is important in comparing the safety
and usefulness of one drug with another.
• - The higher the TI the safer is the drug.
Generally, drugs with TI > 3 are
• considered to be safe.
67. B- Quantal response:
Where ED50 is the median effective dose which
gives the desired response in 50% of the
subjects.
LD50 is the dose which kills 50% of
experimental animals
TD50 is the dose which gives a specified
toxicity (adverse effect) in 50% of animals.
Probit (a linearity technique) can be used in
case of quantal responses to obtain a
linear relationship between log-doses and
responses.
68. Variations in tissue responsiveness
• A- Causes of reduction in tissue responsiveness
(tolerance):
• 1- Tolerance:
• - Tolerance means reduction in responsiveness of the
drug after repeated
• administration or prolonged exposure of the tissue
(receptor) to the agonist i.e.
• more dose of the drug is needed to obtain the same
previous effect obtained with a
• smaller dose.
• - It develops gradually over time, depending on type of
tolerance.
• - It may cause failure of therapy.
69. Types of tolerance:
• a) Pharmacokinetic tolerance:
• - It develops gradually and slowly over days after
prolonged or repeated exposure to microsomal enzymes
inducing drug.
• - In this subtype of tolerance, there is reduction in drug
plasma concentration which can be due to enzyme
induction e.g. phenobarbitone causes
• autoinduction (an increase in its own metabolism) and
reduction of its plasma level and pharmacological effect.
70. • b) Pharmacodynamic tolerance:
• - It develops gradually and slowly over hours or
days after prolonged or repeated exposure to
the receptor agonist.
• - In this type of tolerance, there is no reduction in
drug plasma concentration.
• - It can be due to down-regulation of receptors
or a change in the post-receptor events (slow
receptor desensitization).
71. Down-regulation of receptors:
• It occurs slowly and has slow recovery, because
it may involve degradation of receptors by the
lysosomes which requires new receptor
synthesis for recovery.
• c) Immunological tolerance:
• - It required repeated exposure to the drug
which induces production of antibodies against
it.
• - Drugs of peptide or protein nature e.g. insulin
are more susceptible for production of
antibodies against them.
72. • d) Cross tolerance:
• - It is tolerance to action of a drug after repeated
administration of another.
• - It occurs between drugs of: Similar structure
e.g. tolerance between opioids.
• Same mechanism of action e.g. tolerance
between CNS depressants such as between
73. • 2- Tachyphylaxis (desensitization):
• - It develops quickly (over seconds or minutes) after
exposure to an agonist
• probably due to:
• Phosphorylation of receptors to become inactive.
• Exhaustion of mediators required for the response to
take place.
• - It is usually reversible within few minutes of termination
of exposure of the tissue to the agonist (rapid recovery),
because it requires only
• dephosphorylation of receptors by phosphatases (no
need for synthesis of new receptors compared to down-
regulation of receptors).
74. • As an example: Repeated administration of
doses of ephedrine (directly and
• indirectly acting sympathomimetic) cause
tachyphylaxis because they deplete
• noradrenaline from adrenergic nerve terminal
(indirect action)
• i.e. less noradrenaline is available to be
released by subsequent doses than the initial
ones
75. • 3- Physiological adaptation (compensation):
• - It is adaptation by the body to the drug's action.
• - As an example: Reduction of blood pressure by
the vasodilatation produced by hydralazine and
minoxidil stimulates baroreceptors in carotid
bodies causing
• an increase in sympathetic activity, producing
tachycardia and less hypotensive effect.
76. • Congenital reduction in responsiveness:
• - This type of reduction in responsiveness to some drugs
is genetic (not induced by repeated administration of a
drug), such as:
• Rabbits have low response to atropine probably because
they synthesize atropinase enzyme which destroys
atropine.
• Black people have less response to ACE inhibitors, so
these drugs are not effective for treatment of
hypertension or heart failure in these individuals.
77. • B- Causes of elevation of tissue
responsiveness:
• - Elevation of tissue responsiveness may
cause unexpected adverse effects and
• toxicity.
• - It may be as a result of:
78. • 1- Supersensitivity (hypersensitivity):
• - It can be due to up-regulation of receptors after
prolonged use of the antagonist or lack of the
agonist.
• - Excessive response is obtained when the
supersensitive tissue is exposed to the
• exogenously administered agonist or sudden
stoppage of the antagonist, e.g.
• stopping a ẞ-blocker, such as propranolol, after
prolonged use may cause angina,
• tachycardia, tremors and raised blood pressure.
79. • Hypersensitivity (receptors up-regulation)
can also be produced by cutting the
• nerve releasing the neurotransmitter (the
receptor agonist), e.g. cutting the
• cholinergic nerve causes an increase in
number of nicotinic receptors in skeletal
• muscle motor end plate.
80.
81. • Up-regulation of receptors:
• - It means an increase in number of
receptors after prolonged exposure to their
• antagonist or lack of their agonist.
• - It is reversible.
82. • 2- Synergism:
• a) Summation: 1+1 = 2
• It means that the response produced by 2 drugs, given
concurrently, equals the sum of
• their responses when given separately.
• b) Potentiation: 0+3 = 4
• It means that one drug (which may have no response)
increases the potency of
• another.
83. 3- Microsomal enzyme inhibition:
• It causes an elevation in drug plasma
concentration and hence produces an
increase in its action.
84. Agonists
• Agonists
• The agonist is the drug which binds the receptor (has
affinity) and produces a
• response (has intrinsic activity, has no efficacy).
• Affinity:
• It is ability of the drug to bind (fit into) its receptor to form
drug-receptor complex.
• K1 k3
• D+R DR effect (can be dealt with an equation
analogous to Michaelis Menten equation).
• K2 Enzyme (Km)
• substrate ↔ product
85. • Intrinsic activity:
• It is ability of the drug to initiate a response.
• State of the receptor:
• Ri inactive ↔ Ra active
• Inactive, nonfunctional form Active configuration,
functional form
• (has thermodynamic activity)
• Agonist has higher affinity for Ra configuration of the
receptor and stabilizes it (no
• more has thermodynamic activity), so upon binding of
the agonist to the receptor,
• large % of the total pool resides in the Ra-D fraction and
a large effect is produced
86. • Occupancy theory:
• In most cases, the response to a drug is
directly proportional to the number of
• receptors occupied by the agonist, and the
maximal response can be obtained when
all receptors are occupied.
87.
88. • Spare receptors:
• Because maximal response can be
occasionally obtained without occupancy
of the total receptors available, it was
concluded that some of the receptors are
spare receptors which do not take part in
production of the response.
89.
90. • The theory of the spare receptors can be demonstrated
by giving a small dose of an
• irreversible antagonist (e.g. phenoxybenzamine which is
an irreversible antagonist of alpha
• -receptors) to prevent binding of the agonist to a
proportion of the available
• receptors and showing that high concentration of the full
agonist can still produce the maximal response in spite
some of the receptors are irreversibly bound.
91. Types of agonist:
• 1- Full (pure) agonist:
• - It is the drug which binds the receptor (has
affinity) and produces a maximal
• response (high intrinsic activity) that
corresponds to the largest response the
• tissue is capable of giving.
• - Full agonist causes shift of almost all of the
receptor pool to the Ra-D, so it can give maximal
effect.
• - Examples of the full agonist are
ACh,adrenaline, morphine, ….
92. 2- Partial agonist (agonist-antagonist):
• - It is the drug that binds the receptor and produces a
response which falls short
• of the full response even at a full receptor occupancy,
and it inhibits activation of the receptor by the full
agonist.
• - Partial agonist does not stabilize the Ra configuration
as fully as the full agonist i.e. significant fraction of
receptors exists in the Ri-D pool, so it produces
submaximal effect
• - Examples of the partial agonist are Nalorphine,
pentazocine, pindolol, ….
93. 3- Inverse agonist:
• - It is the drug which produces effects opposite
to the response produced normally by activation
of the receptor by its full agonist.
• - Inverse agonist has much stronger affinity to Ri
than to Ra state of the receptor and stabilizes a
large fraction in the Ri-D pool, so it reduces any
• existing constitutive activity and hence produces
an effect that is opposite of the effect produced
by conventional agonist
94. • Examples of inverse agonist are -
carbolines which are inverse agonists for
• benzodiazepine receptor, where
benzodiazepines (the usual agonist)
produce sedation and anticonvulsant
effect while -carbolines produce
restlessness and convulsions.
95. Antagonist
• Antagonists
- The antagonist is the drug which binds the
receptor (has affinity) but produces no
• response (no intrinsic activity)
• i.e. it has zero efficacy, and it inhibits
action of the agonist on the receptor.
96. • Types of antagonists:
• 1- Competitive antagonist (surmountable):
• - Increasing concentration of the competitive
antagonist progressively inhibits action of the
agonist until it reaches complete blockade.
• On the other hand,increasing concentration of
the agonist reduces this antagonism
• i.e. there is competition between the agonist and
the antagonist for the receptor.
98. • The competitive antagonism increases dose of the
agonist required for a certain degree of response and
causes parallel shift to the right of the dose-response
• curve, but by increasing dose of the agonist the maximal
response still can be reached.
• - Examples of the competitive antagonist are
• proranolol (antagonizes e.g.adrenaline on beta -
receptors),
•
• Atropine (antagonizes e.g. ACh on muscarinic
receptors), ….
99. • 2- Irreversible (noncompetitive) antagonists:
• - After binding with the irreversible antagonist,
the receptor becomes unavailable
• for binding with its agonist even with increasing
the concentration of the agonist.
• - Bonds between the receptor and the
irreversible antagonist are covalent bonds
• (strong).
100. • Duration of action of the irreversible antagonist
is to some what independent of its
• rate of elimination but more dependent on the
rate of turnover of the receptors it binds.
• - Irreversible antagonism increases
concentration of the agonist required for a
• certain degree of response (shift to the right of
the dose-response curve), but even high
concentrations of the agonist can not reach the
maximal response.
102. • Examples of the irreversible antagonists
are phenoxybenzamine (on alpha- 1
receptors,
• -bungarotoxin toxin of snake muscle paraylsis
(on nicotinic receptors), ….
• - Both of the competitive and irreversible
antagonists are pharmacological antagonists
because the antagonism takes place on
receptors.
103. • Other types of antagonism:
• 1- Chemical antagonism:
• - No receptors are involved in the
antagonism.
• - Examples:
104. • Heparin (negatively charged) + protamine
sulphate (positively charged) in blood.
• Antacids + gastric acid in stomach.
• Cholestyramine + digoxin in GIT.
neutralization
• Chelating agents + heavy metals.
105. • 2- Physiological antagonism:
• - One drug opposes actions of another by
acting on different receptors (different
• mechanisms).
• - Examples:
• Histamine and Adrenaline Brochospasm and
hypotension H1 rece and adrenaline stimulate B2
bronchodilation stimulate alpha 1 in blood vessels
107. • 3- Allosteric inhibitors:
• They are drugs that bind the receptor in a
site different from the agonist binding
• site, so they do not prevent binding of the
agonist to the receptor, but they reduce
• action of the agonist and their inhibitory
effect is not overcome by increasing
• agonist concentration (no competition).
108.
109. • NB: Allosteric activators: They are drugs
that bind the receptor in a site different
• from the agonist binding site and increase
action of the agonist e.g.
• benzodiazepines which cause
conformational changes in GABAA-
receptor,
• increasing its affinity to GABA.
110. • Factors modifying drug action
• 1- Dose of the drug:
• The larger the dose the more is the action.
• 2- Route of drug administration:
• Drugs with extensive first-pass effect if given I.V. in the
same dose that is given
• orally may cause toxicity e.g. verapamil.
• 3- Age:
• Elimination of many drugs can be reduced in elderly
persons and also it is less in
• neonates especially the premature.
111. • 4- Body weight:
• If the dose is given per kg body weight, then
obese individuals may get larger doses.
• 5- Diet and environmental factors:
• e) Absorption of many drugs is delayed if taken
with or immediately after meals.
• f) Some food may cause hepatic microsomal
enzymes induction or inhibition.
112. • 1- Pathological conditions:
• Aminoglycosides and digoxin accumulate in
blood of patients with renal failure.
• 2- Sex:
• Males have more muscle bulk and females have
more fat and oestrogen.
• 3- Genetic factors:
• Hydrolysis of succinylcholine Muscle relaxant surgery,
as an example, is reduced in people with
genetically determined defects of
pseudocholinesterase.
113. • 4- Psychological state of the patient:
• The placebo effect, which is related to the
psychological state of the patient, can be
• assessed by giving the patient a formulation of a
pharmaceutically inert substance
• which is similar physically (colour, size and
shape) to the formulation of the active
• drug and comparing effects of the two
formulations.
114. • 5- Racial (ethnic group):
• About 90% of Egyptians are slow
acetylators (less elimination of e.g.
isoniazid).
• 6- Drug-drug interactions:
• One drug alters the intensity of the
pharmacological action of another drug
given concurrently.
115. • Adverse drug reactions (ADRs)
• They are undesirable (unwanted) effects
produced by therapeutic doses of drugs.
• They are usually reversible but rarely
can be irreversible.
116. • Some types of adverse drug reactions:
• 1- Result from exaggerated action of the
drug (type A, Augmented):
• They are the most common type (up to
80% of ADRs).
• Usually acute.
• They have high morbidity but low
mortality.
• Often preventable (dose-dependent).
117. • They are predictable (usually a
consequence of the drug's primary
• pharmacological effect (related to drug's
mechanism of action) e.g.:
• - Bleeding from warfarin.
• - Dry mouth caused by atropine.
• - Hypotension induced by antihypertensive
drugs.
• - Bradycardia induced by beta-blockers.
118. • - Headache from nitroglycerin.
• They may resemble a disease which is then
called iatrogenic or induced
• disease e.g. parkinsonism-like symptoms
produced by antipsychotic drugs and
• peptic ulceration caused by aspirin.
• They can be due to:
• - Over dose of the drug.
• - Reduced elimination of the drug.
• - Supersensitivity.
119. • 2- ADRs unrelated to the intended
pharmacological action (Type B, Bizarre):
• They are unpredictable (not extension of
pharmacological action i.e. not
• related to drug's mechanism of action).
• Bizarre.come from noware
• They are infrequent (uncommon).
• Frequently severe (low morbidity, high mortality).
• Can be acute or subacute.
• Dose-independent.
• They include:
120. • a) Idiosyncratic reaction (idiosyncracy):
• It is an abnormal (unusual) response to a
drug or its metabolites.
• It is genetically determined (immune
system may be involved).
•
• An example: Haemolytic anaemia caused
by primaquine antimalarial in people with
G-6-PDehydrogenase deficiency.
121. • b) Allergic reaction (hypersensitivity reaction):
• It is an abnormal (unusual) response to a drug
or its metabolites.
• It is due to immunological factors.
• Usually, it does not occur on first exposure to the
drug (except if the drug has cross
hypersensitivity with another substance which
has been taken by the person) i.e. appears on
subsequent exposure.
122. • 3- Carcinogenesis:
• It is formation neoplasms cancers due to
exposure to drugs which might:
• a) interact directly with DNA (genotoxic
drugs): new mutation
• b) Interact indirectly: By influencing gene
expression and growth control. gene
transcription
123. • 4- Mutagenesis:
• It is the process which causes visible
changes in the hereditary material (DNA)
of the cell in the offspring.
• Pregnant women takes drug affects fetus
• Synthetic glucocorticoids
124. • 5- Teratogenesis:
• - It is the congenital abnormalitiesin the
foetus produced by a drug ingested by
• the pregnant woman, usually during the
first trimester of pregnancy
• (organogenesis organ formation).
• - Example: Thelidomide in germany taken by
pregnant woman causes phocomelia no
hands or amelia in their neoborns.
