Pharmacodynamics

1. PHARMACODYNAMICS
Muhammad Usman Khalid
DPT,MS-NMPT

2. PHARMACODYNAMIC
Pharmacodynamics refers to the relationship between the drug
concentration at the site of action (receptor) and pharmacologic
response, including biochemical and physiologic effects that influence
the interaction of drug with the receptor.
The interaction of a drug molecule with a receptor causes the initiation
of a sequence of molecular events resulting in a pharmacologic or toxic
response.

3. RECEPTORS
'Receptor' is sometimes used to denote any target molecule with
which a drug molecule (i.e. a foreign compound rather than an
endogenous mediator) has to combine in order to elicit its specific
effect.
For example, the voltage-sensitive sodium channel is sometimes
referred to as the 'receptor' for local anesthetics , or the enzyme
dihydrofolate reductase as the 'receptor' for methotrexate.
 The term drug target is preferable in this context.

4. CONTINUED
In the more general context of cell biology, the term receptor is used to
describe various cell surface molecules (such as T-cell receptors) involved in
the immunological response to foreign proteins and the interaction of cells
with each other and with the extracellular matrix.

5. CONTINUED
Various carrier proteins are often referred to as receptors, such
as the low-density lipoprotein receptor that plays a key role in
lipid metabolism and the transferrin receptor involved in iron
absorption.
These entities have little in common with pharmacological
receptors.

7. LIGAND
 (Latin: ligare-to bind) Any molecule which attaches selectively to
particular receptors or sites.
The term only indicates affinity or binding without regard to
functional change.

8. CHEMISTRY OF RECEPTORS AND
LIGANDS
 Interaction of receptors with ligands involves the formation of chemical bonds,
most commonly electrostatic and hydrogen bonds, as well as weak interactions
involving van der Waals forces.
 The mechanism of the “lock and key” is a useful concept for understanding the
interaction of receptors with their ligands. The precise fit required of the ligand
echoes the characteristics of the “key,” whereas the opening of the “lock”
reflects the activation of the receptor.
 The interaction of the ligand with its receptor thus exhibits a high degree of
specificity.

10. AFFINITY & INTRINSIC
ACTIVITY(Efficacy)
 The ability to bind with the receptor designated as affinity, and the
capacity to induce a functional change in the receptor designated as
intrinsic activity (IA) or efficacy.

11. AGONIST
An agent which activates a receptor to produce an effect
similar to that of the physiological signal molecule.
Agonists, which 'activate' the receptors.
High Affinity + High Intrinsic activity
e:g Morphine, Adrenaline

12. INVERSE AGONIST
An agent which activates a receptor to produce an effect in the
opposite direction to that of the agonist.
It has the full affinity towards the receptors but produces effect just
opposite to that of an agonist.
e:g benzodiazepines produces anti-anxiety and anti-convulsant
effects by interacting with their receptors, but β-carbolines acts as
inverse agonist at benzodiazepines receptors and produce anxiety
and convulsions.

13. ANTAGONIST
Antagonist, which may combine at the same site
without causing activation, and block the effect of
agonists on that receptor.
An agent which prevents the action of an agonist
on a receptor or the subsequent response, but does
not have any effect of its own.
High affinity without intrinsic activity
E:g Naloxone, atropine

14. PHYSICALANTAGONISM
The opposing action of the two drugs is due to
their physical property.
E:g activated charcoal absorb toxic substances in
case of poisoning

15. CHEMICALANTAGONISM
The opposing action of two drugs is due to their
chemical property.
E:g antacids are weak bases which neutralize
gastric acid

16. PHYSIOLOGICALANTAGONISM
Two drugs act on the same physiological system
and produce opposite effects
E:g adrenaline and histamine on bronchial smooth
muscle
Histamine produces bronchoconstriction hence
adrenaline helps to reverse bronchospasm in
anaphylactic shock

17. RECEPTOR ANTAGONISM
The antagonist binds to the same receptor as the
agonist and inhibits its effects it can be competitive
or non-competitive.

18. COMPETITIVE ANTAGONISM
A competitive antagonist is a receptor antagonist that
binds to a receptor but does not activate the receptor.
The antagonist will compete with available agonist for
receptor binding sites on the same receptor.
E:g Acetylcholine & Atropine
The competitive antagonism can be overcome by
increasing the conc. Of the agonist.

19. NON-COMPETITIVE ANTAGONISM
The antagonist binds ta a different site or to the same site
with higher affinity so that the agonist cannot displace if
from the receptor.
E:g Phenoxybenzamine and noradrenaline binds to the
same site on receptors. In this type antagonistic effects
cannot be overcome by increasing the concentration of the
agonist.

20. PARTIALAGONIST
Drugs that has affinity to the receptor but less intrinsic activity is
called partial agonist.
Affinity + less intrinsic activity
E:g pindolol, buprenorphine

22.  AGONISTS have both affinity and maximal intrinsic activity (lA = 1), e.g. adrenaline,
histamine, morphine.
 COMPETITIVE ANTAGONISTS have affinity but no intrinsic activity (lA = 0), e.g.
propranolol, atropine, chlorpheniramine, naloxone.
 PARTIAL AGONISTS have affinity and submaximal intrinsic activity (lA between 0 and
1), pentazocine (on µ opioid receptor).
 INVERSE AGONISTS have affinity but intrinsic activity with a minus sign (lA between
0 and -1 ), e.g. DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) (on
benzodiazepine receptor).

24. MAJOR RECEPTOR FAMILIES
Pharmacology defines a receptor as any biologic molecule to which a
drug binds and produces a measurable response. Thus, enzymes and
structural proteins can be considered to be pharmacologic receptors.
These receptors may be divided into four families:
1) ligand-gated ion channels,
2) G protein–coupled receptors,
3) enzyme-linked receptors, and
4) intracellular receptors

25. LIGAND-GATED ION CHANNELS
 The first receptor family comprises ligand-gated ion channels that are responsible for
regulation of the flow of ions across cell membranes. The activity of these channels is
regulated by the binding of a ligand to the channel.
 Response to these receptors is very rapid, having durations of a few milliseconds. The
nicotinic receptor and the γ-aminobutyric acid (GABA) receptor are important
examples of ligand-gated receptors, the functions of which are modified by numerous
drugs.
 Stimulation of the nicotinic receptor by acetylcholine results in sodium influx,
generation of an action potential, and activation of contraction in skeletal muscle.
Benzodiazepines, on the other hand, enhance the stimulation of the GABA receptor by
GABA, resulting in increased chloride influx

27. G PROTEIN–COUPLED RECEPTORS
 A second family of receptors consists of G protein–coupled receptors.
 These receptors are comprised of a single peptide that has seven membrane-spanning
regions, and these receptors are linked to a G protein (Gs and others) having three
subunits, an α subunit that binds guanosine triphosphate (GTP) and a βγ subunit.
 Binding of the appropriate ligand to the extracellular region of the receptor activates
the G protein so that GTP replaces guanosine diphosphate (GDP) on the α subunit.
 Dissociation of the G protein occurs, and both the α-GTP subunit and the βγ subunit
subsequently interact with other cellular effectors, usually an enzyme or ion channel.

28. G PROTEIN–COUPLED RECEPTORS
 These effectors then change the concentrations of second messengers that are responsible for
further actions within the cell. Stimulation of these receptors results in responses that last
several seconds to minutes.
 SECOND MESSENGERS: These are essential in conducting and amplifying signals
coming from G protein–coupled receptors.
 A common pathway turned on by Gs, and other types of G proteins, is the activation of
adenylyl cyclase by α-GTP subunits, which results in the production of cyclic adenosine
monophosphate (cAMP)—a second messenger that regulates protein phosphorylation.
 G proteins also activate phospholipase C, which is responsible for the generation of two other
second messengers, namely inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).
These effectors are responsible for the regulation of intracellular free calcium concentrations,
and of other proteins as well.

30. ENZYME-LINKED RECEPTORS
 A third major family of receptors consists of those having cytosolic enzyme activity as an
integral component of their structure or function. Binding of a ligand to an extracellular
domain activates or inhibits this cytosolic enzyme activity.
 Typically, upon binding of the ligand to receptor subunits, the receptor undergoes
conformational changes, converting from its inactive form to an active kinase form. The
activated receptor auto phosphorylates, and phosphorylates tyrosine residues on specific
proteins.
 The addition of a phosphate group can substantially modify the three-dimensional
structure of the target protein, thereby acting as a molecular switch.

33. INTRACELLULAR RECEPTORS
 The fourth family of receptors differs considerably from the other three in that the
receptor is entirely intracellular and, therefore, the ligand must diffuse into the cell
to interact with the receptor. This places constraints on the physical and chemical
properties of the ligand in that it must have sufficient lipid solubility to be able to
move across the target cell membrane. Because these receptor ligands are lipid
soluble, they are transported in the body attached to plasma proteins, such as
albumin.
 For example, steroid hormones exert their action on target cells via this receptor
mechanism. Binding of the ligand with its receptor follows a general pattern in
which the receptor becomes activated because of the dissociation of a small
repressor peptide. The activated ligand–receptor complex migrates to the nucleus,
where it binds to specific DNA sequences, resulting in the regulation of gene
expression.

36. Protease-Activated Receptor Signaling
Some receptors are not presented by the cell in a form readily accessible to
agonist. Proteases that are anchored to the plasma membrane or that are
soluble in the extracellular fluid (e.g., thrombin) can cleave ligands or
receptors at the surfaces of cells to either initiate or terminate signal
transduction. Peptide agonists often are processed by proteolysis to
become active at their receptors. Tumor necrosis factor (TNF-α)–
converting enzyme (TACE) cleaves the precursor of TNF-α at the plasma
membrane, releasing a soluble form of this pro-inflammatory cytokine.
Similarly, angiotensin-converting enzyme (ACE), which is also an integral
membrane protein preferentially expressed by endothelial cells in the
blood vessels of the lung, converts angiotensin I to angiotensin II (Ang II),
thereby generating the active hormone near receptors for Ang II on

37. Cytoplasmic Second Messengers
Binding of an agonist to a receptor provides the first message in receptor
signal transduction to effector pathways and an eventual physiological
outcome. The first messenger promotes the cellular production or
mobilization of a second messenger, which initiates cellular signaling
through a specific biochemical pathway. Physiological signals are integrated
within the cell as a result of interactions between and among second-
messenger pathways. Second messengers include cyclic AMP, cyclic GMP,
cyclic ADP–ribose, Ca2+, inositol phosphates, diacylglycerol, and nitric
oxide.

38. Cyclic AMP
Cyclic AMP is synthesized by adenylyl cyclase under the control of many
GPCRs; stimulation is mediated by Gs; inhibition, by Gi.
There are nine membrane-bound isoforms of adenylyl cyclase (AC) and
one soluble isoform found in mammals. The membrane-bound ACs are
glycoproteins of approximately 120 kDa with considerable sequence
homology: a small cytoplasmic domain; two hydrophobic transmembrane
domains, each with six membrane-spanning helices; and two large
cytoplasmic domains. Membrane-bound ACs exhibit basal enzymatic
activity that is modulated by binding of GTP-liganded α subunits of the
stimulatory and inhibitory G proteins (Gs and Gi).

39. Cyclic GMP
Cyclic GMP is generated by two distinct forms of
guanylyl cyclase (GC). Nitric oxide (NO) stimulates
soluble guanylyl cyclase (sGC), and the natriuretic
peptides, guanylins, and heat-stable Escherichia coli
enterotoxin stimulate members of the membrane-
spanning GCs (e.g., particulate GC).

40. Cyclic Nucleotide–Dependent Protein
Kinases
PKA holoenzyme consists of two catalytic(C) subunits reversibly
bound to a regulatory (R) subunit dimer. The holoenzyme is
inactive. Binding of four cyclic AMP molecules, two to each R
subunit, dissociates the holoenzyme, liberating two catalytically
active C subunits that phosphorylate serine and threonine residues
on specific substrate proteins. PKA can phosphorylate both final
physiological targets (metabolic enzymes or transport proteins) and
numerous protein kinases and other regulatory proteins in multiple
signaling pathways.

41. Cyclic Nucleotide–Gated Channels
In addition to activating a protein kinase, cyclic AMP also
directly regulates the activity of plasma membrane cation
channels referred to as cyclic nucleotide–gated (CNG) channels.
CNG ion channels have been found in kidney, testis, heart, and
the CNS. These channels open in response to direct binding of
intracellular cyclic nucleotides and contribute to cellular control
of the membrane potential and intracellular Ca2+ levels. The
CNG ion channels are multisubunit pore-forming channels that
share structural similarity with the voltage-gated K+ channels.

42. Cyclic AMP–Regulated GTPase Exchange
Factors (GEFs)
The small GTP-binding proteins are monomeric GTPases
and key regulators of cell function. They integrate
extracellular signals from membrane receptors with
cytoskeletal changes and activation of diverse signaling
pathways, regulating such processes as phagocytosis,
progression through the cell cycle, cell adhesion, gene
expression, and apoptosis.

43. Calcium
 The entry of Ca2+ into the cytoplasm is mediated by diverse channels: Plasma membrane channels regulated
by G proteins, membrane potential, K+ or Ca2+ itself, and channels in specialized regions of endoplasmic
reticulum that respond to IP3 or, in excitable cells, to membrane depolarization and the state of the Ca2+
release channel and its Ca2+ stores in the sarcoplasmic reticulum. Ca2+ is removed both by extrusion (Na+–
Ca2+ exchanger and Ca2+ ATPase) and by reuptake into the endoplasmic reticulum (SERCA pumps). Ca2+
propagates its signals through a much wider range of proteins than does cyclic AMP, including metabolic
enzymes, protein kinases, and Ca2+-binding regulatory proteins (e.g., calmodulin) that regulate still other
ultimate and intermediary effectors that regulate cellular processes as diverse as exocytosis of neurotransmitters
and muscle contraction. Drugs such as chlorpromazine (an antipsychotic agent) are calmodulin inhibitors.

44. DOSE-RESPONSE RELATIONSHIP
The pharmacological effect of a drug depends on its
concentration at the site of action, which in turn
determined by the dose of the drug administered,
such a relationship is called dose-response
relationship.

45. GRADED DOSE RESPONSE
This curve when plotted on a graph takes the form of a rectangular
hyperbola, whereas log-response curve is sigmoid shape

47. THERAPEUTIC INDEX
Therapeutic index (TI) is an index of drug safety
TI = Median lethal dose (LD50)/Median effective
dose (ED50)

48. LD50
 It is the dose of a drug required to kill 50% of the animal population.
ED50
 It is the dose of drug which produces desired effect in 50% of
population.

49. QUANTAL DOSE RESPONSE
Certain pharmacological effects which cannot be
quantified but can only be said to be present or absent are
called as quantal response. E:g drugs causing vomiting etc

50. DRUG POTENCY
The quantity of a drug required to produced a desired
response is potency of the drug. The lower the dose
required for a given response the more potent is the drug.

51. DRUG EFFICACY
It is the maximum effect of a drug.

52. COMBINED EFFECTS OF DRUGS
Additive effect
Potentiation
Synergism

53. ADDITIVE EFFECT
The combined effect of two or more drugs is equal to the
sum of their individual effect.
Effect of drugs A+B= effect of drug A+ effect of drug B
E:g ibuprofen and paracetamol

54. POTENTIATION
The enhancement of action of one drug by another drug
which is inactive is potentiation
Effect of drug A+B > Effect of drug A + Effect of drug B
E:g levodopa + carbidopa
Carbidopa inhibits the breakdown of levodopa thus
enhancing their effects.

55. SYNERGISM
When two or more drugs are administered simultaneously
their combined effect is greater than that elicited by either
drug alone.
E:g sulphamethoxazole + trimethoprim

56. PLACEBO EFFECT
Placebo (latin word) means
I will please
It is the dummy medicine having no
pharmacological activity. The effect produced by
placebo called the placebo effect.

57. IDIOSYNCRACY
It is usually genetically determined adverse reaction. It is
the unusual response of the drug.
E:g aplastic anemia caused by chloramphenicol.

58. TOLERANCE
Repeated administration of certain drugs can result in a
decrease in their pharmacological effect. Hence higher
doses of such drugs are needed to produce a given
response.
E:g ephedrine, organic nitrates, opoids etc.
Tolerance develop to nasal decongestant effect of
ephedrine on repeated dose.

59. TYPE OF TOLERANCE
Natural tolerance ( Blacks tolerant to mydriasis)
Acquired tolerance (Morphine tolerance on
analgesic effect not on miotic effect)

60. TACHYPHYLAXIS
When a drug is administered repeatedly at
short intervals, the response diminish rapidly.
This is commonly seen with non-
catecholamine e:g ephedrine

61. IATROGENIC DISEASE
Physician induced disease due to drug therapy.
E:g acute gastritis and peptic ulcer due to NSAID’s

62. ADVERSE DRUG REACTION
Adverse drug reaction as "an appreciably harmful
or unpleasant reaction, resulting from an
intervention related to the use of a medicinal
product, which predicts hazard from future
administration and warrants prevention or specific
treatment, or alteration of the dosage regimen, or
withdrawal of the product."

63. CONTINUED
Adverse drug reactions are classified into six types (with
mnemonics):
Dose-related (Augmented),
Non-dose-related (Bizarre),
Dose-related and time-related (Chronic),
Time-related (Delayed),
Withdrawal (End of use),
and failure of therapy (Failure).

64. SIDE EFFECTS
Problems that occur when treatment goes beyond the desired
effect. Or problems that occur in addition to the desired
therapeutic effect.
Unintended effect occurring at normal dose related to the
pharmacological properties
Example -- A hemorrhage from the use of too much anticoagulant
(such as heparin) is a side effect caused by treatment going
beyond the desired effect.
Example -- The common side effects of cancer treatment
including fatigue, nausea, vomiting, decreased blood cell
counts, hair loss, and mouth sores are instances of side effects that
occur in addition to the desired therapeutic effect.

65. DRUG INTERACTION
An interaction is said to occur when the effects of one drug are
changed by the presence of another drug, herbal medicine, food,
drink or by some environmental chemical agent. Much more
colorful and informal definitions by patients are that it is “. . .
when medicines fight each other.

67. Jazak Allah!