PHARMA A 1.

3 - PHARMACODYNAMICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. J. Ona Cruz – 06.16.14 2B-Medicine

PHARMACODYNAMICS DRUG BINDING & RECEPTOR CONFORMATION

 The biochemical & physiologic effects of a drug on the body  “Lock & Key Model": A specific drug/ligand is designed to fit
 Quantitative description of the drug-receptor binding & to its complement binding site
interaction that produces effects in the organism
*when a drug interacts w/ receptor, conformational changes
*most drugs elicit their effect through receptor binding, but not usually occur in the binding site which sometimes alters
all  Antacids (Maalox or kremil-s w/c is composed of bases receptor’s affinity
Mg & Al hydroxide) decrease pH of the stomach only by
 “Induced-fit Model”: increased affinity of a receptor to a
neutralizing its hyperacidity, no receptor binding involved
drug due to a conformational change which enhanced drug-
Drug & ligand is used interchangeably in this lecture; But receptor binding quality
technically:
- ligand: endogenous subs. (e.g. neurotransmitters (NTA))
- drug: more of exogenous chemicals

THE RECEPTOR
 A part of the cell, tissue or organism that interacts with a
drug or endogenous ligand (e.g. hormone, NTA) to produce
a chain of events leading to changes in the organism
 Binding site: specific area in the receptor to w/c a drug binds
to
RECEPTOR STRUCTURE:
 made up of amino acids arranged in 3D conformation
 Determines binding affinity to drugs or ligands
 constitutive tendency/baseline:
 Structure varies in different locations
conformational/structural switches that receptors
 protein receptors w/ large lipophilic areas: found in
undergo even w/o ligand interaction
plasma membranes (lipid based)
 2 Main types of receptor conformation
 Receptors transversing entire CM (cell membrane): have
1. Open (active)
lipophilic areas penetrating the membranes while
2. Closed (inactive)
hydrophilic areas are exposed at ends in contact w/ intra
*Refractory (3rd state for other cells neurons): state
& extracellular spaces
wherein receptors do not respond to a ligand/drug *parang
 Receptors w/ hydrophilic areas only: found in cytoplasm
refractory phase sa action potential noon
&/or nucleus
BONDS FORMED BETWEEN RECEPTORS & DRUGS
DRUG STRUCTURE:
BOND TYPE BOND STRENGTH  Determines how it reaches the receptor
Van der Waals +  Highly water soluble: less ability to negotiate with CM &
Hydrogen ++ access target molecules in the cytoplasm
Ionic +++  Highly lipid soluble: can pass through CM or utilize
Covalent ++++ transmembrane channels to access receptors in
*weak bonds: usually reversible cytoplasm
*strong bonds: usually irreversible, effect is of long duration
Ex. Aspirin is a cyclooxygenase (COX) inhibitor. COX enzyme RECEPTOR CHANGES AFTER DRUG BINDING:
converts arachidonic acid to prostaglandin (PG) (for 1. Changes in extracellular domain brings about changes in
inflammation) & thromboxane (TX) (promotes clotting). intracellular domains
Aspirin’s inhibitory effect on COX results to no PG & TX giving 2. Formation of extracellular dimmers
aspirin’s anti-inflamm & anticoagulant effects. Now, aspirin
irreversibly binds to COX, so these enzymes run out & it will *4 types of drug effects isama ko nalang later sa full
take days or weeks for COX reproduction; this results to discussion*
prolonged effect of aspirin. (rationale why aspirin should be
stopped a week before pt go to surgery)
*warfarin example in doc’s handout

1
PHARMA A 1.3 - PHARMACODYNAMICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. J. Ona Cruz – 06.16.14 2B-Medicine

FOUR MAJOR TYPES OF RECEPTORS C. SECOND MESSENGER REGULATED

1. Transmembrane ion channels - Movement of ions across the channel is determined by
2. Transmembrane G protein-coupled receptors ligands binding to plasma membrane receptors linked to
3. Transmembrane receptors with enzymatic cytosolic the channel
domains - D + R = activate 2nd messenger w/c in turn activate
4. Intracellular receptors opening of a channel letting ions pass through
- cAMP is usually the 2nd messenger

State Dependent Ion Channel Blockade

- Channels are selective for the ions they conduct (Na
channels are only for Na)
- Most have similarities in structure, size of conductance &
mechanism of activation or inactivation (difference only in
ions they conduct)
- Several conformations: open, closed, refractory (non
responsive/cannot be reactivated)
- Drugs have different receptor affinities depending on the
conformational states
Ex. Anti-arrhythmic drugs have greater affinity to active
TRANSMEMBRANE ION CHANNELS conformation receptors which are present in arrhythmic
 Site of drug-receptor (DR) interaction: extracellular, cardiac cells. (Receptors in the normal cells are usually
intracellular or intrachannel closed or refractory so they will not be targeted)
 Site of consequent action: cytoplasm *class III anti-arrhythmic drugs exhibit state dependent ion channel
blockade
 Three main types: ligand gated channels, voltage gated
channels & 2nd messenger regulated
 Examples: local anesthetics & benzodiazepines
TRANSMEMBRANE G PROTEIN-COUPLED CHANNELS
A. LIGAND GATED CHANNEL - Span the thickness of cell membrane with:
- Ligands/molecule/drug binding to the channel controls  Extracellular region: contains drug binding site
the conductance of ions across the channels  Intracellular region: noncovalently bound to G protein
- D + R = opening of channel to let ions enter cell & (signaling molecule) made up of α & βγ subunits
stimulate effects  Some utilize 2nd messengers, some do not
- Most abundant receptors in the body
- example: β adrenergic receptors on w/c cathecolamines
(epinephrine,NE,etc) bind to resulting in ↑ cAMP

STEPS: *pls refer to the image on next page

1. Drug binds to extracellular region of the receptor
2. Binding causes conformational changes on receptor that
exposes G protein binding site
3. GDP, which is originally bound to α subunit (inactive) will
B. VOLTAGE GATED CHANNEL
dissociate & be replaced by GTP forming α-GTP (active)
- Voltage gradient across membrane controls the ion
4. GTP binding to α subunit will cause it to dissociate from βγ
conductance
subunits & they subsequently diffuse along inner surface
- Ex. Nerve & cardiac cells
of the CM to interact with several receptors:
- D + R = change in
 If effector is adenylyl cyclase conversion of ATP to
voltage gradient causes cAMP
opening of ion channels  If effector is Phospholipase C cleaveage of
which enable it to elicit phosphatidyl inositol to DAG & IP3
effect

2
PHARMA A 1.3 - PHARMACODYNAMICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. J. Ona Cruz – 06.16.14
5. Dissociation of drug from receptor returns it to original
conformation.
TRANSMEMBRANE RECEPTORS W/ ENZYMATIC CYTOSOLIC
DOMAINS
- Receptors that convert (transduce) drug binding
interaction (extracellular) into intracellular events via
stimulation of associated enzymes
- Most are involved in phosphorylation type of signaling
(change proteins by reversibly adding or removing
phosphate groups)
- All subclasses have same mechanism, they only differ in
enzymes used
- Five subclasses: Tyrosine Kinase, Tyrosine Phosphatase,
Tyrosine Kinase-Associated, Serine Threonine, Guanylyl
cyclase
A. RECEPTOR TYROSINE KINASE
- Largest subgroup; type of most receptors
- Example: insulin
- D + R (extracellular) = initiate phosphorylation of
tyrosine residues in cytosolic area w/c causes cascade of
signaling events
tyrosine kinase is involved in growth & differentiation, so
mutations in the genes coding for it may cause
uncontrolled cell growth & cancer
*example: translocation between chromosomes 9 & 22
(philadelphia chromosome) increases activity of receptor TK
that can cause uncontrolled growth of myeloid cells called
myeloid leukemia -- drug Imatinib was developed that
inhibits phosphorylation process decreasing myeloid prod.
3
2B-Medicine
B. RECEPTOR TYROSINE PHOSPHATASE
- Take away phosphate groups from tyrosine residues to
trigger intracellular events
- Regulators of immune cell activation
C. TYROSINE KINASE-ASSOCIATED RECEPTORS/CYTOKINE
RECEPTORS
- Do not have an inherent catalytic activity
- initiation of events in the cell similar to those that occur
with tyrosine kinases but it is nonreceptor kinases that
get activated
- also involved in immune cells
D. RECEPTOR SERINE THREONINE
- exemplified by members of the transforming growth
factor β receptor family (TGF β) which are involved in cell
growth regulation and differentiation
- associated with progression and spread of cancer
- These kinases phosphorylate serine & threonine residues
on target proteins in the cytoplasm
- no clinical agents of this type
E. RECEPTOR GUANYLYL CYCLASE
- smallest number of transmembrane receptors
- exemplified by B-type natriuretic peptide which is
secreted by the ventricles in response to volume overload
- receptor guanylyl cyclases are activated directly by its
ligand without any intervening G protein
INTRACELLULAR RECEPTORS
- Located in the cytosol
- Ligands are LIPOPHILIC that can easily pass through CM
- Regulation of DNA transcription and RNA translation
- Example: Steroids, transcription regulatory factors
PHARMA A 1.3 - PHARMACODYNAMICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. J. Ona Cruz – 06.16.14 2B-Medicine

PROCESSING AND INTEGRATION OF SIGNALS AFTER DRUG-
RECEPTOR INTERACTIONS
These are processes in which some drugs must undergo to
elicit its effect after binding to the receptor:
1. Second messenger system – explained above
2. Intracellular ionic concentration – explained above
Ex. Β receptor to repeated epinephrine stimulation
comes about from epinephrine-induced phosphorylation of
cytoplasmic end of the receptor facilitates β-arrestin binding
to the receptorinhibited ability of receptor to stimulate the
G protein (Gs)lower levels of Gs lower production of cAMP
by adenyl cyclaseless cellular effects over time

Signal amplification
- Even if you only stimulate 1 or 2 receptors, there would be
a chain of events that would lead to many reactions
- When a ligand binds to a G protein-coupled receptor, one
G protein molecule is activated. This binds and stimulates
many effector molecules (e.g. adenylyl cyclase), which in
INACTIVATION
turn activates even more second messengers (2nd
- complete blockade of its signaling activity upon receptor
messenger system)
phosphorylation
- Similarly, a small influx of Ca+ 2(so-called trigger Ca+2) via
the voltage-gated Ca+2 channels causes the release of large
DOWN REGULATION
quantities of stored Ca+ 2 into the cytoplasm (ionic conc)
- a change in the number of receptors on the cell
*actually guys medyo paulit ulit yung mga concepts.. - endocytosis & receptor sequestration from the cellular
membrane surface into endocytotic vesicles upon
prolonged exposure
- receptors will come out again
once stimulant is removed
- takes longer time to recover
- the cell itself can change the
level of synthesis of receptors
thereby regulating what is
available for binding to a
particular drug or ligand
- These two processes occur over a longer period of time
than the phosphorylation process described above and
CELLULAR REGULATION OF DRUG-RECEPTOR INTERACTIONS
therefore may have longer cellular effects
- built-in processes exists that serve to protect the receptor
from overstimulation as this may have deleterious effects
RECEPTOR REFRACTORINESS
on the cell or the whole organism
- Receptor assumes a refractory or nonresponsive state for
some time after drug binding; the receptor will recover
TACHYPHYLAXIS & DESENSITIZATION
after some time and can again respond to stimulation
- refers to the diminishing response to repeated
- exemplified by the voltage-gated channels mediating the
administration of a drug w/ the same dosage that occurs
firing of nerve cell action potentials.
w/ time that leads to reduced clinical effects (receptor can
*the refractory period of the neuron is characterized by
be said to be DESENSITIZED to drug action at this point) spontaneous closure of the sodium channels following channel
- two types of desensitization: opening or depolarization. At this point, the cell is refractory
 Homologous: diminished action of agonists at one class and does not reopen for a while. This regulates the maximum
of receptors rate of neuronal firing and transmission
 Heterologous: diminished action of agonists on a number
of classes of receptors

4
PHARMA A 1.3 - PHARMACODYNAMICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. J. Ona Cruz – 06.16.14 2B-Medicine

DRUG SELECTIVITY DRUG RECEPTOR BINDING

*We all know: when a drug/ligand binds to a receptor, they

SPECIFICITY: a drug will bind and interact only to a particular
will usually form a complex & create a response
receptor and not to others.

An ideal drug is one that will interact only with a specific

molecular target and thus produce only the desired clinical
effect. It does not affect other targets and will not produce
unwanted side effects or toxicities. Dissociation constant (Kd)
Ex: Haloperidol, a dopamine (DA) antagonist, is given for - intrinsic property of any LR
schizophrenia (theory is that they have excessive DA); now there are 4
- is an expression of the tendency of an LR complex to bind
DA pathways, mesocortical, mesolimbic, nigrostriatal &
together or dissociate
tuberoinfundibula. Schizophrenia is caused by ↑ DA in the
mesocortical & mesolimbic pathways, but haloperidol is non selective - A number that is usually given
so it will also affect the nigrostiratal pathway which is responsible for - ↓Kd = ↑ affinity of ligand to receptor
motor coordination, patient will now have an adverse effect of EPS - ↑Kd = ↓affinity = greater chance of dissociation
(extrapyramidal symptoms: dyskinesia, *referring to Eq 1: ↓Kd favors eq’n to go to the right, ↑Kd
bradykinesia,jerkynesia,chorea & tardive dyskinesia). favors eq’n to go to the left
*specific is good because we narrow the effects to the desired only.
Currently, there is no drug in existence as all drugs have the
potential for both beneficial and toxic effects. Still, drug
selectivity is a goal that drug development continues to aim for
and there is a growing list of new medications that are more
specific in terms of molecular targets and clinical effects than
their predecessors.

DETERMINANTS OF DRUG SELECTIVITY:

DEDUCTIONS FROM ABOVE:
 cell-type specificity of receptor subtypes
 as ligand conc increases, conc of bound receptors increases
- Some receptors are distributed less than others and drug
 as free receptors increase, bound receptor concentration
interaction with these leads to more selective
increases
therapeutic effects
Therefore, an increase in the effect of a drug can result from
- Example: Imatinib is used in treatment of certain cancers.
an increase in the conc of either the ligand or the receptor.
Unlike chemotherapeutic agents which target DNA
synthesis which is common in almost all cells (normal and
cancer cells alike), Imatinib is extremely selective because
it targets the BCR-Abl protein expressed only in cancer
cells

 cell-type specificity of receptor-effector coupling

- drugs may have same targets but have different effects
because of differences in receptor-effector coupling
mechanisms or in the requirements for the targets in the
different cell types
- ex. cardiac pacemaker cells (SA nodal cells) are more
sensitive to Ca channel blockers than cardiac ventricular
cells even if both have voltage-gated calcium channels.
Such is due to the fact that Ca channels play a greater
role in impulse propagation in pacemaker cells whereas
this role is delegated to Na channels in the ventricular *just take note of the relationship of the variables
cells. INCREASE IN LR COMPLEX = INCREASED RESPONSE

5
PHARMA A 1.3 - PHARMACODYNAMICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. J. Ona Cruz – 06.16.14 2B-Medicine

E= quantifiable response to a drug (e.g. increase in BP) of the effect

 Kd in the graph corresponds the drug concentration at
which 50% of the receptors are bound
 Basing on the graph, Drug A is more potent because it
needs less conc. to bind to 50% of the receptors
**potency is the ability of a drug to promote at least 50%
response
DRUG RESPONSE RELATIONSHIPS
EC50= potency of the drug (the concentration at which the drug
elicits 50% of its maximal effect
L= drug concentration
Emax=efficacy
The curves above resemble the previous curves but the
fraction of occupied receptors [LR]/[Ro] has been replaced by
the FRACTIONAL EFFECT E/EMAX.

*The response to a drug is proportional to the concentration of Both drugs in the graph is efficacious since they can both reach the
Emax(maximal efficacy); but Drug A is more potent than Drug B
the receptors that are bound or occupied by the drug.
because it takes Drug A less concentration to achieve EC50.

NOTE:
 potency and efficacy are not intrinsically related: a drug
can be very potent but have little efficacy and vise versa
(although what we want is a very potent & very effective
drug)
 the clinical effectiveness of a drug depends on its maximal
efficacy and its ability to reach the relevant receptors, not
on its potency (ec50)
*Of the 4, Drug B is the
Graded Dose-Response: response of an individual to a drug
most potent; Drug A is
Quantal Dose-Response: response of a population to a drug also potent
The pharmacologic
(more accurate)
potency of Drug A is less
than Drug B, a partial
GRADED DOSE-RESPONSE RELATIONSHIPS
agonist because the EC50
- response continuously increases as the administered dose
of DRUG A is greater than
continuously increases
the EC 50 of DRUG B.
- response to the drug is directly related to the no. of DRUG A HAS A LARGER
receptors with which the drug effectively interacts MAXIMAL EFFICACY THAN
 POTENCY (EC50) *effective concentration DRUG B
 the conc at w/c the drug elicits 50% of its maximal *Drugs A,C & D are efficacious
response *DRUG D exhibits a very steep dose-response curve. This may
 EFFICACY (EMAX) have important clinical consequences if the upper part of the
 the maximal response produced by the drug curve represenst an undesireable extent of response –needs
 represents the state at which all receptors are monitoring (e.g. coma from sedative hypnotics)
occupied by drug (such that additional drug will not **magbibigay daw siya ng ganito sa exam**
produce added response)

6
PHARMA A 1.3 - PHARMACODYNAMICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. J. Ona Cruz – 06.16.14 2B-Medicine

This ability to reach receptors depends on or influenced by DRUG RECEPTOR INTERACTION

several factors: *recall yung nasa first page regarding the 2 main states of the
1- route of administration receptors: active & inactive; and also that the receptors have a
2-absorption constitutive tendency
3-distribution ** I discarded na yung eq’n kasi parang mas magulo, eh ang
4-clearance from the blood or site of action kailangan lang naman yung principles. **

NOTE: AGONIST
 In choosing which of two drugs to administer to a patient, - Drugs or endogenous ligands that stabilize their
the clinician considers their relative effectiveness rather corresponding receptors in their active conformation upon
than their relative potency. binding
 Potency largely determines the administered dose of the - Simply said: if an agonist binds to its receptor, it will become
chosen drug. So potency is usually stated in dosage units in activated and an effect will be elicited
relation to a particular therapeutic goal (e.g. mild sedation)  Full Agonist: provide full activation (100%)
 Partial Agonist: submaximal effect only; usually
QUANTAL DOSE-RESPONSE RELATIONSHIPS considered antagonist
- Plots the fraction of the population that responds to a
given dose of drug versus the drug dose. ANTAGONIST
- Describes the concentrations of a drug that produces a - A drug that inhibits the action of an agonist but has no
given effect in a population effect in the absence of the latter
- useful in predicting the effects of a drug when it is given to
a population of individuals, and for determining
population-based toxic doses and lethal doses:
 ED50 – dose at which 50% of subjects exhibit a
therapeutic response (median effective dose)
 TD50 – dose at which 50% of subjects experience a toxic
response (median toxic dose)
 LD50 – dose at which 50% of subjects die (median lethal
dose)
NOTE: The ED50 is the dose at which 50% of subjects respond
to a drug whereas EC50 is the dose ate which a drug elicits a
half-maximal effect in an individual subject.
RECEPTOR ANTAGONISTS
- Binds either to the active site (which prevents the binding
of the agonist to the receptor) or to an allosteric site
(prevents the conformational change required for receptor
activation.
- Can be reversible or nonreversible

COMPETITIVE RECEPTOR ANTAGONISTS

- REVERSIBLY binds to the active (agonist) site of the
receptor
- DOES NOT stabilize the conformational change required for
receptor activation
*In the above figure: the response is reported as present or
- Blocks an agonist from binding to its receptor
absent therefore hence term quantal rather than graded
- Maintains the receptor in the inactive configuration
* Quantal dose-response relationships seek to GENERALIZE a
result to a population rather than to examine the graded effect
of different drug doses on an individual.
*this graph was not discussed*

7
PHARMA A 1.3 - PHARMACODYNAMICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. J. Ona Cruz – 06.16.14
*Although the potency of the agonist decreases as the concentration
of competitive antagonists increases, the efficacy of the agonist is
unaffected. This is because the agonist concentration [D] can be
increased to counteract or outcompete the antagonist: washing out or
reversal of antagonist.
*In the curve above note that the presence of the competitive
antagonist shifts the agonist dose-response curve to the right, causing
a decreased potency while maintaining agonist efficacy.
Exs: Statins are competitive antagonists of HMG CoA for the active
site of HMGCoA reductase. This reductase catalyzes the rate-limiting
step in cholesterol biosynthesis. Statins and HMG CoA are similar in
structure. This allows statins to bind to the active site in the reductase
to decrease endogenous cholesterol synthesis.
NON COMPETITIVE RECEPTOR ANTAGONISTS
 Irreversibly Binding to Active site: Noncompetitive active
site antagonists bind covalently or with very high affinity
(IRREVERSIBLE) no outcompetition
 Binding to Allosteric site: Noncompetitive allosteric site
antagonists prevents receptor activation even if the
agonist is bound to the active site
o Reversible effects wash out over time as it dissociates
o Irreversibleeffects do not diminish
*A noncompetitive antagonist reduces the efficacy of an agonist but
do not generally affect agonist potency if they are allosteric site
binders since they do not compete for the binding site.
*review mechanism of action of aspirin I have explained above
8
2B-Medicine
NON RECEPTOR ANTAGONISTS:
- Inhibits the ability of an agonist to initiate a response via:
 binds to a downstream molecule in the activation
pathway (antibodies)
 activating a pathway opposite to the action of the
agonist
 physiologic antagonism-causes a physiologic affect
opposite to the agonist effect
CHEMICAL ANTAGONISTS
- Inactivates the agonist by modifying or sequestrating it
such that said agonist is unable to bind to not activate its
receptor
- Ex. Protamine, antidote for Heparin toxitiy by capturing the
drug itself preventing Heparin from binding to the receptor
PHYSIOLOGIC ANTAGONISTS
- Activates or blocks a receptor that mediates a response
physiologically opposite to that of the original receptor for
the agonist
- e.g. beta blockers in tachycardia of hyperthyroidism by
reducing heart rate
PARTIAL AGONIST /MIXED AGONIST-ANTAGONISTS
- A drug that binds to a receptor at its active site but
produce only a partial response even with full receptor
occupancy by the drug.
- In the presence of a full agonist, the partial agonist
REDUCES the maximum response such that the partial
agonists acts as a competitive inhibitor.
- Reasons for partial response:
 May stabilize both DR and DR* forms of a drug-receptor
complex
 Formation of multiple DR* forms
*efficacy is diminished here because partial agonist can
compete with the full agonist
*Partial agonists are beneficial if you don’t want the full effect
of a drug (e.g. coma effect of some sedative-hypnotic drug)
PHARMA A 1.3 - PHARMACODYNAMICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. J. Ona Cruz – 06.16.14 2B-Medicine

SPARE RECEPTORS
- Makes possible maximum response or effect even without
reaching full receptor occupancy by use of signal
amplification
- Ex. Beta adrenergics
- Mechanisms :
 Receptor remains activated even after agonist departs
(so one agonist molecule can activate several receptors)
 Amplification (intracellularly) of small signals so that
*The above are curves of several alkyl derivatives of the drug activation of a few receptors can produce a maximal
trimethylammonium and are all stimulators of muscarinic Ach response*
receptors in the GUT musculature. As indicated, they produce different
maximal responses even with full receptor occupancy.
* Butyl TMA is a full agonist
*Octyl TMA is a partial agonist at this receptor.

INVERSE AGONIST
- A drug which binds to the active site of a receptor (similar to
an agonist) and abolishes the inherent stability of receptors
to stay in the R or R* forms
- e.g. stabilization of receptors in the DR (inactive form of
drug-receptor complex), deactivating receptors formerly in
In the absence of spare receptors, there is often a close correlation
R* prior to its presence
between a drug-receptor binding curve and a dose-response curve-
the binding of additional to the recptor causes an incremental
increase in response and EC50 is approximately equal to Kd. If there
are spare receptors, fewer than 50% of the receptors must be
occupied to elicit half-maximal response (so EC50<Kd). The term spare
implies that in some cases, it is not necessary to occupy every receptor
with drug to elicit a full response.

Effect of Noncompetitive Antagonist on Agonist Dose-

response curve in the presence of Spare Receptors.
- without spare receptors: a noncompetitive antagonist
causes efficacy to decrease
- with spare receptors: potency is decreased but efficacy is
unaffected at low concentrations of the noncompetitive
antagonist because a sufficient number of free receptors is
**review daw on how to interpret the graphs here**
available to generate a maximum response.

9
 PHARMA A 1.3 - PHARMACODYNAMICS
FEU-NRMF Institute of Medicine
Lecturer: Dr. J. Ona Cruz – 06.16.14 2B-Medicine

 at low conc the NCA binds receptors that are not required
to produce a maximal response:
 efficacy of the agonist is not affected
 But the potency of the agonist is decreased because
potency is proportional to the fraction of available
receptors that must be occupied to produce 50%
response.
 Recall that some NCAs bind to the active site
covalently rendering them permanently unavailable.
 At high antagonists conc, the NCA binds not only to spare
receptors but to the rest, so efficacy and potency are both
reduced.

THERAPEUTIC INDEX & THERAPEUTIC WINDOW

Therapeutic window
- The range of doses or concentration of a drug that
produces a therapeutic response WITHOUT undesirable
side effects or toxicity.
- A drug with a small therapeutic window mandates
monitoring of serum or plasma levels

 The therapeutic index (Ti) is a single number that quantifies

the relative margin of safety of a drug in a population of
people
 Large TI: large window so toxic dose is 1000x more than
therapeutic dose
 Small TI: toxic dose is very close to the therapeutic dose
E.g. theophylline, digoxin

**remember the formula because it might be given**

10