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1.1 (Pharmacology A) - Ona-Cruz's Pharmacodynamics (BHND)
1.1 (Pharmacology A) - Ona-Cruz's Pharmacodynamics (BHND)
Pharmacology A – 1.2
LECTURER: JESSICA OÑA-CRUZ, MD, MHPED, FPOGS
PHARMACODYNAMICS MEDISINA 2019
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 1 of 11
PHARMACODYNAMICS Pharmacology A
Drug Structure D+R = opening of channel to let ions enter cell & stimulate effects
Determines how it reaches the receptor Ligand (molecule or drug) binding to the channel controls the
Hydrophilic ligands interact with receptors that are found on the conductance of ions across the channel
cell surface
Hydrophobic ligands enter cells through the lipid bilayers of the Voltage-Gated Channels
cell membrane or utilize the transmembrane channels to
interact with receptors found inside the cell (i.e., cytoplasm or
nucleus)
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 2 of 11
PHARMACODYNAMICS Pharmacology A
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 3 of 11
PHARMACODYNAMICS Pharmacology A
SIGNAL TRANSDUCTION
Drugs act as signals & their receptors act as signal detectors
Receptors transduce their recognition of a ligand that binds to a
site on a receptor protein & activates it by initiating a series of
reactions that ultimately result in a specific intracellular
response
“Second messenger” or effector molecules are part of the
Represent the smallest number of transmembrane receptors
cascade of events that translate ligand binding into a cellular
Exemplified by B-type natriuretic peptide which is secreted by response
the ventricles in response to volume overload
Has two important features:
Unlike the other receptor types, they are activated directly by its ◌ Ability to amplify small signals
ligand without any intervening G protein ◌ Mechanisms to protect the cell from excessive stimulation
SIGNAL AMPLIFICATION
Appears to be an inherent ability of the cell
Cellular responses to signals from drug-receptor binding is often
much greater than the quantity of the stimulus that initiates it
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 4 of 11
PHARMACODYNAMICS Pharmacology A
◌ For example, a single ligand-receptor complex can interact ◌ At this point, the cell is refractory and does not reopen for
with many G proteins thereby multiplying the original signal a while regulating the maximum rate of neuronal firing &
manifold transmission
◌ Additionally, activated G proteins persist for a longer
duration than does the original agonist-receptor complex DOWN REGULATION
Characteristic of G protein-linked & enzyme-linked receptors is Another effect of drug-receptor binding is a change in the
their ability to amplify signal intensity & duration number of receptors on the cell
◌ For example, when a ligand binds to a G protein-coupled Receptors may be down-regulated such that they are
receptor, one G protein molecule is activated (+) binding internalized (endocytosed) & sequestered within the cell,
& stimulation of many effector molecules (e.g., adenylyl unavailable for further ligand interaction
cyclase) which in turn activates even more second These receptors may be recycled to the cell surface, restoring
messengers sensitivity or alternatively may be further processed & degraded,
◌ Similarly, a small influx of Ca2+ (so-called trigger Ca2+) via the decreasing the total number of receptors available
voltage-gated Ca2+ channels cause the release of large Recycling of the receptors back into the surface ensues when
quantities of stored Ca2+ into the cytoplasm stimulation by the drug subsides
Alternatively, the cell itself can change the level of synthesis of
DESENSITIZATION & DOWN-REGULATION OF RECEPTORS
receptors thereby regulating what is available for binding to a
Repeated or continuous administration of a ligand may lead to particular drug or ligand
changes in the responsiveness of receptor
Occur over a longer period of time than inactivation & therefore
To prevent potential damage to the cell (e.g., high may have longer cellular effects
concentrations of calcium initiating cell death), several
mechanisms have evolved to protect a cell from excessive SUMMARY OF MECHANISMS OF RECEPTOR REGULATION
stimulation such as tachyphylaxis
Tachyphylaxis Repeated administration of the same dose of a
Tachyphylaxis & Desensitization drug results in a diminishing effect of the drug
Occurs when a receptor is exposed to repeated administration over time
of an agonist which then causes the receptor to become Desensitization Decreased ability of a receptor to respond to
desensitized resulting in a diminished effect stimulation by a drug or ligand
This phenomenon is due to either phosphorylation or a similar Inactivation Loss of ability of a receptor to respond to
chemical event that renders receptors on the cell surface stimulation by a drug or ligand
unresponsive to ligand Refractory After a receptor is stimulated, a period of time
Refers to the diminishing response to repeated administration of is required before the next drug-receptor
drug with the same dosage that occurs with time leading to interaction can produce an effect
reduced clinical effects Receptor can be said to be Down-regulation Repeated or persistent drug-receptor
desensitized to drug action at this point interaction results in removal of the receptor
Two types of desensitization from sites where subsequent drug-receptor
◌ Homologous – diminished action of agonists at one class of interactions could take place
receptors
◌ Heterologous – diminished action of agonists on a number DETERMINANTS OF DRUG SELECTIVITY
of class of receptors Specificity: a drug will bind & interact only to a particular
Example of desensitization receptors & not to others
◌ -receptor to repeated epinephrine stimulation comes An ideal drug is one that will interact only with a specific
about from epinephrine-induced phosphorylation of molecular target & produce only the desired clinical effect. It
cytoplasmic end of the receptor facilitates -arresting does not affect other targets & will not produce unwanted side
binding to the receptor inhibition of ability of receptor effects or toxicities
to stimulate the G protein receptor (Gs) lower levels of Still, drug selectivity is a goal that drug development continues
Gs lower production of cAMP by adenylyl cyclase less to aim for & there is a growing list of new medications that are
cellular effects over time more specific in terms of molecular targets & clinical effects than
their predecessors
INACTIVATION Example: Haloperidol, a dopamine (DA) antagonist, is given for
Upon receptor phosphorylation, there is complete blockade of schizophrenia to block D2-dopamine receptors, suggesting that
its signaling activity schizophrenia is associated with increased activity in the
dopaminergic mesolimbic and/or mesocortical pathway
RECEPTOR REFRACTORINESS ◌ Since Haloperidol is nonselective, it also blocks dopamine
Some receptor, particularly ion channels, require a finite time receptors in the basal ganglia which frequently results in
following stimulation before they can be activated again distressing & disabling extrapyramidal side-effects such as
During this recovery phase, unresponsive receptors are said to akathisia (motor restlessness), tardive dyskinesia (orofacial
be “refractory” & trunk movements), bradykinesia, etc
Exemplified by the voltage-gated channels mediating the firing
of nerve cell action potentials Several mechanisms that confer drug selectivity
◌ Here, the refractory period of the neuron is characterized 1. Cell-type specificity of receptor subtypes
by spontaneous closure of the sodium channels following 2. Cell-type specificity of receptor-effector coupling
channel opening or depolarization
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 5 of 11
PHARMACODYNAMICS Pharmacology A
Cell-type specificity of receptor subtypes Applying the law of mass action (which explains & predicts
Some receptors are distributed less than others & drug behaviors of solutions in dynamic equilibrium, the relationship
interaction with these leads to more selective therapeutic between free & bound receptors can be described in the
effects & possibly less potential for certain toxicities equation below:
Example: Imatinib, used in treatment of certain cancers. Unlike
chemotherapeutic agents with target DNA synthesis which is Equation 2 (Relationship between free & bound receptors)
common in almost all cells (normal & cancer cells alike), Imatinib
[𝐿][𝑅] [𝐿][𝑅]
is extremely selective because it targets the BCR-Abl protein 𝐾𝑑 = 𝑜𝑟 𝐿𝑅 =
expressed only in cancer cells [𝐿𝑅} 𝐾𝑑
In general, the more restricted the cell-type distribution of the
receptor targeted by a particular drug, the more selective the From the above equation, several deductions are made as Kd is
drug is likely to be constant:
◌ As the ligand concentration increases, the concentration of
Cell-type specificity of receptor-effector coupling bound receptor likewise increases
Drugs may have same target molecule drug but have different ◌ As the free receptor concentration increases, the
effects because of differences in the receptor-effector coupling concentration of bound receptor also increases
mechanisms in the requirements for the targets in the different Therefore, an increase in effect of the drug may result from an
cell type increase in the concentration of either the ligand or the receptor
Example: Cardiac pacemaker cells (SA nodal cells) are more However, it is usually assumed that the total receptor
sensitive to Ca2+ channel blockers than cardiac ventricular cells concentration is constant thus the equation below:
even if both have voltage-gated Ca2+ channels
◌ Such is due to the fact that Ca2+ channels play a greater role [𝐿𝑅] + [𝑅] = 𝑅𝑜
in impulse propagation in the pacemarker cells whereas this Ro = Total number of receptors bound & free
role is delegated to sodium channels in the ventricular cells Which when rearranged & LR is substituted with the equation
In general, the more the receptor-effector coupling mechanisms earlier will be:
differ among the various cell types that express a particular
Equation 3 (Computing for total number of receptors)
molecule target for a drug, the more selective the drug is likely to
be [𝐿][𝑅] [𝐿]
𝑅𝑜 = + 𝑅 [𝑅] (1 )
DRUGS ACTING BY NONRECEPTOR-MEDIATED MECHANISMS 𝐾𝑑 𝐾𝑑
To solve for R & substituting & substituting Equation 3 to
Some drugs exert effects not by interacting with the four basic
Equation 2 will result to:
receptor types above but by other means [𝑅𝑜][𝐿]
Example: Osmotic diuretics & antacids [𝐿𝑅] =
[𝐿] + 𝐾𝑑
◌ Osmotic diuretics – influence the amount of water When rearranged will be:
reabsorbed from the filtrate in the descending limb of loop
of Henle by altering the osmolarity within Equation 4 (Computing fraction of bound receptors)
◌ Antacids – act by neutralizing hydrochloric acid secreted by
the stomach [𝐿𝑅] [𝐿]
=
[𝑅𝑜] [𝐿] + 𝐾𝑑
DRUG-RECEPTOR BINDING [𝑳𝑹]
= represents the fraction of all bound receptors in
Consider a receptor (R) which is free (unoccupied) or reversibly [𝑹𝒐]
bound (occupied) to a drug or ligand (L) which can be expressed relation to the total amount of receptors (Fractional Occupancy)
by the equation below: ◌ in LR complex = response
𝐾𝑑 = 𝐿 + 𝑅 ↔ 𝐿𝑅
L = drug or ligand
R = Receptor
LR = Bound drug-receptor complex
Kd = Dissociation Constant
Kd in the graph
Dissociation Constant (Kd) ◌
represents the concentration of drug that produces a
Intrinsic property of any drug-receptor complex response equal to 50% of the maximal response
Expression of the tendency of drug-receptor complex (LR) to ◌ corresponds to the drug concentration at which 50% of the
bind together or dissociate receptors are occupied by the drug
At state of equilibrium, the fraction of receptors in free & in Since Kd of drug A is lower, it has a greater affinity for the
bound forms is dependent upon the Kd receptor than drug B & therefore will bind to more receptors
◌ Kd = affinity of ligand to receptor than drug B at any given concentration
□ Favors equation above to go to the right ◌ The smaller the Kd = the more potent the drug
◌ Kd = affinity = greater chance of dissociation ◌ Potency – ability of a drug to promote at least 50% response
□ Favors equation to go to left Since the rang of drug concentrations (from 1% to 99% of the
maximal response) usually spans several orders of magnitude,
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 6 of 11
PHARMACODYNAMICS Pharmacology A
semi logarithmic plots (Plot B above) are used so that the dose range for candesartan is 4 to 32 mg, as compared to 75 to
complete range of doses can be graphed 300 mg for irbesartan.
Therefore, candesartan is more potent than is irbesartan (it has
DOSE-RESPONSE RELATIONSHIPS a lower EC50 value similar to Drug A in the figure above)
For most drugs, the drug or ligand-receptor binding relationship
& the dose-response relationship are closely related Efficacy
The dose-response relationship is the quantitative AKA maximal efficacy
representation of pharmacodynamics Represented by Emax
Relationship between the amount of a drug (concentration) & Magnitude of response a drug causes when it interacts with a
the patient’s response to it receptor
Often assumed that this said response is proportional to the Largest effect that can be achieved with a particular drug
concentration of receptors occupied by the drug, as is shown in regardless of dose
the equation below:
Dependent on the number of drug-receptor complexes formed
Equation 5 (Drug-Dose Relationship)
& the intrinsic activity of the drug (its ability to activate the
𝑹𝒆𝒔𝒑𝒐𝒏𝒔𝒆 [𝑫𝑹] [𝑫] receptor & cause a cellular response)
𝑴𝒂𝒙𝒊𝒎𝒖𝒎 𝑹𝒆𝒔𝒑𝒐𝒏𝒔𝒆
=
𝑹𝒐
=
[𝑫] + 𝑲𝒅 Assumes that all receptors are occupied by a drug & no increase
in response is observed if a higher concentration of drug is
[D] = Concentration of free drug administered
[DR] = Concentraiton of drug-reeptor complex More clinically useful than drug potency since a drug with
[Ro] = concentration of total receptors greater efficacy is more therapeutically beneficial than is one
Kd = equilibrium dissociation constant for the drug- that is more potent
receptor complex
Potency
Represented by EC50
Measure of the amount of drug necessary to produce an effect Drug A & B are said to be more potent than C & D
of a given magnitude Drug A, C & D have equal maximum efficacy & all have a greater
Concentration of drug producing 50% of the maximum effect maximal efficacy than drug B
(EC50) Although the responses depicted in curves A, B & C
In the figure above, the EC50 for drug A & B indicate that Drug A approximated the shape of a simple Michaelis-Menten relation
is more potent than Drug B. Why? (transformed to a logarithmic plot), some clinical responses do
◌ Because a lesser amount of Drug A is needed when not
compared to Drug B to obtain 50% effect Extremely steep dose-response curves (e.g., curve D) may have
Therapeutic preparations of drugs reflect their potency. For important clinical consequences if the upper portion of the curve
example, candesartan & irbesartan are angiotensin receptor represents an undesirable extent of response (e.g., coma caused
blockers that are used to treat hypertension. The therapeutic by a sedative-hypnotic)
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 7 of 11
PHARMACODYNAMICS Pharmacology A
Note:
In choosing a drug to administer to a patient, the clinician
considers their relative effectiveness rather than their relative
potency
Potency largely determines the administered dose of the chosen
drug which is usually stated in dosage units in relation to a
particular therapeutic goal (e.g., mild sedation)
Agonists
Drug that activates its receptor upon binding
Drug or endogenous ligand that stabilizes their corresponding
receptors into their active conformation upon binding
If an agonist binds to its receptor, it will become activated & an
effect will be elicited
Full Agonists
Drug capable of fully activating the effector system when it binds
to the receptor
If a drug binds to a receptor & produces a maximal biologic
response that mimics the response to the endogenous ligand, it
Graph of the increasing fraction of a population that shows a is a full agonist
specified response at progressively increasing doses Binds to a receptor, stabilizing the receptor in its active state &
Describe the drug concentrations that elicit a particular effect in are said to have an intrinsic activity of one
a population
Partial Agonists
Plots plot the fraction of the population that responds to a
certain dosage of the drug versus the drug dose Have intrinsic activities greater than zero but less than one
These curves show the average drug effect elicited by particular Produces less than the full effect even when it has saturated the
dosages in a population receptors
These curves show the percentage of individuals that respond to Even if all the receptors are occupied, partial agonist cannot
each drug dose produce the same Emax as a full agonist
Useful in predicting the effects of a drug when it is given to a In the presence of a full agonist, a partia agonist acts as an
population of individuals & for determining population-based inhibitor
toxic & lethal doses As the number s of receptors occupied by the partial agonist
Concerned with the following important drug doses: increases, the Emax would decrease until it reached the Emax of
◌ ED50 – drug dose that causes a therapeutic response in half the partial agonist this potential of partial agonists to act as
of the population (median effective dose) both an agonist & antagonist may be therapeutically utilized
□ Vs. EC50 – dose at which a drug elicits a half-maximal For example, aripiprazole, an atypical antipsychotic, is a partial
effect in an individual subject agonist at selective dopamine receptors
◌ TD50 – drug dose that causes a toxic response in half of the ◌ Dopaminergic pathways that are overactive tend to be
population (median toxic dose) inhibited whereas pathways that are underactive are
◌ LD50 – drug dose at which 50% subjects die (median lethal stimulated
dose)
Inverse Agonists
DRUG-RECEPTOR INTERACTIONS Typically, bound receptors are inactive & require interaction
Generally speaking, drug receptors have two conformational with an agonist to assume an active conformation. However,
states: some receptors show a spontaneous conversion from the
◌ Active State inactive form to active form in the absence of an agonist
◌ Inactive States Inverse agonists, unlike full agonists, stabilize the inactive form
These 2 forms are in reversible equilibrium Causes active form of receptor to convert to inactive form
Pharmacologic properties of drugs reside in their ability to affect decreasing the number of activated receptors to below that
this balance by favoring receptors to assume one configuration observed in the absence of drug
over the other Thus, inverse agonists have an intrinsic activity less than zero,
reverse the activity of receptors & exert the opposite
pharmacologic effect of agonists
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 8 of 11
PHARMACODYNAMICS Pharmacology A
ANTAGONISTS ◌
Although the potency of the agonist decreases as the
Antagonists bind to a receptor with high affinity but possess zero concentration of competitive antagonist increases, the
intrinsic activity efficacy of the agonist is unaffected. WHY?
Has no effect in the absence of an agonist BUT can decrease the □ Because the agonist concentration can be increased to
effect of an agonist when present fight off antagonistic effect – “outcompete”
Antagonism may occur either by blocking the drug’s ability to antagonist’s effect is said to be “reversed or washed
bind to the receptor or by blocking its ability to activate the out”
receptor Example: Statins
◌ Competitive antagonists of HMG CoA on the active site of
HMGCoA reductase enzyme (rate-limiting step in
cholesterol biosynthesis)
◌ Statins & HMG CoA are similar in structure allowing statins
to bind to the active site of the reductase enzyme leading
to decreases endogenous cholesterol synthesis
Types of Antagonists
◌ Receptor antagonists
□ Competitive receptor antagonists
□ Noncompetitive receptor antagonists
◌ Non Receptor antagonists
□ Chemical antagonists
□ Physiologic antagonists
Receptor antagonists
Can bind to the active site or allosteric site in the receptor
Irreversible binding
◌Occurs when a drug is bound covalently or has a very high
affinity to a receptor
◌ Cannot be outcompeted by increasing the dose of the
agonist & is therefore noncompetitive
Allosteric binding
Binds either to the ◌ Drug that binds to a receptor molecule without interfering
◌ active site (where the agonist binds) preventing binding with normal agonist binding but alters the response to the
of the agonists to the receptor (competitive binding) normal agonist
◌ allosteric site of the receptor preventing the ◌ Occurs when antagonists binds to an allosteric site of the
conformational change required for receptor activation receptor preventing the receptor from being activated by
(noncompetitive binding) the agonist
can be reversible or irreversible ◌ Also a form of noncompetitive antagonism whether the
binding is reversible or irreversible
Competitive Receptor Antagonists □ If reversible, effects wash out over time as it
dissociates
□ If irreversible, effects will not diminish
Characteristically causes a downward shift of the Emax, with no
shift of EC50 values
If both the antagonist & the agonist bind to the same site on the
receptor in a reversible manner, they are said to be
“competitive”
Prevents an agonist from binding to its receptor & maintains the
receptor in its inactive state
Competitive agonists
Can be overcome by increasing the concentration of agonist
◌ Reduces agonist potency (increase EC50)
relative to antagonist
◌ Shifts the agonist curve to the right
Characteristically shift the agonist dose-response curve to the
Noncompetitive antagonists
right (increased EC50) without affecting Emax
◌ Reduce agonist efficacy (decrease Emax)
End Result: potency but efficacy remains the same ◌ Shifts the agonist curve downward
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 9 of 11
PHARMACODYNAMICS Pharmacology A
Physiologic Antagonists
Drug that counters the effect of another drug by binding to a
different receptor & causing opposing effects
Binds to a different receptor molecule producing an effect
opposite to that produce by the drug it antagonizes In a system with spare receptors, the EC50 is less than the Kd,
Example: -blockers in tachycardia induced by hyperthyroidism indicating that to achieve 50% of maximal effect, less than 50%
◌ -blockers can relieve the condition by blocking cardiac - of the receptors must be activated
adrenergic stimulation to produce an opposite physiologic In some cases, it is not necessary to occupy every receptor with
effect to that produced by thyroid hormones (which bind drug to elicit a full response
receptors found in the nuclear membrane) ◌ Presence of spare receptors increases sensitivity to the
◌ Note that the tachycardia produced by elevated thyroid agonist because the likelihood of a drug-receptor
hormones is not mediated through stimulation of - interaction increases in proportion to the number of
adrenergic receptors in the heart receptors available
Example: Epinephrine in histamine-induced bronchoconstriction
◌ Histamine binds to H1 receptors on bronchial smooth Effect of Noncompetitive Antagonist in the
muscle causing bronchoconstriction of the bronchial tree absence & presence of spare receptors
◌ Epinephrine is an agonist at 2-adrenoceptors on bronchial
smooth muscle which causes the muscles to relax
Summary
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 10 of 11
PHARMACODYNAMICS Pharmacology A
Therapeutic Window
More clinically useful index of safety
Describes the dosage range between the minimum effective
therapeutic concentration or dose & the minimum toxic
concentration or dose
For example, if the average minimum therapeutic plasma
concentration of theophylline is 8 mg/L & toxic effects are
observed at 18 mg/L, the therapeutic window is 8-18 mg/L
Ratio of the dose that produces toxicity in half the population Both the therapeutic index & the therapeutic window depend on
TD50 to the dose that produces a clinically desired or effective the specific toxic effects used in the determination
response ED50 in half the population
Measure of a drug’s safety because a larger value indicates a
wide margin between doses that are effective & doses that are
toxic
Act at same site as full agonist, but with lower maximal effect ( efficacy)
Partial Agonist (alone)
Potency is an independent variable
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + Golan, 4th Ed Page 11 of 11