Lecture 2- E1 : drug-receptor interactions Flashcards
what is pharmacodynamics (PD)
how the drug affects the body (drug fixes disease)
what is pharmacokinetics (PK)
the effect of the body on the drug (the body reacting to a foreigner what it does to metabolize, eliminate)
what is PK sometimes referred to as
ADME
absorption, distribution, metabolism, excretion
what are some drugs that do NOT require a target receptor to evoke their response
osmotic diuretics (mannitol), antidotes for heavy metal poisoning, most laxative (lactulose, polyethylene glycol), and antacids neutralizing the hydrochloric acid in stomach
Where did the concept of receptor evolve from
pioneering work of Lanley and Ehrich (early 20th century)
how do most drugs work?
most drugs work in a structurally specific way stemming from how they react at each target molecule (receptor) to excrete their therapeutic or toxic effects
what can bind to a receptor?
specific molecules such as neurotransmitters, hormones, metabolites, or drug molecules
all initiating some type of cellular response
how do biological actions of drug come to be enforced?
a drug can cause biological and biophysical changes in the receptor site which then create physiological changes in the body that show the drugs actions/effect
what do receptors largely determine
the relations between the dose/ concentration of drug and its pharmacological effects
what determines the drug concentration needed to form an adequate amount of drug receptor complexes
affinity for (attraction for) binding a drug
what can limit the maximal effect a drug may produce
the total amount of receptors
( which is determined by the concentration of drug needed)
van der waals bond strength
very weak
also hydrophobic
high affinity
less drug dose
(because its easier for the drug to bind and produce a strong cellular signal so you don’t need as many receptors- which the number is determined by concentration)
the specificity of the overall drug-receptor interaction is determined by what?
the ensemble of the interactions between chemical interactions (different types/strengths of bonds)
how is affinity measured/reported?
by the Kd value
what is the Kd value
a concentration
a measure of the favorability for a particular drug for its receptor
If the Kdis low, the binding affinity is high, and vice versa.
kd is the value it will take to fill 50% of receptors (E50)
can tell us how well a drug can bind to a receptor
affinity contributes to overall..
potency
efficacy
duration of drug action
what can significantly alter binding interactions of drugs
even a minor variation in functionality of the drug molecule
Non-covalent bonds
- Ionic Bonds
- Dipole Interactions
- Hydrogen Bonds: a specialized type of Dipole-Dipole bond ( a hydrogen and individual atoms)
- van der Waals Interactions
- Hydrophobic Bonding
- Chelation and Complexation
- Charge Transfer Interactions
hydrophobic and van der waals work closely together
ionic bond
complete transfer of valence electron to attain stability
Dipole interaction
partial charge bonded with opposite partial charge
Hydrogen bond
H–F,O,N
van der Waals
all Carbons
hydrophobic
hydrophobic interaction
arise as a consequence of the interaction of their hydrophobic (i.e., “water-disliking”) amino acids with the polar solvent, water.
the tendency of nonpolar molecules to minimize their contact with water.
chelation and complexation
Chelation is the complexation process by which a metal ion is bound to more than one atom in a single ligand.
What is a charge transfer interaction
an electron donor acceptor complex can be defined as an association of two or more molecules, or of different parts of a large molecule, in which a fraction of electronic charge is transferred between the molecular entities.
which bonds are permenant
covalent
most drug receptors are…
proteins
what produces a fractional occupancy of 50%
the concentration of a drug
Categories of protein receptors
enzymes,
ionotropic receptors or ion channels,
metabotropic receptors, kinase linked/related receptors,
nuclear receptors,
cytoskeletal or structural proteins, transporters/carrier proteins
example of enzyme as a protein drug receptor
dihydrofolate reductase, the receptor for the antineoplastic drug methoxetrate
example of metabotropic receptors as a protein drug receptor
G protein coupled receptors that bind to endogenously produced hormones, neurotransmitters, etc
example of kinase linked and related receptors as a protein drug receptor
receptors for various growth factors and thus for some anticancer drugs
example of nuclear receptors as a protein drug receptor
receptors for thyroid hormone, some fat soluble vitamins and steroids
example of cytoskeletal or structural proteins as a protein drug receptor
tubulin, the receptor for colchicine, anti inflammatory agent
example of transporters or carrier proteins as a protein drug receptor
Na+, K+, ATPase, the receptor for cardiac glycosides
what are the non protein receptors
nucleic acids (DNA, RNA) membranes, and fluid compartments
what receptor classes can be coupled as executioners or effector components and what do they do?
G protein couple receptors and growth factor receptors can be coupled as effector components as they create diverse cellular effects which can occur over a wider time scale
speed of effect production by ion channels
very fast (milleseconds)
speed of effect production by steroid and thyroid hormones
very slow ( several minutes to hours)
speed of GPCR effect production
intermediate time scale - seconds to minutes
what does the occupancy theory really mean?
that a response or effect is only elicited when a drug or ligand is BOUND to the receptor- it isn’t the receptor that elicits this response
% bound = % response
Emax values
full Emax =1
partial Emax <1
super Emax >1
Occupancy theory ( laws of mass action) variables
D+R bind reversibly to form DR complex
DR complex creates E (effect)
in the occupancy theory, the magnitude or intensity of the response (E) is directly proportional to what
the amount or concentration of the DR complex
how is Kd derived from occupancy theory graphs?
where the fractional occupancy is quantified by using the equilibrium
- the graph will flatten out even if you continue to increase concentration of drug because you met the equilibrium where the effect (response) maximum has hit showing where the drug concentration (x axis) needs to be for that effect
When is Emax hit
when all of the receptors (Rt) are occupied by the drug (forming the DR complex)
For an agonist in the occupancy theory, what is E
E can only come from the DR complex, and E is a function of the fractional occupancy ( which is determined by the concentration of a drug)
According to the Clark’s occupancy theory, the maximal response to the drug …
is equal to the maximal tissue response, leading to the expectation that all agonists would produce the same maximal response.
For some drugs, e.g., the partial agonists, maximum response can never be achieved even at extremely high doses. (Limitation 1 of the theory)
examples of Therapeutic index (TI)
penicillin (high window) and warfarin (low window)
how fast are effects produced by the following receptors channels:
- ion channels:
- steroid and thyroid hormones:
- GPCRs:
- ion channels: (milliseconds)
- steroid and thyroid hormones: (several minutes)
- GPCRs: (seconds to minutes)
equation for fractional occupancy
Limitations of occupancy theory
1.) According to the Clark’s occupancy theory, the maximal response to the drug is equal to the maximal tissue response, leading to the expectation that all agonists would produce the same maximal response. For some drugs, e.g., the partial agonists, maximum response can never be achieved even at extremely high doses. (Limitation 1 of the theory)
2.) Second, the occupancy theory assumes that the relationship between occupancy and response is linear and direct. Therefore, a 50% receptor occupancy will result in a half-maximal response and thus KD equals to EC50 (i.e. the concentration of drug producing 50% of Emax).
This is rarely seen in biological systems. Nickerson (1956) first showed that agonists such as histamine could produce a maximal tissue response at extremely low receptor occupancies (far less than maximal). (Limitation 2 of the theory)
According to the Clark’s occupancy theory, the maximal response to the drug is equal to
the maximal tissue response
what are spare receptors?
“receptor reserve”
- likely play a role in amplifying signal intensity and duration
-these remain unbound when an agonist produces its full effect ( so agonists don’t need to fill every receptor to maximize effect)
- may never come into play
- may allow cell activation by weak ligands
- allows for higher maximal effect when there are spare receptors present
Agonist vs Antagonist on a dose response curve graph
a pure agonist will reach maximal effect at a lower concentration (EC50 at lowest and equal to Kd)
pure antagonist will need more dose because it needs a higher concentration in order to reach Kd and maximum effect ( still able to reach this max because there are an adequate number of spare receptors
- as more antagonist is introduced, the number of spare receptors decreases and eventually can no longer hit the maximal effect
Are Kd and EC50 always equal?
NO
what is coupling
the overall transduction process that links drug occupancy of receptors and pharmacologic response
what is coupling determined by?
downstream biochemical events that transduce receptor occupancy into cellular responses
when are receptors said to be spare for a given pharmacological repsonse
if its possible to elicit a maximum biologic response (Emax) at a concentration of agonist that doesn’t result in occupancy of every available receptor
what does an agonist do
mimics body function or function of endogenously produced ligands
what does an antagonist do
opposed body function or can oppose biological effects of endogenous ligands
in the presence of a fixed agonist concentration what can inhibit this response
increasing the concentrations of competitive antagonist
high antagonist concentrations prevent the response almost completely
antagonist binds at the same place as agonist so they’re now competing for a place
define efficacy
the ability of a ligand to initiate receptor activation
what kind of ligand has both affinity and efficacy for cognate receptors?
agonists
what is a full agonist
mimic the physiologic agonist, e.g., isoproterenol (β-adrenergic agonist).
what is a partial agonist
- activate receptors but are unable to elicit the maximal response of the receptor system;
- e.g., Dobutamine (a partial agonist at β-adrenergic receptor).
- doesn’t keep the max effect on the curve- can act as a full agonist, or antagonist
what is an inverse agonist
-Inverse agonists cause constitutively active targets to become inactive
- e.g., antihistamines are considered as inverse agonists of H1 receptor.- very potent only need low dose
- powerful antagonist
competitive or reversible inhibition antagonist
bound to active site (noncovalent) - Examples: ACEI, rennin inhibitors, angiotensin receptor inhibitors.
what are non competitive or irreversible inhibitor antagonists
bound to active site (covalent) - Examples: inhibitors of acetylcholine esterase such as physostigmine, neostigmine etc., cyclooxygenase (COX) inhibition by aspirin, phenoxybenzamine antagonism of α-adrenergic receptor.
agonist and noncompetitive antagonist on a graph- EC50 is the same but cant get as high of effect as agonist alone
what are allosteric inhibition antagonists
different binding site which morphs the active site (dont bind to same active site in receptor)
-noncovalent mostly, can be covalent - Examples: nonnucleotide reverse transcriptase inhibitors, antihistamines binding to histamine H1 receptor.
what kind of ligand has affinity but lacks efficacy?
antagonists
advantages of noncompetitive (irreversible) antagonism
duration of action is independent on the drug half life. e.g. Aspirin and proton pump inhibitors (esomeprazole, omeprazole)
disadvantages of noncompetitive (irreversible) antagonism
reversal of drug effect in case of toxicity is complicated.
what are physiological antagonists:
two drugs acting on different cognate receptors have opposing pharmacological actions; e.g., histamine acts on receptors of the parietal cells of the gastric mucosa to stimulate acid secretion, while omeprazole blocks this effect by inhibiting the proton pump; the two drugs can be said to act as physiological antagonists.
- antagonist of particular receptor without direct interaction with that receptor
what are pharmacokinetic antagonists
reduce bioavailability, and thus the concentration of an agonist at its site of action through induction of drug metabolizing enzymes in the liver (e.g., Phenobarbital reducing the anticoagulant effect of warfarin this way), impaired absorption from GI tract or enhancement of renal excretion.
-antagonist of particular receptor without direct interaction with this receptor
___ produce a lower response at full receptor occupancy than do ___
partial agonist; full agonist
failure of partial agonists to produce max response is NOT due to
decreased affinity for binding to receptors
what do partial agonists do to full agonists
partial agonists competitively inhibit responses produced by full agonists…. “agonist-antagonist” property
can be beneficial or deleterious
ex-buprenorphine, partial agonist for u-opioid receptors, is gen. safer analgesic drug than than morphine bc less respiratory depression in overdose. however buprenorphine is effectively anti analgesic when administered with more efficacious opioid drugs
when there is [ ] of a full agonist and partial agonist together, what is the relationship?
inverse
potency refers to …
the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect.
how is potency stated
in dosage units (50 mg for mild sedation)
the potency of the drug depends on …
affinity Kd
coupled response
what is a quantal dose response
drug effect which is either present or absent
what do quantum dose effect curves show
-therapeutic index, median effective dose, median lethal dose, and other parameters to determine safe dose recommendations
- potential variability of responsiveness among individuals
limitations of quantal dose effect curves
-cant construct if pharmacological response is a quantal (either or) event such as prevention of convulsions, arrhythmia, death
- relevance of response in one patient is limtited in application to other patients
what is the therapeutic window?
the range between the minimum toxic dose and the minimum therapeutic dose
- of greater practical value in choosing the dose for the pt
define idiosyncratic drug response
unusual and infrequent response mostly due to genetic factors
define pharmacodynamics and describe its role in therapeutics
The drugs effect on the body
pharmcotherapeutics , our drug choice is dictated by what we need our drug to do, its pharmcodynamics if you will. Example, tissue plasminogen activator TPA is a powerful medicine that can break down blood clots. It is useful for a situation like ischemic stroke where a blood clot is the problem. However we wouldn’t use it for a cold since we have no reason to assume it will alleviate cold symptoms or otherwise combat rhinovirus
what is TD50
TD50 is the dose required to produce a toxic effect in 50% of the population
LD50 is
the amount of a material, given all at once, which causes the death of 50% (one half) of a group of test animals
What is ED50
The ED50 (median effective dose) is the dose of a medication that produces a specific effect in 50% of the population that takes that dose.
Define Therapeutic Index
defined as the ratio of the TD50 to ED50 from some therapeutically relevant effect
narrow therapeutic index is observed with_____
highly potent drug
(digoxin has small window while aspirin has large window)
- bigger window is safer
example for when therapeutic drug monitoring (TDM) is recommended
use with lithium (bipolar disorder) due to its narrow therapeutic range and phenytoin
what are quantitative variations
hyper reactive or hypo reactive
what is tolerance
decrease in the intensity of response to a given dose (usually over time)
what is tachyphylaxis
rapid tolerance
mechanisms of variation in drug responsiveness
variation in drug concentration at active site, variation in receptor coupling effect
what is therapeutic drug monitoring (TDM)
-drugs with narrow therapeutic range may have dosage adjusted according to actual blood levels in the person taking it
-recommended for use with lithium (bipolar disorder) and phenytoin (anticonvulsant)
- may do this in hospital before discharge
