Lecture 2: drug-receptor interactions Flashcards
Examples of drugs that don’t require a target receptor to evoke biological responses
osmotic diuretics (e.g., mannitol),
antidotes for heavy metal poisoning, and most laxatives (e.g., lactulose, polyethylene glycol),
antacids neutralizing the hydrochloric acid in stomach)
Where did the concept of receptor evolve from
pioneering work of Lanley and Ehrich
how do most drugs work?
in a structurally specific way (their therapeutic and toxic effects stem from their interactions with specific cellular target molecules collectively known as receptors
What determines the concentration of drug required to form a significant number of drug-receptor complexes?
affinity for binding a drug
high affinity =
less drug dose
what limits the maximal effect a drug may produce?
the total number of receptors
what provides the specificity of the overall drug-receptor interaction
the ensemble of the interactions
receptor is associated with
enzyme(?)
van der Waals
hydrophobic (dislikes water)
weak bond
how is affinity measured/reported?
by the Kd value
affinity contributes to overall..
potency
efficacy
duration of drug action
Non-covalent bonds
Ionic Bonds
Dipole Interactions
Hydrogen Bonds: a specialized type of Dipole-Dipole bond
van der Waals Interactions
Hydrophobic Bonding
Chelation and Complexation
Charge Transfer Interactions
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 drugs are…
proteins
What is Kd?
a concentration and it quantifies the ‘affinity’ for a particular drug for its receptor.
If the Kdis low, the binding affinity is high, and vice versa.
It is the ____ of the drug that produces a fractional occupancy of 50%…
concentration
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)
list of protein receptors
enzymes
ionotropic/ion channels
metabotropic
kinase linked and related receptors
nuclear receptors
cytoskeletal or structural proteins
transporters/carrier proteins
example of enzyme receptors
dihydrofolate reductast: receptor for antineoplastic drug methotrexate
example of iontropic receptors/ion channels
ligand gated channels and voltage gated channels
example of metabotropic receptors
G-protein coupled receptors binding to endogenously produce hormones
neurotransmitters
what are kinase linked and related receptors
receptors for various growth factors and for some anticancer drugs
examples of nuclear receptors
receptors for thyroid hormone
some fat-soluble vitamins and steroids
examples of cytoskeletal or structural proteins
tubulin, the receptor for colchicine, and anti-inflammatory agent
examples of transporters or carrier proteins
NA+, K+, ATPase, the receptor for cardiac glycosides
examples of non-protein receptors
nucleic acids (DNA/RNA)
membranes
fluid compartments
____ receptors can be coupled to respective executioner or effector components that orchestrate diverse cellular effects which may occur over a wider time scale
GPCR
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)
laws of occupancy theory:
The drug (D) and receptor (R) bind reversibly to form a drug-receptor complex (DR) in 1:1 stoichiometry. The DR complex generates a response (E): D + R ↔️ DR → E.
The magnitude or intensity of the response is directly proportional to the amount or concentration of the DR complex ([DR]) formed: (E ∝ [DR]).
The maximum possible response (Emax) is elicited when all the receptors (RT) become occupied by the drug, forming the DR complex: (when [DR] = [RT], E = Emax).
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?
receptors that remain unbound when an agonist is producing its maximal biologic response
receptor reserve’ –> and drugs need to occupy only a minor proportion (≤10%) of the total receptor population to evoke a maximum response.
Are Kd and EC50 always equal?
NO
what is the overall transduction process that links drug occupancy of receptors and pharmacologic response?
coupling
what is coupling determined by?
downstream biochemical events that transduce receptor occupancy into cellular responses
define efficacy
the ability of a ligand to initiate receptor activation
what kind of ligand has both affinity and efficacy?
agonist
types of agonists
1.) Full agonists: mimic the physiologic agonist, e.g., isoproterenol (β-adrenergic agonist).
2.) Partial agonists: activate receptors but are unable to elicit the maximal response of the receptor system; e.g., Dobutamine (a partial agonist at β-adrenergic receptor).
3.) Inverse agonists: Inverse agonists cause constitutively active targets to become inactive; e.g., antihistamines are considered as inverse agonists of H1 receptor.
types of antagonists
1.) Competitive or reversible inhibition - bound to active site (noncovalent) - Examples: ACEI, rennin inhibitors, angiotensin receptor inhibitors.
2.) Non-competitive or irreversible inhibition - 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.
3.) Allosteric inhibition - different binding site which morphs the active site (noncovalent mostly) - Examples: nonnucleotide reverse transcriptase inhibitors, antihistamines binding to histamine H1 receptor.
what kind of ligand has affinity but lacks efficacy?
antagonists
advantages and disadvantages of noncompetitive (irreversible) antagonism
Advantages: duration of action is independent on the drug half life. e.g. Aspirin and proton pump inhibitors (esomeprazole, omeprazole)
Disadvantage: reversal of drug effect in case of toxicity is complicated.
less commonly know antagonists that act as antagonists of particular receptors without direct interaction with these receptors
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.
Pharmacokinetic antagonists: decreases another drug’s concentration at the site of action—-> 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.
___ produce a lower response at full receptor occupancy than do ___
partial agonist; full agonist
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.
the potency of the drug depends on …
affinity Kd
coupled response
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
example for when therapeutic drug monitoring (TDM) is recommended
use with lithium (bipolar disorder) due to its narrow therapeutic range and phenytoin
