Lecture 2- PD and drug-receptor interactions Flashcards
Pharmacodynamics (PD)
The effect of the drug on the body
Pharmacokinetics (PK)
Effect of the body on the drug (ADME)
- absorption
- distribution
- metabolism
- excretion
Is a target receptor necessary?
A few clinically useful drugs do not require a target receptor to evoke biological response (osmotic diuretics i.e. mannitol, antidotes for heavy metal poisoning
How do drug receptors function?
Most drugs have a specific structural interaction with specific cellular target molecules (receptors)
Who pioneered the concept of receptor?
Langley and Ehrlich in early twentieth century
Where is a receptor located pharmacologically?
Mostly on the cell membrane, but also within the cytoplasm or cell nucleus that binds to a specific molecule such as a neurotransmitter, hormone, metabolite, or a drug molecule and thereby initiating cellular response
What is the result of drug-induced changes in the biochemical and biophysical properties of the receptor?
physiological changes that constitute the biological actions of the drugs
What does a receptor’s affinity for binding a drug determine?
The concentration of drug required to form a significant number of drug-receptor complexes
What might the total number of receptors limit?
the maximal effect a drug may produce
Ensemble
Multiple chemical interactions (ie van der Waals, covalent..)
What does ensemble provide?
Specificity of the overall drug-receptor interaction
What is affinity (KD value)?
A measure of the favorability of a drug-receptor interaction
What contributes to the overall potency, efficacy, and duration of drug action?
Minor variation in the functionalities of the drug molecules can significantly alter the binding interactions
Bond Types
Covalent Bond
Non-covalent bonds
- ionic
- dipole
- hydrogen bonds (specialized dipole dipole)
- van der waals
- hydrophobic
- chelation and complexation
- charge transfer interactions
Covalent Interaction examples
alkylation and acylation
Receptor Classes
Protein and Non-protein
Types of protein drug receptors
Enzymes
Ionotropic
metabotropic
kinase
nuclear
cytoskeletal or structural
transporters or carrier
Types of non-protein receptors
nucleic acids (dna, rna), membranes, and fluid compartments
Enzyme example
dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate
ionotropic receptors or ion channels
ligand gated channels and voltage gated channels
metabotropic receptors
G-protein coupled receptors that bind to endogenously produced hormones, neurotransmitter, etc.
nuclear receptors
receptors for thyroid hormone, some fat-soluble vitamins and steroids
kinase linked and related receptors
receptors for various growth factors and thus for some anticancer drugs
cytoskeletal and structural proteins
ie tubulin, the receptor for colchicine, an anti-inflammatory agent
transporters or carrier proteins
ie Na+-K+ ATPase, the receptor for cardiac glycosides
Effector components
Can be coupled with a receptor (particularly GPCR) orchestrate diverse cellular effects which may occur over a wider time scale.
Also known as a respective executioner
Occupancy Theory
The maximal response of the drug is equal to the maximal tissue response
KD
It is the concentration of the drug that produces a fractional occupancy of 50%
Concentration: quantifies the ‘affinity’ of particular drug for its receptor
low Kd
binding affinity is high
high Kd
low binding affinity
What occurs with a large increase in drug concentration
Concentration of a receptor is finite within a tissue, so will saturate the receptor pool leading to secondary, less affinity binding to various non-specific sites other than the receptor protein. This may create unwanted side effects
1st limitation of 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, ie partial agonists, maximum response can never be achieved even at extremely high doses
Partial agonist
activate receptors but are unable to elicit the maximal response of the receptor system
Second limitation of Clark’s occupancy theory:
it assumes the relationship btwn occupancy and response is linear and direct.
(ie a 50% receptor occupancy will result in a half-maximal response and thus KD equals to EC50 –> the concentration of drug producing 50% of Emax)
What did Nickerson (1956) first show regarding agonists in occupancy theory?
that they could produce a maximal tissue response at extremely low receptor occupancies (far less than maximal)
Spare receptors
receptor reserve, drugs need to occupy only a minor proportion (<10%) of the total receptor population to evoke a maximum response
Dose-response curves
drug effect (y-axis) against the log of the dose or concentration (x-axis), transforming the hyperbolic curve into a sigmoid curve with a linear mid-portion
hyperbolic curve
drug dose and drug response are plotted in a linear way, produces a hyperbolic curve (plat
coupling
the overall transduction process that links drug occupancy of receptors and pharmacologic response
By what is coupling determined?
“downstream” biochemical events that transduce (causes) receptor occupancy into cellular response
What defines a receptor as “spare”
if it is possible to elicit a maximal biologic response at a concentration of agonist that does not result in occupancy of all of the available receptors
Two actions drugs can elicit upon binding at specific binding sites on their receptors
- Mimic the action of endogenously produced ligands as agonists
- Oppose the biological effects of the endogenous ligands as antagonists
Competitive antagonist
Increasing concentrations can progressively inhibit the (fixed concentration) agonist response.
High antagonist concentrations prevent the response almost completely
High agonist concentrations
Can surmount the effect of a given concentration of the antagonist (Emax for the agonist remains the same for any fixed concentration of antagonist)
Agonist of a receptor action:
activates the receptor (the binding of a drug induces changes in the structure of that receptor in such a way that a biologic response is elicited)
Efficacy
the ability of a ligand to initiate receptor activation
Full agonists (agonist subtype)
mimic the physiologic agonist (ie isoproterenol (B-adrenergic agonist))
Partial agonists (agonist subtype)
activate receptors but are unable to elicit the maximal response of the receptor system (ie dobutamine (partial agonist at B-adrenergic receptor))
inverse agonists (agonist subtype)
constitutively active targets to become inactive (ie antihistamines considered inverse agonists of H1 receptor)
cognate receptor
two typical biomolecules interacting
(ie ligand and receptor)
Two things agonists have
affinity and efficacy for cognate receptors
Antagonists
Have affinity but lack efficacy
Ways a drug can antagonize a receptor
Competitive or reversible inhibition
Non-competitive or irreversible inhibition
Allosteric inhibition
Competitive inhibitor
Occupies the active site and prevents binding of the physiological (ie endogenously produced) ligands. (ie ACEI, rennin inhibitors, angiotensin receptor inhibitors
Non-competitive or irreversible inhibitor
covalently binds at the active site of the enzyme and irreversibly inhibits it.
(ie inhibitors of acetylcholine esterase such as physostigmine, neostigmine, COX inhibition by aspirin, phenoxybenzamine antagonism of a-adrenergic receptor)
Allosteric inhibitor
binds at sites other than the active site, causing a conformational change in the enzyme that prevents it from binding to its physiological substrate.
(ie nonnucleotide reverse transcriptase inhibitors, antihistamines binding to histamine H1 receptor)
Agonist concentration-effect curves produced by a competitive antagonist or by an irreversible antagonist
Advantages Irreversible Antagonism
duration of action is independent on the drug half life (ie aspirin and proton pump inhibitors: esomeprazole, omeprazole)
Disadvantage Irreversible Antagonism
reversal of drug effect in case of toxicity is complicated
Physiological antagonists
two drugs acting on different cognate receptors have opposing pharmacological actions
(ie 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
reduce bioavailability, and thus the concentration of an agonist at its site of action through induction of drug metabolizing enzymes in the liver
Partial agonists vs full agonists
partial produces a lower response at full receptor occupancy and competitively inhibits the responses produced by full agonists.
Percentage of receptor occupancy resulting from full agonist (present at a single concentration) binding to receptors in the presence of increasing concentrations of a partial agonist.
How many main signaling mechanisms are there?
Five basic mechanisms of transmembrane signaling are well understood
- transmembrane signaling mechanism
A lipid-soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor
- transmembrane signaling mechanism
the signal binds to the extracellular domain of a transmembrane protein, thereby activating an enzymatic activity of its cytoplasmic domain
- transmembrane signaling mechanism
signal binds to the extracellular domain of a transmembrane receptor bound to a separate protein tyrosine kinase, which it activates
- transmembrane signaling membrane
the signal binds to and directly regulates the opening of an ion channel
- transmembrane signaling mechanism
signal binds to a cell-surface receptor linked to an effector enzyme by a G protein
Potency
concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect
What 2 things does potency depend on?
Affinity (Kd)
Coupled response
Maximal Efficacy
Max effect it can have while occupying the lowest proportion of receptors
(even if you add more drug, it won’t cause more response)
Graded dose-response curves limitations
impossible to construct if pharmacological response is an either-or (quantal) event (such as prevention of convulsions, arrhythmia, or death)
variability amongst patients in dose-response relation
Quantal dose-effect curves
plotting the cumulative frequency distribution of responders versus the log dose and the dose of drug required to produce a specified magnitude of effect
(variability in persons dose to elicit same response)
Therapeutic Index (TI)
the ratio of the TD50 (or LD50) to the ED50 for some therapeutically relevant effect.
TI examples
Digoxin has a narrow TI
Aspirin has a high TI
LD50 (TD50)
median lethal (toxic) dose
ED50
median effective dose
Therapeutic Window
range between minimum toxic dose and the minimum therapeutic dose
Idiosyncratic drug response
unusual and infrequent response mostly due to genetic factors
quantitative variations
hyper reactive or hyporeactive
tolerance
decrease in the intensity of response to a given dose (usually over time)
tachyphylaxis
rapid tolerance
mechanisms
variation in drug conc. at active site, variation in receptor expression, variation in receptor-coupling effect, etc
Therapeutic Drug Monitoring (TDM)
may have dosage adjusted according to measurements of the actual blood levels achieved in the person taking it
When is TDM recommended?
Lithium (for bipolar disorder due to narrow therapeutic range)j
Phenytoin (anticonvulsant)
