LECTURE: 2-4 PHARMACODYNAMICS Flashcards
Receptor definition
broadly, any target molecule with which a drug molecule must combine in order to elicit an effect. Usually, a site through which some molecule (drug, hormone, neurotransmitter) acts to initiate a biochemical or physiological chain of events
Ligand definition
any molecule that binds to another biological entity, regardless of effect
Agonist
a molecule that acts at a receptor to initiate a response
Antagonist
a molecule that binds to a receptor without causing activation
Ways to measure drug-receptor interaction
- direct measurement of biological repsonse (concentration effect or dose effect curves)
- Indirect measurement of biological response (e.g. receptor binding)
C-E and D-E curves should not be used to measure affinity because
1) Response is not always directly proportional to occupancy
2) The concentration of a drug at a receptor is usually unknown
Graded dose reponse curves
- The response of a system is measured against increasing concentrations of a drug
- Continuous: e.g. smooth muscle contraction, change in blood pressure, change in rate of urine production
- Change in biological effect is plotted against the dose of the drug administered
- Gives us some information on the properties of the drug relevant to the system
- Referred to as concentration-effect, dose-effect, or dose-response curves (all the same thing)
- Doesn’t tell us occupancy or affinity
Emax
maximum effect drug has on the system
EC50/ED50
concentration of a drug that will elicit 50% of the maximum effect
Quantal dose response curves
- Quantal dose-response: effect is all or nothing
- E.g. live or dead, seizure or no seizure, conscious or unconscious
- Gives a population (normal) distribution
- Can be used to determine the lethal dose of a drug
- An example from the lab: murine tail flick test
- An experiment to test analgesics in mice, which flick the tail in response to pain (e.g. to heat)
LD50
dose which kills 50% of the population
difference in ED50 between graded and quantal dose-response curves
- In the graded dose-response curve, the ED50 refers to the concentration of a drug that will elicit 50% of the maximum effect
- In the quantal dose-response curve, the ED50 refers to the concentration of the drug that produces an effect in 50% of the population
difference in ED50 between graded and quantal dose-response curves
- In the graded dose-response curve, the ED50 refers to the concentration of a drug that will elicit 50% of the maximum effect
- In the quantal dose-response curve, the ED50 refers to the concentration of the drug that produces an effect in 50% of the population
TI
the window between the effective (therapeutic) dose and the lethal dose, which tells us the safety of the drug
TI = LD50/ED50
efficacy
the ability or “strength” of a single drug-receptor complex in evoking a response in tissue. This applies only to those compounds that elicit a response (agonists). For antagonists, efficacy is zero
affinity
the ‘tightness’ with which a ligand and receptor will bind (in general, a drug with low affinity for a receptor will need a higher concentration of drug to exert maximum effect and vice versa). Doesn’t comment on effectiveness of the drug and applies to agonists and antagonists. Measured by the equilibrium constant Kd.
potency
the amount of drug required to produce a given effect. In general, this is influenced by the combination of efficacy and affinity
efficacy vs. potency graph
Drug specificity
can be biological specificity or chemical specificity
Targets of drug action
1) drugs that depend on chemical properties and do not interact with cellular components
2) drugs that combine with specific molecular components
* lipids
* DNA
* protein - main focus
4 classes of protein receptors
- enzymes
- carrier molecules
- ion channels
- classical receptors
Enzymes (protein receptors)
- Inhibitor:
- A substrate analogue that acts as a competitive or non-competitive inhibitor - False substrate:
- The drug competes for the enzyme’s binding site, but produces an abnormal metabolite (e.g. different from the endogenous product) which ‘hijacks’ the normal pathway - Prodrug:
- These drugs are inactive when administered and are converted into the active compound by an enzyme (usually in the liver). Many drugs are prodrugs!
Carrier molecules (protein receptor)
- Transport molecules across lipid membranes (or blood brain barrier)
- Drugs may either utilize or block these carriers
- Normal transport: transport of ions and small molecules across membrane requires transporter protein- facilitated transport systems
- False substrate: similar to enzymes, hijacks carrier molecule to get across barrier
Ion channels
- Ion channel blockers: permeation of the channel blocked, ions cannot move through the channel
- Ion channel modulators: promote or repress normal function by binding to a specific site on the channel
Voltage-gated ion channels
- Target for many drug classes and toxins
Ligand-gated ion channels
- Target for many drug classes and toxins
Classical receptors (protein receptor)
- receptors found on cell membranes or inside the cell
- can be activated or inactivated
- G-protein coupled receptors (cAMP pathway and Phosphatidylinositol pathway)
- Enzyme-linked receptors
- Nuclear receptors
Classical receptors - activation by agonist leads to
o Ion channel modulation
o Enzyme activation or inhibition
o Activation or suppression of cell signaling molecules
o DNA transcription
Classical receptors - inactivation by an antagonist causes
activity to be blocked
G-protein coupled receptors involved in two main signal transduction pathways
o cAMP pathway
o Phosphatidylinositol pathway
G-protein coupled receptors are only found in
eukarytoes
what are G proteins
- Guanine nucleotide-binding proteins
- Transmit signals from stimuli outside cell to inside cell
- Turned ON when bound to GTP
- Turned OFF when bound to GDP
Occupancu of receptors refers to
the proportion of receptors occupied by a drug
Kd
dose that results in binding to 50% of the receptors
Spare receptors
receptors that do not bind drug in order for the maximum biological effect to be produced
spare receptor theory
- This means that the maximum biological response often occurs when fewer than 100% of receptors are activated
full agonist
Only a few receptors are activated for maximum response
Partial agonist
All receptors are occupied but maximum response is not reached
Inverse agonist
Bind to constitutive receptors and reduce activity
What happens when a full and partial agonist are given together
the partial agonist acts as a competitive antagonist and decreases net activation
Co-agonists
require two ligands to activate a receptor
Allosteric modulators
- Drugs that bind to an allosteric site (or regulatory site) and not the active site of a receptor
- This allows them to enhance or inhibit the effects of the endogenous ligand
- Conformational change by drug binding changes the binding affinity of the endogenous ligand, to regulate the ‘strength’ of its effects
irreversible agonists
- These permanently and irreversibly bind to a receptor by forming covalent bonds
Physiological agonists
- These are molecules that produce the same effects in the body as another molecule without binding to the same receptor
Mixed agonist-antagonists
- Drugs that act as an agonist in some tissues and antagonist in other tissues (e.g. selective oestrogen receptor modulators)
OR - Is an agonist at some receptor subtypes and an antagonist at other subtypes (e.g. lots of opioids)
Do antagonists have affinity and efficacy?
they have affinity for receptors, but dont have efficacy
Where do antagonists bind
- active site
- allosteric site
competiive antagonists
- The antagonist competes with the agonist for the binding site
- Reverdsible or irreversible
Reversible competitive antagonism
- Surmountable
- Bind via non-covalent bonds and will eventually dissociate from the receptor
- Addition of enough agonist will displace the antagonist, allowing a full response to occur
- Expressed as a parallel shift in the agonist dose-response curve
Irreversible competiitve antagonism
- Non-surmountable
- Bind via covalent bonds and will permanently antagonize the receptor (until it is ubiquitinated or the drug metabolized)
- No amount of agonist will displace the antagonist from the receptor, so no full response can occur
- Expressed as a decrease in the agonist dose-response curve
Non competitive antagonists
- These bind somewhere other than the active site and block the chain of events that leads to an agonist response
- Reduce the magnitude of the maximal response that can be achieved by an agonist
- May be reversible or irreversible
Uncompetitive antagonists
- Not the same as non-competitive antagonists
- Require the receptor to be activated by an agonist before they can bind to an allosteric site
- Somewhat paradoxical kinetics: the same concentration of antagonist is better able to block higher concentrations of an agonist than it is lower concentrations
Chemical antagonists
- Chemical antagonism occurs when two substances combine in solution (e.g. the body) and the agonist is inactivated, thereby reducing the concentration of active drug circulating
- An important class of chemical antagonists are chelating agents used to treat heavy metal poisoning
Pharmacokinetic antagonists
- This refers to a drug reducing or inhibiting the effect of another by interfering with its absorption, distribution, metabolism or elimination
- Lots of drugs do this by accelerating the hepatic metabolism of others
Physiological antagonists
- Physiological antagonism refers to the interaction of two drugs whose opposing actions cancel each other out
Inverse agonists
- Drugs that bind to a receptor and have the opposite effect to an agonist
- Receptors must have an intrinsic level of activity in the absence of a ligand for an inverse agonist to induce a ‘negative’ effect
- Inverse agonists are considered to have negative efficacy
- Many drugs previously assumed to be antagonists are actually inverse agonists (e.g. most antihistamines)
Inverse agonists: mechanism
- Theoretically, G protein-coupled receptors exist in an equilibrium of either active or inactive states whilst no ligand is present
- Inverse agonists induce conformational changes that shift this equilibrium and switch the receptor from an active to inactive state
- The inactive state is ‘stabilized’ by the inverse agonist, which suppresses agonist-independent activity of the receptor
- The magnitude of effect of the inverse agonist depends on the intrinsic activity of the receptor
- Also may depend on other drugs: e.g. Naloxone is an antagonist of the mu opioid receptor under basal conditions, but in the presence of morphine acts as an inverse agonist
