Lecture 2: Pharmacodynamics Part 2 Flashcards
We decide whether something is a full or partial agonist solely based on:
Efficacy. Potency doesn’t have any part in determining if something is an agonist.
An agonist makes it more likely that a receptor will exist in the (more/less) active state
More active state. An agonist shifts the equilibrium toward the active receptor state.
T/F: Receptors can spontaneously convert to the active state without the agonist
True, there can be spontaneous conversion and the biological effect will be the same.
Inverse agonists
Drive equilibrium of the receptor from the active to the inactive state. It may destabilize the active state or stabilize the inactive state to do this.
Spontaneous dissociation of the agonist is caused by :
Random kinetic fluctuations
What would you expect to happen if you added an antagonist alone to an experimental setup?
No change in the experiment subject (e.g. blood vessel diameter would stay the same). Antagonists bind to receptors, but the receptor activity is only impacted in the presence of an agonist.
What would happen if you added an inverse agonist to an experimental setup?
The inverse agonist would cause the opposite effect of the agonist. For example, if the agonist causes a blood vessel to dilate the inverse agonist causes it to constrict.
______ have an independent impact upon receptor activity
Agonists and inverse agonists
______ have no functional impact on a receptor when they act alone
Antagonists
Types of Antagonism
- Chemical
- Physiological
- Pharmacological
Chemical Antagonism
Direct interaction of two substances in solution such that the effect of one or both is lost.
E.g. protamine (acidic anticoagulant) and heparin (basic anticoagulant); these drugs will associate with each other due to their opposite pH and the activity of both drugs is lost.
Physiological Antagonism
Indirect interaction of two substances with opposing physiological actions
E.g. Histamine lowers BP through vasodilation by binding histamine H1 receptor. Epinephrine raises blood pressure through vasoconstriction by binding alpha1-adrenergic receptors. These substances act on two different receptors to have two opposing effects.
Pharmacological Antagonism
Blockage of interaction of one substance with its receptor by another substance.
E.g. Cimetidine blocks binding of histamine to H2 receptors resulting in lower gastric acid secretion. It is a good drug for treating ulcers.
Pharmacological Antagonists bind receptors but do not __________. Their biological effects are derived from ______.
- activate signal transduction mechanisms. There is no functional impact on the receptor.
- blocking the ability of an agonist to bind and/or activate a receptor.
Two major subgroups of pharmacological antagonists
Competitive antagonists and non-competitive antagonists
Competitive antagonists
- Bind reversibly to the receptor
- Inhibition can be overcome by increasing agonist concentration
- Primarily affect agonist potency
Non-competitive antagonists
- Bind irreversibly to the receptor or allosterically (bind in a spot different than where the agonist binds)
- Inhibition cannot be overcome by increasing agonist concentration
- Primarily affect efficacy
What happens if the amount of agonist is increased in the presence of a competitive antagonist?
The competitive antagonist will be replaced by the agonist and restore the maximum biological effect.
Compare the potency and efficacy of an agonist in the absence and presence of a competitive antagonist
- Absence: maximum potency and maximum efficacy
- Presence: Potency is reduced, but maximum efficacy is retained. The full effect can still happen, but more of the agonist is needed to reach it.
- The same number of drug-receptor complexes can be formed, we just need more drug present because it must outcompete the antagonist.
T/F: Competitive antagonists reduce the number of receptors available for activation by the agonist
False. The same number of receptors are available because the antagonist binds reversibly to the receptor and a higher concentration of agonist can compete with the antagonist, causing it to unbind the receptor.
In the presence of a competitive antagonist, the dose-response curve for an agonist will shift:
Right. This is because the potency of the agonist is reduced.
Non-competitive antagonists bind ___ to receptors.
Irreversibly/covalently
What happens when you add more agonist in the presence of a non-competitive antagonist?
Nothing happens because the non-competitive antagonist is bound covalently to the receptor, so the higher concentration of agonist cannot compete with it. The full magnitude of biological effect cannot be retained.
Compare the potency and efficacy of an agonist in the absence and presence of a non-competitive antagonist
Absence: maximum potency and efficacy
Presence: There is no change in potency, but efficacy is reduced. This is because a non-competitive antagonist reduces the number of receptors available to be activated so less drug-receptor complexes can be formed the magnitude of the biological effect is lowered.
T/F: Non competitive antagonists reduce the number of receptors available for activation by the agonist
True. Because the antagonist binds covalently/irreversibly, the number of available receptors decreases.
Propanolol function
Antagonist of heart B1-adrenergic receptors. It blocks the interaction of epinephrine and B1-adrenergic receptors.
When you give increasing doses of propanolol, you would expect ____.
Decreasing heart rate.
ED50/ID50/IC50
ID50= inhibitory dose IC50= inhibitory concentration
The antagonist dose at which 50% of Emax is achieved. This is also a reflection of potency.
Emax of an antagonist
Reflects the maximum biological effect achieved by an antagonist. This is NOT a measure of efficacy, because only agonists have efficacy.
-Efficacy refers to the functional impact a ligand has on a receptor. An antagonist does not have an impact on receptor function; it will bind, but it doesn’t change receptor function. It just blocks the agonist from binding.
T/F: Antagonists have efficacy
FALSE. Efficacy refers to the functional impact a ligand has on a receptor. An antagonist does not have an impact on receptor function; it will bind, but it doesn’t change receptor function. It just blocks the agonist from binding.
Most endogenous receptor ligands such as hormones and neurotransmitters are:
Full agonists. Generally, the reference point for measuring efficacy is the effect of the endogenous ligand, so this makes sense.
Endogenous inverse agonist example
These are VERY RARE.
Example: Agouti-related peptide (AGRP).
-It reduces constitutive receptor activity of melanocortin receptor (McR). Physiologically this increases food intake and reduces energy expenditure.
Endogenous pure antagonist example
Rare.
-Kynurenic acid is an NMDA receptor antagonist. May play a role in neurotransmission and neuropathogenesis.
Isoproterenol is a drug that mimics _____
the effect of the endogenous agonist epinephrine at the cardiac B1-adrenergic receptor. It is a full agonist.
Why would you want to mimic the effect of an endogenous agonist? (2 reasons)
- Enhance the function of the endogenous agonist
- Replacement for a deficit in production of an endogenous agonist
Buprenorphine is an example of a ______. It mimics ______. It is safer than morphine because ____.
- Partial agonist
- Endogenous endorphins at μ-opiod receptors.
- as a partial antagonist, you can still get a good level of pain relief and you also lower the risk of respiratory depression with overdose that is possible with morphine, a full agonist.
Superagonists have less/greater efficacy than endogenous agonists.
Greater efficacy. Emax > 100%. Uncommon in clinical practice.
Propanolol (increases/reduces) potency and/or efficacy of endogenous agonists.
Reduces.
It is a pure antagonist of epinephrine at cardiac B1-adrenergic receptors. By doing this it can reduce heart rate.
Partial and inverse agonists can function as _______ with respect to full agonists.
Competitive antagonists.
Partial and inverse agonists will interact with the same receptors as endogenous full agonists, so in that way they can be competitive.
Drug Desensitization
When the effect of a drug diminishes when given continuously or repeatedly. Can be receptor-mediated or non-receptor-mediated.
aka: tachyphylaxis, refractoriness, resistance, tolerance
Receptor mediated drug desensitization
- Loss of receptor function
- Reduction of receptor number
Non-receptor mediated drug desensitization
- Reduction of receptor-coupled signaling components
- Reduction of drug concentration
- Physiological adaptation
Loss of receptor function causes _____ desensitization due to _______ caused by __________. There is no change in ________
- Rapid.
- change in receptor function
- feedback of cellular effects of agonists
- The number of receptors
Explain GPCRs as an example of losing receptor function during receptor mediated desensitization.
GPCRs have no gated activity on their own. When an agonist binds it promotes G protein binding to the receptor. This turns on enzymatic activity. This may cause the generation of 2nd messengers such as cAMP, which stimulates protein kinases that phosphorylate proteins and cause a cellular effect. Protein kinases can target GPCRs themselves, leading to phosphorylation of the GPCR receptor, which can interfere with coupling to the G proteins and therefore can reduce receptor function. This is a consequence of persistent receptor stimulation.
Reduction of receptor number is _______ desensitization. This is usually due to _________.
- slower, long term.
- feedback of cellular effects of agonists.
Explain GPCRs as an example of receptor mediated desensitization due to a reduced number of receptors.
- GPCRs -> 2nd messenger cAMP -> activation of protein kinases -> protein phosphorylation.
- Protein kinases can phosphorylate sites on GPCRs that control its localization on the cell surface i.e. can cause the receptor to be removed from the cell surface so that it is no longer available for activation. This is a consequence of the persistent stimuli and results in a reduction of receptor number.
Explain GPCRs as an example of non-receptor mediated desensitization caused by a reduction of receptor-coupled signalling components.
ATP is required to generate cAMP. With persistent stimulation of the pathway, ATP stores will be depleted and the amount of cAMP will therefore decrease, reducing the biological effect. This doesn’t entail any change in receptor function or number.
Non-receptor mediated desensitization (3)
- Reduciton of receptor-coupled signaling components
- Increased metabolic degradation
- Physiological adaptation
Explain non-receptor mediated desensitization caused by increased metabolic degradation
- An increase in drug metabolism such that the plasma concentrations go down over time and therefore the magnitude of effect decreases.
- Some drugs induce their own rate of metabolism, such that over time you have to increase the dosage with use over time.
Explain non-receptor mediated desensitization caused by physiological adaptation
An opposing homeostatic response reduces drug effects. A generalized change in physiology over time makes the drug less effective over time.
Adverse drug effects can be classified in 3 ways:
- Side effects
- Toxic reaction
- Allergic reaction
Side effects (3 main points)
- Dose dependent (more drug exposure= greater chance of side effect)
- Not directly related to desired effect of drug
- Action of drug at other sites to produce undesirable effects
Toxic reaction (3 main points)
- Dose dependent
- Directly related to desired effect of drug
- Excessive action of drug at intended target site. Intimately linked to what you are trying to achieve pharmacologically
Allergic reactions (3 main points)
- Not dose-dependent (different doses can cause same magnitude of reaction)
- Not related to desired effect of drug
- Immunologic response to drug (largely unpredictable)
Cyclosporine
An immunosuppressant commonly used in transplant medicine. Helps patient’s body accept the organ instead of rejecting it.
Desirable beneficial therapeutic effects of Cyclosporine
-Promotes survival of transplanted organs. Immunosuppression is a consequence of this intended pharmacological action. The magnitude of effect is dose-dependent.
Adverse effects of Cycolsporine in relation to the three types of adverse drug effects:
- Toxic reaction: Increased susceptibility to infection. Magnitude is dose-dependent
- Side effect: Kidney damage. Not related to immunosuppression, cyclosporine just does this to the kidney. Magnitude is dose-dependent.
- Allergic reaction: Rash, hives, itching, breathing difficulties. An allergic response to the drug that is not dose-dependent.
T/F: The nature of a drug determines its toxicity
False. The amount of a drug determines toxicity. Everything is potentially toxic in excess.
What is used to measure drug safety? Why is this beneficial?
Therapeutic index
-Considers dose required for a toxic or other adverse drug effect versus that required for the desired beneficial effect.
How do we devise a therapeutic index?
Find the ED50 for the beneficial effect and the toxic effect, and then divide toxic by beneficial.
Why shouldn’t we think of therapeutic indexes in absolute terms?
-We can tolerate smaller therapeutic indexes depending on the toxic effect (e.g. vomiting). However, if the toxic effect is something such as dying we cannot tolerate a small therapeutic index. We must only compare indexes when we are comparing two drugs with the same toxic effect.
Therapeutic Window can be expressed in two ways:
- With respect to blood levels of a drug
- With respect to dosages of a drug
Drug levels can exist in three levels in a patient:
High level: Unacceptable toxicity
Low level: No drug benefit
In between: THERAPEUTIC BENEFIT
In terms of blood levels, therapeutic window is defined as
The range of blood concentrations between the drug having no benefit and a level of unacceptable toxicity.
Define therapeutic window in respect to drug dosage
A measure of drug safety that considers the range of dosages of a drug that are associated with toxic (or other adverse drug effects), therapeutic benefit or lack of effect within a population
How is the therapeutic window defined in relationship to dosage? Assume that the clinical target is a beneficial effect in >90% of patients and toxicity is <10% in patients
We create a dosage effect curve, plotting both beneficial and toxic effects for the % of population. We then create a range/window from 90% on the beneficial curve to 10% on the toxic curve. We know that if the dosage falls between this range we will achieve the clinical target.
