Drug Receptor interactions Flashcards
Describe the importance of understanding receptors
• PHARMACEUTICAL INDUSTRY AND DRUG DEVELOPMENT
34 of the top 100 drugs on the market target G-protein coupled receptors. Drugs induce effects by binding to receptors
• PHYSIOLOGY OF ENDOGENOUS TRANSMITTERS
Transmitters and hormones act primarily upon receptor targets
• CHEMICAL TOXICITY
Many toxic mechanisms are receptor mediated
• VIRAL TOXICITY
Viruses and other microorganisms can target receptors. Viruses can enter cells through receptor-mediated methods
• Million dollar business
• Pharmacodynamics : What drug does to body, its mechanism of action
• Pharmacokinetics : What the body does to drug, how drug is absorbed, distributed, metabolised, excreted (ADME)
Describe how a ligand-gated ion channel works and G-protein coupled receptor
• Ligand gated ion channels – ionotropic receptors.
With this type of receptor an ion binds to the receptor (negative or positive). This causes hyperpolarisation or depolarisation of your cell. This induced a biological effect. It is a very fast response as it takes milliseconds to open the ion channel. By binding this can induce a physiological or pharmacological effect.
• G-protein coupled receptors – metabotropic receptors
The ligand or drug binds to the receptor, this activates the receptor, this will stimulate a second messenger which will eventually produce a pharmacological effect. This takes a bit longer to activate the second messenger.
Define the fundamentals terms of pharmacology
AGONIST – produces a biological effect.
• A drug that binds to a receptor and elicits a biological response
ANTAGONIST – this will block the biological effect. Binds and blocks
• A drug that blocks the action of an agonist compound: commonly by binding to a receptor without eliciting a biological response
PARTIAL AGONIST.
• An agonist drug that produces a biological effect, but never the maximal of which the tissue is capable - partial agonists possess antagonist properties. Used for the treatment of various diseases.
• INVERSE AGONIST
An agonist that produces an opposing biological response to that observed by a full agonist
• AFFINITY
Ability of a drug molecule to bind to a receptor site. How tightly does it bind? Is it loose or tight? BINDING
• EFFICACY
Ability of a drug to elicit a biological response from a drug receptor interaction. Induce a response such as heartrate. INDUCE REPONSE
Describe what happens when a drug binds to a receptor
• How do we measure and compare affinities and efficacies of drugs?
Important for understanding how a correct dose is determined
• The drug binds to the free (binding site not occupied) receptor forming an agonist-receptor complex.
• Conformational change of receptor.
• This complex will get activated and induce a second mechanism and eventually produce a response. The efficacy governs the response.
• Affinity and efficacy drive the potency of the drug.
Binding of antagonists is mainly reversible
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Why is binding reversible?
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What determines affinity?
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Describe the outcome of affinity
- The first graph shows as you increase the concentration of the agonist you get increase interactions between receptor and agonist and you reach maximal value.
- This graph is then converted to a logarithmic scale for concentration of agonist producing a sigmoid curve. At low concentrations of agonist you have little interactions (law of mass action is not being driven). Then as you increase concentration (greatly pushes reaction to the right, due to the association constant) and then you reach a maximum value.
- Ka is when 50% of interactions are occurring – can be read of graph.
- Maximum effect as a finite number of receptors.
How do pharmacologists determine the affinity for a drug?
- They perform important experiments
- You increase concentration of your agonists, the drug you want to measure
- Then how much binds to the receptor your measuring. The more that binds the more saturated the receptor becomes.
- Does not increase fully because there are a finite number of receptors. It then becomes saturated.
- Tell you the maximum number of receptors which can be bound by the drug. This is known as Bmax.
- Kd is the amount of drug you need to occupy half the maximum number of receptors. Bmax divide by 2. This is what we call affinity. They talk about these two numbers. The higher the kd the lower the affinity. The lower the kd the higher the affinity.
What determines the efficacy of a drug?
- It reaches a saturation point.
- (a) Threshold concentration of adrenaline. How much is the min needed to get a responses?
- (b) EC50 is the concentration of the drug to get half the maximum biological effect of the drug. This correlates to how effective the drug is in terms of biological response.
- C) reaches a maximum saturation
- Affinity and efficiency do not correlate.
Why is Affinity (KA) and Efficacy (EC50) of a drug are not equal?
- The red line is the measurement of the amount of Agonist against biological response.
- It shows that you only need a small amount of receptor occupancy to get a biological response.
- We only need a small concentration because the receptors amplify the signal
Describe partial agonists
- Some agonists only bind to a receptor; however, it is not so good at inducing a biological response.
- Heroin highs can be reduced using a partial agonist.
Describe competitive antagonists
- There are two types of antagonists: competitive and non-competitive.
- Competitive antagonists are molecules which compete for the same active site of the receptor.
- If agonist binds you get a response, if antagonist binds you only get affinity and no biological response. They bind to it reversibly.
- If the Kant is smaller than the Ka, it means a lower concentration of the antagonist is needed to bind to the receptor than the agonist. So, the antagonist will outcompete the agonist, it has higher affinity for the receptor.
- If the antagonist has a higher affinity for the receptor it will keep outcompeting, we overcome this by increasing the concentration of the agonist.
- This shows if we want the same biological effect we have to increase the concentration of the agonist.
Describe non-surmountable antagonism
• The maximum response is lower because those receptors that have ketamine bound to cannot be outcompeted by increasing agonist concentration. There is a different binding site. Agonist will only work where ketamine is not bound to.
