BP 3 – Agonists and dose response curves Flashcards
What is an agonist?
Ligand (drug, hormone/ neurotransmitter) combines with receptors to give a cell action
What does salbutamol treat?
Asthma
What is the interaction of salbutamol as a drug?
- Combines with ß2 adrenoreceptor forming a complex
- Increased cAMP
- Bronchodilation
Why is dose important?
Too much - toxic
Too little - useless
What does a dose-response log graph show?
Therapeutic range Where there is no more effect No effect Over effect Max response - efficacy 50% response - potency
What is the difference between graded and quantal dose-response relationships?
Graded
- Individual measure
- Response of a particular system – isolated tissue, animal or patient
- Measured against agonist conc
Quantal
- Drug doses – agonist/ antagonist
- Produce a specified response determined in each member of a population
- Population data – number of …
- All or nothing – absolute measure – show range
What shape is the correct quantal dose-response curve?
Bell shaped
Define affinity.
Strength of which an agonist/drug binds to the receptor
What determines a drug to have high affinity?
The forward reaction of the drug binding to the receptor having a larger response relative to the dissociation from the receptor having a small response. Therefore the forward reaction is greater than the backwards reaction.
What is easy and hard to measure in drug binding?
Easy - saturation of receptors - no max binding sites
Hard - affinity of a drug
What is the equilibrium dissociation constant?
Kd
small d
What can Kd quantitively compare?
Affinity of diff drugs on the SAME receptor
What does a Kd value show?
Tighter ligand-receptor interaction – higher affinity.
What is the potency of a drug?
Drug amount needs to produce a given effect (EC50)
Potent drugs give a response by binding to a critical number of receptors at a low conc (high affinity)
What is said about the efficacy of a drug that has a lower EC50?
Greater potency
What is potency dependent on?
Affinity, efficacy, receptor density and efficiency of stimulus-response mechanisms used
What are receptor reserves?
Linear relationship between receptor occupation and biological effect then Kd and EC50 are equal
But …
- Many receptors can amplify signal duration and intensity
- Due to amplification only, a fraction of total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell
- Systems that have this behaviour are said to have spare receptors
Max response with only a small fraction of the receptors occupied
What is the efficacy of a drug?
Ability of agonist to activate a receptor
Refers to the max effect an agonist can produce (regardless of the dosage)
What is the efficacy of… and number of receptors occupied by…
- Full agonist
- Partial agonist
- High efficacy, producing max tissue response, occupying few available receptors
- Low efficacy, no producing capable max response and occupying all available receptors
What is the use of these partial agonists and what receptors do they target?
- Varenicline
- Tamoxifen
- Aripiprazole
- Nicotine receptor partial agonist for smoking cessation
- Estrogen receptor partial agonists for use in estrogen dependent breast cancer
- Antipsychotic – partial agonists at selected dopamine receptors
What do inverse agonists have higher affinity for?
Prefer to be in the inactive complex of drug-receptor instead of the active state, which would in turn cause a response
What is a positive allosteric modulator?
Not active alone but can increase affinity and/or efficacy of endogenous agonists
What is a negative allosteric modulator?
Not active alone but can decrease affinity and/or efficacy of endogenous agonists
Give examples of positive allosteric modulators.
PAM - Diazepam, Propofol, Isoflurane
What is tachyphylaxis of a drug?
Drug effect reduces with continual/repeated administration
What are the contributing factors to the desensitisation of receptors?
- Conformational changes in receptors
- Internalisation of receptors
- Depletion of mediators
- Altered drug metabolism
