M&R Session 8 (Lecture 8.1 + 8.2) Flashcards
What is the formula for molarity (M) ?
Molarity (M) = g/L / MWt
How do most drugs bind to receptors?
Reversibly
What law does binding of drugs obey?
Law of mass action (related to concentrations of reactants & products)
What is drug action dictated by?
Affinity and intrinsic efficacy
What does an agonist have?
A ligand that causes a response
With both affinity and intrinsic efficacy
What is the difference between intrinsic efficacy and efficacy?
Intrinsic eff - ability for ligand to produce the AR*
Eff - Cell/tissue dependant factors that determine a response
What does an antagonist have and do?
Affinity ( NO INTRINSIC EFFICACY)
Block the effects of agonists i.e. prevent receptor activation by agonists
What is Bmax?
Maximum binding capacity - info about receptor no.
What is Kd and what type of graph can this be obtained from?
Kd = dissociation constant ( a measure of affinity) - concentration of ligand required to occupy 50% of the available receptors
From proportion of bound receptors vs [Drug] log10 nM
A lower Kd value indicates?
Higher affinity
What does -9log10 mean?
10-9 nM or 1nM
What responses are induced by a drug? (2 general points)
Change in a signalling pathway
Change in cell or tissue behaviour (e.g. contraction)
What can be obtained from a concentration - response curve?
EC50 and Emax
What is Emax and EC50?
Emax - Effect maximum
EC50 - Effective concentration giving 50% of the maximal response
What is the difference between concentration and dose?
Concentration - Known [drug] at site of action e.g. cells and tissues
Dose - [] at site of action unknown e.g. in patient
What is a measure of potency and what does it depend on?
EC50
Depends on agonist affinity and intrinsic efficacy and efficacy
Left shift = more potent
What factors affect the ‘making’ of a drug in clinical practice?
Affinity Efficacy Selectivity PK Physicochemical properties e.g. solubility, pH, stability
What is the problem with IV drip salbutamol?
Activates beta 1 and beta 2 receptors which can cure asthma by opening up airways (b2) but causes tachycardia and angina by activating b1 receptors on the heart
What property of cells allows <100% occupancy but generate 100% response?
Spare receptors
(Find that response curve is left shifted to binding curve) i.e. EC50 < Kd so that 50% binding causes 100% response
Why do spare receptors exist?
Amplification in the signal transduction pathway
Response limited by a post-receptor event
What do spare receptors increase?
Sensitivity - allow responses at low concentrations of agonist ([drug] below Kd)
How can changing the receptor number change the maximal response of a drug?
More receptors = lower [drug] for full response
Less receptors = if lower than Kd then 100% occupancy but insufficient receptors for full response
When do receptor numbers change?
Increase with low activity
Decrease with high activity
What are partial agonists and comment on their potency compared to full agonists?
Drugs that cannot produce a maximal effect, even with full receptor occupancy
PA can be more or less potent than full agonists.
PAs can act as an antagonist of a full agonist
Describe the clinical use of partial agonists?
Opioids : Pain relief, Recreational use (heroin) - euphoria
BUT respiratory depression
Acts via Mu opioid receptor GPCR
Give buprenorphine which has a higher affinity but lower efficacy than morphine»_space;> gives adequate pain control, less resp depression and stops other opioids from binding to receptors
How can a partial agonist be changed?
By changing the number of Rs on a cell - from PA to FA.
PA still has low intrinsic efficacy at each receptor but there are sufficient receptors to contribute a full response
Describe reversible competitive antagonists?
Relies on a dynamic equilibrium between ligands and receptors. Competitvely competes with agonist for binding site
Surmountable with increasing [agonist]
Cause parallel shift to the right in conc-resp curve
What is IC50?
[Antagonist] giving 50% inhibition
Give an example of a reversible comp antagonist and its clinical usage?
Naloxone - high affinity, comp ant at mu opioid receptors
Reversal of opioid-mediated resp depression- high affinity means it will compete effectively with other opioids for receptors.
Describe irreversible competitive antagonism.
Occurs when the antagonist dissociates slowly or not at all.
Non-surmountable
Cause parallel shift to the right on conc-resp cuve and at higher [] suppress the maximal response
Give an example of a irreversible comp antagonist and its clinical usage?
Phenoxybenzamine - non selec irr alpha 1 adrenoceptor blocker used in HT episodes in pheochromocytoma
Stops excessive vasoconstriction
Also clopidogrel (P2Y antagonist) so stops thrombosis
Describe non competitive antagonism.
Drug binds to allosteric site affecting receptor orthosteric ligand affinity and/or efficacy
e.g. NMDA R for ketamine causing analgesia at low []s
reduced central excitation
