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Quantitative Drugs
Physiology and Pharmacology
| Question | Answer |
|---|---|
| Drug | Chemical compound that when applied to a biological system alters its function in a specific manner |
| Drug targets | Any biological binding/recognition element for drugs |
| Pharmacodynamics | The study of the mechanism of interaction of the drug molecule and the biological target |
| Specificity | Between defined classes of drugs and specific targets No drug is completely specific - increasing the dose of drugs many result in binding to off target molecules |
| Affinity | The strength of interaction between a drug and a receptor Chemical forces between drug and receptor include electrostatic forces, hydrogen bonds, VDW forces and hydrophobic bonds A drug is not statically located - can dissociate |
| What determines probability of drug occupying its binding site | Drug affinity for the site Drug concentration |
| Efficacy | The property that determines the ability of the drug to change the receptor so that a response is triggered |
| Law of mass action | The rate of a chemical reaction is proportional to the concentrations of the reacting substances Total receptors = occupied + unoccupied Converted to conc by dividing by volume But not all receptors are soluble - no conc |
| Occupancy | 1 = proportion of receptors occupied + proportion not occupied 1 = Par +pr The fraction of receptors occupied and free |
| Rate constant in unimolecular transitions | Rate of decrease of inactive = constant x conc inactive = constant x Pr Rate of decrease of Pr = K+1 x Pr dPr/dt = K+1 x Pr dt Rate constant has units s^-1 |
| Rate constant in bimolecular transitions | Rate of decrease of unoccupied = constant x {A} x Conc unoccupied = constant x [A] x Pr Rate of decrease of Pr = K+1 x [A] x Pr dPr/dt = K+1 x [A] x Pr dt Rate constant has units M^-1s^-1 |
| Hill-Langmuir equation | Rate of forwards = Rate of backwards K+1{A] (1-Par) =K-1Par Par = [A]/([A]+Ka) |
| Ka | The equilibrium dissociation constant - a measure of agonist affinity The concentration of the drug which results in 50% of the receptors being occupied Expressed in molar units - a concentration |
| Relationship between amount of drug bound and concentration | At equilibrium the number of drug molecules binding is equal and opposite to those unbinding K+1[A](Bmax-B) = K-1B B/[A] = Bmax/Ka - B/Ka |
| Scatchard plot | A plot of B/[A] against B |
| Basic principles of drug binding | Drug binds to receptor and other structures Bound radioactivity = specific and non-specific binding Apply a saturating content of non-labelled drug Then add labelled drug Bound radioactivity now = only nonspecific |
| Relationship between receptor occupancy and response | Binding can be assessed directly bit it is the biological response we wish to assess Plotted as dose response curves Response = ([A]e)/([A]+Ka) e - efficacy - intended as an agonist specific term |
| EC50 | Concentration that produces 50% of max response Depends on both affinity and efficacy |
| Ka and EC50 | EC50 tends to be lower than Ka Response to an agonist is proportional to the receptor occupancy by Ka and EC50 do not tend to collide |
| Spare receptors | Ec50,<Ka can be explained by spare receptors Number of receptors present is larger than the number needed to provoke full response |
| Types of agonist | Full agonist Partial agonist - same binding site but lower efficacy (cannot produce maximal response) |
| Examples of full agonists | Salbutamol - B2 adrenoreceptor - asthma Morphine - Opioid receptor - relieve moderate to severe pain Sumatriptan - Serotonin receptor - treatment of migraine Ropinirole - D2 receptor - parkinsons disease |
| Examples of partial agonists | Buprenorphine - opioid receptor - opioid dependence Verenicline - a4/b4 nAChR - nicotine dependence |
| Antagonists | Competitive reversible Competitive irreversible Non-competitive |
| Competitive antagonists | Binds to a receptor but produces no response Has affinity but no efficacy Binds in such a way to prevent binding of an agonist Causes a parallel shift of response on log conc curve |
| Ra | Dose ratio The ratio by which [A] has to increase to overcome the antagonist |
| Relationship between conc of antagonist and receptor occupation by agonist | Par = ([A]/Ka)/([A]/Ka + [B]/Ka+1) |
| The schild plot | Ra = 9[B]/Kb)+1 Expressed as log(Ra-1) = log[B] -logKb Ra depends on {B{ and equilibrium constant of the competing drug The value of Ra allows estimation of Kb |
| Irreversible competitive antagonist | Antagonist that presents reactive groups that can give rise to covalent bonds with the receptor binding site Not associated with an increase in EC50 Increasing concentration of agonist does not overcome the effect - maximal response not achieved |
| Non competitive antagonist | Antagonist binds to a site seperate to the agonist binding site Reduction in maximal response May or may not be associate with an increase in EC50 |
| Examples of reversible competitive antagonists | Carvedilol - B1 adrenoreceptor - hypertension Naloxone - opioid receptor - opioid induced respiratory depression and opioid overdose |
| Examples of irreversible competitive antagonists | Prasugrel - purinoceptor P2Y12 - antithrombotic agent |
| Examples of non-competitive antagonists | Ketamine - Glutamate receptor - intravenous anaesthetic Verapamil - L type VGCC - hypertension, cardiac arrythmia and angina |
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