| 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 |
