Definition of a drug?
A chemical substance that is able to interact more or less selectively with constituents of living organisms, in order to bring about changes in the physiological function of the organism
What 4 specific sites do drugs act?
1) The whole organism
2) Isolated organs and tissues
3) Specific cell types
4) Subcellular structures
What are the 5 macromolecular targets for drug binding?
- Carrier molecules
- Ion channel proteins
- Nucelic acids
Most drugs act or more than one of these targets
How can a drug be specific to a target?
Ability for the drug to bind to the target.
Highly dependent upon chemical structure and shape.
Not just the drug by also the target
What two things must the drug have a high degree of for the drug to be able to express its effects?
A drug must show a high degree on binding-site specificity.
Drug target must show a high degree of ligand specificity.
Can a drug be completely specific in its actions?
Increase dose leads to effect on other targets- side effects
What does angiotension do?
Act strongly on vascular smooth muscle and kidney tubules.
Very little effect on other smooth muscle or intestinal epithelium.
What 5 things are needed for hormone-receptor mediated events?
- Receptors must possess structural and steric specificity for the hormone.
- Receptors are saturable- limited.
- Hormone-receptor binding is cell specific
- Receptors must possess high affinity for the ligand.
- Early recognisable event must occur once bound.
What 3 compounds are the natural ligand for receptors in the body?
- Other signalling molecule
Define an agonist?
A drug that has an affinity for a cell receptor.
Stimulates physiological activity at cell receptors
Normally stimulated by naturally occurring substances.
Its like a curby clip trying to open a door. It has a 3D structure that fits the lock shape well enough to open it
Define an antagonist?
A drug that binds to a cell receptor
without producing a biological response
blocking binding of substances that could bring about a response.
Like a twig into a lock. Will not open it but will block access for the actual key to fit
What is the problem faced by flexible drug molecules?
Give an example?
it may adopt different confirmations- Some of which may be incorrect for binding.
Example: polypeptide hormones- lots of amino acids and therefore numerous possible confirmations
Equilbrium will take a longer time- takes it a longer time to be in the correct shape
What is the zipper model?
Binding of the drug to receptors occurs 'bit by bit'
In a series of steps
Name the 8 different bond types and the order on the strength?
Reinforced ionic bond
Charge transfer bond
Van der Waals (Weakest)
Covalent bonding properties?
Formed by pairing valence electrons
Not appropriate for agonist
Ionic bonding properties?
An electrostatic force between ions.
Ionic compounds do not form true molecules
In aqueous solution they separate into their hydrated constituent ions
Difference between ionised and unionised?
Ionised are more water-soluble- therefore, as a drug, are more available to tissues.
Unionised: more lipid soluble. Can pass through the plasma membrane.
To seperate into ions
If the original drug was neutral: one part will be postive charged, the other negative when it is ionised.
Usually in a particular liquid
The molecules in their structure are stuck together in such a way in which they do not seperate into parts.
Predicts the degree of ionisation.
pH=pKa+log10 ([base form of drug]/[acid form of drug])
Base form of a drug is?
The OH- ions
So for acidic: A-
For basic: B
The acid form of a drug is?
The H+ ions
Aspirin has a pKa of 3.4. What is the ratio of A- to HA in:
a) the blood- pH=7.4
b) The stomach pH=1.4
A) 104 to 1.
B) 0.01 to 1
What is the significance of -COOH?
Side chain of asporatate and glutamate in proteins.
What is the significance of -NH2?
Side chain of lysine and arginine in proteins
What is the significance of -SH?
Side chain of cysteine
What is the significance of -PH302?
Hydroxyls in phosphoryl groups
Forming sugar-phosphate backbone
Hydrogen bonding properties?
Interaction between two electronegative atoms
With a proton between them
Usually involves H bound covalently to one atom being attracted by lone pair electrons on second atom.
Strength= 1/d4 (d=distance between attracting groups)
Name the 5 major properties of receptors?
Recognition: must exist in a conformational state that allows recognition and binding of a compound.
Saturability: receptors exist in finite numbers.
Reversibility: binding must occur non-covalently due to weak intermolecular forces.
Stereoselectivity: receptors should recognise only one of the naturally occuring optical isomers.
Agonist specificity: Structurally related drugs should bind well.
Define 'Occupancy Theory'
Binding of a drug is reversible.
The extent is determined by this equation
Rate of association= ?
Rate of dissociation=?
What does receptor theory and binding have to obey?
The law of mass action
The basics laws of thermodynamics
What is the dissociation constant?
How to rearrange the occupancy theory to measure the biological effect?
See additional sheet
What does the dissociation constant measure?
The strength of the drug binding
Graphical relationship of concentration-response curve for simple occupancy theory
Graphical relationship of log concentration-response curve for simple occupancy theory?
Graphical relationship of double-reciprocal plot for simple occupancy theory?
How is an equation of a straight line extrapolated from the fractional occupancy equation?
E= ( Emax[D] ) / ( Kd + [D] )
1/E = Kd / Emax ( 1 / [D] ) + 1/Emax
How is the scatchard plot extrapolated from the equation of simple occupancy?
See additional sheet 2
Graphical relationship scatchard plot representing occupancy theory?
What is the ratio between drug molecule and receptor molecule?
1 drug molecule to 1 receptor molecule
What is the drug effect proportional to?
The fraction of receptor population occupied.
When is the drug effect measured?
When binding to the receptor population has reached equilibrium
Related to the dose of a drug required to produce a given effect
The agonist potency.
Effect conc of agonist to produce 50% of maximum response
Fractional occupancy definition?
Maximal response occurs when whole receptor population occupied.
Limited values of 0 (no response) and 1 (maximal response)
Intrinsic activity definition?
The ability to induce an effect after binding
Define a full agonist?
Produces the maximum response in a tissue when it occupies all the receptors in the population.
Partial agonist definition?
They will never be able to produce a maximum response
No matter if they occupy all the receptors in a population.
Has a low intrinsic activity.
Graphical representation of the intrinsic activity for each chemical compound that can bind to a particular receptor?
Can be 1 or 0.
Partial agonist is half way between
How can partial agonist have two effects when added with full agonist?
Increase partial but a low level of full it is additive. Due to the full agonist not being able to occupy all the receptors.
If the levels of full agonist are high the partial agonist will have an antagonist effect. This is due to the full agonist being able to occupy all the receptors alone therefore producing a maximal response- with partial, they compete with each other and wont produce a maximal response which could be produced.
Define spare receptors?
A drug can produce the maximal response when even less than 100% of the receptors are occupied.
Therefore, the remaining recepotrs are served as receptor reserves known as spare receptors
What type of agonist can never had spare receptors?
Since it will never produce the maximum response and to have spare receptors you have had to reach the maximal response.
Magnitude of effect that can be produced by a drug.
With zero efficacy, no tendency to cause receptor activation
It describes protein molecules whose function is to recognise and respond to endogenous chemical signals.
Define competitive antagonism?
What does it do to the log conc curve?
And dose ratio?
Shifts the log conc-effect curve to the right.
Dose ratio increases linearly