Pharmacological basis of Therapeutics Flashcards
What is the definition of drug?
Chemically defined as small molecules but the more modern definition of a drug are biologics or biopharmaceuticals whose synthesis, extraction or manufacture involves living sources. They exert a selective physiological effect which normally requires interaction with a molecular target on cells most often a protein.
What are the key examples of enzymes, transporters, ion channels and receptors as sites of action?
Drugs acting on enzymes > enhancing dopamine neurotransmissions (L-DOPA) reducing symptoms of Parkinsons but also act as inhibitors
Drugs acting at transporters > Block of NA, increasing neurotransmitter action e.g. antidepressants
Drugs acting at voltages gated ion channels > pore blockage go voltage gated ion channels e.g local anaesthetics blocking sodium channels
What are the main receptor superfamilies?
Receptors are proteins which respond to an endogenous messenger by initiating a signal usually from chemical messengers.
- Ligand gated ion channels (ms)
- G protein coupled receptors (sec - min)
- catalytic receptors (min - hrs)
- nuclear receptors (hr-days)
What is meant by the terms substrate?
Substrates are drugs that bind to an enzyme’s active site. These active sites are usually very specific and will only bind to select ligands.
What is meant by the term inhibitor?
Inhibitors are chemical or biological molecules that regulate chemical reactions by slowing down or blocking them from occurring. Inhibitors often work to slow or stop enzymes.
What is meant by the term agonist?
A drug or substance that binds to a receptor and causes the same action as the substance that normally binds to the receptor increasing the action.
What is meant by the term antagonist?
A drug or substance that binds to a receptors and stops the action or effect of another substance.
What is meant by the term affinity?
Affinity is the ability of a drug to bind to its receptor. Drugs with a higher affinity will produce the same effect with lower concentrations.
What is meant by the term efficacy?
Efficacy is the ability of a drug once bound to be activated the receptor by a conformational change.
What is meant by the term selectivity?
Selectivity refers to the the drugs relative affinity to different receptor subtypes and how likely it is to act on the preferred molecular target. This is known as ‘on target’ or ‘off target’ effects.
What is the mechanisms of drug selectivity, and its concentration-dependant nature?
Drug selectivity is concentration dependant as all drugs interact with additional unwanted binding sites leading to unwanted side effect. e.g. at high doses satbuamol will activate heart adrenorecotrs causing an increasing in heart rates.
What is an example of selectivity?
An example is Salbutamol it id selective to the adrenoceptor agonist trans asthma by opening airways. Its selective as
- the cells and tissues have a high concentration of B2-AR
- has a higher affinity for the B2-AR in airways than the B1-AR in heart
targeted delivery by inhaler (pharmacokinetics)
What is an example of a drug action within the automic nervous system?
What is the Law of Mass action?
The Law of mass action is used to quantify the affinity of a drug. It refers to the balance between the amounts of product and reactant in a reversible reaction.
What is the definition of KD and how it is derived?
KD is the concentration of drug needed to occupy 50% of receptors (i.e. a measurement of a drugs binding affinity). It is calculated using Koff and Kon. It can be used to see the difference in rates and duration of binding and dissociation.
KD = [D] [R] / [DR]
D = drug
R = receptor
What is the drug receptor occupancy?
This is DR in the KD equation and it has a symbol (?)
KD = [D] (1 - ?) / ?
1 - ? = the total amount of receptors (R) minus the total amount of occupied receptors.
to calculate the number of occupied receptors the equation can be rearranged to
? = [D] / [d] + KD
What is the definition of binding constants KON and KOFF?
Kon = association rate constant, the rate of the forward reaction (drug binding)
Koff = the dissociation contacts, the rate of the backwards reaction (drug dissociation) .
At equilibrium
Kon [D][R] = Koff [DR]
What is the relevance of KOFF for predicting dissociation rates and drug target interaction?
It is important to see have fast a drug dissociates from its binding site. Can tell us how effect the drug is and how long the effect last.
How can you measure binding and KD?
- radioligand binding (direct measurement of drug receptor interaction using a radio labelled drug probe)
- functional analysis (used for antagonist drugs only, found using a concentration response curve)
What are the principles underlying radioligand binding?
- make a radio-labelled drug (a compound that is know to react to the receptor which is targeted with a radioactive atom)
- Make a preparation containing the receptor (membrane, cells, tissue)
- mix drug and receptor together in a assay buffer
- Leave for equilibrium to be established (KD can then be measured)
- separators the bonded drugs form the free drugs and count the once that have been radio-labeled using filtration.
How is non-specific binding and specific binding measured?
specific binding - drug bound to the receptor we want
non-specific - drug found on different binding sites
specific binding = total binding - non-specific binding
