Lecture one and two Flashcards
2 characteristics of a drug and explanation ?
A drug will contain 2 characteristics, affinity which is the ability of the drug to bind to the site on the receptor, as well as efficacy, which is a measure of the ability of the drug to produce a measurable response. These values can be zero , positive or negative.
John Newport Langley ?
“The receptive substance” was a quote said by John Newport Langley in 1905 when he was analysing the pharmacology of muscarinic agonists and antagonists. It describes that drugs must bind to a specific constituent of a cell to produce their effects, for example the receptor.
what do binding drugs to a receptor share qualities with and give example ?
The drugs that are able to bind to the receptors on a cell often share structural similarities to the natural endogenous ligand of the cell and they have specific affinity to the receptor. An example of this salbutamol, a selective beta 2 agonist which shares similarities in it’s structure to adrenaline.
describe salbutmol
Salbutamol is a selective beta 2 agonist which dilates the airways in asthmatic patients whereas, adrenaline is a nonselective adrenaline receptor agonist. Salbutamol has been designed to only effect one receptor class. Whereas adrenaline binds to all beta and alpha receptors as it is unable to discriminate the receptors.
describe the beta 2 adrenergic receptor ?
The Beta 2 adrenergic receptor is embedded in the membrane of cells, it is bound via a synthetic ligand within the cell. The structure of the receptor is a 7 transmembrane domain which associates with a G protein, with alpha beta and gamma subunits. This G protein can activate an intracellular enzyme which can facilitate changes to the cell physiologically through a signal cascade.
what do receptors normal contain ?
Receptors tend to have a high degree of drug (ligand) specificity as a result the receptors bind only to molecules with a unique three dimensional topography and chemistry , the receptors do not bind to closely related molecules they tend to vary in structures and discriminate between closely related molecules.
describe dopamine , noradrenaline and adrenaline similarities and consequences
The 3 receptors for dopamine , noradrenaline and adrenaline are similar in structure , but dopamine will not bind to receptors associated with noradrenaline or adrenaline as it is a selective agonist that only interacts with dopamine receptors. However, the differences between noradrenaline and adrenaline are not too similar and as a result will interact with similar receptors as they are nonselective adrenergic agonists.
why do drugs exert side effects ?
When considering the side effects of a drug it is the drugs ability to bind to multiple receptors that accounts for the side effects. No drug has a complete specificity for one type of receptor, this is the case for drugs that have a low potency, there will need to be a high dose of the drug to have a pharmacological effect. This is due to these drugs tending to bind to a wide range of receptors and this is when unwanted side effects occur
thalidomide scandal ?
Thalidomide was produced in the 1950’s for morning sickness in pregnancy , it is a racemic mix so they look identical but are mirror images of each other. When distributed it was unknown that it interacted with enzymes and receptors and caused teratogenic effects in the unborn child such as shortening the limbs. Although thalidomide is termed a bad drug it also has some benefits such as it’s use in leprosy and some cancers. After the thalidomide scandal, there was a tightening in regulations around drug productions.
explain epinephrine ?
Epinephrine ( adrenaline) is also a racemic mix , epinephrine is found in EpiPen’s for the treatment of anaphylaxis shock. It had an R and a S form depending on the orientation of the hydroxyl group. It contains a charged nitrogen and a flat ring structure and these bind to the sites on the enzyme shown below. If the orientation is not correct , this produces a poor fit and less of the receptor is activated and the downstream physiology is not as efficient as it is less active. The R form contains the correct orientation of the hydroxyl group and interaction can occur between the 3 sites on the receptor , the fit is better and as a result more of the receptor is activated and this increases the downstream physiological activation of the cell. In the liver the R form can be converted to the less active form of the S , so this needs to be considered so prevent unwanted side effects.
what does acetlycholine act on ?
Acetylcholine acts on nicotinic and muscarinic receptors, the nicotinic receptors are located in the skeletal muscle, ganglia and CNS. The muscarinic receptors are more widely distributed but they are not located in the skeletal muscles
nicotinic receptor type ?
The nicotinic receptors have an integrated ligand gated ion channel, which opens to allow ions to flow in such as sodium, this causes depolarisation to occur which is excitatory.
muscarinic receptor type ?
The muscarinic receptors have an ion channel which is associated with a G protein coupled receptor , there are 5 subtypes ( M1 – M5).
agonists for the nicotinic receptor ?
The agonists include acetylcholine and nicotine
antagonists for nicotinic receptors ?
normally naturally occurring such as atracurium and tubocurarine.
describe the associated G protein for odd numbered muscarinic receptors?
For the muscarinic receptors, the odd numbers, M1 M3 and M5 have the Gq/PLC coupled receptors , it is the Gq protein that sets the nature of the downstream signalling in the cell. It leads to the generation of phospholipase C.
even number muscarinic receptor G proteins ?
The even numbers M2 and M4 have the Gi/o cAMP receptors and these lead to the decrease in the cAMP levels.
agonists for muscarinic receptors ?
The agonist is acetylcholine , muscarine and bethanocol
antagonists for muscarinic receptors ?
The antagonists include atropine, hyoscine ( found in over the counter medicine such as stomach upsets) .
what does noradrenaline act on and location ?
Noradrenaline acts on alpha and beta adrenoreceptors which are widely distributed in the body. The beta receptors are found in the airways and they are G protein coupled while alpha receptors are found in blood vessels and they are also G protein coupled.
Alpha 1 subtype of receptor ?
he alpha one and Gq/PLc coupled activating phospholipase C
alpha 2 subtype of receptor ?
alpha 2 are Gi/o/cAMP and again leads to a decrease in cAMP.
how many subtypes of beta receptors ?
There are 3 subtypes of beta receptors
beta 1 and 3 ?
beta 1 and 3 are Gs/adenylate cyclase which are activated by cAMP and this has a target for protein kinase A
beta 2 ?
beta 2 the receptors are Gi/ cAMP coupled and they cause a decrease in the cAMP production.
agonists for both beta and alpha receptors and what is the preferential agonist?
noradrenaline ( preferential agonist for beta )and adrenaline ( preferential for alpha)
antagonists for beta ?
propanol , sotalol normally
antagonists for alpha ?
phenoxybenzamine and phentolamine normally ( MINE).
verpamil ?
erapamil is a cardiac calcium channels blocker which reduce contractive force and the rate of contraction used in the treatment of high blood pressure.
