lesson 4 Flashcards
Speak about alpha adrenergic receptor antagonists
Just like agonists, adrenergic receptor antagonists can be active on alfa receptors (alfa 1 or 2) or on beta receptors. for both the classes we have non selective and selective antagonists, the non selective alfa ones can not tell alfa receptor from each other, and the same happens for the beta ones; selective receptors only recognize a specific receptors. There are alfa1 and alfa2 selective antagonists but also b1 selective agonists, on the other hand beta2 selective antagonists do not exist because we are not interested in their action, they would only serve to constrict the airways.
Most antagonists are competitive and form a reversible bond with the receptors, some of them though are irreversible.
Alfa receptors selective antagonists are not that many, it is still a very open field in pharmacology. Also, there are no compounds able to select among alfa1a, alfa1b and alfa1d receptors and the same goes for alfa2a, alfa2b and alfa2c. there will probably be new scientific discoveries in this filed in the future.
Alpha1 adrenergic selective antagonists act on alpha1 receptors, let’s remember that these receptors are coupled with Gq proteins and normally trigger contraction in arterial, venous and visceral smooth muscles. In general, selective alfa1 receptors are responsible for the increase of blood pressure and vasoconstriction, so the antagonists can be used for hypertension suffering patients, because they decrease blood pressure. Prazosin is an example of an alfa1 adrenergic selective antagonist. These receptors are also present in the prostate and other smooth muscles, so they can be used to help with benign prostate hypertrophy in aging males subjects. This condition causes the prostate to increase in size and a constriction of the urinary tract. This does not allow the complete emptying of the bladder, that is one of the reason why old people go to the toilet often. If we antagonize the alpha receptors we prevent the constriction and reduce the stimulus. Since we are administering alfa1 receptors antagonists they still cause a decrease of blood pressure as a side effect, this, is only good if the patients also have high pressure, which is pretty common for older people. Tamsulosin is an alfa1 receptor antagonist used for this purpose, which is not completely specific for the bladder alpha1 receptors, so it must be used on a low dosage.
alfa2 adrenergic selective antagonists act on alfa2 receptors which are mainly presynaptic and normally suppress the release of neurotransmitters, that means that their stimulation decreases blood pressure. Both alfa1 and 2 receptors’ activity is linked to the cardiovascular system, and thus, blood pressure. alfa2 targeting drugs block alfa2 receptors and can increase the sympathetic outflow of NE. This will activate the adrenergic receptors present post-synaptically increasing blood pressure. Right now they are not used clinically but in the past Yohimbinewas used extensively to treat male sexual dysfunctions.
The main non selective alfa receptor antagonist is phenoxybenzamine, an irreversible antagonist still used today for a very specific condition: pheochromocytoma, which is a tumor of the adrenal medulla, meaning that the adrenal medulla never stops releasing EPI and NE. To massively decrease the release of these hormone the only possible thing to do is to surgically remove the adrenal medulla, if the doctor touches the tumor during the procedures a strong release of neurotransmitters will be caused, so before the procedure this drug is administered in order to block alpha receptors permanently from stimulating the release of EPI and NE. Another famous drug is also phentolamine which is a reversible antagonist.
Speak about beta adrenergic receptor antagonists
Beta adrenergic antagonists are very useful because beta1 receptors act on the heart making it contract, so these compounds can be very useful for pression issues. Second generation compounds include selective inhibitors of beta1 receptors that have the advantage of not causing issues to the bronchi while controlling the heart and blood pressure.
Beta2 receptors instead cause relaxation of the smooth muscles of the bronchi, meaning that Selective beta2 receptors are not useful, as already said, and thus are not present on the market.
The non selective beta blockers are not very useful since they also block b2 receptors in bronchial smooth muscle, which can cause life-threatening bronchoconstriction in patients with asthma. That said, propranolol, which was the first compound of this kind to be put on the market, was used for the treatment of hypertension, since beta receptors increase heart contraction and blood pressure and when they are blocked the exact opposite happens. So, this compound has been used for hypertension and also for ischemic heart diseases, congestive heart failure and certain arrhythmias. Scientists then realized that since this drug is non selective, meaning it also binds to beta1 and 2 receptors, it has side effects on the bronchi causing their contraction. On the other hand this compound was considered very useful because it does not lower pressure for people with normal or low blood pressure so from this point of view it is considered a safe compound. Propranolol is very useful for people who have increased higher pressure because of stress and other emotional causes. It can also be used to slow down the heart during sport or gym activity, when blood pressure rises and in some people it reaches a too high level.
Speak about the hisory of the anhestetics and about the nociceptor
The first local anaesthetic discovered was nonother then cocaine. Cocaine is an alkaloid molecule found in shrubs (arbusti) common in south America: Erythroxylon coca.
For thousands of years the leaves of this shrubs were chewed by south Americans because in this way they could better sustain the hard conditions of life. But even nowadays, in Bolivia, miners still use these leaves. One of the effects of this process is the numbing of both the tongue and mouth. In the 19th century the westerns also discovered coca leaves when they arrived in America, but the shrubs could not be imported because the trip was too long and the leaves would turn brown.
Anyway, in 1860, scientists were able to extract the cocaine compound from the leaves identifying their active ingredient. At that time Freud used it as an energising compound for patients suffering from depression. However, this use was unsuccessful because of its addictive characteristics. From then on in Europe the use of cocaine was forbidden but not in America.
Freud also gave some cocaine to Carl Koller, an ophthalmologist who worked in Vienna. He started to use cocaine drops for the eyes to perform surgical procedures. Now, he is recognized as the father of local anesthesia. Drops of cocaine for the eye became quite common at that point.
Later on cocaine was also introduced for dentistry and some general surgery. But, as already said, cocaine is very addictive, this was not a problem when used in the eye but it was one for dentistry and general surgery.
A drug company was trying to find a way to use it without having the side effect of addiction. So, in 1905 new compounds were used to substitute cocaine: procaine, known as the famous drug Novocain (novocaina), and now more commonly used compounds like lidocaine and bupivacaine.
LOCAL ANESTHETICS: THE NOCICEPTOR
local anesthetics are used to prevent the feeling of pain caused by a trauma or a little surgical procedure. To understand how local anesthetics work we need to talk about the nociceptor.
Nociception is the activation of this specific neuron and it occurs after an event that causes pain like a lesion, this event is called noxious stimulus and it is defined as something that damages our tissue or that can potentially harm the tissue. Pain is, in fact, necessary for our survival because it represents an alarm for danger. Pain also unconsciously makes us use the damaged part less to make it heal faster. Pain has both a physical and an emotional component. Knowing all this we know that pain perception is a complicated process.
The nociceptor, is not a receptor but an afferent neuron that goes from the periphery to the spinal cord of the CNS. It perceives the sensation of pain from the periphery and this sensation is then elaborated by the CNS. When this sensory neuron feels the pain, it stimulates an action potential mediated by sodium, activating the voltage gated sodium channels.
The nociceptor is composed by different fibres: the ones that deliver feelings of pain, called A, B and C. The **A fibres are myelinated, while the C fibres are not. there are specific A fibres called Adelta fibers, which are myelinated and when we have a tissue injury deliver the first sensation of pain, which is perceived as sharp immediate pain. These fibres also help us localize the pain area very fast. After a few seconds we feel a background long-lasting pain, it is delivered by the C fibres which conduct the stimulus for a longer time and slower since they are not myelinated.
All the fibres are in the peripheral nerve contained in 3 different membranes, the most external one is the epineurium, then we have the perineurium and even deeper the endoneurium.
What are the compounds used for pain control? what is the chemical structure of local anhestetics?
there are compounds able to control pain: analgesics and local anesthetics.
- Analgesics control pain because they inhibit the pain pathway
- Local anesthetics are non-specific to the pain pathway but they inhibit the peripheral nerve transmission. This includes the numbing of pain sensations but also the numbing of the motor and autonomic nerve transmission. Local anesthetics are the most used drugs in dentistry but the are also used in case of surface anesthesia, infiltration anesthesia, , nerve bock anesthesia, intravenous regional anesthesia which is normally used for limbs surgery, spinal anesthesia used for the treatment of abdomen or pelvis or legs and epidural anesthesia used for baby deliveries, so we decrease the pain without decreasing the mother’s contractions.
Among local anesthetics the most used ones are: procaine, lidocaine and bupivacaine. All these compounds have 3 components in common: an aromatic group, an amin group, and an ester or amide (link between the other two). the aromatic group is important for the hydrophobicity it provides, the amin group is important for its ability to became charged and the amide/ester is the link between the other two groups.
We know that the nociceptor has three different membranes, and our local anaesthetic, which is moderately hydrophobic, needs to surpass all three. When we administer a local anaesthetic we do not damage the membrane with the needle, so, the local anaesthetic has to travel a lot.
What is the mechanism of action of local anhestetics?
The target of the compounds is the sodium voltage gated ionic channel found in the plasma membrane, so the local anesthetics need to cross the membrane and act on the cytoplasmic site of the target. that means that poorly hydrophobic anesthetics do no work at all because they cannot cross the plasmic barrier, while extremely hydrophobic ones get into the membrane but do not get out of it, so, the only working anesthetics are the moderately hydrophobic ones, this characteristic, as previously stated, is given by the aromatic group.
The amin group is important for the charge, in fact, depending on the pH of the environment the compound might get ionized, Only non ionized compounds are able to pass the membrane, but once inside the cytoplasm the change in pH causes the amin group to get positively charged, which is fundamental because the charged compound has a much higher affinity for the target.
The voltage gated ion channels can be found in three different status: the resting state, active state, and inactivated state. In the last case the channel is closed thanks to the gate, while for the resting position the channel is closed but the gate is open. all these situations are due to the different conformations of the channel’s proteins.
After staying open for a certain amount of the time, the channel is then inactivated for a while, this timeframe is called the refractory period, and while in this state even if there is an action potential, the channel is not going to open and the stimulus cannot go through.
So going back to the anesthetics, the compounds cross the membrane, acquire the charge and bind to the cytoplasmatic part of the channel, in this way they will increase the refractory period of the channel and delay its reopening. This happens because they have a higher affinity for the inactivated channel, but they can also bind to the other forms of the channel.
At high concentrations of LAs, the number of resting channels that are drug-bound (blocked) is sufficient to prevent impulse conduction altogether.
The action mechanism of local anesthetics is based in their target: the sodium channel. By blocking these channels the compounds block the conduction of action protentional and thus the feeling of pain. The problem is that this happen in all the fibres in the neighbouring area, both afferent end efferent, also belonging to other sensory pathways.
Knowing this, the right definition of the function of an anesthetics is not the inhibition of pain sensation but the inhibition of pain and other sensory modalities, which end up not being transmitted to the brain anymore. These include motor impulses and autonomic impulses. Usually anesthetics block all these fibres in the order in which we lose the transmission:
- the first inhibited fibres are Adelta fibres which carry first order pain
- then C fibers are hit, which carry second order pain
- then temperature sensation
- touch
- proprioception (pressure, position etc)
- and finally the skeletal muscle tone and voluntary tension so we cannot use our limbs for a while.
The recovery process happens in the opposite order.
Local anesthetics are only present where they are injected also because they can be injected with vasoconstrictors like EPI, so they don’t go in all the nearby areas and there is little to no absorption in the bloodstream, so no systemic effects. This is not a rule but sometimes it is needed. vasoconstriction also decreases the peak plasma concentration of the anesthetics, since a little bit still ends up going into the bloodstream.
Also, the degree of inhibition of sodium current by the LA depends on the frequency of impulses in the nerve, this event is called use-dependent inhibition. Basically, the more the channels are opened because of the constant stimuli, the greater the block becomes.
Tissue injury or trauma causes nociceptors in the area of injury to fire at high frequency. In these situations, the application of a local anesthetic tends to block local nociceptors in a phasic
manner, inhibiting pain transmission to a greater extent than the transmission of other local sensory or motor impulses that are blocked only tonically. This in why pain is the first sensation we lose.
What are the future prospectives of local anhestetics?
Improvements in the anesthetics field are still needed, there are two different strategies that can be adopted to improve the LAs. the two strategies derive from new studies in the physiology and knowledge of sodium voltage gated channels. Both strategies focus on trying not to inhibit the nearby fibres when acting on nociceptors. If this approach was already possible we would use to treat neuropathic pain.
- One strategy to do this would be using agents that are able to bind sodium channels which are only present on Adelta or C fibres, depending on the type of pain (sharp or persistent) that we need to block. It was discovered that some people in the world that are not able to feel pain, have a specific in subtype of Na channels found in the pain fibres, so scientists are trying to find a chemical compound that is selectively able to target only those specific channels.
- The other strategy is exploiting charged anesthetics so they will stay outside the cell and thus, when applied on the nerves, they cannot bind to the channels in the cytoplasmic portion for those fibers which are not invested in pain delivery. This would be possible because in the peripheral nerve only the fibers that deliver pain sensations have specific receptors called TRPV1 Transient Receptor Potential Vanilloid. When these channels open, the local anesthetic can still diffuse into the cell. A very common TRPV1 ligand is capsaicin. In the past there was a transdermal patch used for backbone pain that gave the user an itch because of the capsaicin which opens the TRPV1 channel and help the entrance of the anesthetics. in this case it was only to increase the effect of the anesthetic, but in the future it might be used to have a more localized effect. So, to do this we would need to use both a TRPV1 activator and the anaesthetic which would block the sodium channels only in nociceptive neurons.
