Adrenoreceptor 4 Flashcards
alpha one adrenoreceptor agonist clinical use ?
Alpha 1 adrenoreceptor agonists have several clinical uses, phenylephrine is a nasal decongestant. Adrenaline and phenylephrine prolong the local anaesthetic action and anaphylactic shock. Clonidine and methyldopa are alpha adrenoreceptor 2 agonists and are hypertensives.
nasal decongestant act on alpha one ?
Nasal Decongestants act on the alpha 1 agonists to cause smooth muscle constriction through the activation of signal transduction leading to intracellular calcium release. During a cold your arteries dilate with increased blood flow and leakage of fluid and mucus blocks the nose and the sinuses. Alpha 1 agonist constrict the blood vessels and thus reduces the swelling.
anaphylactic shock ?
Anaphylactic shock is the swelling of tissue, shortness of breath, light headedness and hypotension (lowering of blood pressure). Adrenaline is administered as it increases blood pressure via an alpha 1 contractile effect will help with blood circulation (remember too low a blood pressure is bad for circulation as well), heart function and breathing. The systolic and diastolic blood pressure increases and as a result there is an increased cardia work.
clonidine ?
The action of clonidine ( alpha 2 agonist) , leads to the activation of alpha 2 receptors in the NTS by clonidine reduces the nervous activity the sympathetic outflow and thus reduces the release of noradrenaline. In addition, clonidine can promote negative feedback at the nerves through alpha 2 receptors on the terminal of the nerve ending further reducing the release of nor adrenaline. Clonidine was discovered and used originally in the 1960’s and is marketed as Catapres. It is hardly used clinically anymore as there are better alternatives, however it is off patent and is cheap. In the NICE guidelines alpha blockade is recommended for resistant hypertension. These are patients who do not respond to other treatments.
lower blood pressure with alpha methyl noradrenaline ?
Another drug which has a similar effect to lower blood pressure is alpha-methylnoradrenaline. The mechanism of action is an unusual one and it is classified as an indirectly acting sympathomimetic.Alpha methyl noradrenaline is given as alpha methyldopa and this is converted as part of the catecholamine synthetic pathway to give alpha methylnoradrenaline.You can see how this works by comparing both synthetic pathways. On the left is the normal route to make noradrenaline in the nerve terminal and the two key enzymes involved. On the right you see that the same enzymes make the same modification but with a different starting molecule. Alpha Methylnoradrenaline is less active at alpha 1 and more selective for alpha 2 receptors.
Methyldopa is converted to alpha methyl noradrenaline in the brain which activates Alpha 2 receptors in the NTS. This will in turn dampen down the sympathetic outflow reducing the release of nor adrenaline. However, the same situation can occur at the nerve terminal within the blood vessels - again methyldopa is converted to alpha methylnoradrenaline. When this is released it has a poor action at alpha 1 receptors but can promote negative feedback at alpha 2 receptors to further reduce noradrenaline release. An interesting double action using the catecholamine synthetic pathway to make a clinically relevant drug.Methyldopa is sold as ALDOMET and is another old drug. Used again in resistant hypertension when other medicines are ineffective. It has many side effects so it has been superseded by other medicines. However it is used sometimes in pregnancy-induced hypertension because in fact it is thought to be relatively safe for the foetus during pregnancy.
alpha one antagonists ?
Alpha one antagonists are used for hypertension patients that are resistant to other drug classes , these antagonists include TAMSULOSIN , DOXAZOSIN , PRAZOSIN.- selective alpha one antagonist ( vasodilation to lower BP), LABETALOL , indoramin, terazosin. Alpha 1 blockers can be used for resistant hypertension when other drugs such as ACE inhibitors do not work.
cardiovascular system of blood pressure ?
The CV system is always seeking to work at equilibrium and consists of multiple components. If one component is disrupted by a drug there may be compensatory effects elsewhere. Blood pressure is linked to the cardiac output of the heart in terms of blood flow and the resistance it has to work against in the arteries and arterioles and veins. So blood pressure is the Cardiac Output multiplied by the total peripheral resistance, which we call TPR. Cardiac Output (CO) is the heart rate multiplied by the stroke volume.*To control blood pressure all these components must be considered when using drugs.
baroreceptor reflex ?
An additional complication is the baroreceptor reflex, the body usually responds to a change in a parameter by initiating an opposite action to bring that parameter back to the equilibrium state. This is the essence of homeostasis. This very much applies to the CV system.If there is an intervention which causes a reduction in blood pressure the body senses this at stretch (baro) receptors in blood vessels in some key arteries and veins. This then sends impulses to the brain which then increases sympathetic nerve outflow. This activity when it reaches the heart and blood vessels increases the release of nor-adrenaline. Thus heart rate goes up and also the total peripheral resistance would go up due to contraction of arterioles and veins and the blood pressure would increase.
non selective alpha antagonist ?
The overall effect of having a non-selective alpha antagonist , the treatment with this type of drug would have some good effects but could also have problems - blocking of alpha 1 receptors in the arteries will decrease TPR due to more dilation of the blood vessels which is good. However because the body senses this effect there is a rebound increase in heart rate known as a reflex tachycardia. Lack of selectivity also causes additional problems - blockade of alpha 2 mediated negative feedback at the nerves within the heart would tend to increase the release of Noradrenaline and thus increase the tachycardia so this is not a good effect.In fact this may get so bad that cardiac dysrhythmia may result. That means that the cardiac action potential becomes dysregulated.
TPR with alpha one antagonist ?
If a selective alpha one antagonist is used then there would-be good blockage of contraction in the vessels. Thus TPR would fall due to vasodilation. There would be a reflect increase in heart rate but the overall outcome would be a good one.If there is no effect on alpha 2 receptors then this is good- no cardiac dysrhythmia overall. Such drugs include prazosin which is the first alpha 1 antagonist developed. There are others such as doxazosin and terazosin which have longer half lives
venodilation ?
. However for hypertensive patients there is an additional benefit. Alpha 1 blockage also dilates the veins. This venodilation allows for more blood to be pooled within the venous system. This then results in less venous return i.e. less blood coming back to the heart through the veins. Now the amount of contraction in the heart is dependent on how much the heart fills with blood (called the frank starling law). Thus, the stroke volume is less because the heart has less blood to eject.
alpha one selectivity with beta one selectivity ?
In actual fact alpha 1 selectively can be useful if combined with beta 1 selectivity. This is a feature of the drug labetalol- discovered as part of structure activity (SAR) studies to find selective inhibitors. It is a dual alpha 1 and beta blocking drug.So the alpha-1 blocking effect reduces TPR as shown in the previous slides, however the beta 1 antagonist effect prevents the reflect increase in heart rate (remember that an increase in heart rate is via a B1 receptor). So in addition there is the potential to reduce cardiac output. These effects in combination then decease blood pressure (from the equation).Labetalol is not used extensively for normal hypertension but is used to treat hypertension in pregnancy.
Joint receptor blockage is not really what pharmacology strives for but it can be useful. In other areas such as cancer it can be beneficial to have multiple effects of a drug.
benign prostatic hyperplasia ?
Benign prostatic hyperplasia (BPH) , the prostate lies below the bladder and surrounds the urethra, this enlarges due to growth of the stromal cells, urination can be difficult due to obstruction, condition is benign – does not develop into cancer. A more recent use of alpha selective antagonists is in the treatment of benign prostatic hyperplasia (BPH) , the prostate lies below the bladder and surrounds the urethra.
ALPHA ONE RECEPTOR ANTAGONIST BPH ?
Alpha 1 receptor antagonists such as Tamsulosin and Doxazosin relax the smooth muscle in the prostate gland and neck of the bladder. This results in lessening the obstruction of the urethra and decreased restriction in blood flow.Tamsulosin – is a useful drug for the treatment of BPH. Tamsulosin is a selective Alpha 1A adrenoceptor inhibitor.This is a good example of why understanding and further characterising adrenoceptors subtypes can still give rise to more targeted therapies. Selectivity for the Alpha 1A subtype may make a better drug for BPH as there may be less of an effect in smooth muscle of blood vessels. But this has not been fully established.
side effect of alpha one antagonists /
There are also some side effects that occur due to alpha antagonists, for example, this can include postural hypotension – loss of blood pressure when you stand which causes dizziness or fainting , Diarrhoea, Erectile dysfunction, Drowsiness.Rebound hypertension is when you stop the drug and the high blood pressure returns or in some cases is worse than the patient had before medication. So the doctor in collaboration with the patients try to find the best medicine for the patient. It is also interesting that a drug can be used simply in a patient population due to the absence of adverse clinical trial data. For example methyldopa is used in pregnant women because trial data for ACE inhibitors for example is negative in terms of foetus safety.
