"Discuss classification of catecholamine receptors, their distribution, effects on activation and typical agonists and antagonists"
Catecholamines are a class of compounds so named because of their catechol group at one end and an amine at the other. The receptors that bind these compounds were classified initially into two groups a and b . These classifications were defined in terms of the order of potency of three agonists.
a -receptors Noradrenaline > adrenaline > soprenaline
b -receptors Isoprenaline > adrenaline > noradrenaline
Further work showed that the relative potency of agonists and antagonists varied in different tissues. This has shown the presence of two main a -receptor subgroups and two main b -receptors (A third b -receptor has recently been discovered in adipose tissue)
Adrenoceptors are distributed widely throughout the body. They occur in much smooth muscle. In many of these there is a balance between two subtypes of receptor. In areas such as the blood vessels, the bronchi, and the uterus activation of an a 1 receptor will cause contraction of the smooth muscle whereas activation of a b 2-receptor will relax the smooth muscle. It was the unmasking of the b 2-receptor effect, by blocking the a -receptor that first showed the presence of two adrinergic receptors.
The other b -receptor occurs in the heart. Activation of these b 1-receptors increases the rate and force of contraction.
All the adrenoceptors are coupled via G-proteins to produce their effects. The G-protein once activated itself releases a second messenger. In a 1-receptors the protein activated is phospholipase C and this produces IP3 and DAG as second messengers. a 2-receptors inhibit adenylate cyclase and hence decrease the amounts of cyclic AMP in the cell. All the b -receptors stimulate adenylate cyclase and increase cyclic AMP levels.
Activation of a 1-receptors causes vasoconstriction, relaxation of the gastrointestinal smooth muscle, salivary secretion and production of glycogen in the liver.
These effects occur mainly due to a rise in intracellular calcium levels.
Activation of a 2-receptors can lead to inhibition of release of neurotransmitter (both noradrenaline and acetylcholine), aggregation of platelets, contraction of smooth muscle and synaptic transmission in the central nervous system.
The main mechanism of action of a 2-receptors is the decrease in concentration of cyclic AMP and the subsequent reduction in activity of cyclic-AMP-dependent protein kinase. This is then not able to activate other proteins in the cell.
b -Receptors all increase the levels of cyclic AMP when activated. As such they increase the activity of c. AMP-dependent protein kinase. The increase in phosphorylation of further proteins showing the effects of b -receptor binding.
b 1-receptors occur in the heart. Stimulation of these causes an increase in heart rate and the force of contraction as the increased levels of c. AMP increase the calcium levels in the cells.
Activation of b 2-receptors causes bronchodilation, vasodilation, relaxation of visceral smooth muscle, production of glucose in the liver and muscle tremor.
b 3-Receptors are found only in adipose tissue and initiate the breakdown of lipid in the cell for release into the blood stream.
Adrenaline and small amounts of noradrenaline are released from the adrenal medulla of the adrenal glands situated just superior to the kidneys. Most noradrenaline is released from post-ganglionic sympathetic neurons. These differ from cholinergic neurons. Adrinergic neurons tend to end in a branching terminal network of filaments along which are strung many varicosities. Each of these varicosities is the site of noradrenaline release. Noradrenaline is released from secretory vesicles in the varicosities. When the nerve is stimulated there is a low chance (about 1 in 50) of an individual varicosity releasing a vesicle. Because of the numbers of varicosities a few hundred vesicles are released over a wide area. This can be compared to a cholinergic synapse where there are few boutons but the probability of release is much higher and the transmitter is sharply localised.
There are drugs that act as agonists and antagonists at each of these receptors. (There are also some partial agonists.) The general agonists of all four types of receptor in clinical use is adrenaline. This is the major hormone released in the fear response and its actions are to prepare the body for the "flight or fight" response. This not only stimulates the heart by activating b 1 receptors but it is also able, by stimulating b 2-receptors to dilate the bronchi.. Thus the body allows more oxygen to flow to muscles in preparation for fighting or fleeing. Adrenaline is used clinical in emergency cases of anaphylactic shock where it encourages bronchial dilation and vasoconstriction. In cardiac arrest, adrenaline is also used as a powerful stimulant of the heart. The vasoconstrictor effects of adrenaline can also be used in the administration of local anaesthetics. By mixing adrenaline with the local anaesthetic solution the effects of the anaesthesia can be prolonged.
Agonists that are selective for the receptors are found to be more clinical useful. b 2 receptor agonists such as salbutamol and terbutaline are used in the treatment of asthma for their bronchodilatory effects without increasing the heart rate. Salbutamol can also be used to stop premature labour because of its relaxing action on the smooth muscle of the uterus.
Phenylephrine is a selective a 1 agonist used as a nasal decongestant by direct administration into the nasal cavity. Selective a 2 agonists can cause a fall in blood pressure. Drugs such as methylnoradrenaline, act partly to inhibit noradrenaline release, and partly on the CNS. Methylnoradrenaline is formed by the noradrenaline synthesising enzymes from methyldopa which was developed as a hypotensive drug. It is now no longer used as it has been superseded by b 2 antagonists that do not cause the same drowsiness associated with it.
b 1 agonists such as dobutamine could be clinically useful in their stimulation of increased contractility of the heart. However, there is a risk of causing cardiac dysrhythmias and so this rules them out for clinical use.
Adrinergic antagonists are a very useful class of drugs. a adrenoceptor antagonists are irreversible competitive antagonists such as phenoxybenzamine, or reversible competitive antagonists such as phentolamine and tolazine. They all have similar physiological effects in that they cause a fall in arterial pressure due to block of a -receptor mediated vasoconstriction. There is a reflex reaction of increased cardiac output and heart rate due to the reduced pressure. This is not blocked by the drug as it is mediated through b -receptors. Phenoxybenzamine mainly differs in action because it bonds covalently with the receptor. This has a very slow dissociation rate. This can be over 24 hours as it involves cleavage of a covalent bond. Phentolamine and tolazine do not bind covalently and as such dissociate much faster.
The first drug to be selective for a 1-receptors was prazosin. This causes vasodilation but with less increase in cardiac output as it does not increase the of a 2-mediated release of noradrenaline.
Yohimbine is famed in herbal law as an aphrodisiac. This is due to its vasodilatory effects by blocking post-synaptic receptors. Pre-synaptically, the block of a 2-receptors increases the release of noradrenaline in the sympathetic nervous system.
b -Adrenoceptor antagonists (beta-blockers) are an important class of drugs. Propanolol is an important tool in the armoury against hypertension. It is not selective for b 1 or b 2 receptors. At rest it causes little change in the heart rate. In hard exercise or excitement it reduces the changes in cardiac output, arterial pressure and heart rate. Partial agonists such as oxprenolol increase the heart rate at rest but lower it during exercise. Because of the limitation of cardiac response and the reduction in b -mediated vasodilation in skeletal muscle the tolerance to exercise is reduced in normal substances. A major potential problem with non-selective b -antagonists is that they also produce an amount of bronchoconstriction by inactivating the b 2 receptors responsible for bronchodilation. In the normal subject this is not particularly noticeable. In asthmatic patients (and those suffering from other respiratory disorders such as emphysema and chronic bronchitis), however, it can be fatal to overlook this. It was thought that the production of b 1 specific antagonists such as atenolol would provide a safe method of treatment. So far, no drug has been found that is specific enough to b 1 receptors to eliminate the risk completely. Of course an asthma attack brought about by use of b -blockers will not respond to the usual doses of salbutamol or adrenaline. Diabetic patient also have to be careful in use of b -blockers as they can lead to increased risk of hypoglycaemia. This is partly to do with the block of adrenaline induced release of glucose from liver based store of glycogen, and partly to do with the masking of symptoms of the sympathetic nervous system that warn a diabetic to consume carbohydrate.
Adrinergic receptors occur in many regions of the human body and moderate response in smooth muscle and cardiac output. Other effects not mentioned include inducing amylase secretion in saliva, aggregation of blood platelets and inhibition of histamine release. The drugs developed have tended to be either for reduction of hypertension and have focused on the b -receptors or for prevention of the symptoms of asthma and focused on a receptors. Much thought has gone into producing receptor specific drugs to avoid some of the unwanted side effects and reduce the risks to patients. Clinical practice has so far failed to provide drugs specific enough to negate the risk. But as our understanding increases a b 1-specific antagonist may not be impossible to find.
(c)1998 Nick Manville