(for FANZCA part I)

This web page covers four main topics:

  1. catecholamines and their metabolism - we look at noradrenaline and adrenaline (epinephrine), including brief notes on their clinical usefulness;
  2. adrenergic receptors;
  3. adrenergic drugs (agonists and blockers);
  4. agents that interfere with adrenergic function

We assume that you have ploughed through our introduction to the ANS, and understand terms such as 'homotropic regulation'. Your enjoyment of the page should be greatly enhanced if you have the CHIME plugin, as you can then view many of the molecules discussed, in 3 dimensions. Catecholamines are all based on the aromatic molecule catechol . Here's a picture of this molecule - if you click on the image and have CHIME installed (in an appropriate browser), a window will pop up containing a rotating molecule!

the catechol molecule. CLICK HERE!

Note that it's traditional to draw a benzene ring with alternating double bonds - in CHIME you may be able to turn on/off the display of double bonds (Right click on the CHIME image for all the options). We have generally shown such rings with a contained circle - imagine the rings with a delocalised 'pi' distribution of electrons above and below the ring.

Catecholamine synthesis and disposal

Here's the noradrenaline molecule

noradrenaline (norepinephrine). Click me!

Noradrenaline is the adrenergic neurotransmitter. Therapeutically, as an inotrope and pressor agent it is a somewhat controversial drug, but some would regard it as the agent of choice in septic shock, given (of course) by continuous infusion. The potentially marked alpha agonist effect elicited by noradrenaline mandates cautious use, in an intensive care setting with appropriate monitoring. Note that septic patients often have profound vasodilatation and a blunted response to alpha agonists.

In our previous page, we discussed the synaptic vesicle cycle, and also the cycling of neurotransmitter release and uptake. We need to integrate this knowledge with the actual biosynthesis of catecholamines. Here are the synthetic pathways for noradrenaline, and adrenaline. (All images are CHIME clickable; carbon atoms are grey, oxygen red and nitrogen blue. Hydrogen atoms are not shown).

tyrosine Click me!


DOPA Click me!


dopamine. Click me!


noradrenaline. Click me!


adrenaline. Click me!

tyrosine hydroxylase
DOPA decarboxylase
dopamine ß-hydroxylase
phenylethanolamine N-methyl transferase

The enzymes

Tyrosine hydroxylase

A pretty specific cytosolic enzyme that is the main control point for catecholamine synthesis - only found in catecholamine-containing cells. Noradrenaline inhibits the enzyme, providing feedback control. Potent inhibition also occurs with the analogue alpha-methyltyrosine.

DOPA decarboxylase

This widespread enzyme catalyses the next step in noradrenaline synthesis, with a host of other functions besides (decarboxylation of many other aromatic L-amino acids).

dopamine ß-hydroxylase

Found in synaptic vesicles, this predominantly membrane-bound enzyme is actually released in tiny quantities when synaptic vesicles discharge (so a sensitive assay can give an idea of sympathetic activity)! As an aside, disulfiram inhibits the enzyme. (Examination candidates may wish to explore the challenge of giving an anaesthetic to someone on disulfiram)!

phenylethanolamine N-methyl transferase

This is an enzyme of the adrenal medulla whose production within 'A' cells is strangely enough modulated by adjacent adrenal steroid production! There is a small amount of the enzyme also present in certain areas of the brain!

Note that the noradrenaline ==> adrenaline step occurs almost exclusively in the adrenal cortex, and not in (most) neurones. Once synthesized, noradrenaline is actively taken up into synaptic vesicles, using hydrogen ion gradients to drive uptake (The transport protein is similar to those that mediate reuptake from the synaptic cleft, but those transporters use sodium ion gradients). Noradrenaline content of most tissues is tightly controlled, so that as more is released, more is synthesized to compensate. In the mythical 'average man', it takes about ten hours for 'complete' turnover of noradrenaline stores! ATP is complexed with noradrenaline in the synaptic vesicle, and acts as a co-transmitter.

Noradrenaline release is profoundly influenced by homotropic and heterotropic regulation. Presynaptic alpha-2 receptors, when stimulated, inhibit its release, but other agents (acetylcholine, angiotensin II, prostaglandins, etc) also influence release.

Reserpine blocks transport of noradrenaline into presynaptic vesicles.

We have already discussed disposal of neurotransmitters released into the synaptic cleft - much noradrenaline is taken up by transporter proteins back into the presynaptic terminal. There is a long tradition of distinguishing between "uptake 1 " and "uptake 2 ", terms respectively applied to our by now well-known neuronal uptake, and uptake into cells that are not neurones (uptake 2 is "extraneuronal").

The pumps

Uptake 1 is very important in the re-cycling of noradrenaline, while uptake 2 simply mops up the rest.

Vesicular uptake

There appear to be two distinct vesicular amine transporters, called VAT1 and VAT2.

Presynaptic uptake - 'uptake 1'

This noradrenaline transporter protein ('NET') was discussed in our previous lecture.

'Uptake 2'

Quantitatively, uptake 2 gobbles up a lot more neurotransmitter into smooth and cardiac muscle and even the endothelium. As one might expect, uptake 1 is particularly good at grabbing noradrenaline; uptake 2 is more specific for adrenaline.

Noradrenaline degradation

Now that we've briefly covered synthesis (and release), let's consider removal of noradrenaline from the synaptic cleft. In the peripheral nervous system, neuronal reuptake is the major mechanism for terminating noradrenaline's action at the synapse. Things are different in the central nervous system , where a degradative enzyme is pretty important in dealing with noradrenaline. The enzyme is monoamine oxidase (MAO). Hence the previous importance of MAO inhibitors in management of depressive disorders in man.

There is yet another enzyme, catechol O-methyl transferase (COMT) that is widespread both inside and outside neuronal tissue. It inactivates both noradrenaline and adrenaline.

There are several metabolic steps in the activation of catecholamines, and the amount of end-product depends on where the catecholamines are being broken down. CNS noradrenaline is predominantly metabolised to 3 methoxy 4 hydroxy phenylglycol (MOPEG), while peripherally the same transmitter is metabolised to a heady cocktail that includes a fair amount of vanillylmandelic acid (VMA). Traditionally we have measured urinary VMA to diagnose phaeochromocytoma, but we now know that this is a pretty insensitive test (and thus rely on a combination of clinical suspicion, urinary metanephrines, and possibly blood levels of catecholamines too). For completeness, here are the main noradrenaline degradative pathways. The enzymes are COMT, MAO, aldehyde dehydrogenase (ADH) and aldehyde reductase (AR).

                           noradrenaline [NA]
                               /      \
                        (COMT)/        \(MAO)
                             /          \
          normetanephrine [NM]       NA aldehyde
                        \            /   \     \
                   (MAO) \    (COMT)/     \(AR) \(ADH)
                          \        /       \     \
                          NM aldehyde    DOPEG    \
                           \      \      /         \
                            \  (AR)\    /(COMT)     \
                             \      \  /             \
                              \     MOPEG           DOMA
                               \                  /
                           (ADH)\                /(COMT)
                                 \              /
                                  \            /
                              vanillylmandelic acid 

The importance of Monoamine oxidase - MAO

Examination candidates are still often asked about MAO inhibitors (MAOI) - this may be because such questions illustrate important principles within the autonomic nervous system. These agents were very popular years ago for treatment of depression, but potentially life-threatening drug interactions made them rather unpopular. One may occasionally encounter MAOI - phenelzine, tranylcypromine, and isocarboxazid.

In addition to their unfortunate interaction with tyramine in foods, MAOI have other undesirable effects, including the occurrence of fatal interaction when used with opioids (notably pethidine), tricyclic antidepressants (TCAs), and selective serotonin uptake inhibitors; and profound CNS depression when used with alcohol, or general anaesthetics. Exam candidates might wish to explore the "neuroleptic malignant syndrome" that occurs when MAOIs interact with, for example, TCAs. This would appear to be a heterogeneous syndrome, and the interaction with pethidine, for example, seems quite distinct from that with TCAs.

Selegiline is an interesting MAOI in that it specifically inhibits only one of the two MAO isoforms - MAO-B, which degrades dopamine. The drug is thus useful in Parkinson's disease.


We already know about the synthesis of adrenaline in the suprarenal gland. Removal of adrenaline is similar to noradrenaline degradation, but uptake-1 is not important. Both COMT and MAO act on adrenaline. Metabolites are analogous to those produced during noradrenaline metabolism.

Adrenaline is well-recognised as an important agent in resuscitation notably following cardiac arrest, and with severe anaphylaxis. Recently, the use of high-dose adrenaline has been frowned upon, and other agents such as vasopressin may eventually partially supplant it. (Amiodarone also deserves mention in this setting). Adrenaline has been disparaged as an inotrope in septic shock for a variety of reasons, including its propensity to raise lactate levels, but this latter effect does not necessarily carry the same grave prognosis seen with other causes of hyperlactataemia. Dosage should rapidly be titrated to effect, as discussed in our page on inotropic support.

Uptake-1 inhibitors like cocaine will greatly enhance the magnitude of the response to administered adrenaline, as well as the duration of this response. Alpha blockade will 'unmask' predominant beta effects, and conversely, ß blockade will permit nasty unopposed alpha effects (think phaeochromocytoma)! Arrhythmias (related to both endogenous and exogenous adrenaline) are a well-recognised complication of halothane administration, related to halothane's sensitizing effect on the myocardium, which is made even worse by hypocapnia.

Adrenergic Receptors

All adrenergic receptors work via G proteins. The end results of stimulation of the different receptors are however profoundly different. Beta receptors stimulate adenylate cyclase resulting in increased intracellular levels of cyclic AMP; alpha-1 receptors cause release of intracellular calcium (via Phospholipase C), and stimulation of alpha-2 receptors lowers the activity of adenylate cyclase.

We will discuss:

  1. Alpha receptors (alpha 1, alpha 2)
  2. Beta receptors (beta 1, beta 2, beta 3)
(Note that some authorities prefer to regard alpha-1, alpha-2 and beta receptors as being on the same footing, and then talk about the subtypes)
Man vs rat

It's important to note that much of the work on adrenergic receptors was done on laboratory animals such as rats. These animals are quite different from man - for example, in the rat, cardiac beta receptors are beta-1. In man, there also numerous beta-2 and beta-3 adrenoceptors in the myocardium, although we're not clear how important they are here!

Alpha receptors

The alpha-1 and alpha-2 receptors both have well-characterised subtypes, confirmed by gene sequencing. These include:

  1. alpha-1:
    1. alpha-1A
    2. alpha-1B
    3. alpha-1D
  2. alpha-2:
    1. alpha-2A (the same as the rat alpha-2D receptor)!
    2. alpha-2B
    3. alpha-2C

Alpha-1A receptors mediate positive inotropic responses in the heart, and are also mainly responsible for cardiac hypertrophy ! [Can J Physiol Pharmacol 2000 Apr;78(4):267-92]. They also mediate vasoconstriction and metabolic effects of alpha-1 receptor stimulation. They are coupled via Gp/q to phospholipase C, D and A2 (we will abbreviate these to PLC, PLD, PLA2). Alpha-1B receptors appear mainly to activate phospholipase C, resulting in production of IP3 and DAG from PIP2, with a consequent rise in intracellular calcium ion concentration. Alpha-1D receptors are probably only important in vasoconstriction. Stimulation of PLC is greatest for alpha-1A (> alpha-1B > alpha-1D). [Eur J Pharmacol 1999 Jun 30;375(1-3):261-76]. Splice variants of alpha-1A have been described.

When stimulated, alpha-2 receptors lower cAMP levels by inhibiting adenyl cyclase, an action mediated by G i . This is probably not the whole story, with other G proteins probably mediating effects. The major alpha-2 receptor in the spinal cord appears to be alpha-2A. Alpha 2A receptors mediate central anti-hypertensive effects; alpha 2C receptors are also important in homotropic regulation, and alpha 2B receptor stimulation may cause vasoconstriction (mediating the trasient peripheral vasoconstriction seen when IV alpha-2 agonists are given). Genetic polymorphism in these receptors is well-documented.

Alpha-1 receptors

These receptors are commonly found on smooth muscle, and generally cause contraction of the muscle (but may relax smooth muscle in the gastrointestinal tract). They have a few other effects - liver glycogen is broken down when they are stimulated, and production of saliva is increased. (Note that adrenaline-induced hyperglycaemia is contributed to by alpha receptors, as beta blockade alone doesn't obliterate this hyperglycaemic response).


adrenaline = noradrenaline >>>isoprenaline

(also the selective agonists phenylephrine and oxymetazoline)

Partial agonists



prazosin, doxazocin are selective antagonists

Alpha-2 receptors

Alpha-2 receptors are pretty different from alpha-1. They are important in homotropic regulation of neurotransmitter release at adrenergic synaptic junctions, but in addition are found on platelets (mediating aggregation), and beta cells in the pancreas (inhibiting insulin secretion). These receptors do have something in common with alpha-1 receptors, in that both are found on vascular smooth muscle, and participate in vasoconstriction.


adrenaline = noradrenaline >>> isoprenaline

(also the selective agonist clenbuterol; and alpha-methylnoradrenaline; and other agents such as dexmedetomidine, and mivazerol; etomidate and pethidine have some alpha-2 agonist activity. )

Partial agonists

clonidine is a selective agonist.


yohimbine, idazoxan are alpha-2 selective antagonists, as are atipamezole, efaroxan and rauwolscine. BRL44408 and BRL48962 antagonise alpha-2A receptors, imiloxan alpha-2B.

Beta receptors

The structure and function of the beta-1 and beta-2 receptors have been well characterised. Seven-spanning transmembrane proteins, they transduce signals using G proteins, notably G s . In many ways they are strangely similar to muscarinic receptors! All beta receptors increase cellular levels of cyclic AMP. ß-adrenergic receptor kinase modifies their function.

Beta receptors change both in numbers and responsiveness to stimulation quite quickly. Denervation or blockade rapidly increase numbers; conversely, prolonged stimulation results in down regulation of the response to beta agonists, especially at ß-1 receptors. The latter 'desensitisation' is complex, perhaps related to:

Beta-1 receptors

Classically ('rat-ically') these receptors are cardiac, and cause the characteristic effects of adrenaline on the heart - tachycardia, increased contractility, increased rate of impulse conduction, and impaired relaxation. (The fancy terms are of course 'positive chronotropy, inotropy & dromotropy, and negative lusiotropy', respectively).

Beta-1 receptors also increase amylase secretion from the salivary glands.


isoprenaline > adrenaline = noradrenaline

(also dobutamine, xamoterol: specific for ß-1)

Partial agonists

dichloroisoprenaline (the first 'beta blocker'); the 'blockers' oxprenolol and alprenolol actually have significant partial agonist activity.


A whole slew of beta blockers {see below}, but beta-1 selective are atenolol and metoprolol.

Beta-2 receptors - not for noradrenaline

ß-2 receptors can be neatly contrasted with alpha-1 receptors, in that the former generally relax smooth muscle, wherever they are found. In addition, they have several metabolic effects, causing breakdown of glycogen in both liver and skeletal muscle. Remember that noradrenaline has minimal ß-2 effect.

One useful effect of beta-2 receptor stimulation is inhibition of release of histamine (and other granule components) from mast cells. Lymphocytes are also inhibited by ß-2 agonists, although the clinical importance of this effect is far from clear.

Beta-2 receptor stimulation also increases the tension generated in fast-twitch skeletal muscle fibres (especially if they're tired). Changes in muscle kinetics combined with a (probable) effect on the muscle spindle probably contribute to the tremor seen with administration of beta-2 agonists like adrenaline. Other longer-term effects probably account for the improvement in rate and force of muscle contraction seen with beta agonists like clenbuterol (used as an illegal 'performance-enhancing' agent by some 'sportsmen').

It is thought that the reduction in portal venous pressure seen with propranolol or nadolol therapy is mainly related to blockade of beta-2 receptors. This is useful in management of portal hypetension. An even more pronounced effect has been reported with carvedilol 12.5mg daily [Aliment Pharmacol Ther 2002 Mar;16(3):373-80].


isoprenaline > adrenaline >> noradrenaline

selective are salbutamol, terbutaline, salmeterol



Beta-3 receptors

These receptors have been best characterised in brown fat, where they mediate thermogenesis (in infants and hibernating animals). We now know that they are also present in sites such as the myocardium, where they may antagonise the effects of beta-1 and beta-2 receptor stimulation, although such speculation may be simplistic [Circulation 2001 Nov 13;104(20):2485-91]! It is also thought that (unlike ß-1 receptors) they do not undergo down-regulation with long-term stimulation. The role of beta-3 receptors in the white adipose tissue of rats is well established, but controversial in humans - the advent of specific human ß-3 blockers may clear things up [J Pharmacol Exp Ther 1999 Aug;290(2):649-55].


isoprenaline = noradrenaline > adrenaline

(BRL 37344 is specific, at least in rats)


Have been described (L-748,328 and L-748,337); most conventional beta-blockers have no effect on beta-3 receptors.

Drugs acting on adrenoceptors

After we've considered how drug structure influences actions, we'll look at:

  1. Adrenergic agonists
  2. Alpha blockers
  3. Beta blockers
After much tinkering, drug designers have become fairly smart at predicting the effects of various drugs on receptors. They've coined the name "structure activity relationships" for the 'rules' they've derived. Here are a few of the generalisations they've come up with, when it comes to modifying the noradrenaline molecule, especially as regards effects at beta receptors (They're fairly hopeless for predicting alpha effects, on the main). Here's the noradrenaline molecule again, followed by a list of modifications and their effects:

noradrenaline (norepinephrine). Click me!

Adrenergic receptor agonists

Above we discussed adrenaline and noradrenaline, and we have previously covered the distribution of adrenergic receptors in the various tissues. We know the various effects of stimulation of the several types and sub-types of adrenergic receptor, and structure-activity relationships for the various agents. We will thus confine our further discussion of adrenergic agonists to specific drugs:


This agent acts at alpha, beta and dopaminergic receptors; it even has an indirect noradrenaline-releasing effect! It has traditionally been taught that it improves mesenteric blood flow in shock; this simplistic view is not supported by any substantial evidence! There are also still intensive care units around the world where dopamine is administered in a ritualistic fashion to 'improve renal function', a practice based more on myth than science. Some authorities regard dopamine as the initial drug of choice in states such as septic shock.

The half-life of dopamine in the circulation is short (about 1 minute). Again, it is traditionally taught that low doses (~3 µg/kg/min) have predominant dopaminergic effects, intermediate doses beta effects, and higher doses (> 10µg/kg/min) predominant alpha effects, but such differentiation may not be encountered clinically.

Dopamine receptors are not without interest. Five receptors have been cloned; the most important are D1 and D2. (Otherwise known as DA1 and DA2). The D5 receptor is like D1, the others like D2. DA1 receptors are post-synaptic, and prominently present in the smooth muscle of the kidneys and mesenteric vessels. DA2 receptors are presynaptic, and appear to modulate noradrenaline release. Stimulation of central DA2 receptors causes emesis (cf. eg. apomorphine).


We have briefly reviewed this agent elsewhere, (concentrating on its misuse in "splanchnic resuscitation"). In summary, dobutamine is a racemic mixture with good beta-1 agonist activity, and minuscule agonist effects on beta-2 receptors. Unfortunately, it doesn't stop there, for (-)dobutamine is a partial agonist at alpha receptors, and (+)dobutamine has insignificant alpha agonist effects. Overall, in the presence of other alpha agonists, we might expect dobutamine to act as an alpha blocker! In addition, dobutamine antagonises the beta effects of adrenaline both in vitro and in vivo.

The principle use of dobutamine appears to be in short-term support of patients with heart-failure, where it can indeed be extremely useful. Here's the molecule:

dobutamine. Click me!


Consult our brief review of dopexamine here! Dopexamine has both dopaminergic and ß-2 agonist effects, and fenoldopam is a selective agonist at DA1 receptors.

Isoprenaline (isoproterenol)

A relatively pure, non-selective beta agonist, this is now an 'orphan' drug. Isoprenaline is a vital drug in the management of paediatric cardiac patients. Adult clinical use is limited to increasing heart rate as a temporising measure in patients with complete heart block (while preparing for pacing), although even this use has fallen into disfavour. Metabolism is by COMT, with no uptake-1.


"Beta-2 selective" (but only partially so, and remember that the heart also has beta-2 receptors), this agent finds its main use as an aerosol in asthma. Terbutaline and albuterol are similar. ß-2 agonists have also been used as tocolytics. Side effects include tachycardia, arrhythmias, and hypokalaemia.

salbutamol. Click me!


Salmeterol represents an interesting wrinkle in beta-2 therapy of asthma. A long-acting beta agonist, salmeterol has a long lipophilic side chain that binds to an 'exosite' near the beta receptor with high affinity. This binding results in sustained (over 12 hour) receptor stimulation, with substantial clinical improvement in symptom control. Salmeterol is transformed by CYP 3A4 to the alpha-hydroxy derivative which is eliminated in the faeces.


This is a selective alpha-1 agonist. It has rapid onset, and short duration of action (5-10 min) when given IV, so infusion is the best method of administration. The agent is logically used to provide vasoconstriction where there is hypotension due to vasodilatation, for example due to neuraxial block. (Phenylephrine is also used as a mydriatic and nasal decongestant).

phenylephrine. Click me!

Methoxamine has similar alpha-1 activity, but longer duration of action (30-60 min).


Clonidine is the prototypic alpha-2 agonist. It's main anti-hypertensive action appears to be due to central alpha-2 receptor stimulation (with lowered sympathetic outflow). It has also been used in treatment of a wide variety of disorders, such as chronic pain, withdrawal syndromes, management of nausea, treatment of diarrhoea in diabetic with autonomic neuropathy, and postmenopausal symptoms.

clonidine. Click me!

In addition, alpha-2 agonists may be used as anaesthetic adjuvants. One such agent is dexmedetomidine..


The alpha-2 agonists are potentially very useful agents in anaesthesia. Drugs such as xylidine have been used for years in veterinary anaesthesia, and now we have dexmedetomidine, which we have reviewed previously - also look here. Alpha-2 agonists seem to be a favoured topic in recent post-graduate anaesthetic exams.

Adrenergic receptor blockers

There is a vast array of agents now available for blocking adrenergic receptors. Most block either alpha or beta receptors, although some are widely touted as agents that block both (for example, labetalol, which is a beta blocker with relatively modest alpha-blocking effects).

Alpha blockers

These may be non-selective (the older agents phenoxybenzamine and phentolamine), or selective. Note that the nonselective agents are largely obsolete because of the high rate of side effects, notably postural hypotension and tachycardia; phenoxybenzamine irreversibly binds alpha receptors and is thus still, in the opinion of some, a good agent for pre-operative management of phaeochromocytoma. (Roisen's criteria are traditionally used to establish the presence of effective blockade). Once a decent degree of alpha blockade has been established, then only may beta blockade be instituted in phaeochromocytoma (Consider why this should be)! The various alpha-1 and alpha-2 selective alpha blockers are considered below.

Note that alpha blockers seem to be falling into disfavour for the management of hypertension, especially in patients with associated heart failure (largely because the doxazosin arm of the ALLHAT study was stopped due to an increased incidence of heart failure and cardiovascular events).

Alpha-1 blockers


Prazosin is a selective, reversible alpha-1 blocker, and has been used to manage hypertension, and even in pre-operative preparation of patients with phaeochromocytoma. It should not be used in heart failure.

prazosin. Click me!

Other similar agents include doxazosin, terazosin.


This agent is 'super-selective', having a preference for alpha 1A and alpha 1D receptors. Such selectivity may be of value as these receptors are prominent in the bladder neck, rendering tamsulosin useful in management of lower urinary tract symptoms. See [Drugs 2002;62(1):135-67].

Alpha-2 blockers

Agents such as yohimbine and idazoxan are mainly experimental curiosities used to analyse alpha receptor subtypes.

Beta blockers

Many beta blockers such as propranolol block beta-1 and beta-2 receptors equally. Exceptions are the ß-1 selective agents atenolol and metoprolol. (The first beta-1 selective agent was practolol, but it unfortunately caused fibrosing syndromes, and has been abandoned).

The ways that beta-blockers combat hypertension are still poorly understood. Possible mechanisms are:

Beta blockers are also of great use in management of ischaemic heart disease, mainly through lowering of myocardial oxygen demand. Control of heart rate is an important effect, as tachycardia selectively lessens the relative duration of diastole, and as we know, coronary flow is mainly in diastole. Several studies now attest to the protective effect of beta-blockers in the peri-operative period, in patients with underlying ischaemic heart disease. The mechanism of this observed effect is still obscure. Conversely, it is generally extremely unwise to stop beta-blockers suddenly, especially in the peri-operative period, as there is a risk of tachycardia and even myocardial infarction.

Beta blockade is also useful in management of thyrotoxicosis, hypertension, migraine headaches (prophylaxis), hypertrophic cardiomyopathy, and certain arrhythmias.

Of fairly recent interest is the observation that heart failure is a hyper-adrenergic state. Careful introduction of beta-blockade in patients in heart failure seems paradoxical but probably has survival benefits! Carvedilol has featured prominently in this regard.

Side effects of beta-blockers can largely be predicted through knowledge of where beta receptors are present. These agents may precipitate life-threatening bronchospasm in asthmatics, and they should be used with extreme caution in patients in heart failure (but see above)! We are now much less jumpy about appropriate use in diabetics (despite a theoretical propensity to mask the symptoms of hypoglycaemia) and there seems to be scant evidence that beta blockers worsen limb ischaemia in patients with peripheral vascular disease. The bradycardic effects of beta blockers may be a problem, and are even occasionally life threatening, making them contra-indicated in patients with heart block. One reason why beta blockers are unpopular in young active persons with hypertension is the tiredness that may occur. Lipophilic beta blockers may be associated with particularly vivid nightmares.

"Intrinsic sympatomimetic activity"

There is confusion in the literature as to whether this magical property of some beta blockers (such as pindolol and acebutolol) is merely a manifestation of partial agonist properties, or whether it is mediated by other mechanisms. The bottom line is that such agents appear to cause less bradycardia than agents devoid of "ISA". Other ß-blockers with ISA are carteolol, celiprolol, dilevalol, oxprenolol and penbutolol.

"Membrane-stabilizing activity"

These are insignificant for most beta blockers, although "quinidine-like" effects have been claimed for propranolol and acebutolol.


Many beta blockers are rather lipid soluble. These (such as propranolol, metoprolol and pindolol) are rapidly metabolised in the liver, mainly by CYP 2D6, although the attendant problems seen with other drugs and this enzyme appear less common with beta blockers, although dose requirements may vary considerably between individuals. Half-lives are generally short unless controlled-release formulations are used.

In contrast, the water-soluble beta blockers (atenolol, sotalol and nadolol) have longer half-lives and are mainly renally excreted. CNS penetration is lower, with fewer CNS side effects such as depression and nightmares.

Non-selective beta blockers

There's a confusing array of these agents, including propranolol, nadolol, pindolol, sotalol, oxprenolol and timolol. From a practical (and examination) point of view, it's probably important to know the following well:

Here's propranolol again:

propranolol. Click me!

Beta-1 selective blockers

These include atenolol and metoprolol (as well as betaxolol, bevantolol, and perhaps esmolol).


This beta blocker lacks ISA and MSA; one can deduce its metabolism and short half-life from its lipophilicity. Some slow-release formulations of metoprolol have peculiar doses.


Examination candidates should probably know this agent fairly well. Important topics to discuss would be its water solubility, metabolism, ß-1 selectivity, and recent studies showing improved post-operative survival even after very short-term use in the peri-operative period. Here's some information on Mangano's papers.


This beta blocker is relatively beta-1 selective. hydrolysis by nonspecific esterases accounts for its tiny half-life of about 9 minutes. The traditional approach of starting therapy with a 0.5mg/kg IV bolus is excessive, silly, and potentially life-threatening. Be more gentle. This agent has been much abused to "manage tachycardia" intra-operatively, where the anaesthetist should rather be thinking about the cause of the tachycardia, for example, pain)!

Drugs that interfere!

There are several agents that by devious means interfere with noradrenergic transmission. Here are a few mechanisms by which they work:

  1. Interference with adrenergic terminals
  2. 6-hydroxydopamine

    This experimental agent is taken up by noradrenergic terminals - its toxic metabolites then then destroys these, causing "chemical sympathectomy".

  3. Interference with synaptic vesicle uptake
  4. Reserpine

    Binds the vesicle noradrenaline transporter and blocks noradrenaline uptake. An anti-hypertensive, obsolete because of its main side-effect of depression.

    reserpine. Click me!

  5. Interference with synaptic vesicle release
  6. As mentioned above, reserpine depletes neuronal stores of noradrenaline in synaptic vesicles. There are other groups of drugs that interfere with the vesicles in interesting ways:

    1. Block - 'noradrenergic neuron blocking drugs'
    2. Drugs such as guanethidine , another obsolete anti-hypertensive, potently inhibit release of noradrenaline from sympathetic nerve terminals. The mechanisms are complex including (a) initial uptake by uptake-1; (b) concentration in vesicles, with displacement of noradrenaline from the vesicles, and possibly even (c) structural damage to sympathetic neurones.

      (Bretylium is taken up in a similar fashion to guanethidine, but initially releases noradrenaline, before causing profound block of noradrenaline release, without depletion of noradrenaline stores. It has vanishingly small utility as an anti-arrhythmic, formerly often administered as the "last rites" in terminal ventricular arrhythmias)!

    3. Release - 'indirectly acting sympathomimetics'
    4. Ephedrine is perhaps clinically the most important of these agents, which undergo uptake-1 and then displace noradrenaline from the presynaptic vesicles. Some of this noradrenaline then escapes via the uptake-1 pump, and ends up acting on post-synaptic receptors (the rest of the displaced noradrenaline is degraded by MAO)! These agents are 'dirty' in the sense that some of their action is in fact direct agonist activity at post-synaptic alpha-1 receptors. In addition, by their competition for uptake-1 they prolong the life of noradrenaline in the synapse (Several other drugs also mess with uptake-1 - they are discussed below)! Here's ephedrine:

      ephedrine. Click me!

      These agents are sitting ducks for drug interaction:

      Of particular 'classical' importance is the interaction between MAOI and the indirectly acting agent tyramine , found in a host of foods such as parmesan cheese and Chianti. Tyramine is normally removed by MAO in the gut. You now understand how this combination may produce fatal hypertension.

      Amphetamine acts in a similar fashion .. one only has to contemplate the mechanism of action of such drugs to see why tolerance to their effects develops with time. Here's the amphetamine molecule again:

      amphetamine. Click me!

    5. Homotropic and heterotropic effects
    6. See our introductory page.

  7. Interference with pre-synaptic re-uptake
  8. The classical agents here are the tricyclic antidepressants - they inhibit the noradrenaline re-uptake pump. An example is desipramine :

    desipramine. Click me!

    Cocaine has similar actions with increased sympathetic outflow, and massive potentiation of the effect of noradrenaline:

    cocaine. Click me!

    Other agents also interfere with uptake-1. They include amphetamine, phenoxybenzamine and guanethidine.


  1. Chime - you must first register to download the software, but it's free.

  2. Search Swiss-prot protein database!

  3. There's a fair amount of support for the use of perioperative beta blockade. See for example this ACP Journal club review of one of Mangano's papers. (N Engl J Med. 1996 Dec 5;335:1713-20). Here's a follow up paper (Anesthesiology 1998 Jan;88(1):7-17) Of late however, the popularity of this approach seems to be waning, as the original research seems to be open to criticism.

  4. Adrenoceptor online is worth a visit!