Sympathomimetics

This chapter is relevant to Section M2(i) of the 2023 CICM Primary Syllabus, which expects the exam candidates to “understand the pharmacology of drugs acting upon the autonomic nervous system”. That’s a lot of drugs, might scream the beleaguered exam candidate, clutching at their head. Indeed, reader, the idea that one might have to structure their study of these agents is already sufficiently daunting, let alone to contemplate that the college wants you to Know All The Things. Fortunately, it appears that CICM examiners have never asked a single question about the pharmacology of sympathomimetic agents, beyond the predictable SAQs on the pharmacology of adrenaline and noradrenaline (which are understandably committed to the cardiovascular physiology section).  The pharmacopea in the syllabus document only lists these two as "Level 1" ("detailed knowledge and comprehension"), and only under the cardiovascular section, whereas for autonomic pharmacology only cholinergic and anticholinergic agents are mentioned by name. The even more generic Second Part Exam General Syllabus of 2023 only lists "poisoning and drug intoxication" as an item, teasing the possibility that their sympathomimetic toxicity questions are loaded into the toxicology SAQ Russian roulette, and are as likely to click into the chamber as as any other toxidrome. 

In summary,

Advice regarding the Best Possible Article for the time-poor exam candidate is basically impossible here, or at least it would be if somebody were fixated on recommending a source which covered Every Possible Thing. Perhaps that would be Catecholamines by Baschko et al (1972), but this is a 1054 volume from the Handbook of Experimental Pharmacology series, and moreover we have learned much over the subsequent fifty years, making this comprehensive resource a largely obsolete work of mostly  historical interest. The point, however, remains - that this topic is vast, with even the following superficial treatment requiring two chronically verbose people to write it. If the CICM exam candidate needed something quick to refer to in the last minutes, Hoffman & Nelson's 2017 chapter from Brent's  Critical Care Toxicology would probably give enough of an overview to pass whatever terrible SAQ or viva one might encounter in this area.

What is a “sympathomimetic”?

Before embarking on a chapter like this, one ought to become clear about what is being examined and expected. “Sympathomimetic” is not a formal chemical classification, but it is in such wide circulation that it enjoys support at an upper IUPAC level, appearing in their Glossary for Chemists of Terms Used in Toxicology (Duffus, 1993). From this document, which is as official as they get, we have: 

1. adj., Producing effects resembling those of impulses transmitted by the postganglionic fibres of the sympathetic nervous system 
2. n., Agent that produces effects resembling those of impulses transmitted by the postganglionic fibres of the sympathetic nervous system.
   
   SN adrenergic 

In short, this description embraces all agents that, once administered, make it look like your sympathetic nervous system has become activated. This sort of an effect could obviously be exerted at multiple levels. For example, drugs can act on the CNS to flip the control switches of the sympathetic nervous system and increase its activity, or they can act directly on peripheral receptors to activate post-receptor secondary messenger systems. 

Because of the wide range of possible ways one could activate or fake-activate the sympathetic nervous system, the number of possible agents is vast, and the management of their classification is therefore a nightmare. And we need classifications, because without them we become like deer in headlights when we are asked by CICM examiners to describe a group of substances; especially where the group might be large and mostly similar in properties. For example, this table from Vree et al (1969) lists all the amphetamines the authors were able to get hold of for testing, illustrating the span of the problem: 

“Amphetamine-like drugs” is how the authors grouped this listing of wakefulness promoters, appetite suppressants, inotropes, ADHD medications, recreationally abused stimulants, and decongestants, but as you can see there are other ways to classify them and none are superior to the other. Incidentally, wherever the reader sees “amfetamine”, the “f” substitutes for “ph” for reasons of international consistency, which is a principle applied to most recommended International Non-proprietary Names (rINNs) by the WHO (Mehta & Aronson, 2007). The idea is to preserve the pronounciation of the name via phonemic orthography, which means changing “ph” to “f” and “th” to “t”.  

Chemical classes of sympathomimetics 

There is a tendency among textbooks and article authors to represent these drugs in terms of their chemical class and structure, which - though they admittedly have a considerable and predictable influence on their pharmacological properties – would be entirely lost on CICM exam candidates who (we hope) will never be expected to sketch those structures. Moreover, learning the chemical classes does not get one anywhere, as drugs of the same class can have dramatically different properties, and drugs of different classes can have very similar properties. For example, the dominant chemical group of sympathomimetics, the phenylethylamines, includes indirect agonists such as amphetamine, methamphetamine, MDMA and tyramine, as well as classical direct agents such as adrenaline and noradrenaline, but not the classical direct agents xylometazoline and oxymetazoline, which are imidazoline derivatives more closely related to clonidine. Cocaine is a tropane alkaloid more related to anticholinergic drugs like hyoscine and scopolamine, and knowing this does nothing to help you guess its properties. Similarly, yohimbine is an indolalkylamine alkaloid resembling reserpine, L-dopa is an endogenously abundant amino acid, and entecapone is a nitrocatechol (making it closely related to toxic contaminants produced in the course of making military explosives). In short, the reader is reminded that biochemistry is interesting but clearly not essential to the effective use of these substances.

Functional classes of sympathomimetics 

CICM exam candidates have an official syllabus, which contains a book list, and some of those books contain competing classification schema which should be viewed as “official”, even though there may be no wide acceptance for them in the literature. Again, the reader is reminded that these systems are merely the tools of an educator, meant to conceptualise this field to make it easier for students. A good example of one of these “official” systems is this one from Katzung: 

This is another way of looking at the same material, but suffers from the omission of some key players (for example where would you put the MAOIs and L-dopa?) It does, however, have the advantage of helping you remember which drugs affect which receptors.  

Indirect agonists  Releasers  Amphetamine  Methamphetamine  Phentermine  MDMA  Caffeine  Theophylline  Theobromine  Reuptake inhibitors  Cocaine  Tricyclic antidepressants

Direct agonists  Widely nonselective  Adrenaline  Dopamine  α nonselective  Also adrenaline  α1 selective  Catecholamines  Noradrenaline  Phenylephrine  Imidazoline derivatives  Oxymetazoline  Xylometazoline  Ethanolamines Midodrine α2 selective  Clonidine  β non-selective  Isoprenaline  β1 selective  Dobutamine  β2 selective  Salbutamol  β3 selective  Mirabegron

An unofficial classification system for sympathomimetics 

On the basis that all abovementioned official systems are insufficiently cumbersome for this website, the rogue classification below is offered to the reader, in case it helps create a memorable structure. It represents the efforts of the sleep-deprived authors to incorporate the beneficial elements of all the other classification systems by grafting them all together into some kind of nightmarish frankensystem.  

Of course some (most) of these drugs act via more than one of these mechanisms, which makes this classification no better than the usual “direct vs indirect” classification system, as both are disadvantaged by the pharmacological promiscuity of these substances. This is another one of those situations where accuracy must be sacrificed to clarity. If you tried to classify these by their receptor effects, the same problem would arise, as most of them affect multiple receptors within their therapeutic dose range.  

Weird agents could have been included here because they, strictly speaking, fit the “adrenergic agonist” description. For example, clonidine is an α2 selective agonist; but it is not a sympathomimetic, as it has purely sympatholytic effects under virtually all circumstances other than massive horrible overdose, so it was not listed. Similarly, yohimbine is an α2 receptor antagonist but was included here because it has a sympathomimetic effect (increasing sympathetic outflow by central presynaptic effects). 

Some other elements were intentionally omitted from the abovelisted classification because to include them would have defeated the self-confessed intention to make this resource exam-focused, given their obscurity and irrelevance (but of course the authors could not resist the temptation to include them in an aside). For example, alongside the agents that increase the release of catecholamines from presynaptic terminals by various subtle and clever effects (for example by acting on TAAR1 to force the reuptake transport pumps to reverse their function), some other agents stupidly force the terminals to uncontrollably disgorge their contents like drunk undergrads. These are, for example, agents that cause increased intracellular calcium like the neurotoxin veratridine, or ganglionic agonists like largely experimental nicotinic agents dimethylphenylpiperazinium and carbachol, or tetramethylammonium which is sometimes encountered by deranged foodies who like to eat random weird things such as the Neptunea giant sea whelk. Many of these are rapidly fatal for reasons unrelated to their effects on the sympathetic nervous system (eg. by causing respiratory paralysis), which makes the sympathomimetic chapter the wrong place to discuss them. The easily distracted reader is redirected to Biology and ecology of edible marine gastropod molluscs by Santhanam, 2018. 

Administration and routes of absorption 

It can be fairly said that humans are a resourceful species when it comes to achieving central sympathomimetic effects, and have developed highly sophisticated methods of getting wasted on amphetamines and their relatives, with routes of administration that could boggle an unprepared imagination even among critical care personnel not otherwise known to be prudes. Despite their varying solubility in water and occasionally poor oral bioavailability it would appear that basically all of these drugs have been administered in basically all of the ways, and the range is definitely broadest for centrally active agents with pleasing stimulant effects. However, the CICM trainee should be warned against correctly listing vaginal transmucosal absorption as a route of administration for cocaine, to avoid having their moral fibre unfairly estimated by their senior colleagues.  

Absorption and bioavailability of sympathomimetics 

Drug	Oral bioavailability
L-dopa	Poor oral bioavailability (10-20%), and even poorer CNS effect site bioavailability due to systemic decarboxylation into dopamine
Amphetamine	Good oral bioavailability (about 75%)
Methamphetamine	Good oral bioavailability (about 67%)
Phentermine	Almost 100% bioavailability
MDMA	Not measured in humans, highly variable between individuals, and nonlinear, due to MDMA inhibiting its own first pass metabolism - higher doses have higher bioavailability, such that increasing the dose from 50mg to 150mg can increase the plasma concentration by ten times
Yohimbine	Highly variable bioavailability, 7 to 87%, likely due to a individual polymorphism in first pass enzymes
Caffeine	Rapidly and completely absorbed (99% bioavailability)
Theophylline	Rapidly and completely absorbed (99-96% bioavailability)
Amitryptilline	Rapidly and completely absorbed; 33-62% oral bioavailability due to first pass effect
Cocaine	Oral bioavailability 30-40%
Metaraminol	Good oral bioavailability (enough for oral administration to be feasible)
Ephedrine	Good oral bioavailability (88%)
Pseudoephedrine	Good oral bioavailability (91%)
Midodrine	Good oral bioavailabiliy (93%)
Tyramine	Extremely poor bioavailability, ~ 1%, because of inactivation by MAO in the liver
Adrenaline	Basically zero oral availability due to destruction by brush border enzymes in the gut (COMT and MAO)
Dopamine	Extremely poor bioavailability, ~ 3%, because of inactivation by MAO in the liver
Noradrenaline	Basically zero oral availability due to destruction by brush border enzymes in the gut (COMT and MAO)
Phenylephrine	Oral bioavailability 30-40%
Oxymetazoline	Almost 100% bioavailability
Naphazoline	Almost 100% bioavailability
Xylometazoline	Almost 100% bioavailability
Isoprenaline	Oral bioavailability 33%
Dobutamine	Basically zero oral availability due to destruction by brush border enzymes in the gut (COMT and MAO)
Salbutamol	Poor oral bioavailability; but it is still somehow available as a syrup. When given as a nebuliser, approximately 10% of an inhaled salbutamol dose is deposited in the lungs.
Mirabegron	Oral bioavailability 29-35%
Tranylcypromine	Rapidly and completely absorbed; bioavailability ~ 50%
Selegiline	Well absorbed (even better with food); only about 10% bioavailability due to extensive first pass effect
Moclobemide	Rapidly and completely absorbed; bioavailability is about 50%
Entecapone	Oral bioavailability 35%

General rules of thumb do exist: 

• Phenylethylamines that penetrate the blood brain barrier (i.e. anything that can be taken as a recreational stimulant) have an excellent bioavailability because the same molecular modification that makes them more lipid soluble also makes them invulnerable to metabolism by MAO and COMT.  
• Classical “indirect” sympathomimetic agents, such as ephedrine pseudoephedrine and, surprisingly, metaraminol, all have reasonably good oral bioavailability. 
• Catecholamines, which are too polar to penetrate the blood brain barrier, also have a catechol ring which makes them very vulnerable to MAO and COMT, and therefore have virtually zero bioavailability. The only exceptions are salbutamol and isoprenaline, which have sufficiently bizarrely shaped molecules to fool hepatic enzymes and which have historically been available as oral formulations (yes, it appears there were people in the 1970, wandering around in the community, not dying of complete heart block purely because they were constantly swigging from a hipflask full of isoprenaline).  
• Imidazolines, such as the nasal decongestants oxymetazoline naphazoline tetrahydrozoline and xylometazoline, have excellent oral bioavailability, as they absorb readily and undergo minimal hepatic metabolism. Yes, this does mean that these agents can be toxic when accidentally swallowed. Musshoff et al (2014) presented a report of a 40-fold dose error that resulted in toxicity that resembled the effects of clonidine (also an imidazoline)– bradycardia, depressed respiration, and a decreased level of consciusness, all attributed to the central α-2 effects. 

Special mentions can be made of: 

• MDMA, which – try as you might to google it – does not seem to have a bioavailability value listed for humans, mostly because the bioavailability is wildly erratic, individual (as it depends on CYP450 enzyme polymorphisms) and nonlinear. When De La Torre et al (2000) gave healthy volunteers doses in the range of 50 to 150mg, the plasma drug concentration varied by a factor of ten, largely because one of the metabolites binds to a CYP450 enzyme and inhibits the metabolism of the parent molecule. The upshot of this is that a relatively small dose escalation can lead to a disproportionally large increase in bioavailability. This has implications for the summer party-goer who, when confronted with police sniffer dogs at the gates of a music festival, experiences the harebrained instinct to immediately take all the pills they brought (originally intended for staggered dosing). 
• Yohimbine seems to have something similar, with a bioavailability that varies from 7% to 87%, likely due to some kind of genetic variation in first pass enzymes, as absorption appears to be fairly good (Guthrie et al, 1990). 
• Monoamines, such as dopamine and tyramine, are metabolised effortlessly by MAO at the intestinal brush border and the liver, and have a bioavailability of less than 1-3%, unless one happens to be taking an MAO inhibitor. Similarly, L-dopa has extremely poor bioavailability orally due to intestinal L-amino acid decarboxylase, and even less so if you take into account the extensive metabolism by peripheral dopa decarboxylase, which needs to be blocked in order for L-dopa to have a chance of producing any useful CNS effects. When Cotzias et al first introduced L-dopa into the routine management of Parkinson disease, they did not have a peripheral metabolism inhibitor available, and used massive doses (up to 16 grams over 24 hours), relying mainly on brute force to get enough L-dopa to its active site. The peripheral conversion must have produced a tremendous amount of dopamine, because hypotension and tachycardia (as well as various indescribable gastrointestinal symptoms) were commonly reported by the patients. 

pKa and solubility of sympathomimetics 

A surprising wealth of physicochemical data for these agents was available from a 1969 letter to the editor of J Pharm Pharmacol by Vree and colleagues. Unless otherwise stated, that papers, as well as DrugBank, is where the material in this table has come from. 

Drug	Physicochemical properties
L-dopa	pKa = 2.32, sparingly soluble in water (66mg/L).
Amphetamine	pKa = 9.9, poor water solubility; good lipid solubility
Methamphetamine	pKa = 10.11, poor water solubility; excellent lipid solubility
Phentermine	pKa = 10.11, good water solubility; enough lipid solubility to cross the blood-brain barrier
MDMA	pKa = 9.9, good water solubility; enough lipid solubility to cross the blood-brain barrier
Yohimbine	pKa = 14.3, good water solubility; enough lipid solubility to cross the blood-brain barrier
Caffeine	pKa = 14.0, good water solubility
Theophylline	pKa = 8.77, slightly soluble in water
Amitryptilline	pKa = 9.76, insoluble in water
Cocaine	pKa = 8.6, slightly soluble in water (but often available as a highly soluble hydrochloride salt)
Metaraminol	pKa = 8.79, excellent water solubility
Ephedrine	pKa = 10.25, highly water soluble, but also reasonably lipid soluble, so it crosses the blood brain barrier
Pseudoephedrine	pKa = 9.86, highly water soluble, but also reasonably lipid soluble, so it crosses the blood brain barrier
Midodrine	pKa = 13.77, good water solubility
Tyramine	pKa = 9.7, slightly soluble in water
Adrenaline	pKa = 9.69, good water solubility
Dopamine	pKa = 9.27, good water solubility
Noradrenaline	pKa = 8.85, good water solubility
Phenylephrine	pKa = 8.77, good water solubility
Oxymetazoline	pKa = 10.15, good water solubility
Naphazoline	pKa = 10.19, good water solubility
Xylometazoline	pKa = 10.29, good water solubility
Isoprenaline	pKa = 8.96, good water solubility
Dobutamine	pKa = 10.14, sparingly soluble in water
Salbutamol	pKa = 10.3, freely soluble in water.
Mirabegron	pKa = 8, insoluble in water
Tranylcypromine	pKa = 9.6, reasonably water-soluble
Selegiline	pKa = 8.6, highly lipid-soluble
Moclobemide	pKa = 9.8, very poor water solubility; highly lipophilic
Entecapone	pKa = 4.5, practically insoluble in water

A few broad class generalisations can be made about these substances, largely on the basis of how they handle the blood brain barrier: 

• Anything you can get high on can be expected to be highly lipid soluble, as this is one of the conditions of entry for the blood brain barrier. Into this group one can put all the amphetamine-like drugs, as well as ephedrine and pseudoephedrine. 
• Anything you tend to use as an infusion in the ICU can be expected to be highly water soluble, polar, and therefore incapable of penetrating the blood brain barrier, which is why adrenaline and noradrenaline do not have CNS effects. 
• Orally available agents which depend on CNS effects, such as the MAO inhibitors, tricyclic antidepressants and entecapone, are largely insoluble in water (hence the lack of an injectable form) and are highly lipid-soluble (all the better to sneak through the blood brain barrier)  

A few interesting side comments may be made here to distingusih some drugs from these expected class-wide descriptions:  

• Levodopa is a very strong base, fully ionised at physiological pH, and should by all rights be unable to penetrate the blood brain barrier, if it were not for the activity of the large neutral amino acid transporter (LAT1) which is expressed on the surface of endothelial cells and which actively transports it into the brain (Contin & Martinelli, 2010) 
• Neutral forms of amines, colloquially referred to as “free base”, are weak bases with poor water solubility but excellent lipid solubility. This is the form referred to in the table for amphetamine-like substances and cocaine. The hydrochloride salts of these amines (eg. cocaine hydrochloride) are water-soluble and therefore injectable, whereas the neutral amine is not; but the neutral amine is typically more heat-stable and can be smoked or absorbed sublingually.  

Protein binding and distribution of sympathomimetics 

Deranged Physiology was defeated by tyramine, for which the seminal article about plasma protein binding was a) out of print, b) available not even in abstract, and c) present exclusively in the authors’ native Spanish. One can only assume it is as protein-bound as other monoamines, which is to say minimally. For other catecholamines, valiant efforts by various authors were unearthed after much searching (eg. Franksson, & Änggård, 1970), which revealed that dopamine is only 13% protein-bound, and so for tyramine the figure is most likely not far from this. Its volume of distribution had to be reconstructed from oral data by Vandenberg et al (2003), an imperfect estimate. Anyone who possesses accurate information on the pharmacokinetics of tyramine, or is able to translate from Spanish, would be rewarded with a hilarious Tshirt.  

Similarly, the imidazoline alpha-agonists like oxymetazoline are not very well studied, insofar as their plasma protein binding seems to be largely unknown . Unhelpfully, all the other imidazolines have had their protein binding measured, and their characteristics tend to vary quite considerably, making it difficult to guess the trend. One can draw the conclusion that these topical agents are highly unlikely to ever end up in the systemic circulation (so why would anyone want to know whether they bind to plasma proteins), except they are hellishly toxic in oral overdose, which suggests there should be at least some forensic interest in their pharmacokinetics.  

Still, here’s the data, such as it is: 

Drug	Distribution
L-dopa	VOD= 2-4 L/kg, minimally protein-bound
Amphetamine	VOD= 4L/kg, 20% protein-bound
Methamphetamine	VOD= 8L/kg, 20% protein-bound
Phentermine	VOD= 5L/kg, 17.50% protein-bound
MDMA	VOD= 5L/kg, 40% protein-bound
Yohimbine	VOD= 2.6L/kg, 97% protein-bound
Caffeine	VOD = 0.7L/kg, 10-20% protein-bound
Theophylline	VOD= 0.45L/kg, 58-82% protein-bound
Amitryptilline	VOD= 19L/kg, 84% protein-bound
Cocaine	VOD= 1-3L/kg, 92% protein-bound
Metaraminol	VOD= 4L/kg, 45% protein-bound
Ephedrine	VOD= 3L/kg, 3-6% protein-bound
Pseudoephedrine	VOD= 2.1-3.3L/kg, 22% protein-bound
Midodrine	VOD= 5L/kg, less than 30% protein-bound
Tyramine	VOD= 77L/kg, minimally protein-bound
Adrenaline	VOD= 0.1-0.2L/kg, 12% protein-bound
Dopamine	VOD= 0.78 - 1.58L/kg, 13% protein-bound
Noradrenaline	VOD= 0.12L/kg, 25% protein-bound
Phenylephrine	VOD= 2.9-7.1L/kg, minimally protein-bound
Oxymetazoline	VOD= 19L/kg, 56% protein-bound
Naphazoline	VOD unknown, presumably small; 95% protein-bound
Xylometazoline	VOD= 1L/kg, probably about 50% protein-bound
Isoprenaline	VOD= 1.5L/kg, 14-18% protein-bound
Dobutamine	VOD= 0.2L/kg, unknown but presumably minimally protein-bound
Salbutamol	VOD= 1.3L/kg, minimally protein-bound
Mirabegron	VOD= 24L/kg, 71% protein-bound
Tranylcypromine	VOD= 1.75L/kg, probably highly protein-bound
Selegiline	VOD= 25L/kg, 96% protein-bound
Moclobemide	VOD= 2L/kg, 50% protein-bound
Entecapone	VOD= 0.3L/kg, 98% protein-bound

The reader will be able to note the distinct lack of class-level generalisations. Still, patterns are visible: 

• Direct sympathomimetics are generally poorly protein bound and distribute exclusively into the circulating volume. These include your standard infusions of inotropes and vasopressors, as well as midodrine. 
• Indirect sympathomimetics also tend to be poorly protein-bound, but have a larger volume of distribution because they tend to disappear into presynaptic vesicles and broadly have a higher fat solubility. This group incluse the amphetamine-like CNS agents and metaraminol. 

Metabolism and elimination of sympathomimetics 

As with all their other properties, the chemical diversity of sympathomimetics makes it difficult to generalise them into groups according to their metabolism. The enormous table that follows is buffered by a brief summary which will hopefully make it easier to scroll past it. 

• The vast majority of these drugs are metabolised in the liver. Notable exceptions which are eliminated almost exclusively by the kidneys include: 
  • Phentermine 
  • Ephedrine 
  • Pseudoephedrine 
  • All the imidazoline derivatives used as nasal decongestants (oxymetazoline, xylometazoline, naphazoline) 
  • Metaraminol, which apparently is not metabolised by anything, and possibly remains forever in the presynaptic vesicles, leaching out very slowly (molecule by molecule) to presumably escape via the urine.  
• Substrates for COMT and MAO are metabolised rapidly and completely, leaving them with short half-lives. These are the catecholamines: 
  • Adrenaline 
  • Noradrenaline 
  • Dopamine 
  • Tyramine 
  • Phenylephrine 
  • Dobutamine 
  • A notable mention is isoprenaline, which is metabolised by COMT but not MAO (which still breaks down fast enough that it does not matter) 
• Everything else undergoes various biotransformations that can be lazily waved away as “extensive hepatic metabolism”. Specific mention can be made of drugs that do something interesting: 
  • Midodrine and L-dopa are the only sympathomimetics that are pro-drugs (the latter being metabolised into dopamine, which can itself be viewed as a pro-drug as it is the metabolic precursor for all the catecholamines. To a lesser extent methamphetamine is a prodrug as well, insofar as it gets N-demethylated to amphetamine, but apparently this effect is so trivial that no examiner could possibly be interested in it. Also worth mentioning is lisdexamphetamine, a prodrug consisting of dexamphetamine covalently bound to lysine, which is itself pharmacologically inert but which undergoes rapid hydrolysis in erythrocytes to yield the active drug. 
  • MDMA, as already mentioned, inhibits its own metabolism, and has huge interpersonal variability in its rate of clearance due to CYP2D6 polymorphisms 

Anyway, that giant table: 

Drug	Metabolism
L-dopa	Crosses the blood-brain barrier and is metabolised to dopamine primarily via decarboxyation by aromatic amino acid decarboxylase; minor metabolic pathways include O-methylation, transamination and oxidation. Can be metabolised by bacterial enzymes in the gut; implications for bioavailability.
Amphetamine	Undergoes hepatic metabolism primarily by CYP2D6; CYP1A2, CYP3A4, and CYP2B6 involved to a lesser extent. First step may be oxidative deamination, beta-hydroxylation, or para-hydroxylation. Some metabolites are also psychoactive. A significant amount, estimated to be around a quarter, is excreted unchanged in urine.
Methamphetamine	Primarily hepatically metabolised by CYP2D6 via aromatic hydroxylation (to 4-hydroxymethamphetamine) and N-demethylation (to amphetamine, however peak levels are reached ~12hrs post peak levels of MA and this is therefore not likely to contribute significantly to effects), and b-hydroxylation (to norephedrine). Metabolites are excreted in the urine, plus approximately 10% of the unchanged drug.
Phentermine	The majority of a dose (70-80%, some sources estimate higher) is excreted unchanged in urine; the portion which is metabolised is metabolised primarily by CYP3A4.
MDMA	Hepatic metabolism is erratic and varies depending on CYP2D6 polymorphisms (that is the CYP enzyme that catalyses O-demethylenation). N-dealkylation deamination and oxidation is the alterantive pathway
Yohimbine	Rapidly metabolised by hepatic CYP450 enzymes to inactive hydroxylated metabolites
Caffeine	MetaAlmost completely metabolised in the liver to paraxanthine, which is at least as pharmacologically active as the parent drug, and which is ultimately itself broken down into inactive products
Theophylline	90% of theophylline is metabolised by CYP 450 enzymes which have significant polymorphism, with about fourfold interindividual variation, and which are susceptible to indiuction or inhibition by other agents, which means theophylline interacts with everything (erythromycin, rifampicin, nicotine, etc)
Theobromine	Largely metabolised by CYP3A4 and 1A2, minor direct renal excretion. (https://analyticalsciencejournals.onlinelibrary.wiley.com/doi/full/10.1002/dta.2970 - reference amelia to add)
Amitryptilline	Hepatic metabolism mainly by CYP2D6 into breakdown products which all have some degree of antidepressant activity
Cocaine	Rapidly metabolised by plasma pseudocholinesterase and hepatic carboxylesterases
Metaraminol	Not metabolised, it seems (not susceptible to COMT or MAO)
Ephedrine	A small and variable quantity is metabolised into norephedrine, but otherwise it is eliminated unchanged
Pseudoephedrine	Similar to ephedreine: a very small amount is metabolised, and the rest of the drug is eliminated renally in its original form
Midodrine	A prod-drug: metabolised in the liver (by deglycinatio) into the pharmacologically active metabolite, desglymidodrine. Desglymomidodrine is in turn metabolised by hepatic oxidation via the CYP2D6.
Tyramine	Metabolised by numerous systems, including MAO, COMT, CYP450, and several others.
Adrenaline	Metabolised rapidly and completely by COMT and MAO
Dopamine	Metabolised rapidly and completely by COMT and MAO
Noradrenaline	Metabolised rapidly and completely by COMT and MAO
Phenylephrine	Extensively metabolised in the gut wall (by sulfate conjugation and MAO)
Oxymetazoline	Minimally metabolised
Naphazoline	Minimally metabolised
Xylometazoline	Minimally metabolised
Isoprenaline	A poor substrate by MAO, but is easily and rapidly metabolised by COMT
Dobutamine	Metabolised rapidly and completely by COMT and MAO
Salbutamol	Metabolised in the liver (extensive first-pass metabolism); The main metablite is the biologically inective salbutamol-o-sulphate. It can also be de-aminated by oxidative   deamination or conjugated with glucuronide.
Mirabegron	Metabolised in the liver by various pathways (dealkylation, oxidation, glucuronidation, hydrolysis) into inactiove metabolites
Tranylcypromine	Extensively metabolised, probably in the liver, into N-acetylated and ring-hydroxylated metabolites, which retain some limited MAO-inhibitory activity
Selegiline	Hepatic metabolism; rapidly metabolized by the microsomal enzymes to amphetamine, methamphetamine, and desmethyl-deprenyl
Moclobemide	Hepatic metabolism; oxidation of the morpholine ring moiety, aromatic hydroxylation and deamination; multiple inactive metabolites
Entecapone	hepatic metabolism - primarily metabolised to its glucuronide

Cytochrome P450 2D6 in the metabolism of sympathomimetics 

CYP2D6 is a hepatic enzyme which is partially or largely responsible for the metabolism of many of the sympathomimetics we have discussed. It has many other substrates from a range of drug classes which are notable for the frequency of their medical use, including:  

• Beta blockers metoprolol, propranolol, and timolol, 
• A handful of antiarrhythmics, including flecainide, 
• Several antidepressants, including amitriptyline and fluoxetine, 
• Some neuroleptics, including haloperidol and risperidone; and, 
• various other agents, including codeine (which it converts to active drug morphine), tramadol, and dextromethorphan (an NMDA receptor antagonist, commonly used as an antitussive, which dips its fingers into many neuropsychological pies).  

It is therefore arguably impolite of it to be among the most highly polymorphic clinically significant metabolic enzymes studied. The count of known alleles varies between publications, but certainly appears to be in the triple digits. 

Kane 2021 provides an excellent overview detailing common CYP2D6 polymorphisms, their phenotypic implications, and their estimated population prevalence by geographic location and ethnic background. There appears to be no limit to how far the pharmacogenetically inclined could wander into this topic; to attempt to summarise... Metabolic phenotypes are classified relative to a baseline of enzymatic activity, where a single functional copy of the CYP2D6*1 allele (regarded as the benchmark allele) defines an activity score of 1. “Extensive metabolisers” or “normal metabolisers” are those individuals, comprising 43-67% of a population, who possess two copies of CYP2D6*1 allele (which would confer an activity score of 2), or of any of the alternative alleles, of which there are several, which confer similar function (activity scores of the normal metaboliser phenotype may be anywhere between 1.25 and 2.25). Highly population prevalent may be any of a diverse assortment of single nucleotide polymorphisms which reduce activity of the enzyme (“intermediate metabolisers” comprise 10-44% of a population) or render it entirely nonfunctional. Not satisfied with being wildly internally variable, it is additionally not uncommon for the gene to be duplicated or triplicated, resulting in the “ultrarapid metaboliser” phenotype (activity score greater than 2.25; this has a percentage prevalence in the single digits in most studied populations). Members of one Swedish family, first described by Johansson et al (1993), were found to possess an astonishing twelve extra functional copies of CYP2D6*2 (an allele each copy of which confers an activity score of 1).  

The reader, understandably shaken by the level of detail above,  is reminded that while interesting it is of course vastly in excess of anything which a CICM trainee could be reasonably expected to memorise. The author recounts it primarily to illustrate that enormous variability in metabolic phenotype is not just possible but common, with significant pharmacokinetic and therefore clinical implications.  One should leave this section with the understanding that there are sound pharmacokinetic reasons as to why the dose required to party is also often the dose required for seizures coma and cardiac arrest.

Half-lives of sympathomimetics 

Again, to facilitate scrolling past the long tables, three broad groups emerge from these half-life values: 

• Drugs which are substrates for MAO or COMT are inevitably short-lived, with half-lives measuring minutes 
• Drugs which are substrates for hepatic enzymes or which are renally excreted have long half lives measured in hours 
• Drugs with intermediate short halflives (measuring an hour or so) are generally metabolised by specific high affinity enzyme systems, and include cocaine (which is susceptible to metabolism by pseudocholinesterases, like suxamethonium) and L-dopa (which gets decarboxylated into dopamine by dopa decarboxylase). 

Drug	half-life
L-dopa	Half life is 1 hour (but the clinical response is more durable because of nigrostriatal neuronal dopamine synthesis and storage)
Amphetamine	Half-life 4-12 hours
Methamphetamine	Half-life 6-15 hours
Phentermine	Half-life ~20 hours
MDMA	Half-life 4-6 hours
Yohimbine	Half-life 0.5-2 hours
Caffeine	Half-life is about 5 hours
Theophylline	Half-life is 8 hours, or 4-5 hours in smokers
Theobromine	Half-life is around 9 hours
Amitryptilline	Elimination half-life of around 20 hours
Cocaine	Half-life around 1 hour
Metaraminol	Effect lasts 20-60 minutes
Ephedrine	Average half-life is about 6 hours
Pseudoephedrine	Half-life 5-8 hours
Midodrine	Half-life of the prodrug is 30 minutes; the half-life of desglumidodrine is about 3 hours
Tyramine	Half-life of about 30 minutes
Adrenaline	Very short acting, very rapid onset of effect
Dopamine	Very short acting, very rapid onset of effect
Noradrenaline	Very short acting, very rapid onset of effect
Phenylephrine	Half-life is 2.5 to 3.0 hours
Oxymetazoline	Half-life is 5 hours
Naphazoline	Half-life is 4-8 hours
Xylometazoline	Half-life is 10-12 hours
Isoprenaline	Half-life is 2 minutes
Dobutamine	Very short acting, very rapid onset of effect
Salbutamol	Airway resistance decreases within 5 to 15 minutes after inhalation of salbutamol; maximum effect is seen at 60 to 90 minutes, and some level of activity persists for 3 to 6 hours.
Mirabegron	Half-life is ~50 hours
Tranylcypromine	Half-life is only about 2 hours, but this does not have any relationship to the duration of its effect
Selegiline	Elimination half-life of the parent drug is only aout 1.5 hours, but it leaves behind active metabolites with longer periods of activity, and its MAO-I effect is long lasting
Moclobemide	Half-life is only about 2 hours, but the duration of MAO-I effect is much greater
Entecapone	Half-life 1.-0-2.5 hours

Pharmacological drug targets of sympathomimetics 

Sympathomimetic activity (sympathomimesis?) can occur at multiple levels, so the discussion pharmacological drug targets of sympathomimetics should probably be structured along the same lines as the unofficial classification system listed in the beginning of the chapter, to give the reader the illusion of consistency and professionalism.  

Catecholamine synthesis stimulators and metabolic precursors 

The group of sympathomimetics that act as catecholamine precursors is small. Of the commonly available agents, the only one with this mechanism is levodopa, the precursor for dopamine, which definitely fits into this group. However under normal circumstances it does not produce any detectable sympathomimetic effects, because it is administered along with a peripheral dopa decarboxylase inhibitor which means the only dopamine production that happens is in the CNS, and peripheral dopamine effects are not seen unless truly gigantic doses are administered. Another agent, less well known but more classically sympathomimetic, is droxidopa, otherwise known as dihydroxyphenylserine, an orally bioavailable synthetic amino acid that also acts as a substrate for dopa decarboxylase, but produces noradrenaline as the daughter molecule. This one is genuinely sympathomimetic and is indicated for the management of orthostatic hypotension, much in the same way as midodrine. In terms of drugs which are not precursors for catecholamines, but which increase the synthesis of catecholamines, none come to mind other than corticosteroids (Tischler et al, 1983) and thyroxine (Waldstein, 1966).  

Centrally acting α-2 antagonists 

The critical care trainee will surely be more aware of centrally acting α-2 agonists such as clonidine and dexmedetomidine. Yohimbine, the only commonly encountered centrally active antagonist of these receptors, is rarely seen in clinical practice outside of the domain of toxicology. It really only comes to the attention of critical care staff when it causes seizures that disrupt weird sex and gym rituals. The main mechanism of its action is to inhibit α-2 presynaptic receptors, thereby increasing the release of noradrenaline (i.e. the opposite of what clonidine does). Nasimudeen et al (2022) describes its various activities in more detail, and concludes that “despite some observed adverse effects, yohimbine use should be reconsidered for its associated benefits and clinical value”, even after explaining its toxic neurological and cardiovascular effects. Other drugs that act by the same mechanism are even more obscure, including pemoline (a hepatotoxic stimulant used for ADHD) and mirtazapine (a tetracyclic antidepressant).  

Catecholamine reuptake inhibitors 

Interfering with the reuptake of a monoamine is a popular method of increasing its synaptic concentration and many CNS-active sympathomimetics act in this way. Tricyclic antidepressants, amphetamines and cocaine are some of the agents that act in this way. The specific mechanism is a blockade of reuptake transporters DAT, NET and SERT which are normally responsible for the reuptake of monoamines from the synaptic cleft. The increased synaptic concentration of noradrenaline therefore produces the sympathomimetic effect.  

Agents that increase the release of catecholamines by presynaptic mechanisms 

This category contains amphetamine, methamphetamine, phentermine, MDMA and a whole uncountable host of psychoactive phenylethylamines. These molecules are so numerous and varied that they exceed even the imaginations of drug enforcement agencies, such that for every one molecule they ban, two different ones are synthesised in biker labs as a replacement. For an earnest methodical attempt to document and detail these agents the reader is referred to the works of Alexander and Ann Shulgin. These agents achieve their desirable and undesirable effects by a whole range of mechanisms. To list only the dominant three:  

1. Inhibition of vesicular monoamine transporter 2 (VMAT2)  

1. Inhibition of MAO 

1. Stimulation of the intracellular presynaptic receptor TAAR1, and therefore the internalisation or transporter reversal of DAT, NET and SERT  

Other drugs also do 1) and 2), but 3) is unique to the phenylethylamines. TAAR1, or Trace Amine Associated Receptor 1, is a G-protein-coupled receptor that is normally supposed to bind endogenous ligands amines that are present in trace quantities, such as tyramine. β-phenethylamine and octopamine. It also happens to be a high affinity receptor for amphetamine-like drugs. Activating this thing leads to a reversal of the polarity of reuptake transporters DAT, NET and SERT: cleverly, amphetamines not only block and prevent the reuptake, but also increase the release of neurotransmitters by reversing the direction of these transporters, turning them into efflux pumps (Sitte & Freissmuth, 2014).  

Adenosine receptor antagonists 

The authors could not, with any decency, omit caffeine from this list of stimulant agents, for reasons none less important than the debt that is owed to this substance by both of them, and because of how much of Deranged Physiology is the direct effect of its gratuitous abuse. It is hoped that the reader will not notice that they only realised this late in the process of writing this chapter, and awkwardly inserted caffeine, theophylline, and theobromine into the discussion as an afterthought. Caffeine is an adenosine receptor antagonist, and adenosine is a regulatory neurotransmitter that is normally responsible for hyperpolarising presynaptic terminals, mainly through its activity on potassium channel and voltage-gated calcium channel activity. Neurotransmitter release from these terminals is therefore inhibited by adenosine; and to reverse this inhibition allows moar neurotransmission, and therefore sport, love, art, and military victory. 

Caffeine, the predominant methylxanthine naturally found in critical care staff, is a purine alkaloid structurally similar to uric acid, with excellent oral bioavailability (though its routes of administration are inventively comprehensive). It has excellent water solubility and is not especially protein-bound, making it an ideal substrate for haemodialysis in massive overdose. It undergoes extensive hepatic metabolism into paraxanthine, an active metabolite, and has little renal elimination, mostly because of extensive tubular reabsorption - something like 98% of the freely filtered caffeine is actively transported back into the circulation, the nephron correctly identifying this molecule as something worth keeping. It therefore has a half-life of about five hours. Human behavioural effects are seen at doses ranging from 100-300mg, consisting of elevated mood and increased motor reaction time, which at higher doses (15mg/kg) progress through tremor and agitation all the way to muscle twitching, delirium, seizures coma and death. 200mg/kg appears to be the lethal dose in humans.  It also acts as a weak diuretic at the proximal tubule, and its haemodynamic effects are predictably inotropic and chronotropic, but it would not be a popular therapy for heart failure as it also increases the propensity towards arrhythmias (as it shortens the effective refractory period, i.e. basically the opposite effect to the antiarrhythmic properties of β-blockers).

Theobromine, the predominant methylxanthine present in cocoa, is somewhat less thoroughly studied than caffeine, its precursor, or theophylline, its more clinically useful isomer. Much of the literature regarding it is (understandably) primarily concerned with why dark chocolate is so delicious and generally excellent, and how we might medically justify eating absurd quantities of it under guises ranging from weight loss to cardiovascular health to prevention of neurodegenerative disease. These tend to be supraorganismal level studies, and the authors have struggled to find detailed accounts of its molecular pharmacology. It does appear to have the adenosine receptor antagonist effect of caffeine and theophylline, and so enhances the release of dopamine and noradrenaline, with less than half the affinity for A1 (compared to caffeine) but with more than twice the half-life.  Evidence regarding its haemodynamic effects is limited and inconclusive, suggesting mostly that theobromine is not an inotrope or vasopressor. It was observed to lower blood pressure in normotensive volunteers, and coadministration with caffeine has been observed to negate the elevation in blood pressure found with administration of caffeine alone. Compared to caffeine, the central activity of theobromine appears to be minor relative to its peripheral one, which had a far greater effect on mood and attention. A 2020 systematic review of evidence regarding the efficacy of theophylline and theobromine as performance-enhancing drugs in sport concluded that both substances may act as performance enhancing drugs, if with variable efficacy and tolerability.

The authors reluctantly resist the temptation to dive head-first from this digression into an even less relevant one on the topic of cocoa and chocolate and what you might be missing out on if your experience is limited to the supermarket shelf.  

Agents that interfere with vesicular catecholamine storage  

Many agents, including amphetamine-like drugs and cocaine, interfere with the function of VMAT2. This is a transport protein that transports monoamine molecules into storage vesicles. The effect of interfering with this produces an increase in the concentration of cytosolic catecholamines, which are then free to leak out through the reversed monoamine tranporters mentioned above. Apart from misused psychoactive agents, VMAT2 are targets for drugs like tetrabenzene (used to treat Huntington's chorea) and ketanserin, an α-blocking antihypertensive with unpopular side effects. 

“False neurotransmitters” 

Several commonly used agents interfere with the storage of catecholamines by acting as competing substrates for vesicular uptake mechanism, replacing and displacing the original neurotransmitter into the cytosol and the synapse. Metaraminol, ephedrine, pseudoephedrine, octopamine and tyramine fit into this category. The term “false neurotransmitter” is a colloquial one, and is occasionally also used to refer to antihypertensives such as methyldopa; most authors hold the term to mean that a substance is accumulated in place of the normal “true” neurotransmitter, and is released by the same physiological stimuli.  

Direct catecholamine receptor agonists 

These are agents that interact with noradrenaline receptors directly, i.e. they do the thing that noradrenaline does, and occasionally they do it better. Adrenoceptors are g-protein coupled receptors which, like all receptors of their kind, are cell membrane receptors consisting of seven transmembrane domains with an extracellular ligand binding site. Intracellularly, they are (as the name would suggest) coupled with a heterotrimeric g-protein; receptor activation triggers dissociation of its constituent subunits, which proceed to initiate various intracellular shenanigans, before reassociating and returning to their inactive states. The molecular details of this process are addressed in greater detail here. 

Adrenoceptors are grouped into alpha and beta types, with several recognised subtypes. Classification of adrenergic receptors into these types was historically based on their comparative affinity for adrenaline, noradrenaline, and isoprenaline; and it appears that everyone who has ever written a textbook chapter on these agents leads with this. Now that this fact is a part of the forgotten past, the reverse has happened, and these days one finds sympathomimetic classification systems organising the drugs according to which receptors they interact with. A representative example is this table borrowed from page 139 of Katzung’s Basic and Clinical Pharmacology, which additionally includes dopaminergic receptors and relevant ligands. It does not hurt that this is an official CICM First Part exam study resource. 

This table, and the mechanism of classifying direct sympathomimetics according to their receptor preferences, brings up two interesting digressions. One is regarding dopamine, and is indulged below; the other is about noradrenaline, and its affinity for its own receptors. 

Receptor affinities of endogenous direct sympathomimetics 

An attentive reader may already be puzzled by the realisation that, though noradrenaline is said to be the main sympathetic neurotransmitter, the sympathetic nervous system features synapses that express not only α-1, but also α-2, β-1, β-2 and β-3 receptors. But how, one might ask, does this work – if noradrenaline is said to be a “pure” α-1 agonist? When we infuse it into patients, we expect it to mainly have an α-1 vasoconstrictor effect, and nobody ever really sees much of a β-1 effect, let alone β-2 or β-3. How, then, can it continue to act as a neurotransmitter in – for example – skeletal muscle vascular beds, where its job is to vasodilate the vessels via a β-2 mechanism? 

Indeed, noradrenaline has approximately ten times less affinity for β-2 receptors than for β-1 receptors (Xu et al, 2021). Perhaps it’s just present in a high enough concentration at the synapse, one might think? The selectivity of any receptor-ligand interaction is contingent on the number of available molecules. If there was a huge amount of noradrenaline around, then surely it would eventually start to function as a β-1, β-2 and β-3 agonist? Yes, this is a good theory, but the synaptic concentration of noradrenaline during a “proper” sympathetic response is thought to be only in the order of 560 pg/ml, or 3 nmol/L (Goldstein et al, 1986). Whereas the concentration of noradrenaline achieved during a high dose central venous infusion might be something closer to 30-40 nmol/L, according to human studies by Ensinger et al (1992). So, it would seem that flooding the synapse with excessive amounts of noradrenaline is not the physiological mechanism of achieving β-receptor activation. Nor is this a sensible answer anyway, as that would be an extremely inefficient use of a neurotransmitter, and the “spillover” from such a flood would probably distribute systemically to produce undesirable effects elsewhere. In short, that is obviously not how the sympathetic nervous system works. 

Instead it appears that noradrenaline is only used as a neurotransmitter where α and β-1 effects are necessary, and that elsewhere adrenaline is the neurotransmitter. Russel & Moran (1980) demonstrated that the sympathetic innervation of muscle does not produce β-2 receptor activation – this is purely the effect of circulating adrenaline, secreted from the adrenal gland. Whereas the sympathetic nerve endings in muscle are mainly noradrenargic, and feature mostly α-1 receptors, being responsible for the resting tone of skeletal muscle vasculature, and for the impressive factor-of-ten blood flow restriction to these vessels during states of shock. Similarly, the stimulation of the sympathetic supply of the lung by electrotorture of the stellate ganglion did not produce any changes in bronchomotor tone for Kadowitz & Hyman (1973), suggesting that those β-2 receptors were also disconnected from sympathetic nerve endings.  

For β-1 receptors, noradrenaline remains important. The myocardium is heavily infested with sympathetic nerve endings and β-1 receptors are ultrastructurally localised to the sites of connection between the myocytes and the neurons. In short, noradrenaline very clearly mediates the sympathetic control of the myocardium via β-1 receptors. In fact, the original experiments by Lands et al (1966) that classified β -receptors into β-1 and β-2 did so on the basis of the difference in their response to adrenaline and noradrenaline, where β-1 was the receptor species that had roughly the same affinity for both. In other words, noradrenaline does the same thing in the heart as adrenaline does; but a systemic infusion of noradrenaline has an overwhelmingly afterload-increasing α-1 effect, making it impossible to see the β-1 stimulation because it becomes obscured by the baroreceptor reflex.  

Anyway: noradrenaline is an important agent in critical care and it is probably good for CICM trainees to know how it works and what effects it has in very granular detail. It would be harder to defend squandering the reader’s attention on the other direct agents: 

The spectrum of direct sympathomimetics 

 There are teeming billions of directly acting sympathomimetic agents, in the same way as the number CNS stimulants defy counting, and so it would be pointless to list or discuss them here. It seems each time somebody shakes the catecholamine tree, ten or so new sympathomimetic monoamines fall out. Just as one example, when Tuttle & Mills were developing dobutamine, they created this pile of related molecules: 

There are other examples; for instance the experiments by Baker (2010) who marinaded myocytes in solutions of about fifty different β-agonists, or Hieble et al (1982) who worked with such obscure α-agonists that none had names and were described exclusively in terms of their molecular structure. The distracted reader is gently redirected back to the mainstream with the reminder that none of these agents are available anywhere and that all of these biochemical sidequests are pointless for the greater purpose of passing exams. A more fruitful digression is the question of dopamine receptors, and where they belong in the sympathomimetic universe. 

The dopamine neurotransmitter system as a participant in the sympathetic nervous system 

Because the Katzung table lists these agents, and because other textbooks also often list dopamine receptors alongside adrenergic receptors, their presence and participation in the autonomic nervous system needs to be addressed. First of all, why are they even listed here? Several possible reasons come to mind, which all seem good enough to influence the mind of the textbook editor: 

• Dopamine is a precursor for the synthesis of other endogenous catecholamines (so it belongs in any text that describes their origins and biosynthesis) 
• Dopamine is classified as a catecholamine and can act as a direct adrenergic agonist (so it belongs in any functional classification of adrenergic agonists) 
• In general catecholamines and dopamine seem to cross-react with each other’s receptors to a considerable degree 
• Both dopamine and noradrenaline receptors tend to be grouped together as “catecholamine-binding G-protein-coupled receptors” in the literature (eg. Strange, 1996) and there is sufficient homology between these to suggest a common evolutionary origin (together with the rhodopsin receptor) 

But otherwise it makes little sense to lump these together, as the effects they have are fairly different, making it harder to discuss them in a chapter supposedly all about sympathomimetics. 

Are dopamine agonists sympathomimetics? 

With all the abovementioned receptor and substrate similarities, one might have expected drugs that increase the activity of dopamine to be sympathomimetic, i.e. to have pharmacological effects that resemble the activation of the sympathetic nervous system, but in actual fact apart from dopamine itself the rest of them are anti-sympathetic. Drugs which are classical dopaminegic agents – bromocryptine, cabergoline, amantadine, apomorphine, pramipexole, rotigotine – are all inhibitors of catecholamine release (Lim et al, 2002), which appears to be the effect of D4 and D5 receptor activation (Dahmer & Senogles, 1996). Their side effects are often bradycardia and hypotension. So: sympathomimetics they are not. 

Is dopamine even a sympathomimetic? 

Dopamine itself, as we have already noted, is classified as a catecholamine on purely chemical grounds, and has sufficient structural similarities to adrenaline and noradrenaline that it gets adventurous when present at sufficiently high concentrations and acts as a nonspecific direct agonist at alpha 1, alpha 2, and beta 1 adrenoceptors (Farzam et al 2023). Even under normal conditions it is present at concentrations similar to those of adrenaline and its plasma concentration increases in parallel to the increase in other catecholamines in times of stress (Van Loon, 1983), which might make you think that it is contributing to the sympathetic discharge somehow.  

On the other hand, as mentioned above, the activation of some dopamine receptors appears to dampen sympathetic activity. For example, using six adrenalectomised human subjects and vast doses of domperidone, Massimo et al (1999) were able to demonstrate that this dopamine (D2) receptor antagonist resulted in a marked increase in noradrenaline release associated with exercise, suggesting that D2 receptor activation downregulates catecholamine release. Lokhandwala et al (1988) quote numerous studies on the theme of “inject dopamine agonist/antagonist directly into the brain of small fluffy animals” where similar downregulation was observed with activation of D1 and D2 receptors. At low doses, infusions which simulate baseline endogenous release, dopamine acts as a vasodilator (Brodde, 1982). In short, it appears that dopamine is accidentally sympathomimetic when infused at high doses by an intensivist, because it can impersonate noradrenaline for alpha and beta receptors, whereas endogenous circulating dopamine at normal low concentrations probably plays a sympatholytic role mediated by its own receptor system.  

Agents that interfere with catecholamine clearance 

Catecholamines are eliminated by monoamine oxidase and catechol-o-methyltransferase, enzymes which are expressed at the cell surface and mitochondrial membrane of most tissues. Drugs which inhibit these enzymes increase the availability of catecholamines, both centrally and systemically.

• Monoamine oxidase inhibitors 
  • Tranylcypromine, selegiline, moclobemide 
• Catechol-o-methyltransferase inhibitors 
  • Entecapone, tolcapone, opicapone – anti-Parkinsonian medications 

Interestingly, most of the desirable therapeutic effects of these agents seem to be central, even though many of them have peripheral effects (and in fact entecapone is predominantly a peripheral COMT inhibitor). These drugs definitely do potentiate the effects of catecholamines (infused or endogenous) and patients chronically treated with these drugs do tend to have an increased sensitivity to standard doses of ICU-like vasoactive agents, which means CICM trainees need to be at least vaguely aware of them. Another valuable perspective is the role of these agents in the metabolism of catecholamine metabolic substrates: monoamine oxidase inhibition can produce an unpleasant increase in the systemic availability of tyramine, a catecholamine precursor with amphetamine-like effects of its own. The result of this interaction is often a cheese-induced hypertensive crisis. We are grateful to the early pioneers Blackwell & Mabbitt (1965) who mapped the distribution of tyramine content in a random selection of cheese using liquid chromatography, and determined that mature English cheddar was the highest in tyramine content (1620 μg per gram, of 162 mg/100g). 

Considering that even 25mg of tyramine could precipitate a hypertensive crisis, it would appear that 100g of cheddar (not a huge amount) is well above the lethal dose for a person with inactive MAO-A, but foods with an even higher tyramine content exist. In fact, some food sources of tyramine may be too much even for the individual with relatively normal MAO activity. Apparently "the "no observed adverse effect level" (NOAEL) for healthy individuals is 200 mg per single oral administration", which means the regular 70kg human could feel unwell after consuming only about 150g of that specific "goaty, mature" cheddar. Fortunately, even though according to the Food composition and nutrition tables (2000) some cured meat and fish products can contain up to 500mg of tyramine per 100g (i.e. 0.5% tyramine by mass),  normal healthy adults should not be able to achieve lethal tyramine toxicity (an oral dose of more than 2000 mg/kg body weight) because to do so would require 28kg of pickled herring. 

Mechanisms of action of sympathomimetics 

The mechanisms of direct agents are essentially just receptor effects. To list them here would be a pointless duplication of the content from the chapter on the effects of catecholamine receptor activation, and would therefore be entirely on brand for Deranged Physiology. In short, all adrenerhic receptors are G-protein coupled receptors, dependent on the activation of intracellular second messenger systems, and therefore function over timeframes of something like tens of milliseconds (Vilardaga et al, 2003, measured 40 milliseconds from the binding of noradrenaline to an α-2 receptor to the deactivation of adenylate cyclase). 

Receptor	Mechanism of activation	Second messenger system
α1	Gq protein coupled – second messenger is IP3, causing an increase of intracellular calcium	Inositol triphosphate, which binds to IP3 gated calcium channels in the endoplasmic reticulum. They open, raising intracellular calcium. Also increased diacylglycerol leads to the activation of Protein Kinase C.
α2	Gi protein coupled – inhibit adenylyl cyclase, decrease cAMP production	cAMP, in this case the decrease of cAMP
β1	All Gs protein coupled – activate adenylyl cyclase, increase cAMP levels	cAMP, in this case increased intracellular cAMP, leading to the activation of protein kinase A and various other intracellular targets. The downstream signal cascades are complex and vary between cells, but in general will result in increased tissue excitability.
β2
β3

Indirect agents obviously also act on the same receptor systems, bit because they only increase the availability of neurotransmitters without acting as neurotransmitters themselves, all kinds of non-standard unselective effects can develop. Or the clinical effects of the drug can contradict what the receptor effects are supposed to be developing, because the human organism is a marvellously complex magical robot. For example, metaraminol, which is supposed to have a β₁-agonist effect, has the opposite effect in clinical practice because of (probably) baroreceptor responses, unless it ends up pushing more blood into the coronaries during diastole, in which case it can even be used as a positive inotrope in cardiogenic shock. But of course this is not really a "receptor effect" and more a physiological effect, which means it's time for

Physiological effects of sympathomimetics 

Again self-plagiarising from the chapter on the effects of catecholamine receptor activation, the  physiological effects of different adrenergiuc receptors are reproduced below:

• α-1: 
  • Arteriolar vasoconstriction
  • Contraction of the radial muscle of the iris (dilates pupil)
  • Contraction of the gut sphincters
  • Decreased secretion of intestinal glands
  • Contraction of the urethral sphincter
  • Increased sodium reabsorption in the renal tubule, and increases renin release
  • Contraction of piloerector muscles
• α-2:
  • Peripheral effects:
    • Relaxation the walls of the gut wall smooth muscles
    • Inhibition of noradrenaline release from nerve terminal
    • Inhibition of adrenaline release from the adrenal cortex
    • Inhibition of insulin release (α-2A)
  • Central effects:
    • Sedating, antinociceptive effects
    • Presynaptic inhibition of norepinephrine, dopamine and serotonin release - thus, systemic sympatholytic effects
• β-1: equal affinity for adrenaline and noradrenaline
  • accelerates sinoatrial node
  • accelerates ectopic pacemakers
  • increases contractility of the heart
  • increases rennin release by the kidney
• β-2: minimal affinity for noradrenaline; found on tissues which do not receive direct sympathetic innervation; mostly a receptor to catch circulating adrenaline
  • accelerates sinoatrial node
  • accelerates ectopic pacemakers
  • increases contractility of the heart
  • relaxes the smooth muscle of skeletal muscle arterioles
  • relaxes bronchiolar smooth muscle
  • relaxes gut wall smooth muscle
  • relaxes the bladder wall
  • relaxes the pregnant uterus
  • increases gluconeogenesis and glycogenolysis in the liver
• β-3: minimal affinity for noradrenaline
  • all these do is increases the rate of lipolysis in fat cells

Sympathomimetic toxicity 

 The sympathomimetic toxidrome is well described in the toxicology section, where the pragmatic reader has no time for hilarious case reports, and the focus is on toxicity of amphetamine, MDMA and cocaine, as these are the most important from the exam perspective. Weird asides, for example the  psychosis due to L-dopa, and the surprising fact that oxymetazoline is hella toxic when ingested, are already peppered through the text and the reader's patience will not be burdened with any further reference to these. For pragmatic revision purposes, typical physiological consequences of a sympathomimetic toxidrome are listed below:

• Respiratory
  • Tachypnoea, increased minute volume
  • Irregular respiratory pattern
• Circulatory
  • Tachycardia
  • Hypertension (with severe overdose, hypotension)
  • ECG changes suggestive of coronary ischaemia
  • Raised troponin
  • Flushing, brisk capillary refill
• Neurological
  • Agitation, anxiety
  • Hallucinations
  • Psychosis
  • Seizures
  • Hyperthermia
  • Mydriasis
  • Piloerection
  • Hyper-reflexia
• Fluid, electrolyte and endocrine-related
  • Diaphoresis
  • Increased insensate fluid loss though tachypnoea and diaphoresis
  • Hyponatremia through psychogenic increase in water intake
  • Hyperkalemia
  • Metabolic acidosis
• Renal
  • Rhabdomyolysis-induced myoglobinuria
  • Concomitant acute pre-renal failure due to dehydration