Without sounding stupid, it is difficult to define the term "sympathomimetic" without discussing how these drugs mimic the physiological effects of stimulating the sympathetic nervous system. This is in fact the widely accepted definition, and it includes both drugs which are direct agonists of monoamine receptors (eg. adrenaline), drugs which have indirect action at those synapses (eg. amphetamines), drugs which modulate the sympathetic nervous system indirectly (such as caffeine) and drugs which are sympathetic depressants but for which the withdrawal syndrome is sympathomimetic (such as benzodiazepines and baclofen).
That's a fairly wide net to cast for a quick revision resource. Particularly where the college does not seem particularly interested in three quarters of the toxicology spectum abovementioned. Apart from Question 15 from the second paper of 2022 (MDMA), the only sympathomimetic toxicity question has been about methamphetamine (Question 11 from the first paper of 2018), which is surprising because in Australia amphetamine toxicity has the second highest mortality among illicit substances, second only to heroin (Li & Gunja, 2012). Deaths from methamphetamine specifically have doubled in the period between 2009 to 2015. Generally speaking, it seems like something ICU trainees should be familiar with.
In terms of published peer-reviewed resources, there is much to choose from. An excellent review hanging off a case report is offered by Williams et al (2018), and probably contains enough to score a passing mark. For a more extensive and academic treatment, one can be directed to the systematic review by Richards et al (2015). Local management recommendations are available (Jenner et al, 2006) but are somewhat dated.
Not only intoxication, but also withdrawal from sympathetic suppressants can give rise to a sympathomimetic toxidrome picture
It is surprising to see caffeine up there, but it can produce this toxidrome in vast doses (Laitselart et al, 2018)
Control of agitation is the main clinical priority. If you control agitation, you will also ameliorate the cardiovascular effects and risk of haemorrhagic stroke.
When ingested orally methamphetamine concentration peaks after 2-4 hours. When injected or smoked, the peak effect is obviously immediate. These drugs arre all highly lipophilic and have large volumes of distribution. Because they differ structurally from catecholamines (i.e. they have no OH groups on their phenyl ring) these substances are not susceptible to metabolism by COMT or MAO.
Amphetamines in general undergo all sorts of complex metabolic modification, and are therefore cleared predominantly by the liver. Methamphetamine specifically has a relatively long half-life (19-34 hours is the figure given by Goldfranks' Manual).
The effects of amphetamines are exerted by a number of mechanisms:
Methamphetamine lack the capacity to activate noradrenaline receptors directly. Most of its effect is exerted indirectly, by displacing noradrenaline (as well as dopamine and serotonin) from presynaptic storage vesicles. It also inactivates the catecholamine reuptake transporters. The consequence of this is increased neurotransmitter presence in the synapse. This relates to the toxicty: the cardiovascular effects are predominantly due to noradrenaline displacement, the behaviour alteration and psychotic symptoms are likely due to the dopamine, and serotonin is held responsible for the mood alteration and bizarrely distorted response to thirst and hunger. The selectivity for reuptake transporters determines much of the pharmacological effects; for instance MDMA is much more selective for the serotonin reuptake transporter and therefore manifests predominantly serotonergic effects.
MDMA, according to Kalant et al (2001) and Capela et al (2009), is an indirect sympathomimetic monoamine agonist. It mainly exerts its effects by preventing the reuptake of neurotransmitters (mainly serotonin, but also to a lesser extent dopamine), and these account for most of its desirable effects, whereas the minor noradrenaline reuptake effects are responsible for the haemodynamic effects it shares with amphetamines. The R and S stereoisomers each have a slightly different physiological effect and of the two the S(+) isomer is more amphetamine-like. There's a lot of interindividual variation in the reported effects from the same racemic dose which suggests that individuals differ in their pharmacokinetic handling of these isomers. The molecular targets appear to be the 5HTT NET and DAT reuptake transporters, with affinities ranked in that order - something conferred upon the molecule by the introduction of the methylenedioxy ring. Specifically for the serotonin release, it appears that MDMA not only reduces reuptake, but actually reverses the action of 5HTT, turning it into an exocytosis transporter instead of a reuptake mediator (Capela et al, 2009). Lastly, it appears MDMA disrupts vesicular storage of monoamines, where MDMA acts as a substrate for VMAT and displaces serotonin and dopamine from their vesicles.
That's the mechanism of action of MDMA, asked about in . The college asked about the mechanism of action, but the comments of the examiners hint that they expected mechanisms of toxicity, which is a slightly different kettle of fish. MDMA toxicity is mainly manifested in terms of sympathomimetic cardiovascular effects, neurotoxicity by mechanism of excitotoxicity, serotonergic hyperthermia and rhabdomyolysis. In brief:
Control of agitation
Control of hypertension
Fluid and electrolyte correction