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Don’t try this at homeGavin Francis
Vol. 35 No. 16 · 29 August 2013

Don’t try this at home

Gavin Francis

2955 words
by Brian Hoffman.
Harvard, 298 pp., £18.95, April 2013, 978 0 674 05088 4
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There’s a scene in Tarantino’s Pulp Fiction in which John Travolta’s character, a hitman called Vincent Vega, who has escorted his boss’s wife home after an evening out, returns from the bathroom to find her unconscious on the floor. Mia (Uma Thurman) has taken a bag of heroin from his jacket pocket and, mistaking the white powder for cocaine, snorted a line and collapsed. Vincent throws her into a car and hurtles round to his dealer’s house. The dealer fills a syringe with adrenaline and tells him to stab it into Mia’s heart; Vincent slams it through her breastbone and pushes the plunger. Her eyes flicker, she convulses, and then, shocked into life like the Bride of Frankenstein, she suddenly sits up, wide awake and gasping for breath.

I was a medical student when Pulp Fiction came out, and my understanding of human bodies was based largely on dead ones, but I knew that an intracardiac injection of adrenaline was a bad idea. It’s the wrong drug (the correct antidote is naloxone), and the wrong technique: an IV injection is the thing. But a stab in the heart makes better cinema, and everyone thinks they know about adrenaline’s effect on the body. We hear of adrenaline junkies and adrenaline highs; we talk about ‘running on adrenaline’.

I first learned about adrenaline, and the glands that produce it, from a headless and limbless torso, skinned and sprayed with preserving fluids. Each Friday afternoon in anatomy class it was unzipped from a white body bag labelled ‘1101-Female’. The smell of the preserving fluids was overwhelming at first, as was the nip they brought to the eyes. Once you recovered, you could see that the abdominal wall had been cut from the flanks to the pubis bone so that a frontal flap of stomach muscles could be lifted, the way you’d open a car bonnet. The abdominal viscera are covered by the peritoneum, a sheeny lining like shrink-wrap, which makes it possible for the organs to glide against one another without causing irritation (it’s inflammation of this lining that causes the pain of appendicitis). Some of the organs had been liberated from the peritoneum, so it was possible to heft the intestines out of the way, weigh them down with the spleen, wedge up the liver and reveal the retroperitoneal organs, such as the kidneys, pancreas, parts of the colon and the adrenal glands.

The adrenal glands have that name because they lie by the kidneys: ad-renal. Ancient anatomists like Herophilus and Galen didn’t notice them because in death the glands look similar to fat, and the kidneys are embedded in particularly rich fat (this is suet, present in humans as it is in animals). It was the Renaissance anatomist Bartolomeo Eustachi who first spotted the glands, though he had no idea what their purpose was. He observed their excellent blood supply and their close association with the kidneys. They have bulky bundles of nerves, connected to the sympathetic nervous system, parallel trunks of nerves that run down either side of the spine like train tracks – part of the ‘autonomic’ system, the internal calibration of our bodies over which we have little control. Among other functions the sympathetic system is involved in preparing our bodies for action, in what have become known as ‘fight or flight’ responses, and it is aided in this by the hormone adrenaline. Sympathetic nerves work locally, but adrenaline is released into the bloodstream and so acts throughout the body. It is released when we’re frightened or angry, and when we exert ourselves physically. It incites the liver to pour out glucose as fuel for muscles, the airways to open in order to make breathing more effective, the heart to accelerate and the pupils to dilate. Its effect on the brain is to make us more attentive and alert. An overdose can be fatal.

The cadaver’s adrenals curled around the upper poles of the kidneys like inverted commas. Grey, thin and embedded in porridge-like fat, they were easy to overlook – no wonder it took so long for them to be noticed. I traced the veins from the glands to the vena cava, and tried to imagine the life of 1101-Female. The arteries elsewhere in her abdomen were stiff and furred on the insides, like pipes choked with limescale, a sign of high blood pressure and probably the cause of the stroke or heart attack that led to her death. Adrenaline increases the force of contraction of the heart, as well as constricting the arteries; both of these boost blood pressure. Lifelong exposure to high levels of circulating adrenaline – increased sympathetic activity – has been linked to pathologically raised blood pressure. Over in biochemistry class I learned how different drugs could mimic adrenaline. Caffeine was the most familiar: it was pleasing to discover that my all-night cramming sessions learning retroperitoneal anatomy, or the intracellular mechanisms of wakefulness and attention, were fuelled by the very process I was trying to understand.

Later on, as a surgical trainee, I had to learn the anatomy of adrenal glands all over again: sometimes, if diseased or overactive, they have to be removed. The difference between the procedure in the operating theatre and our clumsy student dissections was stark; during surgery the bowels, gall bladder and liver were gently, almost reverently separated from one another, to avoid tearing blood vessels or nerves. At the very back of the abdomen, through a glistening web of peritoneum, my boss would tunnel down to the adrenal glands. Rocking with each beat of the patient’s heart they shone a lustrous gold, like jewels buried in the treasure chest of the abdomen. Before handling and removing the glands, the adrenal vein had to be clamped: otherwise a life-threatening quantity of adrenaline could escape into the patient.

Brian Hoffman, a professor of medicine at Harvard, describes not just the process by which adrenaline was identified, purified and became clinically useful, but also supplies a series of biographies of the individuals who made it happen. In the 1880s a German pathologist called Felix Fränkel wrote up the clinical case of an 18-year-old farm girl who suffered from episodes of high blood pressure and palpitations, associated with headaches and vomiting. The attacks seemed to come on spontaneously and the patient died within a year of the first attack. At autopsy she was found to have widespread organ damage caused by hypertension, as well as tumours of the central part of the adrenal glands known as the adrenal medullas. Fränkel didn’t know whether there was a connection between the tumours and the hypertension, but his report alerted other doctors to look out for similar cases, and further reports over subsequent decades echoed his findings.

Ten years later, a Harrogate physician called George Oliver found that purified extract of sheep and calf adrenal glands – which he gave to his son – could cause narrowing of the arteries and a rise in blood pressure. The effect was short-lived but Oliver went on to replicate the experiment with greater finesse in dogs. A year or so after that, in 1895, two Polish physicians, Władysław Szymonowicz and Napoleon Cybulski, demonstrated that extracts from the adrenal vein had the same effect; they concluded that the active substance was being secreted into the bloodstream. The realisation that some substances were internally secreted gave rise to the field of endocrinology and the concept of the hormone – a word coined shortly afterwards. But no one yet knew what the substance secreted from the adrenal gland was.

A drug that could raise blood pressure had enormous potential, and a race ensued to be the first to isolate the secreted substance. The leaders were an academic pharmacologist – John Jacob Abel at Johns Hopkins University – and an industrial chemist called Jokichi Takamine who was working in New York for the pharmaceutical company Parke-Davis. Takamine won by being the first to identify – and name – adrenaline, but confusingly Parke-Davis chose to drop the ‘e’ when marketing the drug, as Adrenalin. This substance reliably raised blood pressure and caused the constriction of blood vessels, meaning that it could be used to staunch bleeding wounds. Large-scale production soon followed. Abel believed he had also managed to isolate the substance, and chose to call it epinephrine, going for Greek not Latin, leading to further confusion in the naming.

Physicians quickly began to experiment with potential uses for the drug. Since it was known to constrict blood vessels they tried using it to treat any ailment in which blood flow or excessive moisture was thought to play a significant part: runny noses, gonorrhoea, deafness, hives, water on the lungs, oral cancer and bubonic plague. Soaked on a rag it was found to stop bleeding when applied to boxers’ wounds, and applied with a camel-hair brush it could stop haemorrhaging from the eyes, ears, nose, throat, stomach, intestines and vagina. Potential immigrants on Ellis Island who were suffering from ocular infections found that it could be used to blanch the whites of their eyes in order to mask the signs. Injections of it could open the airways and arrest severe asthma attacks. It was thought to cure bedwetting. It even revivified the heart of a dog that had been dead for five minutes, though the effect was disappointingly temporary. In 1945, when Franklin Roosevelt’s heart stopped following a massive stroke, he was given an intracardiac injection of Adrenalin in a doomed attempt to resuscitate him. Adrenalin’s popularity had the trajectory common to other wonder drugs: Heroin, Valium and Prozac were all greeted with rapturous enthusiasm but are now handled with caution by the majority of physicians. It’s surprising all the same that in general medical practice adrenaline’s use is restricted essentially to four situations: to reduce blood loss in minor operations (mixed with local anaesthetic); to boost blood pressure and cardiac output after cardiac arrest; to treat life-threatening allergic reactions (anaphylactic shock); and to treat severe croup in babies, inhaled as a mist through a mask.

After their success in purifying an adrenal extract, laboratory scientists turned from the glands themselves to investigate the sympathetic nervous system, stimulation of which provoked effects similar to those seen after direct injection of adrenaline. Thomas Elliott, a Cambridge physiologist, claimed in 1904 that sympathetic nerves produced adrenaline in tiny quantities over such target tissues as lungs, heart muscle and the walls of arteries. Adrenaline, it seemed, worked both as a hormone carried by the bloodstream, and as a neurotransmitter, released by nerves where it was most needed. Eventually it was realised that the neurotransmitter and the hormone were subtly different. The neurotransmitter is a substance that appears earlier in the synthesis process, and was given the name noradrenaline.

There is a poetry to the concinnity of biochemical processes, the improbably intricate reactions which make life possible. Without dumbing down his pharmacological nomenclature Hoffman takes us through the interlocking symmetries of the four-stage cascade that produces adrenaline from the amino acid tyrosine: ‘In sympathetic nerve endings, synthesis stops at the third step, resulting in noradrenaline; in the adrenal medulla, an additional step produces adrenaline … Since four chemical modifications are needed, there are at least 24 … hypothetical sequences between tyrosine and adrenaline.’ It took the work of several different labs over more than two decades to identify which of the 24 potential sequences was correct.

The adrenal glands don’t just produce adrenaline and noradrenaline: the cortex, or surface, of the glands produces the steroid hormones cortisol and aldosterone. These steroids work much more slowly than adrenaline and are related to the inflammation-suppressing drugs used to treat conditions like rheumatoid arthritis, Crohn’s disease and exacerbations of chronic bronchitis. Cortisol in particular is responsible for a huge range of actions: regulating blood pressure, co-ordinating response to injury and infection and maintaining our circadian rhythms (secretion of cortisol starts rising just before we wake up naturally in the mornings). It is also released in situations of physical and emotional stress, and in recent years measurements of cortisol levels in saliva samples have been used in studies looking at the stress levels experienced by groups as diverse as soldiers, victims of domestic abuse and the parents of autistic children with behavioural problems. The relationship is complex, but during stressful situations high levels of cortisol flow undiluted in the venous blood from the adrenal cortex down through the adrenal medulla, and stimulate the expression of the enzymes necessary to synthesise ever greater quantities of adrenaline. This means that cortisol begets adrenaline in a stress-fuelled cycle that can act pathologically to raise our blood pressure.

Once pharmacologists had identified the enzyme cascades that synthesise adrenaline and noradrenaline they started to investigate the way these hormones effect their actions on individual cells. Experiments revealed that adrenaline locks into lumpy molecules called G proteins that span the cell membrane, and thus have both an external component (exposed to nerve endings and the bloodstream) and an internal component (dangling into cytoplasm, the chemical soup within the cell). When adrenaline fits into a receptor on the G protein’s external surface the whole molecule twists, exposing active parts of the inner surface, which are then able to catalyse the conversion of adenosine triphosphate (ATP, one of the carriers of energy within the cell) to cyclic adenosine monophosphate (cAMP). The cAMP activates other enzymes which ultimately effect adrenaline’s actions. High cAMP levels in the lung tissue will cause the airways to open out; in the heart muscle they cause the pulse rate to quicken; in the arteries they cause constriction. Thus the same biochemical effect will have widely varying results in different tissues throughout the body, all of them useful in preparing the body for action.

It’s at this point in Hoffman’s narrative that I recalled those coffee-fuelled study sessions at medical school. Caffeine prevents the breakdown of cAMP, which then accumulates, ‘fooling’ the cell into thinking that there’s more adrenaline around than there actually is. That’s why too much caffeine makes you feel wired: more focused, with a racing pulse, sweaty palms and trembling muscles. It’s the biochemical equivalent of telling your body to prepare for fight or flight. Amphetamines and cocaine work through parallel, though subtly different mechanisms: cocaine prevents the re-uptake of noradrenaline into nerve endings (artificially boosting the amount of the neurotransmitter that reaches the G proteins) while amphetamines trigger the nerve endings to produce more neurotransmitters than they ordinarily would (mostly noradrenaline but also dopamine). Minor differences in the way these drugs are absorbed, and take effect in the brain and the body, give rise to the various ways in which they are experienced. Drugs like Ecstasy work through similar pathways, but tend to affect brain synapses that communicate with serotonin rather than dopamine or adrenaline.

The pharmacologists who research in these areas have been less interested in the recreational possibilities of drugs than in how they could be used to alleviate illness, and thus be marketable. For that, they had to find out more about the receptors on the cell surface, and work out how they could be artificially stimulated or blocked. Four main subtypes of adrenaline receptor have been identified: α1, α2, β1 and β2. That four different receptors are involved was a magnificent stroke of luck for clinical pharmacologists because it meant that different elements of adrenaline’s actions could be closely mimicked or prevented. The drugs developed are now a standard part of the clinician’s armoury. Drugs that block the α receptors help reduce blood pressure (medications like doxazosin) and relax swollen prostate glands (tamsulosin). β1 receptors can be blocked to slow the heart and dilate coronary arteries, preventing angina and heart failure (bisoprolol). β2 receptors can be selectively stimulated to relieve asthma attacks (salbutamol inhalers). One of the first beta blockers was propranolol, developed by the Scottish pharmacologist James Black at ICI; it’s still extensively used today, not only to slow the heart and prevent angina but to mask the external signs of anxiety (flushing, sweaty palms and tremor.)

In 1994, when I was watching Pulp Fiction and dissecting 1101-Female, the UK death rate from heart disease for men under 75 was 137 per 100,000. By 2008 that figure was down to 57. (For women, the figures were 47 and 17 respectively.) To go even further back, in 1968 the coronary death rate for men aged 65-74 was more than 1600 per 100,000. Now it is under 400. The reasons for these dramatic changes are complicated, but new and improving adrenaline-blocking drugs are a big part of the story. These days, my knowledge of human bodies is based more on the living than the dead. Each morning after clinic I sit down with a strong coffee and sign stacks of prescriptions. Beta blockers for angina, hypertension and heart failure, alpha blockers for enlarged prostates, and β2 agonists for asthmatics are some of the commonest drugs I’ll sign off. In consultations I regularly meet patients looking for methylphenidate (Ritalin) to help improve their powers of concentration. And like many physicians I’ve seen the dark side of adrenergic drugs: cocaine can trigger cardiac arrest and arrhythmias, and amphetamines and designer chemicals like MDMA can cause psychosis and paranoia that persist long after comedown.

Hoffman’s book offers a straight history of adrenaline’s discovery, purification and the research that has been carried out into how it works. For most of us the stories from the lab may be of less interest than the wider implications: how the drugs that have been developed through it have transformed medicine. Tarantino notwithstanding, adrenaline to the heart is unlikely to save your life, but through the judicious blocking or mimicking of adrenaline’s actions, these drugs may just postpone your death.

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Vol. 35 No. 18 · 26 September 2013

Gavin Francis forgets his biochemistry when he writes that ‘adrenaline locks into lumpy molecules called G proteins that span the cell membrane’ (LRB, 29 August). Nor do the G proteins, as Francis claims, convert ATP to cAMP. Adrenaline binds to alpha or beta receptors that span the cell membrane. It is these receptors that are linked to G proteins, which reside on the underside of the membrane. The G proteins in turn activate various subcellular targets, including an enzyme (adenylyl cyclase) that converts ATP to the messenger molecule cAMP. The multi-component process is essential for fine control and further amplification of the adrenaline signal; it also allows cells to integrate the signal with those from other hormones and neurotransmitters.

Richard Sever
New York

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