This chapter is only slightly relevant to Section G8(iii) of the 2017 CICM Primary Syllabus, which asks the exam candidate to "understand the pharmacology of anti-hypertensive drugs". To be sure, what's discussed below is a whole selection of antihypertensive agents, and yes, the vast majority of ICU doctors will at one stage or another end up using some of these. But they are not included in any of the CICM First Part exam papers, and appear only as footnotes in the "management options" questions from the Second Part exam. In contrast, six SAQs had interrogated the trainee's understanding of nitrate vasodilators. If you are revising, it is clear where your priorities should be.
To revisit this classification system, there are five common classes of antihypertensives:
To these, you would probably have to add pulmonary vasodilators, purely for completeness. These are common enough in the CICM Part One to merit their own chapters, probably because they all have a large role to play in our clinical practice. In addition, there are several minor classes in the antihypertensive arsenal which need to be mentioned somewhere, but not in any great detail:
- Alpha-1 antagonists
- Alpha-2 agonists
- Potassium channel activators
- Ganglion blockers
And there are still more. In addition to the already mentioned, there are - for lack of a better word - poisonous substances which happen to have a vaguely desirable antihypertensive effect as a part of their toxicity profile. We will also get to those.
Fifth sixths and seventh line agents
Following a trend set in other antihypertensive chapters, these drugs will be listed together with the year they became available, in order of ascending weirdness and obsolescence.
|Drug||Year of availability|
Potassium channel activators
|late 1890s (discovered in 1848)|
Monoamine transporter or synthesis antagonist
Creme de la misc
This class of antihypertensives exerts its beneficial effects by blocking the alpha-1 receptors, which are responsible for a lot of the sympathetic arteriolar tone (the main mechanism of peripheral vascular resistance).
|Class||Alpha antagonist||Alpha antagonist||Alpha antagonist|
|Routes of administration||Oral only||IV only||Oral only|
|Absorption||Oral bioavailability is 43-69%; high first-pass metabolism.||Bioavailability is variably reported as 30% or 100%||Bioavailability is about 20-30%, mainly because of incomplete and variable gut absorption|
|Solubility||pKa 8.42; slightly water-soluble; also only slightly lipid-soluble, but enough that it can cross the blood-brain barrier.||pKa = 9.78; highly lipid-soluble||Highly lipid-soluble, but poorly water-soluble. pKa = 7.97|
|Distribution||Highly protein bound (92-97%). VOD ~ 42L/kg||54% protein bound; VOD is large, about 6L/kg||The VOD is massive because of the high lipid solubility and protein binding, but nobody seems to have a number for it in the literature|
|Target receptor||Alpha-1 adrenoceptor||Fairly unselective alpha-1 and alpha-2 receptor blocker; as well as an agonist of beta-receptors||Slightly more selective for alpha-1 adrenoceptors, vs. alpha-2 receptors|
|Metabolism||Hepatic metabolism, primarily by demethylation and conjugation. Of the metabolites, basically everything is excreted in the bile.||Extensive hepatic metabolism, 80% renal excretion (10% to 13% excreted as unchanged drug) and 20% faecal excretion.||Hepatic metabolism into inactive metabolites (very slow, as little free drug is available in the circulation)|
|Elimination||Half-life is about 2.5 hrs||Half-life is 19 minutes||Inactive metabolites are eliminated in the bile and urine. Half-life is about 24 hrs.|
|Time course of action||Relatively slow onset, 1-3 hrs after oral administration. Duration of effect is 6-8hrs||After IV administration, the onset and offset of effect are rapid.||Onset of effect is about 1-2 hrs; however the duration of effect is 3-4 days, as this is roughly how long it takes you to synthesise new alpha-receptors|
|Mechanism of action||Competitive alpha-1 adrenergic receptor blocker: by binding to this Gq-protein-coupled receptor, this drug decreases the activation of phospholipase C, resulting in a decreased concentration of the secondary messengers IP3 and DAG. The result is decreased intracellular calcium availability, which in turn leads to decreased smooth muscle contraction tone.||The antihypertensive effect is as a NON-competitive (irreversible) alpha-1 adrenergic receptor blocker. By covalently binding to this Gq-protein-coupled receptor, this drug decreases the activation of phospholipase C, resulting in a decreased concentration of the secondary messengers IP3 and DAG. The result is decreased intracellular calcium availability, which in turn leads to decreased smooth muscle contraction tone.|
|Clinical effects||Produces systemic vasodilation without affecting heart rate and cardiac output; also produces venodilation; acts as a smooth muscle relaxant at the level of the urethral sphincter, decreasing symptoms of prastatic hypertrophy. Also decreases risk of PTSD. Has been used to manage Rayhaud's phenomenon. Postural hypotension is one of the possible side effects.||Systemic vasodilation; because of its non-selective blockade of all alpha receptors, there is usually some reflex tachycardia and increased cardiac output.||Postural hypotension, tachycardia, arrhythmias, drowsiness, fatigue, inhibition of ejaculation, nasal congestion, miosis, and dry mouth. Also penetrates the CNS, causing stimulation, nausea, vomiting, motor excitation, and occasionally seizures.|
|Single best reference for further information||TGA PI||Gould, L., and C. V. Reddy. "Phentolamine." American heart journal 92.3 (1976): 397-402.||Gruetter, Carl A. "Phenoxybenzamine." (2007): 1-4.|
Prazocin is a quinazoline derivative, which is a group containing several other members, notably terazocin bunazocin and ketanserin (Tsushihashi & Nagatomo, 1989). It is just lipid-soluble enough that it can cross the blood brain barrier, which appears to have some unusual CNS effects (for instance, it may helpfully numb your reaction to war atrocities). One typically thinks of it as an arteriodilator drug, but it is actually at least as good at dilating veins as it is at dilating arteries. One major advantage o this drug, and the main thing which has led to its popularity, is the high alpha-1 selectivity. By avoiding alpha-2 receptors, prazocin does not stimulate central sympathetic output, which ameliorates the compensatory effects of the cardiac reflexes which one might expect to occur in response to vasodilation. In short, prazocin should not produce a reflex tachycardia and an increased cardiac output, making it a safe choice in severe untreated ishacemic heart disease and aortic dissection.
Ketanserin is another quinazoline derivative which has been used an oral antihypertensive (as it blocks alpha-1 receptors). Its One Weird Trick is the ability to vasodilate pulmonary arteries, and at least one author has reported using it to reverse the pulmonary hypertension associated with protamine use. However, it is far more effective at blocking of 5-HT2 serotonin receptors then it is at blocking alpha-adrenoceptors, and therefore has a tendency to depress consciousness, prolong the QT interval, and harsh the buzz from MDMA. Some of these side effects have made it unpopular in clinical practice, and these days it is mainly used for experiments which require serotonin receptor blockade.
Phenoxybenzamine is a haloalkylamine. There's a few of them around; a 1952 paper by Stone & Loew lists numerous chemical relatives (N-ethyl-N-(2-chloroethyl)-benzhydrylamine hydrochloride, N-ethyl-N-(2-bromoethyl)-1-naphthalene-methylamine-hydrobromide, 2-(2-biphenyloxy) - 2'chlorotriethylamine hydrochloride, N-ethyl-N-(2-chloroethyl) - 9-fluorenamine hydrochloride). All of them have the same mechanism of action, but phenoxybenzamine is the only one which went to market in the 1950s, probably because it was the most selective for the pharmacologically interesting alpha-1 receptors. Its unique effect is the receptor binding kinetics: phenoxybenzamine is an irreversible antagonist which disables alpha-1 receptors by binding to them covalently. It is, unfortunately, not perfectly selective, which means at high doses it will bind to all the other neurotransmitter receptors(serotonin, dopamine, histamine, acetylcholine). The effect lasts for days, as this is how long it takes for you to create new receptors. It is also extremely lipid-soluble, which means it penetrates the CNS without any problems, and can do weird things up in there, like produce "motor excitation" and seizures.
Phentolamine is an imidazoline, related to tolazoline (which is used for pulmonary hypertension in neonates). At one stage, it was being considered as an oral antihypertensive (as it has reasonably good oral bioavailability) but the experiments came to an end due to something described as "intolerable gastrointestinal manifestations" (specifically Moyer et al in 1953 reported diarrhoea that was "prohibitively severe"). Because it blocks all alpha receptors (it is not selective for the alpha-1 group), this drug causes stimulation of sympathetic responses to hypotension, essentially acting as an indirect inotrope. Tachycardia and increased cardiac output which are seen with its use are also exacerbated by the fact that it is a direct beta-agonist. To avoid these adverse effects, its systemic use is therefore limited to patients who are already seriously beta-blocked.
By acting on central presynaptic alpha-2 receptors, these drugs act as neuromodulators, leading to sedation, analgesia, vasodilatation, and bradycardia. There's actually quite a few of them, and only the ones mentioned in the table below are considered antihypertensives. In fact, clonidine is really only used as an antihypertensive in the ICU, and elsewhere this dirty drug is being deployed because of its many delightful side-effects. Similarly, though guanabenz, guanfacine, tizanidine, medetomidine and dexmedetomidine all have some antihypertensive effects, these days they find themselves being used for chronic and acute pain, sedation, ADHD, opiate and alcohol withdrawal, nicotine dependence and panic disorders (Giovannitti et al, 2015).
|Chemistry||Phenylalanine derivative||Imidazoline derivative||Imidazoline derivative|
|Routes of administration||Oral only||IV and oral||Oral only|
|Absorption||Bioavailability is 25% (range 8 to 62%).||Well absorbed orally, and has minimal first-pass metabolism. Bioavailability is 70-80%||Well absorbed orally, 88% bioavailability|
|Solubility||pKa 9.85||Reasonably amphoteric: dissolves quite well in both water and fat. pKa is 8.0||pKa is ~ 7.4; moderately lipophilic|
|Distribution||Less than 15% protein-bound; small VOD, 0.6L/kg||30-40% protein-bound; VOD is 2.1 L/kg||VOD is 1.83L/kg; about 10% protein-bound|
|Target receptor||Presynaptic alpha-2 receptors||Presynaptic alpha-2 receptors, as well as imidazoline receptors., where it acts as an agonist (which account for a lot of its non-antihypertensive effects)||Mainly affects imidazoline receptors (where it acts as an agonist), rather than alpha-2 receptors (40:1 selectivity).|
|Metabolism||Metabolised in the liver into methyldopamine and multiple other metabolic byproducts, of which many are active(in fact more active than the parent compound||About 30% is metabolised in the liver into numerous metabolites, and the rest is excreted unchanged in the kidney.||Undergoes minimal hepatic metabolism; most of the dose is excreted unchanged in the urine|
|Elimination||Up to 50% of the dose is cleared renally as unchanged drug, leading to accumulation in renal failure. Half-life is about 1-2hrs||Mainly renally eliminated; half-life is biphasic: by distribution is about 20min, and by elimination 5-7 hrs||Half-life is only 2.2 hours|
|Time course of action||Onset of action is over 1-2 hrs, and the duration of effect is about 10 hrs (i.e. needs twice daily dosing)||Duration of the effect is ~ 6 hrs||Duration fo effect is quite prolonged, something in the order of 24 hours,|
|Mechanism of action||Central alpha-2 agonist effect decreases sympathetic outflow by presynaptic downregulation of noradrenaline release. Apart from this, methyldopa and its metabolites (methyldopamine and methylnoradrenaline) interfere with neurotransmission and neurotransmitter synthesis||Central alpha-2 agonist effect decreases sympathetic outflow by presynaptic downregulation of noradrenaline release.||Like clonidine and methyldopa, moxonidine decreases sympathetic outflow by a presynaptic alpha-2 effect, but it also acts on the rostral ventrolateral medulla to downregulate sympathetic activity.|
|Clinical effects||Class effects (bradycardia, decreased blood pressure), as well as depression and sedation. Also, can cause haemolytic anaemia and drug-induced lupus||Class effects (bradycardia, decreased blood pressure), as well as sensitisation of opiate receptors, sedation, analgesia, and an initial hypertensive phase following IV administration||Because of the mainly imidazoline agonist effect, this drug produces a decrease in blood pressure without much bradycardia or sedation.|
|Single best reference for further information||TGA PI for Aldomet||TGA PI for IV version of Catapres||Morris & Reid (1997)|
α-methyldopa is a phenylalanine derivative which remained obscure for decades until its antihypertensive effect was discovered in 1960 by Oates et al. In fact, at that stage, how it accomplished the decrease in blood pressure was unknown, and the main effect was thought to be the decrease of dopamine and catecholamine synthesis by the blockade of dopa decarboxylation. Which, in truth, it does, producing CNS effects: "all patients had a temporary change in mental status, apparent to observers and manifested as sedation, tranquility, or fatigue". To this decline in central neurotransmitter concentrations has been attributed the profound melancholy which methyldopa patients often experience, according to the old monoamine hypothesis of mood. It also has a tendency to cause haemolytic anaemia and drug-induced lupus. To add to everything, it is not an especially potent antihypertensive, and often needs to be combined with another drug to have a satisfactory effect.
Because of these unpleasant side-effects, it has lost much of its former popularity, and the modern intensive care trainee will only really see it in the context of hypertensive pregnancy, where it is still for some reason commonly used. An interrogation of the O&G literature did not reveal any major advantage of this drug over the others (eg. nifedipine or labetalol), except that it appears to be without teratogenic effects. "Established long term safety" is the line they tend to use, which defies logic considering that these women don't need any more reasons to be depressed.
Clonidine was the next member of this class to become available in 1966. It was discovered quite accidentally, when the monstrous capitalists of Boehringer Ingelheim were trying to come up with some new market-ready nasal decongestants (Stähle, 2000, gives a beautiful account of this). In classic 1960s style, they accidentally gave about 1500mcg of it to a female secretary. "She fell asleep for 24 h, developed low blood pressure, marked bradycardia, and dryness of the mouth", the boys guffawed heartily. All subsequent research focused on its sympatholytic effects. The factor which limited its popularity was the shot duration of action, the sedating effect, and the very impressive rebound hypertension which tends to occur when chronic use is interrupted. Fortunately, it has a myriad of possibly useful side-effects, and has found a role in the management of pain, ADHD, substance dependence and anxiety.
Moxonidine, after a hiatus of 30 years, was the next imidazoline derivative made available to the public in 1996. It is a "cleaner" drug than clonidine or methyldopa, in the sense that it does not seem to have such pronounced alpha-2 blocker effects. It has about 40 times greater affinity for imidazoline receptors, and exerts most of its effect in the vasomotor centre of the medulla, which means there is little heart rate effect. As such, it is a solid antihypertensive adjunct, mostly used together with other drugs (eg. when you just can't bring yourself to give any more prazocin). Unfortunately, large-scale trials (the MOXCON trial, 2003) determined that it increased mortality in CCF patients.
- They are all renally excreted, at least to some extent (most of all moxonidine), which means they will accumulate in renal failure
- They are all lipophilic, as they would need to cross the blood-brain barrier in order to have any effect, and therefore they cause some degree of CNS depression (moxonidine least of all)
- None of them are really suitable for long term control of blood pressure, except moxonidine - but moxonidine is contraindicated in CCF.
Potassium channel activators
The only member of this group which will be immediately recognisable to the millennial ICU trainee is hydralazine, as it remains ubiquitous in intensive care units. The others need to be mentioned only in passing, to demonstrate that this class of drugs has more than one member. In short, these drugs are thought to have an effect on ATP-sensitive potassium channels in vascular smooth muscle (the same ones which are probably responsible for the potassium-mediated regional vasodilation). The common feature of this class is the need for concomitant therapy with beta-blockers and diuretics. There is a tendency for the cardiac reflexes to interfere with their antihypertensive effect by causing tachycardia, and for the humoral defence of blood volume to interfere by producing fluid retention. Unlike nitrates, none of these drugs cause much venodilation, and most of their effect is seen at the level of the precapillary arterioles.
|Chemistry||Phthalazine derivative||pyrimidine N-oxide||pyrimidinecarboxamide|
|Routes of administration||Oral and IV||Oral, IV, topical||Oral only|
|Absorption||Rapidly and completely absorbed in the GIT; 22-66% bioavailability due to first-pass effect||Well absorbed (95%);||Well absorbed; bioavailability is > 75%|
|Solubility||pKa 7.3||pKa 4.61; slightly water-solible||pKa = 3.18; reasonably amphoteric|
|Distribution||87% protein-bound; VOD = 1.34L/kg||VOD = 200L/kg; minimally protein-bound||VOD = 1.0-1.4L/kg; about 24% protein-bound|
|Target receptor||Presumably, ATP-sensitive potassium channels||ATP-sensitive potassium channels||ATP-sensitive potassium channels|
|Metabolism||Hepatic metabolism by polymorphic acetylation. Those that are slow acetylators require lower doses of the drug.||90% is metabolised in the liver||Mainly hepatic metabolism by denitration and then introduction into the nicotinamide metabolism|
|Elimination||Mainly eliminated renally as inactive metabolites; plasma half-life is about 1 hour||10% is excreted unchanged in the kidneys; half-life is about 3 hours||Inactive metabolites are eliminated in urine. Half life is about 2 hrs.|
|Time course of action||Onset of effect is slightly delayed following an IV dose, 5-30 minutes. Duration of effect is 2-4 hours.||Therapeutic effect can last significantly longer then the half life (up to 72 hours)||Long-acting, duration of effect is close to 12 hrs|
|Mechanism of action||The mechanism of action is not entirely clear, but seems to have something to do with ATP-sensitive potassium channels. Activation of these channels inhibits the opening of voltage-dependent calcium channels indirectly, by hyperpolarising the membrane.|
|Clinical effects||Class effects (arterial vasodilation, reflex tachycardia, RAAS activation)|
|Anorexia, nausea, dizziness, and sweating. Does not act as a venodilator.||Does not act as a venodilator. Causes hypertrichosis, which may be desirable, ...or not.||Unlike the other members of this class, nicorandil DOES act as a venodilator, because it has some nitrate-like nitric oxide donor properties.|
|Single best reference for further information||Powers et al (1998)||Campese (1981)||Markham (2000)|
Hydralazine is a phthalazine derivative with a mechanism of action which remains unclear even after eighty years of clinical experience and research. It is grouped here with the ATP-sensitive potassium channel activators mainly because this is one of its more plausible mechanisms (Kajioka et al, 1991). It's a really old drug, discovered in the late 1940s by people who were trying to find a good antimalarial (Gross, 1950). To their surpise, their test rabbits ended up developing hypotension; and it is unclear how they responded to the malarial parasites, because the article is in German, making it impossible to parse the besonderem Wirkungcharakter of the Substanzen. Powers et al (1998), probably the best hydralazine-related monograph out there, tellingly eschews these details, probably because they are absolutely without relevance.
The activity of hydralazine is clearly predominantly as an arteriodilator, specifically on the precapillary than the postcapillary resistance vessels. There also appears to be a preferential effect on the coronary, cerebral, and renal vascular beds (i.e skin and muscle seem to be spared, according to Ebeigbe & Aloamaka, 1985; though in all honesty those were rat skin and rat muscle, so caveat lector). It does not appear to have any venodilator properties (D'Oyley et al, 1989), which means it will not reduce preload. It will, however, drop arterial blood pressure enough to activate all sorts of cardiac reflexes, leading to all sorts of unproductive tachycardia and compensatory salt/water retention. In short, the use of this drug in chronic community management of hypertension is limited by its uselessness as a solo agent. In the ICU, however, it remains extremely popular, mainly because we often want to both reduce afterload and preserve preload, and rarely care overmuch about the details of chronic maintenance therapy.
The other drugs in this group need to be mentioned mainly to satisfy some demented need for completeness, rather than to emphasise their clinical relevance, which is probably minimal. That's not to assert that these drugs are without useful effect, which would be incorrect - they are antihypertensives, and certainly will lower the blood pressure - but, for various often non-pharmacological reasons, they became banished from routine practice. Minoxidil, for example, failed horribly as an antihypertensive drug, not because it was an ineffective vasodilator (it is in fact extremely potent), but because at the time there was no other satisfactory treatment for alopecia (Bryan, 2011). It is still available for severe treatment-refractory hypertension, in case the risk of death and critical illness outweigh the cosmetic concerns. Diazoxide, an ancient benzothiadiazine, is similarly effective as an antihypertensive, but these days mainly finds its uses in the management of insulinoma, as it has the unique effect of decreasing insulin secretion. Nicorandil is probably the only one of these which is in regular use in a cardiovascular role, and its main application seems to be as an angina preventor. It also happens to have some nitrate-like venodilator properties and it is free from horrible adverse effects, making it more attractive than some of the others.
Renin must seem like an attractive target for pharmacological blood pressure control, as the renin-angiotensin-aldosterone system is responsible for much of the humoral regulation of extracellular blood flow and volume. Other methods of targeting this system (eg. ACE-inhibitors and ARBs) have been wildly popular, and therefore surely it must be a stroke of genius to block the uppermost rate-limiting part of the pathway.
|Routes of administration||Oral only|
|Absorption||Poor oral bioavailability, ~ 2.5% (mainly because of poor absorption)|
|Solubility||pKa = 9.49; good solubility in water|
|Distribution||VOD=2L/kg; minimally protein-bound|
|Target receptor||Renin, the soluble peptidase|
|Elimination||Excreted unchanged via the bile- half-life is 23.7 h|
|Time course of action||Slow onset of effect - peak around 3-6 hours following an oral dose|
|Mechanism of action||Inhibits the activity of renin, which reduces the activation of angiotensin and therefore prevents all the downstream signalling effects associated with RAAS activation|
|Clinical effects||Arterial vasodilation, and decreased neurohormonal response to volume loss or hypotension|
|Single best reference for further information||Allikmets (2007)|
A review article by Allikmets (2007) lists multiple members of this class, including aliskiren enalikiren remikiren and zankiren. Their marketability was severely hampered by their very poor oral bioavailability, which is why you've probably never heard of them. For some reason, they sent aliskiren for approval anyway, even though it only has a bioavailability of 2.5%. Its only pharmacokinetically interesting feature is that virtually 100% of it is excreted unchanged in the bile. Its promise of cutting the head off the RAAS snake has unfortunately failed to materialise into massive long-term clinical benefits; Pantazris (2017) complained about "discouraging results on several morbidity and mortality endpoints in large prospective trials" and concluded that it is "just another viable option in the armory of clinicians to achieve adequate BP control".
With the availability of beta blockers, these primitive and brutal methods of blood pressure control have all but vanished, and these days one would probably have great difficulty tracking down any trimethapham or hexamethonium bromide, even if one actually wanted to use them. And nobody should ever find the need to use them, because one no longer needs to block neurotransmission proximally to the alpha and beta receptors, considering how many safe and effective receptor blockers are available.
|Class||Ganglionic blocker||Ganglionic blocker||Ganglionic blocker|
|Chemistry||complex heterocyclic sulfonium compound with an imidazolium core||bis-quaternary ammonium compound||Quarternary amine|
|Routes of administration||IV||IV, IM||IV, IM|
|Absorption||Unknown; "erratically and incompletely absorbed"||Poor GI absorption, perhaps 25% of the oral dose is absorbed||Poor GI absorption|
|Solubility||pKa = -2.0; minimal water solubility||Highly water-soluble; does not cross the blood-brain barrier; high pKa||Soluble in both water and ethanol; pKa = 10.8|
|Distribution||VOD = 0.6L/kg, i.e confined to the extracellular fluid||VOD = 0.23 L/kg||VOD = 0.6L/kg, i.e confined to the extracellular fluid|
|Target receptor||Nicotinic acetylcholine receptors||Nicotinic acetylcholine receptors... Except, "While selective for the ganglia in vivo, its in vitro potency at muscle and neuronal nAChRs is similar"||Nicotinic acetylcholine receptors|
|Metabolism||May be metabolised by cholinesterase||Minimal metabolism||Minimal metabolism|
|Elimination||Half life is about 10 minutes||Half life is about 10 minutes; most of the dose (close to 100%) is excreted in the urine||Most of the dose excreted unchanged in the urine (undergoes active secretion at the tubule); half-life is 1-2 hrs|
|Time course of action||Rapid onset and offset of effect - needs to be given as an infusion||Duration of action is about 2 hrs||Duration of action is about 2 hrs|
|Mechanism of action||Blocks ganglionic autonomic neurotransmission, therefore decreasing both sympathetic tonic input to the vascular smooth muscle, and to the myocardium. Also blocks vagal neurotransmission.|
|Clinical effects||Vasodilation (arterial and, presumably, venous) without compensatory tachycardia, as well as ileus, bladder atony, and pupil dilation. Also, probably a degree of neuromuscular junction block.|
|Single best reference for further information||Mason, 1980||Mason, 1980||Mason, 1980|
Trimethaphan, tetraethylammonium and hexamethonium bromide are the better-known members of this group, but there are many others, listed by Mason (1980) and Green (1954). They were even able to classify them somewhat, on a fairly robust chemical basis:
- "Onium" compounds (water soluble)
- Secondary and tertiary amines
Their pharmacology and effects are lovingly detailed by Moe & Freyburger (1950). These are some of the oldest antihypertensives, second only to GTN; for example tetraethylammonium was first described by Burn & Dale in 1915. The "oniums" are quartenary amines, which means they structurally resemble acetylcholine - enough that they can fool nicotinic receptors at the ganglion, producing their effects. And what effects they are. As one might imagine, blood pressure control is only one small fragment of what the autonomic nervous system does, and turning it off at the socket will have numerous other consequences, most of them undesirable. Parasympathetic blockade effects tend to dominate sympathetic effects, and so the total picture might look like ileus, bladder atony and fixed dilated pupils. Because the sympathetic output is also blocked, cardiac reflexes are blunted, and there should not be much tachycardia. With a large enough dose, selectivity for the ganglionic nicotinic receptors will be lost, and depolarising neuromuscular blockade will ensue. For hexamethonium, in fact, "while selective for the ganglia in vivo,...in vitro potency at muscle and neuronal nAChRs is similar", i.e. hexamethonium is basically a depolarising neuromuscular junction blocker which also happens to have some antihypertensive side-effects. That sounds like it would be a problem for the marketing department.
Data regarding the pharmacokinetics and pharmacodynamics of these drugs was difficult to track down. No prescribing information PDFs are available, probably because nobody prescribes them any more. In case anybody ever needs a definitive set of notes for the pharmacokinetics of this class, the best a casual Google search can offer is this paywalled chapter by Mason from Pharmacology of Ganglionic Transmission (1980), which was useful up to a point. Occasionally trimethaphan still end up being mentioned in book chapters on hypertensive emergencies (Mann, 2008), which means that somebody somewhere still has access to it, but there's little practical information out there on how to actually use it safely. Hexamethonium is almost completely lost in the Western world, but does appear in some of the self-test questions in this pharmacology workbook from the Medical Academy of Dnipropetrovsk. In short, what the author is trying to say here is that the data presented in the table above is accurate to his best knowledge, but comes from shoddy sources and is unreliable even by the standards of Deranged Physiology. For example, the half-life and duration of action of tetraethylammonium were inferred from an adverse event report by Graham (1950), and is basically the time frame over which his accidentally overdosed patient had completely recovered:
"An hour after injection the subject could partly open her eyes, and after tilting her head backwards could count fingers. Power of hand muscles and of speech was returning, though cerebration was still very slow. Two hours after injection walking was possible. There were no further after-effects."
Though phosphodiesterase inhibitors are a class well known for their pulmonary vasodilator effects, they are not really seen much in the treatment of systemic blood pressure problems. One might be tempted to bring up the discussion of the famous synergistic interaction between sildenafil and GTN, which - to be sure - is an antihypertensive effect, but it seems nobody has ever confessed to taking advantage of it intentionally. Of the phosphodiesterase inhibitors still used for their systemic or peripheral vasodilator effect, papaverine is probably the only representative.
|Chemistry||Opioid (benzylisoquinoline) alkaloid|
|Routes of administration||IV, but mainly used as an intra-arterial injection|
|Absorption||Variable, and mainly poor oral absorption; bioavailability is ~50%|
|Solubility||Completely insoluble in water|
|Distribution||VOD 20-25L/kg; 95% protein bound|
|Target receptor||Phosphodiesterase 10 (PDE 10)|
|Metabolism||Mainly hepatic metabolism|
|Elimination||Very rapid distribution half-life (several minutes); overall elimination half life is closer to 100 minutes|
|Time course of action||Rapid onset and offset of effect; needs to be given as an infusion|
|Mechanism of action||Increases cyclic AMP by inhibiting phosphodiesterase (with maximum selectivity for PDE10), which is responsible for cAMP catabolism. Selective for vascular smooth muscle.|
|Clinical effects||Vasodilation, tachycardia, hypotension, hepatotoxicity, drowsyness, respiratory depression, hyperthermia, metabolic acidosis, and constipation|
|Single best reference for further information||Garrett et al, 1978|
The main use for this drug these days is intraarterial injection for the treatment of cerebral vasospasm. Oral formulary was developed at some stage - we've had this drug since the early 20th century, when little else was available - however, for various reasons, it was not particularly popular. That is not to say that it was completely without fans - enthusiastic proponents such as Elek & Katz (1942) produced copious case studies to support its safety and efficacy when used as an angina-preventing coronary vasodilator. "After a course of papaverine she had only ten attacks in a fortnight, walked 3 blocks, had less pain and could perform more housework", the authors helpfully reported from the experience of one 52-year-old housewife. The arrival of beta-blockers and other safe alternatives had decreased its appeal, and it has all but disappeared from the formularies of the world (though it is still present in dangerous herbal remedies).
Monoamine transporter or synthesis antagonists
Rather than blocking cAMP synthesis, or the catecholamine receptors which stimulate it, why not just abolish catecholamines altogether? That is one of the mechanisms of action of reserpine, guanethidine and α-methyltyrosine. These drugs interfere in various ways with the cardiovascular effect-site availability of catecholamine neurotransmitters, either by interfering with their synthesis, or by inhibiting their transport.
|Class||Monoamine reuptake inhibitor||Monoamine reuptake inhibitor||Catecholamine synthesis inhibitor|
|Chemistry||indole alkaloid extracted from Rauwolfia serpentine roots||guanidine||L-tyrosine derivative|
|Routes of administration||Oral and IV||Oral and, occasionally, IV||Oral|
|Absorption||Rapid GI absorption, bioavailability 50-70%||Bioavailability 3-50%, absorption is variable||Well absorbed, 100% bioavailability|
|Solubility||Highly lipid soluble; penetrates the blood brain barrier. pKa = 6.6||Poor solubility in water; highly lipid soluble; penetrates the blood-brain barrier||Minimally water-soluble; pKa 9.6|
|Distribution||VOD unknown; presumably large, as it binds irreversibly to VMAT targets and to red blood cells||VOD unknown; presumably large, as it binds irreversibly to VMAT targets and to red blood cells||VOD = around 70L/kg|
|Target receptor||VMAT-2 (vesicular monoamine transporter-2)||VMAT-2 (vesicular monoamine transporter-2)||Tyrosine hydroxylase, the enzyme which hydroxylates tyrosine to make dopa|
|Metabolism||Hepatic metabolism into inactive metabolites||Hepatic metabolism accounts for 50% of elimination||Minimally metabolised|
|Elimination||Minimal renal clearance of unchanged drug; half-life of about 4-5 hours by distribution, but very long elimination half-life, ~ 160 hours||Half of the dose is eliminated unchanged in the urine. Elimination half-life is 5 days, but plasma distribution half-life is much more rapid, ~ 10 minutes||Up to 88% is recovered form the urine as unchanged drug; half-life is about 3-4 hours|
|Time course of action||Prolonged duration of effect due to irreversible binding||Long acting; after a loading dose, can be dosed daily||Long-acting; daily dosing|
|Mechanism of action||Irreversibly blocks VMAT-2 in the adrenergic neurotransmission pathway. This results in catecholamines and serotonin lingering in the cytoplasm where they are destroyed by intraneuronal monoamine oxidase, thereby causing the depletion of catecholamine and serotonin stores in central and peripheral nerve terminals||Irreversibly blocks VMAT-2 in the adrenergic neurotransmission pathway. This results in catecholamines and serotonin lingering in the cytoplasm where they are destroyed by intraneuronal monoamine oxidase, thereby causing the depletion of catecholamine and serotonin stores in central and peripheral nerve terminals||By inhibiting the conversion of tyrosine into dopa, this drug effectively blocks the synthesis of catecholamines|
|Clinical effects||Sedation, hypotension, bradycardia, depression. Can act an antipsychotic||Hypotension, bradycardia,unopposed parasympathetic excess(eg. diarrhoea), volume expansion, oedema, but interestingly little in the way of CNS effects.||Drowsiness, parkinsonian tremor, crystalluria, withdrawal syndrome (insomnia, agitation)|
|Single best reference for further information||INCHEM article||Lukas (1974)||Brogden et al (1981)|
Reserpine remains in use, occasionally bundled with a thiazide diuretic. It is a potent sympatholytic, with some good ICU potential. Siddiqui et al (2020) reported some promising effects on patients with refractory hypertension (on five other agents), which certainly sounds like an ICU population. Unfortunately, owing to its mechanism of effect, it is known to cause severe depression, even in previously cheerful patients. Fortunately, where monoamine excess is the problem (eg. psychosis), reserpine may have some beneficial effect, notwithstanding the crudeness of monoamine-based reasoning in psychiatry. Guanethidine has the same basic mechanism of action, but somehow less CNS penetration, and is therefore unlikely to cause depression or sedation. In contrast to both of these drugs, α-methyltyrosine does not interfere with neurotransmitter storage. It acts by inhibiting the hydroxylation of tyrosine to form dopa. That sounds like an elegant way to decrease blood pressure, but it tends to block all catecholamine synthesis, which means no dopamine either, and that leads to Parkinsonian side-effects and all kinds of other movement disorders. Not only that, but it is a drug with low potency, which means it must be given in high doses, and it is excreted renally as unchanged drug, which basically means that you can expect a large amount of it to precipitate in the urine as crystals. In short, it has a host of unattractive features which resulted in its abandonment as an antipsychotic and antihypertensive. It is still mentioned occasionally alongside phenoxybenzamine as a treatment option in phaeochromocytoma.
Misc of the misc
It would be a violation of standard Deranged Physiology operating procedure to not complete this chapter with an utterly irrelevant historical footnote. In such a fashion, forgotten drugs will be listed here, which fall into the antihypertensive category only accidentally. Many are antihypertensives only in the same sense as E.coli endotoxin is an antihypertensive, i.e. you inject them into people, and the blood pressure surely decreases, but only as one effect among a host of other disturbing phenomena. For instance, sodium thiocyanate can be mentioned here, as it was probably the first antihypertensive ever used for the purpose of hypertension. This was in the early 1900s, when hypertension was not universally believed to be harmful (some eminent physicians contested the idea, claiming that "hypertension may be an important compensatory mechanism which should not be tampered with, even if we were certain that we could control it"). Even more weird substances, unknown to modern readers, are unearthed when one peruses papers from the distant past. Green (1954) is particularly illuminating, listing yohimbine, lysergic acid, piperoxan, diborane, dibenamine, azapetine and pendiomide as valid options. The task of hunting down their pharmacological details will be left up to the reader.