Clonidine

This chapter is relevant to Section G7(ii) of the 2023 CICM Primary Syllabus, which asks the exam candidate to "understand the pharmacology of anti-hypertensive drugs", and is a specific response to Question 7 from the second paper of 2023, which asked everything about clonidine. The college examiners have decided to group it with antihypertensive, but this old drug could realistically also fit very easily into the autonomic section (where it could be discussed as either a sympathomimetic or a sympatholytic), or the nervous systems section (where it could be either a sedative or an analgesic).

In summary:

Class α-2 agonist
Chemistry Imidazoline derivative
Routes of administration IV and oral; dose is 50-300mcg up to a maximum dose of 2400 mcg daily, in divided doses. 
Absorption Well absorbed orally, and has minimal first-pass metabolism. Bioavailability is 70-80%
Solubility Reasonably amphoteric: dissolves quite well in both water and fat. pKa is 8.0
Distribution 30-40% protein-bound; VOD is 2.1 L/kg
Target receptor 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)
Metabolism About 30% is metabolised in the liver into numerous metabolites, and the rest is excreted unchanged in the kidney.
Elimination Mainly renally eliminated; half-life is biphasic: by distribution is about 20min, and by elimination 5-7 hrs
Time course of action Duration of the effect is ~ 6 hrs
Mechanism of action Central alpha-2 agonist effect decreases sympathetic outflow by presynaptic downregulation of noradrenaline release. In overdose, peripheral alpha agonist effects dominate, making hypertension a dominant feature.
Clinical effects Class effects (bradycardia, decreased blood pressure, due to central sympatholytic effect), as well as sensitisation of opiate receptors, sedation, analgesia, and an initial hypertensive phase following IV administration. No respiratory depression with sedation, nor any airway reflex loss.
Single best reference for further information Houston (1981)

One is torn as to what to offer as an article recommendation here, as the consumer of online clonidine content will be either a disinterested trainee looking for maximum marks or a curious post-exam explorer of bizarre pharmacology. For the former, Houston (1981) or Sarwat (2024) will be sufficient, both offering a simple clear list of properties suitable for last-minute revision. For the latter, the reflections of Helmut Stähle will be a fascinating diversion. Stähle, a veteran chemist in the autumn of his career, recalls with fondness the early days of his work in Barad-dûr, when his overlords demanded novel α-agonist to market as a nasal decongestant. The efficacy of the resulting compounds was tested on dogs, using a yecnhinuque whereby the volume and pressure of the nasal mucosa could be measured with a manometry bulb in the nasopharynx. He sent some of the more successful compounds to medical colleagues for testing, who of course failed some basic morality rolls and immediately did something monstrous:

"...a small sample of St 155 was supplied to the medical department of C. H. Boehringer Sohn to be used to test its nasal decongestive properties in humans. Dr Wolf, a physician and a member of the trial group, allowed his secretary, Mrs Schwandt - at that time still Miss Nickel - to administer herself a few drops of a 0.3% solution into her nostrils since she had a cold. There was, however, some surprise and embarrassment when the lady fell asleep for 24 hours. She also developed a rather low blood pressure, a marked bradycardia and dryness of the mouth. The dose amounted, as determined later, to the equivalent of approximately 20 tablets of Catapres."

"Some surprise and embarrassment" from having to explain an unconscious woman in his office was followed by enthusiastic research activity, as "it became clear to Dr Wolf that the drug's decongestant properties were far less interesting than its potent anti-hypertensive activity". We do not know what became of Mrs Nickel, née Schwandt, not Dr Wolf who does not appear to have any publications from the same time period, suggesting that his input into the subsequent manuscripts was limited to a monograph in this obscure 1978 bibliography of pharmacological research. According to other authors on the subject, aside from drugging his secretary he also administered it to himself. The light comic relief achieved by this historical digression is mostly intended to shed light on the contrast between the modern day and the past, in terms of the range of what is considered acceptable workplace behaviour. 

Chemical structure and chemical relatives

Clonidine is an imidazoline derivative, which says nothing to the casual reader, unless their biochemistry background has them nodding knowingly with instant recognition of the term. Imidazolines are a class of five-member diazole aromatic rings (heterocycles which include two nitrogen atoms), and there are  numerous examples of them in medicine, including familiar drugs such as the decongestants oxymetazoline and xylometazoline,  antihypertensives moxonidine and rilmenidine, less known agents such as tolazoline  tizanidine and tolonidine, as well as a bunch of detergents.

Class-wise, at least in terms of receptor affinity, clonidine would have to be grouped alongside sympathomimetics, as technically it poses as noradrenaline and binds to α2 receptors. However, unlike the other "proper" sympathomimetic  α2 agonists (eg oxymetazoline and xylometasoline) clonidine acts on central α2 receptors, where it exerts an inhibitory effect on the persynaptic release of noradrenaline, and therefore produces a sympatholytic antihypertensive effect within the normal dose range. A couple of other similar centrally acting α2 agonists are listed here for comparison:

ame α-methyldopa Clonidine Moxonidine
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)

The group of α2 agonists is much larger, and recent papers (eg. Head & Mayorov, 2020) list numerous others (guanabenz, agmatine, medetomidine, lofexidine, guanfancine, etc etc) but none of these are so important that they should merit more than a mention, and moreover they are completely absent from the Australian ICU formularies and the CICM First Part syllabus, which suggests that these comparison tables are a waste of time. On the other hand, it feels like there is no harm in having a few different tools to achieve the same goal.

Pharmacokinetics

The pharmacokinetics of clonidine are the most boring aspect of this drug and are unlikely to become the centrepiece of a hard-hitting exam question.

Routes of administration

Clonidine is well absorbed orally, and has minimal first-pass metabolism. Bioavailability is 70-80% by that route, and repeated dosing seems to reduce this from 90% to 60% purely because of reduced gastric emptying and splanchnic perfusion. The only interesting finding with IV administration is the earlier onset of peripheral vasoconstrictor activity, which is due to its direct α-agonist effects on postjunctional α receptors. Apart from this conventional use, people have injected it intrathecally as an adjunct to morphine, used it in transdermal patches as a long-acting antihypertensive, and injected it into the articular capsules of knees as a means of taking advantage of some mysterious peripheral analgesic effects

Distribution

Clonidine is 30-40% protein-bound, mostly to albumin, and the VOD is 2.1 L/kg mostly because it is highly lipid solubl, and distributes effortlessly into the fatty tissues. 

Metabolism, clearance and half-life

Most of the clonidine you give will be eliminated in the urine. Some minority (perhaps 30%) will undergo heatic metabolism into a whole host of mostly inactive metabolites, the most interesting of which is probably 4-hydroxyclonidine. This one can also act as an α2 agonist but does not penetrate the blood brain barrier because it is less lipophilic than the parent compound. Generally, the distribution half life is said to be about 20 minutes, and the elimination half-life is about 5-7 hours, though some sources quote elimination half-lives of up to 23 hours, and much longer in renal failure.

Pharmacodynamics

It would be amiss to credit clonidine with nothing but the crude α2 effect. It also acts on the mysterious imidazoline receptors, which is probably how it produces its analgesic effect, not to mention all the other interesting effects it has in all the various off-label uses. In short:

  • Sympathetic receptor effects:   
  • Imidazoline receptor effects
    • I1 receptors are a lesser target, though other agents (eg. moxonidine) seem to exert their antihypertensive effects mostly by this mechanism
  • Anticholinergic effects
    • Taira (1998) and Buccafusco et al (1979) reported various anticholinergic effects, and users report the dry eyes and dry mouth one might expect from anticholinergic agents, but the receptors being affected remain uncharacterised.

The affinity of clonidine for α2 receptors is much higher than for α1, with the college answer to Question 7 from the second paper of 2023 specifically remarking that the affinity ratio was 200:1. This factoid seems to be widely repeated, but none of the repeaters seem to be quoting a specific study (and some seem to be cyclically quoting each other) which makes this value difficult to believe. 

Mechanism of action of clonidine

All three α2 receptor subtypes are Gi-protein coupled receptors which reduce concentration of intracellular cAMP by the deactivation of adenylyl cyclase.  The effect of activating these presynaptic receptors is the decrease in the release of noradrenaline from the synapse, which is a normal negative feedback mechanism designed to put the brakes on noradrenaline release.

  • The antihypertensive effect this thought to be an α-2A effect
  • α-2A receptors also probably mediate the intestinal and pancreatic clinical effects (decreased gut motility and insulin secretion)
  • The peripheral vasoconstrictor effect is thought to be due to the α1 and α2B effects
  • α-2C effects and imidazoline receptor effects are probably involved in the analgesic and sedating properties

Haemodynamic effects of clonidine

For the intensivist or anaesthetist, nothing is more eloquent than graphs of vital signs, and readers from these specialties will appreciate these images from Brod et al (1972), illustrating the effects of the injection iv  of 300 μg of Catapresan on healthy volunteers:

The reader will readily note the initial rise in blood pressure, driven by the peripheral alpha agonist effects, which is followed by hypotension. Bord et al noted that "in 2 patients blood pressure fell to disquietingly low levels", as the dose of 300 μg is a solid whack. On average MAP decreased by 20%, cardiac index by 23%, and the heart rate was transiently depressed. More interstingly there was no corresponding increase of heart rate when the MAP and CI decreased, suggesting that the baroreceptor reflexes were suppressed. Total peripheral resistance remained essentially unchanged, suggesting that the main reason for the drop in blood pressure was mostly a lower stroke volume and reduced contractility.

Central nervous system effects of clonidine

Hall et al (2001) gave eight healthy volunteers infusions of clonidine and found that all tested doses were sedating to some degree but only at around 4µg/kg/hr (i.e. something like 300 4µg/hr) did these people exhibit "significant decreases in psychomotor performance". The patients were asleep, but the sedation was "easily overcome by calling the patient’s name in a normal or loud voice". Even at these heroic doses the respiratory rate did not change. The EEG patterns resembled those of early nonREM sleep. In patients with head injury, clonidine decreases cerebral perfusion pressure in a way which seems completely logical (i.e. it reduces the MAP), and has no effect on the ICP. 

Other side effects of clonidine

Clonidine has nontrivial side effects which may make it undesirable in certain populations.

  • Dry mouth
  • Dry eyes
  • Slowed gastric emptying
  • Slowed peristalsis, constipation
  • Erectile dysfunction
  • Miosis

Of these, some (eg. the gut slowing effects) will be of greater importance than others, when it comes to the critically ill. 

Toxicology of clonidine

Huge doses of clonidine tend to override the central sympatholytic effect with a profound peripheral sympathomimetic effect. Frye & Vance (2000) report a case where a woman was accidentally injected with 12.24 mg of clonidine, resulting in a hypertensive crisis. From the case series by Ron et al (1981), it appears that doses in excess of 6mg (something like 40 of the 150μg tablets) are required for the peripheral vasoconstrictor effects to dominate.  Interestingly, the respiratory depression and decreased level of consciousness can be reversed with high dose naloxone, with Seger et al (2018) reporting good effects from doses of around 10mg. 

References

Houston, Mark C. "Clonidine hydrochloride: review of pharmacologic and clinical aspects." Progress in Cardiovascular Diseases 23.5 (1981): 337-350.

SCHMITT, H. "The Pharmacology of Clonidine and Related Products." Antihypertensive Agents 39 (2012): 299.

Amna, Sarwat, et al. "Review of clinical pharmacokinetics and pharmacodynamics of clonidine as an adjunct to opioids in palliative care." Basic & Clinical Pharmacology & Toxicology (2024).

Dollery, C. T., et al. "Clinical pharmacology and pharmacokinetics of clonidine." Clinical Pharmacology & Therapeutics 19.1 (1976): 11-17.

Sharma, Ashwani, and Lalit Gupta. "Clonidine a wonder drug." Inidian Journal of Anesthesia and Analgesia 6.6 (2019): 2057-62.

Tyagi, Rashmi. "Imidazoline and its derivatives: an overview." Journal of oleo science 56.5 (2007): 211-222.

Bousquet, Pascal, et al. "Imidazoline receptor system: the past, the present, and the future." Pharmacological reviews 72.1 (2020): 50-79.

Talke, Pekka O., et al. "Clonidine-induced vasoconstriction in awake volunteers." Anesthesia & Analgesia 93.2 (2001): 271-276.

Engelman, Edgard, and Corinne Marsala. "Efficacy of adding clonidine to intrathecal morphine in acute postoperative pain: meta-analysis.British Journal of Anaesthesia 110.1 (2013): 21-27.

Stähle, Helmut. "A historical perspective: development of clonidine." Best Practice & Research Clinical Anaesthesiology 14.2 (2000): 237-246.

Wolf, M., and H. Morr. "Imidazoline—new facets of a Cinderella molecule." Future trends in therapeutics 15 (1978): 179-189.

Brod, J., et al. "Acute effects of clonidine on central and peripheral haemodynamics and plasma renin activity." European Journal of Clinical Pharmacology 4 (1972): 107-114.

Hall, Judith Elizabeth, T. D. Uhrich, and T. J. Ebert. "Sedative, analgesic and cognitive effects of clonidine infusions in humans." British Journal of Anaesthesia 86.1 (2001): 5-11.

Bonhomme, Vincent, et al. "The effect of clonidine infusion on distribution of regional cerebral blood flow in volunteers.Anesthesia & Analgesia 106.3 (2008): 899-909.

Ter Minassian, Aram, et al. "Changes in cerebral hemodynamics after a single dose of clonidine in severely head-injured patients." Anesthesia & Analgesia 84.1 (1997): 127-132.

Gregoretti, C., et al. "Clonidine in perioperative medicine and intensive care unit: more than an anti-hypertensive drug." Current drug targets 10.8 (2009): 799-814.

TAIRA, CARLOS ALBERTO. "Anticholinergic action of clonidine in rats with sinoaortic denervation." Pharmacological research 37.4 (1998): 255-263.

Buccafusco, JERRY J., J. P. Finberg, and S. Spector. "Mechanism of the antihypertensive action of clonidine on the pressor response to physostigmine.Journal of Pharmacology and Experimental Therapeutics 212.1 (1980): 58-63.

Klein-Schwartz, Wendy. "Trends and toxic effects from pediatric clonidine exposures." Archives of pediatrics & adolescent medicine 156.4 (2002): 392-396.

Seger, Donna L. "Clonidine toxicity revisited." Journal of Toxicology: Clinical Toxicology 40.2 (2002): 145-155.

Frye, Carla B., and Michael A. Vance. "Hypertensive crisis and myocardial infarction following massive clonidine overdose.Annals of Pharmacotherapy 34.5 (2000): 611-615.

Seger, Donna L., and Justin K. Loden. "Naloxone reversal of clonidine toxicity: dose, dose, dose." Clinical Toxicology 56.10 (2018): 873-879.

Anderson, Ron J., et al. "Clonidine overdose: report of six cases and review of the literature." Annals of Emergency Medicine 10.2 (1981): 107-112.