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Clonidine a Wonder Drug

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DOI: 10.21088/ijaa.2349.8471.6619.30

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 Indian Journal of Anesthesia and Analgesia
Review Article 2019; 6(6) (Part - I): 2057-2062
DOI: http://dx.doi.org/10.21088/ijaa.2349.8471.6619.30

Clonidine a Wonder Drug

Ashwani Sharma1, Lalit Gupta2

1
Senior Resident, 2Associate Professor, Department of Anaesthesia and Critical Care, Maulana Azad Medical College and Lok Nayak
Hospital, Bahadur Shah Zafar Marg, New Delhi 110002, India.

Abstract

Background and Aims: The alpha-2-adrenergic agonist drugs are now widely used in anesthesiology for multiple
purposes and are not limited only to intraoperative and postoperative analgesia. Clonidine, an imidazoline
derivative belongs to this class and has selectivity ratio of 200:1 for alpha-2: alpha-1 receptors. Contents: Apart
from its antihypertensive and anti-adrenergic effects, recent studies have established clonidine as a wonder drug
to be an effective analgesic, sedative and has an opioid sparing effect with decreased anesthetic requirements
intraoperatively. Therefore, a detailed analysis and discussion for possible new role of clonidine in anesthetic
armamentarium seems to be need of the hour. This review highlights pharmacological aspects, mechanisms of
action, opioid sparing effect, potential indications and adverse effects. Conclusion: Although Clonidine reduces
post-operative pain intensity and nausea apart from some other uses like alcohol withdrawal, acute hypertension,
smoking cessation, cancer pain management and adjuvant to local anesthetics. However, one should be vigilant
while using it for high risk of perioperative low blood pressure and bradycardia.
Keywords: Clonidine; 2 adrenoceptor agonist, Antihypertensive.

How to cite this article:

Ashwani Sharma, Lalit Gupta. Clonidine a Wonder Drug. Indian J Anesth Analg. 2019;6(6 Part -I):2057-2062.

Introduction Imino] Imidazoline Mono hydrochloride. Clonidine

is a derivative of well-known sympathomimetic
Clonidine is an 2 adrenoceptor agonist. It carries drugs naphazoline and tolazoline. It was develoved
central sympatholytic action. Clonidine shows in early 60s. It was synthesized originally as a nasal
reduction in peri-operative hemodynamic vasoconstrictor. In its clinical trials it was found
instability and enhances the effect of anesthesia. to cause hypotension, bradycardia, and sedation.
Clonidine reduces sympathetic out ow by acting In 1966, in Europe it was rst introduced as an
on central nervous system. Clonidine hydrochloride antihypertensive and then later in United States of
is an imidazoline derivative. It was synthesized in America. It was the rst-known antihypertensive to
1960 and was used clinically as nasal decongestant act on central nervous system.
attributed to its 1 agonist mediated vasoconstrictor
action. Antihypertensive action of clonidine is
derived from its 2 agonist property. In 1966, it was
rst used in Europe in clinical context and later in
United States as antihypertensive and since, than
its prevailed worldwide.
Fig. 1: Clonidine is chemically C9H9Cl2N3. HCL

Contents
Mechanism of Action1,2
Pharmacology
Clonidine is selective -2 agonist. It has selectivity
Clonidine is chemically 2 [(2, 6 Dichlorophenyl) ratio of 200:1 for -2: -1 receptors. It acts on
Corresponding Author: Lalit Gupta, Associate Professor, Department of Anaesthesia and Critical Care, Maulana Azad Medical
College and Lok Nayak Hospital, Bahadur Shah Zafar Marg, New Delhi 110002, India.
E-mail: lalit.doc@gmail.com
Received on 01.08.2019, Accepted on 04.09.2019

© Red Flower Publication Pvt. Ltd.

2058 Indian Journal of Anesthesia and Analgesia

imidazoline receptors I1 and I2 with a higher Pharmacological Effects

selectivity for I1 receptors. Its action comes from
1. Cardiovascular System:3 The actions are
modulation of inhibition of noradrenaline release
classi ed as peripheral and central.
by acting on presynaptic imidazoline receptors.
Clonidine produces wide variety of its actions by Effects on heart: Clonidine inhibits
acting on these receptors, the receptor distribution norepinephrine release from the peripheral
on the target organs, clonidine selectivity to bind, prejunctional nerve endings and causes
and type of endogenous ligand activated. bradycardia. There are no postjunctional
-2 receptors in myocardium. Hence a
Pharmacokinetics direct effect on heart is unlikely. It causes
hypotension due to centrally mediated
Clonidine is almost completely absorbed from reduction in sympathetic out ow. Clonidine
gastrointestinal tract. Its absorption is very rapid. exerts vagomimetic effect on heart by
Its bioavailability is nearly 100 percent. Onset of stimulating nucleus tractussolitarius which
action starts within 30 to 60 minutes after oral intake. can be attenuated completely by highly
Peak plasma concentration reaches with 90 minutes. selective muscarinic M2 receptor antagonists.
The elimination half life is 6 to 24 with a mean of It can cause bradycardia and reduction
12 hours. Routes of administration are oral, parentral, in cardiac output without affecting the
intra-muscular, intra-venous, transdermal, cardiac contractility and peripheral vascular
nebulization, extradural, and intrathecal routes. resistance. It enhances the barore ex
Rectal administration is known in children also. sensitivity. In higher doses it depresses
It is well absorbed through skin because of its low the atrioventricular nodal conduction
molecular weight and high lipid solubility. After with slight prolongation of P-R interval.
transdermal clonidine patch implantation, stable It has antiarrhythmic action mediated via
plasma concentrations are reached after 2–3 days. imidazoline receptors and vagus.
The uctuation in plasma concentration is very less.
Clonidine is distributed throughout the body, the • Effects on Coronary Vessels:4 In vivo,
highest concentration being in organs of elimination clonidine causes coronary vasodilatation
i.e., kidney, gut and liver. The brain concentrations by releasing Endothelium Derived Relaxing
are low but higher than plasma concentrations. Factor (EDRF). It also enhances the
Clonidine is metabolized mainly by the liver to vasodilatation caused by endogenous and
produce Hydroxyclonidine which subsequently exogenous adenosine. The vasoconstrictive
undergoes glucuronidations to produce action on proximal coronary bed is due
O-glucuronide and is excreted in urine. 40 to 60% of to predominance of -2 adreno receptors
an orally administered dose is excreted unchanged causing direct vasoconstriction. This effect is
in urine within 24 hours. In presence of renal offset by the central reduction in sympathetic
insuf ciency, renal clearance is markedly reduced out ow.
and 95% of clonidine administered is excreted in • Effect on Hemodynamics;5 Clonidine
urine and faeces in 72 hours and complete clearance potently inhibits the ring rate of locus
occurs in 5 days. Clonidine given as an adjuvant in coerulus which mediates the normal
local anesthesia for epidural infusion accts by three response, and exerts its hypotensive action
different mechanism of action: by a net reduction in Central Sympathetic
1. 2 receptors in dorsal horn stimulation Out ow. The -2 agonists hyperpolarize
decreases the pain transmission; and depress the locus cerulus through
2. Local vasoconstriction caused by clonidine potassium channels and markedly
decreases absorption of local anesthetic agent; reduce the noradrenaline concentration.
The studies on receptor binding have
3. Clonidine stimulates production of neuraxial
stressed that imidazoline I1 receptors in
opioids and it produces additive effects
ventrolateral medulla are responsible for
along with fentanyl.
mediating the blood pressure reduction.
By its action on post junctional -2 and -1
Dosage adrenoreceptors in vascular smooth muscle
it causes vasoconstriction. This activation is
Clonidine has been used in a wide dose range for a result of in ux of extracellular calcium and
various studies. The clinically effective range is 2 to could be blocked by -2 antagonists or the
7 g/kg body weight. dihydropyridine calcium channel blocker,
IJAA / Volume 6 Number 6 (Part - I) / Nov - Dec 2019
 Ashwani Sharma, Lalit Gupta / Clonidine a Wonder Drug 2059

nifedepine. It causes vasodilatation by its diuretic Hormone (ADH) release, decrease in

release of Endothelium Derived Relaxation vasopressin level, blockade of action of ADH
Factor (EDRF). Bradycardia caused by on renal tubules, increase in glomerular
-2 adrenergic agonist clonidine has been ltration rate. Other possible mechanisms
attributed to either increased barore ex are release of atrial natriuretic peptide and
sensitivity,6 stimulation of nucleus tractus an -2 action on juxta glomerular apparatus.
solitarius causing vagomimetic effect, or 6. Neuroendocrine System: Clonidine inhibits
depression of AV conduction. the centrally mediated sympathicoadrenal
2. Central Nervous System: Clonidine causes dose out ow as seen by the decreased levels of
related sedation, EEG con rmed increase in catecholamines in circulation and decreased
stage I and stage II sleep with a decrease in level of their metabolites in urine. It enhances
rapid eye movement sleep. In small doses it the release of growth hormone by its action
causes anxiolysis7 almost comparable to that post-synaptically on the hypophyseal cells.
seen with benzodiazepines. It has biphasic It can inhibit steroidogenesis, by virtue of
effect, being anxiolytic in small doses with the imidazole ring in its molecule. It inhibits
-2 stimulation and anxiogenic in higher ACTH release from pituitary, thus preventing
concentrations through -1 action. This effect the rise in Cortisol level as a consequence
is lost with chronicity of administration. of surgical stimulation. Clonidine directly
It has a powerful analgesic action both at acting on beta cells of Islet of Langerhans
supraspinal and spinal levels. Its potency is inhibits insulin secretion. This does not cause
enhanced synergistically by opioids, acting signi cant hyperglycemia and is short lived.
through independent receptors.8 Clonidine, It is known to inhibit lipolysis in adipose
by its action on -2 rece=ptors reduces tissues. Clonidine reduces the plasma renin
the anesthetic requirements. It reduces activity, as a result of decreased sympathetic
the minimum alveolar concentration of activity or direct inhibition of renin release.
Halothane and Iso urane.9 This action is not It also suppresses aldosterone production.
limited to volatile anesthetics. It also causes There are no demonstrable effects on glucose
a reduction in the required dose of induction tolerance and potassium balance.
agents. Clonidine reduces the cerebral blood 7. Hematologic System: It produces platelet
ow, in subjects anesthetised with Halothane aggregation in vivo. This effect is clinically
or Iso urane and blunts the cerebrovascular not seen because the norepinephrine levels
response to hypoxia. It reduces intracranial required for the aggregation are not achieved
pressure and cerebral metabolic oxygen in vitro.
requirement. 8. Reproductive System: The -2
3. Respiratory System: Clonidine has minimal adrenoreceptorare found post-synaptically
respiratory depressant effect, much less in myometrium, which may mediate uterine
compared to that of opioids. In clinical dose relaxation. This effect of clonidine is largely
settings it is rarely encountered. It does unde ned.
not potentiate the respiratory depression 9. Effects on Lipids: Clonidine has been reported
caused by opioids,10 Nebulised clonidine
to reduce the atherogenic low-density
attenuates the bronchoconstriction produced lipoprotein without affecting the cardio
by histamine in asthmatics and also is
protective high-density lipoprotein. The net
used in patients with obstructive sleep
result is a decrease in LDL/HDL ratio thus
apnea syndrome. decreasing the cardiovascular risk.
4. Gastro Intestinal System: Clonidine has a
prominent antisialagogue effect with a direct
action. While activation of prejunctional Adverse Effects
-2 adrenoreceptors inhibit the vagally There are no known contraindications to clonidine
mediated release of gastric acid from parietal therapy other than known hypersensitivity. The
cells and also reduces gastric motility. most commonly seen adverse effects are dry
It does not alter the gastric pH signi cantly11. mouth, drowsiness, hypertension and bradycardia,
Clonidine reduces the secretion of water and if large doses are used. Withdrawal phenomenon
electrolytes from large bowel. is reported after chronic clonidine treatment
5. Renal System: Clonidine causes diuresis. The and sudden withdrawal. There is no evidence of
possible mechanisms are inhibition of Anti- sympathetic over activity after single dose therapy.
IJAA / Volume 6 Number 6 (Part - I) / Nov - Dec 2019
2060 Indian Journal of Anesthesia and Analgesia

It probably takes up to six days of continuous antagonists like prazosin, a potent -1 antagonist
therapy to produce adaptive changes. In single dose and yohimbine, a potent -2 antagonist.
peri-anesthetic therapy such rebound phenomena B. Physiology: The transmembrane signalling
are not seen. And the hypertensive rebound for the -2 adrenergic responses involve the
when occurs is effectively treated with Labetolol. combination of three separate components:
Sudden withdrawl of clonidine should be avoided
otherwise rebound hypertension and withdrawl 1. Receptor Protein: -2 adrenoreceptor is a
symptoms will occur. Dose titration should be done G-Protein membrane receptor consisting of
in renal impairment, severe coronary artery disease, 415–480 amino acids, which are arranged in
bradycardia, hypotensive patients. It should not be a fashion forming helical embedded in cell
given above C4 dermatome in epidural infusion. membrane. This transmembrane protein is
responsible for binding with ligands.
Alpha-2 Antagonists: Potent, selective and speci c
-2 antagonists such as Idazoxan and antipamezole 2. G Proteins: All sub-units have a single
have been developed. The -2: -1 selectivity ratio high af nity binding site for guanine
of antipamezole is 200 times higher than Idazoxan. nucleotide, have intrinsic GTPase activity
and are substrate for ADP ribosylation.
Common side effects 3. Effector Mechanism: There are at least
ve separate effector mechanisms that are
Hypotention; Nausea; Vomiting; Drowsiness;
modulated by activated -2 adrenoreceptors.
Headache; Fatigue; Dizziness; Abdominal pain;
Any one receptor may couple with more
Emotional instability; Sedation; Sexual dysfunction;
than one effector mechanisms.
Xerostomia; Constipation.
The effector mechanisms are:
Serious side effects (i) Inhibition of Adenylate Cyclase: Causing
Bradycardia; Syncope; Severe hypotension; a fall in cyclic AMP level. This results in
Severe allergic reaction; Angioedema; A-V block; cAMP dependent protein kinase activity
Depression; and decrease phosphorylation, which
alters biologic response.
Use in Parturients: It is not advised to use
epidural clonidine in parturients because of the (ii) Acceleration of Na+/H+ exchange:
risk of development of severe hypotension and Activation of -2 adrenoreceptor
bradycardia; accelerates Na+/H+ exchange which in
turn stimulates phospholipase A2 to initiate
Clonidine addiction: Clonidine has a potential the arachidonic acid breakdown pathway
to be used as a habit forming drug, and it can be leading to release of thromboxane A2.
used as a potential substance of abuse. It should be
monitored while prescribing this drug. (iii) Activation of potassium channels: The
G-protein mediated ef ux of potassium
Physiology 1,12,13 channels hyperpolarize the membrane and
thus suppress neuronal ring.
Receptor Classi cation:12
(iv) Inhibition of voltage sensitive calcium
channels: The -2 adrenoreceptors
Adrenoreceptors
mediated blockade of calcium++ channel
A. Classi cation: Ahlquist R P (1943) differentiated suppresses the calcium ++ entry into the
adrenergic receptors into and beta based nerve terminals and blocks the fusion
on responses of various amines in different of transmitter containing vesicles with
physiological preparations. The next advancement synaptic membrane.
was the nding that there are sub-classes of (v) Modulation of phosphatidyl inositol
receptors at pre-synaptic nerve endings which turnover: This turnover mediated by
regulate the release of neurotransmitter. This led phospholipase C, in certain circumstances
to sub-classi cation of adrenoreceptors based is modulated by -2 adreno receptor
on their synaptic locations into post-synaptic -1 activity.
and pre-synaptic 2. These were further con rmed
by the use of newly developed adrenoreceptor
Imidazoline Receptors
agonists and antagonists. This sub-classi cation
was pharmacologically supported using speci c The rst evidence for different sites of action of
IJAA / Volume 6 Number 6 (Part - I) / Nov - Dec 2019
 Ashwani Sharma, Lalit Gupta / Clonidine a Wonder Drug 2061

clonidine was proposed by Bousequet et al. Later • Use: Alcohol withdrawal, attention
it was found that Ventrolateral Medulla (VLM) in de cit hyperactive disorder, smoking
the cervical region was an important connecting cessation, menopausal ushing, restless
component of the baroreceptor re ex. The leg syndrome, Tourette syndrome, post-
Ventrolateral Medulla contains both imidazoline therapeutic neuralgia, dysmenorroea
and -2 receptor binding sites. Ernsberger and psychosis.
con rmed this observation and classi ed the 2. Tablet (fast release):
imidazoline receptors into Imidazoline receptor I1
and I2 based on pharmacological studies. • Dosages: 100 mcg, 200 mcg, 300 mcg;
Physiology: The functional receptor binding • Uses: Opioid withdrawal,
studies have shown that it was almost exclusively the pheochromocytoma, acute hypertension
I1 receptor and not -2 adrenoreceptor responsible and hypertension.
for mediating the blood pressure reduction. 3. Transdermal patch (extended release):
The application of idazoxan which is I2 receptor
• Dosages: 100 mcg/day, 200 mcg/day, 300
antagonist can blunt the effects of clonidine induced
mcg/day, patch should be changed every
at ventrolateral Medulla, while the 2 antagonists
7th day;
that do not have imidazolinemoities are devoid of
this property. The different imidazoline compounds • Uses: Opioid withdrawal, hypertension,
with -2 agonist activities have different selectivity menopausal ushing, smoking
for I1 and -2 adrenoreceptors. Clonidine has 3.8 times cessation, hypertension and cyclosporine
higher selectivity for I1 than -2 adrenoreceptors. nephrotoxicity.
This selectivity is the factor that mediates blood 4. Injectable
pressure reduction in the ventrolateral medulla,
• Dosages: 100 mcg/ml, 500 mcg/ml;
while -2 adrenoreceptors mediate expression of
drowsiness and dry mouth, typical side effects • Uses: Can be used for epidural infusion
of clonidine therapy, The chromaf n cells of the in case of cancer pain management and
adrenal medulla14 almost exclusively possess it can be used as an aduvent in local
imidazoline receptors. A protein molecule has been anesthesia;
isolated from these cells of adrenal medulla that
• Epidural dose is 30 mcg/hr as initial dose
shows speci c binding sites for imidazolines but not
and then titrated as per pain score and
for -2 adrenoreceptor ligands.
side effects.
The endogenous ligand for this -2
Dosages need to be titrated in cases of renal
adrenoreceptor has been discovered, isolated from
impairment and to be started with a low dose.
calf brain, called as Clonidine Displacing Substance
(CDS) in 1984. It has a molecular weight of 500,
and could displace clonidine, yohimbine from -2 Future prospects
adrenoreceptors. Clonidine Displacing Substance
is the naturally occurring agonist for imidazoline Clonidine has been approved by FDA for
receptors. A structural similarity to a certain extent
treatment of attention de cit hyperactive disease
exists between -2 and imidazoline receptors
children in 2010, Tics associated with Tourette
because guanidine possesses a high af nity for
syndrome, and severe pain related to cancer16 has
both these types of receptors. Therefore, an anti-
a treatment option with clonidine. Management
hypertensive effect mediated via I1 receptors in
of withdrawal symptoms associated with opioids,
distinction to an action at -2 receptor should result
benzodiazepines,alcohol and treatment of insomnia,
in hypotension with less centrally mediated side
effects.This understanding of receptor sub-types anxiety and post-traumatic stress disorder are some
helps to achieve the desired effect15 by activation of the off label uses of clonidine.
of speci c receptors and its complete reversal by Clonidine suppression test:17 Catecholamine levels
selective antagonists are measured before and after giving oral dose
of clonidine in pheochroma patients. In normal
Clonidine uses and dosages healthy people there should be decrease in the level
of catecholamines in circulation because of the
1. Tablet (extended release): effect of clonidine on sympathetic nervous sytem
• Dosages: 100 mcg; it decreases the level of epinephrine in circulation.
IJAA / Volume 6 Number 6 (Part - I) / Nov - Dec 2019
 2062 Indian Journal of Anesthesia and Analgesia

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