Effects of Clonidine on Cerebral Blood Flow and the Response to Arterial CO<sub>2</sub>

Kanawati, Isa S.; Yaksh, Tony L.; Anderson, Robert E.; Marsh, Roger R.

doi:10.1038/jcbfm.1986.60

Cited by 39 publications

(3 citation statements)

References 26 publications

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“…These moderate decreases in brain oxygenation may also result from drug-induced decreases in sympathetic activity due to alpha-2 agonism and subsequent tonic decreases in respiratory activity. Alternatively, the weak hypoxic effect of xylazine may be independent of respiratory depression, resulting from cerebral vasoconstriction due to the stimulation of alpha-2 adrenoceptors on cerebral vessels [42].…”

Section: Discussionmentioning

confidence: 99%

Xylazine effects on opioid-induced brain hypoxia

Choi

Irwin

Kiyatkin

2023

Preprint

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Xylazine has emerged in recent years as an adulterant in an increasing number of opioid-positive overdose deaths in the United States. Although its exact role in opioid-induced overdose deaths is largely unknown, xylazine is known to depress vital functions and cause hypotension, bradycardia, hypothermia, and respiratory depression. In this study, we examined the brain-specific hypothermic and hypoxic effects of xylazine and its mixtures with fentanyl and heroin in freely moving rats. In the temperature experiment, we found that intravenous xylazine at low, human-relevant doses (0.33, 1.0, 3.0 mg/kg) dose-dependently decreases locomotor activity and induces modest but prolonged brain and body hypothermia. In the electrochemical experiment, we found that xylazine at the same doses dose-dependently decreases nucleus accumbens oxygenation. In contrast to relatively weak and prolonged decreases induced by xylazine, intravenous fentanyl (0.02 mg/kg) and heroin (0.6 mg/kg) induce stronger biphasic brain oxygen responses, with the initial rapid and strong decrease, resulting from respiratory depression, followed by a slower, more prolonged increase reflecting a post-hypoxic compensatory phase, with fentanyl acting much quicker than heroin. The xylazine-fentanyl mixture eliminated the hyperoxic phase of oxygen response and prolonged brain hypoxia, suggesting xylazine-induced attenuation of the brain compensatory mechanisms to counteract brain hypoxia. The xylazine-heroin mixture strongly potentiated the initial oxygen decrease, and the pattern lacked the hyperoxic portion of the biphasic oxygen response, suggesting more robust and prolonged brain hypoxia. These findings suggest that xylazine exacerbates the life-threatening effects of opioids, proposing worsened brain hypoxia as the mechanism contributing to xylazine-positive opioid-overdose deaths.

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Section: Discussionmentioning

confidence: 99%

Xylazine effects on opioid-induced brain hypoxia

Choi

Irwin

Kiyatkin

2023

Preprint

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“…Alpha 2 -agonists induce a reliable dose dependent sedation, analgesia and muscle relaxation, and are widely used in veterinary medicine. The α 2 -receptors are located both in neuronal and also in non-neuronal tissues, including in the vascular endothelium and platelets throughout the body; norepinephrine (NE) is the most important endogenous ligand for these receptors (Kanawati et al, 1986;Tsukahara et al, 1986).…”

Section: Influence Of α 2 -Agonistsmentioning

confidence: 99%

Brain perfusion part 2: anesthesia and brain perfusion in small animals

Waelbers¹,

Peremans²,

Gielen³

et al. 2010

Vlaams Diergeneeskundig Tijdschrift

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Sedatives and anesthetics can influence cerebral metabolism and respiratory and cardiovascular dynamics, which results in changes in cerebral perfusion. This is of major importance when functional brain imaging techniques are used to measure cerebral blood flow or to evaluate neurotransmitter systems, and also during neurosurgery. In the present review, the influences on brain perfusion of different sedatives including opioids and anesthetics commonly used in veterinary medicine are summarized. SAMENVATTINGSedativa en anesthetica kunnen de ventilatie, het cardiovasculaire systeem en het metabolisme van de hersenen beïnvloeden. Dit kan resulteren in veranderingen in de hersendoorbloeding, hetgeen van belang kan zijn wanneer functionele beeldvormingstechnieken gebruikt worden om de hersenperfusie te meten, om neurotransmittersystemen te beoordelen of ook tijdens neurochirurgie. In dit tweede deel over hersenperfusie wordt de invloed van diergeneeskundig regelmatig gebruikte sedativa, opiaten en anesthetica op de hersenperfusie besproken.

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“…Neben einem anästhetikaeinsparenden Effekt wird der zerebrale Blutflui3 sowohl nach Clonidin als auch nach Dexmedetomidin signifikant gesenkt (58,113). Dies wird wahrscheinlich durch eine az-adrenozeptorvermittelte Zunahme des zerebrovaskulären Widerstandes hervorgerufen.…”

Section: Experimentelle Befundeunclassified

Alpha₂-Agonisten in Anästhesie und Intensivmedizin

Bischoff

Kochs²

1993

Anästhesiol Intensivmed Notfallmed Schmerzther

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The neurotransmitters adrenaline and noradrenaline are non-selective adrenergic agonists which interact with both subtypes of alpha- and beta-receptors. Clonidine, an alpha 2-adrenergic drug with a selectivity ratio of 200/1 for alpha 2/alpha 1 has been used in clinical practice for more than 20 years. Although alpha 2-agonists have vasoconstrictor properties, sympatholytic effects on the central nervous system predominate. As a result, the sympathetic outflow from the medullary pressor centres is decreased mediating the hypotensive effects of the alpha 2-agonists. These compounds also exhibit sedative, anxiolytic, analgesic, and haemodynamic stabilising properties. The identification of alpha 2-adrenoceptors has yielded information on their biochemical properties, signal transduction, modulation of the sympathetic nervous system and neurotransmission. The classification of alpha 2-receptors based on anatomical locations and identified as presynaptic alpha 2-receptors and postsynaptic alpha 1-receptors proved to be untenable after postsynaptic and extrasynaptic alpha 2-receptor locations had been identified. At least 3 isoreceptors which are heterologously distributed in the brain have been identified. Guanine nucleotide proteins (G proteins) couple the receptor to an effector mechanism (i.e. intracellular messenger cascade, ion channel). More selective for the alpha 2-adrenoceptor than clonidine is dexmedetomidine (1600/1 of alpha 2/alpha 1), a very potent agonist at the alpha 2-adrenoceptor. Imidazole derivatives (like clonidine and dexmedetomidine) also bind to other nonadrenergic receptors ("imidazoline receptors") which may produce some effects (i.e. vagotonia) previously ascribed to alpha 2-adrenoceptors. alpha 2-receptors exist in brain tissue and several peripheral organs and tissues including the liver, eye, kidney, pancreas and platelets. Anaesthetic interest has focussed on reductions in anaesthetic requirements since experimental and clinical studies have shown that alpha 2-agonists expert powerful analgesic and anaesthetic effects. The hypnotic response is probably mediated by activation of alpha 2-adrenoceptors in the locus coeruleus. Analgesia is induced by modulation of the nociceptive pathway at the level of the dorsal root neuron and other sites not yet unambiguously characterised. Dexmedetomidine reduces the anaesthetic requirements for halothane by more than 90%. Cerebral blood flow and intraocular pressure are reduced by alpha 2-agonists. Epidural, intrathecal, intravenous and transdermal application of clonidine resulted in pain reduction, during and following surgery and in patients with neurogenic or otherwise intractable cancer pain. Administration of alpha 2-agonists induces only minor respiratory effects. Salivary flow is reduced by alpha 2-agonists and gastric and small-bowel motility is decreased.(ABSTRACT TRUNCATED AT 400 WORDS)

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Effects of Clonidine on Cerebral Blood Flow and the Response to Arterial CO₂

Cited by 39 publications

References 26 publications

Xylazine effects on opioid-induced brain hypoxia

Xylazine effects on opioid-induced brain hypoxia

Brain perfusion part 2: anesthesia and brain perfusion in small animals

Alpha₂-Agonisten in Anästhesie und Intensivmedizin

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Effects of Clonidine on Cerebral Blood Flow and the Response to Arterial CO2

Cited by 39 publications

References 26 publications

Xylazine effects on opioid-induced brain hypoxia

Xylazine effects on opioid-induced brain hypoxia

Brain perfusion part 2: anesthesia and brain perfusion in small animals

Alpha2-Agonisten in Anästhesie und Intensivmedizin

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Product

Resources

About

Effects of Clonidine on Cerebral Blood Flow and the Response to Arterial CO₂

Alpha₂-Agonisten in Anästhesie und Intensivmedizin