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09-15-14 How does naloxone work to reverse the effects of ACE inhibitor toxicity?

HI-dose Naloxone (10mg) has reversed the clinical effects of non-opiate drugs such as clonidine and ACEI.  There are many theories as to why this reversal occurs.  Naloxone impacts both opiate and non-opiate receptors.  The following explains naloxone reversal of somnolence/hypotension due to its effects on  the opiate receptors.  Naloxone also has effects on other receptors (such as imidazoline) that also play a part.   There are both responders and non-responders to hi-dose naloxone, but that is a question for another day.

 

HI dose naloxone (10mg) is usually required for the reversal (one of the reasons subsequently explained).  This amount is required for both children and adults.   There is no life-threatening effects from administering naloxone to either children or adults (with the exception of heroin overdose) / ds

Question of the Week

September 15, 2014

How does naloxone work to reverse the effects of ACE inhibitor toxicity?

Angiotensin-converting enzyme (ACE) inhibitors are a class of medication used primarily for the treatment of hypertension, congestive heart failure, and diabetic nephropathy. Their principal effect within the renin-angiotensin-aldosterone system (RAAS) involves the prevention of angiotensin II formation and inhibition of bradykinin degradation into inactive peptides.

The RAAS is primarily activated by decreased renal perfusion (most often due to hypotension or loss of blood volume) and activation of renal β1-adrenergic receptors, though other mechanisms do exist. Once activated, the enzyme renin is secreted directly into circulation which initiates a metabolic cascade that ultimately results in the production of angiotensin II and activation of angiotensin receptors.

Angiotensin II is a potent vasoconstrictor that also stimulates the secretion of aldosterone from the adrenal cortex and anti-diuretic hormone (ADH/vasopressin) from the pituitary gland. Aldosterone acts upon the renal tubules to increase retention of sodium and water at the expense of urinary potassium excretion. The net result of RAAS activation is an increase in blood pressure and fluid retention.

Administration of an ACE inhibitor will block the conversion of angiotensin I to angiotensin II and thereby increase venous capacity, decrease cardiac output, and promote urinary sodium and water excretion at the expense of potassium retention. The stimulant effect of angiotensin II on aldosterone synthesis is enhanced under conditions of hyponatremia and hyperkalemia (e.g. patients with heart failure and salt-depletion). These patients are reliant upon the RAAS to maintain hemodynamic stability and are rendered hyper-responsive to ACE inhibitor-induced hypotension.

In relation to its hemodynamic effects, ACE also degrades the potent endothelium-dependent vasodilator bradykinin to inactive peptides. Inhibition of ACE leads to increased levels of bradykinin and contributes to the decrease in blood pressure. Bradykinin also induces contraction of non-vascular smooth muscle in the bronchus (bronchoconstriction) which may cause a dry cough, a common adverse reaction seen with ACE inhibitor therapy. Furthermore, bradykinin increases vascular permeability and overstimulation of bradykinin receptors is thought to play a role in ACE inhibitor-induced angioedema.

Interactions between the RAAS, ACE Inhibitors, and Endogenous Opioids

Endogenous opioids are a group of biologically active peptides that bind to opioid receptors and are produced primarily by the central nervous system (CNS) and pituitary gland. These peptides act as neurotransmitters and neuromodulators in a complex system that plays an important role in motivation, emotion, responses to stress and pain, attachment behavior, and control of appetite.

Several distinct families of endogenous opioids have been identified, with the most well-characterized being the endorphins, enkephalins, and dynorphins. Each family of opioid peptide is derived from a large precursor protein that is subject to multiple enzymatic cleavages and modifications. The result is the synthesis of multiple peptides with variable receptor binding affinities and potencies.

Table 1-1 Actions and Relative Potencies of Selected Opioids

Substrate

Opioid Receptor Subtype

 

Mu (μ)

Delta (δ)

Kappa (κ)

Met-enkephalin

++

+++

 

Leu-enkephalin

++

+++

 

β-Endorphin

+++

+++

 

Dynorphin A

++

 

+++

Dynorphin B

+

+

+++

α-Neoendorphin

+

+

+++

Endomorphin-1

+++

 

 

Naloxone

---

-

--

Naltrexone

---

-

---

*The number of symbols is an indication of potency; the ratio for a given opioid denotes selectivity.

Key: + agonist, – antagonist

The angiotensin-converting enzyme (also known as peptidyl-dipeptidase A, dipeptidyl-carboxypeptidase, and kininase II among other designations) has been shown to participate in the breakdown of multiple endogenous opioid peptides. Clinical studies have documented increased levels of endogenous opioids, particularly the enkephalins and β-endorphin, in patients on ACE inhibitor therapy. Potentiation of opioid activity in the presence of ACE inhibitors is mainly attributed to a decrease in their metabolism.

Despite the ability of ACE inhibitors to lower blood pressure through vasodilation, they do not provoke the expected compensatory tachycardia. This decrease in baroreceptor sensitivity is mediated by the activation of mu- and delta-opioid receptors (MOR & DOR) in the nucleus tractus solitarii (NTS) of the medulla which inhibits the tonic discharge of sympathetic nerves and excites the vagal innervation of the heart. Therefore, tachycardia is not an expected feature of ACE inhibitor toxicity.

Table 1-2 Selected Pharmacology of Opioid Receptors

Receptor

Subtypes

Function

delta (δ)

DOR

δ

  • Analgesia
  • Cardiovascular Regulation
  • Dopamine Release Modulation
  • GI Dysmotility
  • Modulation of μ-opioid Receptor

kappa (κ)

KOR

κ1, κ2, κ3

  • Analgesia
  • Delirium/Hallucinations
  • Diuresis
  • Dysphoria
  • GI Dysmotility
  • Miosis
  • Physical Dependence
  • Respiratory Depression
  • Sedation

mu (μ)

MOR

μ1, μ2

  • Analgesia
  • Cardiovascular Regulation
  • Euphoria
  • GI Dysmotility
  • Miosis
  • Physical Dependence
  • Respiratory Depression
  • Sedation
  • Thermoregulation

 

 

There have been a number of case reports that suggest the development of hallucinations in response to ACE inhibitor therapy in patients with conditions that elevate endogenous opioids (e.g. bone fracture and acute heart failure). Hallucinations persisted despite a reduction in ACE inhibitor dose but resolved when either naloxone was administered or within 24 hours of ACE inhibitor discontinuation. This effect is likely mediated by an endogenous opioid with activity at the kappa-opioid receptor (KOR).

Furthermore, preclinical and clinical studies have shown that administration of naloxone reversed the effect of ACE inhibitors on blood pressure. This suggests that the decreased metabolism and accumulation of endogenous opioids due to ACE inhibition may contribute to its primary mechanism.

How much Naloxone is enough?

ACE inhibitors’ opioid-related effects are mediated primarily by DOR and MOR-activation through the decreased metabolism of the enkephalins and β-endorphin. The enkephalins are highly potent and selective at DOR with moderate activity at MOR while β-endorphin is selective for both. The relative potency of β-endorphin at MOR is approximately 80 times that of morphine (comparable to fentanyl).

In comparison, naloxone competes at all opioid-receptor subtypes but is highly selective for MOR with moderate activity at KOR and very minimal activity at DOR. To overcome receptor selectivity and the relative potencies of the endogenous opioids, a high-dose (10mg) of naloxone will likely be needed.

This question prepared by: Justin Loden, PharmD, CSPI (Certified Specialist in Poison Information) Tennessee Poison Center