Opioids And The Cardiovascular System

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Contrarily to many other anesthetics, opioids in general do not depress the cardiovascular system. This is also reflected in the higher therapeutic range (LD50/ED50) being derived in the animal (Table II-11). Such data can also be conveyed to the human, since a wide therapeutic margin of safety is directly correlated with a lack in cardiovascular impairment.

While carfentanil, with a potency twice that of sufentanil, is solely used in veterinary medicine for the immobilization of wild animals [153], lofentanil (20fold potency of fentanyl), due to its intensive receptor binding, is characterized by a duration of action of 24 h [154]. Both fentanyl derivates are not in clinical

Figure 11-61. Different postoperative gastrointestinal transit times (min) in patients after a fentanyl-, a ketamine-, and an isoflurane-based anesthesia regimen respectively. Note the significant longer delay of gastrointestinal transit in the fentanyl-based technique. Adapted from [151]
Table 11-11. Margin of safety of different opioid ligands in comparison to barbiturates and the hypnotic etomidate

Pharmacological agent

Therapeutic margin of safety LD50/ED50

Tramadol

3

Pentazocine

4

Thiopental

8

Pethidine

6

Methohexital

11

Ketamine

11

Methadone

12

Meptazinol

18

Etomidate

32

Butorphanol

45

Morphine

71

Dextromoramide

105

Lofentanil

112

Fentanyl

277

Nalbuphine

1034

Alfentanil

1080

Buprenorphine

7933

Carfentanil

10.000

Sufentanil

26.716

Remifentanil

33.000

use, because the high potency and the intense receptor binding would be difficult to handle in patients. From the table, however, it is obvious that the higher the selectivity to the receptor site, and the higher the potency, the lesser the amount of cardiovascular depression [33, 35, 103, 155, 156, 157].

Following the injection of potent opioids, bradycardia is the most prominent cardiovascular effect seen in patients. This is due to a direct central stimulation of the nucleus nervi vagi and a typical effect of ^-ligands. Thereafter, a reduction of the sympathetic drive is initiated resulting in an overexpression of parasympathetic activity. Also, a direct peripheral negative inotropic activity with a potentiation of acetylcholine release at the sinus node of the heart is discussed [158]. The increase in vagal tone and the reduction of sympathetic drive on the peripheral vasculature results in a decline of mean arterial pressure. A reduction of sympathetic tone on vessel tone and a reduction of resistance is also termed as "pooling" of circulating blood volume. Such a reduction of peripheral resistance in certain cases may be of benefit for the patient, as it is accompanied by a reduction in afterload of the heart [159, 160]. Bradycardia, the reduced peripheral resistance (i.e. afterload of heart) as well as the pooling effect with a reduction of preload of the heart, can be of benefit for a patient with myocardial infarction. This is because those three variables are major determinants in myocardial oxygen consumption (MVO2) [160, 161]. It, however, should be noted that the sympatholytic action with pooling of blood volume induced by potent opioids might demask a previously compensated hypovolemic condition in a patient resulting in significant hypotension. For instance, in patients with multiple trauma a reduced dose of the opioid should be given, either diluted or slowly injected while measuring blood pressure continuously. In general, however, especially in polytraumatized patients, opioids are of benefit, as they reduce the stress-related release of hormones and particularly of angiotensin II, maintaining the effect of circulating catecholamines on the vasculature.

Opioid-related bradycardia with an accompanying hypotension can rapidly be reversed with increasing doses of the vagolytic agent atropine (0.25-05-1.0 mg/kg body weight). The incidence and the severity of such a drop in blood pressure cannot be foreseen. It is related to the autonomic basal tone of the patient and the dose of the injected potent ^-ligand (Figure II-62).

Depending on the product, the autonomic basal tone of, and the applied dosages to the patient, either parasympathetic (inhibitory) and/or a sympathetic (excitatory) symptoms are induced (Table II-12). Such clinical effects can be diminished by atropine, an a-blocker (e.g. phenoxybenzamine), a 6-blocker (e.g. propranolol), and a ganglionic blocker (e.g. hexamethonium) respectively [103].

The stimulatory effects of opioids can also be explained in the laboratory where stimulation of cyclic AMP formation, phosphinoside hydrolysis, and the elevation of intracellular calcium, resulting from mobilization of calcium stores and by stimulating influx, which leads to an increased neurotransmitter release and neurotransmission [163]. Thus, at the cellular level these changes may underlie the opioid stimulatory effect. In addition, such stimulation is also discussed as playing a part in the development of tolerance to opioid drugs [164].

Phase [

Phase II

Phase Nt

Oil el of si

V é"

¿y f i

100 200

300 i.00 500

Doses which

Doses which

Doses which

Dose-s which

induce vagal

result in

result in

result in

act ivity

equilibrium of

dominance of

pronounced

veg etative

sympathetic

a d ranergic

tone

activity

effects

Figure 11-62. The effect of increasing doses (mg/kg body weight) of potent opioids on the cardiovascular system of the canine, where low amounts result in parasympathetic activation, and high to massive doses induce an increase of sympathetic drive. Adapted from [103]

In opioid-based anesthesia, vagal- or sympathetic-induced side effects can be reduced or eliminated by the following techniques:

1. The preliminary administration of atropine (up to 1 mg/kg body weight).

2. The simultaneous administration of a volatile anesthetic (N2O, enflurane, desflurane, sevoflurane).

3. The simultaneous use of a neuroleptic agent (e.g. droperidol, haloperidol).

4. The simultaneous use of a benzodiazepine (e.g. diazepam, midazolam, lorazepam).

5. The simultaneous use of a hypnotic (e.g. barbiturate, etomidate, propofol).

Table 11-12. The main inhibitory (parasympathetic) and excitatory (sympathetic) effects induced by different doses of opioids

Dominant sympathetic drive

Dominant parasympathetic drive

Hypertonia

Bradycardia

Tachycardia

Hypotonia

Hyperglycemia

Emesis

Hyperlactemia

Sweating

Acrocyanosis

Salivation

Scleral injection

Bronchospasm

Reddening of the face

Sphincter spasm

Antidiuresis

Miosis

Adapted from [103, 162]

Adapted from [103, 162]

All these agents induce a depression of CNS activity in different areas of the central nervous system, which results in equilibrium of the autonomic nervous system discharge, thus, reducing the overshoot of sympathetic and/or parasympathetic tone (Figure II-63).

Mixed agonist/antagonists, when given in dosages above the therapeutic range, induce a cardiostimulatory sympathomimetic effect, which purportedly is induced via stimulation of a-receptor sites [165]. As a result, tachycardia, an increase in peripheral vascular resistance, and an increase in pulmonary artery pressure are induced (Table II-13), all of which increase myocardial oxygen consumption (MVO2). Therefore agonist/antagonists should not be given above their therapeutic range in patients with MI or with a preexistent cardiovascular disease [166].

A malfunction at the atrio-ventricular node in the myocardium, followed by prolongation of the P-Q interval is a phenomenon, which can be induced in patients demonstrating a preexisting abnormal conduction system in the heart. Such prolongation manifests itself especially when potent opioids are being administered (fentanyl, sufentanil), whereby the opioid-induced acetylcholine release induces a stimulation of vagal activity. Thus, patients already having a prolongation of P-Q time or who present a sick-sinus syndrome, extreme bradycardia has to be anticipated, which could result in concomitant cardiac arrest. In order to prevent such a scenario, the opioid should not be given as a bolus, but rather as a diluted solution. In addition, the solution should be injected slowly over a long period of time

Figure 11-63. Site of action of different pharmacological agents in the CNS to potentiate opioid action. Neuroleptics block afferents from entering the ascending reticular formation, which increase vigilance; tranquillizers protect the hippocampus from an excitatory activation, while barbiturates, hypnotics and volatile anesthetics primarily block the cerebral cortex from arousal

y Neuroleptics

- Tranquilizer

- MAO inhibitors y Neuroleptics

- Tranquilizer

- MAO inhibitors

Table 11-13. Different cardiovascular effects of ^-ligands, mixed agonist/antagonists, and partial agonists resulting in a decrease (ft) or an increase (-ft-)

Opioid

Blood pressure

Heart rate

Pulmonary artery pressure

Morphine

4 to 0

ft to 0

Buprenorphine

4 to 0

0

Butorphanol

ft to 0

0

-

Pentazocine

ft

ft

-

Meptazinol

(ft)

(ft)

-

Nalbuphine

0

4 to 0

0

Fentanyl

4

4

0

Sufentanil

4

4

0

Adapted from [166, 167, 168]

Adapted from [166, 167, 168]

of at least 2 min. If, however, extreme bradycardia is recognized on the monitor, atropine is the agent of choice (0.5-1.0 mg/kg body weight) for rapid reversal. In very extreme cases, the antiarrythmic agent metaproterenol may become necessary, as it is able to increase atrio-ventricular conduction.

High doses of methadone or its derivative a-levoacetylmethadol (LAAM) may result in life threatening torsades de points with the potential of ensuing ventricular fibrillation. Predisposing factors for the development of such a situation are a prolongation of atrio-ventricular conduction time, hypopotassemia, and/or the simultaneous intake of agents, which inhibit metabolism of the opioid (e.g. tricyclic antidepressants, imidazol derivatives, antimalaria agents, or antihistaminics).

A direct negative inotropic effect on the myocardium has been demonstrated in the isolated papillary muscle and in the Langendorff preparation of the heart for a variety of opioids [169, 170]. Such direct effects, however, are not of clinical significance, because such a depression is only evident in concentrations above the therapeutic range. In addition, compensatory cardiovascular and the autonomic regulatory mechanisms come into play when an opioid is given to a subject.

Following the intravenous injection of pethidine (meperidine, USP), hypotonia and syncope may result. Because of the atropine-like molecular structure of this agent, tachycardia, as well as reflex bradycardia can be observed [171]. For the reason of these potential side effects pethidine should not be given to patients with myocardial infarction [109].

In addition, it is observed that in a shock-like situation, due to the release of endogenous opioids (enkephalins, endorphins), the additional administration of an exogenous opioid results in an additional occupation of opioid binding sites within the myocardium. This aspect is followed by a negative inotropic effect with an unfavorable consequence on hemodynamics [172].

Some experimental work has postulated a putative direct negative inotropic effect of N2O in an opioid-based anesthetic regimen [173]. Since this is mainly seen when N2O is given in concentrations above 50% with a resultant drop in FIO2, this very

0.5 1 2 5 10 20 50100 I 500 12000 ngkg

200 1000

1000

Figure 11-64. Antiarrythmic effect of fentanyl and morphine in comparison to the B-blocker pindolol. Both agents dose-dependently reduce adrenaline-induced ventricular extrasystoles. Adapted from [180] PVC-premature ventricular countraction

Control Adrenalin inim U-n-1

0.5 1 2 5 10 20 50100 I 500 12000 ngkg

200 1000

1000

Figure 11-64. Antiarrythmic effect of fentanyl and morphine in comparison to the B-blocker pindolol. Both agents dose-dependently reduce adrenaline-induced ventricular extrasystoles. Adapted from [180] PVC-premature ventricular countraction likely is due to an insufficient myocardial oxygen supply. In addition, high concentrations of N2O have a direct vasodilatory effect, resulting in a reduction of venous return to the heart and a drop in blood pressure [174]. It therefore is advocated that in patients receiving opioid anesthesia with a preexisting cardiovascular disease, the optimal concentration in FIO2 should be around 0.5.

Opioids also have been demonstrated to induce an anti-arrhythmic effect. This has been shown in the animal for meptazinol [175] and in experimental coronary artery occlusion, using fentanyl, sufentanil and carfentanil respectively [176, 177, 178] (Figure II-64). The reason for such an antifibrillatory effect seems to be due to the increase in vagal tone [179].

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