Comparison of nicardipine, diltiazem and verapamil for controlling the cardiovascular responses to tracheal intubation

We have compared the efficacy of three calcium channel blockers, nicardipine, diltiazem and verapamil, in attenuating the cardiovascular responses to laryngoscopy and intubation in 60 normotensive patients (ASA I) undergoing rapid sequence induction of anaesthesia with thiopentone and fentanyl. We also examined whether or not these blockers inhibited catecholamine release induced by intubation. The patients were allocated to one of four groups (n = 15 for each): saline (control), nicardipine 30 micrograms kg-1, diltiazem 0.2 mg kg-1 or verapamil 0.1 mg kg-1. Verapamil and the three other drugs were administered 45 s and 60 s before the start of direct laryngoscopy, respectively, in a double-dummy design. Anaesthesia was induced with thiopentone 4 mg kg-1 i.v. and fentanyl 2 micrograms kg-1 i.v. Tracheal intubation was facilitated with vecuronium 0.2 mg kg-1. During anaesthesia, ventilation was assisted or controlled with 1% isoflurane and 50% nitrous oxide in oxygen. Laryngoscopy lasting 30 s was attempted 2 min after administration of thiopentone and vecuronium. Patients receiving saline exhibited significant increases in systolic and diastolic arterial pressures (AP), heart rate (HR) and plasma concentrations of catecholamines associated with tracheal intubation. The increase in AP was attenuated in patients treated with any calcium channel blocker. The greatest effect was elicited by verapamil, which attenuated the increase in HR, although nicardipine seemed to enhance tachycardia. All three drugs failed to suppress the increase in plasma catecholamine concentrations in response to tracheal intubation. These findings suggest that bolus injection of verapamil 0.1 mg kg-1 was a more effective method of controlling hypertension and tachycardia associated with intubation than diltiazem 0.2 mg kg-1 or nicardipine 30 micrograms kg-1, and that these prophylactic effects were not caused by inhibition of the catecholamine response.      

Combined negative inotropic effects of calcium entry blockers and isoflurane on canine isolated heart muscles

The combined negative inotropic effects of isoflurane and calcium entry blockers (verapamil, diltiazem, nifedipine, nicardipine) were studied utilizing isolated heart preparations of ventricular muscles from dogs. All of these calcium entry blockers exerted dose-dependent decreases in maximal velocity of shortening (Vmax), maximal developed isometric force (Fm), and the maximal first derivative of Fm (maximal dF/dt). Dose-dependent decreases of these variables of muscle mechanics were augmented in isoflurane-depressed myocardium. At equimolar concentrations, direct myocardial depression was demonstrated in the following order of severity: nifedipine > diltiazem = verapamil > nicardipine. Percent depressions of Vmax, Fm and maximal dF/dt were significantly greater in muscles when calcium entry blockers were combined with 1MAC isoflurane than in muscles of calcium entry blockers alone. These data suggest that the negative inotropic effects of verapamil, diltiazem, nifedipine, and nicardipine were potentiated by isoflurane.(Nakata F, Kemmotsu O: Combined negative inotropic effects of calcium entry blockers and isoflurane on canine isolated heart muscles. J Anesth 5: 48–55, 1991)     

Cardiovascular interactions of lidocaine with verapamil or diltiazem in the dog

Lidocaine in low and high doses was given by sequential infusions to isoflurane-anesthetized dogs (1.75 +/- 0.03% end-tidal concentration) with or without concurrent infusions of diltiazem or verapamil, to assess changes in cardiovascular function. When lidocaine was administered alone, the low plasma levels (approximately 2 micrograms/ml) caused only a modest reduction in left ventricular dP/dt. The higher plasma lidocaine levels (approximately 6 micrograms/ml) reduced both left ventricular dP/dt and cardiac index, and increased pulmonary capillary wedge pressure and systemic vascular resistance. Diltiazem or verapamil, when administered alone at plasma concentrations of approximately 150-200 ng/ml, prolonged atrioventricular conduction, decreased heart rate and cardiac index, and, in the case of verapamil, also decreased left ventricular dP/dt and mean arterial pressure. When lidocaine was added to diltiazem or verapamil, the low plasma levels of lidocaine depressed cardiac function in the presence of either calcium channel blocking drug. In the presence of these levels of verapamil or diltiazem, only one of six verapamil-treated animals and three of six diltiazem-treated animals were able to maintain a mean arterial pressure greater than 50 mmHg with the higher dose of lidocaine. Caution may be advised if the addition of lidocaine, by whatever route, is indicated in subjects who have recently received intravenous verapamil or diltiazem.     

Influence of Voltage-sensitive Ca++ Channel Drugs on Bupivacaine Infiltration Anesthesia in Mice

Background : Local anesthesia has been traditionally associated with blockade of voltage-sensitive sodium (Na+) channels. Yet in vitro evidence indicates that local anesthetic mechanisms are more complex than previously understood. For example, local anesthetics bind and allosterically modify 1,4-dihydropyridine-sensitive Ca++ channels and can reduce Ca++ influx in tissues. The current study examines the influence of voltage-sensitive Ca++ channels in bupivacaine infiltration anesthesia.

Methods : Baseline tail-flick latencies to radiant heat nociception were obtained before subcutaneous infiltration of bupivacaine and Ca++-modulating drugs in the tails of mice. No musculature is contained in the tail that could result in motor block. The magnitude of infiltration anesthesia over time, as well as the potency of bupivacaine alone or in the presence of Ca++-modulating drug, was assessed by obtaining test latencies.

Results : The 1,4-dihydropyridine L-type Ca++ channel agonist S (-)-BayK-8644 reduced the duration of action and potency of bupivacaine anesthesia. In opposite fashion, nifedipine and nicardipine increased the effects of bupivacaine. Neither nifedipine nor nicardipine alone elicited anesthesia. Alternatively, the phenylalkylamine L-type blocker verapamil elicited concentration-dependent anesthesia. Other Ca++ channel subtype blockers were investigated as well. The N-, T-, P-, and Q-type channel blockers, [omega]-conotoxin GVIA, flunarizine, [omega]-agatoxin IVA, and [omega]-conotoxin MVIIC, respectively, were unable to modify bupivacaine anesthesia.     

Influence of Voltage-sensitive Ca(++) channel drugs on bupivacaine infiltration anesthesia in mice.

BACKGROUND: Local anesthesia has been traditionally associated with blockade of voltage-sensitive sodium (Na(+)) channels. Yet in vitro evidence indicates that local anesthetic mechanisms are more complex than previously understood. For example, local anesthetics bind and allosterically modify 1,4-dihydropyridine-sensitive Ca(++) channels and can reduce Ca(++) influx in tissues. The current study examines the influence of voltage-sensitive Ca(++) channels in bupivacaine infiltration anesthesia. METHODS: Baseline tail-flick latencies to radiant heat nociception were obtained before subcutaneous infiltration of bupivacaine and Ca(++)-modulating drugs in the tails of mice. No musculature is contained in the tail that could result in motor block. The magnitude of infiltration anesthesia over time, as well as the potency of bupivacaine alone or in the presence of Ca(++)-modulating drug, was assessed by obtaining test latencies. RESULTS: The 1,4-dihydropyridine L-type Ca(++) channel agonist S(-)-BayK-8644 reduced the duration of action and potency of bupivacaine anesthesia. In opposite fashion, nifedipine and nicardipine increased the effects of bupivacaine. Neither nifedipine nor nicardipine alone elicited anesthesia. Alternatively, the phenylalkylamine L-type blocker verapamil elicited concentration-dependent anesthesia. Other Ca(++) channel subtype blockers were investigated as well. The N-, T-, P-, and Q-type channel blockers, omega-conotoxin GVIA, flunarizine, omega-agatoxin IVA, and omega-conotoxin MVIIC, respectively, were unable to modify bupivacaine anesthesia. CONCLUSIONS: These results indicate that heat nociception stimulates Ca(++) influx through L-type channels on nociceptors in skin. Although other voltage-sensitive Ca(++) channels may be located on skin nociceptors, only the L-type channel drugs affected bupivacaine in the radiant heat test.     

The interaction between gamma-aminobutyric acid agonists and diltiazem in visceral antinociception in rats

To examine whether the gamma-aminobutyric acid (GABA) receptor agonists and L-type voltage-dependent calcium channel blockers potentiate each other on the visceral antinociceptive effects at the spinal cord, we assessed visceral nociception with colorectal distension (CD) test in rats with an intrathecal catheter. The measurements were performed after intrathecal administration of a GABA agonist (muscimol or baclofen), a calcium channel blocker (diltiazem), or the combination of the two. CD threshold did not change after muscimol 0.1 microg, baclofen 0.01 microg, or diltiazem 100 microg, but increased slightly after muscimol 1 microg and baclofen 0.1 microg. When muscimol 0.1 microg or 1 microg was administered with diltiazem, the increase in CD threshold was significantly larger than muscimol alone (at 5 min, 26.2% versus 0.6% MPE (maximum possible effect) or 84.5% versus 19.5%MPE, respectively; P < 0.01). The CD threshold after the combination of baclofen 0.1 microg and diltiazem also showed a significantly larger increase than that seen after baclofen alone (at 5 min, 48.0% versus 14.3% MPE; P < 0.01). Motor paralysis observed with muscimol 1 microg did not increase when muscimol was coadministered with diltiazem. In conclusion, intrathecal diltiazem in combination with a GABA agonist, muscimol or baclofen, potentiated the GABA agonists-induced visceral antinociception without increasing motor paralysis. IMPLICATIONS: Intrathecal administration of diltiazem in combination with a gamma-aminobutyric acid (GABA) agonist, muscimol or baclofen, potentiated the GABA agonists-induced visceral antinociception but did not affect motor paralysis. The present results indicate that the coadministration of the two types of drugs may be clinically useful.     

Esophageal blood flow in the rabbit: response to calcium channel blockers

Calcium channel blockers have recently been added to the therapeutic regimen for patients who have chest pain of esophageal origin. Although relief of symptoms has been reported, this has not always been associated with changes in esophageal contraction pressures or luminal pH. Myoischemia has been proposed as one possible mechanism for esophageal chest pain. We have investigated the effect of the calcium channel blockers verapamil, nifedipine, and diltiazem on esophageal blood flow in the rabbit model. Esophageal blood flow was measured three times in each rabbit with use of the radiolabeled microsphere technique after a 30-minute continuous infusion of (1) saline solution (baseline), (2) a low dose, and (3) a high dose of each agent. Esophageal mucosal blood flow significantly decreased with nifedipine but was unchanged with verapamil and diltiazem. Esophageal muscle blood flow significantly increased--approximately 100% after administration of each of the calcium channel blockers. Thus esophageal muscle blood flow is enhanced after administration of calcium channel blockers, and this may be one therapeutic mechanism of the calcium channel blockers in the relief of esophageal chest pain in some esophageal diseases.     

Evidence that calcium channel blockade prevents cyclosporine-induced exacerbation of renal ischemic injury.

The following study was performed to determine whether calcium channel blockers, delivered before or after an ischemic insult, were effective at reducing cyclosporine-induced exacerbation of renal ischemic injury. When cyclosporine (5 mg/kg) was administered intravenously to rats after 30 min of renal ischemia, GFR fell by 60% compared with values observed in rats subjected to ischemia alone (190 +/- 30 vs. 330 +/- 40 microliters/min/100 g; P less than 0.05). Pretreatment with verapamil (10 micrograms/kg/min delivered intravenously) prevented the fall in GFR (320 +/- 70 microliters/min 100 g), as did pretreatment with nitrendipine, 1 micrograms/kg/min (460 +/- 90 microliters/min/100 g). Verapamil was less effective if given after the ischemia-cyclosporine insult (GFR 260 +/- 90 microliters/min/100 g), and nitrendipine given at this time had no beneficial effect at all (GFR 180 +/- 10 microliters/min/100 g). The doses of calcium channel blockers used had no protective effect on renal ischemic injury alone. Blood pressure during study ranged between 105 and 119 mm Hg with minor differences between groups. Sodium and potassium excretion and urinary flow rates were similar in all groups, except for a slight increase in sodium excretion in verapamil-treated rats. These values demonstrate that calcium channel blockers ameliorate the exacerbation or renal ischemic injury induced by cyclosporine if given before but not after the ischemia-cyclosporine insult. The protective effect of these agents, used preischemia in cyclosporine-treated rats, is observed with intravenous use of the drugs at doses that have no protective effect on renal ischemic injury alone.     

Calcium blockers enhance cisplatin-induced nephrotoxicity in rats

To examine the effects of calcium blockers on nephrotoxicity caused by cisplatin, the renal function and renal accumulation of Pt in Sprague-Dawley rats given 6.5 mg/kg i.v. cisplatin simultaneously with several doses of verapamil or nicardipine were evaluated. BUN, serum creatinine and kidney Pt concentrations in rats given more than 5.0 mg/kg of verapamil were significantly higher than those of the control animals injected with 6.5 mg/kg i.v. cisplatin alone, and the increase of each value was dependent upon the dose of verapamil. BUN, creatinine and kidney Pt in rats injected with more than 0.5 mg/kg i. p. nicardipine were also significantly higher than those of the controls. Calcium blockers enhanced the renal accumulation of Pt and the nephrotoxicity of cisplatin.     

Calcium channel blockade and contractile responses in the isolated human vas deferens

The effects of removal of extracellular calcium and of the calcium channel blockers nifedipine, verapamil and diltiazem were studied on contractions induced by electrical field stimulation and high K+-solution in isolated preparations of the human vas deferens. Electrically induced contractions were blocked by tetrodotoxin and alpha-adrenoceptor blockade. They were abolished in calcium-deficient medium, and suppressed by the calcium channel blockers in the order of potency nifedipine greater than verapamil greater than diltiazem. The maximum blocking effect of nifedipine was approximately 40%. All the blockers practically abolished K+-induced contractions. It is concluded that even if the contractile response of the human vas deferens to electrical stimulation is dependent on extracellular calcium, calcium channel blockers seem to have only a limited effect on this contraction and their capability of impairing the function of the vas deferens in patients is questioned.     

Effects of calcium channel-blocking agents on platelet-osteogenic sarcoma interaction: platelet aggregation and electron microscopic findings

A variety of tumors stimulate platelet activation. Because platelet activation may, in part, require calcium channel mobilization, we evaluated whether calcium channel blocking agents inhibit osteogenic sarcoma induced platelet aggregation. Platelet rich plasma (PRP) from normal subjects was incubated with one of four calcium channel-blocking agents: nifedipine, diltiazem, verapamil, or amlodopine, all 0-25 micrograms/ml, or diluent. Osteogenic sarcoma cells (2 or 4 x 10(6)/ml) were then added. Platelet aggregation was monitored by light transmission through PRP, and residual PRP was processed for electron microscopy. MG63 cells caused aggregation of PRP in most subjects (mean, 36 +/- 3%). Calcium channel-blocking agents (nifedipine greater than diltiazem greater than amlodopine greater than verapamil) caused partial inhibition of osteogenic sarcoma-induced platelet aggregation, at high concentrations only. Electron microscopy showed platelets aggregating to each other and to tumor cell membranes within 1-5 minutes. Changes in pattern of platelet clumping around tumor cells occurred when PRP was incubated with high concentration of diltiazem (50 micrograms). This study shows that calcium channel-blocking agents inhibit osteogenic sarcoma-induced platelet aggregation when used in high doses.     

Comparison of the effects of nitric oxide donors and calcium channel blockers on the intrinsic myogenic tone of sheep isolated internal anal sphincter

BACKGROUND: Chronic anal fissure is associated with considerable pain and anal hypertonia. Numerous clinical studies attest to the effectiveness of individual nitro-containing drugs and organic calcium channel blockers in this condition but there are few comparative studies. METHODS: Isolated segments of sheep internal anal sphincter were prepared for isometric tension recording. The effect of various drugs on myogenic tone was examined in the absence or presence of sodium orthovanadate (SOV), an agent used to mimic anal hypertonia by increasing myogenic tone. RESULTS: All the drugs tested produced concentration-dependent inhibition of myogenic tone, with the maximum effect ranging from 66.4 per cent (verapamil) to 100 per cent (sodium nitroprusside). Sodium nitroprusside and diltiazem were the most potent, followed by glyceryl trinitrate (GTN), nifedipine and verapamil, which had similar potency, and finally nicorandil. The potency of GTN and diltiazem was reduced threefold in the presence of 1 mmol/l SOV. The combined effect of GTN and diltiazem was greater than the effect of either agent alone, even in the presence of 3 mmol/l SOV. CONCLUSION: Nitro-containing drugs and organic calcium channel blockers are potent inhibitors of anal sphincter myogenic tone that may be used in combination to treat chronic anal fissure.     

Potentiation of vincristine effect in human and murine gliomas by calcium channel blockers or calmodulin inhibitors

The effects of calcium channel blockers and calmodulin inhibitors on vincristine cytotoxicity were studied in vitro with five glioma cell lines: three human glioblastomas, one rat glioma, and one mouse ependymoblastoma. One human glioblastoma and the rat glioma were resistant to vincristine in contrast to other glioma cells. The resistance to vincristine was considerably decreased by nontoxic or marginally toxic concentrations of calcium channel blockers or calmodulin inhibitors, although the former was more effective than the latter. In the presence of verapamil, the vincristine cytotoxicity, as measured by cell doubling times, increased 90- and 84-fold in the vincristine-resistant human glioblastoma and rat glioma, respectively. The decrease in the resistance to vincristine was related to a marked increase in the intracellular level of that drug, probably mediated by inhibiting its outward transport. The in vivo studies showed that verapamil or nicardipine administered daily with vincristine for 10 days significantly enhanced the chemotherapeutic effect of vincristine in an intracranially transplanted rat glioma model. An approximately 32% to 118% increase in life span occurred with 15 mg/kg/day of verapamil, depending on the doses of vincristine.     

Effects of cardioplegic solution and calcium entry blockers on coronary artery contraction

We studied the effects of the electrolyte composition (K, Ca, Na) and calcium entry blockers of the extracellular fluid on the tension development of isolated canine coronary arterial strips. In 20 mEq/l K solution, 4.7 mEq/l calcium produced coronary artery contraction. This Ca-induced contraction was inhibited dose-dependently by calcium entry blockers-nifedipine, nicardipine, diltiazem and verapamil. In the presence of 20 mEq/l K, the reduction of sodium concentration to 12 mEq/l increased the tension of coronary artery. Calcium entry blockers did not affect this tension development. After 5 or 30 min perfusion of calcium entry blockers, Ca-induced contraction was inhibited. It is concluded that low calcium, high sodium cardioplegic solution or addition of calcium entry blockers may relax the canine coronary artery.     

Alteration of Epidermal Growth Factor Receptor Expression Following Ischaemia of Renal Tissue

This study was aimed to investigate Epidermal Growth Factor Receptor (EGF-R) expression after ischaemic injury in renal tissue and the effects of calcium channel blockers in the prevention of damage due to ischaemic insult. Simple nephrectomy was performed in a group of Sprague-Dawley rats, and kidneys were grouped according to cold ischaemia time (1, 6, 12, 24 and 48 hours, respectively) and to the type of calcium channel blockers (diltiazem and verapamil) used. EGF-R expression status was investigated in each group by immunohistochemistry on paraffin sections. Overall expression of EGF-receptor was detected in 8 822.8%) kidneys. In terms of localization of EGF-receptor expression cortical tubular staining was detected in 8 (100%) kidneys, medullar tubular staining in (62.5%) kidneys and glomerular mesangial staining in 5 (62.5%) kidneys. There was no difference between various ischaemia times and different calcium channel blockers used. It has been concluded that hypoxia and cold ischaemia causes widespread down-regulation of EGF-receptor expression in renal tissue regardless of treatment with calcium channel blockers.     

Slow channel calcium inhibition blocks proinflammatory gene signaling and reduces macrophage responsiveness

BACKGROUND: This study investigates the possible intracellular mechanisms responsible for calcium antagonist protection in tissue-fixed macrophages, a central modulator of the proinflammatory phenotype. METHODS: Rabbit alveolar macrophages were exposed to lipopolysaccharide in the presence of different specific calcium antagonists. Cellular and nuclear protein were extracted and analyzed by Western blot for the phosphorylated forms of PYK2, ERK 1/2, and p38, and nuclear translocation of NF-kappaB and AP-1. Tumor necrosis factor-alpha (TNF-alpha) expression was measured by an L929 bioassay on cellular supernatants. Statistical analysis was performed by unpaired Student's t tests. RESULTS: Cells pretreated with 100 to 500 micromol/L of diltiazem or 50 to 100 micromol/L of verapamil, both slow channel calcium blockers, led to dose-dependent reductions in lipopolysaccharide-induced PYK2 and ERK 1/2 phosphorylation, and nuclear translocation of AP-1 when compared with controls (p < 0.05). Neither inhibitor had any significant effect on p38 or NF-kappaB translocation. EGTA an extracellular calcium chelator, had no significant effect on any intracellular process studied. A dose-dependent reduction in TNF-alpha production was demonstrated with diltiazem and verapamil (p < 0.05), with no effect induced by EGTA. CONCLUSION: Slow channel calcium influx is essential for optimal intracellular signaling through PYK2 and ERK 1/2. This reduced intracellular signaling correlated with reduced AP-1 translocation and TNF-alpha production. Extracellular calcium chelation had no significant effect on intracellular signaling or TNF-alpha production. This study further elucidates the protective mechanism of action of calcium channel blockade by diltiazem and verapamil by reducing intracellular calcium release and down-regulating the excessive proinflammatory phenotype.     

Reversal of preexisting vasospasm in coronary artery conduits

BACKGROUND: To reverse preexisting coronary graft spasm, we investigated the vasodilative effect of the average therapeutic plasma concentration of nitroglycerin (NTG) alone and various calcium antagonists in combination with NTG in human arterial and venous conduits. METHODS: Vasodilative effects of 2 x 10(-8) mol/L NTG alone and 10(-8) mol/L NTG in combination with 2.2 x 10(-7) mol/L diltiazem, 2.8 x 10(-7) mol/L nifedipine, 10(-7) mol/L verapamil, or 5.6 x 10(-8) mol/L nicardipine were assessed in human radial artery, internal thoracic artery, and saphenous vein segments precontracted with a mixture of ten times the maximum plasma concentrations of endothelin-1 (8.6 x 10(-13) mol/L), angiotensin II (36 x 10(-11) mol/L), 5-hydroxytryptamine (3.4 x 10(-7) mol/L), and norepinephrine (1.7 x 10(-8) mol/L). The studies were done in organ baths. RESULTS: The therapeutic concentration of NTG alone or nifedipine, verapamil, diltiazem, or nicardipine in combination with NTG caused equal relaxation in a particular group of vascular segments (average vasodilation: radial artery, 83% to 95% [p = 0.7608 by analysis of variancel; saphenous vein, 47% to 70% [p = 0.3142]; internal thoracic artery, 54% to 79% [p = 0.27831). These combinations were not equally effective when compared between different groups of vascular segments (vasodilation; radial artery > internal thoracic artery > saphenous vein [p < 0.0001 by analysis of variance]). Although not significant, in comparison with NTG alone, NTG in combination with a calcium antagonist caused less vasodilation in any group of vascular segments. CONCLUSIONS: Nitroglycerin alone or in combination with nifedipine, verapamil, diltiazem, or nicardipine effectively reverses preexisting vasospasm in coronary artery conduits.     

Influence of calcium channel blockers and beta-blockers on pain relief with iontophoresis]

We studied usefulness of iontophoresis on pain relief using several Ca channel blockers, propranolol and guanethidine. Subjects were 18 healthy adult volunteers. We used 4% lidocaine with/without several drugs (2 mg of nicardipine, verapamil, diltiazem, propranolol and 10mg of guanethidine), and evaluated the pain relief effect with Nakahama's algesimeter. In all groups except for propranolol group, the pain recognition time was elongated significantly in comparison with control. In making comparison between each Ca channel blocker, we did not observe any significant differences, but, in propranolol group, elongation of pain threshold time was observed in some subjects. During these processes, systemic blood pressure and heart rate showed no remarkable changes. Our results suggest that it is possible to achieve more prolonged analgesic effect by the Ca channel blockers.     

Effects of adrenaline and hyaluronidase on plasma concentrations of lignocaine and bupivacaine after peribulbar anaesthesia

We have measured peak plasma concentrations of lignocaine and bupivacaine after dual injection peribulbar block and investigated the influence of adrenaline and hyaluronidase. Twenty-four patients were allocated randomly to one of four groups: (I) local anaesthetic alone (lignocaine 10 mg ml-1-bupivacaine 3.75 mg ml-1); (II) local anaesthetic with adrenaline (5 micrograms ml-1); (III) local anaesthetic with hyaluronidase (75 iu ml-1); or (IV) local anaesthetic with adrenaline and hyaluronidase. Venous plasma concentrations of lignocaine and bupivacaine were measured in 24 patients using gas liquid chromatography before and at 5, 10, 15, 20, 25, 30, 45, 60, 90, 120, 180, 300 and 540 min after completion of the peribulbar injections. Main outcome measures were analysed using two-way analysis of variance. All patients, with one exception, received 10 ml of the local anaesthetic mixture. Overall peak plasma concentrations varied from 230 to 1910 micrograms ml-1 for lignocaine and from 160 to 1090 micrograms ml-1 for bupivacaine. Adrenaline significantly reduced peak plasma concentrations of lignocaine to 57% (P = 0.001) and bupivacaine to 61% (P = 0.004) compared with the nonadrenaline groups. Hyaluronidase had no significant effect on peak plasma concentrations of lignocaine and bupivacaine, which were 90% (P = 0.34) and 100% (P = 0.84) of the non-hyaluronidase groups. The area under the plasma concentration-time curves to 300 min (AUC300) behaved similarly. There was a reduction in AUC300 for lignocaine (P = 0.005) and bupivacaine (P = 0.011) in the adrenaline groups compared with the non-adrenaline groups, in contrast with no significant effects of hyaluronidase on AUC300 for lignocaine (P = 0.14) or bupivacaine (P = 0.53) compared with the non-hyaluronidase groups.