Ischemic heart disease

β-Blocker and Calcium Channel Blocker Toxicity

Nifedipine, a hypertensive calcium channel blocker, is commonly administered to subjects with coronary heart disease who often exhibit hyperlipidemia. In general, the pharmacokinetic consequences of hyperlipidemia include increased total drug concentrations and decreased unbound fraction in plasma. However, the pharmacodynamic consequences of hyperlipidemia are conflicting; unaltered, increased, or decreased pharmacological effects are reported. In this study, the effect of experimental hyperlipidemia on pharmacokinetic and pharmacodynamic consequences of nifedipine was studied. After establishing a dose (0.05-0.3 mg.kg(-1))-effect relationship, single 0.1 mg.kg(-1) i.v. doses of nifedipine were administered to control and poloxamer 407-induced hyperlipidemic (with and without cholesterol-lowering agent atorvastatin) rats. Mean arterial pressure, total as well as unbound nifedipine plasma concentrations, and total cholesterol were monitored. Hyperlipidemia significantly decreased systemic clearance of nifedipine by 40% and increased T(1/2) and area under the plasma concentration-time curve by 85 and 65%, respectively. Compared with the hyperlipidemic group, atorvastatin-treated rats had significantly lower total plasma cholesterol (0-70%), increased systemic clearance (39%), and decreased T(1/2) (27%) and area under the plasma concentration-time curve (24%). Hyperlipidemia prolonged pharmacological T(1/2) of nifedipine by 300%. Atorvastatin treatment significantly reduced this prolongation to 46%. There was a significant correlation between mean blood pressure and the total but not unbound nifedipine plasma concentrations. Hyperlipidemia potentiates the hypotensive effect of nifedipine by increasing its total plasma concentrations despite decreased unbound drug concentration.

Pharmacokinetics and pharmacodynamics of nifedipine in untreated and atorvastatin-treated hyperlipidemic rats.

https://www.medicinejournal.co.uk/article/S1357-3039(11)00348-3/pdf

Calcium Channel Blockers

https://www.annemergmed.com/article/S0196-0644(00)50098-5/pdf

Hypertonic sodium bicarbonate is effective in the acute management of verapamil toxicity in a swine model

1. The influence of hypoventilation or hyperventilation on blood pressure and pulse rate responses to verapamil and nifedipine was studied in chloralose-anaesthetized rats. 2. Artificial ventilation with room air at a fixed volume of 10 ml kg-1 successfully induced combinations of hypoxaemia, hypercarbia and acidosis at a ventilator rate of 37 strokes min-1 and of hyperoxaemia, hypocarbia and alkalosis at 160 strokes min-1. 3. Hypoventilation caused significant decreases in both the blood pressure and pulse rate, whereas hyperventilation produced significant increases in these parameters. 4. In the controls, intravenous injections of graded doses of either verapamil or nifedipine caused dose-dependent decreases in mean blood pressure. The effects on pulse rate were not marked. 5. The hypotensive effects of verapamil were significantly more intense in hyperventilated rats, whereas those of nifedipine were significantly less pronounced in hypoventilated animals. The hypoventilated rats exhibited a significant dose-dependent decrease in pulse rate in response to verapamil administration. 6. It is concluded that cardiovascular responses to verapamil, nifedipine and probably other calcium antagonists are altered in the presence of blood gas abnormalities.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1990.tb12059.x

Cardiovascular responses to verapamil and nifedipine in hypoventilated and hyperventilated rats.

Influence of pH changes on the actions of verapamil on cardiac excitation-contraction coupling.

1. Blood pressure and pulse rate responses to intravenously (i.v.) administered nifedipine were studied in chloralose-anaesthetized rats subjected to hypoxaemia, hyperoxaemia, alkalosis, acidosis, hypocarbia with alkalosis, or hypercarbia with acidosis. 2. Ventilation with a gas mixture of 17% O2, 28% O2, or 23% O2 with 5% CO2 at a fixed stroke volume (10 mL/kg) and rate (80 strokes/min) induced hypoxaemia, hyperoxaemia or hypercarbia, respectively. Hypocarbia was induced by ventilation with 17% O2 at 160 strokes/min. Acidosis or alkalosis was produced by intravenous infusion of 1 mol/L HCl or 1 mol/L NaHCO3, respectively, in animals ventilated with room air. 3. There were significant decreases in blood pressure and pulse rate during acidosis, and increases in pulse rate during alkalosis and hypercarbia. No marked changes in these parameters were observed under the other experimental conditions. 4. The control animals showed a dose-dependent decrease in blood pressure without marked changes in pulse rate in response to nifedipine injection. 5. Significant reductions in the hypotensive effect of nifedipine were observed in rats subjected to alkalosis, acidosis, or hypercarbia. A similar tendency was also found during hypocarbia while the responses to nifedipine during hypoxaemia and hyperoxaemia were statistically the same as those in the controls. 6. It is concluded that alterations of blood pH reduce the hypotensive effect of nifedipine, and we suggest that blood pH changes probably play a more important role than PO2 or PCO2 abnormalities in altering the cardiovascular responses to nifedipine in hypoventilated or hyperventilated rats.

Cardiovascular responses to nifedipine in anaesthetized rats with abnormal blood gas/ph levels

Blood pH and the actions of nifedipine on cardiac excitation-contraction coupling.

1. The effects of extracellular or intracellular pH changes on agonist- or depolarization-induced contractions of the rat tail artery were investigated. 2. Vessels were perfused initially (25 min) with physiological salt solution (PSS) at a pressure of 30 mmHg. Perfusion was then continued with calcium-free PSS containing either 3.0 micromol/L noradrenaline (NA) or 100 mmol/L K+, which had been made either acidotic or alkalotic. Contractile responses to graded concentrations of calcium were assessed. 3. A reduction in the intracellular or extracellular pH was induced by the addition of a weak acid (30 mmol/L sodium propionate) or reduction of the concentration of HCO3- in the PSS, respectively; an elevation of the intracellular or extracellular pH was produced by the addition of a weak base (10 mmol/L trimethylamine) or by increasing HCO3-, respectively. The PSS was bubbled with 5% CO2/95% O2. 4. Lowered intracellular pH did not alter NA- or K+-stimulated contractions. During lowered extracellular pH, contractile responsiveness and peak response were significantly reduced in K+-stimulated arteries, but were not affected in NA-stimulated arteries. 5. Elevated intracellular pH did not alter NA-induced contraction, but reduced the sensitivity to K+-stimulated contractions. Elevated extracellular pH had little effect on the magnitude of K+-induced contractions, but slightly enhanced (although not significantly) NA-induced contractions. 6. It is concluded that reduced contractile responses to K+ during extracellular acidosis are due to the modulation of potential-operated calcium channels (POC). Alkalotic vasodilatation is mediated by intracellular events and is POC-modulated, whereas alkalotic vasoconstriction appears to be due to extracellular events and is modulated by receptor-operated calcium channels (ROC).

Francis I. Achike

Papers

Cardiovascular responses to verapamil and nifedipine in hypoventilated and hyperventilated rats.

Influence of pH changes on the actions of verapamil on cardiac excitation-contraction coupling.

Cardiovascular responses to nifedipine in anaesthetized rats with abnormal blood gas/ph levels

Blood pH and the actions of nifedipine on cardiac excitation-contraction coupling.

Influence of extracellular pH, sodium propionate and trimethylamine on excitation-contraction coupling in the rat tail artery.