Advanced Cardiovascular Pharmacology Update JOHN SHIELDS, DNP, CRNA Systemic Circulation BP=CO x SVR CO dependent on o Stroke volume o Preload o Contractility o Afterload o Heart rate Vascular tone Blood viscosity Pulmonary Circulation Pulmonary vessels are very thin-walled o Pulmonary circulation resembles venous capacitance vessels o Diversion of blood from one region to another is facilitated ▪ Recruitment ▪ Distension ▪ HPV RV function is very afterload dependent Biventricular Circulation Management LV failure managed differently than RV failure LV is a stupid pump o Inotropes o Volume manipulation via Frank- Starling Curve o Ohm’s Law RV is a bellows that responds best to contractility drugs and afterload reduction o Inodilators o Ventilation Drugs Used to Treat Low Systemic Cardiac Output/Hypotension Vasopressors Alpha-adrenergic drugs Mixed agonists Vasopressin Methylene blue Other Inotropes Beta-adrenergic drugs Mixed agonists PDE III Digitalis Calcium Glucagon Triiodothyronine Levosimendan Other Alpha-Adrenergic Receptor Pharmacology Alpha-1 activation results in increased calcium and contraction of vascular smooth muscle (IP3) Effects include vasoconstriction, intestinal relaxation, pupillary dilation Theory evolving regarding multiple alpha receptors Beta-Adrenergic Receptor Pharmacology Beta-1 activation results in chronotropic and inotropic effects (cAMP) Counterpart to vagal system via SNS Beta-2 activation affects vascular and pulmonary smooth muscle Vasopressin Receptor Pharmacology V1 receptor activation results in IP3 signal pathway and contraction of vascular smooth muscle Effects include vasoconstriction, similar to alpha with weak inotropic effect Side effects include myocardial ischemia and reduction in splanchnic blood flow Dopamine Receptor Pharmacology Unique in ability to simultaneously increase o Myocardial contractility o Renal/mesenteric blood flow o GFR, excretion of sodium o UOP Dose-dependent pharmacodynamics and effect on cAMP and Ca++ PDE-3 Receptor Pharmacology cAMP increases contractility PDE3 breaks down cAMP to AMP Inhibition of PDE3 increases cAMP levels and increases o Contractility (inotropy) o Heart rate (chronotropy) o Conduction velocity (dromotropy) Calcium Receptor Pharmacology Changes in force of contraction and SVR result from incremental degrees of binding between myosin and actin Degree of binding depends on calcium ion concentration in the cell Catecholamines affect the concentration of calcium in the cell Muscarinic Receptor Pharmacology Parasympathetic blockade or activation can mediate SA node firing and resting membrane potential Parasympathetic receptor activation can influence IP3, cAMP and nitric oxide release Muscarinic receptor blockade increases cardiac norepinephrine spillover when HF is not present Blunting of parasympathetic influence on sympathetic activity is present in HF Dysrhythmia Pharmacology Dysrhythmias may be due to disturbances in automaticity, Tachyarrhythmias conduction and/or re-entry Enhanced Re-Entry Etiology may be mechanical, Automaticity reflex, pharmacologic, Altered Altered Impulse Impulse disease, ion channel or Formation Conduction adrenergic Decreased Conduction Automaticity Blocks Treatment should target action potential and Bradyarrhythmias automaticity Phenylephrine Sympathomimetic amine, direct alpha agonist, (?) mild beta agonist Indicated for hypotension with low-normal CO o Useful in counteracting decrease in SVR from anesthetic agents o Useful for drop in SVR from spinal and epidural blocks Useful in patients with ischemic heart disease (no inotropic or chronotropic effects) Ephedrine Mild indirect alpha agonist, direct beta agonist (causes release of NE from neurons) Indicated for hypotension with low CO and low HR Efficacy is blunted when NE stores are low, tachyphylaxis (>150 mg) CV effects of ephedrine resemble those of epi, but BP ↑ is less intense and lasts about 10x longer Vasopressin Produces direct peripheral vasoconstriction via V1 receptors Acts independently of adrenergic receptors o Useful in refractory hypotension in sepsis, patients taking ACE inhibitors o Useful for hypotension refractory to phenylephrine or ephedrine o More effective than alpha or beta in vasoplegic/acidotic state Minimal decrease in pulmonary vascular resistance Dose is 0.5-2 mcg bolus, infusion 0.04 mcg/minute Calcium Increases inotropy without increase in HR Increases SVR and PVR in dose dependent fashion Reverses hypotension due to volatile, CCB’s, hypocalcemia, Mg, K+ Provokes digitalis toxicity Promotes coronary spasm and pulmonary hypertension Anticholinergic Drugs Block inhibitory effects of the parasympathetic neurotransmitter acetylcholine on heart rate leading to tachycardia Atropine inhibits acetylcholine- induced decreases in cAMP by acting as an allosteric PDE type 4 (PDE4) inhibitor o Increase in HR o Increase in contractility Glycopyrrolate increases heart rate but has no real effect on contractility Ruwan et al. Atropine augments cardiac contractility by inhibiting cAMP-specific phosphodiesterase type 4Sci Rep. 2017; 7: 15222 Norepinephrine Potent α1-adrenergic receptor agonist with β-agonist activity almost equal to epinephrine, no beta 2 Powerful vasoconstrictor with less potent direct inotropic properties o Used for hypotension refractory to phenylephrine o Used for heart failure in ischemic heart disease o Used in sepsis/vasoplegia May confer risk of ischemia of bowel and kidneys at higher doses Bolus 3-12 mcg/infusion rate 2-30 mcg/minute Epinephrine Increases cardiac inotropy and chronotropy, but alpha effects predominate at higher doses o 0.003-0.02 mcg/kg IV for refractory hypotension/CHF (10-20 mcg) o Infusion start at 2 mcg/minute for CO, up to 5 mcg/minute for hypotension/CHF Very effective bronchodilator but also enhances gluconeogenesis and elevated lactate Tachycardia, dysrhythmias and lactate are dose limiting effects Dobutamine Direct beta-1 adrenergic agonist, limited beta-2 and alpha-1 Higher safety index than epinephrine Very mild vasodilation, no effect on glucose Increases CO with less of an increase in MVO2 and heart rate Low cardiac output states, especially with high SVR or PVR Excellent drug for right ventricular failure Dose as infusion is 2-20 mcg/kg/min Dopamine Receptor Pharmacology Direct alpha 1, beta 1, beta 2 and dopaminergic (DA1) Indirect release of stored neuronal NE Dose response relationship between DA1, beta-1 and alpha-1 0.5 – 2 g/kg/min renal vasodilation, ↑ GFR and Na++ excretion (dopamine 1 receptors) 2 – 10 g/kg/min beta1 agonism cardiac contractility and output are increased (beta 1 receptors) > 10 g/kg/min alpha1 and beta1agonism, alpha-adrenergic vasoconstriction and benefit to renal perfusion may be lost Digitalis Positive inotropic effect but minor compared to catecholamines and others Digitalis works by inhibiting sodium-potassium ATPase, and increases calcium availability by increasing intracellular sodium (less extrusion of calcium) Therapeutic effects develop at approximately 35% and dysrhythmias typically manifest at approximately 60% of the fatal dose Methylene Blue for Vasoplegia Methylene blue seems to be a potent approach to refractory vasoplegia Nitric oxide is a mediator of systemic inflammatory response and is inhibited by methylene blue Useful when high doses of norepinephrine are required 1-2 mg/kg over 20”, 1 mg/kg/hr infusion Steroids?? Hydrocortisone 200 mg every 8 hours for vasoplegia May reduce catecholamine requirements Indicated only if adequate fluids and vasopressor use ineffective Lack of consistent evidence for outcomes Milrinone Useful if other receptors are down-regulated or desensitized (chronic heart failure) High utility with RV dysfunction Longer half-life (2 hours) than other inotropes Milrinone is an inodilator, and is used at 0.25-0.75 mcg/kg/minute Mild vasodilation occurs unless administered as a bolus (profound > 1 mg) Isoproterenol Profound beta-1 affinity, causing increased heart rate and contractility o Bradycardia not responsive to atropine o AV block, beta blocker overdose Binds to beta-2 receptors to produce vasodilation Used clinically for transplanted heart and electrophysiology for testing of re-entrant pathways Levosimendan Pharmacology Increased intracellular calcium may impair relaxation, increase MVO2 and ischemia Levoisimendan increases contractility and vasodilates o Increases troponin sensitivity to calcium o Activates adenosine triphosphate K+ channels causing vasodilation and myocardial protection o Cardiac output increased with decreased SVR and PVR Loading dose of 6–12 µg/kg over 10 minutes Continuous 24-hour infusion of 0.05–0.2 µg/kg/min Nicardipine Does not decrease myocardial contractility Mild suppression of automaticity and conduction Selective for vascular smooth muscle, especially coronary and cerebral Dose 50-200 mcg bolus, 1-15 mg/hour infusion Onset 2 minutes, half-life 40 minutes Clevidipine (Cleviprex) Ultra-short-acting (5”) Little or no effect on contractility or conduction Arterial only (no venous dilation or effect on filling volumes) Contraindicated in egg/soy allergies, aortic stenosis, HOCM Typical initial dosing is 1-2 mg/hour Epoprosterenol Potent peripheral vasodilator of all vascular beds; also prevents platelet aggregation Used primarily to decrease pulmonary vascular resistance without affecting SVR (inhaled) 50/ng/kg/min inhaled via nebulizer in circuit 2 ng/kg/min IV infusion