Alpha receptors post synaptic cardiac alpha1 receptors:- stimulation causes significant increase in contractility without an increase in rate- not mediated by cAMP- effect more pronounced at low heart rates- slower onset and longer duration than beta1 receptor mediated response- presynaptic alpha2receptors in heart and vasculature appear to beactivated by norepinephrine released by sympathetic nerve itself andmediate negative feedback inhibition of further norepinephrine release post synaptic alpha1 and alpha2receptors in peripheral vessels mediatevasoconstriction
Beta receptorspost synaptic beta1 receptors are predominant adrenergic receptors in heart. Stimulation causes increased rate and force of cardiac contraction. Mediated by cAMPpost synaptic beta2 receptors in vasculature mediate vasodilatation
Dopamine receptors peripheral DA1 receptors mediate renal, coronary and mesenteric arterial vasodilatation and a natriuretic response DA2receptors: presynaptic receptors found on nerve endings, inhibit norepinephrine release from sympathetic nerve endings, inhibit prolactin release and may reduce vomiting stimulation of either DA1 or DA2 receptors suppresses peristalsis and may precipitate ileus
EpinephrinePharmacokineticsAdmin: IV/IM/infiltrationElimination: mostly degraded by conjugation with glycuronic and sulphuric acids and excreted in the urine. Smaller part is oxidised by amine oxidase and inactivated by o-methyl- transferasePharmacodynamics- stimulates alpha1 and both beta1 and beta2 receptors. Effects are mediated by stimulation of adenyl cyclase resulting in an increase in cAMP- beta2 receptors more sensitive to epinephrine than alpha1
CVS- positive inotrope and chronotrope ( mediated by all 3 receptors)- - increases incidence of dysrhythmias by increasing irritability of automatic- conducting system- - constricts vessels of skin, mucosa, subcutaneous tissues, splanchnic area,- kidneys (alpha effects)- - vessels of muscle and liver are dilated at physiological doses (beta effect)- but are constricted at higher doses.- - cerebral and pulmonary arteries are constricted- - may precipitate angina in patients with IHD- - CVS effects reduced by acidosis- - at low doses causes: increased cardiac output, slight reduction in SVR,- increase in effective circulating volume and increased venous return. Net- result: systolic BP rises but diastolic falls- - higher doses: rise in SVR, decreased cardiac output and rise in both systolic- and diastolic BP
RenalRBF and urine output reducedRS- bronchial tone decreased- depth of respiration slightly increased- irregular breathing sometimes seen- decreases mucosal blood flow; results in reduced mucosal oedema and bronchial secretionsGI tract- muscle of gut relaxed, pyloric and ileocolic sphincters constricted: leads to ileus- intestinal secretion inhibited- spleen contracts and empties its cells into the circulation
Metabolic- beta stimulation causes increased insulin and glucagon secretion, alpha decreased. Overall epinephrine has anti-insulin effect.- increased blood glucose due to increased mobilization of glycogen.- rise in metabolic rate. Initial rise is independent of liver and is probably due to cutaneous vasoconstriction, causing a rise in body temperature, or increased muscle activity or both. Later, smaller rise is probably due to increased oxidation of lactose by liver- increased lipolysis, muscle catabolism. Results in increased serum cholesterol, phospholipids and LDL- plasma K rises initially due to increased release from liver. Followed by aprolonged fall due to entry into skeletal muscle cells, mediated by beta2receptors- net result is an increase in O2 consumption- may result in lactic acidosis
CNS- CNS stimulation usually very modest- pupillary dilatation- elevates pain threshold- at high doses: anxiety, restlessness from mild cerebral stimulation, throbbing headache, vertigo
Norepinephrine- alpha and beta1 agonist with no clinically significant beta2 effects- equipotent with epinephrine as a beta1 agonist but less potent an alpha agonist in most tissues- used for refractory hypotension- may result in no change or slight decrease in cardiac output and oxygen delivery due to increased afterload- in the non-septic patient produces vasoconstriction in all vascular beds, including the renal circulation- in septic patients increases BP and SVR, often without altering cardiac output. However in some patients may Þ CO by stroke volume. Often improves renal blood flow and urine output in these patients by increasing perfusion pressure without compromising cardiac output- may be useful in cardiogenic shock: increases coronary perfusion pressure.
NB norepinephrine has no effect on renal blood flow in patients with established acute renal failure and in hypotensive patients both epinephrine and norepinephrine may increase renal blood flow by increasing perfusion pressure Little effect on PAWP. Mean PA pressure unchanged or slightly .Clinical use in doses of 0.01-2 m g/kg/min reliably and predictably improves haemodynamic variables to normal or supranormal values in the majority of septic patients effect on oxygen transport variables cannot be determined from current data
DopamineImmediate precursor of norepinephrine and epinephrine Pharmacodynamics Dose dependent effects: <5 m g/kg/min predominantly stimulates DA1 and DA2 receptors in renal, mesenteric and coronary beds. Þ vasodilatation 5-10 m g/kg/min: b 2 effects predominate. Þ cardiac contractility and HR >10 m g/kg/min: a effects predominate Þ arterial vasoconstriction and -BP Pharmacokinetics Marked variability in clearance in the critically ill. As a result plasma concentrations cannot be predicted from infusion rates
Clinical use-variable effects due to variable clearance-increases cardiac output (mainly due to increased stroke volume) with minimal effect on SVR in patients with septic shock-increases pulmonary shunt fraction-effects on splanchnic perfusion unclear-increases urine output without increasing creatinine clearance in a number of settings.-Low dose dopamine does not prevent renal failure in critically ill patients
DopexamineSynthetic catecholamine structurally related to dopaminePharmacokinetics-Admin: IV infusion-Distribution: extensive tissue distribution. Drug acts as a substrate for extra-neuronal catecholamine uptake mechanism (uptake 2).-Elimination: short t1/2 of 7 mins (11 mins in patients with low cardiac output). Extensively metabolised in the liver. Both metabolites and parent drug excreted in urine and faeces.Pharmacodynamics-marked intrinsic agonist activity at beta2 receptors-lesser agonist activity at beta1 adrenoreceptors, DA1 and DA2 dopaminergic receptors inhibits neuronal catecholamine uptake by uptake 2-net effect is reduction in afterload by pronounced arterial vasodilatation, increased renal perfusion by selective renal vasodilatation and mild direct and indirect positive inotropism. Also has positive chronotropic effect.-probably not as effective as dopamine at increasing renal blood flow, but causes a substantially greater increase in cardiac index.
Adverse effects-nausea and vomiting most common adverse effect. Respond well to dosage reduction.-tachycardia may precipitate angina in patients with ischaemic heart disease.-said not to have arrhythmogenic potential but is associated with ventricular ectopics.-tremor-reversible reductions in neutrophil and platelet counts.Dosage for acute heart failure and haemodynamic support in patients following cardiac surgery start at 0.5 mcg/kg/min and titrate upwards in increments of 1 mcg/kg/min to a maximum of 6 mcg/kg/min.Contraindications- thrombocytopaeniaCaution- patients with hyperglycaemia and hypokalaemia in view of beta-adrenergic activity.
DobutaminePossesses the same basic structure as dopamine but has a bulky ring substitution on the terminal amino group.Synthetic catecholaminePhysical properties- supplied in lyophilized form which should be reconstituted with 10 ml ofwater or 5% dextrose- compatible with 5% dextrose, N/saline and D/saline but, like dopamine israpidly inactivated under alkaline conditions- stable for 24 hrs after reconstitution. May turn slightly pink during this timebut this is not associated with a change in potency- racemic preparation
Pharmacodynamics- strong +ve inotropy due to beta1 agonist effects and alpha1 agonism- mild +ve chronotropy due (+) isomer effect on beta receptors- weaker alpha receptor blockade and beta2 stimulation, produced by (+) isomer and alpha1 agonism produced by (-) isomer- overall peripheral effect should be an increase in blood flow to skeletal muscle (beta2 agonism) and some reduction in skin blood flow (alpha1agonism balanced by some alpha blockade). These effects are weak compared to the myocardial effects- net effects are an increase in SV and CO. SVR may be unchanged or moderately decreased and arterial pressure may thus rise, fall slightly or remain unchanged- at doses > 15 mcg/kg/min tachycardia and arrhythmias are more likely- tolerance may be seen after 48-72 hrs, presumably due to down- regulation of beta receptors. May necessitate an increase in dose. Dose required to produce toxic effects seems to be increased equivalently
Isoproterenol- powerful beta agonist with virtually no alpha effects- lowers vascular resistance mainly in skeletal muscle but also in renal andmesenteric vascular beds.- diastolic BP falls but with usual doses the increase in cardiac output isusually enough to maintain or raise mean BP- positive inotrope and chronotrope- renal blood flow is decreased in normotensive subjects but is markedlyincreased in patients with cardiogenic or septic shock- PA pressures are unchanged
MethoxaminePharmacodynamics- direct and indirect effects- alpha agonist and beta blocker- primary effect is peripheral vasoconstriction resulting in rise in systolic anddiastolic BP- HR slows due to beta blocking effects and reflex slowing due to rise in BP- no effect on cardiac contractility and so cardiac output fallsIndications and dosage- hypotensive states due to excessive vasodilatation eg spinal or epiduralblock- 5-10 mg IV acts within 2 mins. Effect persists for about 20 mins. Dose can betitrated against effect in 2 mg bolusesContra-indications- patients on MAOIs- history of hypertensionToxicity- - excessive rise in BP; may precipitate myocardial ischaemia- - vomiting, headache, desire to micturate, significant reduction in HR- - treat with IV alpha blocker (eg phentolamine)
Phenylephrine- similar effects to norepinephrine but probably even shorter acting- direct acting- potent alpha and weak beta agonist- causes peripheral vasoconstriction and thus a rise in BP, especially diastolic- often reflex reduction in heart rate- only direct effect on heart is to slightly increase myocardial irritability- largely replaced by catecholamines
EphedrineNaturally occurring amine with both direct and indirect (stimulatesnorepinephrine release from postganglionic sympathetic nerve endings)sympathomimetic effects.Pharmacodynamics- both alpha and beta agonist effects- haemodynamic effects are similar to epinephrine but it has a longer duration of action and is active when administered orally- increased cardiac contractility and heart rate and thus cardiac output- peripheral vasoconstriction is balanced by vasodilation with little overall change in SVR- rise in arterial BP - systolic > diastolic- may increase cardiac irritability- relaxes bronchial and other smooth muscle, but less effective than epinephrine- reduces uterine muscle activity - side effects similar to epinephrine Admin: PO/IV Elimination: not broken down by MAO. Excreted unchanged by kidney
Phosphodiesterase III Inhibitors (I) Inhibit PDE III isoenzyme increase intracellular cAMP + cGMP in myocardial & sm. muscle cells cAMP phosphorylates cellular protein kinases Myocardium: Ca2+ influx more Ca2+ for contraction & improved Ca2+ reuptake improved relaxation Sm. Muscle: relaxation & 20 vasodilatation Clinical effects 1. Increased cardiac contractility without increasing myocardial oxygen consumption 2. Decreased preload and afterload 3. Minimal chronotropic effect
Phosphodiesterase III Inhibitors (II) Clinical uses: Short term treatment for acute on chronic severe CCF Synergistic effect with beta agonists Role in cardiopulmonary bypassEnoximone Yellow, effect for 4-6 hours Loading dose then infusion Monitor for hypotension Hepatic metabolism, renal excretion
Levosimendan Calcium sensitizer Action Stabilises interaction between Ca2+ & Troponin C by binding Troponin C in Ca2+ dependent manner K+-ATP channel opener (PDE III inhibit effect in vitro) Clinical effects Increased cardiac contractility – no increase in myocardial oxygen demand Vasodilatation resulting in decreased preload & afterload Not proarrythmogenic
Vasoactive drugs for shock statesShock state First-tier agents Second-tier agentsAnaphylactic shock Epinephrine, 1 mL of 1:10,000 Norepinephrine infused at 0.1–1 solution (100 mg),can be mg/kg/min (0.5–30 mg/min) given as a slow IV push, then as a 0.02 mg/kg/min infusion (5–15 mg/minCardiogenic shock, SBP 70, norepinephrine Amrinone, 0.75 mg/kg loadingleft ventricular infused at 0.1–1 mg/kg/min dose, then 5–10 mg/kg/min(not (0.5–30 mg/min) recommended post-MI) SBP 70–90, dopamine Milrinone, 50 mg/kg loading infused at 15 mg/kg/min dose, then 5–10 mg/kg/min(not SBP O90, dobutamine recommended post-MI) infused at 2–20 mg/kg/minCardiogenic shock, Dobutamine infused at 5 Phenylephrine infused at 10–20pulmonary mg/kg/min mg/kg/minembolism Norepinephrine infused at 0.1–1 mg/kg/minHemorrhagic shock Volume resuscitation Dopamine infused at 5–15 mg/kg/min as a temporizing adjunct
Neurogenic shock Dopamine infused at 5– Norpinephrine infused 15 mg/kg/min at 0.1–1 mg/kg/min Phenylephrine infused at 10–20 mg/kg/minSeptic shock Norepinephrine infused Dopamine infused at 5–15 at 0.1–1 mg/kg/min mg/kg/min Dobutamine infused at 5 Epinephrine infused at mg/kg/min 0.02 mg/kg/minToxic drug overdose with Norepinephrine infused Phenylephrine infused atshock at 0.1–1 mg/kg/min 10–20 mg/kg/min Glucagon given as a 5-mg IV bolus, then as a 1–5 mg/h infusion Calcium salts: calcium gluconate, 0.6 mL/kg bolus, then a 0.6–1.5 mL/kg/h infusion Insulin started at 0.1 units/kg/h IV and titrated to a goal of 1 unit/kg/h
Conclusions and Recommendation Smaller combined doses of inotropes and vasopressors may be advantageous over a single agent used at higher doses to avoid dose-related adverse effects. The use of vasopressin at low to moderate doses may allow catecholamine sparing, and it may be particularly useful in settings of catecholamine hyposensitivity and after prolonged critical illness. In cardiogenic shock complicating AMI, current guidelines based on expert opinion recommend dopamine or dobutamine as first-line agents with moderate hypotension (systolic blood pressure 70 to 100 mm Hg) and norepinephrine as the preferred therapy for severe hypotension (systolic blood pressure <70 mm Hg). Routine inotropic use is not recommended for end-stage HF. When such use is essential, every effort should be made to either reinstitute stable oral therapy as quickly as possible or use destination therapy such as cardiac transplantation or LV assist device support.