Vasopressors & Inotropes
High-yield Verified · Oct 2026Two second messengers explain most of the class: Gq → calcium squeezes vessels (α1, V1), and cAMP speeds and strengthens the heart while relaxing smooth muscle (β1, β2, and milrinone’s PDE3 block).
Nursing view → administration, monitoring and patient teaching
Drugs
Mechanism
Stimulate adrenergic receptors: α1 (vasoconstriction → ↑ SVR/BP), β1 (↑ heart rate & contractility → ↑ cardiac output), and β2 (vasodilation/bronchodilation). Each agent has a distinct receptor profile — norepinephrine α1>β1, phenylephrine pure α1, dobutamine β1, epinephrine α+β, dopamine dose-dependent, isoproterenol nonselective β (β1 + β2) with very low α affinity, midodrine an oral prodrug whose metabolite desglymidodrine is an α1 agonist, and ephedrine a direct α and β agonist that also releases norepinephrine from sympathetic neurons. Vasopressin is non-adrenergic — it constricts vessels through vascular V1 receptors. Milrinone is also non-adrenergic — it inhibits phosphodiesterase 3 in cardiac and vascular muscle, raising cAMP (↑ contractility, vasodilation).
Receptors and their second messengers
All adrenergic receptors are G-protein-coupled. α1 receptors are Gq-coupled: phospholipase C forms IP3 and DAG, intracellular calcium rises, and vascular smooth muscle contracts. Vasopressin reaches the same end by a different receptor — V1 on vascular smooth muscle is coupled to the Gq/11–phospholipase C–IP3 pathway and releases intracellular calcium — while its V2 receptors in the kidney are coupled to adenylyl cyclase and drive antidiuresis.
β1 receptors are Gs-coupled: adenylyl cyclase raises cAMP, and protein kinase A phosphorylates L-type calcium channels and increases calcium release from ryanodine receptors in the sarcoplasmic reticulum. More calcium means stronger contraction in working myocytes and, in pacemaker cells, a steeper phase 4 slope, so threshold is reached sooner and heart rate rises. β2 receptors also raise cAMP, but in smooth muscle protein kinase A inactivates myosin light chain kinase, so bronchial and vascular smooth muscle relax.
Dopamine adds its own receptors. Its label describes dose-dependent effects: at low infusion rates it activates D1 and D2 receptors in the renal, mesenteric and coronary vasculature (vasodilation), at intermediate rates β1 (heart rate and contractility), and at high rates α1 (vasoconstriction and higher blood pressure).
Milrinone: cAMP without a receptor
Phosphodiesterases hydrolyze cAMP and end its signal. Milrinone selectively inhibits the peak III (PDE3) cAMP phosphodiesterase in cardiac and vascular muscle, so cAMP accumulates downstream of any receptor. In cardiac muscle that means more intracellular calcium and contractile force — and better relaxation (lusitropy); in vascular muscle cAMP-dependent protein phosphorylation relaxes the vessel. It is not a β-adrenergic agonist and does not inhibit the Na⁺/K⁺-ATPase as digoxin does.
The result is an inotrope and vasodilator with little chronotropic activity. In heart failure it raises cardiac output and lowers pulmonary capillary wedge pressure and vascular resistance, with mild-to-moderate increases in heart rate and no increase in myocardial oxygen consumption. Its vasodilator effect is more potent than that of the β2-active catecholamines dobutamine and isoproterenol.
Reflexes decide the heart rate
Raising blood pressure triggers the baroreceptor reflex. With pure α1 agonism (phenylephrine), mean arterial pressure rises, vagal activity increases and reflex bradycardia follows; because afterload rises, cardiac output may fall in some patients. Norepinephrine constricts vessels and stimulates the heart, but the higher resistance and pressure also cause reflex vagal slowing, so cardiac output is generally unaffected and blood pressure rises more than heart rate.
The β agonists go the other way. Isoproterenol (β1 + β2, very low α affinity) lowers peripheral resistance, so diastolic and usually mean arterial pressure fall while inotropy and chronotropy raise cardiac output. Dobutamine raises output to a similar degree in depressed hearts, but mainly through stroke volume, with less tachycardia — isoproterenol raises cardiac index mainly by heart rate. Epinephrine depends on dose: at low doses β2-mediated vasodilation lowers systemic resistance and diastolic pressure, while at higher doses α1-mediated vasoconstriction takes over and diastolic pressure rises.
Midodrine: an oral prodrug for standing blood pressure
Midodrine itself is a prodrug. Deglycination, which appears to occur in many tissues, forms desglymidodrine, an α1 agonist that activates α-receptors of the arteriolar and venous vasculature and raises vascular tone. Desglymidodrine does not stimulate cardiac β receptors and diffuses poorly across the blood–brain barrier, so it has no central nervous system effects.
Because it is an α1 agonist, the same receptor acts wherever it is found: α-receptors of hair follicles give pilomotor reactions (paresthesia, pruritus, piloerection, chills), and those of the bladder neck give urinary urgency, retention and frequency. Vascular tone does not switch off when the patient lies down, so supine pressure rises too — which is why doses are timed for the hours when the patient is upright.
Comparing the drugs
Receptor map
| Drug | α1 | β1 | β2 | D1 (dopamine) | V1 / other |
|---|---|---|---|---|---|
| Norepinephrine | Yes — slightly more than its β activity | Yes (β1 more than β2) | Less than β1 | — | — |
| Epinephrine | Yes — dominates at higher doses | Yes | Yes — dominates at low doses | — | — |
| Phenylephrine | Yes (pure α1) | — | — | — | — |
| Dopamine | High rates | Intermediate rates | — | Low rates (with D2): renal, mesenteric, coronary vasodilation | — |
| Dobutamine | Least (β1 > β2 > α) | Yes — main action | Some | — | — |
| Isoproterenol | Very low affinity | Yes | Yes | — | — |
| Vasopressin | — | — | — | — | V1 (vasoconstriction); V2 (antidiuresis) |
| Milrinone | — | Not a β agonist | — | — | PDE3 inhibition → ↑ cAMP |
| Midodrine | Yes, via desglymidodrine | No cardiac β stimulation | — | — | Prodrug (oral) |
| Ephedrine | Yes — direct, plus norepinephrine release | Yes — positive inotrope and chronotrope | Yes — vasodilation; bronchodilation | — | Indirect: releases norepinephrine from sympathetic neurons |
Selectivity is relative: these drugs bind more receptor types at higher doses.
Hemodynamic effects
| Drug | Heart rate | Contractility / cardiac output | Systemic vascular resistance | Blood pressure |
|---|---|---|---|---|
| Norepinephrine | Reflex vagal slowing offsets β1 | Output generally unaffected (can fall) | ↑ | ↑ — more than heart rate |
| Epinephrine | ↑ | ↑ | ↓ at low doses (β2), ↑ at higher doses (α1) | ↑ systolic |
| Phenylephrine | ↓ (reflex bradycardia) | Variable — may fall as afterload rises | ↑ | ↑ systolic, diastolic and mean |
| Dopamine | ↑ at intermediate rates | ↑ at intermediate rates | Renal/mesenteric vasodilation at low rates; constriction at high rates | ↑ at high rates |
| Dobutamine | Mild ↑ | ↑ — mainly stroke volume | Usually ↓ | Little change |
| Isoproterenol | ↑ — main driver of output | ↑ | ↓ | Diastolic ↓; mean usually ↓ |
| Vasopressin | Tends to ↓ | Tends to ↓ | ↑ | ↑ (reduces norepinephrine needs) |
| Milrinone | Mild-to-moderate ↑ | ↑ (wedge pressure ↓) | ↓ | Small fall; larger at high doses |
| Midodrine | No clinically significant change (slight vagal slowing possible) | No direct cardiac effect | ↑ arteriolar and venous tone | ↑ standing — and supine |
| Ephedrine | ↑ | ↑ cardiac output | Variably ↑ | Usually ↑ |
Pharmacokinetics
- Catecholamine half-lives — norepinephrine, epinephrine, dopamine, dobutamine
- Norepinephrine’s half-life is about 2.4 minutes, dopamine’s under 2 minutes, dobutamine’s 2 minutes and epinephrine’s under 5 minutes. Hence continuous infusion and titration: norepinephrine’s pressor effect stops within 1–2 minutes of stopping the infusion.
- How catecholamines are cleared — norepinephrine, epinephrine, dopamine, dobutamine
- Norepinephrine’s action ends mainly by uptake and metabolism in sympathetic nerve endings. Epinephrine is degraded by MAO and COMT, mostly in the liver and kidneys, to the inactive vanillylmandelic acid. Dopamine is metabolized by MAO and COMT, and dobutamine by catechol methylation and conjugation. Norepinephrine and dopamine do not cross the blood–brain barrier to a significant extent.
- Isoproterenol — isoproterenol
- Metabolized by COMT in the liver and other tissues; it is a poor MAO substrate and is taken up by sympathetic neurons less than epinephrine and norepinephrine, so its action may last longer than epinephrine’s but is still brief (half-life 2.5–5 minutes).
- Phenylephrine — phenylephrine
- Effective IV half-life about 5 minutes, with a large volume of distribution (340 L). It is extensively metabolized by the liver, mainly by MAO deamination; only 12% is excreted unchanged.
- Vasopressin — vasopressin
- A peptide cleaved by peptidases (only about 6% excreted unchanged), with an apparent half-life of 10 minutes or less in shock. The pressor effect peaks within 15 minutes and fades within 20 minutes of stopping. Placental vasopressinase raises clearance through pregnancy — about 4-fold by the third trimester.
- Milrinone — milrinone
- Half-life about 2.3 hours, 70% protein-bound. It is excreted mainly in the urine (83% unchanged), with renal clearance indicating active secretion, so renal impairment prolongs the half-life and the infusion rate is reduced.
- Midodrine — midodrine
- Oral bioavailability (as desglymidodrine) is 93%. The prodrug peaks at about 30 minutes (half-life about 25 minutes); desglymidodrine peaks at 1–2 hours with a half-life of 3–4 hours. Desglymidodrine is cleared mainly by active renal secretion and is dialyzable; neither compound is an MAO substrate.
Uses & drug choice
- Septic and other distributive shock (norepinephrine first-line; vasopressin added if hypotension persists, then epinephrine as the next step)
- Cardiogenic shock / decompensated heart failure (dobutamine — inotropic support)
- Cardiac arrest and anaphylaxis (epinephrine); symptomatic hypotension/bradycardia
- Milrinone for short-term IV treatment of acute decompensated heart failure
- Isoproterenol for distributive shock, shock from reduced cardiac output, and bronchospasm during anesthesia (labeled); also used for bradyarrhythmias
- Oral midodrine for symptomatic orthostatic hypotension that impairs daily life despite standard care
- Ephedrine (IV bolus) for clinically important hypotension in the setting of anesthesia
Adverse effects
- Tachycardia, palpitations and arrhythmias
- β1 stimulation raises cAMP and intracellular calcium, steepening phase 4 in pacemaker cells and increasing excitability. Norepinephrine is less likely than some other pressors to cause arrhythmias, probably because it is more α1-selective.
- Hyperglycemia
- Epinephrine increases glycogenolysis, reduces tissue glucose uptake and inhibits pancreatic insulin release; isoproterenol causes less hyperglycemia than epinephrine.
- Tremor and anxiety
- β2 stimulation causes tremor, tachycardia, palpitations and anxiety.
- Extravasation necrosis
- Leaked drug causes intense local α1-mediated vasoconstriction, ischemia and necrosis; phentolamine, a nonselective α antagonist, blocks those receptors and restores perfusion.
- Limb, digit and mesenteric ischemia
- α1 agonism constricts most vascular beds, including renal and splanchnic; norepinephrine’s rise in resistance reduces blood flow to the abdominal organs and skeletal muscle.
- Sulfite reactions
- The reaction is to the sulfite in the formulation, not to the catecholamine; sulfite sensitivity is more frequent in people with asthma.
- Milrinone: arrhythmias and hypotension
- Raised cAMP increases myocardial calcium, which can provoke ventricular arrhythmias; these are not dose-related. Hypotension comes from vasodilation, including greater venous capacitance that lowers preload, and is dose-related.
- Isoproterenol: myocardial ischemia
- β1 drive raises heart rate and myocardial oxygen demand while β2 vasodilation lowers diastolic pressure.
- Midodrine: supine hypertension
- Desglymidodrine raises arteriolar and venous tone regardless of posture, and with a 3–4-hour half-life, a late dose is still active when the patient lies down.
- Midodrine: goosebumps, scalp tingling, urinary retention
- α1 receptors on hair follicles (pilomotor reactions) and on the bladder neck.
Toxicity & antidote
Catecholamine overdose looks like the receptor profile pushed too far — severe hypertension, tachycardia, arrhythmias and peripheral vasoconstriction (dopamine overdose can cause gangrenous extremities). Half-lives of a few minutes mean that stopping the infusion usually ends the effect quickly. For dopamine toxicity that persists, StatPearls’ Dopamine chapter suggests an α-blocker such as phentolamine, although StatPearls’ Adrenergic Drugs chapter says α-blockers are not generally indicated for α-agonist overdose; β-blockers can treat tachycardia and hypertension caused by vasopressors, and IV metoprolol can reverse dobutamine-induced tachycardia.
For the longer-acting drugs, midodrine overdose (hypertension, piloerection, coldness, urinary retention) is treated with an α-sympatholytic such as phentolamine, and desglymidodrine is dialyzable. Milrinone overdose causes vasodilator hypotension: reduce or stop the infusion and support the circulation — there is no specific antidote. Isoproterenol has no known antidote either; management is supportive.
Interactions
Contraindications
- Uncorrected hypovolemia use caution — Squeezing an empty tank raises pressure at the cost of perfusion — restore volume first; pressors are not a substitute for fluid.
- Tachyarrhythmias / uncorrected tachycardia use caution — β1 stimulation can worsen a fast, unstable rhythm.
- Peripheral/mesenteric vascular disease use caution — Potent α1 vasoconstriction can precipitate limb or gut ischemia in already-compromised circulation.
- MAOIs / tricyclic antidepressants use caution — These potentiate catecholamine effects, risking severe, prolonged hypertension — and, with dopamine and MAOIs, cardiac arrhythmia.
- Halothane (halogenated) general anesthesia with an adrenergic pressor other than ephedrine — Adrenergic agents are contraindicated with halogenated anesthetics, which raise the risk of ventricular tachycardia or fibrillation. Ephedrine is left out of this row only because its own label lists no contraindications (it is indicated for hypotension during anesthesia); that label does not address halogenated anesthetics either way.
- Dopamine with pheochromocytoma — Labeled contraindication for dopamine; adrenergic vasopressors in general should be avoided in pheochromocytoma.
- Dobutamine with idiopathic hypertrophic subaortic stenosis — Labeled contraindication for dobutamine (as is a previous hypersensitivity reaction to it).
- Isoproterenol with tachycardia, ventricular arrhythmias or angina — Labeled contraindications for isoproterenol: its β1 drive speeds the heart and raises oxygen demand, and it can induce arrhythmias and myocardial ischemia.
- Midodrine with severe organic heart disease, acute renal disease, urinary retention, pheochromocytoma or thyrotoxicosis — Labeled contraindications for midodrine. Its active metabolite is cleared by the kidneys and acts on α receptors of the bladder neck.
- Midodrine with persistent, excessive supine hypertension — The label says not to use it: midodrine raises supine as well as standing blood pressure (boxed warning).
- Milrinone with severe obstructive aortic or pulmonic valve disease use caution — Not a substitute for surgical relief of the obstruction; like other inotropes, milrinone may also worsen outflow-tract obstruction in hypertrophic subaortic stenosis.
High-yield
- Gq squeezes — α1 and V1 receptors: phospholipase C → IP3 → calcium → vasoconstriction
- cAMP speeds the heart — β1 (Gs) raises cAMP: stronger contraction and a steeper phase 4
- …and slackens smooth muscle — β2 cAMP inactivates myosin light chain kinase: vessels and airways relax
- Milrinone keeps the cAMP — PDE3 inhibition gives both the heart and vessel effects without a receptor
- S — supine hypertension (the boxed warning)
- T — take it during the upright daytime hours, not near bedtime
- A — α1 agonist, via the active metabolite desglymidodrine
- N — no cardiac β stimulation and no CNS effects
- D — dysuria and retention (bladder neck), plus goosebumps (hair follicles)
Practice questions
Q1During an electrophysiology study, a 45-year-old man receives an IV catecholamine infusion. His heart rate rises from 70 to 115/min and diastolic pressure falls from 80 to 60 mm Hg, while systolic pressure is unchanged.
Which drug was most likely infused?
- A.Phenylephrine
- B.Norepinephrine
- C.Midodrine
- D.Vasopressin
- E.Isoproterenol
Show answer
E. Isoproterenol — Isoproterenol is a nonselective β agonist with very low α affinity. β1 raises heart rate and contractility, while β2 lowers peripheral resistance, so diastolic and usually mean pressure fall and systolic pressure may stay the same. Phenylephrine and norepinephrine raise resistance (with reflex slowing), vasopressin acts on V1 receptors, and midodrine is oral.
Q2A 63-year-old woman with acute decompensated heart failure has cool extremities and a low cardiac index. She is started on an IV inotrope that also lowers her wedge pressure and systemic vascular resistance. Its label states that it is not a β-adrenergic agonist.
Which enzyme does this drug inhibit?
- A.Adenylyl cyclase
- B.Na⁺/K⁺-ATPase
- C.Catechol-O-methyltransferase
- D.Phosphodiesterase 3
- E.Phosphodiesterase 5
Show answer
D. Phosphodiesterase 3 — Milrinone selectively inhibits the peak III (PDE3) cAMP phosphodiesterase in cardiac and vascular muscle. cAMP accumulates, increasing contractility in the heart and relaxing vascular muscle — an inotrope and vasodilator. It is not a β agonist and does not inhibit the Na⁺/K⁺-ATPase as digoxin does.
Q3A 70-year-old woman becomes hypotensive after induction of general anesthesia. After an IV bolus of a vasopressor, her blood pressure rises from 82/48 to 128/76 mm Hg and her heart rate falls from 84 to 56/min.
What best explains the fall in heart rate?
- A.Direct blockade of cardiac β1 receptors
- B.Baroreceptor-mediated increase in vagal activity
- C.Activation of V1 receptors in the SA node
- D.Inhibition of phosphodiesterase in pacemaker cells
- E.Stimulation of presynaptic D2 receptors
Show answer
B. Baroreceptor-mediated increase in vagal activity — Phenylephrine is a pure α1 agonist. As mean arterial pressure rises, vagal activity increases and causes reflex bradycardia. It has no β-blocking action; the slowing is a reflex response to the rise in pressure.
Q4A 74-year-old man with autonomic failure takes an oral drug three times daily for orthostatic dizziness. He reports scalp tingling, goosebumps and, at night in bed, a pounding headache with a supine blood pressure of 196/104 mm Hg.
Which advice best addresses his night-time symptoms?
- A.Move the last dose to bedtime
- B.Add a second α1 agonist from the pharmacy
- C.Sleep with the head of the bed raised and take doses only in the upright daytime hours
- D.Lie completely flat to improve venous return
- E.Take each dose with a high-fat meal
Show answer
C. Sleep with the head of the bed raised and take doses only in the upright daytime hours — Midodrine’s active metabolite, desglymidodrine, is an α1 agonist that raises supine as well as standing pressure (boxed warning). Supine hypertension is controlled by not lying fully flat (head of the bed elevated) and by dosing during the day — not after the evening meal or within about 4 hours of bedtime. The scalp tingling and goosebumps are pilomotor α1 effects.
Q5A 58-year-old man with septic shock remains hypotensive on a high-dose norepinephrine infusion after adequate fluids. A non-catecholamine vasopressor is added, and his mean arterial pressure rises while his norepinephrine requirement falls.
Through which pathway does the added drug constrict vascular smooth muscle?
- A.V1 receptors coupled to Gq/11, phospholipase C and IP3, releasing intracellular calcium
- B.V2 receptors coupled to adenylyl cyclase
- C.α1 receptors coupled to Gs and cAMP
- D.Inhibition of PDE3 in vascular smooth muscle
- E.Blockade of presynaptic norepinephrine reuptake
Show answer
A. V1 receptors coupled to Gq/11, phospholipase C and IP3, releasing intracellular calcium — Vasopressin constricts vessels through V1 receptors on vascular smooth muscle coupled to the Gq/11–phospholipase C–IP3 pathway, releasing intracellular calcium. Its V2 receptors (adenylyl cyclase) mediate antidiuresis instead. In vasodilatory shock it raises systemic resistance and pressure and reduces norepinephrine requirements.
Sources
- Inotropes and Vasopressors — receptor profiles, indications, titration — StatPearls (NCBI)
- Norepinephrine — first-line pressor in septic shock, adverse effects — StatPearls (NCBI)
- LEVOPHED (norepinephrine) — prescribing information — DailyMed (NLM)
- ADRENALIN (epinephrine) — prescribing information — DailyMed (NLM)
- Dopamine HCl Injection — prescribing information — DailyMed (NLM)
- Dobutamine Injection — prescribing information — DailyMed (NLM)
- Phentolamine Mesylate for Injection — extravasation of norepinephrine — DailyMed (NLM)
- Phenylephrine HCl Injection — prescribing information — DailyMed (NLM)
- Drugs@FDA — VAZCULEP (NDA 204300) marketing status — U.S. FDA
- Insights from the 2026 Surviving Sepsis Campaign guidelines (MAP target, peripheral vasopressors) — Acute and Critical Care (PMC)
- Autonomic nervous system — adrenergic agonists (Ch. 4) — Open RN — Nursing Pharmacology
- High alert medications off the radar: a systematic review (ISMP list, Table 6) — PMC (open access)
- Advanced Cardiac Life Support (ACLS) — epinephrine, dopamine — StatPearls (NCBI)
- Septic Shock — perfusion assessment — StatPearls (NCBI)
- VASOSTRICT (vasopressin) — vasodilatory shock despite fluids and catecholamines (FDA label) — DailyMed (NLM)
- Shock — norepinephrine first, vasopressin added if refractory — StatPearls (NCBI Bookshelf)
- Epinephrine — next-step pressor after norepinephrine and vasopressin in septic shock (StatPearls, citing the Surviving Sepsis Campaign) — StatPearls (NCBI Bookshelf)
- Milrinone Lactate Injection (Hospira) — FDA label: PDE3 mechanism, short-term use in acute decompensated HF, arrhythmia warnings, renal dosing — DailyMed (NLM)
- Milrinone — inotropy and lusitropy, chronotropy vs catecholamines, monitoring — StatPearls (NCBI)
- Isoproterenol Hydrochloride Injection (Amphastar) — FDA label: indications, contraindications, interactions — DailyMed (NLM)
- Isoproterenol — β1/β2 effects, bradydysrhythmias, monitoring — StatPearls (NCBI)
- Midodrine Hydrochloride Tablets (Apotex) — FDA label: boxed warning (supine hypertension), prodrug desglymidodrine, dosing-time principle — DailyMed (NLM)
- The use of stems in the selection of INN (2018) — -rinone, -drine — World Health Organization
- Akovaz (ephedrine sulfate) — hypotension during anesthesia; direct α/β agonist and norepinephrine release; tachyphylaxis, oxytocic interaction (FDA label) — FDA / DailyMed
- Emerphed (ephedrine sulfate) — FDA label — FDA / DailyMed
- Adrenergic Drugs — receptor subtypes and G-protein coupling, adverse effects by receptor — StatPearls (NCBI)
- Dobutamine — β1 inotropy, baroreceptor response, toxicity — StatPearls (NCBI)
- Dopamine — pharmacokinetics, overdose and phentolamine — StatPearls (NCBI)
- Phenylephrine — α1 agonism, reflex bradycardia, cardiac output — StatPearls (NCBI)
- Physiology, Vasopressin — V receptors and the PLC–IP3 pathway — StatPearls (NCBI)
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.