Toxicology – Amrinone (Inamrinone) and Milrinone

Core Concept

Amrinone, now generally called inamrinone, and milrinone are phosphodiesterase-3 (PDE3) inhibitors with combined:

• Positive inotropic effects – increase cardiac contractility
• Vasodilator effects – decrease systemic and pulmonary vascular resistance

For this reason they are sometimes called inodilators.

Milrinone has largely replaced inamrinone in contemporary clinical practice because of more favorable pharmacologic and adverse-effect characteristics.

The major acute toxic effects are:

Excessive vasodilation → hypotension

and

Increased myocardial excitability → tachyarrhythmias/ventricular dysrhythmias

There is no specific antidote.

Modern Clinical Role

Milrinone may be used for short-term hemodynamic support in selected patients with:

• Acute decompensated heart failure with low cardiac output
• Severe ventricular dysfunction
• Post-cardiac-surgery low-output states
• Selected right ventricular failure
• Selected pulmonary hypertension situations

Its use requires careful hemodynamic assessment because increased contractility may be offset by substantial vasodilation.

Inamrinone is now rarely used compared with milrinone.

PDE3 Physiology

Normally:

Adenylyl cyclase → cAMP

while:

PDE3 breaks down cAMP

PDE3 inhibition therefore increases intracellular cAMP.

Cardiac Mechanism

In cardiac myocytes:

PDE3 inhibition → ↑ cAMP → ↑ protein kinase A activity → ↑ intracellular Ca²⁺ availability → stronger contraction

The result is:

• Increased myocardial contractility
• Increased stroke volume
• Increased cardiac output in appropriately selected patients

Unlike catecholamines, the drug does not require direct β-receptor stimulation to generate its primary inotropic effect.

Vascular Mechanism

In vascular smooth muscle, increased cAMP promotes relaxation.

Therefore:

PDE3 inhibition → vasodilation → ↓ systemic vascular resistance

It can also decrease pulmonary vascular resistance.

Thus the overall pharmacologic profile is:

↑ Contractility + ↓ afterload = inodilation

Why Hypotension Occurs

The same vasodilating action that may improve forward cardiac output can become excessive.

In toxicity:

Excessive vasodilation → ↓ SVR → hypotension → impaired organ perfusion

This is especially important in patients who already have:

• Low blood pressure
• Volume depletion
• Severe heart failure
• Other vasodilating medications

Toxic Dose

A reliable universal toxic threshold has not been established.

Most clinically important toxicity historically occurred through:

• Therapeutic dosing errors
• Excessive IV administration
• Drug accumulation

Clinical severity is more useful than a reported amount.

Milrinone and Renal Function

Milrinone is substantially dependent on renal elimination.

Therefore:

Renal impairment → reduced clearance → prolonged exposure → greater risk of hypotension and dysrhythmias

Renal function is consequently an important consideration during both therapeutic use and suspected toxicity.

Dose accumulation may occur even without a single dramatic overdose.

Acute Cardiovascular Toxicity

The major findings are:

• Hypotension
• Tachycardia
• Palpitations
• Ventricular ectopy
• Supraventricular dysrhythmias
• Ventricular dysrhythmias

Severe hypotension can lead to:

• Altered mental status
• Myocardial ischemia
• Acute kidney injury
• Shock

Dysrhythmias

PDE3 inhibition can increase myocardial excitability.

Possible rhythm disturbances include:

• Premature ventricular complexes
• Atrial tachyarrhythmias
• Ventricular tachycardia
• Other ventricular dysrhythmias

Risk may be increased by:

• Hypokalemia
• Hypomagnesemia
• Structural heart disease
• Myocardial ischemia
• Other proarrhythmic medications

Electrolytes

Electrolyte abnormalities can increase dysrhythmia risk.

Particular attention should be given to:

• Potassium
• Magnesium
• Calcium

Hypokalemia may occur in patients receiving intensive heart-failure treatment, particularly when concurrent diuretics are being used.

Gastrointestinal Effects

Reported adverse effects include:

• Nausea
• Vomiting
• Diarrhea
• Abdominal discomfort

These are generally less important than cardiovascular toxicity during acute poisoning.

Thrombocytopenia

Inamrinone has historically been associated with thrombocytopenia, particularly during sustained therapy.

It is generally:

• Dose/exposure related
• Reversible after dose reduction or discontinuation

This adverse effect was one factor limiting long-term use.

Milrinone has a substantially lower tendency to produce this complication.

Hepatic Effects

Inamrinone has also been associated with:

• Aminotransferase abnormalities
• Rare clinically significant hepatotoxicity

This is more relevant to prolonged exposure than a brief acute overdose.

Why Chronic Oral PDE3 Therapy Fell Out of Favor

An important modern point is that chronic oral PDE3 inhibitor therapy for heart failure did not improve long-term survival and was associated with adverse outcomes.

Therefore, contemporary milrinone use is primarily short-term IV therapy in selected patients, rather than routine chronic oral heart-failure treatment.

Diagnosis

Diagnosis is based primarily on:

• Medication history
• Infusion history
• Hemodynamic findings
• ECG
• Renal function
• Electrolytes

There is no routinely useful serum inamrinone or milrinone concentration for emergency toxicologic decision-making.

Essential Assessment

In clinically important toxicity, evaluate:

• Blood pressure
• Heart rate
• Mental status
• Peripheral perfusion
• ECG
• Continuous cardiac rhythm

Laboratory evaluation may include:

• Electrolytes
• Potassium
• Magnesium
• Calcium
• Creatinine
• Glucose

Additional tests depend on severity.

Chronic-Therapy Evaluation

If adverse effects develop during prolonged inamrinone exposure, additional evaluation can include:

• CBC with platelet count
• Liver enzymes
• Renal function
• Electrolytes

For milrinone, renal function is especially important because impaired clearance can substantially prolong its effects.

Initial Management of IV Overdose

The first step in excessive IV administration is straightforward:

Stop the infusion.

Then assess:

• Airway and breathing
• Blood pressure and perfusion
• Cardiac rhythm
• Renal function
• Electrolytes

Significant hypotension or dysrhythmia warrants monitored critical care.

Hypotension Management

Treatment depends on both volume status and cardiac function.

Appropriate isotonic crystalloid may be useful if the patient is volume depleted.

However, many patients receiving PDE3 inhibitors already have severe heart failure, so indiscriminate fluid loading may cause:

• Pulmonary edema
• Worsening congestion
• Respiratory compromise

Fluid therapy should therefore be individualized.

Trendelenburg – Modern Correction

Routine Trendelenburg positioning is obsolete as treatment for hypotension.

It does not provide reliable sustained improvement in organ perfusion and may worsen respiratory mechanics in some patients.

Vasopressors

Persistent vasodilatory hypotension may require a vasopressor.

A vasoconstricting agent such as norepinephrine is commonly appropriate when significant vasodilatory shock persists.

Selection should account for:

• Cardiac function
• Rhythm
• Degree of vasodilation
• Perfusion
• Other medications

Atropine

The historical source recommends atropine if hypotension is caused by bradycardia.

Atropine may be appropriate for clinically important symptomatic bradycardia, but bradycardia is not the characteristic toxicity of PDE3 inhibition.

Hypotension should not automatically be treated with atropine unless the heart-rate disturbance is actually contributing to poor perfusion.

Dysrhythmia Management

Management includes:

• Stop the offending drug
• Correct hypoxemia
• Correct significant potassium abnormalities
• Correct magnesium abnormalities
• Treat acid–base disturbances
• Evaluate myocardial ischemia
• Follow contemporary resuscitation principles for unstable dysrhythmias

Electrical cardioversion/defibrillation is used when indicated by the rhythm and hemodynamic state.

Drug Interactions

Concomitant medications may amplify toxicity.

Examples include:

• Other vasodilators → greater hypotension
• Other positive inotropes → greater myocardial oxygen demand or arrhythmia risk
• Diuretics → electrolyte depletion
• Other proarrhythmic drugs → greater dysrhythmia risk

Medication compatibility is also important for IV therapy; drugs should not be mixed in the same line unless compatibility is established.

Outflow Obstruction

Increasing contractility while reducing vascular resistance can be undesirable in some forms of dynamic ventricular outflow obstruction.

Therefore, PDE3 inhibitors require caution in conditions where stronger contraction may worsen an obstructive pressure gradient.

Sulfite Hypersensitivity – Modern Nuance

Some older inamrinone formulations contained sulfite preservatives.

The historical statement that asthma itself is an absolute contraindication is too broad.

Sulfite-sensitive individuals, particularly some patients with asthma, may be at greater risk of hypersensitivity reactions depending on the formulation.

Current product ingredients should be checked rather than assuming all PDE3 inhibitor preparations carry the same risk.

GI Decontamination

Modern milrinone and inamrinone toxicity is usually related to parenteral therapy, making gastrointestinal decontamination irrelevant in most cases.

For an unusual oral exposure:

• Do not induce vomiting.
• Routine gastric lavage is obsolete.

Activated charcoal might be considered only in selected recent clinically significant oral exposures when the airway is safe.

It should not delay cardiovascular stabilization.

No Specific Antidote

There is no specific reversal agent for inamrinone or milrinone toxicity.

Treatment consists of:

• Discontinuing exposure
• Hemodynamic support
• Correction of electrolytes
• Dysrhythmia treatment
• Management of complications

Extracorporeal Removal

Extracorporeal removal is not a routine antidotal strategy for PDE3 inhibitor toxicity.

In severe milrinone toxicity with renal dysfunction, management should involve toxicology, cardiology, and critical-care specialists because prolonged pharmacologic effects may occur.

Monitoring

Significant toxicity requires monitoring of:

• Blood pressure
• Heart rate
• ECG/rhythm
• Oxygenation
• Mental status
• Urine output
• Renal function
• Potassium
• Magnesium

Additional monitoring is guided by the clinical course.

Observation

The historical fixed 6-hour observation period should not be applied universally.

Duration depends on:

• Agent
• Route
• Magnitude of exposure
• Renal function
• Symptoms
• ECG findings
• Hemodynamic stability

Milrinone toxicity may be prolonged when renal clearance is impaired.

Admission

Monitored inpatient care is appropriate for:

• Persistent hypotension
• Significant dysrhythmia
• Evidence of poor organ perfusion
• Significant electrolyte abnormalities
• Renal dysfunction with suspected drug accumulation

Severe hemodynamic instability generally warrants intensive-care management.

Pregnancy

The historical FDA pregnancy letter category is obsolete.

Clinically significant toxicity during pregnancy should be treated according to maternal physiology.

Particularly important goals are maintaining:

• Maternal blood pressure
• Oxygenation
• Cardiac output
• Uteroplacental perfusion

Necessary treatment should not be withheld solely because of pregnancy.

Prognosis

Mild toxicity usually improves after:

• Drug discontinuation
• Clearance of the medication
• Correction of hemodynamic and electrolyte abnormalities

Prognosis becomes more serious when there is:

• Refractory shock
• Sustained ventricular dysrhythmia
• Severe underlying cardiac disease
• Renal failure causing prolonged milrinone exposure
• Multiorgan hypoperfusion

Important Modernization of the Older Source

• Amrinone is now generally called inamrinone.
• Inamrinone and milrinone are PDE3 inhibitors/inodilators.
• Milrinone has largely replaced inamrinone in contemporary practice.
• PDE3 inhibition → ↑ cAMP → increased cardiac contractility plus vascular relaxation.
• Acute toxicity is dominated by hypotension and dysrhythmias.
• Milrinone depends substantially on renal clearance; renal impairment can prolong toxicity.
• Inamrinone is more strongly associated with thrombocytopenia during prolonged exposure.
• Chronic oral PDE3 inhibitor therapy is not routine modern heart-failure treatment because long-term outcome data were unfavorable.
• Asthma alone is not a universal absolute contraindication; sulfite sensitivity depends partly on formulation.
• Routine Trendelenburg positioning is obsolete.
• Fluid resuscitation must be cautious in patients with heart failure.
• Persistent vasodilatory shock may require norepinephrine or another appropriately selected vasopressor.
• Atropine is relevant only when clinically important bradycardia is actually present.
• Routine gastric lavage is obsolete.
• There is no specific antidote.
• Observation should account for renal function and clinical trajectory rather than follow a fixed 6-hour rule.

Key Points

• Inamrinone/milrinone = PDE3 inhibitors.
• ↑ cAMP in myocardium → ↑ intracellular Ca²⁺ → positive inotropy.
• ↑ cAMP in vascular smooth muscle → vasodilation.
• Together these effects make them inodilators.
• Main acute toxicities: hypotension + dysrhythmias.
• Check and correct K⁺, Mg²⁺, and other relevant electrolyte abnormalities.
• Milrinone toxicity can be prolonged in renal impairment.
• Inamrinone can cause thrombocytopenia, especially with prolonged exposure.
• Stop an excessive infusion immediately and provide hemodynamic and rhythm support.
• No specific antidote exists.

237. Toxicology – Amrinone (Inamrinone) and Milrinone

Core Concept

Amrinone, now generally called inamrinone, and milrinone are phosphodiesterase-3 (PDE3) inhibitors with combined:

Positive inotropic effects – increase cardiac contractility   Vasodilator effects – decrease systemic and pulmonary vascular resistance

For this reason they are sometimes called inodilators.

Milrinone has largely replaced inamrinone in contemporary clinical practice because of more favorable pharmacologic and adverse-effect characteristics.

The major acute toxic effects are:

Excessive vasodilation → hypotension

and

Increased myocardial excitability → tachyarrhythmias/ventricular dysrhythmias

There is no specific antidote.

⸻

Modern Clinical Role

Milrinone may be used for short-term hemodynamic support in selected patients with:

Acute decompensated heart failure with low cardiac output   Severe ventricular dysfunction   Post-cardiac-surgery low-output states   Selected right ventricular failure   Selected pulmonary hypertension situations

Its use requires careful hemodynamic assessment because increased contractility may be offset by substantial vasodilation.

Inamrinone is now rarely used compared with milrinone.

⸻

PDE3 Physiology

Normally:

Adenylyl cyclase → cAMP

while:

PDE3 breaks down cAMP

PDE3 inhibition therefore increases intracellular cAMP.

⸻

Cardiac Mechanism

In cardiac myocytes:

PDE3 inhibition → ↑ cAMP → ↑ protein kinase A activity → ↑ intracellular Ca²⁺ availability → stronger contraction

The result is:

Increased myocardial contractility   Increased stroke volume   Increased cardiac output in appropriately selected patients

Unlike catecholamines, the drug does not require direct β-receptor stimulation to generate its primary inotropic effect.

⸻

Vascular Mechanism

In vascular smooth muscle, increased cAMP promotes relaxation.

Therefore:

PDE3 inhibition → vasodilation → ↓ systemic vascular resistance

It can also decrease pulmonary vascular resistance.

Thus the overall pharmacologic profile is:

↑ Contractility + ↓ afterload = inodilation

⸻

Why Hypotension Occurs

The same vasodilating action that may improve forward cardiac output can become excessive.

In toxicity:

Excessive vasodilation → ↓ SVR → hypotension → impaired organ perfusion

This is especially important in patients who already have:

Low blood pressure   Volume depletion   Severe heart failure   Other vasodilating medications

⸻

Toxic Dose

A reliable universal toxic threshold has not been established.

Most clinically important toxicity historically occurred through:

Therapeutic dosing errors   Excessive IV administration   Drug accumulation

Clinical severity is more useful than a reported amount.

⸻

Milrinone and Renal Function

Milrinone is substantially dependent on renal elimination.

Therefore:

Renal impairment → reduced clearance → prolonged exposure → greater risk of hypotension and dysrhythmias

Renal function is consequently an important consideration during both therapeutic use and suspected toxicity.

Dose accumulation may occur even without a single dramatic overdose.

⸻

Acute Cardiovascular Toxicity

The major findings are:

Hypotension   Tachycardia   Palpitations   Ventricular ectopy   Supraventricular dysrhythmias   Ventricular dysrhythmias

Severe hypotension can lead to:

Altered mental status   Myocardial ischemia   Acute kidney injury   Shock

⸻

Dysrhythmias

PDE3 inhibition can increase myocardial excitability.

Possible rhythm disturbances include:

Premature ventricular complexes   Atrial tachyarrhythmias   Ventricular tachycardia   Other ventricular dysrhythmias

Risk may be increased by:

Hypokalemia   Hypomagnesemia   Structural heart disease   Myocardial ischemia   Other proarrhythmic medications

⸻

Electrolytes

Electrolyte abnormalities can increase dysrhythmia risk.

Particular attention should be given to:

Potassium   Magnesium   Calcium

Hypokalemia may occur in patients receiving intensive heart-failure treatment, particularly when concurrent diuretics are being used.

⸻

Gastrointestinal Effects

Reported adverse effects include:

Nausea   Vomiting   Diarrhea   Abdominal discomfort

These are generally less important than cardiovascular toxicity during acute poisoning.

⸻

Thrombocytopenia

Inamrinone has historically been associated with thrombocytopenia, particularly during sustained therapy.

It is generally:

Dose/exposure related   Reversible after dose reduction or discontinuation

This adverse effect was one factor limiting long-term use.

Milrinone has a substantially lower tendency to produce this complication.

⸻

Hepatic Effects

Inamrinone has also been associated with:

Aminotransferase abnormalities   Rare clinically significant hepatotoxicity

This is more relevant to prolonged exposure than a brief acute overdose.

⸻

Why Chronic Oral PDE3 Therapy Fell Out of Favor

An important modern point is that chronic oral PDE3 inhibitor therapy for heart failure did not improve long-term survival and was associated with adverse outcomes.

Therefore, contemporary milrinone use is primarily short-term IV therapy in selected patients, rather than routine chronic oral heart-failure treatment.

⸻

Diagnosis

Diagnosis is based primarily on:

Medication history   Infusion history   Hemodynamic findings   ECG   Renal function   Electrolytes

There is no routinely useful serum inamrinone or milrinone concentration for emergency toxicologic decision-making.

⸻

Essential Assessment

In clinically important toxicity, evaluate:

Blood pressure   Heart rate   Mental status   Peripheral perfusion   ECG   Continuous cardiac rhythm

Laboratory evaluation may include:

Electrolytes   Potassium   Magnesium   Calcium   Creatinine   Glucose

Additional tests depend on severity.

⸻

Chronic-Therapy Evaluation

If adverse effects develop during prolonged inamrinone exposure, additional evaluation can include:

CBC with platelet count   Liver enzymes   Renal function   Electrolytes

For milrinone, renal function is especially important because impaired clearance can substantially prolong its effects.

⸻

Initial Management of IV Overdose

The first step in excessive IV administration is straightforward:

Stop the infusion.

Then assess:

Airway and breathing   Blood pressure and perfusion   Cardiac rhythm   Renal function   Electrolytes

Significant hypotension or dysrhythmia warrants monitored critical care.

⸻

Hypotension Management

Treatment depends on both volume status and cardiac function.

Appropriate isotonic crystalloid may be useful if the patient is volume depleted.

However, many patients receiving PDE3 inhibitors already have severe heart failure, so indiscriminate fluid loading may cause:

Pulmonary edema   Worsening congestion   Respiratory compromise

Fluid therapy should therefore be individualized.

⸻

Trendelenburg – Modern Correction

Routine Trendelenburg positioning is obsolete as treatment for hypotension.

It does not provide reliable sustained improvement in organ perfusion and may worsen respiratory mechanics in some patients.

⸻

Vasopressors

Persistent vasodilatory hypotension may require a vasopressor.

A vasoconstricting agent such as norepinephrine is commonly appropriate when significant vasodilatory shock persists.

Selection should account for:

Cardiac function   Rhythm   Degree of vasodilation   Perfusion   Other medications

⸻

Atropine

The historical source recommends atropine if hypotension is caused by bradycardia.

Atropine may be appropriate for clinically important symptomatic bradycardia, but bradycardia is not the characteristic toxicity of PDE3 inhibition.

Hypotension should not automatically be treated with atropine unless the heart-rate disturbance is actually contributing to poor perfusion.

⸻

Dysrhythmia Management

Management includes:

Stop the offending drug   Correct hypoxemia   Correct significant potassium abnormalities   Correct magnesium abnormalities   Treat acid–base disturbances   Evaluate myocardial ischemia   Follow contemporary resuscitation principles for unstable dysrhythmias

Electrical cardioversion/defibrillation is used when indicated by the rhythm and hemodynamic state.

⸻

Drug Interactions

Concomitant medications may amplify toxicity.

Examples include:

Other vasodilators → greater hypotension   Other positive inotropes → greater myocardial oxygen demand or arrhythmia risk   Diuretics → electrolyte depletion   Other proarrhythmic drugs → greater dysrhythmia risk

Medication compatibility is also important for IV therapy; drugs should not be mixed in the same line unless compatibility is established.

⸻

Outflow Obstruction

Increasing contractility while reducing vascular resistance can be undesirable in some forms of dynamic ventricular outflow obstruction.

Therefore, PDE3 inhibitors require caution in conditions where stronger contraction may worsen an obstructive pressure gradient.

⸻

Sulfite Hypersensitivity – Modern Nuance

Some older inamrinone formulations contained sulfite preservatives.

The historical statement that asthma itself is an absolute contraindication is too broad.

Sulfite-sensitive individuals, particularly some patients with asthma, may be at greater risk of hypersensitivity reactions depending on the formulation.

Current product ingredients should be checked rather than assuming all PDE3 inhibitor preparations carry the same risk.

⸻

GI Decontamination

Modern milrinone and inamrinone toxicity is usually related to parenteral therapy, making gastrointestinal decontamination irrelevant in most cases.

For an unusual oral exposure:

Do not induce vomiting.   Routine gastric lavage is obsolete.

Activated charcoal might be considered only in selected recent clinically significant oral exposures when the airway is safe.

It should not delay cardiovascular stabilization.

⸻

No Specific Antidote

There is no specific reversal agent for inamrinone or milrinone toxicity.

Treatment consists of:

Discontinuing exposure   Hemodynamic support   Correction of electrolytes   Dysrhythmia treatment   Management of complications

⸻

Extracorporeal Removal

Extracorporeal removal is not a routine antidotal strategy for PDE3 inhibitor toxicity.

In severe milrinone toxicity with renal dysfunction, management should involve toxicology, cardiology, and critical-care specialists because prolonged pharmacologic effects may occur.

⸻

Monitoring

Significant toxicity requires monitoring of:

Blood pressure   Heart rate   ECG/rhythm   Oxygenation   Mental status   Urine output   Renal function   Potassium   Magnesium

Additional monitoring is guided by the clinical course.

⸻

Observation

The historical fixed 6-hour observation period should not be applied universally.

Duration depends on:

Agent   Route   Magnitude of exposure   Renal function   Symptoms   ECG findings   Hemodynamic stability

Milrinone toxicity may be prolonged when renal clearance is impaired.

⸻

Admission

Monitored inpatient care is appropriate for:

Persistent hypotension   Significant dysrhythmia   Evidence of poor organ perfusion   Significant electrolyte abnormalities   Renal dysfunction with suspected drug accumulation

Severe hemodynamic instability generally warrants intensive-care management.

⸻

Pregnancy

The historical FDA pregnancy letter category is obsolete.

Clinically significant toxicity during pregnancy should be treated according to maternal physiology.

Particularly important goals are maintaining:

Maternal blood pressure   Oxygenation   Cardiac output   Uteroplacental perfusion

Necessary treatment should not be withheld solely because of pregnancy.

⸻

Prognosis

Mild toxicity usually improves after:

Drug discontinuation   Clearance of the medication   Correction of hemodynamic and electrolyte abnormalities

Prognosis becomes more serious when there is:

Refractory shock   Sustained ventricular dysrhythmia   Severe underlying cardiac disease   Renal failure causing prolonged milrinone exposure   Multiorgan hypoperfusion

⸻

Important Modernization of the Older Source

Amrinone is now generally called inamrinone.   Inamrinone and milrinone are PDE3 inhibitors/inodilators.   Milrinone has largely replaced inamrinone in contemporary practice.   PDE3 inhibition → ↑ cAMP → increased cardiac contractility plus vascular relaxation.   Acute toxicity is dominated by hypotension and dysrhythmias.   Milrinone depends substantially on renal clearance; renal impairment can prolong toxicity.   Inamrinone is more strongly associated with thrombocytopenia during prolonged exposure.   Chronic oral PDE3 inhibitor therapy is not routine modern heart-failure treatment because long-term outcome data were unfavorable.   Asthma alone is not a universal absolute contraindication; sulfite sensitivity depends partly on formulation.   Routine Trendelenburg positioning is obsolete.   Fluid resuscitation must be cautious in patients with heart failure.   Persistent vasodilatory shock may require norepinephrine or another appropriately selected vasopressor.   Atropine is relevant only when clinically important bradycardia is actually present.   Routine gastric lavage is obsolete.   There is no specific antidote.   Observation should account for renal function and clinical trajectory rather than follow a fixed 6-hour rule.

Key Points

Inamrinone/milrinone = PDE3 inhibitors.   ↑ cAMP in myocardium → ↑ intracellular Ca²⁺ → positive inotropy.   ↑ cAMP in vascular smooth muscle → vasodilation.   Together these effects make them inodilators.   Main acute toxicities: hypotension + dysrhythmias.   Check and correct K⁺, Mg²⁺, and other relevant electrolyte abnormalities.   Milrinone toxicity can be prolonged in renal impairment.   Inamrinone can cause thrombocytopenia, especially with prolonged exposure.   Stop an excessive infusion immediately and provide hemodynamic and rhythm support.   No specific antidote exists.