Protocol for Angiotensin converting enzyme inhibitors (ACEIs) poisoning management

Transcription

1 Protocol for Angiotensin converting enzyme inhibitors (ACEIs) poisoning management Category/Use Treatment of hypertension, congestive heart failure (CHF), diabetic nephropathy, and post myocardial infarction Specific substances Benazepril; Captopril; Enalapril; Fosinopril; Lisinopril; Quinapril; Ramipril; Trandolapril Range of toxicity Adults: Patients have ingested the following with only mild hypotension reported: 7.5 g captopril, 300 mg enalapril, and 420 mg lisinopril. Fatalities have occurred after ingestions of 1125 mg captopril and 180 mg perindopril. Children: Less than 6 years old remained asymptomatic after ingestion of up to 8 mg/kg captopril or up to 2 mg/kg enalapril or lisinopril without gastrointestinal decontamination. In one study, children remained asymptomatic after ingestions of up to 100 mg captopril or 30 mg enalapril. Mortality rate/survival rate: Not available Clinical presentation Ingestion: Common symptoms may include dizziness and drowsiness. A small percentage of patients will have hypotension, bradycardia, and renal impairment. Comprehensive listing by system (listed alphabetically): Cardiovascular: Bradycardia, edema, hypertension, hypotension, tachycardia Central nervous system: Coma, confusion, dizziness, drowsiness, headache, lethargy, loss of consciousness Dermatologic: Angioedema (rare), dermatitis Endocrine & metabolic: Hyperglycemia, hyperkalemia, hyponatremia, metabolic acidosis Gastrointestinal: Diarrhea, intestinal edema, nausea, vomiting Renal: Elevated BUN, elevated serum creatinine, oliguria, renal dysfunction Respiratory: Cough, cyanosis, dyspnea Mechanism of toxicity:

2 Angiotensin I is formed by the action of renin on circulating angiotensinogen which is then converted to the vasoconstrictor angiotensin II by angiotensin-converting enzyme (ACE). ACE also blocks the metabolism of the vasodilator bradykinin; thus, ACE inhibitors produce vasodilation and decrease blood pressure by inhibiting the formation of angiotensin II and preventing the breakdown of bradykinin. As angiotensin II also enhances the release and inhibits the reuptake of norepinephrine from sympathetic adrenergic neurons, the effect of ACE inhibitors also includes diminished cardiovascular sympathetic activity. ACE inhibitors cause fluid and electrolyte abnormalities by preventing the angiotensin II-mediated release of aldosterone Pharmaco kinetics: DRUGS ONSET OF ACTION ABSORPTION DISTRIBUTION METABOLISM ELIMINATION Benazepril Peak effect: 1-2 after 2- Rapid (37%); food does not alter significantly; V d : 8.7 L Rapidly and extensively Nonrenal clearance appears to contribute to 20 mg dose metabolite(benazeprilat) hepatic to its the elimination (11% to Duration: >90%inhibition for 24 after 5-20 mg dose itself unsuitable for oral administration due to poor absorption active metabolite, benazeprilat, via enzymatic hydrolysis; extensive firstpass effect 12%), particularly patients with severe renal impairment; hepatic clearance is the main elimination route of unchanged benazepril Captopril Peak effect: 60% to 75%; reduced Protein binding: 50% Urine (95%) within 24 Blood pressure 30% to 40% by food 25% to 30% reduction:1-1.5 after dose Duration: Dose-related, may require several weeks of therapy before full hypotensive

3 effect Enalapril Oral: 1 hour Oral: 55% to 75% Protein binding: Metabolism: Urine (60% to 80%); Duration: Oral: % to 60% Prodrug, undergoes hepatic biotransformation some feces to enalaprilat Fosinopril 1 hour 36% Protein binding: Prodrug, Urine and feces (as Duration: 24 95% hydrolyzed to its active metabolite fosinoprilat by fosinoprilat and other metabolites in roughly equal proportions, 45% intestinal wall and to 50%) hepatic esterases Bioavailability: 36% lisinopril Onset of Well absorbed; Protein binding: Primarily urine (as action: 1 hour unaffected by food 25% unchanged drug) Peak effect: Hypotensive: Oral: 6 Duration: 24 Quinapril Onset of Quinapril: 60% Protein binding: Rapidly Urine (50% to 60% action: 1 hour Quinapril: 97%; hydrolyzed to primarily as Duration: 24 Quinaprilat: 97% quinaprilat, the quinaprilat) active metabolite Rampiril Onset of Well-absorbed (50% to Plasma levels Hepatic to the Urine (60%) and feces action: %) decline in a active form, (40%) as parent drug triphasic fashion; ramiprilat and metabolites rapid decline is a Duration: 24 distribution phase to peripheral compartment, plasma protein and tissue ACE (halflife 2-4 ); second phase is an apparent elimination phase representing the clearance of free

4 ramiprilat (halflife: 9-18 ); and final phase is the terminal elimination phase representing the equilibrium phase between tissue binding and dissociation DRUG HALF LIFE ELIMINATION TIME TO PEAK Benazepril Effective: ; Time to peak: Parent drug: hour Terminal: Children: 5, Adults: 22 Captopril Adults, healthy volunteers: 1.9 ; Congestive heart failure: 2.06 ; Anuria: hour Enalapril Adults: Healthy: 2 ; Congestive heart failure: serum: Oral: Enalapril: ; Enalaprilat (active): Infants 6 weeks to 8 months old: 6-10 ; Adults: Fosinopril serum (fosinoprilat): 12 serum: 3 hourz Lisinopril Quinapril Quinapril: 0.8 ; Quinaprilat: 3 ; serum: Quinapril: 1 hour; Quinaprilat: 2 increases as Cl cr decreases Ramipril Effective: ; Terminal: >50 serum: 1 hour Criteria for hospital admission: No specific information available. However a patient with toxic ingestion needs medical assistance. Monitoring parameters:

5 Monitor vital signs frequently. Routine laboratory tests are not usually necessary. Other labs such as serum electrolytes, renal function, and ECG should be ordered, if clinically indicated First aid measures: Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Treatment Stabilisation: Initially, evaluate and correct immediate life-threatening complications (eg, airway, breathing, and circulation). The most common symptom of ACE-inhibitor overdose is hypotension. Decontamination method: Emesis Indications/cautions: Ipecac should only be considered for treatment of patients in whom: 1) There is no contraindication. 2) There is a substantial chance of serious toxicity based on the substance and quantity ingested. 3) There is no alternative available to decrease GI absorption. 4) There will be a delay of more than 1 hour before a patient can reach an emergency medical facility. 5) Ipecac can be administered within 30 to 90 minutes of ingestion. 6) It should generally NOT be administered if the patient is already vomiting, or if ipecac induced emesis might interfere with more definitive treatment provided at a hospital. Dose of ipecac syrup : Adult: Dose: 15 to 30 milliliters Adolescent: Dose: 15 to 30 milliliters Child 1 to 12 years: Dose: 15 milliliters Child 6 to 12 months: Dose: 5 to 10 milliliters. Position: child in left lateral decubitus position to reduce risk of aspiration. Child under 6 months of age: Not recommended for prehospital use. Fluids Prior to or after the dose is given, encourage clear fluids, 8 ounces (240 milliliters) in adults and adolescents and 4 to 8 ounces (120 to 240 milliliters) in a child.

6 Activated charcoal Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis. Dose: Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old. Specific antidote: No specific antidote Supportive treatment: Most patients will have no symptoms, but patients with mild orthostatic hypotension can be treated by remaining prone. Those who remain hypotensive can be treated with IV fluids. For severe toxicity, adequate circulatory support with IV fluids and vasopressors (if needed) should be assured if the patient presents with circulatory collapse. Correct severe hyperkalemia using standard treatments such as glucose, insulin, calcium, sodium bicarbonate, sodium polystyrene sulfate and hemodialysis. Airway management : Early endotracheal intubation should be considered in patients with ACE inhibitor induced angioedema. Orotracheal intubation may be technically difficult in patients with severe tongue swelling; be prepared to obtain a surgical airway. Hypotensive episode : Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy. Hypotension may respond to naloxone. Dopamine

7 Preparation: Add 400 milligrams to 250 milliliters of normal saline or dextrose 5% in water to produce 1600 micrograms per milliliter or add 400 milligrams to 500 milliliters of normal saline or dextrose 5% in water to produce 800 micrograms per milliliter. Dose: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed. Norepinephrine should be added if more than 20 micrograms/kilogram/minute of dopamine is needed. Caution: If ventricular dysrhythmias occur, decrease rate of administration. Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred. Norepinephrine Preparation: Add four milligram norepinephrine to 250 milliliters of dextrose 5% in water to produce a concentration of 16 micrograms/milliliter. Dose Adult: begin infusion at 0.5 to 1 microgram/minute and titrate to maintain adequate blood pressure (American Heart Association, 2005). Child: begin infusion at 0.1 microgram/kilogram/minute and titrate to maintain adequate blood pressure. Caution: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised. Angiotensin Amide Angiotensin infusion at doses ranging from 8.5 to 18 mcg/minute has been successful in reversing hypotension in patients who did not respond to volume and pressor infusions. NALOXONE Summary: Administration of naloxone has been reported to antagonize the hypotensive effect of captopril in animals and humans. There is a single case report stating naloxone was ineffective in a hypotensive, 22-year-old male, with a history of intravenous drug abuse. Additional clinical evidence is needed to evaluate the efficacy of naloxone for treatment of hypotension secondary to ACE inhibitor overdose. Elimination enhancement method: Summary ACE inhibitors are dialyzable, but hemodialysis is not used because supportive care is usually effective.

8 Hemodialysis Hemodialysis is expected to effectively remove captopril, but has not been necessary in overdoses to date (Prod Info captopril tablets, 2003a; Hirakata et al, 1981). In one study of chronic hemodialysis patients, a 4-hour run of hemodialysis removed 35 percent of a dose of captopril. In one study hemodialysis clearance of perindopril and its active metabolite perindoprilat is 52 ml/min and 67 ml/min, respectively. Criteria for emergency department discharge: Observe asymptomatic patients for a minimum of 6. If symptomatic or hypotensive, observe patient for at least 24 in the emergency department or hospital. Complications: No specific information available Contraindications: No specific information available References: 1. David A Tenon. Angiotensin converting enzyme inhibitors. In: Kent R Olson (ED.). Poisoning and drug overdose, fifth edition, Mc Graw-Hill S, Editorial Staff: Angiotensin converting enzyme inhibitors (Management/Treatment Protocol). In: Klasko RK (Ed): POISINDEX System. Volume 143. Thomson Micromedex, Greenwood Village, Colorado. 3.