DIURETIC & ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS

Oral diuretic agents include:

- Thiazides (eg, chlorothiazide, hydrochlorothiazide),

- loop diuretics such as furosemide, and

- Potassium-sparing agents such as - spironolactone (aldosterone antagonist) and triamterene.

- Osmotic diuretics, administered by injection, include mannitol.

Diuretic overdose

Most common signs of diuretic overdose include: - vomiting,

- Polyuria and polydipsia

- Depression.

Laboratory changes as electrolyte changes: especially potassium, may shift subsequent

to a large ingestion of a diuretic.

Management

It should include monitoring hydration and electrolytes, with correction as needed

ANGIOTENSIN- CONVERTING ENZYME INHIBITORS (ACEI)

Several angiotensin-converting enzyme (ACE) inhibitors (e.g., enalapril, captopril, lisinopril,

benazepril) are used therapeutically to treat hypertension & congestive heart failure.

Sings of overdose:

Hypotension : The primary concern in case of acute ACE inhibitor overdose. If

hypotension is severe, secondary renal damage may result. Onset occurs within a few

hours of exposure, depending on the agent (Extended-release formulations may have a

delayed onset of action).

Other signs : Vomiting, weakness & tachycardia or bradycardia.

Monitoring of BUN and serum creatinine is important, particularly if significant

hypotension is present or if the patient has preexisting renal disease, congestive heart

failure or hypovolemia.

Management

1. Patients should be given adequate IV fluids to maintain a satisfactory blood pressure and

good urine output.

2. Activated charcoal is effective in binding the drug from the GI tract if administered

within 1-2 hr of ingestion.

3. Renal function should be monitored if severe or persistent hypotension develops.

BETA BLOKERS TOXICITY

Epidemiology

Common medications used in the treatment of various cardiovascular, neurologic,

endocrine, ophthalmologic, and psychiatric disorders.

Accidental and intentional toxicity is common.

Selectivity is often lost following large overdoses.

Sotalol is unique among beta-blockers in its ability to block potassium channels.

Sotalol is class III antiarrhythmic drugs.

Sotalol is more often associated with ventricular dysrhythmias (ventricular tachycardia, ventricular fibrillation, torsades de pointes)

Under normal conditions, the heart uses free fatty acids as its primary energy source, but

during times of stress, it switches to using carbohydrates to maintain metabolism.

Inhibition of glycogenolysis and gluconeogenesis reduces the availability of

carbohydrates for use by cells.

Hypoglycemia occurs as a consequence of beta -blocker toxicity, it is actually very rare.

In the presence of adequate glucose stores, euglycemia and hyperglycemia are more

common than hypoglycemia.

Clinical Presentation

Neurologic manifestations include depressed mental status, coma, and seizures.

More lipophilic beta-blockers, such as propranolol, cause greater neurologic toxicity than

the less lipophilic agents.

Seizures can occur but are generally brief, and status epilepticus is rare.

Absorption of regular-release beta -blockers occurs rapidly, often with peak effects

within 1 to 4 hours .

Sustained-release cardiac drugs, it is assumed that symptoms may be delayed >6 hours

after ingestion

Co-ingestants that alter gut function, such as opioids and anticholinergics, may affect

absorption of beta -blockers and subsequent onset of symptoms.

Diagnosis

Cardiac monitoring

ECG

Check glucose, potassium, renal function

Chest x-ray

Treatment

1. General Management

ABCs, protect air way

2. GI Decontamination

Activated charcoal may be of benefit if it can be given within 1 to 2 hours after

ingestion. Multiple dose of activated charcoal therapy following ingestion of

sustained-release -blockers

Use of ipecac syrup is not recommended

Gastric lavage is not routinely used, but may be considered for life-threatening

ingestions when the airway is adequately protected from aspiration.

Whole-bowel irrigation may be beneficial after ingestion of a sustained-release

product.

Treat seizures with benzodiazepines

Ventricular tachycardia: lidocaine

3. Glucagon

Glucagon is a first-line agent in the treatment of acute beta –blocker induced

bradycardia and hypotension.

Effects from an IV bolus of glucagon are seen within 1 to 2 minutes, duration of

action of 10 to 15 minutes.

Due to the short duration of effect, a continuous infusion is often necessary after

bolus administration.

The positive inotropic and chronotropic effects of glucagon may not be

maintained for a prolonged period due to possible tachyphylaxis.

Side effects of high-dose glucagon therapy :

Nausea and vomiting

Esophageal sphincter relaxation

4. Adrenergic Receptor Agonists

The beta -adrenergic receptor agonists—such as norepinephrine, dopamine,

epinephrine, and isoproterenol

The most effective adrenergic receptor agonist may be norepinephrine due to its

ability to increase heart rate and blood pressure.

5. High Dose Insulin

Insulin facilitates myocardial utilization of glucose, the desired substrate during

stress.

The initial dose is regular insulin, 1 unit/kg IV bolus followed by 0.5 to 1.0

unit/kg/h continuous infusion.

0.5 gram/kg bolus of glucose should accompany the initial insulin bolus in a

patient whose serum glucose level is <400 milligrams/dL.

Serum potassium levels may fall during therapy.

Serum potassium level should be monitored.

6. Atropine

A muscarinic blocker, is unlikely to be effective in the management of beta

blocker–induced bradycardia and hypotension,

7. Calcium

Calcium administration is not routinely recommended in beta -blocker overdose,

Calcium for IV administration is available in two forms, gluconate and chloride,

both in a 10% solution. Calcium chloride solution contains three times more

elemental calcium than calcium gluconate solution

Ionized calcium levels should be checked every 30 minutes initially and then

every 2 hours to achieve an ionized calcium level of twice the normal value.

8. Phosphodiesterase Inhibitors (Milrinone, Amrinone)

These agents inhibit the breakdown of cAMP thereby maintaining intracellular calcium levels

9. Cardiac Pacing

May be most beneficial in treating torsades de pointes associated with sotalol

toxaicity.

10. Hemodialysis

Ineffective for lipid soluble agents; may help with water soluble agents such as

atenolol, acebutolol.

CALCIUM CHANNEL BLOCKERS TOXICITY

Overview

Examples: amlodipine, diltiazem, verapamil

Calcium channel blockers account for ~40% of deaths in cardiovascular drug

overdose.

Available in immediate and extended release.

Overdoses of immediate-release characterized by rapid progression to

hypotension,

bradydysrhythmia,

cardiac arrest

Overdoses of extended-release result in delayed onset of dysrhythmias,

shock, sudden cardiac collapse, &bowel ischemia.

Physiology/Pharmacology

Calicum is critical for myocardial contractility and conduction.

Maintains tonic constrictior vascular smooth muscle; contraction of skeletal and cardiac

muscle cells

CCB block calcium channels →→ vasodilation, ↓ myocardial contractility or

altering conduction and pacemaker cells

At toxic levels will also inhibit insulin release from pancreas by blocking Ca channels in

β cells

Clinical features

Onset

The onset of symptoms with standard preparation of CCB is typically within 1-2 hr. of

ingestion.

Slow release preparation, the onset of significant toxicity may be delayed 12-16 hr. with

peak effect after 24 hr.

1. Cardiovascular manifestations

The early sign of toxicity are usually bradycardia, first degree heart block and

hypotension.

This may progress to refractory shock and death without appropriate

intervention

Complication may include myocardial ischemia, & stroke.

2. Hyperglycemia (metabolic manifestation)

3. Neurological (seizures & coma)

4. Other

Pulmonary edema

Renal failure

Nausea & vomiting.

Diagnosis

1. Abnormal finding on blood tests in patients with CCB toxicity include the following:

Hyperglycemia

Hypokalemia

Acidosis

2. ECG, toxicity from CCB blockers may manifest as any of the following:

Bradycardia

2nd and 3rd degree heart block

3. Evidence of organ dysfunction due to shock (e.g increased creatinine)

4. Chest x-ray

5. Echocardiography: evidence of impaired contractility.

Treatment………. Focus on 4 Elements

STABILIZATION - ABCs

DECONTAMINATION

ANTIDOTE(S)

SUPPORTIVE THERAPY

1. Stabilization

Correct immediate life threatening complication (most commonly hypotension and

bradycardia )

Intubation (Atropine)

IV access, fluids

2. GI decontamination

Gastric lavage within 1-2 hr. of ingestion

Activated charcoal within 1 hr. of ingestion

Whole bowel irrigation.

3. Antidote administration

Administration of calcium salts (calcium chloride, calcium gluconate) used to overcome

the cardiovascular effects of CCB.

4. Supportive therapy

Vasopressor Following fluid resuscitation; phenylephrine, dopamine, norepinephrine,

epinephrine. Positive inotropy, chronotropy , vasoconstrictive effects of agents

Glucagon

↑ intracellular cyclic AMP→→ activates calcium channels →→↑ HR

Insulin and Glucose…….. Mechanism is not clear

Not all patients will need glucose, because CCB may cause hyperglycemia

At high doses insulin will actually act as an inotrope ,120-150 units/hr...monitor glucose

Lipid Emulsion Therapy

Lipid surrounds CCB drug molecule Prevents it from binding to calcium channel

Lipid provides readily available energy source for myocardial cells.

Transvenous pacing assists with electrical conduction.

Other Therapies

Methylene Blue ( used in CCB overdose with cardiogenic shock)

Levosimendan (calcium "sensitizer")

Used in sever CHF

Sensitizes calcium channels and promotes influx into cell; increase contractility.

Dialysis

Antiarrhythmic Agents Toxicity

Antiarrhythmic Agents

Antiarrhythmic drugs have been classified based upon a primary mechanism of action:

Class I (Na+ channel blockers ), which is sub-classified into:

IA: includes - Procainamide

- Disopyramide

- Quinidine

IB: includes - Lidocaine

- Mexiletine

- Tocainide

IC: includes - Flecainide

- Propafenone

Class II (β-adrenergic blockers)→ as Beta-adrenergic blockers

Class III (drugs that prolong action potential duration, especially K+ channel

blockers)→ as - Amiodarone

- Bretylium

- Sotalol

Class IV (Ca2+ channel blockers) Calcium channel blockers

Diltiazem & Verapamil

Miscellaneous: Digoxin & Adenosine

Na+ channel blockers (class I)

The primary concern of Na+ channel blocker toxicity is that proarrhythmic effects are seen at

a much higher incidence in those with a previous history of myocardial infarction or with

acute myocardial ischemia. The proarrhythmic effects of these drugs would also be more

prevalent in patients with other cardiac complications.

ClassIA → Procainamide

Signs and Symptoms of Overdose

- Agranulocytosis, granulocytopenia, leukopenia, neutropenia,

- Coagulopathy, hemoptysis

- Anticholinergic toxidrome, confusion, drowsiness, mania

- Hyperthermia, hypotension, myasthenia gravis (exacerbation or precipitation)

- Oliguria, renal failure, respiratory failure

- AV block, torsade de pointes

- Intraventricular conduction delay, junctional tachycardia.

Overdosage /Treatment

1. Airway, breathing, and circulatory support; and ECG monitoring are of the most

importance.

2. Decontamination:

Ipecac (drug used to induce vomiting) within 30 minutes or lavage (within 1

hour)/activated charcoal

3. Supportive therapy:

For hypotension

I.V. fluids or

Parenteral inotrope (If un-response to the above) e.g., norepinephrine 0.1-0.2

mcg/kg/minute.

Concurrent sodium bicarbonate and sodium lactate infusions have been effective in

reversing the drug-induced cardiac toxicity.

4. Enhancement of elimination:

Multiple dosing of activated charcoal may be effective

Hemodialysis or charcoal hemoperfusion are effective in decreasing half-life.

(Note: Forced diuresis or peritoneal dialysis is not effective).

Class III→ Amiodarone

The most common adverse effect of Amiodarone is bradycardia,

Amiodarone may also have cardiotoxic effects by stimulating excessive Ca2+

uptake, especially in the presence of procaine.

Signs and Symptoms of Overdose

Patients should be monitored for several days following ingestion.

Sinus bradycardia, AV block, heart block

Hypotension, chest pain, thrombocytopenia

Hyperthyroidism, hypothyroidism, sweating, syncope

Delirium, insomnia, myopathy

Extension of pharmacologic effect, hemoptysis, cirrhosis

Photosensitivity, pseudotumor cerebri, toxic epidermal necrolysis

Admission Criteria/Prognosis

Admit any patient with ECG abnormalities or any adult ingestion > 3 g.

Toxic effects can be observed at levels >2.5 mg/L for parent compound or 1.5 mcg/mL for

desethylamiodarone.

Overdosage/Treatment

1. Decontamination

Lavage (within 1 hour)/activated charcoal;

Cholestyramine can also decrease absorption.

2. Supportive therapy:

Atropine can be used to treat bradycardia (atropine resistant bradycardia has been

reported). ↓ In case of the resistance

Injectable isoproterenol or a temporary pacemaker may be required.

(ECG monitoring is necessary with amiodarone overdose).

3. Corticosteroids may be useful to treat amiodarone pulmonary toxicity; corticosteroid

therapy can be used to treat amiodarone- induced pleural disease.

4. Propylthiouracil (with lithium) has been used to treat amiodarone-induced thyrotoxicosis

with normalization of T4 levels within 5 weeks.

5. Angiotensin amide may be useful in treating hypotension due to amiodarone toxicity.

6. Acetazolamide (125-250 mg twice daily) for Amiodarone-induced ataxia.