Midterms Toxicology PDF

MIDTERMS TOXICOLOY Cardiovascular acting agents TOXICOKINETICS Beta-blockers vary significantly...

MIDTERMS TOXICOLOY Cardiovascular acting agents TOXICOKINETICS Beta-blockers vary significantly in their 1. Beta-adrenoceptor antagonists pharmacokinetics. 2. Calcium channel blockers Hydrophobic (Lipid-Soluble) Agents: 3. ACE inhibitors and angiotensin receptor antagonists Examples: Propranolol, metoprolol, labetalol. 4. Antidysrhythmic drugs Characteristics: 5. Nitrates − Large volumes of distribution. 6. Digoxin − Distribute widely, including to the CNS. 7. Theophylline − Metabolized by the liver, sometimes forming active metabolites (e.g., propranolol). BETA-ADRENOCEPTOR ANTAGONISTS − Substantial first-pass metabolism, limiting oral “Beta-Blockers” bioavailability – Propranolol widely used for the treatment of: Hydrophilic Agents: o ischemic heart disease Examples: Atenolol, nadolol, sotalol. o hypertension Characteristics: o thyrotoxicosis − Small volumes of distribution. o migraine prophylaxis − Eliminated in the urine. o arrhythmias Limited information is available on the toxicokinetics o anxiety after overdose. MECHANISMS OF TOXICITY RISK FACTORS FOR TOXICITY competitive antagonists at the beta-adrenergic Cardiac features of toxicity: receptor. → Co-ingestion with Other Cardiovascular Drugs: cardio-selective agents → binds to 1 receptor in − Calcium Channel Blockers: Increased cardiac tissue; less affinity to 2 receptor in likelihood of heart block. respiratory tissue. − Antihypertensive Agents: More profound Clinical effects may vary due to functional crossover hypotension. between receptor subtypes. High-Risk Populations: o highly beta1 selective agents (e.g., bisoprolol, − Elderly patients. atenolol) − Patients with established ischemic heart o non-selective agents (e.g., propranolol) disease. Some -blockers have: − Patients with renovascular disease. o Na+ channel blocking effects sometimes termed as: CLINICAL FEATURES − ‘Quinidine-like effects’ Onset of Toxicity: − ‘Membrane stabilizing activity’ − Non-sustained release preparation: within 6 o Partial agonist activity at adrenoceptors hours. − ‘Intrinsic sympathomimetic activity’ (ISA) − Sustained release preparation: within 8 hours. Toxicological Effects Related to Beta- − Sotalol ingestion: within 12 hours. Adrenoceptor Blockade: Cardiovascular Features: Beta1 Receptor Blockade (Predominant Effects): − Common: Bradycardia, hypotension. o Bradycardia − Possible: Cardiac conduction defects (e.g., first- o Hypotension or second-degree AV block), peripheral o Reduced cardiac output cyanosis. o Cool peripheries − Severe Poisoning: Pulmonary oedema, Beta2 Receptor Blockade: cardiogenic shock, asystole. o Bronchospasm − Sotalol-specific: QT prolongation, torsade de pointes ventricular tachycardia (due to Beta3 Receptor Blockade: potassium channel antagonism). o Negative inotropic effects Central Nervous System Features: High Drug Concentrations − Reduced consciousness, seizures, o irreversible receptor blockade. hallucinations. o Toxicity can be prolonged and resistant to − Absent pupillary reflexes, coma. conventional treatments for bradycardia and − More common with agents of high lipid solubility. hypotension.  Other Features: → Other Inotropic Agents: − Bronchospasm, especially in patients with pre- − Dobutamine existing pulmonary disease. − Epinephrine − Uncommon: Hypoglycemia, hypocalcemia. − Norepinephrine GLUCAGON → Can restore the beta-adrenoceptor-linked intracellular cascade. → considered if there are features of severe toxicity − Severe hypotension − Heart failure − Cardiogenic shock → Administration of Glucagon: − Intravenous Bolus: o Adults: 5-10 mg over 10 minutes. − Followed by Infusion: o 1-5 mg per hour, titrated to clinical response. Discuss with the duty pharmacist to ensure adequate glucagon supply. → Adverse Effects: − Vomiting (require reducing administration rate). Other effects: − Hyperglycemia − Hypokalemia − Hypocalcemia INVESTIGATIONS Hyperinsulinemia Euglycemic Therapy (HIET) Laboratory Tests: − Considered if other measures failed − Urea and Electrolytes (U&E) − may be effective by stimulating glucagon secretion. − Creatinine − Glucose Cardiac Pacing and Mechanical Support: Electrocardiogram (ECG): Internal or External Cardiac Pacing − 12-Lead ECG: Assess for heart block and QT − May correct bradycardia but may not restore BP. interval prolongation (especially with sotalol). − Can be ineffective due to electromechanical − QRS Duration: Check for prolongation, dissociation. indicating significant sodium channel blockade. Intra-Aortic Balloon Counter-Pulsation and Monitoring: Cardiopulmonary Bypass: − Frequent Hemodynamic Monitoring: To detect − Mechanical support for severe poisoning. cardiovascular effects. − may be considered for use until drug toxicity has − Frequent Electrocardiographic Monitoring: To resolved. continuously assess heart function. Beta-blockers with quinidine-like effects MANAGEMENT − e.g., Propranolol Oral Activated Charcoal − prolonging the QRS duration and causing arrhythmia − Consider if patient presents within 1 hour of − Intravenous bicarbonate might help theoretically, but significant ingestion clinical data is lacking. − And no contraindication exists. Intravenous Fluids – ensure adequate hydration. Nebulized Salbutamol - effective treatment for bronchospasm. Bradycardia management → Atropine - Large doses may be required: Intravenous Lipid Emulsion and Hemodialysis − Adults: 3 mg. − Administration have been reported but limited data − Children: 0.04 mg/kg. − Hemodialysis/hemoperfusion – may be less effective → Isoproterenol (isoprenaline) infusion to lipid-soluble beta-blockers due to their large vol. − May restore hemodynamic stability. of distribution. − Initial infusion rate: 5-10 micrograms/minute in adults, titrated as needed. − Very large doses sometimes effective: up to 800 micrograms/minute. CALCIUM CHANNEL BLOCKERS Sustained-Release Preparations: Uses: − Absorbed slowly. Cardiovascular − Onset of clinical features may be delayed for more − Hypertension than 12-18 hours after ingestion. − Ischemic heart disease − Drug concentrations may not peak until over 24-36 − Arrhythmias hours after ingestion. Non-cardiovascular: RISK FACTORS FOR TOXICITY − Migraine − Raynaud’s phenomenon Increased risk of cardiac features: CCB Toxicity: − Co-ingestion with beta-adrenoceptor blockers. Severe and life-threatening clinical effects ▪ Risk of heart block Increasing use of modified-released preparations can − Co-ingestion with antihypertensive agents. cause: ▪ Profound hypotension − Delayed onset of toxicity − Prolonged toxicity High-Risk Populations: − Elderly Patients. MECHANISMS OF TOXICITY − Patients with: CCBs binds to L-type Ca+ channels in cardiac and vascular ▪ Established ischemic heart disease. smooth muscles. ▪ Renovascular disease. → Will decreased calcium availability within myocardial and − Toddlers - significant toxicity can occur with ingestion vascular smooth muscle cells resulting to: of just one or two tablets → Decreased myocardial contractility. → Impaired myocardial conduction. CLINICAL FEATURES → Peripheral arterial vasodilatation. Features of toxicity are usually evident: Standard, non-sustained-release preparation: Within 6-8 CCBs also binds to L-type Ca+ channels in beta-islet cells in hours of ingestion. the pancreas resulting to: Sustained-release preparation: Within 12-28 hours of → decreased pancreatic insulin release (hypo- ingestion. insulinemia) → peripheral insulin resistance Cardiovascular features This combination results in poor cellular glucose supply myocardial depression and peripheral vasodilatation and hyperglycemia. leading to hypotension. Glucose = the preferred energy substrate for the ischemic − Severe hypotension can occur rapidly, it is important myocardium. to assess cardiovascular status. o  Glucose = worsens myocardial performance Myocardial conduction delay − lead to bradycardia, AV conduction abnormalities, and CCBs have limited/no binding to other L-type Ca+ in skeletal heart block. muscles & neurological tissues. Dihydropyridine Toxicity: (e.g., nifedipine) − toxicity may initially experience reflex tachycardia due Three Classes of Calcium Channel Blockers in to marked peripheral vasodilation. Clinical Use: − bradycardia is more common in patients with severe 1. Dihydropyridines – “-ipine” calcium channel blocker toxicity. Nifedipine, nimodipine, amlodipine, felodipine Patients with severe toxicity can develop: greater peripheral vascular activity (vasodilatation) − Cardiogenic shock 2. Benzothiazepines − Pulmonary edema Diltiazem − Complete heart block mixed cardiac and peripheral effects − Asystole (absence of heart contractions) 3. Phenylalkylamines Metabolic effects Verapamil Lactic acidosis → worsens toxicity due to  ionized greater cardiac effects (negative inotropic and calcium conc. chronotropic actions) Hyperglycemia Toxicity - The relative selectivity for these classes remains but Hyperkaliemia and hypocalcemia may occur. is less prominent in overdose. Other features TOXICOKINETICS Central Nervous System (CNS) Toxicity: CCBs have good oral bioavailability. → Patients with severe toxicity may experience CNS Peak conc. of standard-release preparations occurs within effects due to severe hypotension. 1-2 hours. → These effects can include: metabolized by various hepatic pathways − Agitation − can be saturated in overdose: − Confusion o Decreases hepatic first-pass metabolism. − Seizures o Prolongs half-life. − Occasionally, coma o Increases drug concentrations. → If significant drowsiness occurs without cardiovascular CCBs are highly protein-bound, have large volume of effects, consider co-ingestants or alternative causes distribution = extracorporeal techniques (dialysis) are of of neurological depression. no value in managing toxicity.  Gastrointestinal Effects: Loading bolus dose → Ileus (intestinal obstruction) can occur as a secondary − 1 unit/kg of short-acting insulin (Humulin-S® or effect in patients with marked cardiovascular toxicity. Actrapid®) with: → Other gastrointestinal effects are uncommon. ▪ 50 mL of 50% or; Other Reported Complications: ▪ 100 mL of 20% dextrose → Acute pancreatitis Maintenance infusion → Hepatotoxicity (liver damage) − 0.5–2.0 units/kg/hour, titrated to blood → Mesenteric infarction (intestinal blood supply pressure/cardiac output. blockage) − May increase to a maximum of 10 units/kg/hour if needed. INVESTIGATIONS Maintain euglycemia Electrolytes, Renal Function, and Glucose − Sufficient 10% dextrose Arterial Blood Gas (ABG) – assess acid-base status − checking capillary glucose every 15–20 minutes 12-lead ECG – assess features of heart block initially and after an insulin dose change and; − 30–60 minutes when on a stable insulin dose. MANAGEMENT Serum potassium concentration should be checked every Oral activated charcoal 2–4 hours & supplementary potassium given as required. → considered for patients presenting within 1 hour of a monitor closely for hypoglycemia and hypokalemia significant ingestion (no contraindications exist) good marker of clinical improvement is increasing glucose and potassium requirements = indicates Multiple-dose activated charcoal and/or whole bowel a decrease in insulin resistance irrigation (WBI) → considered in patients with significant sustained-release Conventional inotropes and vasopressors Observe → used alongside/after HIET Standard-release preparation ingestions → at least 12 hours Sustained-release ingestions → up to 24 hours Norepinephrine preferred for peripheral vasodilatation- related hypotension All patients should be placed on a cardiac monitor and have Epinephrine or dobutamine preferred for hypotension regular observations of HR and BP. due to myocardial depression Bradyarrhythmias Alternative inotropes like phosphodiesterase inhibitors are Treat initially with atropine limited in efficacy due to peripheral vasodilatation. → Adult initial dose: 0.5–1.2 mg Metaraminol may be used in patients with resistant → Pediatric initial dose: 0.02 mg/kg hypotension in calcium channel blocker toxicity → Maximum dose: 3 mg in adults, 0.04 mg/kg in children Consider temporary pacing if significant heart block is Glucagon present. (not responding to atropine) Antidote of choice for Beta-blocker toxicity. If available, isoproterenol (isoprenaline) may be useful. Less effective for CCBs toxicity → it requires effective intracellular calcium signaling Hypotension In Resistant hypotension – it can be considered. Initial management with a standard fluid challenge. − initial dose of 5–10 mg IV over 1–2 min. Intravenous Calcium - use if hypotension does not respond to the fluid challenge Mechanical support − Use cautiously in patients with concomitant digoxin May be considered in severe poisoning. toxicity. − mechanical support using intra-aortic balloon counter- Calcium Chloride (Preferred): pulsation − Contains higher ionized calcium content. − cardiopulmonary bypass − Initial dose: 5-10 mL of 10% calcium chloride over 5 − extracorporeal membrane oxygenation (if available) minutes. − Repeat up to three or four times if needed. Intravenous lipid emulsion Calcium Gluconate (Alternative): preliminary data: may have a role in the management of − Initial dose: 20-30 mL given over 5 minutes. severe hypotension resistant to other therapy Calcium Infusion (if responsive): recommended intravenous bolus dose is 1.5 mL/kg of − Continue with an infusion if the patient responds. 20% Intralipid® − Infusion rate: Up to 10 mL/hour of 10% calcium followed by an infusion at a rate of 0.25–0.5 chloride. mL/kg/minute for 30–60 minutes (up to a maximum Regularly monitor serum calcium concentrations during of 500 mL) infusion. − can be repeated once or twice if necessary. Hyper-Insulinemia Euglycemia Therapy (HIET) For severe hypotension not responding to a fluid challenge and calcium facilitates myocardial glucose supply, improves calcium signaling, and insulin acts as a positive inotrope. serum potassium = 5 mmol/L indicates significant also make interpreting serum potassium levels as a toxicity in acute poisoning. marker of acute digoxin poisoning less 2. Plasma Creatinine: straightforward. Measure to assess renal function. 3. 12-Lead ECG: MANAGEMENT Perform and repeat at regular intervals (4– Monitoring: 24 hours) in acute or acute-on-chronic − Measure pulse and blood pressure frequently. poisoning. − Place the patient on an ECG monitor to detect 4. Plasma Digoxin Concentration: cardiac rhythm disorders. Delay measurement until at least 6 hours Activated Charcoal: after ingestion, except in symptomatic − May reduce digoxin absorption if administered patients. soon (e.g., within 1 hour) after ingestion of a Levels >4 ng/mL (5.2 nmol/L) suggest potentially toxic overdose (e.g., more than 3 mg severe poisoning, especially after chronic in an adult or more than 50 micrograms/kg in a accumulation. child for a single acute overdose). 5. Arterial Blood Gases: − Lower amounts may be toxic in patients taking Measure in patients with hyperkalemia or acute overdoses in the context of chronic other signs of severe toxicity. therapy. Hyperkalemia often accompanies metabolic Hyperkalemia: acidosis. − Indicates the urgent need for digoxin antibody. − Treat life-threatening hyperkalemia with insulin TOXICITY ASSESSMENT IN DIGOXIN POISONING: and glucose while preparing the antibody. Based on Clinical Features: Nausea, vomiting, and − Correct hypokalemia and hypomagnesemia, as bradycardia are key indicators. they increase digoxin's myocardial toxicity. Investigations: Results, particularly hyperkalemia, − Avoid using calcium first line for hyperkalemia or plasma digoxin concentrations, and ECG changes hypocalcemia, as it increases ventricular (e.g., heart block), contribute to toxicity assessment. automaticity and may precipitate arrhythmias Poor Prognostic Factors: High-degree AV block, (consult an expert if considering). hyperkalemia, and episodes of ventricular Metabolic Acidosis: tachycardia. − Treat with intravenous sodium bicarbonate. Plasma Concentrations in Acute Poisoning: Other Glycosides Ingestion: o Only useful to confirm ingestion. − Laboratory digoxin assay is less accurate but Clinical Management: helpful in confirming ingestion of active material. o Should be based on poisoning features, not just Monitoring: plasma digoxin concentrations. − Repeat digoxin concentrations may be needed o Acute changes in plasma concentration can help before commencing therapy. determine poisoning extent. − Serum potassium measurements, more easily obtained, may help monitor progress of digitalis CLINICAL COURSE IN ACUTE POISONING effect on the myocardium. Clinical features develop within 1–2 hours of acute Bradycardia: ingestion, but cardiac effects typically take longer, − Treat with atropine (e.g., 0.5-1 mg initial dose in with maximal effects usually not present for at least an adult, 0.02 mg/kg for a child). Repeat doses 6–12 hours. may be necessary. Asymptomatic patients should be observed for at Refractory Bradycardia: least 6 hours after an acute digoxin overdose. − If bradycardia does not respond to atropine and an appropriately calculated dose of digoxin  antibody, insert and use a temporary pacing Initially, administer approximately 50% of the dose wire. calculated to completely neutralize digoxin, and Ventricular Arrhythmias: monitor the response. − Secondary to digoxin, may respond to A clinical effect should be clearly seen within 1–2 intravenous magnesium, even if the serum hours. If inadequate, further doses can be magnesium concentration is initially normal. administered. − Infusion of 4–8 mmol/hour may be required in Monitor patients for at least 6–12 hours, and cases of recurrent ventricular arrhythmia. administer a second dose of antibody only in the − Avoid Class Ia and Ic antiarrhythmics (e.g., event of recurrence of toxicity. quinidine, flecainide, disopyramide) as they may Further measurements of serum digoxin are not adversely affect AV nodal conduction. useful after antibody administration, as the assay measures both free and bound digoxin. DIGOXIN-SPECIFIC ANTIBODY FRAGMENTS Haemodialysis does not remove digoxin antibody Antigen Binding Fragments (Fab) for Digoxin complex, but it can reduce acute effects of digoxin Toxicity: on the heart in patients with acute kidney injury. Derived from antidi-goxin antibodies raised in sheep. The dose of digoxin antibodies required for full Effective in managing digoxin toxicity but should be neutralization can be calculated based on the restricted to patients with severe poisoning. patient's weight and digoxin levels. The affinity constant of digoxin antibody fragments for digoxin is higher than that of the Na+/K+-ATPase. Digoxin binds preferentially to the antibody fragments, becoming pharmacologically inactive. Digoxin antibody complexes are eliminated in the urine, with a half-life of 16–20 hours in patients with normal renal function. Features of severe poisoning are usually reversed within an hour of antibody administration, although complete reversal may take as long as 24 hours. Indications for Digoxin Antibody: Treatment indications are based on the patient’s clinical condition and serum potassium levels. Patients with no impairment of cardiac output and well-maintained heart rate may not require antidotal therapy. Indications for digoxin antibody include: Digoxin assay kits are not designed to measure − Life-threatening dysrhythmias. levels greater than 5 ng/mL (6.4 nmol/L), so caution − Severe heart block or marked bradycardia. is advised when using high digoxin levels to − Cardiac compromise in patients with underlying calculate the dose. cardiac disease. − Serum potassium higher than 6 mmol/L. − Elevated serum digoxin in a symptomatic patient. − An arbitrary cut-off of 7 ng/mL (9 nmol/L) in patients with acute overdose, or 4 ng/mL in chronic toxicity, may be considered a useful The estimated number of vials required for full marker. neutralization for adults and children heavier than 20 kg is provided in Table 6.4 for DigiFab®. Dose Calculation for Digoxin Antibody: The estimated dose of DigiFab® (in mg) required for Digoxin antibodies (Fab fraction) bind digoxin in a full neutralization for infants and children less than molar ratio, but complete neutralization of digoxin is 20 kg is shown in Table 6.5. Dilution may be usually unnecessary. necessary for very small doses. In patients on chronic therapy, complete Digoxin antibody fragments can also be used to treat neutralization of digoxin is inappropriate as it impairs cardiac glycoside poisoning from plant ingestion, the beneficial effects of the drug. with dosing based on clinical severity and response In patients who have ingested an acute overdose, monitoring. the goal is to prevent or reverse the acute toxic effects of digoxin; excess use of antibody is unnecessary and costly. Adverse Effects of Digoxin Antibody Fragments: Use of Elimination Techniques: Allergy: Haemodialysis and Haemoperfusion: − Anaphylactic, hypersensitive, or febrile reactions − Unlikely to be effective for removing digoxin due have been reported but are not common due to to its large volume of distribution. the lower antigenicity of the Fab fragment − Haemodialysis may be necessary to treat compared to the intact antibody. hyperkalemia and acidosis in the context of − Rash (sometimes purpuric), facial swelling, renal failure. urticaria, and thrombocytopenia have occurred. Multiple-Dose Activated Charcoal: − Risk is likely increased in patients with asthma − Can reduce the half-life of digoxin, but its role in or antibiotic allergies. therapy for managing digoxin poisoning is − Patients with allergy to papain, chymopapain, or uncertain. other papaya extracts are at increased risk, as papain is used to cleave the antibody to derive the Fab fragments. Hypokalemia: − May be precipitated by digoxin antibody fragments. − Plasma potassium should be monitored frequently during therapy. Recurrence of Underlying Disease Symptoms: − In patients on chronic therapy, the use of digoxin antibody fragments may cause features of the underlying disease to recur, such as heart failure or arrhythmias. Use in Pregnancy: − Limited information is available on the use of digoxin antibody fragments during pregnancy. − However, in the context of severe digoxin toxicity, pregnancy is not a contraindication, as the risk of adverse maternal and fetal effects from poisoning likely outweighs any possible adverse effects of the antibody fragments. THEOPHYLLINE − Life-threatening toxic effects: Serum concentrations of: BACKGROUND AND THERAPEUTIC USE ▪ >60 mg/L (330 micromol/L), Theophylline (1,3 dimethylxanthine) is a Fatalities: prescription-only medication. ▪ >80 mg/L (440 micromol/L). Mainly used as modified-release tablet or capsule − In chronic accumulation, severity of poisoning is preparations. less correlated with concentration, with more Primarily used for the treatment of chronic severe clinical features at lower concentrations obstructive pulmonary disease (COPD) and asthma. (>40 mg/L or 220 micromol/L). Available as a combination product (Do-Do Acute Overdose: ChestEze®) with theophylline, caffeine, and − Acute overdose ingestions of >3 g in adults (>40 ephedrine, without prescription via pharmacies. mg/kg in children) are potentially serious. Intravenous preparation aminophylline, containing theophylline and ethylenediamine, is used for acute RISK FACTORS FOR TOXICITY asthma exacerbations and neonatal apnoea. Neonates and Premature Infants: Toxicity can occur from administering aminophylline − Enhanced risk of toxicity. to patients already taking oral theophylline or from Elderly Individuals: dose calculation errors, especially in neonates. − Higher risk of toxicity. Underlying Cardiac or respiratory disease: MECHANISMS OF TOXICITY − Increased susceptibility to toxicity. Theophylline and other methylxanthines exert their Drug Interactions: actions through increased adrenergic activity. − Drugs that inhibit theophylline metabolism can − This occurs by: precipitate toxicity. 1. Increased release of catecholamines and ▪ Examples include macrolide and quinolone stimulation at ß1/ß2-receptors. antibiotics, cimetidine, verapamil, and 2. Adenosine antagonism, leading to increased allopurinol. noradrenaline (norepinephrine) and Chronic vs. Acute Intoxication: adrenaline (epinephrine) release, and − Risk of toxicity is higher with chronic intoxication inhibition of histamine-related compared to acute intoxication at any particular bronchoconstriction. theophylline concentration. 3. Inhibition of intracellular phosphodiesterase, responsible for degrading cAMP, the post- CLINICAL FEATURES synaptic second messenger involved in ß- Vomiting: receptor activity. − Common, occurring in 75% of cases. − Often pronounced and resistant to anti-emetic TOXICOKINETICS treatment. Oral Bioavailability and Absorption: − Protracted vomiting can lead to haematemesis. − Nearly 100% oral bioavailability. − Diarrhoea and abdominal pain may accompany − Maximal absorption of standard-release vomiting. theophylline within 6-10 hours. Respiratory Effects: − Modified-release preparations have maximal − Theophylline stimulates the respiratory center, absorption within 15-20 hours. leading to hyperventilation and respiratory Distribution and Metabolism: alkalosis. − Small volume of distribution (about 0.5 L/kg). − Severe toxicity can result in respiratory failure − Over 90% metabolized by hepatic CYP450 and/or respiratory arrest. system, particularly CYP1A2. Neurological Symptoms: − Half-life approximately 4-5 hours in healthy non- − Anxiety, agitation, insomnia, tremor, irritability, smoking adults. dilated pupils, hallucinations, and convulsions Factors Affecting Clearance and Elimination: are common. − Factors that inhibit CYP activity can alter − Convulsions can be prolonged, recurrent, and theophylline clearance. resistant to conventional anti-epileptic − Elimination may be prolonged after overdose, medications. with an apparent half-life up to 30 hours. Complications: Toxic Effects and Serum Concentrations: − Rhabdomyolysis can occur. − Acute toxic effects correlate well with serum Cardiac Effects: theophylline concentrations. − Cardiac arrhythmias associated with toxicity − Therapeutic range: 10-20 mg/L (55-110 include sinus tachycardia or atrial or ventricular micromol/L). ectopy. − Severe poisoning can progress to ventricular tachycardia or fibrillation. TOXICITY ASSESSMENT Plasma Theophylline Concentrations: The clinical features of acute theophylline toxicity − Measure urgently in patients with clinical can be graded, as shown in Table 6.6. features of toxicity, including hypokalaemia. This grading system is useful in determining the − Repeat measurements every 2-4 hours in need for enhancing elimination of theophylline. severe poisoning (>60 mg/L). − The grading system is a better guide to severity than concentrations alone. MANAGEMENT Airway and Ventilation: − Ensure a clear airway and adequate ventilation and oxygenation. − Monitor oxygen saturation, especially in patients with underlying respiratory disease. Observation: − Asymptomatic patients should be observed for at least 4 hours (standard-release) or 12 hours (modified-release) after overdose. Activated Charcoal Administration: − For adults, administer 50 g; for children, administer 1 g/kg. − Consider in patients who present within an hour of ingestion of a potentially toxic amount of theophylline (>20 mg/kg). CHRONIC THEOPHYLLINE TOXICITY − Administration more than 1 hour after ingestion Causes of Chronic Theophylline Toxicity: may be appropriate for modified-release − Excess dosing or concurrent use of medications preparations. that inhibit theophylline metabolism. − Be cautious not to induce vomiting if there is an Pattern of Toxicity: unprotected airway. − Differs from acute overdose. Whole Bowel Irrigation: − Increased incidence of convulsions, often − Used to prevent further absorption of modified- resistant to treatment. release preparations. − Tachycardias more common, occurring in − Efficacy is uncertain. approximately 35% of chronic poisonings Treatment of Theophylline-Induced Vomiting: (compared to 10% in acute poisonings). − Use anti-emetics. − Vomiting and hypokalaemia less frequent with − Ondansetron (e.g., 8 mg by slow IV injection) chronic toxicity. appears most effective. Risk of Aspiration: INVESTIGATIONS − Patients with severe neurotoxicity (coma and/or Initial Investigations: convulsions) are at increased risk of aspiration if − ECG to determine underlying cardiac rhythm. they have significant vomiting. − Continuous cardiac monitoring if evidence of Sinus Tachycardia and Supraventricular theophylline toxicity. Tachycardias: Urea and Electrolytes: − Not associated with hemodynamic compromise − Pay particular attention to plasma potassium. do not need treatment routinely. − Theophylline-associated ß2-receptor stimulation Hemodynamically Compromised Cases: can lead to intracellular hyperkalaemia and − For sinus or supraventricular tachycardias with systemic hypokalaemia (present in 85% of acute evidence of hemodynamic compromise: poisonings). First-line therapy: Short-acting beta-blockers − Monitor electrolytes every 1-2 hours in severe (e.g., esmolol or metoprolol). poisoning. Caution advised in individuals with Other Metabolic Disturbances: underlying COPD and/or asthma; consider − Hypomagnesaemia, hypocalcaemia, calcium channel blockers such as verapamil. hypophosphataemia, and hyperglycaemia may occur. Arterial Blood Gases: − Perform in patients with clinical features or substantial overdose. − May show metabolic acidosis or respiratory alkalosis.  Ventricular Tachycardia: Use of elimination techniques − With cardiac output: Multiple-Dose Activated Charcoal (MDAC): Treat with IV magnesium by infusion initially, − Enhances theophylline elimination by reducing then consider DC cardioversion. entero-hepatic circulation. Some evidence suggests amiodarone may − Almost as effective as charcoal haemoperfusion. be safe, but avoid other antiarrhythmics like − Use may be limited by intractable vomiting lidocaine due to increased risk of and/or paralytic ileus in acute theophylline convulsions. poisoning. − Without cardiac output: − Consider for patients with significant toxicity, Treat according to standard Advance Life especially when associated with a plasma Support (ALS) algorithms. theophylline concentration >40 mg/L. Treatment of Theophylline-Related Agitation and Charcoal Haemoperfusion: Anxiety: − Consider in grade 3 or 4 acute theophylline − Best treated with benzodiazepines. toxicity or a theophylline concentration >100 − Dose should be titrated to the patient’s clinical mg/L. condition. − If not readily available or patient is too unstable − Avoid haloperidol as it lowers seizure threshold. for transfer, consider haemodialysis as an Treatment of Convulsions: alternative. − Initially treat with benzodiazepines: − Enhances theophylline clearance to a greater Diazepam: 10-20 mg in adults or 0.1-0.3 extent than haemodialysis but is associated with mg/kg in children. more complications. Lorazepam: 1-4 mg in adults or 0.05 mg/kg Continuous Veno-Venous Haemofiltration: in children. − Case report of successful use for enhancing Potassium Replacement in Theophylline theophylline elimination after overdose. Toxicity: − Replace cautiously due to normal total body potassium burden despite systemic hypokalaemia. − Supplement only if serum potassium is 20 mg/kg, Management: severe toxicity with >60–80 mg/kg. − Stop drug administration. Metabolites complex with pyridoxine, leading to functional pyridoxine deficiency and enzyme system − Ensure patient is well hydrated. inhibition. − Consider renal replacement therapy (e.g., Interferes with gamma-aminobutyric acid (GABA) hemofiltration) in significant renal impairment. synthesis and metabolism, causing agitation and − Refer for specialist assessment of auditory and seizures. vestibular function in cases of ototoxicity and vestibular toxicity. Clinical Features: Seizures, severe metabolic acidosis, coma. Other antibiotics Nausea, vomiting, hypotension, rhabdomyolysis, Chloramphenicol, sulfonamides, and hyper-reflexia, hallucinations, acute tubular necrosis. tetracyclines: − Low toxicity after overdose. Management: − Management is symptomatic and supportive. 1. Observation: All patients for at least 6 hours post- − Chloramphenicol can rarely cause bone marrow ingestion. aplasia after therapeutic use. − Asymptomatic patients at this time can be Metronidazole: discharged. − Overdose symptoms may include anorexia, 2. Supportive Care: vomiting, diarrhea, headache, dizziness, and − Rehydration, maintenance of the airway. occasionally insomnia and drowsiness. 3. Severe Toxicity Treatment: − Green or black urinary discoloration reported. − Seizure management, metabolic acidosis − Adverse effects after therapeutic use: correction, use of pyridoxine antidote. Liver function abnormalities 4. Metabolic Acidosis Correction: Seizures − 1–2 mL/kg intravenous 8.4% sodium Peripheral neuropathy bicarbonate for pH 50 mg/kg for 6 hours post-ingestion. especially in skeletal muscle, myocardium, and − Patients with ongoing symptoms should have adipose tissue. U&Es and LFTs checked. Pharmacological Preparations: Supportive Care: − Vary in onset and duration of action. − Treatment is primarily supportive. − Range from very rapid onset (e.g., Humalog®) to Specific Treatments: very prolonged duration of action (e.g., Glargine®). − Acidosis: Sodium bicarbonate. Pharmacokinetics: − Convulsions: Benzodiazepines. − Therapeutic dosages provide an indication of onset and duration of hypoglycemia. Pyrazinamide − Overdose-induced hypoglycemia is often more Limited information on acute overdose toxicity. severe and prolonged than expected. Therapeutic use toxicity includes hepatotoxicity and Systemic Effects: hyperuricemia, sometimes associated with gout. − Ingestion of insulin does not result in systemic effects due to degradation in the gastrointestinal Ethambutol tract. Acute overdose of ethambutol: Iatrogenic Toxicity: Usually well tolerated − May result from drug administration errors or Reported gastrointestinal effects: nausea, vomiting, changes between insulin types/formulations. abdominal pain − Patients with dementia and poor eyesight are at increased risk due to inadvertent administration More severe effects may include: errors. Confusion Pyrexia Hallucinations Optic neuropathy: May occur with larger ingestions (>10g) Recovery may take weeks or months and may be incomplete Management: Patients should be observed for 6 hours post- ingestion Supportive care is the mainstay of treatment ANTIDIABETIC DRUGS BACKGROUND A wide range of antihyperglycaemic agents exist with different pharmacological mechanisms of action and toxicological profiles. Severity of Poisoning: − Poisoning by sulphonylureas is associated with moderate to severe poisoning in 5% of cases. − Poisoning by biguanides is associated with moderate to severe poisoning in 12% of cases. Clinical features METFORMIN Hypoglycemia and Neurohormonal Activation: A biguanide that enhances tissue sensitivity to Profound hypoglycemia caused by parenteral insulin. administration of insulin. Inhibits lactate dehydrogenase, preventing the Activation of neurohormonal counter-regulatory conversion of lactate to pyruvate. mechanisms. Inhibition of gluconeogenesis due to lack of Clinical Features of Hypoglycemia: pyruvate. Agitation Toxicity is mainly due to inhibition of lactate Altered behavior dehydrogenase, leading to severe lactic acidosis. Excess sweating Metformin ingestion alone does not cause significant Slurred speech hypoglycemia. Tachycardia Seizures Clinical Features of Overdose: Reduced conscious level Abdominal pain Coma Vomiting Associated Conditions: Diarrhea Insulin overdose may also cause hypokalemia. Metabolic disturbance Severe lactic acidosis associated with: Management Agitation Reversal of Hypoglycemia: Tachypnea Administer intravenous dextrose or glucose. Hypotension Target plasma glucose concentration: ≥4 Reduced conscious level mmol/L. Seizures Higher target concentrations may be needed for diabetes patients with poor glucose control. Management: Prolonged intravenous infusion may be required Measure urea, electrolytes, creatinine, and lactate. after substantial overdose. Perform arterial blood gas analysis in patients with Risk of hepatocellular glycogen accumulation clinical features of toxicity. leading to reversible liver dysfunction. Correct hypoxia. Alternative Substrate: Provide adequate fluid replacement. Lactate provides an alternative substrate for Correct metabolic acidosis using sodium brain metabolism and reduces the risk of bicarbonate. neuroglycopenia. Monitor plasma potassium and sodium. Antagonizing Insulin Effects: For severe lactic acidosis: Glucagon and octreotide can antagonize the Closely observe hemodynamic status, urinary effects of insulin. output, serum electrolytes, and acid–base These may reduce the quantity of carbohydrate balance. administration needed to maintain euglycemia. Correct fluid or electrolyte disturbances as Monitoring and Correction: needed. Prevent hypoglycemic episodes. Consider haemodialysis or haemodiafiltration Monitor fluid balance and electrolytes. using a bicarbonate buffer in cases of severe Correct hypokalemia if needed. toxicity or uncorrectable electrolyte and acid– Surgical Intervention: base disturbances. Consider surgical excision if a large subcutaneous insulin depot is identified and SULPHONYLUREAS ongoing hypoglycemia persists. Include Glibenclamide, Gliclazide, Glimepiride, Prevention of Long-term Sequelae: Glipizide, and Tolbutamide. Profound or prolonged hypoglycemia may cause Bind to a specific islet cell receptor to stimulate persisting neurological deficits (e.g., cognitive insulin secretion, causing hypoglycemia. impairment, delayed reaction times). Enhance peripheral tissue sensitivity to insulin. Emphasize rapid correction and maintenance of Duration of action varies: normal glucose concentrations during the acute Glipizide: t½ = 2-4 hours episode to minimize long-term risks. Chlorpropamide: t½ = 25-60 hours Clinical Features of Overdose: INCRETIN MIMETICS: Onset of hypoglycemia usually within 8 hours of Mechanism of Action: overdose. GLP-1 (Glucagon-like Peptide-1): Naturally Onset may be delayed up to 48 hours with modified- occurring peptide that increases post-prandial insulin release preparations or those with a long t½. secretion. Degraded by dipeptidyl peptidase-IV (DPP-IV). Management: GLP-1 Analogues: Exenatide, liraglutide Correct hypoglycemia as for insulin overdose. (administered by subcutaneous injection). Octreotide: DPP-IV Inhibitors: Saxagliptin, Sitagliptin, A potent inhibitor of pancreatic insulin release. Vildagliptin (available as oral formulations). Reported to lessen the duration of hypoglycemia after sulphonylurea ingestion. Pharmacological Actions: Insulin-dependent. Effective in patients who do not respond to dextrose administration alone. Clinical Features of Overdose: Limited experience with overdose. MEGLITINIDES: Significant hypoglycemia is not expected due to Nateglinide, repaglinide. insulin-dependent mechanism of action. Mechanism of Action: ACARBOSE: Stimulate insulin secretion via a specific receptor site Mechanism of Action: on pancreatic beta cells. Alpha-glucosidase inhibitor. May cause significant hypoglycemia. Prevents hydrolysis of complex carbohydrates in the small intestine. Onset and Duration: Reduces or delays systemic absorption of Onset of hypoglycemia is more rapid, typically within carbohydrates. 30 minutes of overdose. Duration of action is shorter compared to Common Gastrointestinal Effects: sulphonylureas. Diarrhea Abdominal pain Clinical Features and Management: These effects might be anticipated after overdose. Same as for sulphonylureas (e.g., hypoglycemia). Bioavailability: THIAZOLIDINEDIONES: Very low (1-2%). Pioglitazone, rosiglitazone Systemic effects of overdose are unlikely. Hypoglycemia is not a recognized feature. Mechanism of Action: Stimulate peroxisome proliferator-activated receptor Duration of Effect: gamma (PPAR-γ). Approximately 4-6 hours after therapeutic doses. Increase peripheral insulin sensitivity. May be longer after overdose. Adverse Effects: Abnormal liver biochemistry and congestive heart failure have been reported occasionally with therapeutic use. Rosiglitazone was withdrawn in Europe in 2010 due to its association with cardiovascular events, including myocardial infarction and heart failure. Pioglitazone remains widely prescribed. Pharmacokinetics: Pioglitazone has a t½ of 5-6 hours. It is converted to active metabolites with a t½ of up to 23 hours. Clinical Features of Overdose: Limited information available. Serious clinical effects are not anticipated. Hypoglycemia is not expected. ANTITHROMBOTIC DRUGS Causes of Bleeding Disorders: Toxins affecting liver or bone marrow function, BACKGROUND: impairing synthesis of clotting factors or platelets Control of bleeding is complex, involving clotting Immune-mediated platelet destruction (drug-induced factor synthesis, platelet function, and clot immune thrombocytopenia) breakdown (thrombolysis). Clot formation by triggering the clotting cascade, Differential diagnosis of bleeding from a toxicological typically seen with snake venoms perspective is discussed in Bleeding disorders. Effects of Drugs on Clotting Factors and Platelets: Mechanism of Action of Drugs: Both clotting factors and platelets have relatively Drugs reducing clotting interfere with clotting factor short half-lives synthesis, components of clotting cascades, or Drugs that impair their production can cause platelet function. bleeding in a short time frame Clotting cascades: extrinsic (tissue factor) and Recovery requires re-synthesis of the relevant intrinsic (contact activation) pathways. component Both pathways converge at factor X activation, leading to fibrin formation. (Fig. 7.1) Additional Information: Extrinsic cascade is primary for blood coagulation Anticoagulants, particularly coumarins, are also initiation; intrinsic pathway is less important in vivo. used as rodenticides Long-acting anticoagulant agents can cause effects BLEEDING DISORDERS lasting many months Therapeutic Agents that Can Precipitate Bleeding Disorders: COUMARINS Vitamin K Antagonists: Coumarins (e.g., warfarin, Mechanisms of Coumarin Toxicity: phenindione) Warfarin and classical coumarin anticoagulants Specific Clotting Factor Inhibitors: Dabigatran interfere with vitamin K action in synthesizing clotting etexilate (direct thrombin inhibitor), apixaban, factors II, VII, IX, and X rivaroxaban (direct inhibitors of activated factor X) They act as inhibitors of vitamin K 2,3 epoxide- Heparins: Unfractionated or low molecular weight reductase (VKORC1), a key pathway in vitamin K Derivatives of Snake Venoms: Hirudin analogues activation in the liver (e.g., lepirudin, bivalirudin) Effects on Clotting Factors: Thrombolytics: Agents that promote clot Onset of anticoagulant effects depends on the half- breakdown. Two types: life of affected clotting factors Non-specific agents (e.g., streptokinase, Effects commence within about 7-10 hours of urokinase) dosing, with factor VII having a half-life of about 5 Specific tissue plasminogen activators (e.g., hours alteplase, which only act to increase fibrin Maximal effects are generally seen 48-72 hours after breakdown in the presence of a clot) initiation Antiplatelet Drugs: Monitoring and Metabolism: Aspirin Effects of warfarin are monitored using the Adenosine diphosphate receptor inhibitors (e.g., prothrombin time, expressed as the international clopidogrel, ticlodipine) normalized ratio (INR) Glycoprotein IIB/IIIA inhibitors (e.g., abciximab, Warfarin is metabolized in the liver and is eptifibatide—IV use only) susceptible to drug interactions Adenosine reuptake inhibitors (e.g., dipyridamole) Drug Interactions: Risk factors for toxicity Enzyme inhibitors of hepatic microsomal enzymes Higher risk in: (CYP1A2, CYP2C9, CYP3A4) increase bleeding risk − Elderly individuals Commonly prescribed enzyme inhibitors include − Patients with underlying clotting abnormalities antifungals, antibiotics, macrolides, metronidazole, (hereditary or acquired) amiodarone, cimetidine, and some statins − Patients with liver disease Some foodstuffs may contain compounds that inhibit − Patients with potential bleeding sites (e.g., warfarin clearance, but large quantities are normally peptic ulcer, varices, recent surgery, stroke) needed for a clinically important effect Common drug interactions with oral anticoagulants, Genetic Variability: requiring caution with new therapies Recent studies indicate a strong genetic basis for Warfarin sensitivity affected by: warfarin dosing variability between patients − Dietary changes Genetic factors may assist in preventing therapeutic − Starvation over-anticoagulation but have little relevance to − Illness managing overdose Increased risk in: − CYP2C9 slow hydroxylators Toxicokinetics − Individuals with specific VKORC1 Warfarin Isomers: polymorphisms Warfarin consists of R- and S-warfarin isomers Additional risk factors: S-warfarin is up to five times more potent than R- − Failure to attend routine monitoring warfarin in humans − Risk of falls in the elderly, warranting Metabolism: reconsideration of warfarin use S-warfarin is metabolized to 7-hydroxywarfarin by Caution advised in using oral anticoagulants in liver CYP2C9 disease R-warfarin is metabolized to 6- and 8- hydroxywarfarin by CYP1A2 and to 10- Clinical features hydroxywarfarin by CYP3A4 Bleeding is the most important clinical effect of CYP2C9 poor metabolizers have reduced warfarin anticoagulant excess dose requirements Clinical importance of bleeding depends on site and Half-life and Onset of Action: extent of blood loss Racemic warfarin has a half-life of around 35 hours Gastrointestinal bleeding may be covert Onset of action depends on clotting factor synthesis Rectal and nasal bleeding is more obvious inhibition Bleeding may present as catastrophic hemorrhage Excess anticoagulation commonly occurs during therapeutic dosing, leading to maximal effect at Bleeding may cause major neurological deficit or be presentation fatal if intracerebral In acute overdose, onset of maximal effect is Retroperitoneal bleeding may be difficult to diagnose delayed (48-72 hours), and offset depends on warfarin elimination rates and dose Toxicity assessment Reversal Agent: Assessment includes: Vitamin K can competitively reactivate vitamin K − Assessment of acute blood loss epoxide-reductase to overcome warfarin's action Blood pressure Speed of recovery depends on vitamin K dose and Conscious level clotting factor re-synthesis rates Pulse rate Phenindione: − Tests of coagulation Alternative vitamin K antagonist to warfarin National guidelines exist for managing prolongation More likely to cause adverse reactions such as of INR due to warfarin excess in patients receiving leucopenia, rashes, agranulocytosis, renal therapeutic anticoagulation dysfunction, and liver damage Stratifcation against INR is used due to difficulties in Management of overdose is similar to warfarin re-establishing warfarin in patients given large doses Long-Acting Anticoagulants: of vitamin K to treat therapeutic warfarin excess Designed to overcome warfarin resistance in rodents In patients not normally on warfarin, INR results Difenacoum and brodifacoum are commonly used indicate the need for therapy but do not precisely More potent than warfarin with zero-order guide it, as there is no hazard to such patients from elimination, leading to a very long duration of action excess vitamin K Implication for overdose management in humans is the need for prolonged therapy and monitoring over several months Investigations If there is active bleeding or life-threatening Assess blood loss by clinical examination, including hemorrhage, give: measuring blood pressure and pulse rate − Prothrombin complex concentrate (30–50 Establish degree of anticoagulation by using INR units/kg) Measure the full blood count, U&Es, and LFTs − If unavailable, fresh frozen plasma (15 mL/kg) Give vitamin K by slow IV injection: 10–20 mg for an Management of warfarin excess adult (250 micrograms/kg for a child). Management depends on the extent of bleeding; If the history is uncertain or less than 0.25 mg/kg many patients present only with abnormal blood warfarin has been ingested, repeat the INR every tests 24–48 hours after ingestion, depending on the initial In this situation, monitor pulse, blood pressure, and dose and initial INR. urine output, and observe for features suggesting If the INR remains normal for 24–48 hours and there overt or occult bleeding is no evidence of bleeding, no further monitoring is Transfusion and resuscitation are needed in active necessary. bleeding while anticoagulation is being reversed SPECIFIC CLOTTING FACTOR ANTAGONISTS Patients taking chronic warfarin therapy Dabigatran Monitoring and Initial Management: Direct thrombin inhibitor. Measure the INR at presentation. Standard coagulation tests do not reflect its effect. Monitor INR at least 2-hourly for a minimum of 48 Peak plasma concentration: 0.5–2 hours after hours following acute overdose. therapeutic dose. Active Bleeding: Terminal half-life: 12–14 hours in therapeutic use, Give vitamin K (phytomenadione) by slow IV may be prolonged in renal impairment. injection: No specific antidotes; recombinant activated factor − 5–10 mg for adults VII or prothrombin complex concentrates may have − 100 micrograms/kg for children some efficacy based on animal studies, but no good Administer prothrombin complex concentrate (25–50 evidence in humans. units/kg), or if unavailable, fresh frozen plasma (15 mL/kg). Factor Xa Inhibitors (Rivaroxaban and Apixaban) Further management depends on clinical response. Direct inhibitors of activated factor X (factor Xa). Discuss with a local hematologist about when to Standard coagulation tests do not reflect their effect. repeat INR measurements, when to stop vitamin K, Peak plasma concentration of rivaroxaban: 2-4 and the role of recombinant activated factor VII. hours after therapeutic dose. No Active Bleeding but Dangerously Prolonged INR Elimination half-life of rivaroxaban: 7-11 hours after (INR ≥8.0): oral administration of a 10 mg therapeutic dose. Give vitamin K by slow IV injection: Actions of rivaroxaban can be effectively reversed by − 1–3 mg for adults prothrombin complex concentrates. − 0.015–0.030 mg/kg (15–30 micrograms/kg) for children Risk Factors for Toxicity A pediatric preparation containing 2 mg/0.2 mL is Renal impairment is a major risk factor for bleeding available. with dabigatran etexilate, apixaban, and Further doses may be given as necessary, titrated to rivaroxaban. INR. These drugs should be avoided in liver disease. Excess vitamin K may make it difficult to re-establish anticoagulation. HEPARINS Restart warfarin when the INR is less than 5. Mechanisms of toxicity Heparin is a mucopolysaccharide. Patients who are not prescribed warfarin Acts by non-specific binding with clotting factor Take a careful history and measure the INR at serine proteases, particularly antithrombin III, but presentation. also factors IX–XII, kallikrein, and thrombin. Give vitamin K if: Unfractionated heparin is a complex mixture, not a − No active bleeding and more than 0.25 mg/kg single molecule. warfarin has been ingested, or the INR is higher Heparin breakdown products are smaller heparin- than 4.0. like molecules and are also active anticoagulants. − Adult dose: 10–20 mg orally Unfractionated heparin is dosed in units, not mg, − Child dose: 250 micrograms/kg due to its complex nature. Delay oral vitamin K until at least 4 hours after use In repeat dosing, anticoagulant action increases as of activated charcoal, as charcoal absorbs vitamin K. smaller active heparin molecules accumulate. Repeat INR at 24 hours and consider the need for Low-molecular-weight heparins (LMWHs) avoid this further vitamin K. problem and also have more activity against factor X and less against activated factor II. Monitoring and Effect Management The effect of heparin is monitored by the activated Monitoring and Initial Assessment: partial thromboplastin time (APTT). Monitor pulse, blood pressure, and urine output. LMWHs do not affect APTT at therapeutic doses. Observe for features suggesting bleeding. LMWHs are normally prescribed as a weight-related Measure APTT, full blood count, U&Es, and LFTs dose, adjusted for renal function. initially. Management of Prolonged APTT without Bleeding: Toxicokinetics If APTT is prolonged but there is no sign of bleeding, Intravenous Heparins no further acute treatment is required. Rapidly broken down. Monitor for occult blood loss and repeat the APTT Effective half-life is approximately 1–2.5 every 6 hours until it is within the therapeutic range. hours after single doses. Management of Hemorrhage or Excess Heparin: Metabolism results in smaller molecular- Consider administration of protamine sulfate. weight compounds that are often biologically − Dose: 1 mg for every 100 units heparin, up to 50 active and contribute to anticoagulation. mg, not exceeding 5 mg/min. Required dose of heparin varies during − Monitor for severe hypotension and regular therapy as the effective potency anaphylactoid reactions. increases with time due to accumulation of − Repeat APTT after 4 hours. smaller active molecules. Treat hypovolemia with fluids and blood transfusion LMWHs as indicated. Do not share the same problem as Accidental Excess Heparin Administration: unfractionated heparin. Stop heparin and observe for 6 hours if Can be dosed by weight. asymptomatic. Given subcutaneously. Monitor APTT every 6 hours until it is within the Route of administration is the primary factor therapeutic range. affecting duration of action of low-molecular- Restart heparin if clinically indicated. weight agents. If hemorrhage, give protamine sulfate 25–50 mg IV at a rate not exceeding 5 mg/min. Risk factors for toxicity Repeat APTT after 4 hours, monitoring for adverse Increased risk of bleeding in: effects of protamine. Elderly patients. Patients with underlying clotting CLOTTING FACTOR INHIBITORS abnormalities. Hirudin: Irreversibly blocks thrombin and has no natural Patients with liver disease. inhibitors. Patients with potential bleeding sites. Lepirudin: (Not licensed for use in the UK) Derived from Heparin excretion, including that of LMWHs, is renal, hirudin, used in patients with heparin-induced so renal failure is a further risk factor for bleeding. thrombocytopenia. Dose is titrated according to the APTT. Toxicity assessment Bivalirudin: Measurement of the effects of any acute blood loss, Use: Used in acute ischemic heart disease and as including: an anticoagulant. − Blood pressure. Administration: Intravenous. − Conscious level. Overdose Effects and Reversal: − Pulse rate. Overdose of lepirudin or bivalirudin can cause APTT (activated partial thromboplastin time) may bleeding. also be used in assessment. Reversal: Bleeding can be reversed by clotting factor concentrates. Investigations Management and Specialist Use: Assess blood loss by measuring blood pressure and These drugs have specialist hematological use. pulse rate, lying and standing, and repeat as Management of overdose should be discussed with indicated by clinical status. a hematologist. Establish degree of anticoagulation by use of APTT. Indications for Intervention: In the case of LMWHs, discuss with hematologists. Active bleeding or risk of bleeding, e.g., recent Measure full blood count, U&Es (urea and surgery. electrolytes), and LFTs (liver function tests) as a baseline. THROMBOLYTIC PRODUCTS Duration of Antiplatelet Actions: Non-specific agents: Includes streptokinase and − Longer for agents that irreversibly bind to their urokinase. target receptor (aspirin, prasugrel, and Specific tissue plasminogen activators: Such as ticagrelor). alteplase, which specifically increase fibrin − Re-establishment of coagulation is dependent breakdown in the presence of a clot. on synthesis of new platelets. Duration of Action: Generally relatively short- Glycoprotein IIB/IIIA Inhibitors: acting. − Short action: t½ generally 30 minutes Potential Adverse Effects: (abciximab) to 2.5 hours (eptifibatide). − Bleeding: Particularly concerning if it occurs into − Platelet function normally recovers within 48 the CNS or gut. hours after therapeutic dosing. − Management of Bleeding: Manufacturers − Limited experience in overdose. recommend the infusion of fresh frozen plasma or fresh blood as therapy. They also suggest that Risk factors for toxicity synthetic antifibrinolytics may be administered. Elderly Patients: Increased risk of bleeding. Underlying Clotting Abnormalities: PLATELET ANTAGONISTS − Hereditary or acquired. Platelet Antagonists: Examples are shown in Table − Most commonly seen in liver disease. 7.2. Presence of Potential Bleeding Sites: − E.g., peptic ulcer or recent surgery. Management Supportive Management: − Depends on the extent and severity of bleeding. − Transfusion and resuscitation are needed in active bleeding. Platelet Transfusion: − Benefit is unclear, particularly in the presence of excess antagonist as this will also act on donor platelets. Bleeding Risk: All platelet antagonists may cause bleeding. Aspirin Toxicity: Mainly due to its metabolic effects; see Salicylates, pp. 124–127. Acute Overdose and Bleeding: Bleeding is unusual in acute overdose with oral antiplatelet agents. ANTIVIRAL DRUGS Non-nucleoside reverse transcriptase inhibitors Drugs in Clinical Use: BACKGROUND Efavirenz Used for treatment or suppression of infections Etravirine Human immunodeficiency virus (HIV) Nevirapine Influenza viruses Herpes simplex and zoster Adverse Effects in Therapeutic Doses: Cytomegalovirus (CMV) Skin hypersensitivity reactions Respiratory syncytial virus Viral hepatitis Overdose Toxicity: Few reported cases ANTIRETROVIRAL DRUGS Low toxicity observed Background and therapeutic use Toxic features include: Mechanism of Action: − Nausea − Impaired concentration − Majority of drugs inhibit HIV enzymes reverse − Headache − Disinhibition transcriptase or protease. − Fever − Aggression − Reverse transcriptase is required for the HIV − Fatigue − Elevated hepatic virus, an RNA virus, to make complementary − Sleep disturbances transaminases DNA for incorporation into the host DNA for − Edema subsequent transcription of viral proteins. − Protease inhibitors block the HIV protease Protease inhibitors enzyme required for cleaving HIV protein Drugs (or Combinations) in Clinical Use: precursors. Atazanavir Nelfinavir (not licensed Treatment Strategies: Darunavir for use in the UK) − Involve use of multiple drugs. Fosamprenavir Ritonavir − Often includes two nucleoside reverse Indinavir Saquinavir transcriptase inhibitors with a nucleoside reverse Lopinavir with Tipranavir transcriptase inhibitor or protease inhibitor. ritonavir Nucleoside reverse transcriptase inhibitors Adverse Effects in Therapeutic Use: Drugs in Clinical Use: Cause lipodystrophy Abacavir Stavudine Didanosine Tenofovir Acute Overdose: Emtricitabine Zidovudine Limited data available Lamivudine Reported effects include: − Nausea − Abdominal pain Adverse Effects in Therapeutic Doses: − Vomiting − Diarrhea Nausea Life-threatening lactic Nephrolithiasis documented after acute indinavir Vomiting acidosis associated overdose Abdominal pain with hepatic steatosis Headache Myopathy Other antiretrovirals Itching Bone marrow Drugs in Clinical Use: Rash depression Enfuvirtide: Fever Encephalopathy − Fusion inhibitor Specific drugs associated with hypersensitivity − Administered by subcutaneous injection reactions (e.g., abacavir, strongly associated with − Used in HIV unresponsive to other agents HLA-B*5701 allele), pancreatitis (e.g., Maraviroc: didanosine), and peripheral neuropathy (e.g., − CCR5 chemokine receptor antagonist didanosine) − Used in patients infected exclusively with CCR5- trophic HIV Toxicity in Overdose: Raltegravir (not licensed for use in the UK): Limited experience of significant toxicity − HIV integrase inhibitor Reported effects include GI disturbances, − Used when non-nucleoside reverse tiredness, fatigue, nystagmus, ataxia, transient transcriptase inhibitors cannot be used due to bone marrow failure, and convulsions intolerance, drug interactions, or viral resistance Toxicity: No cases of acute overdose reported Low toxicity in therapeutic use Dose-related postural hypotension observed with maraviroc, which may be anticipated after overdose ANTI-HERPESVIRUS DRUGS Mechanism of Action for Specific Drugs: Mechanism of Action: − Adefovir and Lamivudine: Inhibit viral reverse Most drugs inhibit herpesvirus DNA polymerase, transcriptase preventing viral replication. − Telbivudine: Inhibits viral DNA polymerase Inosine acts as an immunostimulant. − Entecavir: Inhibits reverse transcription, DNA replication, and transcription Drugs in Clinical Use: − Interferon-α: Acts as an immunomodulator Aciclovir Inosine pranobex − Ribavirin: May interfere with RNA metabolism Famciclovir Valaciclovir and/or enhance T cell immunity Foscarnet sodium Adverse Effects and Overdose: − Lamivudine and Entecavir: Can cause life- Toxicity and Overdose: threatening lactic acidosis associated with Few cases of acute overdose reported. hepatic steatosis in therapeutic use Oral Overdose: − Entecavir: Can cause severe skin reactions − Unlikely to cause significant toxicity. − Telbivudine: Can cause rhabdomyolysis − Large doses can cause acute renal injury due to − Ribavirin: Can cause hemolysis drug precipitation in the kidney. − Adefovir: May cause renal failure in overdose IV Overdose: − Few cases of acute overdose have been − Large doses of aciclovir and its pro-drugs can reported cause neurotoxic effects: Impaired consciousness Coma ANTI-INFLUENZA DRUGS Dysarthria Hallucinations Background and Therapeutic Use: Myoclonus Seizures Amantadine: Agitation − Blocks ion channel M2 in influenza A, preventing uncoating when the virus is taken up into a cell. ANTI-CYTOMEGALOVIRUS DRUGS − Licensed for prophylaxis and treatment of Drugs in Clinical Use: influenza A infection. Cidofovir Foscarnet sodium − Also used for treatment of Parkinson’s disease, Ganciclovir Valganciclovir with complex actions as a monoamine oxidase A Common Adverse Effects in Therapeutic Use: and NMDA inhibitor, altering effects of Myelosuppression dopamine, noradrenaline, and serotonin. Nephrotoxicity − Clinical use is now very uncommon. Toxicity and Overdose: Oseltamivir and Zanamivir: Few cases of acute overdose reported. − Neuraminidase inhibitors used for the treatment Oral Overdose: of influenza. − Most drugs (except valganciclovir) are poorly absorbed orally, so little toxicity is expected. Amantadine: − Reported effects include GI disturbances, Adverse Effects in Overdose: neutropenia, hyperkalemia, and renal − Severe cardiotoxicity with QRS and QT dysfunction (specifically with ganciclovir). prolongation. − Renal dysfunction also reported with acyclovir − Hypokalemia. overdose. − Anticholinergic-like delirium. Intravenous Overdose: − Seizures. − Foscarnet overdose can cause: − Torsade de pointes. Paresthesia − Cardiopulmonary arrest. Seizures − Adult respiratory distress syndrome. Coma − Features may be delayed up to 36 hours after Electrolyte abnormalities (especially Mg2+ overdose. and Ca2+). Neuraminidase Inhibitors: ANTIVIRAL HEPATITIS DRUGS Oseltamivir: Mechanism of Action: − No intentional overdoses reported. − Most drugs inhibit viral enzymes, preventing viral − Expected toxicity is low. replication. − Adverse effects at high doses (in clinical trials): Drugs in Clinical Use: nausea, vomiting, and dizziness. − Adefovir dipivoxil − Lamivudine Zanamivir: − Entecavir (not licensed for use in the UK) − Ribavirin − Administered as a dry powder for inhalation. − Interferon-α − Telbivudine − Oral bioavailability is very low, so toxic effects from ingestion are not anticipated. MANAGEMENT OF ANTIVIRAL DRUG OVERDOSE General Management: − Supportive care. − Consider use of oral activated charcoal if administered soon after a large overdose. − Check full blood count, U&Es, and liver function. Management of Specific Symptoms: − Convulsions: Treat with a benzodiazepine (e.g., acyclovir, foscarnet, or amantadine overdose). Management of Amantadine Overdose: − Electrolytes: