Specific Antidotes for reversal of Toxicity – Not Listed Elsewhere
SYLLABUS (Fourth Edition, 2023)
| LEVEL 1 | LEVEL 2 | LEVEL 3 |
|---|---|---|
| Digoxin Antibodies | ||
| Flumazenil | ||
| Intralipid | ||
| N-acetylcysteine | ||
| Naloxone | ||
| Pralidoxime |
N.B. The Syllabus tables used in out Pharmacopeia seem incomplete, but that is intentional because we have only included groups/classes/drugs which are mentioned directly in the syllabus or have been asked before in the exams.
TRAINEE EXPECTATIONS
- Trainees are expected to understand a drug’s pharmacology in the context of normal physiology, extremes of age (i.e., neonates, paediatrics, and the elderly), obesity, pregnancy (including foetal implications) and critical illness. An understanding of potential toxicity and relevant antidotes is also expected. Agents may be listed in more than one section when they are used for different indications.
- This is not an exhaustive list of all drugs relevant to or important in ICU practice. Each drug or classes of drugs have been assigned a details of understanding level outlined below. This is a guide to the minimum level of knowledge expected for that drug.
- For classes of drugs where examples are not specified, it is suggested a prototypical drug from the class be studied, as well as the relevant variations within the class exploring the major differences that exist between the agents in that class.
LEVELS OF UNDERSTANDING
| Level 1 | Level 2 | Level 3 |
|---|---|---|
| For these drugs, a detailed knowledge and comprehension of: | For these drugs a detailed knowledge of: | For these drugs a detailed knowledge of: |
| Class, Indications, and dose | ||
| Mechanism of Action | ||
| Pharmacodynamics and Adverse effects | ||
| Pharmacokinetics | Important pharmacokinetic differences or considerations when using in ICU | |
| Pharmaceutics | ||
CICMWrecks Tables (Click to Open)
PAST QUESTIONS
2024B 20
Explain the mechanism of action by which the following drugs exert their clinical and pharmacological effect when used to treat drug toxicity or overdose, including the time taken to exert this clinical effect:
(a) N-acetylcysteine (25% of marks).
(b) Digoxin FAb (25% of marks).
(c) Naloxone (25% of marks).
(d) Lipid emulsion (i.e. Intralipid) (25% of marks).
Examiner Comments
2024B 20: 65% of candidates passed this question.
This question was best answered by using each drug as the heading with their subsequent mechanism of action and time of onset of their clinical effect. Brief discussion of what drug toxicity or overdose these agents offset and how is implied in the mechanism of action and was included in our marking rubric.
MASTER TABLE
Pharmacopeia – Antidotes
PC: Pharmaceutics, PD: Pharmacodynamics, PK: PharmacokineticsColumn Visibility: To filter out some of the drugs
Dropdown Menus: To filter out categories or items
Search bar: To search within table
Print: Print to PDF or printer. Pls remember to change to landscape if the table does not fit in portrait mode.
| CATEGORY | ITEM | NALOXONE | FLUMAZENIL | N-ACETYL CYSTEINE (NAC) | PRALIDOXIME | DIGOXIN ANTIBODIES | INTRALIPID 20% |
|---|---|---|---|---|---|---|---|
| Basics | GROUP | Antidote | Antidote | Antidote | Antidote | Antidote | Antidotes |
| Basics | CICM Level of Understanding | Level 3 | Level 3 | Level 3 | Level 3 | Level 3 | Level 3 |
| Basics | INTRODUCTION | ||||||
| Basics | USES | – the reversal of respiratory depression due to opioids – the diagnosis of suspected opioid overdose and has been used in the treatment of. – clonidine overdose | 1. as an aid to weaning and neurological assessment of ventilated patients who have received benzodiazepine sedation during intensive care 2. as part of the ‘wake-up’ test during scoliosis surgery 3. to reverse oversedation after endoscopy and 4. for diagnosis of, and assessment after, benzodiazepine overdose. | – paracetamol overdose – non-paracetamol induced fulminant hepatic failure – prevention of contrast nephropathy – mucolytic therapy | – Organophosphate poisoning – Acetylcholinesterase Inhibitor toxicity (Neostigmine, Pyridostigmine) | – For treatment of acute and chronic digoxin overdose – Treatment of toxicities of other cardiac glycosides: oleander, bufotoxin (cane toad), Chinese medicines | – TPN mixtures – Local anaesthetic toxicity with or without circulatory arrest – Prevention of essential fatty acid deficiency syndrome |
| PC | Chemical | substituted oxymorphone derivative. pKa = 8.0 | imidazo-benzodiazepine | Synthetic derivative of cysteine | Synthetic oxime of Pyridine-2-carboxaldehyde | Monoclonal antibody (mAB) FAB (Fragment antigen-binding) fragment from sheep immunized with digoxin derivative | fat emulsion |
| PC | Presentation | clear solution for injection containing 0.02/0.4 mg/ml of naloxone hydrochloride | clear, colourless solution containing 100 micrograms/ml of flumazenil | IV or oral formulation 200mg/mL compatible with 5% dextrose | IV: Reconstituted 1gm solution IM: auto-injector 600mg/2ml | powder contains 38-40mg of digoxin-specific Fab fragments (which binds approx. 0.5mg Digoxin) reconstitute with sterile water | white, oil-water emulsion with 20% soybean oil, egg yolk phospholipids, glycerin, sodium hydroxide and water |
| PD | Main Action | competitive antagonist at mu-, delta-, kappa-, and sigma-opioid receptors | Reversal of the actions of benzodiazepines | antioxidant and glutathione inducer | antidote to organophosphate | Binds Digoxin Molecules | – Energy substrate – Reverse local anaesthetic cardiotoxicity |
| PD | Mode of Action | Reversal of MoP receptor effects such as sedation, hypotension, respiratory depression, and the dysphoric effects of partial agonists Will precipitate acute withdrawal symptoms in opiate addicts | – competitive reversible antagonist at benzo site on GABA-A receptor – only intrinsic effect is slight anticonvulsant effect | – Metabolized to cysteine → Regeneration of sulphydril groups and glutathione – acting as an alternate substrate for conjugation – reduces disulfide bonds in mucoproteins | reactivator of phosphorylated Acetylcholinesterase by promoting hydrolysis | Binds excess digoxin or digitoxin molecules circulating in the blood – Fab fragment-digoxin complex excreted by kidney – Net shifts the equilibrium away from binding of digoxin to receptors | – unclear – may involve establishment of concentration gradient away from primary site of action of LA |
| PD | Route & Doses | IV/IM – Reversal of post-operative respiratory depression and coma: 20-40mcg IV PRN – For opioid overdose reversal 0.4-2 mg IM/IV → Via infusion a 5mcg/kg/hr – Reversal of S/Es of opioids: 1-4 mcg/kg – Increased cardiac contractility in septic shock at doses 1mg/kg IV | IV Bolus: Titrated in 100mcg increments Total max adult dose: 1mg/5 mins, 3 mg/1 hr Infusion: 100-400mcg/hr question diagnosis if no response to repeated doses | IV, PO, Neb (inhaled) IV: 1st : 150mg/kg in 200ml dextrose over 15mins 2nd : 50mg/kg in 500ml over 4hrs 3rd : 100mg/kg in 1l over 16hrs | IV/IM/SC OP poisoning: 30 mg/kg IV (max 2gm) (600mg IM every 15min upto 1.8gm, SC if no IV access) over 20 min; follow by 8-10 mg/kg/hr (max 650mg) maintenance IV infusion Acetylcholinesterase Inhibitor Toxicity: (Neostigmine, Pyridostigmine) 1-2 g IV followed by 250 mg increments q5min PRN | IV Empiric: 10vials of Fab fragments Known dose, no level: Total body load = Dose (in mg) x 0.8 (BA of digoxin) Number of vials = TBL x 2 Known concentration: No of vials = [(serum digoxin concentration in ng/mL) x (patient’s weight in kg)]/ 100 | IV For LA tox: 1.5ml/kg bolus over 1 minute → Infusion 15 ml/kg/hr If not stabilized, two subsequent boluses may be given 5 mins apark. Then rate doubled to 30ml/kg/hr Max cumulative dose 12ml/kg |
| PD | Metrics (Onset/ Peak/ Duration) | Onset: 1-3 mins Peak effect: 15 mins Duration: 30 mins > Less than the effect site time of most opioids → requirement for repeat dosing or infusion. | Onset: 30-60 sec Duration: 15-140 min need repeated doses to prevent relapse | Duration: short | Onset: 5-15 min | Onset: 0-60min Peak: 30-360min | (For LA tox) onset: minutes peak: 15-30mins |
| PD | Effects | – CVS: > 0.3 mg/kg → ↑MAP – RESP: nil – CNS: Drowsiness at high dose, Decreased pain tolerance – OTHER: Sphincter of oddi spasm | – Reduces hepatotoxicity – mucolytic | – energy substrate (essential fatty acids) – managing lipophilic drug overdose by binding and facilitating clearance | |||
| PD | Side Effects / Toxicity | Rapid onset of withdrawal symptoms in opioid drug addiction At High Doses: – Hypertension – Tachycardia – Arrhythmias | Minor: – headache/visual symptoms/↑anxiety/N&V Major: – can cause dangerous convulsions if: > benzo’s being taken for epilepsy > mixed ODs with CNS stimulants & antidepressants – seizures & severe withdrawal if taking benzo’s chronically | usually in 1st hr: – rash around infusion site – angiooedema – bronchospasm – hypo/hyper tension Mx: stop, give antihistamine, then restart at slowest infusion rate | Cardiac arrest, hypertension, tachycardia muscle rigidity, weakness Transient transaminitis | Anaphylaxis – rare Digoxin Withdrawal: AF, heart failure, hypokalemia | – Fat embolism – Hyperlipidemia, pancreatitis – Hepatic dysfunction – Allergic reactions |
| PK | Absorption | 91% absorption but Oral BA 2% due to extensive first-pass metabolism | Well absorbed orally (but significant first-pass hepatic metabolism, so not given by this route) | PO: BA low | – | – | IV only |
| PK | Distribution | ||||||
| PK | D – Protein binding | 46% | 50% | 66-97% Albumin | None | – | None |
| PK | D – Volume of distribution | 2 L/kg Highly lipid soluble | 0.9 L/kg | 0.5 L/kg | 0.6-2.7 L/kg may increase in severe organophosphate intoxication | 0.3 L/kg [DigiFab] 0.4 L/kg [Digibind] | Wide – distributed to fat and tissues |
| PK | Metabolism | Liver via glucuronidation to naloxone-3-glucouronide | Liver Inert metabolites: carboxylic acid and glucuronide | Liver Deacetylated to cysteine -> normal metabolism (Rapid) | Liver | Nil | Liver Broken down to Fatty acids and glycerol |
| PK | Excretion | Urine: 95% Unchanged: 0.1% | Unchanged: 40% urine, 3% feces | Urine: 80% metabolites + unchanged | Urine | Liver and kidneys | |
| PK | E – Clearance | 25 ml/min/kg | 700-1100 ml/min | ||||
| PK | E – Half Life | 0.5-1.5 hrs | 53 mins | 5.5 hrs | 3-4 hr (IM, IV) | Unbound: 11 hrs Bound: 15-20 hrs | not well defined |
| Spl | SPECIAL POINTS | effective in alleviating the pruritus, nausea, and respiratory depression associated with the epidural or spinal administration of opioids. | improves the quality of emergence from anaesthesia reduces post-operative shivering | serum amylase or lipase should be monitored for 2 days |
INDIVIDUAL TABLES
Antidotes – Limited 1
Pharmacopeia – Antidotes
PC: Pharmaceutics, PD: Pharmacodynamics, PK: PharmacokineticsColumn Visibility: To filter out some of the drugs
Dropdown Menus: To filter out categories or items
Search bar: To search within table
Print: Print to PDF or printer. Pls remember to change to landscape if the table does not fit in portrait mode.
| CATEGORY | ITEM | N-ACETYL CYSTEINE (NAC) | DIGOXIN ANTIBODIES | NALOXONE | INTRALIPID 20% |
|---|---|---|---|---|---|
| Basics | GROUP | Antidote | Antidote | Antidote | Antidotes |
| Basics | CICM Level of Understanding | Level 3 | Level 3 | Level 3 | Level 3 |
| Basics | INTRODUCTION | ||||
| Basics | USES | – paracetamol overdose – non-paracetamol induced fulminant hepatic failure – prevention of contrast nephropathy – mucolytic therapy | – For treatment of acute and chronic digoxin overdose – Treatment of toxicities of other cardiac glycosides: oleander, bufotoxin (cane toad), Chinese medicines | – the reversal of respiratory depression due to opioids – the diagnosis of suspected opioid overdose and has been used in the treatment of. – clonidine overdose | – TPN mixtures – Local anaesthetic toxicity with or without circulatory arrest – Prevention of essential fatty acid deficiency syndrome |
| PC | Chemical | Synthetic derivative of cysteine | Monoclonal antibody (mAB) FAB (Fragment antigen-binding) fragment from sheep immunized with digoxin derivative | substituted oxymorphone derivative. pKa = 8.0 | fat emulsion |
| PC | Presentation | IV or oral formulation 200mg/mL compatible with 5% dextrose | powder contains 38-40mg of digoxin-specific Fab fragments (which binds approx. 0.5mg Digoxin) reconstitute with sterile water | clear solution for injection containing 0.02/0.4 mg/ml of naloxone hydrochloride | white, oil-water emulsion with 20% soybean oil, egg yolk phospholipids, glycerin, sodium hydroxide and water |
| PD | Main Action | antioxidant and glutathione inducer | Binds Digoxin Molecules | competitive antagonist at mu-, delta-, kappa-, and sigma-opioid receptors | – Energy substrate – Reverse local anaesthetic cardiotoxicity |
| PD | Mode of Action | – Metabolized to cysteine → Regeneration of sulphydril groups and glutathione – acting as an alternate substrate for conjugation – reduces disulfide bonds in mucoproteins | Binds excess digoxin or digitoxin molecules circulating in the blood – Fab fragment-digoxin complex excreted by kidney – Net shifts the equilibrium away from binding of digoxin to receptors | Reversal of MoP receptor effects such as sedation, hypotension, respiratory depression, and the dysphoric effects of partial agonists Will precipitate acute withdrawal symptoms in opiate addicts | – unclear – may involve establishment of concentration gradient away from primary site of action of LA |
| PD | Route & Doses | IV, PO, Neb (inhaled) IV: 1st : 150mg/kg in 200ml dextrose over 15mins 2nd : 50mg/kg in 500ml over 4hrs 3rd : 100mg/kg in 1l over 16hrs | IV Empiric: 10vials of Fab fragments Known dose, no level: Total body load = Dose (in mg) x 0.8 (BA of digoxin) Number of vials = TBL x 2 Known concentration: No of vials = [(serum digoxin concentration in ng/mL) x (patient’s weight in kg)]/ 100 | IV/IM – Reversal of post-operative respiratory depression and coma: 20-40mcg IV PRN – For opioid overdose reversal 0.4-2 mg IM/IV → Via infusion a 5mcg/kg/hr – Reversal of S/Es of opioids: 1-4 mcg/kg – Increased cardiac contractility in septic shock at doses 1mg/kg IV | IV For LA tox: 1.5ml/kg bolus over 1 minute → Infusion 15 ml/kg/hr If not stabilized, two subsequent boluses may be given 5 mins apark. Then rate doubled to 30ml/kg/hr Max cumulative dose 12ml/kg |
| PD | Metrics (Onset/ Peak/ Duration) | Duration: short | Onset: 0-60min Peak: 30-360min | Onset: 1-3 mins Peak effect: 15 mins Duration: 30 mins > Less than the effect site time of most opioids → requirement for repeat dosing or infusion. | (For LA tox) onset: minutes peak: 15-30mins |
| PD | Effects | – Reduces hepatotoxicity – mucolytic | – CVS: > 0.3 mg/kg → ↑MAP – RESP: nil – CNS: Drowsiness at high dose, Decreased pain tolerance – OTHER: Sphincter of oddi spasm | – energy substrate (essential fatty acids) – managing lipophilic drug overdose by binding and facilitating clearance | |
| PD | Side Effects / Toxicity | usually in 1st hr: – rash around infusion site – angiooedema – bronchospasm – hypo/hyper tension Mx: stop, give antihistamine, then restart at slowest infusion rate | Anaphylaxis – rare Digoxin Withdrawal: AF, heart failure, hypokalemia | Rapid onset of withdrawal symptoms in opioid drug addiction At High Doses: – Hypertension – Tachycardia – Arrhythmias | – Fat embolism – Hyperlipidemia, pancreatitis – Hepatic dysfunction – Allergic reactions |
| PK | Absorption | PO: BA low | – | 91% absorption but Oral BA 2% due to extensive first-pass metabolism | IV only |
| PK | Distribution | ||||
| PK | D – Protein binding | 66-97% Albumin | – | 46% | None |
| PK | D – Volume of distribution | 0.5 L/kg | 0.3 L/kg [DigiFab] 0.4 L/kg [Digibind] | 2 L/kg Highly lipid soluble | Wide – distributed to fat and tissues |
| PK | Metabolism | Liver Deacetylated to cysteine -> normal metabolism (Rapid) | Nil | Liver via glucuronidation to naloxone-3-glucouronide | Liver Broken down to Fatty acids and glycerol |
| PK | Excretion | Unchanged: 40% urine, 3% feces | Urine | Liver and kidneys | |
| PK | E – Clearance | 25 ml/min/kg | |||
| PK | E – Half Life | 5.5 hrs | Unbound: 11 hrs Bound: 15-20 hrs | 0.5-1.5 hrs | not well defined |
| Spl | SPECIAL POINTS | effective in alleviating the pruritus, nausea, and respiratory depression associated with the epidural or spinal administration of opioids. | serum amylase or lipase should be monitored for 2 days |
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