Specific Antidotes for reversal of Toxicity – Not Listed Elsewhere
PAST QUESTIONS – ??? (Click to Open)
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)
MASTER TABLE
Pharmacopeia - Antidotes
| DIGOXIN ANTIBODIES | FLUMAZENIL | INTRALIPID | N-ACETYL CYSTEINE (NAC) | NALOXONE | PRALIDOXIME | |
|---|---|---|---|---|---|---|
| GROUP | Antidote | Antidote | Antidotes | Antidote | Antidote | Antidote |
| CICM Level of Understanding | Level 3 | Level 3 | Level 3 | Level 3 | Level 3 | Level 3 |
| INTRODUCTION | ||||||
| USES | - For treatment of acute and chronic digoxin overdose - Treatment of toxicities of other cardiac glycosides: oleander, bufotoxin (cane toad), Chinese medicines | 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 | - the reversal of respiratory depression due to opioids - the diagnosis of suspected opioid overdose and has been used in the treatment of. - clonidine overdose | - Organophosphate poisoning - Acetylcholinesterase Inhibitor toxicity (Neostigmine, Pyridostigmine) | |
| PHARMACEUTICS (PC) | ||||||
| PC: Chemical | Monoclonal antibody (mAB) FAB (Fragment antigen-binding) fragment from sheep immunized with digoxin derivative | imidazo-benzodiazepine | Synthetic derivative of cysteine | substituted oxymorphone derivative. pKa = 8.0 | Synthetic oxime of Pyridine-2-carboxaldehyde | |
| PC: Presentation | powder contains 38-40mg of digoxin-specific Fab fragments (which binds approx. 0.5mg Digoxin) reconstitute with sterile water | clear, colourless solution containing 100 micrograms/ml of flumazenil | IV or oral formulation 200mg/mL compatible with 5% dextrose | clear solution for injection containing 0.02/0.4 mg/ml of naloxone hydrochloride | IV: Reconstituted 1gm solution IM: auto-injector 600mg/2ml | |
| PHARMACODYNAMICS (PD) | ||||||
| PD: Main Action | Binds Digoxin Molecules | Reversal of the actions of benzodiazepines | antioxidant and glutathione inducer | competitive antagonist at mu-, delta-, kappa-, and sigma-opioid receptors | antidote to organophosphate | |
| PD: Mode of Action | 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 | - 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 | 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 | reactivator of phosphorylated Acetylcholinesterase by promoting hydrolysis | |
| PD: Route & Doses | 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 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 - 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/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 | |
| PD: Metrics (Onset/ Peak/ Duration) | Onset: 0-60min Peak: 30-360min | Onset: 30-60 sec Duration: 15-140 min need repeated doses to prevent relapse | Duration: short | 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: 5-15 min | |
| 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 | ||||
| PD: Side Effects / Toxicity | Anaphylaxis – rare Digoxin Withdrawal: AF, heart failure, hypokalemia | 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 | Rapid onset of withdrawal symptoms in opioid drug addiction At High Doses: - Hypertension - Tachycardia - Arrhythmias | Cardiac arrest, hypertension, tachycardia muscle rigidity, weakness Transient transaminitis | |
| PHARMACOKINETICS (PK) | ||||||
| PK: Absorption | - | Well absorbed orally (but significant first-pass hepatic metabolism, so not given by this route) | PO: BA low | 91% absorption but Oral BA 2% due to extensive first-pass metabolism | - | |
| PK: Distribution | ||||||
| Protein binding (PK: Distribution) | - | 50% | 66-97% Albumin | 46% | None | |
| Volume of distribution (PK: Distribution) | 0.3 L/kg [DigiFab] 0.4 L/kg [Digibind] | 0.9 L/kg | 0.5 L/kg | 2 L/kg Highly lipid soluble | 0.6-2.7 L/kg may increase in severe organophosphate intoxication | |
| PK: Metabolism | Nil | Liver Inert metabolites: carboxylic acid and glucuronide | Liver Deacetylated to cysteine -> normal metabolism (Rapid) | Liver via glucuronidation to naloxone-3-glucouronide | Liver | |
| PK: Excretion | Urine | Urine: 95% Unchanged: 0.1% | Unchanged: 40% urine, 3% feces | Urine: 80% metabolites + unchanged | ||
| - Clearance (PK: Excretion) | 700-1100 ml/min | 25 ml/min/kg | ||||
| - Half Life (PK: Excretion) | Unbound: 11 hrs Bound: 15-20 hrs | 53 mins | 5.5 hrs | 0.5-1.5 hrs | 3-4 hr (IM, IV) | |
| SPECIAL POINTS | improves the quality of emergence from anaesthesia reduces post-operative shivering | effective in alleviating the pruritus, nausea, and respiratory depression associated with the epidural or spinal administration of opioids. |
Search bar: To search for something particular within the table.
Recent Comments