PAST QUESTIONS – L02. Musculoskeletal System Pharmacology (Click to Open)
SYLLABUS (Fourth Edition, 2023)
| LEVEL 1 | LEVEL 2 | LEVEL 3 |
|---|---|---|
| Neuromuscular blockers | Dantrolene | |
| Aminosteroids | Sugammadex | |
| Rocuronium | Vecuronium | |
| Pancuronium | ||
| Isoquinolones | ||
| Cisatracurium | Atracurium | |
| Depolarizing | ||
| Suxamethonium | ||
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 TABLES | Neuromuscular Blocking Drugs |
| Miscellaneous | |
| INDIVIDUAL TABLES | Vecuronium |
| Rocuronium vs Cisatracurium | |
| Suxamethonium | |
| Suxamethonium | Rocuronium |
MASTER TABLES
NEURO MUSCULAR BLOCKING DRUGS
Pharmacopeia - Neuromuscular Blocking Drugs
| SUXAMETHONIUM | VECURONIUM | ROCURONIUM | PANCURONIUM | ATRACURIUM | CISATRACURIUM | |
|---|---|---|---|---|---|---|
| GROUP | Depolarizing | Non-Depolarizing Aminosteroid | Non-Depolarizing Aminosteroid | Non-Depolarizing Aminosteroid | Non-Depolarizing Isoquinolone | Non-Depolarizing Isoquinolone |
| CICM Level of Understanding | Level 1 | Level 2 | Level 1 | Level 2 | Level 2 | Level 1 |
| INTRODUCTION | Dicholine ester of succinic acid | Aminosteroid | Aminosteroid | Aminosteroid | Benzylisoquinolinium ester | Benzylisoquinolinium ester |
| USES | 1. Where ever rapid and profound muscle relaxation is required e.g. endotracheal intubation 2. For modification of fits following ECT | to facilitate intubation and controlled ventilation | 1. to facilitate tracheal intubation during routine and modified rapid sequence induction 2. for controlled ventilation. | to facilitate intubation and controlled ventilation | to facilitate intubation and controlled ventilation | to facilitate intubation and controlled ventilation |
| PHARMACEUTICS (PC) | ||||||
| PC: Chemical | Bisquaternary 2 Molecules of ACh joined by acetate methyl groups | Monoquaternary | Monoquaternary | Bisquaternary | Bisquaternary. 10 stereoisomers. | Bisquaternary. 1 of 10 stereoisomers. In atrac (15% wt, 50% pot) |
| PC: Presentation | Clear aqueous solution, 50mg/mL suxamethonium chloride Stored at 4°C | Lyophilised powder with citrate & mannitol buffer, dil in water, stable for 24hrs | Clear, colourless solution, 10mg/mL rocuronium bromide | Clear, colourless solution, 2mg/mL as pancuronium bromide | Clear, 10mg/mL, stored at 4 °C Racemic mixture of 10 stereoisomers: Cis-cis, cis-trans, trans-trans. | Clear, 10mg in 5mL as cisatracurium besylate, stored at 4°C. |
| PHARMACODYNAMICS (PD) | ||||||
| PD: Main Action | ||||||
| PD: Mode of Action | PHASE I (depolarising) block mechanism: 2 molecules of sux binds the 2 alpha subunits of nAChR → activation and channel opening depolarisation → sux is not metabolised by NMJ AChE → remains bound to nAChR → nAChR remains open & in inactive state forms small zone of depolarisation/inactivation around synapse → blocks further depolarisation → muscle relaxation (~ 20% post-synaptic nAChR occupancy required to achieve depolarising block) Sux exerts pre-junctional action → retrograde conduction up motor neuron triggers axon to depolarise entire motor unit → fasciculation observed prior to onset of depolarising block PHASE II (desensitisation) block mechanism: exact mechanism uncertain. After sux has been present for a period of time → motor end plates loses sensitivity to ACh/sux → depolarisation cannot occur Desensitisation continues (for several minutes) even after drug is no longer present | ND-NMB acts as competitive antagonist → competes with ACh for nAChR binding → blocks cholinergic transmission → muscle relaxation (> 70% post-synaptic nAChR occupancy required to result in block) ND-NMB also inhibits pre-synaptic ACh receptors →prevents enhancement of ACh release → fade with repeated stimulation | ND-NMB acts as competitive antagonist → competes with ACh for nAChR binding → blocks cholinergic transmission → muscle relaxation (> 70% post-synaptic nAChR occupancy required to result in block) ND-NMB also inhibits pre-synaptic ACh receptors →prevents enhancement of ACh release → fade with repeated stimulation | ND-NMB acts as competitive antagonist → competes with ACh for nAChR binding → blocks cholinergic transmission → muscle relaxation (> 70% post-synaptic nAChR occupancy required to result in block) ND-NMB also inhibits pre-synaptic ACh receptors →prevents enhancement of ACh release → fade with repeated stimulation | ND-NMB acts as competitive antagonist → competes with ACh for nAChR binding → blocks cholinergic transmission → muscle relaxation (> 70% post-synaptic nAChR occupancy required to result in block) ND-NMB also inhibits pre-synaptic ACh receptors →prevents enhancement of ACh release → fade with repeated stimulation | ND-NMB acts as competitive antagonist → competes with ACh for nAChR binding → blocks cholinergic transmission → muscle relaxation (> 70% post-synaptic nAChR occupancy required to result in block) ND-NMB also inhibits pre-synaptic ACh receptors →prevents enhancement of ACh release → fade with repeated stimulation |
| PD: Route & Doses | ED95 0.3 – 0.6 mg/kg RSI IV 1 mg/kg IV IM 2 mg/kg Infusion- | ED95 0.05 mg/kg Int 0.1 mg/kg Inf 1 mcg/kg/min | ED95 0.3 mg/kg Int 0.6 mg/kg RSI 0.9 ~ 1.2 mg/kg Inf 9 – 12 mcg/kg/min | ED95 0.07 mg/kg Int 0.1 mg/kg Inf - | ED95 0.25 mg/kg Int 0.5 mg/kg Inf 4 – 12 mcg/kg/min | ED95 0.05 mg/kg Int 0.15 mg/kg Inf 1 – 2 mcg/kg/min |
| PD: Metrics (Onset/ Peak/ Duration) | Onset IV 30 ~ 60s IM 60 ~ 120s Duration 5mins | Intubate @ 90 – 120s Duration 35mins | Int @ 100 – 120s RSI @ 60s Duration 35mins | Intubate @ 90 – 150s Duration 85mins | Intubate @ 90 – 120s Duration 45mins | Intubate @ 3 – 5min Duration 45mins |
| PD: Effects | ||||||
| PD: Side Effects / Toxicity | HISTAMINE RELEASE - rash, ↑HR, ↓ BP (NOT bronchospasm) EFFECT ON ANS ↓ HR paeds (mAChR) (agonist at both sym/para ganglia, but kids ↑vagal tone) OTHER - Anaphylaxis Risk 3xND-NMB - Malignant hyperthermia - Myalgia (fasciculn) - ↑ [K+] by 0.5 mmol/L - ↑ICP ↑intraocular pressure - Phase I + II blocks - Sux apnea w BChEmutations - ↑Intragastric pressure | HISTAMINE RELEASE - None EFFECT ON ANS - Minimal OTHER - Anaphylaxis Critical illness myopathy | HISTAMINE RELEASE - None EFFECT ON ANS - Can be vagolytic (↑HR) OTHER - Anaphylaxis - Pain on injection | HISTAMINE RELEASE - None EFFECT ON ANS - Can be vagolytic ( Cardiac M2 AChR block →↑HR) OTHER - Anaphylaxis | HISTAMINE RELEASE - rash, ↑HR, ↓ BP, CAN cause bronchospasm VAGOLYSIS - Minimal OTHER - Anaphylaxis Critical illness myopathy | HISTAMINE RELEASE - None VAGOLYSIS - None OTHER - Anaphylaxis |
| PHARMACOKINETICS (PK) | ||||||
| PK: Absorption | ||||||
| PK: Distribution | Highly ionised & water soluble Limited lipid solubility | Doesn’t cross BBB | Doesn’t cross BBB | Doesn’t cross BBB | Dsn’t crss BBB Min Crosses placenta | |
| Protein binding (PK: Distribution) | Protein bound to unknown extent | PB 10% | PB 10% | PB 20 – 60% | PB 15% | PB 15% |
| Volume of distribution (PK: Distribution) | VD 0.23L/kg | VD 0.2L/kg | VD 0.27L/kg | VD 0.15L/kg | VD 0.15L/kg | |
| PK: Metabolism | Rapid hydrolysis by plasma Butyrylcholinesterase. Sux→succinylmonocholine →succinic acid + choline. (Inactive) Approx 10% of IV dose reaches NMJ | 30-40% hepatic deacetylation to 3-desacetyl-vecuronium → 80% potency of vec with NMB effects, ↓ clearance & ↑duration of action→Accumulates in renal failure | <5% Metabolism Hep | 10-20% hepatic deacetylation to multiple metab: 3-hydroxy derivative → 50% potency of panc. Delayed Total clearance & sign prolonged durn of axn in ren/hep failure | 40% Hofmann degradation → laudanosine and quat. monoacrylates Ester hydrolysis (60%) nonspecific esterases→ quat alcohol & quat acid Inactive metabolites | 77% Hofmann degradation → laudanosine and quat. monoacrylates Minimal ester hydrolysis Inactive metabolites |
| PK: Excretion | Renal: <2% Liver: nil | Renal: 40% (metab) Liver: 10-20% (metab) | Renal: 30-40% Liver: 60% | Renal: 60-80% Liver: 10% | Renal: 10-30% (laud.) Liver: (laudanosine) | Ren: 10-30% (laud.) Liver: (laudanosine) |
| - Clearance (PK: Excretion) | Pl clearance: 3ml/kg/min | Pl cl 3-5ml/kg/min | Pl cl: 3ml/kg/min | Pl cl 2ml/kg/min | Pl cl 7ml/kg/min | Pl cl 4-5ml/kg/min |
| - Half Life (PK: Excretion) | El t1/2: 90mins | El t1/2: 50-110mins | El t1/2: 90mins | El t1/2: 130mins | El t1/2: 20mins | El t1/2: 25mins |
| SPECIAL POINTS | Contraindications: - Hyperkalaemia - Neuromuscular diseases - Denervation (after 2 days) - Immobilization (after 3 days) - Burns (after 2 days) - Chronic NMB use (>3 days) - Sepsis/SIRS (after 3 days) - MH risk - Allergy - Homozygous for atypical plasma cholinesterase (1/3200 incidence; block prolonged by hours) | Duration prolonged by: - ↓K ↓Ca ↑Mg - ↑pH ↑PaCO2 - ↓temp ↓protein Dehydration Reversible with sugammadex | Duration prolonged by: - ↓K ↓Ca ↑Mg - ↑pH ↑PaCO2 - ↓temp ↓protein Dehydration Reversible with sugammadex | Duration prolonged by: - ↓K ↓Ca ↑Mg - ↑pH ↑PaCO2 - ↓temp ↓protein Dehydration Reversible with sugammadex | Duration prolonged by: - ↓K ↓Ca ↑Mg - ↑pH ↑PaCO2 - ↓temp ↓protein Dehydration | Duration prolonged by: - ↓K ↓Ca ↑Mg - ↑pH ↑PaCO2 - ↓temp ↓protein Dehydration |
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MISCELLANEOUS
Pharmacopeia - Neuromuscular Misc.
| DANTROLENE | SUGAMMADEX | |
|---|---|---|
| GROUP | Neuromuscular - Miscellaneous | Neuromuscular - Miscellaneous |
| CICM Level of Understanding | Level 3 | Level 3 |
| INTRODUCTION | Cyclodextrin Selective Relaxant Binding Agent | |
| USES | 1. MH treatment and prophylaxis 2. Neuroleptic malignant syndrome 3. Ecstasy intoxication 4. Chronic muscle spasms 5. Improve voiding in patients with neuromuscular disorders | 1. Reversal of NMB by aminosteroid NMBA (Rocuronium>vecuronium>>pancuronium) |
| PHARMACEUTICS (PC) | ||
| PC: Chemical | ||
| PC: Presentation | Orange powder for reconstitution containing mannitol | Clear colourless or pale yellow solution for injection Contains 100mg/ml of y-Cyclodextrin Sugammadex |
| PHARMACODYNAMICS (PD) | ||
| PD: Main Action | ||
| PD: Mode of Action | Uncouples the excitation contraction process by binding the ryanodine receptor, thereby preventing the release of calcium from the sarcoplasmic reticulum in striated muscle. Vascular smooth muscle and cardiac smooth muscle are not primarily dependent on calcium release and are usually not affected. May produce respiratory failure secondary to skeletal muscle weakness Produces sedation secondary to GABA-ergic activity | Encapsulates steroid portion of aminosteroid molecules. The binding leads to a decrease of free drug in the central compartment, leading to a diffusion gradient away from the NMJ. Median time to recovery 90 seconds |
| PD: Route & Doses | 2.5mg/kg IV every 10-15 mins, up to 10mg/kg Once resolved, continue giving 1mg/kg every 4-6 hours for 24 hrs. | 4mg/kg for deep block 2mg/kg for shallow block 16mg/kg for rescue reversal in RSI CICO scenario |
| PD: Metrics (Onset/ Peak/ Duration) | ||
| PD: Effects | ||
| PD: Side Effects / Toxicity | 1. Sedation 2. Hepatotoxicity (chronic use) 3. Pleural effusions (chronic use) 4. Highly irritant if extravasates 5. Diuresis (mannitol) | 1. Anaphylaxis 2. Fluclox can displace aminosteroids from Sugammadex |
| PHARMACOKINETICS (PK) | ||
| PK: Absorption | Variable oral absorption | |
| PK: Distribution | ||
| Protein binding (PK: Distribution) | 85% protein bound to albumin | Not protein bound |
| Volume of distribution (PK: Distribution) | ||
| PK: Metabolism | Hepatically metabolized | None |
| PK: Excretion | Renally excreted | 95% unaltered in urine |
| - Clearance (PK: Excretion) | ||
| - Half Life (PK: Excretion) | T1/2= 3-12 hours | T1/2 is 1.8 hours |
| SPECIAL POINTS |
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INDIVIDUAL TABLES
VECURONIUM
Pharmacopeia - Neuromuscular Blocking Drugs
| VECURONIUM | |
|---|---|
| GROUP | Non-Depolarizing Aminosteroid |
| CICM Level of Understanding | Level 2 |
| INTRODUCTION | Aminosteroid |
| USES | to facilitate intubation and controlled ventilation |
| PHARMACEUTICS (PC) | |
| PC: Chemical | Monoquaternary |
| PC: Presentation | Lyophilised powder with citrate & mannitol buffer, dil in water, stable for 24hrs |
| PHARMACODYNAMICS (PD) | |
| PD: Main Action | |
| PD: Mode of Action | ND-NMB acts as competitive antagonist → competes with ACh for nAChR binding → blocks cholinergic transmission → muscle relaxation (> 70% post-synaptic nAChR occupancy required to result in block) ND-NMB also inhibits pre-synaptic ACh receptors →prevents enhancement of ACh release → fade with repeated stimulation |
| PD: Route & Doses | ED95 0.05 mg/kg Int 0.1 mg/kg Inf 1 mcg/kg/min |
| PD: Metrics (Onset/ Peak/ Duration) | Intubate @ 90 – 120s Duration 35mins |
| PD: Effects | |
| PD: Side Effects / Toxicity | HISTAMINE RELEASE - None EFFECT ON ANS - Minimal OTHER - Anaphylaxis Critical illness myopathy |
| PHARMACOKINETICS (PK) | |
| PK: Absorption | |
| PK: Distribution | Doesn’t cross BBB |
| Protein binding (PK: Distribution) | PB 10% |
| Volume of distribution (PK: Distribution) | VD 0.23L/kg |
| PK: Metabolism | 30-40% hepatic deacetylation to 3-desacetyl-vecuronium → 80% potency of vec with NMB effects, ↓ clearance & ↑duration of action→Accumulates in renal failure |
| PK: Excretion | Renal: 40% (metab) Liver: 10-20% (metab) |
| - Clearance (PK: Excretion) | Pl cl 3-5ml/kg/min |
| - Half Life (PK: Excretion) | El t1/2: 50-110mins |
| SPECIAL POINTS | Duration prolonged by: - ↓K ↓Ca ↑Mg - ↑pH ↑PaCO2 - ↓temp ↓protein Dehydration Reversible with sugammadex |
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ROCURONIUM vs CISATRACURIUM
Pharmacopeia - Neuromuscular Blocking Drugs
| ROCURONIUM | CISATRACURIUM | |
|---|---|---|
| GROUP | Non-Depolarizing Aminosteroid | Non-Depolarizing Isoquinolone |
| CICM Level of Understanding | Level 1 | Level 1 |
| INTRODUCTION | Aminosteroid | Benzylisoquinolinium ester |
| USES | 1. to facilitate tracheal intubation during routine and modified rapid sequence induction 2. for controlled ventilation. | to facilitate intubation and controlled ventilation |
| PHARMACEUTICS (PC) | ||
| PC: Chemical | Monoquaternary | Bisquaternary. 1 of 10 stereoisomers. In atrac (15% wt, 50% pot) |
| PC: Presentation | Clear, colourless solution, 10mg/mL rocuronium bromide | Clear, 10mg in 5mL as cisatracurium besylate, stored at 4°C. |
| PHARMACODYNAMICS (PD) | ||
| PD: Main Action | ||
| PD: Mode of Action | ND-NMB acts as competitive antagonist → competes with ACh for nAChR binding → blocks cholinergic transmission → muscle relaxation (> 70% post-synaptic nAChR occupancy required to result in block) ND-NMB also inhibits pre-synaptic ACh receptors →prevents enhancement of ACh release → fade with repeated stimulation | ND-NMB acts as competitive antagonist → competes with ACh for nAChR binding → blocks cholinergic transmission → muscle relaxation (> 70% post-synaptic nAChR occupancy required to result in block) ND-NMB also inhibits pre-synaptic ACh receptors →prevents enhancement of ACh release → fade with repeated stimulation |
| PD: Route & Doses | ED95 0.3 mg/kg Int 0.6 mg/kg RSI 0.9 ~ 1.2 mg/kg Inf 9 – 12 mcg/kg/min | ED95 0.05 mg/kg Int 0.15 mg/kg Inf 1 – 2 mcg/kg/min |
| PD: Metrics (Onset/ Peak/ Duration) | Int @ 100 – 120s RSI @ 60s Duration 35mins | Intubate @ 3 – 5min Duration 45mins |
| PD: Effects | ||
| PD: Side Effects / Toxicity | HISTAMINE RELEASE - None EFFECT ON ANS - Can be vagolytic (↑HR) OTHER - Anaphylaxis - Pain on injection | HISTAMINE RELEASE - None VAGOLYSIS - None OTHER - Anaphylaxis |
| PHARMACOKINETICS (PK) | ||
| PK: Absorption | ||
| PK: Distribution | Doesn’t cross BBB | |
| Protein binding (PK: Distribution) | PB 10% | PB 15% |
| Volume of distribution (PK: Distribution) | VD 0.2L/kg | VD 0.15L/kg |
| PK: Metabolism | <5% Metabolism Hep | 77% Hofmann degradation → laudanosine and quat. monoacrylates Minimal ester hydrolysis Inactive metabolites |
| PK: Excretion | Renal: 30-40% Liver: 60% | Ren: 10-30% (laud.) Liver: (laudanosine) |
| - Clearance (PK: Excretion) | Pl cl: 3ml/kg/min | Pl cl 4-5ml/kg/min |
| - Half Life (PK: Excretion) | El t1/2: 90mins | El t1/2: 25mins |
| SPECIAL POINTS | Duration prolonged by: - ↓K ↓Ca ↑Mg - ↑pH ↑PaCO2 - ↓temp ↓protein Dehydration Reversible with sugammadex | Duration prolonged by: - ↓K ↓Ca ↑Mg - ↑pH ↑PaCO2 - ↓temp ↓protein Dehydration |
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SUXAMETHONIUM
Pharmacopeia - Neuromuscular Blocking Drugs
| SUXAMETHONIUM | |
|---|---|
| GROUP | Depolarizing |
| CICM Level of Understanding | Level 1 |
| INTRODUCTION | Dicholine ester of succinic acid |
| USES | 1. Where ever rapid and profound muscle relaxation is required e.g. endotracheal intubation 2. For modification of fits following ECT |
| PHARMACEUTICS (PC) | |
| PC: Chemical | Bisquaternary 2 Molecules of ACh joined by acetate methyl groups |
| PC: Presentation | Clear aqueous solution, 50mg/mL suxamethonium chloride Stored at 4°C |
| PHARMACODYNAMICS (PD) | |
| PD: Main Action | |
| PD: Mode of Action | PHASE I (depolarising) block mechanism: 2 molecules of sux binds the 2 alpha subunits of nAChR → activation and channel opening depolarisation → sux is not metabolised by NMJ AChE → remains bound to nAChR → nAChR remains open & in inactive state forms small zone of depolarisation/inactivation around synapse → blocks further depolarisation → muscle relaxation (~ 20% post-synaptic nAChR occupancy required to achieve depolarising block) Sux exerts pre-junctional action → retrograde conduction up motor neuron triggers axon to depolarise entire motor unit → fasciculation observed prior to onset of depolarising block PHASE II (desensitisation) block mechanism: exact mechanism uncertain. After sux has been present for a period of time → motor end plates loses sensitivity to ACh/sux → depolarisation cannot occur Desensitisation continues (for several minutes) even after drug is no longer present |
| PD: Route & Doses | ED95 0.3 – 0.6 mg/kg RSI IV 1 mg/kg IV IM 2 mg/kg Infusion- |
| PD: Metrics (Onset/ Peak/ Duration) | Onset IV 30 ~ 60s IM 60 ~ 120s Duration 5mins |
| PD: Effects | |
| PD: Side Effects / Toxicity | HISTAMINE RELEASE - rash, ↑HR, ↓ BP (NOT bronchospasm) EFFECT ON ANS ↓ HR paeds (mAChR) (agonist at both sym/para ganglia, but kids ↑vagal tone) OTHER - Anaphylaxis Risk 3xND-NMB - Malignant hyperthermia - Myalgia (fasciculn) - ↑ [K+] by 0.5 mmol/L - ↑ICP ↑intraocular pressure - Phase I + II blocks - Sux apnea w BChEmutations - ↑Intragastric pressure |
| PHARMACOKINETICS (PK) | |
| PK: Absorption | |
| PK: Distribution | Highly ionised & water soluble Limited lipid solubility |
| Protein binding (PK: Distribution) | Protein bound to unknown extent |
| Volume of distribution (PK: Distribution) | |
| PK: Metabolism | Rapid hydrolysis by plasma Butyrylcholinesterase. Sux→succinylmonocholine →succinic acid + choline. (Inactive) Approx 10% of IV dose reaches NMJ |
| PK: Excretion | Renal: <2% Liver: nil |
| - Clearance (PK: Excretion) | Pl clearance: 3ml/kg/min |
| - Half Life (PK: Excretion) | El t1/2: 90mins |
| SPECIAL POINTS | Contraindications: - Hyperkalaemia - Neuromuscular diseases - Denervation (after 2 days) - Immobilization (after 3 days) - Burns (after 2 days) - Chronic NMB use (>3 days) - Sepsis/SIRS (after 3 days) - MH risk - Allergy - Homozygous for atypical plasma cholinesterase (1/3200 incidence; block prolonged by hours) |
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SUXAMETHONIUM | ROCURONIUM
Pharmacopeia - Neuromuscular Blocking Drugs
| SUXAMETHONIUM | ROCURONIUM | |
|---|---|---|
| GROUP | Depolarizing | Non-Depolarizing Aminosteroid |
| CICM Level of Understanding | Level 1 | Level 1 |
| INTRODUCTION | Dicholine ester of succinic acid | Aminosteroid |
| USES | 1. Where ever rapid and profound muscle relaxation is required e.g. endotracheal intubation 2. For modification of fits following ECT | 1. to facilitate tracheal intubation during routine and modified rapid sequence induction 2. for controlled ventilation. |
| PHARMACEUTICS (PC) | ||
| PC: Chemical | Bisquaternary 2 Molecules of ACh joined by acetate methyl groups | Monoquaternary |
| PC: Presentation | Clear aqueous solution, 50mg/mL suxamethonium chloride Stored at 4°C | Clear, colourless solution, 10mg/mL rocuronium bromide |
| PHARMACODYNAMICS (PD) | ||
| PD: Main Action | ||
| PD: Mode of Action | PHASE I (depolarising) block mechanism: 2 molecules of sux binds the 2 alpha subunits of nAChR → activation and channel opening depolarisation → sux is not metabolised by NMJ AChE → remains bound to nAChR → nAChR remains open & in inactive state forms small zone of depolarisation/inactivation around synapse → blocks further depolarisation → muscle relaxation (~ 20% post-synaptic nAChR occupancy required to achieve depolarising block) Sux exerts pre-junctional action → retrograde conduction up motor neuron triggers axon to depolarise entire motor unit → fasciculation observed prior to onset of depolarising block PHASE II (desensitisation) block mechanism: exact mechanism uncertain. After sux has been present for a period of time → motor end plates loses sensitivity to ACh/sux → depolarisation cannot occur Desensitisation continues (for several minutes) even after drug is no longer present | ND-NMB acts as competitive antagonist → competes with ACh for nAChR binding → blocks cholinergic transmission → muscle relaxation (> 70% post-synaptic nAChR occupancy required to result in block) ND-NMB also inhibits pre-synaptic ACh receptors →prevents enhancement of ACh release → fade with repeated stimulation |
| PD: Route & Doses | ED95 0.3 – 0.6 mg/kg RSI IV 1 mg/kg IV IM 2 mg/kg Infusion- | ED95 0.3 mg/kg Int 0.6 mg/kg RSI 0.9 ~ 1.2 mg/kg Inf 9 – 12 mcg/kg/min |
| PD: Metrics (Onset/ Peak/ Duration) | Onset IV 30 ~ 60s IM 60 ~ 120s Duration 5mins | Int @ 100 – 120s RSI @ 60s Duration 35mins |
| PD: Effects | ||
| PD: Side Effects / Toxicity | HISTAMINE RELEASE - rash, ↑HR, ↓ BP (NOT bronchospasm) EFFECT ON ANS ↓ HR paeds (mAChR) (agonist at both sym/para ganglia, but kids ↑vagal tone) OTHER - Anaphylaxis Risk 3xND-NMB - Malignant hyperthermia - Myalgia (fasciculn) - ↑ [K+] by 0.5 mmol/L - ↑ICP ↑intraocular pressure - Phase I + II blocks - Sux apnea w BChEmutations - ↑Intragastric pressure | HISTAMINE RELEASE - None EFFECT ON ANS - Can be vagolytic (↑HR) OTHER - Anaphylaxis - Pain on injection |
| PHARMACOKINETICS (PK) | ||
| PK: Absorption | ||
| PK: Distribution | Highly ionised & water soluble Limited lipid solubility | Doesn’t cross BBB |
| Protein binding (PK: Distribution) | Protein bound to unknown extent | PB 10% |
| Volume of distribution (PK: Distribution) | VD 0.2L/kg | |
| PK: Metabolism | Rapid hydrolysis by plasma Butyrylcholinesterase. Sux→succinylmonocholine →succinic acid + choline. (Inactive) Approx 10% of IV dose reaches NMJ | <5% Metabolism Hep |
| PK: Excretion | Renal: <2% Liver: nil | Renal: 30-40% Liver: 60% |
| - Clearance (PK: Excretion) | Pl clearance: 3ml/kg/min | Pl cl: 3ml/kg/min |
| - Half Life (PK: Excretion) | El t1/2: 90mins | El t1/2: 90mins |
| SPECIAL POINTS | Contraindications: - Hyperkalaemia - Neuromuscular diseases - Denervation (after 2 days) - Immobilization (after 3 days) - Burns (after 2 days) - Chronic NMB use (>3 days) - Sepsis/SIRS (after 3 days) - MH risk - Allergy - Homozygous for atypical plasma cholinesterase (1/3200 incidence; block prolonged by hours) | Duration prolonged by: - ↓K ↓Ca ↑Mg - ↑pH ↑PaCO2 - ↓temp ↓protein Dehydration Reversible with sugammadex |
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