A REFRESHER

ACETYLCHOLINE AND N-ACH R

NEUROMUSCULAR BLOCKADE DRUG

DEPOLARISING

NON-DEPOLARISING

SUXAMETHONIUM
SHORT ACTING INTERMEDIATE ACTING LONG ACTING

SUXAMETHONIUM

Uniqueness: - Rapid onset (30 - 60s) - Short duration (3 5 minutes)

PRESENTATION
Injection solution: a clear, colourless, particle-free solution containing 50 mg/mL suxamethonium chloride.

-Also available in bromide (powder form) , iodide

- All solution is destroyed by alkali (SHOULD NOT mix with thiopentone) Storage: at 4oC

DOSE
Traditional dose to facilitate intubation is IV 1mg/kg. If unsuitable IV access, IM up to 2.5mg/kg can be given (total not exceed 150mg) According to Smith et al 1988, the ED90 for SCh as determined by the administration of thiopental while breathing nitrous oxide is 0.27mg/kg Thus the dose 1mg/kg represents 3.5-4 x the ED95

What if we reduce the intubating dose?

Say from 1mg/kg to 0.6mg/kg It decreases the duration of twitch depression by >90s and still acceptable intubating conditions. (Kopman et a 2003, Naguib et al 2003) But does not shorten the time to spontaneous diaphragmatic movement

What is ED??
ED = effective dose, dose required to produce an effect ED50 50% effect ED95 95% effect

SEQUENCE 0F PARALYSIS
Thumb Orbicularis oculis limbs Trunk

laryngeal muscle
Intercostal muscles diaphragm
RECOVERY

Conceptually..
administration of 1mg/kg Sch to a preO2 patient : results a return of spontaneous breath within 5 minutes YET, the average duration to 90% twitch height recovery following 1mg/kg is greater than 10minutes the diaphragm recovers before the adductor pollicis muscle

MECHANISM OF ACTION

Depolarises the postjunctional membrane

Sustained depolarisation which cannot respond too subsequent release of AC h

PHASE 1 BLOCKADE

SCh attaches to alpha subunits (or both)

PHASE II BLOCKADE

Sch

When do we get Phase II blockade?

Single large dose of Sch ( > 2mg/kg) Repeated doses Prolonged continuous infusion of Sch

Desensitisation neuromuscular blockade

What is Desensitisation of neuromuscular blockade?

When the postjunctional membranes do not respond to Ach, even when the postjunctional membranes have repolarised ? Mechanism Gives an effect similar to non-depolarising neuromuscular bloockade

Duration of Action?
Brief duration of action (3 - 5minutes) d/t hydroysis by plasma cholinesterase (pseudocholinesterase) enzyme Vs acetylcholinesterases enzyme??
- Synthesized by the liver -A tetrameric glycoprotein containing 4 identicals subunits each have active catalytic site - enormous capacity to hydrolyze Sch at a rapid rate , so that only a small fraction of the original IV dose actually reach the NMJ

Take NOTE that:

Plasma cholinesterases are not present in significant amount at the NMJ Hence, blockade by Sch is terminated by its diffusion away from NMJ into ECF Therefore, plasma cholinesterase influences the duration of action of Sch by controlling the amount of NMBD that is being hydrolysed before reaching the NMJ

METABOLISM
SUCCINYLCHOLINE
PLASMA CHOLINESTERASE

SUCCINYLMONOCHOLINE

+ +

CHOLINE

SUCCINIC ACID

CHOLINE

PLASMA CHOLINESTERASE ACTIVITY

DECREASE IN ACTIVITY INCREASE IN ACTIVITY

(PROLONGED BLOCK)

(SHORTER BLOCK)

1) Decrease in hepatic production 1) obese patient - liver disease must be severe b4 2) Myasthenia gravis (ED95 is X 2.6 decrease is sufficent to prolong block normal) 2) Drug interaction 3) juvenile hyaline fibromatosis - neostigmine (> edrophonium), - potent anticholinesterase drugs in insecticides/Rx of MG/glaucoma/cyclophosphamide/nitr ogen mustard) - after IV metoclpromide 10mg 3) Presence of atypical plasma cholinesterase 4) High eostrogen levels

Enzyme deficiency

ACQUIRED

INHERITED

a. the newborn, until 2-6 months Atypical plasma cholinesterase b. acute or chronic liver diseases c. malnutrition d. pregnancy e. collagen diseases f. chronic anaemia g. uraemia h. myxedema i. other chronic debilitating diseases j. severe burns k. chronic pesticide exposure & accidental poisoning l. drugs

ATYPICAL PLASMA CHOLINESTERASE

Often only recognised after an otherwise healthy patient experiences prolonged neuromuscular blockade (1 to 3 hours) A single cholinesterase gene
Any alterations of a nucleotide produces numerous plasma cholinesterase variants

Dibucaine related variants

DIBUCAINE
An LA with an amide linkage , inhibits activity of normal plasma cholinesterase enzyme by approximately 80% (Dibucaine 80) In atypical homozygous enzyme inhibits approx. 20% of enzyme activity (Dibucaine 20)

What is a DIBUCAINE NUMBER?

the percentage inhibition of plasma cholinesterase produced by a standard titre of dibucaine

Kalow & Genest found that the local anaesthetic

dibucaine inhibits normal plasma cholinesterase to a far greater extent than the atypical enzyme
Normal 80% Heterozygus enzyme 40-60% Homozygus atypical enzyme 20%

HEREDITARY VARIANTS OF PLASMA CHOLINESTERASE

Genotype Dibucaine Fluoride number number
E uE u 80 60

Response frequency to Sch

Normal 96%

EaEa
EuEa

20
60

20
45

EuEf EfEa

75 45

50 35

Greatly prolonged Slightly prolonged

Greatly prolonged

1 in 3200
1 in 480

1 in 200 1 in 20000

DIBUCAINE NUMBER
A dibucaine number of 80, which reflects 80% inhibition of enzyme xtvt normal response A dibucaine number of 20, reflects the presence of atypical homozygous enzymes, where blockade persist for > 3hours Heterozygous atypical enzyme manifest prolonged blockade up to 30minutes

A PEEK ON THE PHARMACOKINETICS OF SCH

ABSORPTION DISTRIBUTION METABOLISM ELIMINATION

 Absorption
rapid onset and a short duration of action. complete muscle relaxation occurs within to 1 minute, persists for about 2-3 minutes, and gradually dissipates within 10 minutes. Following IM administration the onset of action occurs in about 2-3 minutes, with a duration ranging from 10-30 minutes.

Distribution
Initial rapid redistribution SUXAMETHONIUM crosses the placenta, generally in small amounts.

 Metabolism
- By plasma pseudocholinesterases to succinylmonocholine and choline. - Succinylmonocholine further hydolyzed to succinic acid and choline

Elimination
- Approximately 10% of drug is excreted unchanged in the urine. - Patients with impaired renal function may occasionally experience prolonged apnoea due to accumulation of succinylmonocholine.

TELL ME ABOUT THE PHARMACODYNAMICS OF SCH

SITE
CNS

EFFECT
- Fasciculation followed by phase I block - with repeated dose or administration of a large dose, results a phase II block -- ICP and IOP raised - Repeated doses might results bradycardia and slight increase in MAP - Apneoa occurs subsequently after paralysis -Increase in intragastric pressure - lower oesophageal sphincter tone decrease - Salivation & gastric secretions are increased - Serum potassium briefly increased by 0.2-0.4mmol/L

CVS Respiratory GI

metabolic

ADVERSE EFFECT
Cardiac dysrhythmias Hyperkalemia Myalgia Myoglobinuria Increased intragastric pressure Increased IOP/ICP Sustained skeletal muscle contraction

CONTRAINDICATIONS OF USE

Thank you!