Knowledge
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A. Physiochemistry
- pKa - 7.3 (58% nonionised @ 7.4)
- Octanol water coeff - 18
- phenylpiperidine opioid
- contain 2 ester bonds so hydrolysed by non-specific tissue esterases.
- Preparation contains 'glycine', so cannot be used epidurally.
- White powder for reconstitution with water - 1, 2, 5 mg packs
B. Pharmacokinetics
- Dose: (100x morphine potency, ~equal to fent)
- TCI: 3-8 ng/mL
- (up to 15 ng/mL for very stimulating procedures)
- Spontaneous ventilation returns @ 1-2 ng/mL
- 0.1-0.3 mcg/kg/min infusion (with propofol 80 mcg/kg/min (= 34 mL/h for 70 kg).
- 0.01-0.05 mcg/kg/min spont vent
- dilute 1 mg to 50 mL = 20 mcg/mL, or 5 mg in 50 mL = 100 mcg/mL.
- paeds: 0.03 mg/kg in 50 mL then 1 mL/h = 0.01 mcg/kg/min.
- Or paediatric whole-ampoule dilutions when advanced pumps are unavailable:
- 1mg in 16.7mLs
- or 2mg in 33.3 mLs
- or 3mg in 50mLs
- → to give a dilution of 60mcg/mL
- then for a patient of XYkg running at X.Y mLs/hr is 0.1mcg/kg/min. eg. for a 42kg patient running at 0.1mcg/kg/min will be 4.2mLs/hr which over 4 hrs uses 16 mL so a 1mg ampoule would be sufficient.
- 1 mcg/kg IV bolus to blunt pressor resp to intubation, better than fentanyl. (equiv. fent 2 mcg/kg, alfent 20 mcg/kg)
- 3-5 mcg/kg for intubation with propofol 2 mg/kg.
- 0.2-0.8 mcg/kg bolus for PCA analgesia (++SEs: sedation, desaturation)
- Absorption - IV
- Distribution - 0.5 L/kg (small)
- Protein binding - 70-90%
- Onset 1-4 min; Offset 4 min (offset due to metab not redist)
- Metabolism - ß½ ~10 min. (CSHT-8h only 4 min!) Metabolised by non-specific plasma esterases to almost-inactive metabolites (GR90291: 1/4600 activity! / t½ 2h).
- Minor pathway - N-dealkylation. NOT metabolised by plasma cholinesterase.
- Clearance - 42 mL/min/kg (30-50% CO)
C. Pharmacodynamics
- Mech - highly selective mu agonist.
- CVS - dec MAP & HR 20-30%. (? low dose glycopyrrolate to attenuate brady).
- No histamine release.
- CNS
- max MAC reduction ~ 85% (0.1-0.2 mcg/kg/min = 60-70% MAC reduction).
- To avoid awareness keep propofol @ at least 80 mcg/kg/min or volatile 0.3 MAC.
- Sedation.
- Beware rapid Opioid Induced Hyperalgesia.
- Resp - ⇣ RR & MV; apnoea. Spontaneous respiration occurs at blood concentrations of 4 to 5 nanogram/mL in the absence of other anaesthetic agents; for example, after discontinuation of a 0.25 microgram/kg/minute infusion of remifentanil, these blood concentrations would be reached in two to four minutes.
- GIT - dec CTZ stimulation as rapidly metabolised; no ion trapping.
- Muscle - muscle rigidity similar to alfentanil, though more than fentanyl.
- May cause chest wall rigidity (inability to ventilate) after single doses of > 1 microgram/kg administered over 30 to 60 seconds or infusion rates > 0.1 microgram/kg/minute.
- Administration of doses < 1 microgram/kg may cause chest wall rigidity when given concurrently with a continuous infusion of remifentanil.
- Foetal - little effect as rapidly metabolised by foetus.
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Etomidate (Amidate™) is short-acting intravenous anesthetic agent first developed in 1964. It is available and used in the United Kingdom, Europe, New Zealand, United States, but not Australia.
Advocates highlight etomidate's hemodynamic stability when used for induction. Critics point to the well-established adrenocortical suppression, and wide-range of suitable alternatives (propofol, ketamine, thiopentone) in trained hands.
A. Physiochemistry
- Carboxylated imidazole
- 2 isomers - only R(+) hypnotic
- Haemodynamic stability, minimal respiratory depression, cerebral protection, wide margin of safety.
- Originally formulated in propylene glycol (painful), now in soybean lipid.
B. Pharmacokinetics
- Dose - 0.3 mg/kg (0.1-0.4 mg/kg)
- Absorption - IV
- Distribution - 4 L/kg
- Protein binding - 75% (like thiopentone)
- Onset 30-60s ; Offset
- Metabolism - alpha1 ½ 2.5m, alpha2 ½ 30m, tß½ 3.5h; hepatic ester hydrolysis of ester side chain.
- Clearance - 20 mL/kg/min
C. Pharmacodynamics
- Mech - probably by GABAa receptors.
- CNS - hypnosis; no analgesic action; ⇣ CBF and CMRO2
- CVS - stable; may have slight dec MAP 15% due to ⇣ SVR.
- Resp - minimal; sometimes brief hypoventilation or apnoea post-induction.
- Endo - adrenocortical suppression - inhibits 11ß-hydroxylase (11-deoxycortisol → cortisol). Temporary & reversed by vit C.
- ⇡ ICU mortality when used for sedation.
- SEs - excitatory phenom, involuntary muscle movement (50%), PONV (30%), thrombophlebitis (20%), pain on injection.
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Pethidine (Meperidine) is a phenylpiperidine synthetic opioid first synthesized in 1938. Although widely used in the 20th century, it has fallen out of favour over the past decade due to abuse potential, limited advantages over other opioids and the existence of toxic metabolites.
A. Physiochemistry
- pKa - 8.5 (9% nonionised @ 7.4)
- Octanol water coefficient - 39 (so 40x lipid solubility of morphine)
- phenylpiperidine opioid
B. Pharmacokinetics
- Dose - 25-100 mg (10% morphine potency). Limit 1000 mg 1st day, then 600 mg/day there after.
- Absorption - IV, IM, epidural, po (55% biov)
- Distribution - Vdss 4.5 L/kg. Crosses placenta - foetal 80% of maternal.
- Protein binding - 60%
- Onset 10 min ; Offset 2-3 h
- Metabolism - ß½ 3 h; N-demethylation to norpethidine and then hydrolysis to norpethidinic acid; also direct hydrolysis to pethidinic acid. Renal elimination.
- Norpethidine - ß½ 15 h; 50% analgesic properties, 2x convulsant effects.
- Clearance - 20 mL/kg/min (same as morph & fentanyl)
C. Pharmacodynamics
- Mech - mu and kappa agonist, causing potent spinal and supraspinal analgesia.
- CNS - more euphoria, less N/V than morphine. No miosis, but may cause mydriasis (pupil dilation -atropine-like kappa action). No EEG changes like morphine. ⇡ latency & amplitude of SSEPs.
- NB: has LA action, so can be used as sole agent for neuroaxial block.
- anti-shivering effect (kappa)
- CVS - ⇣ MAP (> than morphine) due to histamine release & alpha adrenergic blockade (vasodilation). Inc HR (atropine like effect). Large doses depress myocardial contractility. May cause hypertensive crisis in those on MAOIs.
- vasodilation
- tachycardia
- depress myocardial contractility
- Resp - potent resp depressant - greater effect on TV than RR. Histamine release. Chest wall rigidity.
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Suxamethonium chloride (suxamethonium, succinylcholine or sux) is a depolarising muscle relaxant that produces rapid-onset, short-duration, deep muscle relaxation. First identified in 1906 and used medically in 1951, it is one of the oldest anaesthesia drugs still widely used. Due to its unique properties and low cost, it remains on the World Health Organisation's List of Essential Medicines
A. Physiochemistry
- (CH3)3-N-CH2CH2-OCO-CH2CH2-OCO-CH2CH2-N-(CH3)3
- pH 3.5
- Shelf life 3 years at 4°C, though only 'months' at 20°C.
B. Pharmacokinetics
- Dose - ED95 0.5 mg/kg, IV 1.5 mg/kg, IM 2.5-4 mg/kg.
- Absorption - IM, IV.
- Distribution - >0.2 L/kg; crosses placenta slightly but little effect on foetus.
- Protein binding ?
- Onset 30s IV, 2-3 min IM; Offset 3-5 min.
- Metabolism - PChE to succinylmonocholine (5% activity) & choline -> succinic acid & choline.
- tß½ 5 minutes
C. Pharmacodynamics
- Mechanism - binds to alpha subunit of nicotinic ACh receptor, producing persistent depolarisation (phase 1 & phase 2 blocks).
- CNS - ⇡ intra-ocular pressure (4-8 mmHg rise), ⇡ intra-celebral pressure (to 30 mmHg at 2-4 min).
- CVS - arrhythmias (both bradycardia & tachycardia possible), ⇡ systolic blood pressure, (both negative inotropic and chronotropic effects).
- Resp - 'sux apnoea' pharmacogenetic diversity (94% normal, 3.8% heterozyg (10 min duration of effect), <1% homozog (1-2h duration))
- Renal - hyperkalaemia due to K+ release from muscle; beware in neuromuscular conditions, denervation, and extensive burns.
- GIT - ⇡ intragastric pressure, ⇡ secretions, salivation.
- SEs - anaphylaxis, malignant hyperthermia, sux apnoea, muscle pains, masseter spasm.