BASIC PHARMACOLOGY OF ANESTHESIA DRUGS

There are 5 major groups of drug commonly used in anesthesia :-

INTRAVENOUS ANESTHETIC AGENTS INHALATIONAL ANESTHETIC AGENTS OPIOIDS MUSCLE RELAXANTS LOCAL ANESTHETIC AGENTS

INTRAVENOUS ANESTHETIC AGENTS
• Definition • A drug or combination of drugs which will induce anesthesia safely and reversibly when injected in sufficient doses and which could also be used intermittently or by infusion for maintenance of anesthesia. • • Ideal properties of IV anesthetic agents : • Simple preparation • Compatible with other agents and IV fluids • Painless on administration • High potency and efficacy • Predictable action within one arm-brain circulation time • Minimal cardiovascular effects or other toxicity • Depression of airway reflexes for intubation • Rapid and predictable offset of effect • Rapid metabolism for minimal hangover

INTRAVENOUS ANESTHETIC AGENTS
• Possible mode of actions : • GABA receptor modulation at chloride channel; increasing the duration of Cl- channel opening hence preventing neurotransmission. • increased secretions of inhibitory neurotransmitters. • block of excitatory neurotransmitters. • • Classification : Barbiturate vs non-barbiturate

Classification : Barbiturate vs nonbarbiturate
• • • • • • A) Barbiturate eg : thiopentone, methohexital Thiopentone most commonly used IV agents rapid onset:– one arm-brain circulation indications : induction agent, barbiturate coma in severe head injuries, anticonvulsant. MOA : Potentiates GABAA transmission, prolongs channel opening. May depress excitatory transmission by inhibiting Ca2+ transport. Acts at reticular formation, hypothalamus and limbus. physicochemical : 0.5 g in 20 ml glass ampoule. Yellow powder, sodium salt. Stabilized with anhydrous sodium carbonate 60 mg/g. Prepared with water or saline to 25 mg/ml solution with pH 11-12. Precipitates in neutral or acid solution dosage : 4 -5mg/kg lasted 5-10 minutes metabolized in liver and excreted in kidney side-effects : involuntary movements, cough, laryngospasm, hypersensitivity reaction (wheals)


• • •

Thiopentone
• • • • contraindications : – absolute = known allergy to barbiturate, porphyria, – relative = hypovolemia, severe CVS disease, hepatic failure Pharmacodynamics : CNS - Anticonvulsant at hypnotic doses - Decrease in CMRO2, CBF - Not analgesic CVS - Effects depend on dose and rate of administration and filling - Venodilator: decrease in LVEDV - Myocardial depressant at high doses: decrease in SV, CO, MAP Respiratory - Central depressant - Decreased rate, increased VT followed by apnoea - Decrease in CO2 sensitivity - Decrease in upper airway reflexes when deep Renal, hepatic - Minimal decrease in function Uterine - Crosses placenta readily, no effect on tone Local - Thrombophlebitis, pain, thrombosis - Intraarterial injection causes vasospasm due to endogenous vasoconstrictor release - Treat with local anesthetic, vasodilator, heparin, regional anesthesia

Methohexital
• • • • • • not available in Malaysia indications : induction agent, ECT rapid onset with short recovery time Pharmacokinetics and actions similar to thiopentone metabolized in liver and excreted in kidney side-effects : pain on injection, marked excitatory phenomenon, induce seizure in epileptics • contraindications : known allergy to methohexitone, epileptics • B

B) Non-barbiturate eg : propofol, ketamine, etomidate, benzodiazepine (midazolam)
• • • • • • • • • • • Propofol Phenol derivative Fast onset : one-arm brain cycle indications : induction and maintenance agent, anti-emetic physicochemical : available in 1% emulsion consisting of 10 % soy bean oil, 1.2% egg phosphatide and 2.25% glycerol dosage : 2 -3 mg/kg; lasted < 5 minutes due to redistribution metabolized in liver and excreted in kidney side-effects : hypotension, pain on injections contraindications : known allergy to propofol Pharmacodynamics CNS - Excitatory effect but has anticonvulsant properties - dose-dependent decrease in EEG, oxygen consumption, CBF - Little psychomotor effect after awakening, reduce PONV PNS: potentiates effect of NMJ blockers Respiratory: greater incidence of apnea, laryngeal reflexes obtunded CVS: Decreased SVR, SV, MAP

B) Non-barbiturate eg : propofol, ketamine, etomidate, benzodiazepine (midazolam)
• • • • • • • • • • • Ketamine a phencyclidine derivative – related to angel dust (hence infamous for its street abuse) NMDA antagonist : Inhibits thalamic transmission to cortex cause dissociative anesthesia – a cataleptic state with profound analgesia and hallucinations indications : induction agent in hypotensive cases eg trauma, bleeding placenta previa, field anesthesia eg natural disaster, pain relief in burn dressing physicochemical : 500 mg/10 ml, 100 mg/ml 10 ml, 2 ml vials. Benzethonium chloride preservative. dosage : analgesia 0.2 - 0.5 mg/kg, anesthesia 1-2 mg/kg lasted 15-20 minutes; IM 3-5 mg/kg; slow onset (30 – 60 secs) and offset metabolized in liver and excreted in kidney side-effects : hallucinations, excessive secretion (salivary gland, bronchial tree) contraindications : known allergy to ketamine, high ICP and IOP Pharmacodynamics – CNS: Dissociative anaesthesia. Increased CBF, ICP, IOP and hallucinations on emergence (less likely if premedicated with BDZ) – CVS: Increased sympathetic tone (central and decreased NA uptake). Increased HR, MAP, PVR. Direct cardiac depressant – Respiratory: Retention of airway reflexes in low dose. Increased secretions, bronchodilation – Muscle: Increased tone, movements, inhibits plasma cholinesterase

B) Non-barbiturate eg : propofol, ketamine, etomidate, benzodiazepine (midazolam)
• Etomidate • an imidazole group • indications : induction agent in poor cardiovascular state eg dilated cardiomyopathy, poor ejection fraction • physicochemical : 20 mg/ampoule, expensive • dosage : 0.2 -0.3 mg/kg last ~ 6 minutes • metabolized in liver and plasma; excreted in kidney • side-effects : inhibits cortisol production (non-ideal to induce in septic patient), involuntary movements, nausea and vomiting, pain on injection • contraindications : known allergy to etomidate •

B) Non-barbiturate eg : propofol, ketamine, etomidate, benzodiazepine (midazolam)
• • • • • Midazolam a member of benzodiazepine (BDZ); both water (in ampoule) and lipid soluble (upon entering bloodstream) indications : induction agent (slow onset 2-3 min) have distinct characteristics : anxiolysis, anterograde amnesia, anticonvulsant, muscle relaxant, hynopsis, sedation MOA : Benzodiazepines act by binding to a specific receptor site on GABA receptors, facilitating GABAergic transmission. In the CNS, it acts predominantly in the cortex. There are GABA receptors on spinal motor interneurones, which may account for the activity of diazepam in reducing muscle tone. physicochemical : clear, colorless solution 1mg/ml dosage : 0.1 mg/kg lasting 3-4 hours metabolized in liver and excreted in kidney contraindications : known allergy to BDZ antidote : flumazenil 0.1 -0.2 mg; max 3 mg - short acting and may require an infusion to overcome the long acting effect of others BDZ especially diazepam

• • • • • •

INHALATIONAL ANESTHETIC AGENTS
• Inhalational anesthetic agents are used to induce and maintain anesthesia. They are administered by passing oxygen with either air or nitrous oxide over a liquid anesthetic in a vaporizer. The vaporiser adds anesthetic vapour to the fresh gas with the concentration leaving the vaporizer being determined by the amount added. The gases are then delivered to the patient in a variety of anesthetic circuits.

The ideal anaesthetic agent
• Physical properties • Non-flammable, non-explosive at room temperature. Stable in light. Liquid and vaporisable at room temperature i.e. low latent heat of vaporization. Stable at room temperature, with a long shelf life. Stable with soda lime, as well as plastics and metals. Environmentally friendly - no ozone depletion. Cheap and easy to manufacture. • Biological properties • Pleasant to inhale, non-irritant, induces bronchodilatation. Low blood:gas solubility - i.e. fast onset. High oil:water solubility - i.e. high potency. Minimal effects on other systems - e.g. cardiovascular, respiratory, hepatic, renal or endocrine. No biotransformation - should be excreted ideally via the lungs, unchanged. Non-toxic to operating theatre personnel • MOA : not fully understood. Among theory that have been proposed :Protein Receptor Theory, Critical Volume Hypothesis, Membrane Theory, GABA interaction etc.

Summary of physical properties

Halothane

Isoflurane

Enflurane

Desflurane

Sevoflurane

Molecular weight

197

184

184

168

200

Boiling point (oC)

50.2

48.5

56.5

22.8

58.5

Saturated vapour pressure at 20 degrees C

243

238

175

669

157

Minimum alveolar concentration (MAC) in 100% 0.75 O2

1.15

1.8

6

2.05

MAC in 70% N2O

0.29

0.56

0.57

2.5

0.66

% of metabolism

20

0.2

2

<0.1

3-5

Blood / gas partition coefficient (BGPC)

2.2

1.36

1.91

0.45

0.6

Oil / gas gas partition coefficient (OGPC)

224

98

98.5

28

47

The higher the BGPC, the slower the induction and recovery.

POTENCY of an anesthetic agent = MAC MAC = the minimum alveolar concentration of anesthetic agent at 1atm that produces immobility in 50% of subjects exposed to a standard noxious stimulus. The higher the OGPC, the lower the MAC thus higher potency.

Pharmacodynamics CVS All produces varying degree of myocardial depression and vasodilatation- with the exception of halothane (increase in HR in response to reduce SVR). Halothane sensitizes the myocardium to catecholamines and has lead to fatal ventricular arryhtmia esp in light anesthesia and hypoxia. The pungency of desflurane may cause sympathetic stimulation early in anesthesia.
Respiratory All produce dose-dependent respiratory depression and reduction in VT, increase in RR, reduce response to hypoxia and CO2. Most are useful bronchdilators although the pungent agents (desflurane, isoflurane) may result in airway irritation, laryngospasm and bronchospasm if high concentrations are used too early. CNS All agents increase CBF, ICP (not ideal in head injury patient) and reduce oxygen consumption. Enflurane can cause epileptic waveform activity especially in the presence of hypocapnia. Others All produce muscle relaxation and potentiate the action of neuromuscular blockers. Can cause uterine muscle relaxation and post operative nausea and vomiting (PONV). Trigger agent for malignant hyperthermia. Reduce renal blood flow.

• The choice of anesthetic agent : which one to choose ? • Inhalational induction. The most important requirement is that agent is pleasant to breathe and non-pungent :- either halothane or sevoflurane. The latter has the advantage of producing a more rapid induction of anesthesia but expensive and as for halothane it is cheaper but not widely available except in veterinary and third world countries. • Maintenance. Most can be used in all conditions and the choice often come down to personal preference (but now more of COST !!). Isoflurane is very commonly used as it has few troublesome side effects and is minimally. It is a frequent choice in patients with cardiac or CNS disease and the profound vasodilatation means that isoflurane can be used as the sole agent in deliberate hypotension to control surgical bleeding. Halothane is a cheaper alternative but the potential for arrythmias and hepatitis have resulted it in being used mainly for inhalational induction. Sevoflurane and desflurane produce similar anesthetic conditions to isoflurane but are a more expensive option.

Sevoflurane
• • • • • a sweet-smelling, colourless non-flammable halogenated ether used for induction and maintenance of general anesthesia. After desflurane it is the volatile anesthetic with the fastest onset and offset the preferred agent for mask induction due to its lesser irritation to mucous membranes. Dose : Induction dose 5-8%, maintenance 0.5-3% Metabolism : forms at least two degradation products, Compound A and Compound B on contact with the soda lime in a rebreathing apparatus, which absorbs exhaled carbon dioxide, especially at higher temperatures and when the soda lime is desiccated. Compound A has been shown to cause renal necrosis in rats. In humans, direct histological evidence of renal toxicity has not been demonstrated, although there is dose-related proteinuria and glycosuria. During low-flow anaesthesia, when the lower fresh gas flow leads to decreased flushing of the circuit and increased temperature of the soda lime, Compound A may build up to clinically significant levels, although there have never been any reports of adverse events in humans.

Isoflurane
• Clear colourless liquid, with a pungent smell • halogenated methyl ether. Structural isomer of Enflurane. • Induction dose 1-4%, maintenance 0.5-3%.

Desflurane
• • • • • • Halogenated ether used for maintenance of general anesthesia It has the most rapid onset and offset of the volatile anesthetic drugs used for general anesthesia due to its low solubility in blood. The major drawbacks of desflurane are its low potency, its pungency and its high cost. It may cause tachycardia and airway irritability when administered at concentrations greater than 10 vol%. Due to this airway irritability, Desflurane is infrequently used to induce anesthesia via inhalation techniques. Induction dose, 4-11%; maintenance, 2-6% Though it vaporises very readily, it is a liquid at room temperature. Anesthetic machines are fitted with a specialized anesthetic vaporiser unit that heats liquid desflurane to a constant temperature. This enables the agent to be available at a constant vapor pressure, negating the effects that fluctuating ambient temperatures would otherwise have on its concentration imparted into the fresh gas flow of the anesthesia machine. Desflurane, along with enflurane and to a lesser extent isoflurane (DIE) has been shown to react with the carbon dioxide absorbent in anesthesia circuits to produce detectable levels of carbon monoxide through degradation of the anesthetic agent. Dry conditions in the carbon dioxide absorbent are conducive to this phenomenon, such as those resulting from high fresh gas flows.

Halothane
• • • • Halogenated hydrocarbon Colourless and pleasant-smelling, but unstable in light. It is packaged in darkcoloured bottles and contains 0.01% thymol as a stabilising agent. Halothane is a well tolerated, non-irritant potent agent giving rapid induction, low dose maintenance and rapid recovery. Dosage: Induction requires inspired concentrations of up to 3%. Maintenance dose is 1-2% for spontaneously breathing patients and 0.5-1% during controlled ventilation. Contraindications: These include simultaneous administration with adrenaline, especially during spontaneous breathing, or a history of hepatitis following a previous anaesthetic. Avoid high doses during caesarean section or evacuation of retained products of conception or placentae as uterine bleeding may result. Toxicity: Potent trigger agent for malignant hyperthermia. May also cause the appearance of myocardial dysrhythmias, particularly in conjunction with hypoxia, hypercapnia or excessive catecholamine concentrations. Halothane hepatitis :

• •

Halothane
• Two major types of hepatotoxicity are associated with halothane administration. The two forms appear to be unrelated and are termed type I (mild) and type II (fulminant). Type I hepatotoxicity is benign, self-limiting, and relatively common (up to 25-30% incidence). This type is marked by mild, transient increases in serum transaminase and glutathione S-transferase concentrations and by altered postoperative drug metabolism. Type I probably results from reductive (anaerobic) biotransformation of halothane rather than the normal oxidative pathway. It does not occur following administration of other volatile anaesthetics because they are metabolised to a lesser degree and by different pathways than halothane. Type II hepatotoxicity is associated with massive centrilobular liver cell necrosis that leads to fulminant liver failure. No histopathologic findings are specific to this condition. Type II hepatotoxicity is characterised clinically by fever, jaundice and grossly elevated serum transaminase levels. It appears to be immune mediated and is initiated by oxidative halothane metabolism to an intermediate compound. This compound then binds to trifluoroacetylate proteins in the hepatic endoplasmic reticulum. Type II hepatotoxicity is thought to occur in genetically predisposed individuals. Approximately 20% of halothane is oxidatively metabolised, compared with only 2% of enflurane and 0.2% of isoflurane. The occurrence of type II hepatotoxicity after enflurane or isoflurane administration is extremely rare. The Committe on Safety of Medicines in 1986 recommended the avoidance of halothane following : history of previous adverse reactions, previous exposure within 3 months unless the indications are clinically overriding (the safe time interval is not known), history of unexplained jaundice/pyrexia after previous exposure to halothane.

Nitrous oxide (N2O)
• it is a colorless non-flammable gas, with a pleasant, slightly sweet odor and taste. • It is used in surgery and dentistry for its anesthetic and analgesic effects. It is known as "laughing gas" due to the euphoric effects of inhaling it, a property that has led to its recreational use as a dissociative drug. It is also used as an oxidizer in rocketry and in motor racing to increase the power output of engines (NOS in movie ‘The Fast and The Furious’). • Side-effects : expansion of air-filled spaces, diffusion hypoxia, suppress marrow activity and DNA production over long exposure period. Nitrous oxide reacts with ozone and is the main naturally occurring regulator of stratospheric ozone; half-life of N2O is 150 200 years). Nitrous oxide is also a major greenhouse gas and air pollutant. •

• OPIOIDS • • The term ‘opiate’ refers to all naturally occurring substances with morphine like properties, while ‘opioid’ is a more general term that includes synthetic substances that have affinity for opioid receptors. • • MOA • Binding to opioid receptors (µ, κ and δ) lead to activation of Gi proteins leading to inhibiton by increased K+ conductance and hyperpolarization of the cell membrane. Others possibilities are inhibition of adenylate cyclase and Ca2+ channels.

• • • • • • •

Morphine Naturally occurring, derived from poppy seed Used for analgesia. Used intravenously (0.1-0.2 mg/kg 3-4 hourly), intramuscularly, subcutaneously, orally, intraarticular, intrathecal, epidural and occasionally nebulized. It has a high hepatic extraction ratio and so an oral bioavailability of only 30%. It is metabolized in the liver by glucuronide conjugation to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) - a potent analgesic.These metabolites are renally cleared. Effects :– Analgesia : effective for visceral pain than superficial pain. Tolerance develops after repeated doses resulting in dependence – Respiratory depression : sensitivity of brainstem to carbon dioxide is reduced; drop in RR >> VT; may precipitate histamine release and bronchospasm; has anti-tussive effect - decrease in cough reflex – CNS : sedation, euphoria and dysphoria, nausea and vomiting and miosis – CVS : mild bradycardia and hypotension due to histamine release and a reduction in sympathetic tone (no direct myocardial depressant effect) – GIT : contraction of sphincter of Oddi, constipation – Skin : pruritus – Muscle rigidity esp chest wall – mainly seen at high doses – GUT : urinary retention – Endocrine : inhibits ACTH, prolactin, and gonadotrophin hormones. Increases ADH secretions – may impair water excretion and hyponatremia

• • • • • • •

Pethidine synthetic opioid developed as an anticholinergic (1939) 1/10 as potent as morphine is used intravenously, intramuscularly, epidurally and occasionally orally. IV and IM dose 0.5 – 1.0 mg/kg 2-3 hly It has an oral bioavailability of about 60%. It is metabolized in the liver to active and inactive metabolites, the most important of which is norpethidine which is a convulsant. Pethidine and its metabolites are renally cleared resulting in accumulation of metabolites in renal impairment. • Pethidine shares the common opioid effects with morphine, the only difference being :
– Anticholinergic effects – produces less marked miosis and possibly a degree of mydriasis, a dry mouth and tachycardia – GIT : less biliary tract spasm – Drug interactions : serious interactions with monoamine oxidase inhibitors (MAOI). Effects include coma, labile circulation, convulsions and hyperpyrexia.

• • • •

Fentanyl synthetic opioid, 100 x more potent than morphine has rapid onset due to its high lipid solubility used intravenously, intrathecally, epidurally, orally and transdermally. • Intravenous use is in two dose-ranges: 1-2 µg/kg as a co-induction or sedative agent and for brief duration analgesia of 30 minutes and 30-100 µg/kg as an induction agent for cardiac anaesthesia with duration of effect for 6 hours. • It can be combined with droperidol in neurolept anaesthesia. • It is metabolized in the liver by demethylation and hydroxylation to inactive metabolites which are renally cleared.

• • • •

Tramadol Synthetic opioid; analgesic potency is 1/5 – 1/10 of moprhine available in intravenous, intramuscular and oral administration. possesses agonist actions at the μ-opioid receptor and affects reuptake at the noradrenergic and serotonergic systems stimulating presynaptic serotonin releases which provides an alternative pathway for analgesia involving the descending inhibitory pathway within the spinal cord • undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2D6 and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, M1 (O-Desmethyltramadol) is the most significant since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol itself. In the 6% of the population that have slow CYP2D6 activity, there is therefore a slightly reduced analgesic effect. The metabolites are watersoluble, which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic impairment. • Potential for dependence and drug abuse.

• • • • • • • • • • • • • • • • •

MUSCLE RELAXANTS The properties of an ideal neuromuscular blocking agent. Non-depolarizing action Rapid onset (within one circulation time) Short duration, suitable for infusion Rapid metabolism to inactive products Antagonized by cholinesterase inhibitors Actions confined to the NMJ Not transferred across the placenta or blood-brain barrier No local or systemic side-effects Compatibility with other drugs and solutions Long shelf life without refrigeration Cheap Made by chemical synthesis Sterilizable

Depolarizing vs Non-depolarizing muscle relaxants

Depolarizing eg suxamethonium
• • • • • • • Suxamethonium introduced in 1952 to provide rapid onset, dense motor blockade of short duration consists of two molecules of acetylcholine (ACh) joined back-to-back presented as a colourless solution of 50 mg/ml. Should be stored at 4 degrees C indications : rapid sequence induction (RSI), electroconvulsive therapy (ECT) and breaking laryngospasm Mode of action :The drug causes prolonged depolarisation of skeletal muscles to a membrane potential above which an action potential can be triggered. The onset of muscle relaxation will be rapid after intravenous injection (30-60 seconds), and lasts 5-10 minutes. In an emergency, suxamethonium may be administered intramuscularly, but the onset of action is slower and less predictable than when given intravenously. Dose: Intravenous 1-2 mg/kg; Intramuscular 3 mg/kg. Higher dose in neonates and children. Clinical signs of onset: fasciculations Duration: 3-5 minutes (except in suxamethonium apnoea) Metabolism : rapid hydrolysis by plasma pseudocholinesterase and minimal excretion via urine Contraindications : Suxamethonium is contraindicated in patients with recent burns (OK in first 24 hours) or spinal cord trauma causing paraplegia (can be given immediately after the injury, but should be avoided from approximately day 10 to day 100 after the injury), raised potassium levels, severe muscle trauma or a history of malignant hyperpyrexia. Suxamethonium should be used with caution in patients with atypical plasma cholinesterase, or with muscle diseases. There may be prolonged paralysis or dangerous rises in potassium levels.

• • • • •

Depolarizing eg suxamethonium
• Adverse effects :

• Cardiovascular: suxamethonium can cause bradycardia, especially if second or further doses are given. This can be prevented by the prior administration of atropine. Children develop this complication more commonly than adults. • Metabolic: the potassium level in the serum will rise by about 0.2-0.4 mmol/L in normal patients and by much more in patients with recent burns, paraplegias or severe muscle trauma. Seen in burns, denervation and prolonged immobility. Could rise up to 9 mmol/l. In muscle trauma rise of 3-4 mmol/l has been described. • Raised intracranial and intraocular pressure: there is a transient rise in intracranial and intraocular pressure after suxamethonium. This is of no importance in patients without eye or intracranial disease, but the drug should be avoided in patients with these conditions if possible. • Prolonged paralysis: this can occur in patients with abnormal plasma cholinesterases; if suxamethonium is given in excessive doses, e.g. by repeat injections or infusion; in patients receiving certain drugs, e.g. some antibiotics. • Anaphylaxis: suxamethonium can cause allergic reactions, which range in severity from minor flushing of the skin to cardiac arrest and severe bronchospasm. • Malignant hyperthermia: suxamethonium can trigger the onset of malignant hyperthermia in those patients who have this genetic muscle disorder. Muscle pains: the fasciculations seen before the onset of muscle paralysis can cause muscle pain postoperatively, especially in women, the middle-aged and in those ambulant early in the postoperative period.

• Metabolism (suxamethonium apnoea)

Suxamethonium is metabolised by an enzyme in the blood called plasma cholinesterase. Metabolism is normally complete within 510 minutes. Some patients lack this enzyme or have an altered enzyme that does not metabolise the suxamethonium as rapidly. These patients may remain paralysed for many hours after a standard dose of suxamethonium, and must be kept anaesthetised and ventilated until the suxamethonium has been eliminated by other, slower methods. The normal gene encoding plasma cholinesterase is E1u (usual). There are three abnormal genes: E1a (atypical), E1s (silent) and E1f (fluoride-resistant). 94% of the population are heterozygous for the usual gene (hence normal response to suxamethonium); E1a homozygotes occur in 0.03% of the population; E1s homozygotes in 0.001% and E1f homozygotes in 0.0003% of the population. All remain apnoeic for 1-2 hours.

• Non-depolarizing muscle relaxants • Mechanism of action • Non-depolarising muscle relaxant drugs compete with acetylcholine (ACh) molecules released at the neuromuscular junction to bind with the ACh receptors on the post-synaptic membrane of the motor endplate. They therefore block the action of ACh and prevent depolarisation. Nondepolarising muscle relaxant drugs also act on presynaptic receptors interfering with the entry of calcium, which causes an inhibition of the release of ACh. Other drugs such as the aminoglycoside antibiotics (e.g. gentamicin) and volatile agents may also affect this mechanism and increase sensitivity to relaxants. • None of the drugs cross the blood-brain barrier, as they are water soluble, polar molecules and therefore have no effect on the central nervous system. All non-depolarising drugs should be used with care in patients suspected to be suffering with myasthenia gravis or myasthenic syndrome, as patients with these conditions are extremely sensitive to their effects.

• • • • • •

• •

Atracurium a benzylisoquinolinium group a colourless solution fo 10 mg/ml intubation dose of 0.3-0.6 mg/kg (onset 2-3 minutes) will provide relaxation for 20-40 minutes. Supplemental doses should be 1/3 of intubating dose duration : 20-30 minutes depending on storage, patient pH and temperature Although atracurium produces few direct circulatory effects, the absence of vagal blocking activity makes the patient vulnerable to bradycardias during anaesthesia. Histamine release may occur with doses of atracurium greater than 0.6 mg/kg. In standard doses, atracurium rarely causes problems with bronchospasm. Bronchospasm can occasionally occur secondary to histamine release. Metabolism : broken down to inactive metabolites by ester hydrolysis (minor) and spontaneous Hoffman degradation (major pathway) to Laudanosine. This metabolite has been shown to cause seizures in animal models >17 mcg/ml. There is little change in its effects in patients with renal or liver failure. When used for long operations, it is very predictable. Contraindications : Atracurium precipitates in an alkaline pH and it should never be mixed with thiopentone. Always flush the vein with saline if using the two drugs at induction. Storage : Should be kept in a refrigerator at 4 degrees C, as the drug deteriorates at room temperature.

• Vecuronium • An aminosteroid structurally related to pancuronium • a ‘clean’ muscle relaxant; void of cardiovascular effect and histamine release • unstable in solution so presented as dry powder requiring reconstitution with sterile water immediately prior to use, to yield a clear solution 2 mg/ml. • intubating dose is 0.08 - 0.1 mg/kg and reached intubating condition in about 90-120 seconds • duration of action = about 20-30 minutes supplemental doses should be 1-2 mg. • metabolized in the liver and excreted in bile and urine • storage :Vecuronium powder does not need to be refrigerated.

Rocuronium •an aminosteroid structurally related to vecuronium •A clear solution containing 10 mg/ml. Available in 5 ml and 10 ml ampoules. •CVS effects : Minimal; with large doses, a mild vagolytic effect leads to a slight increase in heart rate and mean arterial pressure. RS effects : No significant histamine release. Bronchospasm is extremely uncommon. •rapid onset at 60 -90 seconds; intubating dose ranges from 0.6 -1.2 mg/kg •duration of action 30 minutes •Rocuronium is 30% protein bound in the plasma. No metabolites have been detected in plasma or urine. Excreted primarily by hepatic uptake and hepatobiliary excretion. •can be reversed with sugammadex or neostigmine (usual reversal agent) Dosage and duration of rocuronium
Dose (mg/kg) Duration (minutes) Intubation (seconds)

0.3 - 0.45 0.6

13 - 26 30 - 40

120 60

0.9

53

45

LOCAL ANESTHETIC AGENTS
• Definition • An anesthetic drug that induces local anesthesia by reversibly decreasing the rate of depolarization and repolarization of excitable membranes by blocking the Na channels of the nerves. • • MOA • LA action is dependent on blockade of the Na+ channel. Unionized, lipid soluble drug passes through the phospholipid membrane where in the axoplasm it is protonated (ionized). • It is in this ionized form that it binds to the internal surface of a Na+ channel, resulting in its blockade and consequence inhibition of Na+ conductance. • Other theory is ‘membrane expansion’ ; swelling of Na+ channel/lipoprotein matrix resulting in its inactivation.

• • • • • • • • • • • • • • • • •

Type : Ester vs Amide LA agents are formed by an aromatic group linked via an intermediate chain to an amine group. This intermediate chain can be either an ester or an amide group. Ester eg cocaine, amethocaine, procaine Cocaine derived from the leaves of Erythroxylon coca used for topical anesthesia and local vasoconstriction eg Moffatt’s solution. Usage in anesthesia mainly during fibreoptic intubation via nasal route. MOA : blocks uptake 1 of liver metabolism and MAO enzymes and also stimulating CNS precipitating hypertension, arrythmias and hyperthermia. Side-effects : euphoria, sedation, confusion, hallucinations, seizures, arrythmias Amide eg lignocaine, bupivacaine, levobupivacaine, ropivacaine Lignocaine used as local anesthetic agent, anti-arrythmic (Class Ib) “fast in, fast out” available in solution (0.5-2 %), gel (2%), ointment (5%), or spray (10%). Can be combined with adrenaline (1in 80,000 - 200,000) for its vasoconstrictive properties metabolized in liver and excreted in urine CC : CNS ratio of 8:1.

• Bupivacaine • a racemic mixture containing 50% mixture of dextro and levo –isomers; levo-bupivacaine (chirocaine) solution is the latest in the market • available in plain solution, mixed with adrenaline (1: 200,000) and mixed with glucose (80mg/ml) aka heavy bupivacaine. • Concentration = 0.5% at 5 mg/ml • “fast in, slow out” • Metabolized in liver and excreted in urine • The most cardiotoxic of all LA agents; CC : CNS ratio of 3:1.

• Ropivacaine • a pure S-enantiomer; the advantage is being less toxic and it has lower lipid profile – this results in reduced penetration of the large Aα motor fibres  ‘motor sparing’ hence slower in onset, less dense and of shorter duration when compared an equivalent dose of bupivacaine • the R-enantiomer is less potent and more toxic • is not prepared with adrenaline as ropivacaine has vasoconstrictive properties • concentration = 0.2% and 0.75% at 2 mg/ml and 7.5 mg/ml respectively • Metabolized in liver and excreted in urine • The least cardiotoxic of all LA agents

Summary of local anesthetic properties

The higher the pKa, the slower the onset. The higher the protein binding, the longer the duration. The higher the lipid solubility, the more potent the drug is hence it has longer duration of action and intense motor blockade.
Cocaine Lignocaine Bupivacaine Levobupivacaine Ropivacaine

pKa

8.7

7.9

8.1

8.1

8.1

Lipid solubility

-

3

20

20

6

Plasma protein binding (%)

98

64

96

96

94

Relative potency

-

2

8

8

8

Duration (hr)

0.5 - 2

2

3

3

3

Max dose (mg/kg)

2

4-5 (over 3 hr) 7 (with adrenaline)

2 (over 4 hr)

2 (over 4 hr)

3

• •

Systemic toxicity of LA agents Systemic toxicity is due to elevated plasma levels of LA agents, most often as a result of inadvertent IV injection and less frequently as a result of systemic absorption of LA agents from the injection site. Toxicity involves the CVS and CNS. CNS is generally more sensitive, it is usually affected first. The manifestations are presented below in chronological order. CNS toxicity lightheadedness, tinnitus, perioral numbness, confusion muscle twitching, auditory and visual hallucinations tonic-clonic seizure, unconsciousness, respiratory arrest CVS toxicity hypertension, tachycardia decreased contractility and cardiac output, hypotension sinus bradycardia, ventricular arrythmias, circulatory arrest

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• Regional anesthesia that is associated with the greatest degree of systemic vascular absorption of LA agents : • Intercostal nerve block > caudal > epidural > brachial plexus > sciatic-femoral > subcutaneous :- related to the degree of local vascular supply.

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