Pharmacology

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CHAPTER 11 Pharmacology

Anaesthetic Gases

Oxygen

Discovered by Joseph Priestley in 1777. Manufactured by:

• fractional distillation of liquid air
• passing air over an artificial zeolite, which entraps N2, leaving a gas containing greater than 90% O2.
Critical temperature: 119°C
Critical pressure: 50bar
Boiling point: −182.5°C

Vacuum insulated evaporator (VIE) stores O2 at −180°C at a pressure of ≈︀10bar. One litre of liquid oxygen evaporates to give 842L O2 at standard temperature and pressure (STP). Contents of a VIE are measured by weighing scales on which the VIE sits.

Guideline for Emergency Oxygen Use in Adult Patients

British Thoracic Society 2008

Aims to ensure oxygen is prescribed according to a target saturation range and for those who administer oxygen therapy to monitor the patient and keep within the target saturation range.

Aim to achieve normal or near-normal oxygen saturation for all acutely ill patients apart from those at risk of hypercapnic respiratory failure or those receiving terminal palliative care.

Assessing patients

For critically ill patients, high concentration oxygen should be administered immediately.

Pulse oximetry must be available in all locations where emergency oxygen is used. Oxygen saturation should be checked by pulse oximetry in all breathless and acutely ill patients (supplemented by blood gases when necessary).

Oxygen prescription

The recommended target saturation range for acutely ill patients not at risk of hypercapnic respiratory failure is 94–98%.

For most patients with known chronic obstructive pulmonary disease (COPD) or other known risk factors for hypercapnic respiratory failure (e.g. morbid obesity, chest wall deformities or neuromuscular disorders), a target saturation range of 88–92% is suggested, pending the availability of blood gas results.

For patients with prior hypercapnic failure (requiring non-invasive ventilation or intermittent positive pressure ventilation), treatment should be commenced using a 24% Venturi mask at 2–4 L.min−1 in hospital settings with an initial target saturation of 88–92% pending urgent blood gas results.

Because oxygenation is reduced in the supine position, fully conscious hypoxaemic patients should ideally be allowed to maintain the most upright posture possible.

Nitrous oxide

Sweet-smelling, non-irritant colourless gas. First prepared by Joseph Priestley in 1772. First used as an anaesthetic agent in 1845 by Horace Wells. Now manufactured by heating ammonium nitrate with products washed through water and caustic soda to remove NO and NO2:

image

Critical temperature: 36.5°C
Critical pressure: 71.7 bar
Boiling point: −89°C
Blood:gas solubility: 0.42
MAC: 105%
Filling ratio: temperate, 0.75; tropics, 0.67

Exists in cylinder as a liquid so pressure in cylinder does not reflect contents. Measure contents by weight.

Entonox

• 500 L cylinders – store at >10°C for 2 h or, alternatively, place in water at 37°C for 5 min and invert three times before use
• 2000 and 5000 L cylinders – store at 10–45°C for 24 h in horizontal position. Do not store <0°C for >10 min after delivery.

Only Entonox cylinders contain a dip tube. If Entonox laminates, lower level of fluid contains ≈︀80% N2O and 20% O2, which is delivered to the patient via a dip tube. The mixture gradually becomes richer in O2. If gas was withdrawn from the top of the cylinder, it would initially contain 20% N2O and 80% O2, but as this mixture was withdrawn, the remaining liquid would become very low in O2 and a hypoxic mixture would eventually be delivered to the patient.

Analgesia is due to release of endogenous opioids and direct effect at opioid receptors.

Side-effects

• Diffusion hypoxia
• Diffusion into air-filled cavities (35 times more soluble in blood than N2)
• Diffusion out of gas-filled pockets at end of surgery, e.g. retinal detachment
• SNS stimulant, but if SNS already stimulated, e.g. LVF, N2O causes hypotension, particularly in the presence of opioids
• Reduced bowel motility
• Limits FiO2
• Increases intracranial pressure
• Nausea and vomiting. Meta-analyses show that omission of N2O reduces the incidence of PONV by 30%
• Irreversibly inactivates cob(I)alamin, the active form of vitamin B12, essential for methionine-synthase activity in the brain. Recurrent exposure to nitrous oxide has been documented to cause vitamin B12 deficiency (subacute combined degeneration of the cord, megaloblastic anaemia, spastic paraparesis, encephalopathy). Cobalamin-deficient patients are particularly susceptible (deficient B12 consumption, B12 malabsorption)
• High-dose (>70%) nitrous oxide is teratogenic in rats. There is concern over effects in humans
• Increased spontaneous abortion rate in female staff exposed to waste gas. Dental assistants exposed to >5 h/week of unscavenged N2O take longer to become pregnant than those exposed to lesser amounts
• Greenhouse gas accounts for <1% of all N2O omissions, but t½ of 30 years.

Nitrous Oxide: Neurological and Haematological Toxic Effects, Especially with Prolonged Use

MHRA Guidance 2008

Neurological and haematological toxic effects can occur with prolonged use of nitrous oxide. For this reason, nitrous oxide should not be given continuously for >24 h, or more frequently than every 4 days, without close clinical supervision and haematological monitoring.

• Neurological toxic effects can occur without preceding overt haematological changes.
• Assessment of vitamin B12 levels should be considered before nitrous oxide anaesthesia in people with risk factors for deficiency of this vitamin. Specialist haematological advice should be sought as appropriate.

Xenon

Proposed as a replacement for nitrous oxide. The only inert gas with anaesthetic properties at ambient pressure, having a MAC of 71% and the lowest blood/gas partition coefficient of any anaesthetic gas, making induction and recovery very rapid. Minimal haemodynamic effects. Possibly some degree of neuroprotection. Prepared from air where it is present in a concentration of 0.000 009%, making it very expensive.

Carbon dioxide

Colourless, pungent gas. From a:

• by-product of beer fermentation
• waste gas from burning fuel
• by-product of H2 manufacture.
Critical temperature: –31°C
Critical pressure: 73.8 bar
Filling ratio: temperate, 0.75; tropics, 0.67.

Bibliography

Banks A., Hardman J.G. Nitrous oxide. Contin Educ Anaesth, Crit Care Pain. 2005;5:145-148.

Harris P.D., Barnes R. The uses of helium and xenon in current clinical practice. Anaesthesia. 2008;63:284-293.

Ma D., Wilhelm S., Maze M., et al. Neuroprotective and neurotoxic properties of the ‘inert’ gas, xenon. Br J Anaesth. 2002;89:739-746.

Maze M., Fujinaga M. Recent advances in understanding the actions and toxicity of nitrous oxide. Anaesthesia. 2000;55:311-314.

O’Driscoll B.R., Howard L.S., Davison A.G. British Thoracic Society: British Thoracic Society guideline for emergency oxygen use in adult patients. Thorax. 2008;63(Suppl VI):vi1-vi68. on behalf of the

Sanders R.D., Franks N.P., Maze M. Xenon: no stranger to anaesthesia. Br J Anaesth. 2003;91:709-717.

Sanders R.D., Weimann J., Maze M. Biologic effects of nitrous oxide: a mechanistic and toxicologic review. Anesthesiology. 2009;109:707-722.

Taneja R., Vaughan R.S. Oxygen. BJA CEPD Rev. 2001;1:104-107.

Drug Interactions

• Pharmacokinetics determine the relationship between dose administered and concentration delivered to site of action, i.e. effect of body on drug.
• Pharmacodynamics determine the relationship between concentration of drug at site of action and intensity of effect produced, i.e. effect of drug on body.

Monoamine oxidase inhibitors (MAOIS)

MAO-A is found in CNS, and MAO-B in liver, lungs and kidneys. Most new MAOIs are selective for type A and are reversible within 48 h.

Actions:

• Decrease sympathetic tone with decreased ability to respond to stress
• Postural hypotension
• Decrease plasma cholinesterase and thereby prolong action of suxamethonium
• Synergistic with insulin to cause hypoglycaemia
• No serious interaction with common agents except pethidine. Reaction with pethidine (via norpethidine) causes pyrexia, hypertension, CNS excitation and coma. Unlikely to occur with other opioids
• Indirect sympathomimetics are contraindicated because they cause excess noradrenaline release.

Antiplatelet agents

Non-steroidal anti-inflammatory drugs, aspirin and clopidogrel are being prescribed with increasing frequency and are all implicated in increased surgical blood loss. Ideally, these drugs should be stopped before surgery to allow platelet function to return to normal.

• NSAIDs reversibly inhibit cyclo-oxygenase. Their antiplatelet effects are half-life dependent (usually hours).
• Aspirin causes irreversible cyclo-oxygenase inhibition, the effect lasting for the life span of the platelet (≈︀10 days).
• Clopidogrel is a pro-drug whose action is to irreversibly inhibit the P2Y ADP receptor on platelet membranes to prevent the cross-linking of platelets by fibrin. The active metabolite circulates for approximately 18 h and permanently inhibits any platelets present during this time (whether endogenous or transfused). Delaying surgery for 24 h after the last dose of clopidogrel will improve the response to platelet transfusion.

There is growing evidence that haemorrhagic risk is increased when aspirin and clopidogrel are taken concomitantly. These drugs need to be stopped for 7 days to be confident of adequate platelet function. However, due consideration must be given to the risks associated with stopping these drugs in surgical patients, particularly those with drug eluting coronary artery stents.

Tricyclics

• Inhibit reuptake of noradrenaline at nerve terminals, potentiating action of adrenaline, noradrenaline and other catecholamines
• Anticholinergic side-effects potentiate anticholinergic effect of other drugs, e.g. atropine, glycopyrrolate
• Quinidine-like membrane-stabilizing effects with prolonged PR interval, widened QRS complex and risk of VF.

Therefore tricyclics result in an increased risk of arrhythmias and hypotension.

Selective serotonin reuptake inhibitors (fluoxetine (Prozac), sertraline, paroxetine)

Second-generation antidepressants replacing tricyclics. Selectively inhibit presynaptic 5HT reuptake, causing an increase in serotonin at the synaptic cleft.

• Common side-effects include nausea, diarrhoea, headache, insomnia and syndrome of inappropriate ADH secretion (particularly in the elderly).
• Overdose is usually associated with few symptoms unless combined with MAOIs or tricyclics when a serotonin syndrome may occur, characterized by coma, hyperreflexia, autonomic instability (fever, diarrhoea, tachycardia, labile BP), DIC, myoglobinaemia, renal failure and death.
• P450 inhibition causes interaction with haloperidol, tricyclics, theophylline, phenytoin, carbamazepine and warfarin.

Anaesthetic implications

Exclude hyponatraemia and clotting abnormalities preoperatively. Inhibition of midazolam metabolism prolongs its action. Seratomimetic drugs (pethidine, pentazocine, dextromethorphan) may cause a serotonin syndrome. May antagonize the μ-opioid receptor to cause reduced effects of opioids.

Anticonvulsants

• Barbiturates and phenytoin induce P450 hepatic enzymes with increased dose requirements of anaesthetic drugs
• Also cause resistance to non-depolarizers (except atracurium) possibly via effect on ACh receptors
• No significant reaction of benzodiazepines with anaesthetic drugs.

Angiotensin-converting enzyme (ACE) inhibitors

May improve perioperative CVS stability but are associated with peri- and postoperative hypotension. Consider stopping drug 24 h before surgery.

Potassium channel activators

Nicorandil is a potassium-channel activator with a nitrate component. It activates an ATP-sensitive K+ channel to cause K+ efflux and subsequent cellular hyperpolarization. This reduces contractility and results in both arterial and venous vasodilation. It is effective in the treatment of angina. May exacerbate hypotension induced by GA.

H2 antagonists

Ranitidine. Causes sinus bradycardia and AV block, especially following i.v. administration.

Cimetidine. Inhibits hepatic cytochrome P450, increasing levels and thus toxicity of lidocaine, nifedipine and propanolol (Table 11.1). Potentiation of action of warfarin and theophyllines. Cimetidine competes with creatinine for renal excretion.

Table 11.1 Drugs affecting hepatic enzymes

Hepatic enzyme induction Hepatic enzyme inhibition
Alcohol Cimetidine
Barbiturates Erythromycin
Phenytoin Ciprofloxacin
Carbamazepine  
Sodium valproate  

Droperidol

Butyrophenone; used for neuroleptic anaesthesia and as an antiemetic. Causes:

• mental detachment
• catatonia
• dopaminergic antagonism (acts at chemoreceptor trigger zone)
• α-adrenergic antagonism, causing hypotension. Exacerbates hypotensive effects of anaesthetic agents
• amfetamine antagonism
• gamma-aminobutyric acid (GABA) antagonism.

Large doses cause extrapyramidal movements. Gives some protection against catecholamine-induced arrhythmias. Reduces oxygen uptake. Has minimal effects on CVS, respiratory or liver function.

Leucotriene antagonists (montelukast, zafirlukast)

Leucotriene receptor antagonists block receptors in bronchial smooth muscle and are therefore of use in treating asthma:

• Zafirlukast – inhibits cytochrome P450 enzyme
• Montelukast – metabolized by cytochrome P450 enzyme.

Bibliography

Fee J.P.H., McCaughey W. Preoperative preparation, premedication and concurrent drug therapy. In: Nimmo W.S., Rowbotham D.J., Smith G., editors. Anaesthesia. ed 2. Oxford: Blackwell Scientific; 1994:677-703.

Kam P.C.A., Chang G.W.M. Selective serotonin reuptake inhibitors. Anaesthesia. 1997;52:982-988.

Licker M., Morel D.R. Inhibitors of the renin angiotensin system: implications for the anaesthesiologist. Curr Opin Anaesth. 1998;11:321-326.

Vuyk J. Drug interactions in anaesthesia. Curr Opin Anaesth. 1997;10:267-270.

Ecstasy

Ecstasy (3,4-methylenedioxymethamfetamine, MDMA) is an amfetamine derivate with similar properties to sister drugs ‘Eve’ (3,4-methylenedioxyethamfetamine) and ‘Ice’ (3,4-methylenedioxyamfetamine). First produced in 1914 as an appetite suppressant but not used again until the 1970s when it was reintroduced for psychotherapy to give energy and euphoria.

Acute effects include empathy, heightened alertness, acute psychosis trismus and tachycardia. Positive effects tend to decrease with regular use, while negative effects increase. Hangover lasts 4–5 days and is associated with depression and impaired memory.

MDMA causes the release of 5HT, one of the neurotransmitters implicated in control of mood. In primates, it causes irreversible loss of serotonergic nerve fibres. 5HT is a neurotransmitter triggering the thermoregulatory centre in the hypothalamus to increase body temperature.

Main problems in the management of these patients are:

• Acute side-effects related to hyperpyrexia causing a syndrome similar to malignant hyperthermia with rhabdomyolysis, DIC and multiple organ failure. Mortality relates to the extent and duration of hyperthermia. Rapid cooling and use of dantrolene if core temperature >40°C have been recommended.
• Drinking of large amounts of water at ‘raves’ to prevent dehydration causes dilutional hyponatraemia and cerebral oedema. This may also be associated with the syndrome of inappropriate production of antidiuretic hormone.
• Acute liver failure may occur due to either a reaction to MDMA itself or a reaction to a contaminant.

Bibliography

Hall A.P., Henry J.A. Acute toxic effects of ‘Ecstasy’ (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth. 2006;96:678-685.

Levosimendan

Levosimendan is an intravenous calcium sensitizer approved for the treatment of acute decompensated heart failure. It acts as a positive inotrope and vasodilator through calcium sensitization, avoiding the increase in free intracellular calcium caused by β-agonists which increases myocardial oxygen demand. Inotropic effects result from binding of levosimendan to cardiac troponin C to facilitate actin-myosin cross-bridge formation and also inhibition of phosphodiesterase-3. Vasodilation occurs as a result of the opening of K-ATP channels.

Some (LIDO, REVIVE I, REVIVE II, CASINO), but not all (SURVIVE) studies have shown improvement in symptoms and outcome when compared to conventional β-agonist therapy. Use currently limited by cost.

Bibliography

Mercer S., Rhodes A. Levosimendan. Cashman J., Grounds M., editors. Recent Advances in Anaesthesia and Intensive Care, vol 24. Cambridge University Press, Cambridge, 2007;131-142.

Salmenperä M., Eriksson H. Levosimendan in perioperative and critical care patients. Curr Opin Anesth. 2009;22:496-501.

Intravenous Induction Agents

Thiopentone

Prepared as 6% anhydrous sodium carbonate in nitrogen to prevent thiopentone forming acid with the CO2 present in air. pH of 2.5% solution = 10.8.

image

Highly lipid-soluble and rapidly distributed into the tissues. Pharmacokinetics are those of a three compartment model. Undergoes first-order kinetics.

80% protein bound; t½ = 12 h. Induction dose 4–5 mg.kg−1. Oxidized by liver to inactive metabolites with renal excretion. Serious allergic reactions are rare but severe.

Physiological effects

• ↓ Myocardial contractility and peripheral vasodilation
• ↑ Bronchial muscle tone and laryngeal spasm
• ↓ ICP, ↓ CNS flow, ↓ CNS metabolism
• ↓ IOP
• ↓ SNS > PNS.

Accidental intra-arterial thiopentone injection

• Immediate pain and blanching
• Arterial obstruction due to vascular spasm and obstruction by thiopentone crystals.

Treatment

• Leave needle in place
• Irrigate with saline. Commence anticoagulation with heparin and then warfarin for 2 weeks
• Give 10 mL of 1% procaine to buffer thiopentone and act as LA
• Consider papaverine 40 mg, phenoxybenzamine 0.5 mg or urokinase
• Sympathetic block, e.g. brachial plexus block
• Keep limb warm, elevate and continue with the GA to dilate vessels.

Propofol (di-isopropylphenol)

image

Emulsified in soya bean oil and egg phosphatide (formerly Cremphor EL).

t½ = 4 h. Induction dose 2–3 mg.kg−1. Highly lipid-soluble.

Metabolized by liver and extrahepatic sites (?lung). Hepatic excretion.

Delay in loss of eyelash reflex. Short duration of action makes drug suitable for day-case anaesthesia and ITU sedation.

Physiological effects

• Hypotension due to vasodilation more than myocardial depression
• Tachycardia. Resets baroreceptors to allow ↓ BP
• Bronchial muscle tone unchanged. Less laryngospasm than other induction agents.

Metabolic Infusion Syndrome Related to Propofol

Metabolic decompensation has been reported following long-term high-dose infusion in adults (>5 mg.kg−1.h−1 for >2 days). Similar reports also received of similar reactions in children sedated on intensive care units.

Characterised by Sudden onset of marked bradycardia, progressing to complete heart block.

• Lipaemic plasma
• Hepatomegaly
• Cardiac failure
• Metabolic acidosis
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